Transcranial Magnetic Stimulation and Cranial Electrical Stimulation

Number: 0469

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses transcranial magnetic stimulation and cranial electrical stimulation.

Medical Necessity

Aetna considers transcranial magnetic stimulation (TMS) in a healthcare provider’s office medically necessary when the following criteria are met:
- Administered by an FDA cleared device and utilized in accordance with the Food and Drug Administration (FDA) labeled indications; and
- The member is age 18 years or older; and
- The member has a confirmed diagnosis by a psychiatrist of severe major depressive disorder (single or recurrent episode) without psychosis documented by standardized rating scales that reliably measure depressive symptoms (eg, Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.); severity of depression should be measured during the current depressive episode at baseline with a validated depression rating scale, and changes from baseline with TMS treatment should be assessed using the same depression rating scale though the entire treatment course; and
- The member has no contraindications to TMS (refer to contraindications below); and
- The member has experienced inadequate response during the current depressive episode occurring within the past 5 years. Note: For purposes of this policy, the current depressive episode begins with the most recent onset of acute symptoms) with:
  - Two antidepressants from at least 2 different classes having different mechanisms of action (see Appendix) at the maximally tolerated labeled dose, each used for at least 8 weeks (to qualify as an adequate antidepressant drug trial, the individual’s dose during the failed trials should have been at or above the minimal effective therapeutic dose for that antidepressant); and
  - Augmentation therapy along with the primary antidepressant used for at least 8 weeks (see Appendix); if the augmenting agent is an antidepressant, the augmenting agent must be from a different class than the primary antidepressant. The augmenting agent should have been at or above the minimal effective therapeutic dose (which is typically the minimal labeled dose); and
- Treatment consists of a maximum of 30 sessions (5 days a week for 6 weeks) plus 6 tapering sessions (6 sessions over three weeks). Notes: Treatments beyond 36 sessions (e.g., 30 treatment sessions followed by 6 tapering sessions) may be reviewed for medical necessity. There is a lack of evidence of the effectiveness of additional sessions beyond 36 to treat "late responders", to solidify response, or to attain remission. There is a lack of evidence that persons who fail to respond or become refractory to one brand of repetitive transcranial magnetic stimulation (rTMS) device will respond to another brand of rTMS or deep TMS (dTMS) device; and
- The TMS treatment is delivered by a device that is approved or cleared by the FDA for the treatment of major depressive disorder. Note: TMS treatment should generally follow the protocol and parameters specified in the manufacturer’s user manual, with modifications only as supported by the published scientific evidence base; and
- The order for treatment (or retreatment) will be written by a psychiatrist (MD or DO) or behavioral health nurse practioner who will examine the patient and review the record and determine that TMS is indicated for use in a particular patient. In addition to patient selection, the psychiatrist should oversee initial patient motor threshold determinations, mapping and treatment parameter definitions and overall TMS treatment course planning for each patient. The psychiatrist must certify that the treatment will be given under direct supervision of this physician (i.e., the physician will be in the area and will be immediately available for each treatment). If the psychiatrist is not performing the daily TMS treatment sessions, then the psychiatrist should assign properly trained personnel who may perform the daily treatment sessions. The psychiatrist is also responsible for the evaluation of the patient during the course of their TMS Therapy treatment; and
- The TMS operator will be a clinical professional who is conducting TMS Therapy under the supervision of a physician, nurse practitioner or physician assistant who is at the facility at the time of treatment. The TMS operator should possess sufficient clinical expertise to monitor the patient during the conduct of a TMS treatment session. The operator must be able to observe the patient’s physical status for the potential occurrence of adverse events, and make routine adjustments as required and consistent with product labeling, or determine circumstances under which treatment interruption or treatment termination should be considered. The TMS operator should be present in the treatment room with the patient at all times. The operator must be qualified to monitor the patient for seizure activity and to provide seizure management care.
Aetna considers TMS not medically necessary and experimental and investigational in persons with any of the following contraindications to TMS because the safety and effectiveness in person with these contraindications has not been established:
- Persons with abuse of substances with known abuse potential during the last 90 days; or
- The member is suicidal; or
- The member has a metal implant in or around the head (eg, aneurysm coil or clip, metal plate, ocular implant, stent); or
- The member has neurological conditions (eg, cerebrovascular disease, dementia, history of repetitive or severe head trauma, increased intracranial pressure or primary or secondary tumors in the central nervous system); or
- There is presence of implanted devices, (eg, cardiac pacemaker or defibrillator, cochlear implant, deep brain stimulator, implantable infusion pump, spinal cord stimulator, vagus nerve stimulator, etc.); or
- If the member has severe cardiovascular disease, he has been evaluated and cleared for TMS treatment by a cardiologist.
Aetna considers TMS re-treatment medically necessary for persons with depression relapse who meet all of the following criteria:
- The member meets initiation criteria above; and
- The member has relapsed following TMS despite other treatment approaches (e.g., psychotherapy, pharmacotherapy), as appropriate; and
- The member had previously had at least a 50% reduction in depressive symptoms with TMS, as documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.), and this improvement was maintained for at least two months after the prior TMS treatment course; repeat TMS treatment within 60 days following the termination of the prior TMS course is considered not medically necessary.
Aetna considers one TMS re-mapping during a course of TMS for depression medically necessary. Additional courses of re-mapping are considered medically necessary if the member is not responding to ensure the most accurate treatment location, or if there is concern that motor threshold may have changed (for example, because of a change in medication). Note: Re-mapping does not increase the medically necessary number of TMS sessions, as treatment is provided during remapping.
Experimental and Investigational

Aetna considers the following procedures experimental and investigational because the effectiveness of these approaches has not been established:
1. Adjunctive use of ketamine with transcranial magnetic stimulation (TMS)
2. Combined TMS and electroencephalography (EEG) for evaluation of unconscious state (e.g., medication-induced unconscious state, minimally conscious state, and unresponsive wakefulness syndrome)
3. Delivery of TMS using a non-standard protocol with increased hertz under sedation
4. Navigated TMS for motor function mapping and/or treatment planning of neurological diseases/disorders (e.g., amyotrophic lateral sclerosis, epilepsy, and resection of brain tumors)
5. TMS maintenance therapy (i.e., treatment outside of the established 30 treatment sessions over 6 weeks plus six tapering sessions over 3 weeks)
6. TMS for the following conditions because its value and effectiveness has not been established (not an all-inclusive list):
  - Alzheimer's disease
  - Amyotrophic lateral sclerosis
  - Anxiety disorders
  - Auditory verbal hallucinations
  - Bipolar disorder
  - Blepharospasm
  - Bulimia nervosa
  - Cerebellar ataxia
  - Cerebral palsy
  - Chronic pain including neuropathic pain (e.g., orofacial pain, and central post-stroke pain)
  - Communication and swallowing disorders (e.g., aphasia (including post-stroke aphasia), dysarthria, dysphagia (including post-stroke dysphagia), and linguistic deficits)
  - Complex regional pain syndrome
  - Concussion
  - Differential diagnosis of Alzheimer disease from frontotemporal dementia
  - Epilepsy (including status epilepticus)
  - Congenital hemiparesis
  - Dyslexia
  - Dystonia
  - Fibromyalgia
  - Functional neurological disorder
  - Insomnia
  - Levodopa-induced dyskinesia
  - Major depressive disorder with psychosis
  - Migraine
  - Mood disorders
  - Multiple sclerosis
  - Neurodevelopmental disorders (e.g., attention deficit/hyperactivity disorder, autism spectrum disorder, and tic disorders)
  - Neuropathic pain associated with spinal cord injury
  - Obsessive-compulsive disorder
  - Panic disorder
  - Parkinson disease
  - Peri-partum depression
  - Phantom pain associated with spinal cord injury
  - Post-traumatic stress disorder
  - Psychosis
  - Restless legs syndrome
  - Schizo-affective disorder
  - Schizophrenia
  - Smell and taste dysfunction (e.g., phantosmia and phantageusia)
  - Somatic symptom disorder (somatization disorder)
  - Spasticity
  - Stroke treatment (e.g., motor impairment, post-stroke hemiplegia, and post-stroke spasticity)
  - Substance addiction (substance use disorders)
  - Tourette syndrome (see CPB 0480 - Tourette's Syndrome)
  - Tinnitus
  - Traumatic brain injury
  - Visual hallucinations after stroke.
7. Cranial electrical stimulation (also known as cerebral electrotherapy, craniofacial electrostimulation, electric cerebral stimulation, electrosleep, electrotherapeutic sleep, transcerebral electrotherapy, transcranial electrotherapy, as well as the Fisher Wallace stimulator (formerly known as the Liss Body Stimulator) for any indication (not an all-inclusive list):
  - Alcoholism
  - Alzheimer's disease
  - Anxiety
  - Autism
  - Chemical dependency
  - Chronic pain
  - Dementia
  - Depression
  - Disorders of consciousness
  - Dyslexia
  - Headaches
  - Fibromyalgia
  - Insomnia
  - Mood and sleep disturbances
  - Neuropathic pain
  - Parkinson disease
  - Phantom pain associated with spinal cord injury
  - Progressive supranuclear palsy
  - Restless legs syndrome
  - Stroke treatment (e.g., motor impairment, post-stroke aphasia, and post-stroke hemiplegia)
  - Traumatic brain injury
  - Visual rehabilitation.
Related Policies
- CPB 0480 - Tourette's Syndrome

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Transcranial/navigated transcranial Magnetic Stimulation*:
CPT codes covered if selection criteria are met:
90867	Therapeutic repetitive transcranial magnetic stimulation treatment; planning
90868	delivery and management, per session
90869	subsequent motor threshold re-determination with delivery and management
CPT codes not covered if selection criteria are met:
95700 - 95726	Electroencephalogram (EEG)
95812	Electroencephalogram (EEG) extended monitoring; 41-60 minutes
95813	61-119 minutes
95816	Electroencephalogram (EEG); including recording awake and drowsy
95819	including recording awake and asleep
95822	recording in coma or sleep only
95824	cerebral death evaluation only
Other CPT codes related to the CPB:
90832 - 90838	Psychotherapy
90839 - 90840	Psychotherapy for crisis
90845 - 90853	Other psychotherapy
HCPCS codes covered if selection criteria are met:
G0295	Electromagnetic therapy, to one or more areas
HCPCS codes not covered for indications listed in the CPB:
Ketamine –no specific code
ICD-10 codes covered if selection criteria are met:
F32.2	Major depressive disorder, single episode, severe without psychotic features
F33.2	Major depressive disorder, recurrent, severe without psychotic features
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C71.0 - C71.9	Malignant neoplasm of brain
D33.0 - D33.2	Benign neoplasm of brain
F01.50 - F32.1, F32.3, F32.4 - F33.1, F33.3, F33.40 - F99	Mental and behavioral disorders
F53.0	Postpartum depression
G11.10 – G11.19	Early-onset cerebellar ataxia
G11.2	Late-onset cerebellar ataxia
G11.3	Cerebellar ataxia with defective DNA repair
G11.4	Hereditary spastic paraplegia
G12.21	Amyotrophic lateral sclerosis
G20	Parkinson's disease
G21.4	Vascular parkinsonism
G24.3	Spasmodic torticollis
G24.5	Blepharospasm
G25.81	Restless legs syndrome
G30.0 - G30.9	Alzheimer's disease
G31.0 - G31.9	Frontotemporal dementia
G32.81	Cerebellar ataxia in diseases classified elsewhere
G35	Multiple sclerosis
G40.0 - G40.919	Epilepsy and recurrent seizures
G43.001 - G43.919	Migraine
G44.001 - G44.89	Other headache syndromes
G47.00 - G47.9	Sleep disorders
G54.6 - G54.7	Phantom limb syndrome [associated with spinal cord injury]
G80.0 – G80.9	Cerebral palsy
G81.10 - G81.14	Spastic hemiplegia
G89.0	Central pain syndrome [post stroke]
G90.50 - G90.59	Complex regional pain syndrome I (CRPS I)
H53.40	Unspecified visual field defects.
H93.11 - H93.19	Tinnitus
H93.A1 - H93.A9	Pulsatile tinnitus
I69.020 - I69.028	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following nontraumatic subarachnoid hemorrhage
I69.120 - 69.128	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following nontraumatic intracerebral hemorrhage
I69.220 - I69.228	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following nontraumatic intracranial hemorrhage
I69.320 - I69.328	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following cerebral infarction
I69.820 - I69.828	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following other cerebrovascular disease
I69.920 - I69.928	Aphasia, dysphasia, dysarthria, fluency disorders and other speech and language deficits following unspecified cerebrovascular disease
J38.5	Laryngeal spasm
K22.0	Achalasia of cardia
K22.4	Dyskinesia of esophagus
K31.3	Pylorospasm, not elsewhere classified
K59.4	Anal spasm
K83.4	Spasm of sphincter of Oddi
M54.10 - M54.18	Radiculopathy
M60.811 - M60.9	Myositis
M62.40 - M62.49	Contracture of muscle
M62.830 - M62.838	Muscle spasm
M79.1	Myalgia
M79.2	Neuralgia and neuritis, unspecified
R25.0 - R25.9	Abnormal involuntary movements
R27.0 - R27.9	Other lack of coordination
R41.82	Altered mental status, unspecified
R43.0 - R43.9	Disturbances of smell and taste
R44.0	Auditory hallucinations
R47.01	Aphasia
R47.02	Dysphasia
R47.1	Dysarthria and anarthria
R48.0	Dyslexia and alexia
R51	Headache
S06.0X0A - S06.A1XS	Intracranial injury [traumatic brain injury]
S12.000+ - S12.691+ S22.000+ - S22.089+ S32.000+ - S32.2xx+	Fracture of vertebral column [must be billed with codes for spinal cord injury]
S14.101+ - S14.159+ S24.101+ - S24.159+ S34.101+ - S34.139+	Spinal cord injury
*Cranial Electrical Stimulation*:
HCPCS codes not covered for indications listed in the CPB:
A4556	Electrodes (e.g., apnea monitor), per pair
A4557	Lead wires (e.g., apnea monitor), per pair
A4558	Conductive gel or paste, for use with electrical device (e.g., TENS, NMES), per oz.
A4595	Electrical stimulator supplies, 2 lead, per month, (e.g., TENS, NMES)
A4596	Cranial electrotherapy stimulation (ces) system supplies and accessories, per month
E0720	Transcutaneous electrical nerve stimulator (TENS) device, two leads, localized stimulation
E0730	Transcutaneous electrical nerve stimulator (TENS) device, four or more leads, for multiple nerve stimulation
E0732	Cranial electrotherapy stimulation (ces) system, any type
Other HCPCS codes related to the CPB:
G0283	Electrical stimulation (unattended), to one or more areas for indication(s) other than wound care, as part of a therapy plan of care
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
F01.50 - F99	Mental disorders
G20	Parkinson's disease
G21.4	Vascular parkinsonism
G23.1	Progressive supranuclear ophthalmoplegia [Steele-Richardson-Olszewski]
G25.81	Restless legs syndrome
G30.0 - G30.9	Alzheimer's disease
G43.001 - G43.919	Migraine
G44.001 - G44.89	Other headache syndromes
G47.00 - G47.9	Sleep disorders
G54.6 - G54.7	Phantom limb syndrome [associated with spinal cord injury]
I69.020, I69.120, I69.220, I69.320, I69.820, I69.920	Speech and language deficits following nontraumatic hemorrhage
I69.059, I69.159. I69.259, I69,359, I69.859, I69.959	Hemiplegia and hemiparesis following nontraumatic subarachnoid hemorrhage
M54.10 - M54.18	Radiculopathy
M60.811 - M60.9	Myositis
M79.10 - M79.18	Myalgia
M79.2	Neuralgia and neuritis, unspecified
R40.0 - R40.4	Somnolence, stupor and coma
R51	Headache
S06.0X0A - S06.A1XS	Intracranial injury [traumatic brain injury]
S12.000+ - S12.691+ S22.000+ - S22.089+ S32.000+ - S32.2xx+	Fracture of vertebral column [may be billed with codes for spinal cord injury]
S14.101+ - S14.159+ S24.101+ - S24.159+ S34.101+ - S34.139+	Spinal cord injury

Background

Transcranial magnetic stimulation (TMS) is a non-invasive method of induction of a focal current in the brain and transient modulation of the function of the targeted cerebral cortex. This procedure entails placement of an electromagnetic coil on the scalp; high-intensity electrical current is rapidly turned on and off in the coil through the discharge of capacitors. Depending on stimulation parameters (frequency, intensity, pulse duration, stimulation site), repetitive TMS (rTMS) to specific cortical regions can either increase or decrease the excitability of the affected brain structures.

Transcranial magnetic stimulation has been investigated in the treatment of various psychiatric disorders, especially depression. This procedure is usually carried out in an outpatient setting. In contrast to electroconvulsive therapy, TMS does not require anesthesia or analgesia. Furthermore, it does not affect memory and usually does not cause seizures. However, the available peer-reviewed medical literature has not established the effectiveness of rTMS in the treatment of psychiatric disorders other than major depression. In addition, more research is needed to ascertain the roles of various stimulation parameters of rTMS for its optimal outcome as well as its long-term effectiveness in the treatment of psychiatric disorders.

Depression

Martin et al (2003) conducted a systematic review of randomized controlled trials that compared rTMS with sham in patients with depression. The authors concluded that current trials are of low quality and provide insufficient evidence to support the use of rTMS in the treatment of depression. This is in accordance with the observations of Fitzgerald and colleagues (2002) who noted that TMS has a considerable role in neuropsychiatric research. It appears to have considerable potential as a therapeutic tool in depression, and perhaps a role in several other disorders, although widespread application requires larger trials and establishment of sustained response, as well as Gershon et al (2003) who stated that TMS shows promise as a novel anti-depressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success.

A health technology assessment prepared for the Ontario Ministry of Health and Long-Term Care (2004) concluded: “Due to several serious methodological limitations in the studies (Level 2 to 4 evidence) that examined the effectiveness of rTMS in patients with MDD [major depressive disorder], to date, it is not possible to conclude that rTMS is effective or not effective for the treatment of MDD (treatment resistant or not treatment resistant MDD).”

Nemeroff (2007) stated that the role of non-pharmacological therapies such as electro-convulsive therapy (ECT), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and TMS in the treatment of patients with severe depression remain active avenues of investigation.

A randomized clinical trial (RCT) conducted for the National Coordinating Centre for Health Technology Assessment found that ECT is a more effective and potentially cost-effective antidepressant treatment than 3 weeks of rTMS (McLoughlin et al, 2007). A total of 46 patients with major depression were randomized to receive a 15-day course of rTMS (n = 24) or a course of ECT (n = 22). One patient was lost to follow-up at end of treatment and another 8 at 6 months. The end-of-treatment Hamilton Rating Scale for Depression (HRSD) scores were lower for ECT (95 % confidence interval (CI): 3.40 to 14.05, p = 0.002), with 13 (59 %) achieving remission compared with four (17 %) in the rTMS group (p = 0.005). However, HRSD scores did not differ between groups at 6 months. Beck Depression Inventory-II (BDI-II), visual analogue mood scales (VAMS), and Brief Psychiatric Rating Scale (BPRS) scores were lower for ECT at end of treatment and remained lower after 6 months. Improvement in subjective reports of side-effects following ECT correlated with anti-depressant response. There was no difference between the 2 groups before or after treatment on global measures of cognition. The NCCHTA study also evaluated the comparative costs of ECT and rTMS. The investigators reported that, although individual treatment session costs were lower for rTMS than ECT, the cost for a course of rTMS was not significantly different from that for a course of ECT as more rTMS sessions were given per course. Service costs were not different between the groups in the subsequent 6 months but informal care costs were significantly higher for the rTMS group (p = 0.04) and contributed substantially to the total cost for this group during the 6-month follow-up period. The investigators reported that there was also no difference in gain in quality adjusted life years (QALYs) for ECT and rTMS patients. The report noted that analysis of cost-effectiveness acceptability curves demonstrated that rTMS has very low probability of being more cost-effective than ECT.

The Australian Medical Services Advisory Committee (MSAC, 2007) found insufficient evidence of rTMS to support funding. The Australian MSAC considered the safety and effectiveness of rTMS for moderate to severe refractory treatment resistant depression compared to ECT and found evidence that rTMS is safe and less invasive than ECT. However, MSAC also found limited evidence that rTMS may be less effective than ECT. A more recent MSAC review reached similar conclusions (MSAC, 2014): "After considering the available evidence in relation to safety, clinical effectiveness and cost-effectiveness, MSAC did not support public funding because of uncertain effectiveness and cost-effectiveness due to insufficient comparative data in treatment-resistant patients against current antidepressant treatments and uncertain costs."

On October 8, 2008, the U.S. Food and Drug Administration (FDA) cleared for marketing via the 510(k) process the NeuroStar TMS (transcranial magnetic stimulation) Therapy system, which is specifically indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from 1 prior anti-depressant medication at or above the minimal effective dose and duration in the current episode. A treatment course usually consists of 6 weeks of 40-min sessions (5 days a week). However, the evidence supporting NeuroStar's effectiveness is less clear than its safety profile. The FDA cleared the NeuroStar based on data that found patients did modestly better when treated with TMS than when they received a sham treatment. It was a study fraught with statistical questions that concerned the agency's own scientific advisers. For a more clear answer, the National Institutes of Health has an independent study under way that tracks 260 patients (Associated Press, 2008).

Randomized, controlled studies of rTMS compared to sham treatment have produced conflicting results (O'Reardon et al, 2007; Avery et al, 2008; Mogg et al, 2008).

In a double-blind, multi-site study, O'Reardon et al (2007) examined if TMS over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. A total of 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted 5 times per week with TMS at 10 pulses/sec, 120 % of motor threshold, 3,000 pulses/session, for 4 to 6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all 3 scales at weeks 4 and 6. Remission rates were approximately 2-fold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well-tolerated with a low drop-out rate for adverse events (4.5 %) that were generally mild and limited to transient scalp discomfort or pain. The authors concluded that TMS was effective in treating major depression with minimal side effects reported.

Avery and colleagues (2008) described the results of an open-label extension study of active TMS in medication-resistant patients with MDD who did not benefit from an initial course of therapy in a previously reported 6-week, RCT of active versus sham TMS. Patients with DSM-IV-defined MDD were actively enrolled in the study from February 2004 through September 2005 and treated with left pre-frontal TMS administered 5 times per week at 10 pulses per second, at 120 % of motor threshold, for a total of 3,000 pulses/session. The primary outcome was the baseline to endpoint change score on the MADRS. In those patients who received sham in the preceding RCT (n = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0 (95 % CI: -14.0 to -19.9). Further, at 6 weeks, 36 (42.4 %) of these patients achieved response on the MADRS, and 17 patients (20.0 %) remitted (MADRS score less than 10). For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (n = 73), the mean reduction in MADRS scores was -12.5 (95 % CI: -9.7 to -15.4), and response and remission rates were 26.0 % and 11.0 %, respectively, after 6 weeks of additional open-label TMS treatment. The authors concluded that this open-label study provides further evidence that TMS is a safe and effective treatment of MDD. Furthermore, continued active TMS provided additional benefit to some patients who failed to respond to 4 weeks of treatment, suggesting that longer courses of treatment may confer additional therapeutic benefit.

On the other hand, Mogg and co-workers (2008) noted that the effectiveness of rTMS for major depression is unclear. These investigators performed a RCT comparing real and sham adjunctive rTMS with 4-month follow-up. A total of 59 patients with major depression were randomly assigned to a 10-day course of either real (n = 29) or sham (n = 30) rTMS of the left DLPFC. Primary outcome measures were the 17-item HAMD and proportions of patients meeting criteria for response (50 % reduction in HAMD) and remission (HAMD8) after treatment. Secondary outcomes included mood self-ratings on Beck Depression Inventory-II and visual analog mood scales, Brief Psychiatric Rating Scale score, and both self-reported and observer-rated cognitive changes. Patients had 6-week and 4-month follow-ups. Overall, HAMD scores were modestly reduced in both groups but with no significant group x time interaction (p = 0.09) or group main effect (p = 0.85); the mean difference in HAMD change scores was -0.3 (95 % CI: -3.4 to 2.8). At end-of-treatment time-point, 32 % of the real group were responders compared with 10 % of the sham group (p = 0.06); 25 % of the real group met the remission criterion compared with 10 % of the sham group (p = 0.2); the mean difference in HAMD change scores was 2.9 (95 % CI: -0.7 to 6.5). There were no significant differences between the 2 groups on any secondary outcome measures. Blinding was difficult to maintain for both patients and raters. The authors concluded that adjunctive rTMS of the left DLPFC could not be shown to be more effective than sham rTMS for treating depression.

Demirtas-Tatlidede et al (2008) examined the impact of rTMS throughout the long course of MDD and the effectiveness of rTMS in the treatment of depressive relapses. A total of 16 medication-free patients with refractory MDD (diagnosed according to DSM-IV) who initially had clinically significant anti-depressant responses to a 10-day course of 10-Hz rTMS were consecutively admitted to the protocol from 1997 to 2001 and were followed for 4 years. The cohort was studied during a total of 64 episodes of depressive relapse. Severity of depression was evaluated with the HAMD and the BDI prior to and after completion of each rTMS treatment course. Clinically significant response was defined as a reduction in HAMD score of at least 50 %. Safety was assessed by serial neurological examinations and neuropsychological evaluations. Approximately 50 % of the patients individually sustained a clinically significant response to the repeated courses of rTMS; the mean +/- SD decrease in HAMD scores was 64.8 % +/- 12.6 % (p < 0.0001), and, in BDI scores, 60.4 % +/- 20.6 % (p < 0.0001). Despite the lack of adjuvant anti-depressant medication, the mean interval between treatment courses was approximately 5 months, and the medication-free period ranged from 26 to 43 months. Transcranial magnetic stimulation was well-tolerated, and evaluations regarding the safety of the repeated applications of rTMS revealed no findings of concern. The authors concluded that repeated rTMS applications have demonstrated a reproducible anti-depressant effect in patients with refractory depression who initially showed a clinically significant benefit. The duration of effect varied across patients, but benefits were sustained for a mean of nearly 5 months. They stated that further studies with larger cohorts will be useful in determining the long-term effectiveness of rTMS maintenance therapy.

In a systematic review and meta-analysis, Lam and colleagues (2008) examined the effectiveness of rTMS for treatment-resistant depression (TRD). The systematic review was conducted by identifying published RCTs of active rTMS, compared with a sham control condition in patients with defined TRD (i.e., at least 1 failed trial). The primary outcome was clinical response as determined from global ratings, or 50 % or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in end point scores. Meta-analysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. A total of 24 studies (n = 1,092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17 % and a number-needed-to-treat of 6. The pooled response and remission rates were 25 % and 17 %, and 9 % and 6 % for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Drop-outs and withdrawals owing to adverse events were very low. The authors concluded that for patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggested that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD. This is in agreement with the observations of Daskalakis and colleagues as well as Loo and associates. The former group of researchers (Daskalakis et al, 2008) stated that more studies are needed to address the current limitations of rTMS and to optimize the effectiveness of this promising therapeutic option in TRD. The latter group of investigators (Loo et al, 2008) noted that long-term effects of repeated rTMS sessions are as yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment. It is also interesting to note that Knapp and co-workers (2008) stated that ECT is more cost-effective than rTMS in the treatment of severe depression.

Demitrack and Thase (2009) studied the clinical significance of the treatment effects seen with TMS in pharmaco-resistant major depression in their recently completed studies by comparing these outcomes with the results reported in several large, comprehensive published reference data sets of anti-depressant medications studied in both treatment-responsive and treatment-resistant patient populations. The efficacy of TMS reported in RCTs was comparable to that of anti-depressants studied in similarly designed registration trials and to the adjunctive use of atypical anti-psychotic medications in controlled trials of anti-depressant non-responders. The authors noted that these data may be helpful in treatment-planning decisions when using TMS in clinical practice.

In a prospective, multi-site, randomized, active sham-controlled (1:1 randomization) trial, George et al (2010) examined if daily left pre-frontal rTMS safely and effectively treats major depressive disorder. About 860 outpatients were screened, yielding 199 anti-depressant drug-free patients with unipolar non-psychotic major depressive disorder. These researchers delivered rTMS to the left pre-frontal cortex at 120 % motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 mins (3,000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88 % retention rate (90 % sham and 86 % active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1 % active rTMS and 5.1 % sham) (p = 0.02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95 % CI: 1.32 to 13.24). The number needed to treat was 12. Most remitters had low anti-depressant treatment resistance. Almost 30 % of patients remitted in the open-label follow-up (30.2 % originally active and 29.6 % sham). The authors concluded that the findings of this study suggested that daily left pre-frontal rTMS produced statistically significant and clinically meaningful anti-depressant therapeutic effects for unipolar depressed patients who are refractory to or intolerant of medications.

There are several limitations with the afore-mentioned study:

as a consequence of the extensive work in designing a sham system, which delayed the start of the trial, the study failed to enroll the projected 240 subjects suggested by the initial power analysis. This power issue may be the reason why the treatment condition effect on remission rate in the fully adherent sample analysis was not statistically significant. Treaters were able to guess randomization assignment better than chance, without much confidence, which was not explained by covarying for clinical benefit,
although the treatment effect was statistically significant on a clinically meaningful variable (remission), the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for 3 weeks or more, and
it is unclear how long the clinical benefit lasts once achieved.

Slotema et al (2010) examined if rTMS is effective for various psychiatric disorders. A literature search was performed from 1966 through October 2008 using PubMed, Ovid Medline, Embase Psychiatry, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and PsycINFO. The following search terms were used: transcranial magnetic stimulation, TMS, repetitive TMS, psychiatry, mental disorder, psychiatric disorder, anxiety disorder, attention-deficit hyperactivity disorder, bipolar disorder, catatonia, mania, depression, obsessive-compulsive disorder, psychosis, post-traumatic stress disorder, schizophrenia, Tourette's syndrome, bulimia nervosa, and addiction. Data were obtained from randomized, sham-controlled studies of rTMS treatment for depression (34 studies), auditory verbal hallucinations (AVH, 7 studies), negative symptoms in schizophrenia (7 studies), and obsessive-compulsive disorder (OCD, 3 studies). Studies of rTMS versus ECT (6 studies) for depression were meta-analyzed. Standardized mean effect sizes of rTMS versus sham were computed based on pre-treatment versus post-treatment comparisons. The mean weighted effect size of rTMS versus sham for depression was 0.55 (p < 0.001). Monotherapy with rTMS was more effective than rTMS as adjunctive to anti-depressant medication. Electro-convulsive therapy was superior to rTMS in the treatment of depression (mean weighted effect size -0.47, p = 0.004). In the treatment of AVH, rTMS was superior to sham treatment, with a mean weighted effect size of 0.54 (p < 0.001). The mean weighted effect size for rTMS versus sham in the treatment of negative symptoms in schizophrenia was 0.39 (p = 0.11) and for OCD, 0.15 (p = 0.52). Side effects were mild, yet more prevalent with high-frequency rTMS at frontal locations. While the authors concluded that it is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms, they do not recommend rTMS for the treatment of OCD. Furthermore, the authors also stated that "[a]lthough the efficacy of rTMS in the treatment of depression and AVH may be considered proven, the duration of the effect is as yet unknown. Effect sizes were measured immediately after the cessation of rTMS treatment. There are indications that the effects of rTMS may last for several weeks to months. Future studies should assess symptom relief with longer follow-up periods to assess the cost-effectiveness of rTMS treatment, and to indicate its economic advantages and disadvantages .... Although rTMS cannot replace ECT in depressive patients, there may be subgroups in which rTMS can replace antidepressant medication".

The National Institute for Health and Clinical Excellence's interventional procedure overview of TMS for severe depression (2007) concluded that current evidence suggests there are no major safety concerns associated with TMS for severe depression, but there is no evidence that the procedure has clinically useful efficacy. Thus, TMS should be performed only in the context of research studies. Any future research should focus on factors including dose intensity, frequency and duration. Furthermore, the Institute for Clinical Systems Improvement's guideline on major depression in adults in primary care (2008) stated that results of research studies to date on rTMS for the treatment of MDD have been inconsistent and inconclusive.

The BCBS Association's Medical Advisory Panel (BCBSA, 2009) concluded that the use of rTMS in the treatment of depression does not meet the TEC criteria. The TEC assessment stated that an important limitation of the evidence is lack of information beyond the acute period of treatment. The TEC assessment noted that most of the clinical trials of rTMS evaluate the outcomes at the point of the last rTMS treatment, between 1 and 4 weeks, and that very few studies evaluated patients beyond this time period. Although meta-analyses are consistent with short-term antidepressant effects, the clinical significance of the effect is uncertain. The TEC assessment stated that the large clinical trial of rTMS by O'Reardon et al (2007) that was reviewed in this assessment did not unequivocally demonstrate efficacy, as the principal endpoint was not statistically significant at 4 weeks, and some results were sensitive to the methods of analysis. The TEC assessment stated that patients in whom rTMS is indicated are usually treated with a second course of antidepressant therapy. The clinical trial by O'Reardon et al (2007), which was sham controlled without active treatment, can not determine whether rTMS would be more or less successful than this standard treatment. Referring to the study by George et al (2010), the TEC assessment also noted that a clinical trial sponsored by the National Institute of Mental Health has recruited subjects for another clinical trial of rTMS; however, this trial also appears to have only a short duration (3 weeks) in which the participants are randomized to rTMS or sham before crossovers or alternative treatments are offered.

An assessment by the California Technology Assessment Forum (CTAF, 2009) of rTMS for treatment-resistant depression concluded that rTMS does not meet CTAF technology assessment criteria. This report stated that there is insufficient evidence to conclude that rTMS improves net health outcomes for patients with treatment resistant depression, or that it is as effective as current alternatives (e.g., augmentation, ECT, or new drugs). The report noted that many of the individual studies of rTMS for treatment-resistant depression randomized less than 20 patients and were under-powered to detect changes in net health outcomes, particularly remission of depression. The CTAF assessment stated that the largest and most recent clinical trials of rTMS for depression failed to demonstrate significant improvements on their primary outcome measures. The CTAF assessment noted, in addition, that there is no consensus on how to perform rTMS and a dearth of evidence on the efficacy of rTMS after cessation of therapy. "Undoubtedly because of the evidence that treatment does have some clinical effect, there is active ongoing research into rTMS. However, it is too early to conclude that rTMS improves net health outcomes for patients with treatment resistant depression, much less that it is as effective as current alternatives such as augmentation, new drugs, or ECT."

An assessment of rTMS by the Health Council of the Netherlands (2008) stated that efficacy studies should focus, in particular, on the use of rTMS to treat patients suffering from depression who are not responding well to medication. The assessment stated that it would also be useful to study the longer term effects of rTMS therapy in depression.

An assessment of rTMS for depression by the Swedish Council on Technology Assessment in Health Care (SBU) (Brorrson et al, 2009) concluded that although the results of the studies are promising, they continue to regard the treatment as experimental. The assessment noted that one issue is that it is not known to what extent the treatment is effective in drug-resistant depression. The assessment also called for additional studies examining potential adverse effects of rTMS on memory.

An American Psychiatric Association practice guideline on major depression (2010, reaffirmed 2015) stated: "For patients whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered [I]. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective MAOI [II] after allowing sufficient time between medications to avoid deleterious interactions [I]. Transdermal selegiline, a relatively selective MAO B inhibitor with fewer dietary and medication restrictions, or transcranial magnetic stimulation could also be considered [II] . . . Based on the results of a multisite randomized sham-controlled clinical trial of high-frequency TMS over the left dorsolateral prefrontal cortex, TMS was cleared by the FDA in 2008 for use in individuals with major depressive disorder who have not had a satisfactory response to at least one antidepressant trial in the current episode of illness. However, another large randomized sham-controlled trial of TMS added to antidepressant pharmacotherapy showed no significant benefit of left dorsolateral prefrontal cortex TMS. In comparisons of actual TMS versus sham TMS, most but not all recent meta-analyses have found relatively small to moderate benefits of TMS in terms of clinical response. Although the primary studies used in these meta-analyses are highly overlapping and the variability in TMS stimulus parameters and treat treatment paradigms complicates the interpretation of research findings, these meta-analyses also support the use of high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may be associated with a better acute response to TMS. In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT or comparable in efficacy to ECT, but in the latter studies TMS was more effective and ECT was less effective than is typically seen in clinical trials. A fewer number of studies have compared cognitive effects of TMS and ECT. One randomized trial found no significant difference between TMS and non-dominant unilateral ECT on performance on neuropsychological tests at 2 and at 4 weeks of treatment, although a small open-label trial reported a greater degree of memory difficulties with ECT than with TMS shortly after the treatment course."

In a review on “Transcranial magnetic stimulation in the management of mood disorders”, Allan et al (2011) presented an up-to-date meta-analysis of TMS in the treatment of depression. These investigators searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). They identified 1,789 studies; 31 were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. These researchers found a moderately sized effect in favor of TMS [Random Effects Model Hedges' g = 0.64, 95 % CI: 0.50 to 0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (less than or equal to 50 % reduction in depression scores) was 4.1 (95 % CI: 2.9 to 5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. A total of 9 studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges' g = -0.02, 95 % CI: -0.22 to +0.18) and no heterogeneity in outcome. The authors concluded that TMS appears to be an effective treatment; however, at 4 weeks' follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind RCTs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.

The BlueCross BlueShield Technology Evaluation Center (TEC)'s assessment on TMS for depression (2011) concludes that "[t]he available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives. Comparison to alternatives using other observational studies may not be valid due to unmeasured differences in severity of depression between studies and other differences in studies". It also states that "the current body of evidence can not determine in a rigorous way whether TMS would be as effective as a second course of antidepressant therapy. Other important gaps in current knowledge include whether TMS is effective as an adjunctive treatment to second-line drug therapy, the durability of TMS treatment, and the effectiveness of retreatment".

An Agency for Healthcare Research and Quality's review (Gaynes et al, 2011) reported that there is insufficient evidence to evaluate whether non-pharmacological treatments are effective for TRD. The review summarized evidence of the effectiveness of 4 non-pharmacological treatments:

ECT,
rTMS,
VNS, and
cognitive behavioral therapy (CBT) or inter-personal psychotherapy.

With respect to maintaining remission (or preventing relapse), there were no direct comparisons (evidence) involving ECT, rTMS, VNS, or CBT. With regard to indirect evidence, there were 3 fair trials compared rTMS with a sham procedure and found no significant differences, however, too few patients were followed during the relapse prevention phases in 2 of the 3 studies (20-week and 6-month follow-up) and patients in the 3rd study (3-month follow-up) received a co-intervention providing insufficient evidence for a conclusion. There were no eligible studies for ECT, VNS. or psychotherapy. The review concluded that that comparative clinical research on non-pharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain unanswered. Interpretation of the data is substantially hindered by varying definitions of TRD and the paucity of relevant studies. The greatest volume of evidence is for ECT and rTMS. However, even for the few comparisons of treatments that are supported by some evidence, the strength of evidence is low for benefits, reflecting low confidence that the evidence reflects the true effect and indicating that further research is likely to change our confidence in these findings. This finding of low strength is most notable in 2 cases: ECT and rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than pharmacotherapy. No trials directly compared the likelihood of maintaining remission for non-pharmacologic interventions. The few trials addressing adverse events, subpopulations,subtypes, and health-related outcomes provided low or insufficient evidence of differences between non-pharmacologic interventions. The most urgent next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing non-pharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures following a treatment attempt of adequate dose and duration in the current episode.

Using data from the AHRQ report, the Institute for Clinical and Economic Review (ICER, 2011) conducted a cost-effectiveness modeling study, assuming that transcranial electrical stimulation and electroconvulsive therapy have equivalent efficacy. The model predicted a cost-utility ratio of $216,468 per quality adjusted life year from a payer perspective and $321,880 per quality adjusted life year from a societal perspective.

An assessment by the University of Calgary Health Technology Assessment Unit (Leggett, et al., 2014) stated that, in adults with TRD, rTMS is more effective than no treatment but the optimal protocol remains unclear. The assessment found that few studies have reported on the effectiveness of rTMS compared to ECT. The assessment stated that pooled estimates for response and remission provide conflicting results indicating rTMS may be more effective at achieving response but less effective at achieving remission. The assessment concluded that the effectiveness of rTMS compared to ECT remains unclear. The assessment also concluded that the effectiveness in youth and young adult populations is uncertain.

An assessment by the Galacian Health Technology Assessment Agency (AVALIA-T, 2014) reached similar conclusions: "Transcranial magnetic stimulation is not currently recommended as a treatment for depression, due to uncertainty about its clinical efficacy."

An assessment by the Alberta Health Technology Assessment Unit (2014) concluded that, in adults with treatment resistant depression, repetitive transcranial magnetic stimulation is more effective than no treatment but the optimal protocol remains unclear. No statistically significant differences were found between repetitive transcranial magenetic stimulation and electroconvulsive therapy; it is unclear which is most efficacious. The assessment also found that the effectiveness in youth and young adult populations is uncertain.

Hayes (2014) reported on a metaanalysis of controlled trials of TMS with sham stimulation. Most studies required patients to have 1 or more, and most typically two or more, previously failed trials of antidepressant medication. The post-treatment difference between transcranial magnetic stimulation and sham stimulation favored TMS; most differences were reported to be statistically significant, but the magnitude was generally small as measured by the MADRS scale and the various HAMD scales. No standard definition of clinically relevant improvement or a clinically relevant effect was identified in the literature. There is evidence of a strong placebo effect. A small quantity of data suggested that the durability of effect, i.e., the continued advantage of active transcranial magnetic stimulation over sham transcranial magnetic stimulation, may not last beyond 2 or 3 weeks after the end of treatment. Low quality evidence suggested that transcranial magnetic stimulation may be at least as effective as electroconvulsive therapy under certain circumstances, but under other circumstances, electroconvulsive may be superior; this evidence is of low quality because of unexplained inconsistency in study results. Low quality evidence suggested that if transcranial magnetic stimulation has any effect on quality of life or function, it is very small. The review found insufficient evidence on the use of transcranial magnetic stimulation as maintenance therapy after acute response.

An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2014) concluded that transcranial magnetic stimulation for depression does not meet the TEC criteria. The assessment stated that “adequately powered trials do not provide convincing evidence of improved health outcomes.” The assessment noted that meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large trials. The authors of the TEC assessment found that short-term randomized comparisons from 3 trials (2 reporting adequate power to detect effects and the third trial similar in size) do not provide consistent evidence that TMS improves remission of major depressive disorder compared with a sham procedure in patients failing 1 or more antidepressant trials. The authors stated that comparisons reported beyond the initial treatment period (3 weeks of TMS) in 2 of the trials (O’Reardon et al. 2007; George et al. 2010) are problematic given the planned crossover and dropouts. Analyses that take into account potential confounding introduced by crossovers were not reported. The assessment found no evidence comparing TMS with changing antidepressant or augmentation similar to the strategy employed in the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) study (Rush et al. 2006).

The TEC assessment included meta-analyses published from 2010 through the search date and trials enrolling more than 150 patients. The quality of meta-analyses was appraised using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) criteria. Randomized controlled trial quality was assessed using the U.S. Preventive Services Task Force criteria. Three randomized, controlled trials were identified that met inclusion criteria. Results from 2 trials were published at the time of the assessment -- George, et al. (2010) and O’Reardon, et al. (2007) -- and documents submitted to the FDA for the Brainsway device (subsequently published as Levkovitz, et al., 2015). The 2 published trials employed a so-called “duration adaptive design” or “forced dropout strategy” after 3 weeks of active TMS or sham. The TEC assessment rated trial quality separately for results after 3 and 6 weeks of TMS: O’Reardon et al. (2007) was rated fair at 3 weeks and poor at 6 weeks. Response rates at three weeks for TMS versus sham were 20.6 percent and 11.6 percent at three weeks, which was statistically significant; however, the differences in remission rates at three weeks between TMS and sham were not statistically significant. There was also no statistically significant difference in remission rates at six weeks. George et al. (2010) was rated good at 3 weeks and poor at 6 weeks. There was no statistically significant difference in remission rates between TMS and sham at three weeks. Although statistically significant differences in response and remission rates were reported at six weeks, trial quality for the 6-week results was rated poor because of crossover and dropouts during the second 3 weeks of treatment. Limited data are available from the Brainsway device trial that assessed outcomes at 4 and 16 weeks. Although there were significant differences between TMS and sham in per protocol and "modified intention to treat" analyses treatment differences between TMS and sham in the intention-to-treat (ITT) analysis were not significantly different.

The BlueCross BlueShield Assessment (2014) also looked at the result of the extension studies, finding that the response rates seen in the extension studies were difficult to interpret given the open-label nature of treatment and the lack of randomized comparator. Longer-term follow-up was examined in extension studies to the O’Reardon et al. (2007) and George et al. (2010) trials as well as in the meta-analysis by Allan et al. (2011). Patients in the O’Reardon et al. trial who did not respond (both active TMS and sham) were allowed to participate in an additional 6 weeks of repetitive TMS. The response and remission rates improved for both groups, and these outcome improvements occurred more frequently in the extension phase than in the original randomization phase. Another extension of this trial followed responders from either the initial randomized trial or the extension study above. Participants were followed 12 weeks for recurrence or additional TMS treatments, with a relapse rate of 12.9% with additional TMS treatment in 40.6%. The extension study to the George et al. (2010) trial enrolled 141 patients who failed to achieve remission in the original randomized phase of the trial. These participants were given additional TMS treatment for 6 weeks, but the TEC assessment noted that these results are difficult to interpret because the study lacked a control group. Any participant who remitted in the original trial or the extension study was eligible for inclusion into the third phase of the trial. Fifty patients underwent repetitive TMS tapering and were followed for 3 months. By the end of follow-up, 29 (58%) maintained remission, 2 (4%) were reclassified as partial responders, and 1 (2%) relapsed. The TEC assessment stated that the study’s unblinded, nonrandomized design and high loss to follow-up prevent any conclusions about the efficacy of repetitive TMS. The TEC assessment concluded that, because of the lack of demonstrable efficacy in the randomized comparisons, the results of the longer follow-ups reported in O’Reardon et al. (O’Reardon et al. 2007) and George et al. (George et al. 2010) offer little toward establishing treatment benefit. The TEC assessment stated that the higher response rates seen in the extension studies are difficult to interpret given the open-label nature of treatment and lack of randomized comparator.

The TEC assessment identified concerns about publication bias affecting the conclusions of the metaanalyses. Seven meta-analyses published in 2010 or later were identified. The 4 largest meta-analyses included between 24 and 34 trials. Besides differing by year of publication and available studies, the meta-analyses applied different selection criteria and analytic approaches. All meta-analyses examined clinical end points at the conclusion of TMS treatment (i.e., 1 to 5 weeks). Limited evidence on the durability of outcomes was reported in 1 analysis. The meta-analyses concluded that repetitive TMS is superior to sham for treating medication-resistant depression over the short term, and possibly over a longer term. A single meta-analysis satisfied all AMSTAR criteria, and it was the only analysis to assess trial quality (risk of bias). One meta-analysis suggested a possibility of publication bias, others did not report examining potential publication bias, and some found no indication to suspect it. A large majority of trials were small, and there was considerable overlap among the trials included in the meta-analyses. The only meta-analysis to satisfy all AMSTAR criteria included the 6-week results from O’Reardon et al. (2007), and it was conducted prior to the availability of the Brainsway results. The TEC assessment was unable to identify published results for 11 completed trials registered on ClinicalTrials.gov; the published evidence is incomplete. Concerns by the authors of the TEC assessment about conclusions from the meta-analyses center on the potential for publication bias, and inclusion of the problematic 6-week results from 2 trials. The TEC assessment stated that the three adequately powered trials do not provide convincing evidence of improved health outcomes. The meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large adequately powered trials. The TEC assessment stated that, although durability of any effects is relevant, absent demonstrable benefit compared with a sham, the question is of lesser or even little importance.

An assessment by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) stated that some studies of transcranial magnetic stimulation may show a benefit, but four health technology assessments have been unable to make conclusions. The assessment concluded that “evidence is generally inconsistent and of low quality.”

Dunner and colleagues (2014) evaluated the long-term effectiveness of TMS in naturalistic clinical practice settings following acute treatment for patients not benefiting from antidepressants. Adult patients with a primary diagnosis of unipolar, non-psychotic major depressive disorder (DSM-IV clinical criteria), who did not benefit from antidepressant medication, received TMS treatment in 42 clinical practices. A total of 257 patients completed a course of acute TMS treatment and consented to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. The study was conducted between March 2010 and August 2012. Compared with pre-TMS baseline, there was a statistically significant reduction in mean total scores on the Clinical Global Impressions-Severity of Illness scale (primary outcome), 9-Item Patient Health Questionnaire, and Inventory of Depressive Symptoms-Self Report (IDS-SR) at the end of acute treatment (all p < 0.0001), which was sustained throughout follow-up (all p < 0.0001). The proportion of patients who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. Among 120 patients who met IDS-SR response or remission criteria at the end of acute treatment, 75 (62.5 %) continued to meet response criteria throughout long-term follow-up. After the first month, when the majority of acute TMS tapering was completed, 93 patients (36.2 %) received re-introduction of TMS. In this group, the mean (SD) number of TMS treatment days was 16.2 (21.1). The authors concluded that TMS demonstrated a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. This was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS retreatment for symptom recurrence. The main drawbacks of this study were:

its observational, naturalistic design (no concurrent control group),
conclusions regarding the influence of concomitant treatments, including the role of TMS re-introduction, cannot be fully explored,and
analysis using an LOCF (last-observation-carried-forward) analysis method may exaggerate the consistency of the scores.

Silverstein et al (2015) systematically synthesized the literature on the neurobiological predictors of rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014), and PsycINFO (1806 [???] to 2014) were searched under set terms. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms. The authors concluded that significant methodological variability in rTMS treatment protocols limited the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow, and presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val homozygotes of the brain-derived neurotrophic factor (BDNF) gene.

Noda et al (2015) systematically synthesized the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014) and PsycINFO (1806 [???] to 2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1,647 articles identified, 66 studies met both inclusion and exclusion criteria; rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limited the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggested that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. The authors concluded that more research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Serafini et al (2015) performed a systematic review of the current literature (PubMed/Medline, Scopus and ScienceDirect search) to examine the role of rTMS in improving neuro-cognition in patients with treatment-resistant depression (TRD). Studies were included according to the following criteria:

being an original paper in a peer-reviewed journal, and
having analyzed the effect of rTMS on neurocognitive functioning in TRD.

The combined search strategy yielded a total of 91 articles, of which, after a complete analysis, 22 fulfilled the inclusion criteria. Based on the main findings, most of the selected studies suggested the existence of a trend towards improvements in the neurocognitive profile using rTMS. Negative findings have also been reported. However, most studies were limited by their small sample size or included mixed samples, or the adopted single-blind designs potentially biased the blinding of the study design. The authors concluded that rTMS is a non-invasive brain stimulation that may be considered a valuable and promising technique for cognitive enhancement in TRD.

In an open-label study, McGirr et al (2015) the effectiveness and acceptability of an accelerated rTMS protocol for major depressive disorder (MDD). In this naturalistic trial, 27 patients with moderate-to-severe chronic and treatment-resistant MDD were treated with twice-daily HF-rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2 consecutive weeks (60,000 pulses). The primary outcomes were rates of clinical remission and response (16-item Quick Inventory of Depressive Symptomatology post-treatment score less than or equal to 6, and greater than or equal to 50 % reduction, respectively). Secondary outcomes were self-reported anxious symptoms, depressive symptoms and quality of life, and dropout rates as a proxy for acceptability. A total of 10 (37.0 %) patients met criteria for clinical remission and 15 (55.6 %) were classified as responders, with comparable outcomes for both moderate and severe MDD. Clinician-rated improvements in depressive symptoms were paralleled in self-reported depressive and anxious symptoms, as well as quality of life. No patient discontinued treatment. The authors concluded that an accelerated protocol involving twice-daily sessions of HF-rTMS over the left DLPFC for 2 weeks was effective in treatment-resistant MDD, and had excellent acceptability. They stated that additional research is needed to optimize accelerated rTMS treatment protocols and determine effectiveness using sham-controlled trials. The main drawbacks of this study were:

short treatment duration that might be lengthened with corresponding improvements in effectiveness,
limited duration of follow-up,
small sample size, and
an open-label design requiring randomized controlled replication.

It is not known if maintenance treatment with repetitive TMS for unipolar major depression is beneficial (Holtzheimer, 2019). Although several observational studies of patients who responded to acute TMS suggest that maintenance TMS may perhaps be beneficial. few randomized trials using standard protocols have been conducted. Rapinesi and colleagues (2015) examined the role of deep TMS (dTMS) maintenance sessions in protecting patients with bipolar disorder (BD) or recurrent MDD from developing depressive or manic relapses in a 12-month follow-up period. A total of 24 drug-resistant patients with a current depressive episode and a diagnosis of MDD or BD were enrolled in the study. All the participants underwent daily dTMS sessions for 4weeks. One group (maintenance -- M group) received additional maintenance dTMS sessions weekly or twice-weekly. After the 1st dTMS cycle, a significant reduction of Hamilton Depression Rating Scale (HDRS) scores was observed in all participants. Subsequently, the HDRS mean scores did not significantly change over time in the M group, while it significantly increased in the non-M-group after 6 and 12 months. The authors concluded that the findings of this study confirmed previous evidence of a positive therapeutic effect of dTMS on depressive symptoms and suggested that, after recovery from acute episodes, maintenance dTMS sessions may be helpful in maintaining euthymia in a 12-month follow-up period. The major drawbacks of this study were:

its open design,
small sample size (n =24),
a possible confounding effect of add-on medication,
the lack of a sham control, and
the population heterogeneity.

Moreover, these researchers stated that their results should be considered as preliminary; future studies should use larger and more homogeneous samples with double-blind to better evaluate the potential effectiveness of dTMS in the treatment and the prevention of depressive episodes in mood disorders.

Pridmore, et al. (2018) reported on a prospective 10-month study to determine whether 5 TMS sessions at about monthly intervals are effective in keeping depressed patients relatively well. Thirty-nine patients (72% female) received 168 series of 5 TMS sessions and remained in the program for 21 weeks on average. Pre-post-treatment scores showed significant reductions on all measures. Post-series HAMD6 score 3.30 (2.28) indicates remission has been achieved. Pre-series scores of 6.24 (2.78) indicate a post-series decline in mood, in the direction of relapse. Before TMS series 70% were no longer in remission (being in partial remission or relapse), and after TMS series, 79% were in remission.The authors concluded that, in severe relapsing depression, monthly series of TMS move mood from the relapse/partial remission range in the direction or remission and is appropriately termed early relapse ER-TMS. Limitations of this study include its open nature and lack of a placebo group.

Richieri et al (2013) sought to determine whether maintenance is associated to a decrease in the relapse rate of depression, following successful acute treatment. The investigators enrolled 59 consecutive patients with pharmacoresistant depression who have responded (greater than 50% decrease in symptom severity) up to 6 weeks of acute TMS treatment. These patients received either 20 weeks of maintenance TMS (n = 37) or no additional TMS treatment (n = 22). The investigators performed propensity adjusted-analysis to examine the association between the relapse rate over this 20-week period and maintenance TMS. Propensity analysis eliminated differences in baseline characteristics between patient with and without maintenance TMS and approximated the conditions of random site-of-treatment assignment. At 20 weeks, relapse rate was significantly different between the two groups (p=0.004, propensity analysis): 14 patients in the maintenance TMS group (37.8 %) vs. 18 in the non-maintenance TMS group (81.8%), with an adjusted Hazard Ratio (HR) = 0.288 (0.124 to 0.669). The investigators concluded that maintenance TMS was associated with a significantly lower relapse rate in patients with pharmacoresistant depression in routine practice among responders. The study had several limitations. First, this open labeled trial suffered from the absence of standard features of clinical trials, such as placebo controls and blinding of response-raters. The treatment was not based on random assign ment; therefore, the results may be confounded by other factors. Although the propensity score can adjust for confounding by indication and selection bias, it cannot eliminate residual confounding due to unobserved factors Second, the enrolled subjects were receiving pharmacologic treatment during the acute and maintenance phase, TMS has to be thus considered as add-on therapy. However, changes in medication treatment were not allowed, they may not influence the study findings. Third, the investigators used two different protocols of stimulation in the maintenance treatment. Fourth, the investigators used a self-rating subjective scale (BDI) to measure the severity of depression, instead of more standardized objective tools as the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) or the Bech- Rafaelsen Melancholia Scale (BRMS). The investigators stated that well-designed randomized controlled trials are needed to confirm these findings, and that future research should identify patients who will benefit the most from maintenance TMS.

Wang et al (2017) reported on an assessor-blinded, randomized controlled study to evaluate the efficacy and safety of rTMS as a mono- and combination therapy in the prevention of depressive relapse/recurrence. A total of 281 depressed patients who had achieved stable full or partial remission on a 6-month antidepressant (ADP) run-in treatment were randomly assigned to an rTMS (n = 91), ADP (n = 108), or combined (rTMS + ADP, n = 82) treatment group for 12 months. Monthly clustered rTMS was conducted in 5-10 sessions over a 3-5-day period. Maintenance outcomes were assessed using time to relapse/recurrence and relapse/recurrence rate. Overall, 71.2% (200/281) of the participants completed the treatment per the protocol. rTMS + ADP and rTMS significantly reduced the risk of relapse/recurrence compared with ADP (P = 0.000), with hazard ratios of 0.297 and 0.466, respectively. Both rTMS-containing regimens produced significantly lower relapse/recurrence rates than ADP (15.9% and 24.2% vs. 44.4%, P < 0.001). In the relapsed/recurrent subgroup, first-episode depressed, rTMS-treated patients had a markedly lower relapse/recurrence rate than ADP-treated patients. Five patients on the ADP-containing regimens, but none on rTMS alone, developed acute mania. The rTMS-containing regimens had considerably more certain side effects than did the ADP group. We concluded that TMS, whether as a mono- or additional therapy, is superior to antidepressants in preventing depressive relapse/recurrence, particularly in first-episode depressed patients. The treatment does not increase the risk of manic switch, but may increase the risk of certain side effects. The study had a number of limitations. First, sham rTMS was not included as an inactive control and patients were aware of their assignment. Second, it is unclear if clustered rTMS could be superior to those “usual” rTMS regimens in achieving maintenance efficacy, safety and tolerability. Third, participants who were required to gradually discontinue antidepressants when the maintenance treatment was initiated may have been placed at significant risk of relapse. Finally, participants of this study were those who had achieved partial or full remission during run-in treatment with antidepressants, rather than with rTMS. Whether rTMS as run-in and maintenance treatment could achieve similar outcomes in treatment-resistant depressed populations needs further evaluation.

Janicak et al (2010) assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. The investigators concluded that these initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse. Limitations of the study include a lack of a controlled comparison. Further, all patients were continued on antidepressant medication monotherapy as a primary maintenance strategy during the 24-week follow-up.

Fitzgerald et al (2013) reported on an open label trial of clustered maintenance transcranial magnetic stimulation (rTMS) for treatment resistant depression. Thirty-five patients with treatment resistant depression were included. All patients had responded to two courses of rTMS treatment for depression. Following their second course of rTMS, they received clustered maintenance rTMS which involved monthly maintenance sessions of five rTMS treatments over a two day period. The time to relapse and clinical characteristics are described. Twenty-five patients experienced a relapse within the study period, with a mean treatment duration of 10.5 ± 10.3 months. This was substantially longer than their period of wellness following their initial acute treatment without maintenance (<3 months). Ten additional patients continued maintenance until withdrawal from the study without having experienced relapse (4 at a mean of 6.2 ± 4.3 months) or until study end (6 patients with mean duration of 12.0 ± 9.7 months). The authors concluded that, although preliminary, this study suggests that clustered maintenance rTMS has the potential to substantially delay the occurrence of relapse following a successful course of rTMS treatment.

Connolly et al (2012) reported on a retrospective cohort study examining the effectiveness and safety of TMS in the first 100 consecutive patients treated for depression (full DSM-IV criteria for major depressive episode in either major depressive disorder or bipolar disorder) at an academic medical center between July 21, 2008, and March 25, 2011. TMS was flexibly dosed in a course of up to 30 sessions, adjunctive to current medications, for 85 patients treated for acute depression. The primary outcomes were response and remission rates at treatment end point as measured by the Clinical Global Impressions-Improvement scale (CGI-I) at 6 weeks. Secondary outcomes included change in the Hamilton Depression Rating Scale (HDRS); Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR); Beck Depression Inventory (BDI); Beck Anxiety Inventory (BAI); and the Sheehan Disability Scale (SDS). Enduring benefit was assessed over 6 months in patients receiving maintenance TMS treatment. Data from 12 patients who received TMS as maintenance or continuation treatment after prior electroconvulsive therapy (ECT) or TMS given in a clinical trial setting were also reviewed. The clinical cohort was treatment resistant, with a mean of 3.4 failed adequate trials in the current episode. Thirty-one individuals had received prior lifetime ECT, and 60% had a history of psychiatric hospitalization. The CGI-I response rate was 50.6% and the remission rate was 24.7% at 6 weeks. The mean change was -7.8 points in HDRS score, -5.4 in QIDS-SR, -11.4 in BDI, -5.8 in BAI, and -6.9 in SDS. The HDRS response and remission rates were 41.2% and 35.3%, respectively. Forty-two patients (49%) entered 6 months of maintenance TMS treatment. Sixty-two percent (26/42 patients) maintained their responder status at the last assessment during the maintenance treatment. TMS treatment was well tolerated, with a discontinuation rate of 3% in the acute treatment phase. No serious adverse events related to TMS were observed during acute or maintenance treatment.

Philip et al (2016) reported on a randomized controlled trial that found that initially administering maintenance TMS only once per month provided no advantage over watchful waiting. These investigators reported on a pilot feasibility study investigating 12-month outcomes comparing two maintenance TMS approaches--a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS). Antidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial. Sixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥ 2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38-3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study. The authors concluded that maintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. The authors also observed that those who initially respond to TMS have a strong chance of re-responding if relapse occurs.

Kaster et al (2019) conducted a study to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. The authors concluded that major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. The authors stated that these response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols. The study had several limitations. First, the selection criteria prevent the generalization of results to individuals over age 65, individuals with bipolar depression, and individuals with significant psychiatric comorbidity. Second, two different treatments were used in this study (HFL rTMS and iTBS rTMS), which was a noninferiority trial, and although the investigators performed multiple sensitivity analyses, and despite the fact that the original study found nearly identical longitudinal response trajectories, residual trajectory differences between treatment techniques remain possible. Third, the analysis of the characteristics associated with response trajectories was exploratory and data driven. Fourth, this analysis only considered clinical characteristics associated with response trajectories and did not use any biological markers such as baseline anatomical or functional MRI scans or neurophysiological markers.

Lefkovitz and associates (2015) noted that dTMS is a new technology allowing non-surgical stimulation of relatively deep brain areas. In a double-blind, randomized controlled, multi-center study, these investigators evaluated the safety and effectiveness of dTMS in MDD. They recruited 212 MDD outpatients, aged 22 to 68 years, who had either failed 1 to 4 anti-depressant trials or not tolerated at least 2 anti-depressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. A total of 20 sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then bi-weekly for 12 weeks. Primary and secondary effectiveness end-points were the change in the HDRS-21 score and response/remission rates at week 5, respectively. Deep TMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p = 0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 % versus 21.4 %, p = 0.013; remission: 32.6 % versus 14.6 %, p = 0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. The authors concluded that dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. They stated that these results suggested that dTMS constitutes a novel intervention in MDD, which is safe and effective in patients not responding to anti-depressant medications, and whose effect remains stable over 3 months of maintenance treatment. The major drawbacks of this study were:

14.6 % of the intention-to-treat analysis set were not treated at the stimulation intensity defined by the protocol and had to be excluded from the PP analysis. This was presumably due to the flexibility of the operator in titrating stimulation intensity from 100 % up to 120 % of individual motor threshold in order to improve tolerability. Thus, patients were more likely to stay at an intensity below the optimal level compared to trials where rTMS was defined at a fixed intensity after a brief lead-in period. The importance of adequate intensity (120 % of individual motor threshold) should be highly emphasized when training operators to use this system for anti-depressant treatment, as lower intensity does not allow stimulation of deep prefrontal cortex areas and is therefore less likely to produce the desired clinical response,
patients with psychotic depression were excluded from the study. This decision was based on a previous trial that demonstrated the superiority of electro-convulsive therapy to rTMS in this patient group. However, it cannot be ruled out that psychotic patients may benefit from dTMS treatment, particularly if it is administered concomitantly with anti-psychotic medication, and
in the present study patients were withdrawn from anti-depressant medications prior to dTMS as required by regulatory authorities.

However, in a real-life clinical setting, anti-depressant medication that leads to a partial response might be augmented with dTMS.

Philip et al (2016a) stated that current treatment options for post-traumatic stress disorder (PTSD) offer modest benefits, underscoring the need for new treatments. Repetitive transcranial magnetic stimulation depolarizes neurons in a targeted brain region with magnetic fields typically pulsed at low (1 Hz) or high (10 Hz) frequency to relieve MDD. Prior work suggested an intermediate pulse frequency, 5 Hz, is also effective for treating co-morbid depressive and anxiety symptoms. In this chart review study, these researchers systematically examined the clinical and safety outcomes in 10 patients with co-morbid MDD and PTSD syndromes who received 5-Hz rTMS therapy at the Providence VA Medical Center Neuromodulation Clinic. Self-report scales measured illness severity prior to treatment, after every 5 treatments, and upon completion of treatment. Results showed significant reduction in symptoms of PTSD (p = 0.003, effect size = 1.12, 8/10 with reliable change) and MDD (p = 0.005, effect size = 1.09, 6/10 with reliable change). The authors concluded that stimulation was well-tolerated and there were no serious adverse events. They stated that these data indicated 5-Hz rTMS may be a useful option to treat these co-morbid disorders; larger, controlled trials are needed to confirm the benefits of 5-Hz protocols observed in this pilot study.

Health Quality Ontario’s systematic review and meta-analysis on “Repetitive transcranial magnetic stimulation for treatment-resistant depression” (2016) examined the anti-depressant effectiveness of rTMS in patients with treatment-resistant unipolar depression. A literature search was performed for RCTs published from January 1, 1994, to November 20, 2014. The search was updated on March 1, 2015. Two independent reviewers evaluated the abstracts for inclusion, reviewed full texts of eligible studies, and abstracted data. Meta-analyses were conducted to obtain summary estimates. The primary outcome was changes in depression scores measured by the HRSD, and these researchers considered, a priori, the mean difference of 3.5 points to be a clinically important treatment effect. Remission and response to the treatment were secondary outcomes, and these investigators calculated number needed to treat on the basis of these outcomes. They examined the possibility of publication bias by constructing funnel plots and by Begg's and Egger's tests. A meta-regression was undertaken to examine the effect of specific rTMS technical parameters on the treatment effects. A total of 23 RCTs compared rTMS with sham, and 6 RCTs compared rTMS with ECT. Trials of rTMS versus sham showed a statistically significant improvement in depression scores with rTMS (weighted mean difference [WMD] 2.31, 95 % CI: 1.19 to 3.43; p < 0.001). This improvement was smaller than the pre-specified clinically important treatment effect. There was a 10 % absolute difference between rTMS and sham in the rates of remission or response. This translated to a number needed to treat of 10. Risk ratios for remission and response were 2.20 (95 % CI: 1.44 to 3.38, p = 0.001) and 1.72 (95 % CI: 1.13 to 2.62, p = 0.01), respectively, favoring rTMS. No publication bias was detected. Trials of rTMS versus ECT showed a statistically and clinically significant difference between rTMS and ECT in favor of ECT (WMD 5.97, 95 % CI: 0.94 to 11.0, p = 0.02). Risk ratios for remission and response were 1.44 (95 % CI: 0.64 to 3.23, p = 0.38) and 1.72 (95 % CI: 0.95 to 3.11, p = 0.07), respectively, favoring ECT. The authors concluded that overall, the body of evidence favored ECT for treatment of patients who are treatment-resistant; rTMS had a small short-term effect for improving depression in comparison with sham, but follow-up studies did not show that the small effect will continue for longer periods. The meta-analysis showed a positive, short-term effect. However, the issue is that the larger trials, which is the point that the BCBS TEC assessment made, failed to reach statistical significance on intention to treat analysis, and there was a suggestion of publication bias with the smaller trials.

An assessment by the National Institute for Health and Care Excellence (NICE, 2015) concluded that the evidence on repetitive transcranial magnetic stimulation for depression shows no major safety concerns, and that the evidence on its efficacy in the short‑term is adequate, although the clinical response is variable. The NICE assessment found little data on efficacy in the long-term. The assessment stated that, during the consent process, clinicians should, in particular, inform patients about the other treatment options available, and make sure that patients understand the possibility the procedure may not give them benefit. The NICE assessment cited the need for publication of further evidence on patient selection, details of the precise type and regime of stimulation used, the use of maintenance treatment and long‑term outcomes.

Chronic Pain Syndromes

There is also a lack of scientific evidence in the use of TMS as a diagnostic tool for psychiatric disorders, and treatment for chronic pain. Pridmore et al (2005) stated that in studies of TMS for the treatment of chronic pain, there is some evidence that temporary relief can be achieved in a proportion of sufferers. Work to this point is encouraging, but systematic assessment of stimulation parameters is necessary if TMS is to attain a role in the treatment of chronic pain. Furthermore, Canavero and Bonicalzi (2005) noted that TMS has no role in the management of patients with central pain, a major chronic pain syndrome.

In a double-blind, randomized, cross-over study, Andre-Obadia et al (2008) evaluated, against placebo, the pain-relieving effects of high-rate rTMS on neuropathic pain (n = 28). The effect of a change in coil orientation (postero-anterior versus latero-medial) on different subtypes of neuropathic pain was further tested in a subset of 16 patients. Pain relief was evaluated daily during 1 week. High-frequency, postero-anterior rTMS decreased pain scores significantly more than placebo. Postero-anterior rTMS also out-matched placebo in a score combining subjective (pain relief, quality of life) and objective (rescue drug intake) criteria of treatment benefit. Changing the orientation of the coil from postero-anterior to latero-medial did not yield any significant pain relief. The analgesic effects of postero-anterior rTMS lasted for approximately 1 week. The pain-relieving effects were observed exclusively on global scores reflecting the most distressing type of pain in each patient. Conversely, rTMS did not modify specifically any of the pain subscores that were separately tested (ongoing, paroxysmal, stimulus-evoked, or disesthesic pain). The authors concluded that postero-anterior rTMS was more effective than both placebo and latero-medial rTMS. When obtained, pain relief was not specific of any particular submodality, but rather reduced the global pain sensation whatever its type. Moreover, they stated that these findings were driven from a small number of subjects; thus they need to be replicated.

Plow and associates (2012) stated that chronic neuropathic pain is one of the most prevalent and debilitating disorders. Conventional medical management, however, remains frustrating for both patients and clinicians owing to poor specificity of pharmacotherapy, delayed onset of analgesia and extensive side effects. Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without associated risks of pharmacotherapy. These investigators discussed common clinical and investigational methods of neuromodulation. Compared to clinical spinal cord stimulation, investigational techniques of cerebral neuromodulation, both invasive (DBS and motor cortical stimulation [MCS]) and non-invasive (rTMS and tDCS), may be more advantageous. By adaptively targeting the multi-dimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamo-cortical, limbic and cognitive, cerebral methods may modulate the sensory-discriminative, affective-emotional and evaluative-cognitive spheres of the pain neuromatrix. Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders. These techniques, thus, remain investigational and off-label. These investigators discussed issues implicated in inadequate efficacy, variability of responsiveness, and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in management of chronic neuropathic pain.

Leung et al (2009) performed a meta-analysis on the analgesic effect of rTMS on various neuropathic pain states based on their neuroanatomical hierarchy. Available RCTs were screened. Pooled individual data (PID) were coded for age, gender, pain neuroanatomical origins, pain duration, and treatment parameters analyses. Coded pain neuroanatomical origins consist of peripheral nerve (PN); nerve root (NR); spinal cord (SC); trigeminal nerve or ganglion (TGN); and post-stroke supra-spinal related pain (PSP). Raw data of 149 patients were extracted from 5 (1 parallel, 4 cross-over) selected (from 235 articles) RCTs. A significant (p < 0.001) overall analgesic effect (mean percent difference in pain visual analog scale (VAS) score reduction with 95 % CI) was detected with greater reduction in VAS with rTMS in comparison to sham. Including the parallel study (Khedr et al), the TGN subgroup was found to have the greatest analgesic effect (28.8 %), followed by PSP (16.7 %), SC (14.7 %), NR (10.0 %), and PN (1.5 %). The results were similar when these researchers excluded the parallel study with the greatest analgesic effect observed in TGN (33.0 %), followed by SC (14.7 %), PSP (10.5 %), NR (10.0 %), and PN (1.5 %). In addition, multiple (versus single, p = 0.003) sessions and lower (greater than 1 and less than or equal to 10 Hz) treatment frequency range (versus greater than 10 Hz) appears to generate better analgesic outcome. In short, rTMS appears to be more effective in suppressing centrally than peripherally originated neuropathic pain states. The authors stated that this was the first PID-based meta-analysis to assess the differential analgesic effect of rTMS on neuropathic pain based on the neuroanatomical origins of the pain pathophysiology and treatment parameters. The derived information serves as a useful resource in regards to treatment parameters and patient population selection for future rTMS-pain studies.

Lindholm and colleagues (2015) examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, these researchers assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyl-transferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. A total of 16 patients with chronic drug resistant neuropathic orofacial pain participated in this randomized, placebo controlled, cross-over study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (p = 0.0071) or the sham (p = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than at pre-treatment baseline (p = 0.0127 for the intensity of pain and p = 0.0074 for the interference of pain) or after the S1/M1 (p = 0.001 and p = 0.0001) and sham (p = 0.0491 and p = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The authors concluded that the right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

Jin and colleagues (2015) stated that the optimal parameters of rTMS (stimulation frequency and treatment sessions) for achieving long-term analgesic effects remain unknown. These investigators evaluated the optimal parameters of rTMS for neuropathic pain (NP), including the rTMS sessions needed for inducing acute as well as long-term analgesic effects. They performed a meta-analysis of the analgesic effect of high frequency rTMS (HF- rTMS) for neuropathic patients. This meta-analysis examined all studies involving the analgesic effectiveness of HF-rTMS for NP. PubMed, Embase, and the Cochrane library were searched for clinical studies of rTMS treatment on NP published before December 31, 2014. Crude standardized mean difference (SMD) with 95 % CI were calculated for pain intensity after different treatment sessions (from 1 to 10) and follow-up of 1 or 2 months after rTMS treatment using random effect models. A total of 25 studies (including 32 trials and 589 patients) were selected for the meta-analysis according to the inclusion and exclusion criteria. All 3 HF-rTMS treatments (5, 10, and 20 Hz) produced pain reduction, while there were no differences between them, with the maximal pain reduction found after 1 and 5 sessions of rTMS treatment. Further, this significant analgesic effect remained for 1 month after 5 sessions of rTMS treatment. The authors concluded that HF-rTMS stimulation on primary motor cortex is effective in relieving pain in NP patients. Although 5 sessions of rTMS treatment produced a maximal analgesic effect and may be maintained for at least 1e month, further large-scale and well-controlled trials are needed to determine if this enhanced effect is specific to certain types of NP such as post-stroke related central NP. There main drawbacks of this meta-analysis were: the long-term analgesic effects of different HF-rTMS and low frequency (LF) rTMS sessions, including the single session of rTMS on different NP of varying origins have yet not been evaluated, and the full degree of pain relief is still unclear for many rTMS studies.

Mulla et al (2015) noted that central post-stroke pain is a chronic neuropathic disorder that follows a stroke. Current research on its management is limited, and no review has evaluated all therapies for central post-stroke pain. These investigators conducted a systematic review of RCTs to evaluate therapies for central post-stroke pain. They identified eligible trials, in any language, by systematic searches of AMED, CENTRAL, CINAHL, DARE, EMBASE, HealthSTAR, MEDLINE, and PsychINFO. Eligible trials; enrolled greater than or equal to 10 patients with central post-stroke pain; randomly assigned them to an active therapy or a control arm; and collected outcome data greater than or equal to 14 days after treatment. Pairs of reviewers, independently and in duplicate, screened titles and abstracts of identified citations, reviewed full texts of potentially eligible trials, and extracted information from eligible studies. These researchers used a modified Cochrane tool to evaluate risk of bias of eligible studies, and collected patient-important outcomes according to recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. They conducted, when possible, random effects meta-analyses, and evaluated the certainty in treatment effects using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) System. A total of 8 eligible English language RCTs (459 patients) tested anti-convulsants, an anti-depressant, an opioid antagonist, rTMS, and acupuncture. Results suggested that all therapies had little to no effect on pain and other patient-important outcomes. The certainty in the treatment estimates ranged from very low to low. The authors concluded that these findings were inconsistent with major clinical practice guidelines; the available evidence suggested no beneficial effects of any therapies that researchers have evaluated in RCTs.

Fibromyalgia

In a randomized, controlled pilot study, Short et al (2011) examined the effects of adjunctive left pre-frontal rTMS on patients with fibromyalgia pain. A total of 20 patients with fibromyalgia, defined by American College of Rheumatology criteria, and were randomized to receive 4,000 pulses at 10 Hz TMS (n = 10), or sham TMS (n = 10) treatment for 10 sessions over 2 weeks along with their standard medications, which were fixed and stable for at least 4 weeks before starting sessions. Subjects recorded daily pain, mood, and activity. Blinded raters assessed pain, mood, functional status, and tender points weekly with the Brief Pain Inventory, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire. No statistically significant differences between groups were observed. Patients who received active TMS had a mean 29 % (statistically significant) reduction in pain symptoms in comparison to their baseline pain. Sham-TMS participants had a 4 % non-significant change in daily pain from their baseline pain. At 2 weeks after treatment, there was a significant improvement in depression symptoms in the active group compared to baseline. Pain reduction preceded anti-depressant effects. TMS was well-tolerated, with few side effects. The authors concluded that further studies that address study limitations (small sample size and short follow-up) are needed to determine whether daily prefrontal TMS may be an effective, durable, and clinically useful treatment for fibromyalgia symptoms.

Marlow et al (2013) systematically reviewed the literature to date applying rTMS or tDCS for patients with fibromyalgia syndrome (FMS). Electronic bibliography databases screened included PubMed, Ovid MEDLINE, PsychINFO, CINAHL, and Cochrane Library. The keyword "fibromyalgia" was combined with ("transcranial" and "stimulation") or "TMS" or "tDCS" or "transcranial magnetic stimulation" or "transcranial direct current stimulation". Nine of 23 studies were included; brain stimulation sites comprised either the primary motor cortex (M1) or the dorso-lateral pre-frontal cortex (DLPFC). Five studies used rTMS (high-frequency-M1: 2, low-frequency-DLPFC: 2, high-frequency-DLPFC: 1), while 4 applied tDCS (anodal-M1: 1, anodal-M1/DLPFC: 3); 8 were double-blinded RCTS. Most (80 %) rTMS studies that measured pain reported significant decreases, while all (100 %) tDCS studies with pain measures reported significant decreases. Greater longevity of significant pain reductions was observed for excitatory M1 rTMS/tDCS. The authors concluded that studies involving excitatory rTMS/tDCS at M1 showed analogous pain reductions as well as considerably fewer side effects compared to FDA-approved FMS pharmaceuticals. The most commonly reported side effects were mild, including transient headaches and scalp discomforts at the stimulation site. Yearly use of rTMS/tDCS regimens appears costly ($11,740 to 14,507/year); however, analyses to appropriately weigh these costs against clinical and quality of life benefits for patients with FMS are lacking. Consequently, rTMS/tDCS should be considered when treating patients with FMS, particularly those who are unable to find adequate symptom relief with other therapies. Moreover, they stated that further work into optimal stimulation parameters and standardized outcome measures is needed to clarify associated efficacy and effectiveness.

In a double-blind, randomized, placebo-controlled study, Boyer and colleagues (2014) examined the impact of rTMS on quality of life (QoL) of patients with fibromyalgia, and its possible brain metabolic substrate. A total of 38 patients were randomly assigned to receive high-frequency rTMS (n = 19) or sham stimulation (n = 19), applied to left primary motor cortex in 14 sessions over 10 weeks. Primary clinical outcomes were QoL changes at the end of week 11, measured using the Fibromyalgia Impact Questionnaire (FIQ). Secondary clinical outcomes were mental and physical QoL component measured using the 36-Item Short Form Health Survey (SF-36), but also pain, mood, and anxiety. Resting-state [(18)F]-fluorodeoxyglucose-PET metabolism was assessed at baseline, week 2, and week 11. Whole-brain voxel-based analysis was performed to study between-group metabolic changes over time. At week 11, patients of the active rTMS group had greater QoL improvement in the FIQ (p = 0.032) and in the mental component of the SF-36 (p = 0.019) than the sham stimulation group. No significant impact was found for other clinical outcomes. Compared with the sham stimulation group, patients of the active rTMS group presented an increase in right medial temporal metabolism between baseline and week 11 (p < 0.001), which was correlated with FIQ and mental component SF-36 concomitant changes (r = -0.38, p = 0.043; r = 0.51, p = 0.009, respectively). Improvement of QoL involved mainly affective, emotional, and social dimensions. The authors concluded that the findings of this study showed that rTMS improves QoL of patients with fibromyalgia. This improvement is associated with a concomitant increase in right limbic metabolism, arguing for a neural substrate to the impact of rTMS on emotional dimensions involved in QoL. The major drawback of this study was its small sample size (n = 38). Furthermore, 9 patients did not complete the maintenance phase, reducing the sample size to 29. The authors stated that replication with a larger sample size is needed. They also noted that recent studies recommended that investigators test for the success of blinding, which was not done in this trial.

Winkelmann et al (2012) stated that the scheduled update to the German S3 guidelines on fibromyalgia syndrome by the Association of the Scientific Medical Societies was planned starting in March 2011. The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy, 9 scientific medical societies, as well as 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Center for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. The authors concluded that low-to-moderate intensity aerobic exercise and strength training are strongly recommended; chiropractic, laser therapy, magnetic field therapy, massage, and transcranial current stimulation are not recommended.

Saltychev and Laimi (2017) examined if there is evidence of rTMS being effective in decreasing the severity of pain among patients with fibromyalgia. CENTRAL, Medline, Embase, CINAHL, SCOPUS, Web Of Science, and relevant references of the identified studies were searched. Randomized controlled studies on adults with fibromyalgia were included. The outcome studied was change in pain severity. Methodological quality was assessed using the scale introduced in the Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group. A random-effects meta-analysis was carried out with a test for heterogeneity using the I and pooled estimate as a non-standardized mean of difference in change in pain severity measures by a numeric rating scale. The search resulted in 791 records, 8 relevant, and meta-analyses on 7 trials. The risk of bias was considered low for 7 studies. Pain severity before and after the last stimulation decreased by -1.2 points on 0 to 10 numeric rating scale (95 % CI: -1.7 to -0.8). Pain severity before and 1 week to 1 month after the last stimulation decreased by -0.7 points (95 % CI: -1.0 to -0.3). Both pooled results were below the minimal clinically important difference of 1.5 points. The authors concluded that there is moderate evidence that rTMS is not more effective than sham in reducing the severity of pain in fibromyalgia patients, questioning the routine recommendation of this method for fibromyalgia treatment.

Migraine

Funak and colleagues (2006) noted that in healthy volunteers (HV), 1 session of 1-Hz rTMS over the visual cortex induces dishabituation of visual evoked potentials (VEPs) on average for 30 mins, while in migraineurs 1 session of 10-Hz rTMS replaces the abnormal VEP potentiation by a normal habituation for 9 mins. These investigators examined if repeated rTMS sessions (1-Hz in 8 HV; 10-Hz in 8 migraineurs) on 5 consecutive days can modify VEPs for longer periods . In all 8 HV, the 1-Hz rTMS-induced dishabituation increased in duration over consecutive sessions and persisted between several hours (n = 4) and several weeks (n = 4) after the 5th session. In 6 of the 8 migraineurs, the normalization of VEP habituation by 10-Hz rTMS lasted longer after each daily stimulation, but did not exceed several hours after the last session, except in 2 patients, where it persisted for 2 days and 1 week. The authors concluded that daily rTMS can thus induce long-lasting changes in cortical excitability and VEP habituation pattern. However, whether this effect may be useful in preventing migraines remains to be determined.

Guidance from the National Institute for Health and Care Excellence (NICE, 2014) concluded that the evidence on the efficacy of TMS for the treatment of migraine is limited in quantity and for the prevention of migraine is limited in both quality and quantity. Evidence on its safety in the short and medium term is adequate but there is uncertainty about the safety of long-term or frequent use of TMS.

Moisset et al (2020) noted that several neuromodulation methods exist for migraine treatment. These researchers carried out a systematic review and meta-analysis of RCTs focusing on migraine treatment using neurostimulation methods. They searched Medline and Embase up to July 1, 2020 for RCTs reporting acute or preventive treatment of migraine with either non-invasive or invasive neurostimulation methods. Two researchers independently assessed the eligibility of the retrieved studies and extracted data. Outcomes for the quantitative synthesis were 2 hours pain free for acute treatment and headache days per month for preventive treatment. These investigators also carried out subgroup analyses by treatment (stimulation method and site of application). Estimates were pooled using random-effects meta-analysis. A total of 38 articles were included in the qualitative analysis (7 acute, 31 preventive) and 34 in the quantitative evaluation (6 acute, 28 preventive). Remote electrical neuromodulation (REN) was effective for acute treatment. Data were insufficient to draw conclusions for any other techniques (single studies). Invasive occipital nerve stimulation (ONS) was effective for migraine prevention, with a large effect size but considerable heterogeneity, whereas supra-orbital TENS, percutaneous electrical nerve stimulation (PENS), and high-frequency rTMS over the primary motor cortex (M1) were effective, with small to medium effect sizes. VNS, left prefrontal cortex rTMS, and cathodal tDCS over the M1 had no significant effect and heterogeneity was high. The authors concluded that several neuromodulation methods are of potential interest for migraine management, but the quality of the evidence is very poor. These researchers stated that future large and well-conducted studies are needed and could improve on the present results.

The authors stated that this review had several limitations. First, the meta-analysis was based on a very limited number of articles for each study sub-group and the estimation of effect size may not be properly powered. Thus, the conclusions should be interpreted with caution. Further research is very likely to have a large impact on the confidence in the estimated effect. Even within the subgroups, in which the same technique and target were tested, the parameters could be quite different in terms of stimulation intensity and the number of sessions, again limiting the reliability of the estimates. Second, although the included studies only considered migraine patients, these researchers could not exclude the presence of confounding factors due to migraine frequency at baseline and potential associated medication over-use or the presence of overlapping headache disorders among the included subjects, which could affect the validity of these findings. Third, the methodological quality of the included studies was heterogeneous, with only 12/38 studies being of high or very high quality in the present review, as shown in previous neuro-modulatory reviews for chronic pain in general. Moreover, it is often difficult to obtain proper blinding in studies involving neurostimulation devices that usually induce paresthesia. Finally, the follow-up period was generally relatively short; therefore, long-term benefits of neuromodulation techniques are yet to be proven.

Lloyd et al (2021) stated that migraine is a common disabling primary headache condition. Although strives have been made in treatment, there remains an unmet need for safe, effective acute, and preventative treatments. The promising concept of neuromodulation of relevant neuronal targets in a non-invasive fashion for the treatment of primary headache disorders has led to the trial of numerous devices over the years. These investigators reviewed the evidence on current neuromodulation treatments available for the management of primary headache disorders; RCTs as well as open-label and real-world studies on central and peripheral cephalic and non-cephalic neuromodulation modalities in primary headaches were critically reviewed. The current evidence suggests a role of single-pulse TMS, supra-orbital nerve (SON) stimulation, and remote non-cephalic electrical stimulation as migraine abortive treatments, with stronger evidence in episodic migraine (EM) rather than in chronic migraine (CM). Single-pulse TMS and SON stimulation also hold promising evidence in EM prevention and initial positive evidence in CM prevention. More evidence should clarify the therapeutic role of the external VNS and tDCS in migraine. However, external VNS may be effective in the acute treatment of episodic but not chronic cluster headache, in the prevention of hemicrania continua and paroxysmal hemicrania but not of short-lasting neuralgiform headache attacks. The difficulty in setting up sham-controlled studies has thus far prevented the publication of robust trials. This limitation along with the cost of these therapies has meant that their use is limited in most countries. The authors concluded that neuromodulation is a promising non-pharmacological treatment approach for primary headaches. These researchers stated that more studies with appropriate blinding strategies and reduction of device cost may allow more widespread approval of these treatments and in turn increase clinician's experience in neuromodulation.

Furthermore, an UpToDate review on “Preventive treatment of episodic migraine in adults” (Schwedt and Garza, 2022) states that “Transcranial magnetic stimulation -- Limited observational evidence suggests that single-pulse transcranial magnetic stimulation (sTMS) may be effective for migraine prevention. An open-label, prospective study of subjects with episodic and chronic migraine, with and without aura, assessed preventive (4 pulses twice daily) and acute (3 pulses repeated up to 3 times for each migraine attack) sTMS treatment over a 12-week period. During weeks 9 through 12, the mean reduction of headache days was greater with TMS compared with an estimated placebo response derived from historical data (-2.75 versus -0.63 days). Adverse events were infrequent, but included lightheadedness, tingling, and tinnitus. sTMS received FDA approval for the acute and prophylactic treatment of migraine in 2017”.

Parkinson Disease

Wagle-Shukla et al (2007) examined the effectiveness of rTMS for the treatment of patients (n = 6) with levodopa-induced dyskinesias (LID). They reported that a 2-week course of low-frequency rTMS reduced LID as indexed by both objective as well as subjective evaluations, with no change in parkinsonism as evaluated by Unified Parkinson Disease Rating Scale motor scores. The benefit was observed at 1 day after treatment, but not 2 weeks later. The drawbacks of this study were its small sample size and the open labeled design. Furthermore, benefits were not sustained. More research is needed to ascertain the clinical value, if any, of rTMS in the treatment of LID.

An assessment of rTMS by the Health Council of the Netherlands (2008) stated that the use of rTMS to treat patients with Parkinson’s disease has produced some encouraging results, and that this technology could be useful in identifying the best site for deep brain stimulation. The assessment stated that it is "still open to question" whether or not rTMS has the potential to reduce tremors.

In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2011) examined the safety and effectiveness of intermittent theta-burst stimulation (iTBS) in the treatment of motor symptoms in Parkinson disease (PD); iTBS of the motor and DLPFC was investigated in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neuropsychological, and neurophysiologic measures. These researchers investigated 26 patients with mild-to-moderate PD: 13 received iTBS and 13 sham stimulation. They found beneficial effects of iTBS on mood, but no improvement of gait, bradykinesia, UPDRS, and other measures. Electroencephalography/electromyography monitoring recorded no pathologic increase of cortical excitability or epileptic activity. Few reported discomfort or pain and 1 subject experienced tinnitus during real stimulation. The authors concluded that iTBS of the motor and pre-frontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD.

There are 2 non-invasive methods to stimulate the brain: TMS, and tDCS. Compared to the former approach, the latter does not directly lead to neuronal discharges; tDCS only modulates the excitability level of brain tissue. Furthermore, tDCS can be employed in a dual mode -- increasing excitability on one hemisphere and decreasing excitability on the other hemisphere. In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2010) examined the effectiveness of tDCS in the treatment of PD. The effectiveness of anodal tDCS applied to the motor and pre-frontal cortices was investigated in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility. A total of 25 PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. Transcranial direct current stimulation improved gait by some measures for a short time and improved bradykinesia in both the on and off states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well being, and self-assessed mobility did not differ between the tDCS and sham interventions. The authors concluded that tDCS of the motor and pre-frontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.

In a randomized, double-blind, sham-controlled, multi-center study with a parallel design, Shirota et al (2013) examined the effectiveness and stimulation frequency dependence of rTMS over the supplementary motor area (SMA) in PD. A weekly intervention was performed 8 times, and the effects were monitored up to 20 weeks. By central registration, participants were assigned to 1 of 3 arms of the study: low-frequency (1-Hz) rTMS, high-frequency (10-Hz) rTMS, and realistic sham stimulation. The primary end point was the score change of the UPDRS part III from the baseline. Several non-motor symptom scales such as the Hamilton Rating Scale for Depression, apathy score, and non-motor symptoms questionnaire were defined as secondary end points. Of the 106 patients enrolled, 36 were allocated to 1-Hz rTMS, 34 to 10-Hz rTMS, and 36 to realistic sham stimulation. Results showed 6.84-point improvement of the UPDRS part III in the 1-Hz group at the last visit of the 20th week. Sham stimulation and 10-Hz rTMS improved motor symptoms transiently, but their effects disappeared in the observation period. Changes in non-motor symptoms (NMS) were not clear in any group. No severe adverse event was reported. The authors concluded that 1-Hz rTMS over the SMA was effective for motor, but not non-motor, symptoms in PD. Moreover, they stated that rTMS is a promising add-on therapy for motor symptoms of PD, whereas establishment of an adequate protocol for NMS treatment using rTMS requires further study. They noted that the present findings warrant a confirmatory clinical trial for SMA rTMS on PD, undertaken on a larger scale.

In a systematic review, Chung and Mak (2016) evaluated the effectiveness of rTMS on improving physical function and motor signs over the short- and long-terms in people with PD. A total of 5 electronic databases were systematically searched for English language full-text articles using relevant search terms. Only randomized placebo-controlled trials investigating the effects of rTMS in PD were considered. The primary outcomes were walking performance, upper limb function, and UPDRS section III. Trials with similar outcomes were pooled by calculating Hedges' g using random-effects model. A total of 22 trials comprising 555 people with PD were included. Pooled estimates of effect of rTMS indicated significantly improved short-term upper limb function (Hedges' g, 0.40, p = 0.007), short-term (Hedges' g, 0.61, p = 0.03) and long-term walking performance (Hedges' g, 0.89, p = 0.03), short-term (Hedges' g, 0.31, p = 0.003) and long-term (Hedges' g, 0.54, p = 0.003) UPDRS III scores. Subgroup analyses suggested a more prominent effect for M1 stimulation. Meta-regression revealed that a greater number of total stimulation pulses were associated with more UPDRS III improvements over the long-term. The authors concluded that the pooled evidence suggested that rTMS improves upper limb function in the short-term, walking performance and UPDRS III in the short- and long-terms in PD sufferers. Moreover, they stated that further studies are needed to develop optimal rTMS therapeutic protocols for PD.

Tinnitus

In a pilot study, Smith et al (2007) evaluated the effectiveness of rTMS and its effects on attentional deficits and cortical asymmetry in 4 patients with chronic tinnitus using objective and subjective measures and employing an optimization technique refined in our laboratory. Patients received 5 consecutive days of active, low-frequency rTMS or sham treatment (using a 45-degree coil-tilt method) before crossing over. Subjective tinnitus was assessed at baseline, after each treatment, and 4 weeks later. Positron emission tomography/computed tomography (PET/CT) scans were obtained at baseline and immediately after active treatment to examine change in cortical asymmetry. Attentional vigilance was assessed at baseline and after each treatment using a simple reaction time test. All patients had a response to active (but not sham) rTMS, as indicated by their best tinnitus ratings; however, tinnitus returned in all patients by 4 weeks after active treatment. All patients had reduced cortical activity visualized on PET immediately after active rTMS. Mean reaction time improved (p < 0.05) after active but not sham rTMS. The authors concluded that rTMS is a promising treatment modality that can transiently diminish tinnitus in some individuals, but further trials are needed to determine the optimal techniques required to achieve a lasting response. This is in agreement with the findings of Plewnia et al (2007) who reported that the effects of rTMS for patients with chronic tinnitus are only moderate; inter-individual responsiveness varied; and the attenuation of tinnitus appeared to wear off within 2 weeks after the last stimulation session.

In a pilot study, Lee and colleagues (2008) examined if rTMS may suppress excessive spontaneous activity in the left superior temporal gyrus associated with tinnitus. A total of 8 patients with tinnitus received 5 consecutive days of rTMS (0.5 Hz, 20 mins) to the left temporo-parietal area. Tinnitus Handicap Inventory (THI) measures before sessions 1 and 3 and after session 5 were used to evaluate effectiveness. Patient 1's THI decreased 40 to 34 to 26, patient 4 reported a subjective improvement, patient 8 withdrew, and the remaining patients reported no improvement. Adverse effects included temporary soreness, restlessness, and photophobia. The authors concluded that the parameters for this rTMS study are different from those that reported success with its use. W ith these current parameters, rTMS did not improve tinnitus. There were no permanent adverse outcomes.

Kleinjung et al (2009) investigated if administration of the dopamine precursor levodopa before low-frequency rTMS enhances its effectiveness in tinnitus treatment. A total of 16 patients with chronic tinnitus received 100 mg of levodopa before each session of low-frequency rTMS. Results were compared with a matched control group of 16 patients who received the same treatment, but without levodopa. Treatment outcome was assessed with a standardized tinnitus questionnaire. Both stimulation protocols resulted in a significant reduction of tinnitus scores after 10 days of stimulation; however, there was no significant difference between the 2 groups. The authors concluded that these findings suggested that 100 mg of levodopa does not enhance the effect of rTMS in the treatment of tinnitus. Furthermore, they stated that "[e]ven if the available data clearly demonstrate the therapeutic potential of rTMS in tinnitus, the clinical effects are still relatively limited. A better understanding of the underlying neurobiological mechanisms will be crucial for optimizing stimulation protocols and further improving the efficacy of rTMS".

In a Cochrane review on rTMS for tinnitus, Meng et al (2011) concluded that there is very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. When considering the impact of tinnitus on patients' quality of life, support is from a single study with a low-risk of bias based on a single outcome measure at a single point in time. When considering the impact on tinnitus loudness, this is based on the analysis of pooled data with a large confidence interval. Studies suggest that rTMS is a safe treatment for tinnitus in the short-term, however there were insufficient data to provide any support for the safety of this treatment in the long-term. The authors stated that more prospective, randomized, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rTMS for tinnitus patients. Uniform, validated, tinnitus-specific questionnaires and measurement scales should be used in future studies.

In a systematic review, Peng et al (2012) evaluated the effectiveness of rTMS for the treatment of chronic tinnitus. Data Sources Relevant electronic databases and a reference list of articles published up to January 2012 were searched. Randomized controlled clinical trials of all types of rTMS treatment for patients with chronic tinnitus were included. A total of 5 trials (160 participants) were included in this review. Repetitive TMS showed benefits in the short-term, but the long-term effects are questionable. The Tinnitus Handicap Inventory (THI) and the visual analog scale (VAS) were the major assessment methods used. After active TMS stimulation, the reduction in the THI total score and VAS was significant compared with baseline at the first time-point assessed and in the short-term (2 weeks and 4 weeks). The longest follow-up time was 26 weeks after treatment, and the shortest follow-up time was 2 weeks. No severe side effects were reported from the use of rTMS. Differences in age, hearing level, duration of tinnitus of the included patients, and the condition of sham treatment may influence the effect. The authors concluded that rTMS could be a new therapeutic tool for the treatment of chronic tinnitus, and thus far they have not been able to demonstrate any substantial risk from rTMS treatment. However, they stated that the long-term effects of rTMS treatment for tinnitus are not clear and will require further study.

Plewnia et al (2012) examined if 4 weeks of bilateral rTMS to the temporal or temporo-parietal cortex is effective and safe in the treatment of chronic tinnitus. In this controlled 3-armed trial, 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS). They were randomized to stimulation above the temporal cortex, the temporo-parietal cortex, or as sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. Tinnitus severity was slightly reduced from baseline by a mean (SD) 2.6 (8.2) after sham, 2.4 (8.0) after temporo-parietal, 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (CI: -5.4 to +6.7) or temporo-parietal cTBS (CI: -5.9 to +6.3) or real cTBS (CI: -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. The authors concluded that treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporo-parietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation. However, these results are not to be generalized to all forms of rTMS treatments for tinnitus.

In an editorial that accompanied the afore-mentioned study, Triggs and Hajioff (2012) stated that “At present, rTMS should be classified as “U” by the American Academy of Neurology classification of recommendation: the data are inadequate and conflicting, and the treatment is unproven”.

The American Academy of Otolaryngology - Head and Neck Surgery’s clinical practice guideline on “Tinnitus” (Tunkel et al, 2014) listed transcranial magnetic stimulation as one of the interventions were considered but no recommendation was made or were recommended against.

Liang and colleagues (2020) stated that although the clinical safety and efficacy of rTMS in the treatment of chronic tinnitus have been frequently examined, the results remain contradictory. These researchers carried out a systematic review and meta-analyzed clinical trials examining the effects of rTMS to examine its safety and efficacy. Studies of rTMS for chronic tinnitus were retrieved from PubMed, Embase, and Cochrane Library through April 2020. Review Manager 5.3 software was used for data synthesis, and Stata 13.0 software was used for analyses of publication bias and sensitivity. A total of 29 randomized studies involving 1,228 chronic tinnitus patients were included. Compared with sham-rTMS, rTMS exhibited significant improvements in the THI scores at 1 week (MD: - 7.92, 95 % CI: - 14.18 to - 1.66), 1 month (MD: -8.52, 95 % CI: - 12.49 to - 4.55), and 6 months (MD: -6.53, 95 % CI: - 11.406 to - 1.66) post-intervention; there were significant mean changes in THI scores at 1 month (MD: -14.86, 95 % CI: - 21.42 to - 8.29) and 6 months (MD: -16.37, 95 % CI: - 20.64 to - 12.11) post-intervention, and the tinnitus questionnaire (TQ) score at 1 week post-intervention (MD: -8.54, 95 % CI: - 15.56 to - 1.52). Non-significant efficacy of rTMS was found regarding the THI score 2 weeks post-intervention (MD: -1.51, 95 % CI: - 13.42 to - 10.40); the mean change in TQ scores 1 month post-intervention (MD: -3.67, 95 % CI: - 8.56 to 1.22); TQ scores 1 (MD: -8.97, 95 % CI: - 20.41 to 2.48) and 6 months (MD: -7.02, 95 % CI: - 18.18 to 4.13) post-intervention; and AEs (OR: 1.11, 95 % CI: 0.51 to 2.42). Egger's and Begg's tests indicated no publication bias (p = 0.925). The authors concluded that this meta-analysis demonstrated that rTMS was effective for chronic tinnitus; however, its safety needs more validation. Moreover, these researchers stated that restrained by the insufficient number of included studies and the small sample size, large, randomized, double-blinded, multi-center studies are needed for further verification.

The authors stated that this study had several drawbacks. First, despite the inclusion of recent large randomized trials, the limited number of enrolled subjects in the meta-analysis limited more accurate analyses, and some results were non-significant, which might be attributed to the nature of the population receiving rTMS. Second, this study only analyzed English-language references, which led to lost data from those in other languages. Third, although Egger᾽s and Begg᾽s analyses showed no publication bias in the meta-analysis, because of the limited number of studies included in this analysis, the possibility of false negatives could not be excluded.

Anxiety Disorders

Prasko et al (2007) examined if rTMS would facilitate effect of serotonin reuptake inhibitors (SRIs) in patients with panic disorder (n = 15). Patients suffering from panic disorder resistant to SRI therapy were randomly assigned to either active or to sham rTMS. The objective of the study was to compare the 2- and 4-weeks effectiveness of the 10 sessions low-frequency rTMS with sham rTMS add on SRI therapy. These researchers used 1-Hz, 30-min rTMS, 110 % of motor threshold administered over the right dorso-lateral prefrontal cortex (DLPFC). The same time schedule was used for sham administration. Psychopathology was evaluated by means of the rating scales CGI, HAMA, PDSS and BAI before the treatment, immediately after the experimental treatment, and 2 weeks after the experimental treatment by an independent reviewer. Both groups improved during the study period but the treatment effect did not differ between groups in any of the instruments. The authors concluded that low-frequency rTMS administered over the right dorso-lateral prefrontal cortex after 10 sessions did not differ from sham rTMS add on SRIs in patients with panic disorder.

Pigot and colleagues (2008) noted that rTMS has also been investigated for the treatment of some anxiety disorders (e.g., obsessive-compulsive disorder, post-traumatic stress disorder and panic disorder). While anecdotal reports and open studies have suggested a therapeutic role for rTMS in anxiety disorders, controlled studies, which have varied greatly in terms of rTMS administration, have not shown it to be superior to placebo. Furthermore, reports in animal models of anxiety have not been consistent. Thus, there is currently no convincing evidence for the clinical role of rTMS in the treatment of anxiety disorders. The authors stated that more research is needed, drawing on advances in the understanding of pathological neurocircuitry in anxiety disorders and the mechanisms of action by which rTMS may alter that neurocircuitry. In a review on OCD, Abramowitz and colleagues (2009) stated that although rTMS has not been extensively assessed in this disorder, available data do not support its therapeutic efficacy for this condition.

Berlim et al (2014) stated that rTMS applied to the dorsolateral prefrontal cortex (DLPFC) has yielded promising results as a treatment for post-traumatic stress disorder (PTSD). However, to-date, no quantitative review of its clinical utility has been published. These investigators searched for randomized and sham-controlled trials from 1995 to March 2013 using MEDLINE, Embase, PsycINFO, CENTRAL, and SCOPUS. They then performed an exploratory random effects meta-analysis. Studies on rTMS applied to the right DLPFC included 64 adults with PTSD. The pooled Hedges g effect size for pre- and post-changes in clinician-rated and self-reported PTSD symptoms were, respectively, 1.65 (p < 0.001) and 1.91 (p < 0.001), indicating significant and large-sized differences in outcome favoring active rTMS. Also, there were significant pre- and post-decreases with active rTMS in overall anxiety (Hedges g = 1.24; p = 0.02) and depressive (Hedges g = 0.85; p < 0.001) symptoms. Drop-out rates at study end did not differ between active and sham rTMS groups. Regarding rTMS applied to the left DLPFC, there was only 1 study published to-date (using a high frequency protocol), and its results showed that active rTMS seems to be superior overall to sham rTMS. The authors concluded that this exploratory meta-analysis showed that active rTMS applied to the DLPFC seems to be effective and acceptable for treating PTSD. However, they stated that the small number of subjects included in the analyses limits the generalizability of these findings. They stated that future studies should include larger samples and deliver optimized stimulation parameters.

An assessment by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) concluded that, for PTSD, there is early evidence that TMS may improve clinical outcomes. For generalized anxiety disorder, no evidence was found.

Parikh and colleagues (2022) carried out a systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) in adults with generalized anxiety disorder (GAD). These investigators conducted a systematic literature review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Pre- and post-treatment anxiety scores were extracted, and a random-effects meta-analysis was performed to determine the magnitude of improvement (SMD). Standard assessments of heterogeneity (e.g., Q-statistic, I2, and τ 2) and publication bias were performed. The initial search resulted in 3,194 citations, of which 6 studies were included in the meta-analysis. A total of 152 patients were studied, including 97 patients who received active treatment and 55 who received sham treatment, and heterogeneity was modest (I2 = 13.32, Q = 5.77). In patients with GAD, rTMS produced a SMD of -1.857 (CI: -2.219 to -1.494; p < 0.001) with a prediction interval of -2.55 to -1.16. The authors concluded that the findings of this review suggested a robust effect of rTMS in GAD in the context of limited, heterogenous studies. Moreover, these researchers stated that rigorously designed RCTs of rTMS for GAD and related anxiety disorders are urgently needed. These studies will provide opportunities for biomarker development and integration of concurrent evidence-based psychotherapy to maximize results.

Spasticity

Centonze and associates (2007) examined if investigate rTMS can modify spasticity. These researchers used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting multiple sclerosis and lower limb spasticity. A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased cortico-spinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. The authors concluded that rTMS may improve spasticity in multiple sclerosis. The findings of this study need to be validated by prospective RCTs with larger patient numbers.

Bulimia Nervosa

In a single-center, randomized, double-blind, sham-controlled study, Walpoth et al (2008) examined the effects of rTMS in bulimia nervosa (BN). A total of 14 women meeting DSM-IV criteria for BN were included in the study. In order to exclude patients highly responsive to placebo, all patients were first submitted to a 1-week sham treatment. Randomization was followed by 3 weeks of active treatment or sham stimulation. The main outcome was the change in binges and purges. Secondary outcome variables were the decrease of the HDRS, the BDI and the Yale-Brown Obsessive Compulsive Scale (YBOCS) over time. The average number of binges per day declined significantly between baseline and the end of treatment in the 2 groups. There was no significant difference between sham and active stimulation in terms of purge behavior, BDI, HDRS and YBOCS over time. The authors concluded that these preliminary results indicated that rTMS in the treatment of BN does not exert additional benefit over placebo.

Schizophrenia

Freitas and colleagues (2009) performed meta-analyses of all prospective studies of the therapeutic application of rTMS in refractory schizophrenia assessing the effects of high-frequency rTMS to the left dorsolateral prefrontal cortex (DLPFC) to treat negative symptoms, and low-frequency rTMS to the left temporo-parietal cortex (TPC) to treat auditory hallucinations (AH) and overall positive symptoms. When analyzing controlled (active arms) and uncontrolled studies together, the effect sizes showed significant and moderate effects of rTMS on negative and positive symptoms (based on PANSS-N or SANS, and PANSS-P or SAPS, respectively). However, the analysis for the sham-controlled studies revealed a small non-significant effect size for negative (0.27, p = 0.417) and for positive symptoms (0.17, p = 0.129). When specifically analyzing AH (based on AHRS, HCS or SAH), the effect size for the sham-controlled studies was large and significant (1.04; p = 0.002). The authors concluded that these meta-analyses support the need for further controlled, larger trials to assess the clinical efficacy of rTMS on negative and positive symptoms of schizophrenia, while suggesting the need for exploration for alternative stimulation protocols.

An assessment by the Health Council of the Netherlands (2008) stated that studies of rTMS for hallucinations in schizophrenic patients are both fewer in number and more restricted in scope than in the case of depression.

Slotema et al (2012) provided an update of the literature on the efficacy of rTMS for auditory verbal hallucinations (AVH) and investigated the effect of rTMS 1 month after the end of treatment. A literature search was performed from 1966 through August 2012 using Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Embase Psychiatry, Ovid Medline, PsycINFO and PubMed. Randomized, double-blind, sham-controlled studies with severity of AVH or severity of psychosis as an outcome measure were included. Data were obtained from 17 randomized studies of rTMS for AVH; 5 studies fulfilled the criteria for the meta-analysis on the effect of rTMS 1 month after the end of treatment. Standardized mean weighted effect sizes of rTMS versus sham were computed on pre- and post-treatment comparisons. The mean weighted effect size of rTMS directed at the left temporo-parietal area was 0.44 (95 % CI: 0.19 to 0.68). A separate meta-analysis including studies directing rTMS at other brain regions revealed a mean weighted effect size of 0.33 (95 % CI: 0.17 to 0.50) in favor of real TMS. The effect of rTMS was no longer significant at 1 month of follow-up (mean weighted effect size = 0.40, 95 % CI: -0.23 to 0.102). Side effects were mild and the number of dropouts in the real TMS group was not significantly higher than in the sham group. The authors concluded that with the inclusion of studies with larger patient samples, the mean weighted effect size of rTMS directed at the left temporo-parietal area for AVH has decreased, although the effect is still significant. The duration of the effect of rTMS may be less than 1 month. Moreover, they stated that more research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention.

Stroke

Khedr et al (2009a) examined the therapeutic effect of rTMS on post-stroke dysphagia. A total of 26 patients with post-stroke dysphagia due to mono-hemispheric stroke were randomly allocated to receive real (n = 14) or sham (n = 12) rTMS of the affected motor cortex. Each patient received a total of 300 rTMS pulses at an intensity of 120 % hand motor threshold for 5 consecutive days. Clinical ratings of dysphagia and motor disability were assessed before and immediately after the last session and then again after 1 and 2 months. The amplitude of the motor-evoked potential (MEP) evoked by single-pulse TMS was also assessed before and at 1 month in 16 of the patients. There were no significant differences between patients who received real rTMS and the sham group in age, hand grip strength, Barthel Index or degree of dysphagia at the baseline assessment. Real rTMS led to a significantly greater improvement compared with sham in dysphagia and motor disability that was maintained over 2 months of follow-up. This was accompanied by a significant increase in the amplitude of the esophageal MEP evoked from either the stroke or non-stroke hemisphere. The authors concluded that rTMS may be a useful adjunct to conventional therapy for dysphagia after stroke. These findings need to be validated by well-designed studies.

Regarding the use of rTMS in stroke, the Health Council of the Netherlands (2008) found that few articles have been published on this topic, and that this limited amount of published data reveals only short-term, marginal improvements.

Avenanti et al (2012) examined the long-term behavioral and neurophysiologic effects of combined time-locked rTMS and physical therapy (PT) intervention in chronic stroke patients with mild motor disabilities. A total of 30 patients were enrolled in a double-blind, randomized, single-center clinical trial. Patients received 10 daily sessions of 1 Hz rTMS over the intact motor cortex. In different groups, stimulation was either real (rTMS(R)) or sham (rTMS(S)) and was administered either immediately before or after PT. Outcome measures included dexterity, force, inter-hemispheric inhibition, and corticospinal excitability and were assessed for 3 months after the end of treatment. Treatment induced cumulative rebalance of excitability in the 2 hemispheres and a reduction of inter-hemispheric inhibition in the rTMS(R) groups. Use-dependent improvements were detected in all groups. Improvements in trained abilities were small and transitory in rTMS(S) patients. Greater behavioral and neurophysiologic outcomes were found after rTMS(R), with the group receiving rTMS(R) before PT (rTMS(R)-PT) showing robust and stable improvements and the other group (PT-rTMS(R)) showing a slight improvement decline over time. The authors concluded that these findings indicated that priming PT with inhibitory rTMS is optimal to boost use-dependent plasticity and rebalance motor excitability and suggest that time-locked rTMS is a valid and promising approach for chronic stroke patients with mild motor impairment. Furthermore, the authors stated that "[f]urther studies are needed to evaluate the effect of intervention order of time-locked rTMS in the same patients. Moreover, future studies should assess whether the present findings can be extended to stroke patients with moderate to severe motor impairments".

Corti et al (2012) stated that conceptually rTMS could be used therapeutically to restore the balance of inter-hemispheric inhibition after stroke. Repetitive TMS has been used in 2 ways: low-frequency stimulation (less than or equal to 1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or high-frequency stimulation (greater than 1 Hz) to the motor cortex of the affected hemisphere (AH) to increase excitability of the ipsilesional hemisphere. These investigators reviewed evidence regarding the safety and effectiveness of high-frequency rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. The findings of this review suggested that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. The authors concluded that although the studies included in this review provided important information, double-blinded, sham-controlled phase II and phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.

In a comparative case study, Plow et al (2011) attempted to standardize a protocol for promoting visual rehabilitative outcomes in post-stroke hemianopia by combining occipital cortical tDCS with vision restoration therapy (VRT). Two patients, both with right hemianopia after occipital stroke damage were included in this study. Both patients underwent an identical VRT protocol that lasted 3 months (30 mins, twice-daily, 3 days/week). In patient 1, anodal tDCS was delivered to the occipital cortex during VRT training, whereas in patient 2 sham tDCS with VRT was performed. The primary outcome, visual field border, was defined objectively by using high-resolution perimetry. Secondary outcomes included subjective characterization of visual deficit and functional surveys that assessed performance on activities of daily living. For patient 1, the neural correlates of visual recovery were also investigated, by using functional magnetic resonance imaging. Delivery of combined tDCS with VRT was feasible and safe. High-resolution perimetry revealed a greater shift in visual field border for patient 1 versus patient 2. Patient 1 also showed greater recovery of function in activities of daily living. Contrary to the expectation, patient 2 perceived greater subjective improvement in visual field despite objective high-resolution perimetry results that indicated otherwise. In patient 1, visual function recovery was associated with functional magnetic resonance imaging activity in surviving peri-lesional and bilateral higher-order visual areas. The authors concluded that these findings of preliminary case comparisons suggested that occipital cortical tDCS may enhance recovery of visual function associated with concurrent VRT through visual cortical re-organization. They stated that future studies may benefit from incorporating protocol refinements such as those described here, which include global capture of function, control for potential confounds, and investigation of underlying neural substrates of recovery.

Szaflarsk et al (2011) stated that aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and effectiveness of functional magnetic resonance imaging (fMRI)-guided excitatory rTMS applied to the residual left-hemispheric Broca's area for chronic aphasia treatment. These researchers enrolled 8 patients with moderate or severe aphasia of more than 1 year after left middle cerebral artery stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca's area. Repetitive TMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca's. A total of 6 patients showed significant pre-/post-rTMS improvements in semantic fluency (p = 0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p = 0.025), left temporo-parietal (p = 0.038) regions and global language LI (p = 0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p = 0.075). None of the subjects reported ill effects of rTMS. The authors concluded that fMRI-guided, excitatory rTMS applied to the affected Broca's area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. They stated that this rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/effectiveness for post-stroke aphasia rehabilitation.

Kakuda et al (2012a) stated that both low-frequency rTMS (LF-rTMS) and intensive occupational therapy (OT) have been recently reported to be clinically beneficial for post-stroke patients with upper limb hemiparesis. Based on these reports, these researchers developed an inpatient combination protocol of these 2 modalities for the treatment of such patients. In a pilot study, these investigators examined the safety and feasibility of the protocol in a large number of patients from different institutions, and identified predictors of the clinical response to the treatment. The study subjects were 204 post-stroke patients with upper limb hemiparesis (mean age at admission of 58.5 +/- 13.4 years, mean time after stroke of 5.0 +/- 4.5 years, +/- SD) from 5 institutions in Japan. During 15-day hospitalization, each patient received 22 treatment sessions of 20-min LF-rTMS and 120-min intensive OT daily. Low-frequency rTMS of 1 Hz was applied to the contralesional hemisphere over the primary motor area. The intensive OT, consisting of 60-min 1-on-1 training and 60-min self-exercise, was provided after the application of LF-rTMS. Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT) were performed serially. The physiatrists and occupational therapists involved in this study received training prior to the study to standardize the therapeutic protocol. All patients completed the protocol without any adverse effects. The FMA score increased and WMFT log performance time decreased significantly at discharge, relative to the respective values at admission (change in FMA score: median at admission, 47 points; median at discharge, 51 points; p < 0.001. change in WMFT log performance time: median at admission, 3.23; median at discharge, 2.51; p < 0.001). These changes were persistently seen up to 4 weeks after discharge in 79 patients. Linear regression analysis found no significant relationship between baseline parameters and indexes of improvement in motor function. The authors concluded that the 15-day inpatient rTMS plus OT protocol is a safe, feasible, and clinically useful neuro-rehabilitative intervention for post-stroke patients with upper limb hemiparesis. The response to the treatment was not influenced by age or time after stroke onset. They stated that the effectiveness of the intervention should be confirmed in a randomized controlled study including a control group.

Kakuda et al (2012b) noted that for spastic upper limb hemiparesis after stroke, they developed triple-element protocol of botulinum toxin type A (BoNTA) injection, LF-rTMS, and intensive OT. These researchers investigated the safety and feasibility of the protocol. A total of 14 post-stroke patients with spastic upper limb hemiparesis (mean age of 54.9 +/- 9.2 years, time after onset: 87.1 +/- 48.2 months, +/- SD) were included in this study. In all patients, BoNTA was injected into spastic muscles of the affected upper limb (maximum total dose: 240 units). Four weeks later, they were hospitalized to receive 22 sessions of 20-min LF-rTMS and 120-min intensive OT daily over 15 days. Motor function of the affected upper limb was evaluated mainly using FMA, WMFT, motor activity log (MAL), and the severity of spasticity was measured with modified Ashworth scale (MAS) at BoNTA injection, discharge and 4 weeks post-discharge. All patients completed the protocol without any adverse effects. The FMA score and MAL scores, but not WMFT performance time, improved significantly at discharge. The MAS score of all examined muscles decreased significantly between BoNTA and discharge. The beneficial effect of the protocol on motor function and spasticity was almost maintained until 4 weeks after discharge. The authors concluded that the protocol is safe and feasible, although further larger studies are needed to confirm its effectiveness.

Ayache et al (2012) stated that non-invasive cortical stimulation (NICS) has been used during the acute, post-acute and chronic post-stroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. These investigators reviewed the rationale for using the different NICS modalities to promote motor stroke rehabilitation. A number of open and placebo-controlled trials have investigated the clinical effect of rTMS or tDCS of the primary motor cortex in patients with motor stroke. These studies attempted to improve motor performance by increasing cortical excitability in the stroke-affected hemisphere (via HF- rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via LF- rTMS or cathodal tDCS). The goal of these studies was to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and to then restore a normal balance of inter-hemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neuro-rehabilitation were found to be safe and equally effective at the short-term on various aspects of post-stroke motor abilities. However, they stated that the long-term effect of NICS on motor stroke needs to be further evaluated before considering the use of such a technique in the daily routine management of stroke.

Corti et al (2012) stated that rTMS is known to modulate cortical excitability and has thus been suggested to be a therapeutic approach for improving the efficacy of rehabilitation for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of trans-callosal inhibitory pathways between motor primary areas in both hemispheres: the affected hemisphere (AH) may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere, further reducing the excitability of the AH. Conceptually, therefore, rTMS could be used therapeutically to restore the balance of inter-hemispheric inhibition after stroke. Repetitive TMS has been used in 2 ways: LF stimulation (less than or equal to 1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or HF stimulation (greater than 1 Hz) to the motor cortex of the AH to increase excitability of the ipsilesional hemisphere. These researchers collated evidence regarding the safety and efficacy of HF- rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of cortico-spinal pathways and upper-limb motor function in adults after stroke. The findings of this review suggested that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. The authors concluded that although the studies included in this review provided important information, double-blinded, sham-controlled phase II and phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.

In an evidence-based review, Wong and Tsang (2013) reported an updated evaluation and critical appraisal of available studies that investigated the effectiveness of rTMS on post-stroke aphasia rehabilitation. A literature search was performed to identify studies that investigated the therapeutic effects of rTMS on post-stroke aphasia in various electronic databases, from their inception to 2011. The selected studies were classified according to the types of participants, types of interventions, outcome measures, and results. The methodological qualities of the selected studies were evaluated using the Physiotherapy Evidence Database scale. The current review was based on 12 studies, including open-label designs and controlled trials, which showed a positive effect of rTMS, with or without conventional rehabilitation, on post-stroke aphasia compared with sham or conventional rehabilitation alone. About 41 % of the selected studies reported the long-term effect of rTMS on aphasia recovery. No adverse effect was reported. The authors concluded that the current review revealed that rTMS with or without conventional rehabilitation has positive effects on post-stroke aphasia. The studies also contributed to the plausible mechanisms of stroke recovery. However, they stated that with the concerns over the methodology of the selected studies in this review, a larger-scale, multi-center, well-designed RCT involving different phases and types of aphasia needs to be carried out before recommending rTMS as a complementary treatment for post-stroke aphasia.

In a meta-analysis, Hsu et al (2012) investigated the effects of rTMS on upper limb motor function in patients with stroke. These investigators searched for RCTs published between January 1990 and October 2011 in PubMed, Medline, Cochrane, and CINAHL using the following key words: stroke, cerebrovascular accident, and repetitive transcranial magnetic stimulation. The mean effect size and a 95 % CI were estimated for the motor outcome and motor threshold using fixed and random effect models. Eighteen of the 34 candidate articles were included in this analysis. The selected studies involved a total of 392 patients. A significant effect size of 0.55 was found for motor outcome (95 % CI: 0.37 to 0.72). Further sub-group analyses demonstrated more prominent effects for subcortical stroke (mean effect size, 0.73; 95 % CI: 0.44 to 1.02) or studies applying low-frequency rTMS (mean effect size, 0.69; 95 % CI: 0.42 to 0.95). Only 4 patients of the 18 articles included in this analysis reported adverse effects from rTMS. The authors concluded that rTMS has a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke. Low-frequency rTMS over the unaffected hemisphere may be more beneficial than high-frequency rTMS over the affected hemisphere. Recent limited data suggested that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention. They stated that further well-designed studies in a larger population are needed to better elucidate the differential roles of various rTMS protocols in stroke treatment.

In a Cochrane review, Hao and colleagues (2013) evaluated the safety and effectiveness of rTMS for improving function in people with stroke. These investigators searched the Cochrane Stroke Group Trials Register (April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), the Chinese Stroke Trials Register (April 2012), MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), Science Citation Index (1981 to April 2012), Conference Proceedings Citation Index-Science (1990 to April 2012), CINAHL (1982 to May 2012), AMED (1985 to May 2012), PEDro (April 2012), REHABDATA (April 2012) and CIRRIE Database of International Rehabilitation Research (April 2012). In addition, they searched 5 Chinese databases, ongoing trials registers and relevant reference lists. These researchers included RCTs comparing rTMS therapy with sham therapy or no therapy. They excluded trials that reported only laboratory parameters. Two review authors independently selected trials, assessed trial quality and extracted the data. They resolved disagreements by discussion. A total of 19 trials involving a total of 588 participants were included in this review. Two heterogenous trials with a total of 183 subjects showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (mean difference (MD) 15.92, 95 % CI: -2.11 to 33.95). Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function (standardized mean difference (SMD) 0.51, 95 % CI: -0.99 to 2.01). Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. Few mild adverse events were observed in the rTMS groups, with the most common events being transient or mild headaches (2.4 %, 8/327) and local discomfort at the site of the stimulation. The authors concluded that current evidence does not support the routine use of rTMS for the treatment of stroke. Moreover, they stated that further trials with larger sample sizes are needed to determine a suitable rTMS protocol and the long-term functional outcome.

In a Cochrane review, Elsner et al (2013a) examined the effects for improving aphasia in patients after stroke. These investigators searched the Cochrane Stroke Group Trials Register (April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, March 2012), MEDLINE (1948 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), AMED (1985 to April 2012), Science Citation Index (1899 to April 2012) and 7 additional databases. They also searched trials registers and reference lists, hand-searched conference proceedings and contacted authors and equipment manufacturers. These researchers included only RCTs and randomized controlled cross-over trials (from which they only analyzed the first period as a parallel group design) comparing tDCS versus control in adults with aphasia due to stroke. Two review authors independently assessed trial quality and extracted the data. If necessary, they contacted study authors for additional information. These investigators collected information on drop-outs and adverse events from the trials. They included 5 trials involving 54 participants. None of the included studies used any formal outcome measure for measuring functional communication, which is measuring aphasia in a real-life communicative setting. All 5 trials measured correct picture naming as a surrogate for aphasia. There was no evidence that tDCS enhanced speech and language therapy outcomes. No adverse events were reported and the proportion of drop-outs was comparable between groups. The authors concluded that currently there is no evidence of the effectiveness of tDCS (anodal tDCS, cathodal tDCS) versus control (sham tDCS). Moreover, they stated that it appears that cathodal tDCS over the non-lesioned hemisphere might be the most promising approach.

In a Cochrane review, Elsner et al (2013b) examined the effects of tDCS on generic activities of daily living (ADLs) and motor function in people with stroke. These investigators searched the Cochrane Stroke Group Trials Register (March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, May 2013), MEDLINE (1948 to May 2013), EMBASE (1980 to May 2013), CINAHL (1982 to May 2013), AMED (1985 to May 2013), Science Citation Index (1899 to May 2013) and 4 additional databases. In an effort to identify further published, unpublished and ongoing trials, these investigators searched trials registers and reference lists, hand-searched conference proceedings and contacted authors and equipment manufacturers. They included only RCTs and randomized controlled cross-over trials (from which they analyzed only the first period as a parallel-group design) that compared tDCS versus control in adults with stroke for improving ADL performance and function. Two review authors independently assessed trial quality and extracted data. If necessary, these researchers contacted study authors to ask for additional information. They collected information on drop-outs and adverse events from the trial reports. These researchers included 15 studies involving a total of 455 participants. Analysis of 6 studies involving 326 participants regarding the primary outcome, ADL, showed no evidence of an effect in favor of tDCS at the end of the intervention phase (mean difference (MD) 5.31 Barthel Index points; 95 % CI: -0.52 to 11.14; inverse variance method with random-effects model), whereas at follow-up (MD 11.13 Barthel Index points; 95 % CI: 2.89 to 19.37; inverse variance method with random-effects model), these investigators found evidence of an effect. However, the CIs were wide and the effect was not sustained when only studies with low-risk of bias were included. For the secondary outcome, upper limb function, these investigators analyzed 8 trials with 358 participants, which showed evidence of an effect in favor of tDCS at the end of the intervention phase (MD 3.45 Upper Extremity Fugl-Meyer Score points (UE-FM points); 95 % CI: 1.24 to 5.67; inverse variance method with random-effects model) but not at the end of follow-up 3 months after the intervention (MD 9.23 UE-FM points; 95 % CI: -13.47 to 31.94; inverse variance method with random-effects model). These results were sensitive to inclusion of studies at high-risk of bias. Adverse events were reported and the proportions of drop-outs and adverse events were comparable between groups (risk difference (RD) 0.00; 95 % CI: -0.02 to 0.03; Mantel-Haenszel method with random-effects model). The authors concluded that evidence of very low to low quality is available on the effectiveness of tDCS (anodal/cathodal/dual) versus control (sham/any other intervention) for improving ADL performance and function after stroke. Moreover, they stated that future research should investigate the effects of tDCS on lower limb function and should address methodological issues by routinely reporting data on adverse events and drop-outs and allocation concealment, and by performing intention-to-treat analyses.

In a RCT with a 4-week follow-up, Barros Galvao et al (2014) examined the effectiveness of inhibitory rTMS for decreasing upper-limb muscle tone after chronic stroke. Patients with stroke (n = 20) with post-stroke upper limb spasticity were enrolled in this study. The experimental group received rTMS to the primary motor cortex of the unaffected side (1,500 pulses; 1Hz; 90 % of resting motor threshold for the first dorsal interosseous muscle) in 10 sessions, 3 days/week, and physical therapy (PT). The control group received sham stimulation and PT. Main outcome measures were MAS, upper-extremity Fugl-Meyer assessment, FIM, range of motion, and stroke-specific quality-of-life scale. All outcomes were measured at baseline, after treatment (post-intervention), and at a 4-week follow-up. A clinically important difference was defined as a reduction of greater than or equal to 1 in the MAS score. Friedman test revealed that PT is efficient for significantly reducing the upper limb spasticity of patients only when it is associated with rTMS. In the experimental group, 90 % of the patients at post-intervention and 55.5 % at follow-up showed a decrease of greater than or equal to 1 in the MAS score, representing clinically important differences. In the control group, 30 % of the patients at post-intervention and 22.2 % at follow-up experienced clinically meaningful changes. There were no differences between the groups at any time for any of the other outcome measures, indicating that both groups demonstrated similar behaviors over time for all variables. The authors concluded that rTMS associated with PT can be beneficial in reducing post-stroke spasticity. Moreover, they stated that more studies are needed to clarify the clinical changes underlying the reduction in spasticity induced by non-invasive brain stimulations.

In a randomized, controlled, double-blind clinical trial, Kirton and colleagues (2017) examined if the addition of tDCS to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy (CP). Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, aged 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention-to-treat. A total of 24 participants were randomized (median age of 11.8 ± 2.7 years, range of 6.7 to 17.8); COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001); COPM scores increased more with tDCS compared to sham control (p = 0.004); AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well-tolerated with no decrease in either arm function or serious adverse events (AEs). The authors concluded that tDCS trials appeared feasible and safe in hemiparetic children; lack of change in objective motor function may reflect under-dosing of therapy; marked gains in subjective function with tDCS warrant further study. This study provided Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy did not significantly improve motor function as measured by the AHA. The main drawbacks of this phase II clinical trial were:

modest sample size (n = 24),
single-center setting, and
examination of sustainability was limited to 2 months.

In a systematic review and meta-analysis, Tung and colleagues (2019) examined the effects of rTMS on the post-stroke recovery of lower limb motor function. These investigators searched the databases of PubMed, Cochrane Library, and Embase for RCTs that were published by January 25, 2019. They included RCTs that evaluated the effects of rTMS on lower limb motor recovery in patients with stroke; 2 reviewers independently screened the searched records, extracted data, and assessed the risk of bias. The treatment effect sizes were pooled in a meta-analysis by using the RevMan 5.3 software. The internal validity was assessed using topics suggested by the Physiotherapy Evidence Database (PEDro). A total of 8 studies with 169 subjects were included in the meta-analysis. Pooled estimates demonstrated that rTMS significantly improved the body function of the lower limbs ( (SMD = 0.66; p < 0.01), lower limb activity (SMD = 0.66; p < 0.01), and motor-evoked potential (SMD = 1.13; p < 0.01). The subgroup analyses results also revealed that rTMS improved walking speed (SMD = 1.13) and lower limb scores on the Fugl-Meyer Assessment scale (SMD = 0.63). These researchers found no significant differences between the groups in different mean post-stroke time or stimulation mode over lower limb motor recovery; only 1 trial reported mild AEs. The authors concluded that rTMS may have short-term therapeutic effects on the lower limbs of patients with stroke; the application of rTMS is safe. However, they stated that this evidence is limited by a potential risk of bias.

In a systematic review and meta-analysis, Yang et al (2021) examined the effect of rTMS on recovery of dysphagia following stroke. These investigators searched RCTs and non-RCTs published by PubMed, the Cochrane Library, ScienceDirect, Medline, and Web of Science from inception until April 24, 2021; language was limited to English. After screening and extracting the data, and examining the quality of the selected literature, these researchers performed the meta-analysis with software RevMan 5.3 and summarized available evidence from non-RCTs. Among 205 potentially relevant articles, 189 subjects (from 10 RCTs) were recruited in the meta-analysis, and 6 non-RCTs were qualitatively described. The random-effects model analysis revealed a pooled effect size of SMD = 0.65 (95 % CI: 0.04 to 1.26, p = 0.04), which indicated that rTMS therapy had a better effect than conventional therapy. However, the subgroup analysis showed that there was no significant difference between low-frequency (LF) and high-frequency (HF) groups. Even more surprisingly, there were no statistically significant differences between the 2 groups and the conventional training group in the subgroup analysis; however, the combined effect was positive. The authors concluded that the findings of this study showed that rTMS was more effective than conventional training for the recovery of dysphagia; however, subgroup analysis of HF-rTMS and LF-rTMS did not show significant effectiveness for post-stroke dysphagia when compared with conventional rehabilitation, which was probably due to a small number of included studies. Therefore, larger trials are needed for further study. These researchers noted that this study also found that both inter-hemispheric inhibition theory and compensatory model may play a role in the therapeutic effect of rTMS in treating dysphagia. More clinical studies are needed to help develop better treatment plans for these patients.

The authors stated that this study had several drawbacks. First, the main limitations of the review were the small number of studies and participants included in this review. Second, only sub-group analysis for frequency was carried out in these analyses, whereas heterogeneity was observed in both subgroups. The effectiveness of rTMS could also be affected by other parameters such as stimulation sites and locations of lesions. Third, these researchers chose Penetration-Aspiration Scale (PAS) and dysphagia grade (DD) as evaluation criteria, but did not include other evaluation criteria, which also resulted in a certain bias in the inclusion process of the article. In order to better serve the clinical practice, these investigators will sort out all commonly used clinical evaluation criteria and collect relevant literature for data analysis in the later stage. The authors stated that further clinical controlled trials should be conducted to examine the influence factors on the effectiveness and mechanism of rTMS in treating post-stroke dysphagia.

Amyotrophic Lateral Sclerosis

In a review on the diagnosis of amyotrophic lateral sclerosis (ALS), Elman and McCluskey (2010) stated that rTMS remains a largely experimental technique and is not used routinely for clinical diagnosis. In a Cochrane review on rTMS for the treatment of ALS or motor neuron disease, Guo et al (2011) concluded that there is currently insufficient evidence to draw conclusions about the safety and effectiveness of rTMS in the treatment of ALS. They noted that further studies may be helpful if their potential benefit is weighed against the impact of participation in a RCT on people with ALS.

Autism

In a review on autism, Levy et al (2009) stated that biologically based treatments include anti-infectives, chelation medications, gastro-intestinal medications, hyperbaric oxygen therapy, off-label drugs (e.g., secretin), and intravenous immunoglobulins. Non-biologically based treatments include auditory integration training, chiropractic therapy, cranio-sacral manipulation, facilitated communication, interactive metronome, and transcranial stimulation. However, few studies have addressed the safety and effectiveness of most of these treatments.

Masuda and colleagues (2019) noted that cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain; TMS motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. These investigators carried out a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, these investigators identified 6 articles; 5 studies measured MEP, where 4 studies measured SICI. There were no differences in MEP amplitudes between the 2 groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy (MRS) and post-mortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. The authors concluded that reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Thus, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

The authors stated that the main drawback of this systematic review was the small sample size for each parameter. Also, each study included a limited number of individuals, which did not allow these investigators to control the confounding effects of the age, gender, accompanied medication, or co-morbidity such as other neurodevelopmental disorders. Further, in this study, because of the limited number of articles examining the non-motor areas in ASD, only M1 could be systematically reviewed. These researchers stated that further well-designed studies addressing current limitations and the knowledge gap are needed.

Blepharospasm

In a prospective, randomized, sham-controlled, observer-blinded study, Kranz et al (2010) examined the effects of rTMS on benign essential blepharospasm (BEB). In 12 patients with BEB, these investigators evaluated the effects of a 15-min session of low-frequency (0.2 Hz) rTMS over the anterior cingulate cortex (ACC) with stimulation intensities at 100 % active motor threshold with 3 stimulation coils:

a conventional circular coil (C-coil),
a sham coil (S-coil), and
a Hesed coil (H-coil, which allows stimulation of deeper brain regions.

Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1 hr after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. The authors concluded that rTMS could be used as a therapeutic tool in BEB. Moreover, they noted that compared to the well-established and long-lasting effects of botulinum toxin and in view of the time-consuming nature of rTMS and its short-lasting effects, it should not be used in routine clinical setting at this stage. Furthermore, they stated that further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects.

Dementia

Freitas et al (2011) performed a systematic search of all studies using non-invasive stimulation in Alzheimer's disease (AD) and reviewed all 29 identified articles; 24 focused on measures of motor cortical reactivity and (local) plasticity and functional connectivity, with 8 of these studies assessing also effects of pharmacological agents, and 5 studies focused on the enhancement of cognitive function in AD. Short-latency afferent inhibition (SAI) and resting motor threshold are significantly reduced in AD patients as compared to healthy elders. Results on other measures of cortical reactivity, (e.g., intra-cortical inhibition [ICI]), are more divergent. Acetylcholine-esterase inhibitors and dopaminergic drugs may increase SAI and ICI in AD. Motor cortical plasticity and connectivity are impaired in AD. Transcranial magnetic stimulation/transcranial direct current stimulation (tDCS) can induce acute and short-duration beneficial effects on cognitive function, but the therapeutic clinical significance in AD is unclear. Safety of TMS/tDCS is supported by studies to date. The authors concluded that TMS/tDCS appears safe in AD, but longer-term risks have been insufficiently considered. They stated that TMS holds promise as a physiologic biomarker in AD to identify therapeutic targets and monitor pharmacologic effects. In addition, TMS/tDCS may have therapeutic utility in AD, though the evidence is still very preliminary and cautious interpretation is warranted.

Transcutaneous electrical nerve stimulation (TENS) is the application of an electrical current through electrodes attached to the skin, and is most commonly used for pain relief. It has also been employed for the treatment of a range of neurological and psychiatric conditions such as alcohol and drug dependence, depression, as well as headaches. Transcutaneous electrical nerve stimulation is rarely used for the treatment of dementia. The use of TENS for these indications entails peripherally applied TENS as well as TENS applied to the head, also known as cranial electrical stimulation (CES). Although several studies suggested that TENS may produce short-lived improvements in some neurological or psychiatric conditions, the limited data from these studies did not allow definite conclusions on the possible benefits of this intervention.

Rose and colleagues (2008) noted that family caregivers of persons with dementia and their care recipients frequently experience sleep and mood disturbances throughout their caregiving and disease trajectories. Because conventional pharmacological treatments of sleep and mood disturbances pose numerous risks and adverse effects to elderly persons, the investigation of other interventions is warranted. As older adults use complementary and alternative medicine interventions for the relief of sleep and mood disturbances, CES may be a viable intervention. These investigators examined the effects of CES on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with Alzheimer's disease (Rose et al, 2009). A total fo 38 subjects were randomly assigned to receive active CES or sham CES for 4 weeks. Both intervention groups reported improvement in study measures from baseline scores. A trend toward statistically significant differences in daily sleep disturbances was found between the groups. No differences in depressive symptoms and caregiving appraisal were found between the groups. The authors concluded that these findings did not fully support the efficacy of the short-term use of active CES versus sham CES to improve sleep disturbances, depressive symptoms, or caregiving appraisal.

Guse et al (2010) stated that TMS was introduced as a non-invasive tool for the investigation of the motor cortex. The repetitive application (rTMS), causing longer lasting effects, was used to study the influence on a variety of cerebral functions. High-frequency (greater than 1 Hz) rTMS is known to depolarize neurons under the stimulating coil and to indirectly affect areas being connected and related to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorso-lateral pre-frontal cortex (DLPFC). These researchers performed a systematic review of HF-rTMS studies (1999 to 2009) stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured. The cognitive effect was analyzed with regard to the impact of clinical status (patients/healthy volunteers) and stimulation type (verum/sham). Repetitive TMS at 10, 15 or 20 Hz, applied over the left DLPFC, within a range of 10 to 15 successive sessions and an individual motor threshold of 80 to 110 %, is most likely to cause significant cognitive improvement. In comparison, patients tend to reach a greater improvement than healthy participants. Limitations concern the absence of healthy groups in clinical studies and partly the absence of sham groups. Thus, future investigations are needed to assess cognitive rTMS effects in different psychiatric disorders versus healthy subjects using an extended standardized neuropsychological test battery. Since the pathophysiological and neurobiological basis of cognitive improvement with rTMS remains unclear, additional studies including genetics, experimental neurophysiology and functional brain imaging are necessary to explore stimulation-related functional changes in the brain. The authors noted that "[a]ll in all, investigations have to prove the efficacy of rTMS in randomized sham-controlled trials with higher statistical power using larger sample sizes and improved methodology".

Smell and Taste Disorders

Henkin et al (2011) evaluated the effectiveness of rTMS treatment in patients with phantosmia and phantageusia. A total of 17 patients with symptoms of persistent phantosmia and phantageusia with accompanying loss of smell and taste acuity were studied. Before and after treatment, patients were monitored by subjective responses and with psychophysical tests of smell function (olfactometry) and taste function (gustometry). Each patient was treated with rTMS that consisted of 2 sham procedures followed by a real rTMS procedure. After sham rTMS, no change in measurements of distortions or acuity occurred in any patient; after initial real rTMS, 2 patients received no benefit; but in the other 15, distortions decreased and acuity increased. Two of these 15 exhibited total inhibition of distortions and return of normal sensory acuity that persisted for over 5 years of follow-up. In the other 13, inhibition of distortions and improvement in sensory acuity gradually decreased; but repeated rTMS again inhibited their distortions and improved their acuity. Eighty-eight percent of patients responded to this therapeutic method, although repeated rTMS was necessary to induce these positive changes. The authors concluded that these results suggested that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Moreover, they stated that additional systematic studies are necessary to confirm these results.

Spinal Cord Injury

Awad et al (2015) reviewed the basic principles and techniques of TMS and provided information and evidence regarding its applications in spinal cord injury (SCI) clinical rehabilitation. A review of the available current and historical literature regarding TMS was conducted, and a discussion of its potential use in SCI rehabilitation is presented. Transcranial magnetic stimulation provides reliable information about the functional integrity and conduction properties of the cortico-spinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. Motor-evoked potentials can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with SCI and stroke. Although studies regarding somato-motor functional recovery after SCI have shown promise, more trials are needed to provide strong and substantial evidence. The authors concluded that TMS is a promising non-invasive tool for the treatment of spasticity, neuropathic pain, and somato-motor deficit after SCI. They stated that further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation, may induce more pronounced and beneficial clinical effects.

Nardone and colleagues (2014) reviewed the literature on brain neurostimulation techniques in patients with chronic neuropathic pain due to traumatic SCI and evaluated the current evidence for their effectiveness. A MEDLINE search was performed using following terms: "spinal cord injury", "neuropathic pain", "brain stimulation", "deep brain stimulation" (DBS), "motor cortex stimulation" (MCS), "transcranial magnetic stimulation" (TMS), "transcranial direct current stimulation" (tDCS), "cranial electrotherapy stimulation" (CES). Invasive neurostimulation therapies, in particular DBS and epidural MCS, have shown promise as treatments for neuropathic and phantom limb pain. However, the long-term effectiveness of DBS is low, while MCS has a relatively higher potential with lesser complications that DBS. Among the non-invasive techniques, there is accumulating evidence that repetitive TMS can produce analgesic effects in healthy subjects undergoing laboratory-induced pain and in chronic pain conditions of various etiologies, at least partially and transiently. Another very safe technique of non-invasive brain stimulation -- tDCS -- applied over the sensory-motor cortex has been reported to decrease pain sensation and increase pain threshold in healthy subjects. Cranial electrotherapy stimulation has also proved to be effective in managing some types of pain, including neuropathic pain in subjects with SCI. The authors concluded that a number of studies have begun to use non-invasive neuromodulatory techniques therapeutically to relieve neuropathic pain and phantom phenomena in patients with SCI. Moreover, they stated that further studies are needed to corroborate the early findings and confirm different targets and stimulation paradigms. The utility of these protocols in combination with pharmacological approaches should also be explored.

Moreno-Duarte et al (2014) reviewed initial safety, effectiveness, and potential predictors of response by assessing the effects of neural stimulation techniques to treat SCI pain. A literature search was performed using the PubMed database including studies using the following targeted stimulation strategies: tDCS, high definition tDCS (HD-tDCS), rTMS, CES, TENS, spinal cord stimulation (SCS) and MCS, published prior to June of 2012. These investigators included studies from 1998 to 2012. A total of 8 clinical trials and 1 naturalistic observational study met the inclusion criteria. Among the clinical trials, 3 studies assessed the effects of tDCS, 2 of CES, 2 of rTMS and 1 of TENS. The naturalistic study investigated the analgesic effects of SCS. No clinical trials for epidural MCS or HD-tDCS were found. Parameters of stimulation and also clinical characteristics varied significantly across studies. Three out of 8 studies showed larger effects sizes (0.73, 0.88 and 1.86, respectively) for pain reduction. Classical neuropathic pain symptoms such as dysesthesia (defined as an unpleasant burning sensation in response to touch), allodynia (pain due to a non-painful stimulus), pain in paroxysms, location of SCI in thoracic and lumbar segments and pain in the lower limbs seem to be associated with a positive response to neural stimulation. No significant adverse effects were reported in these studies. The authors concluded that chronic pain in SCI is disabling and resistant to common pharmacologic approaches. Electrical and magnetic neural stimulation techniques have been developed to offer a potential tool in the management of these patients. Although some of these techniques are associated with large standardized mean differences to reduce pain, the authors found an important variability in these results across studies. They stated that there is a clear need for the development of methods to decrease treatment variability and increase response to neural stimulation for pain treatment.

Gao and colleagues (2017) noted that the evidence regarding effectiveness of rTMS on relief of neuropathic pain (NP) in patients with prior SCI is controversial. In a meta-analysis, these researchers evaluated the effectiveness of rTMS in pain relieve in patients suffering from SCI associated NP. Medline, PubMed, Cochrane, Embase, Google Scholar databases were searched for clinical studies on effects of rTMS treatment on NP caused by prior SCI published before March 14, 2016 with various combinations of following keywords: transcranial magnetic stimulation, spinal injury, pain. Standardized difference in means with 95 % CI was calculated for the change of pain scores after rTMS or sham rTMS treatments. A total of 2 RCTs and 4 cross-over RCTs were included for the meta-analysis. The RCTs recruited a total of 27 patients. The cross-over RCTs recruited a total of 100 patients. The combined standardized difference in means indicated that patients who received rTMS intervention had better pain relief than those who received sham rTMS intervention, however, the results did not reach statistical significance (STD difference in means = -0.607, 95 % CI: -1.29 to 0.075, p = 0.081). The authors concluded that rTMS might reduce SCI associated neuropathic pain; however, further studies are needed to support this conclusion.

In a systematic review, Saleh and colleagues (2022) examined the effectiveness of rTMS in neuropathic pain secondary to SCI. These researchers carried out a systematic review using the PubMed/Medline, Embase, and PsycInfo (via OVID) database up April 2021; only RCTs were included. Results regarding the pain intensity scores were pooled using a random-effects model. The search identified a total of 203 potential articles. Of these, 8 RCTs met the eligibility criteria for qualitative synthesis providing the total data of 141 patients. All studies employed high-frequency rTMS. In 7 studies, rTMS was applied over the motor cortex, and in 1 study over the left dorsolateral prefrontal cortex; 5 studies reported a significant improvement in baseline pain scores after treatment, and 3 studies found a significant difference between sham versus non-sham stimulation at any time; 6 RCTs were included in the quantitative synthesis and showed a significant overall reduction of pain intensity in the rTMS groups compared with the sham groups (MD - 0.81, 95 % CI: - 1.45 to - 0.17). The authors concluded that these findings indicated that high-frequency rTMS of the primary motor cortex and left dorsolateral prefrontal cortex might be promising stimulation targets for neuropathic pain in SCI.

Movement Disorders

Schneider et al (2010) stated that dystonia is associated with impaired somatosensory ability. The electrophysiological method of rTMS can be used for non-invasive stimulation of the human cortex and can alter cortical excitability and associated behavior. Among others, rTMS can alter/improve somatosensory discriminatory abilities, as shown in healthy controls. These researchers applied 5Hz-rTMS over the left primary somatosensory cortex (S1) in 5 patients with right-sided writer's dystonia and 5 controls. They studied rTMS effects on tactile discrimination accuracy and concomitant rTMS-induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI). Before rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task-related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG. Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG-S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task.

Traumatic Brain Injury

Demirtas-Tatlidede et al (2012) reviewed novel techniques of non-invasive brain stimulation (NBS), which may have value in assessment and treatment of traumatic brain injury (TBI). Review of the following techniques: TMS, transcranial DCS (tDCS), low-level laser therapy, and transcranial Doppler sonography. Furthermore, these investigators provided a brief overview of TMS studies to date. They described the rationale for the use of these techniques in TBI, discussed their possible mechanisms of action, and raised a number of considerations relevant to translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyper-excitability following TBI and/or counter the excessive GABAergic effects in the sub-acute stage. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI. The authors concluded that different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical re-organization and enable functional restoration in TBI. They noted that future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability.

In a double-blind, sham-controlled, cross-over study, Thibaut et al (2014) examined the effects of left dorsolateral prefrontal cortex tDCS (DLPF-tDCS) on Coma Recovery Scale-Revised (CRS-R) scores in severely brain-damaged patients with disorders of consciousness. Anodal and sham tDCS were delivered in randomized order over the left DLPF cortex for 20 minutes in patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in a minimally conscious state (MCS) assessed at least 1 week after acute traumatic or non-traumatic insult. Clinical assessments were performed using the CRS-R directly before and after anodal and sham tDCS stimulation. Follow-up outcome data were acquired 12 months after inclusion using the Glasgow Outcome Scale-Extended. Patients in MCS (n = 30; interval 43 ± 63 months; 19 traumatic, 11 non-traumatic) showed a significant treatment effect (p = 0.003) as measured by CRS-R total scores. In patients with VS/UWS (n = 25; interval 24 ± 48 months; 6 traumatic, 19 non-traumatic), no treatment effect was observed (p = 0.952). Thirteen (43 %) patients in MCS and 2 (8 %) patients in VS/UWS further showed post-anodal tDCS-related signs of consciousness, which were observed neither during the pre-tDCS evaluation nor during the pre- or post-sham evaluation (i.e., tDCS responders). Outcome did not differ between tDCS responders and non-responders. The authors concluded that tDCS over left DLPF cortex may transiently improve signs of consciousness in MCS following severe brain damage as measured by changes in CRS-R total scores. Moreover, they stated that the long-term non-invasive neuro-modulatory tDCS outcome clinical improvement in this challenging population remains to be shown.

In an editorial that accompanied the afore-mentioned study, Whyte (2014) stated that “If a longer course of tDCS can accelerate recovery for a subgroup of the DOC population, perhaps a positive response to a single session of tDCS can identify the subgroup of individuals who are treatment responders to this or to other treatments that modulate attention and working memory circuitry. If so, tDCS may provide a useful screening approach for other treatment studies, as well as a useful treatment in its own right”.

In a prospective, case series trial with follow-up at 12 months, Angelakis et al (2014) evaluated the effectiveness of tDCS on improving consciousness in patients with persistent UWS (previously termed persistent vegetative state [PVS]) or in a MCS. Inpatients in a PVS/UWS or MCS (n = 10; 7 men, 3 women; age range of 19 to 62 years; etiology: traumatic brain injury, n = 5; anoxia, n = 4; post-operative infarct, n = 1; duration of PVS/UWS or MCS range of 6 months to 10 years). No participant withdrew because of adverse effects. All patients received sham tDCS for 20 minutes per day, 5 days per week, for 1 week, and real tDCS for 20 minutes per day, 5 days per week, for 2 weeks. An anodal electrode was placed over the left primary sensorimotor cortex or the left DLPF, with cathodal stimulation over the right eyebrow. One patient in an MCS received a second round of 10 tDCS sessions 3 months after initial participation. Main outcome measure was JFK Coma Recovery Scale-Revised. All patients in an MCS showed clinical improvement immediately after treatment. The patient who received a second round of tDCS 3 months after initial participation showed further improvement and emergence into consciousness after stimulation, with no change between treatments. One patient who was in an MCS for less than 1 year before treatment (post-operative infarct) showed further improvement and emergence into consciousness at 12-month follow-up. No patient showed improvement before stimulation. No patient in a PVS/UWS showed immediate improvement after stimulation, but 1 patient who was in a PVS/UWS for 6 years before treatment showed improvement and change of status to an MCS at 12-month follow-up. The authors concluded that tDCS seems promising for the rehabilitation of patients with severe disorders of consciousness; severity and duration of pathology may be related to the degree of tDCS' beneficial effects.

Addiction

Gorelick et al (2014) noted that TMS is still in the early stages of study as addiction treatment. These researchers identified 19 human studies using rTMS to manipulate drug craving or use, which exposed a total of 316 adults to active rTMS. Nine studies involved tobacco, 6 alcohol, 3 cocaine, and 1 methamphetamine. The majority of studies targeted high-frequency (5 to 20 Hz; expected to stimulate neuronal activity) rTMS pulses to the dorsolateral prefrontal cortex. Only 5 studies were controlled clinical trials: 2 of 4 nicotine trials found decreased cigarette smoking; the cocaine trial found decreased cocaine use. Many aspects of optimal treatment remain unknown, including rTMS parameters, duration of treatment, relationship to cue-induced craving, and concomitant treatment. The mechanisms of rTMS potential therapeutic action in treating addictions are poorly understood, but may involve increased dopamine and glutamate function in cortico-mesolimbic brain circuits and modulation of neural activity in brain circuits that mediate cognitive processes relevant to addiction, such as response inhibition, selective attention, and reactivity to drug-associated cues. The authors concluded that rTMS treatment of addiction must be considered experimental at this time, but appears to have a promising future.

Makani and associates (2017) stated that addiction and related disorders are devastating with their tremendous social, psychological, and physical consequences for which development of optimally effective treatments are long overdue; rTMS is relatively safe and is becoming an emerging therapeutic tool for these conditions. These investigators carried out a systematic review using PubMed, PsycINFO, PsychiatryOnline and Cochrane Library ranging from year 2001 to 2017. They retrieved 70 related articles of which, based on the Strength of Recommendation Taxonomy (SORT) guidelines, 33 indicated Level-1 study quality and class-B strength of recommendation for rTMS in nicotine addiction (effective in 218/289 subjects who received rTMS as found in 11 studies). Level-2/Class-B evidence was found for alcohol and cocaine addictions (alcohol: effective in 126/193 subjects who received rTMS as found in 8 studies; cocaine: effective in 86/128 subjects, as found in 5 studies). For food cravings, Level-3/Class-B evidence was noted (effective in 134/169, found in 7 studies). However, the evidence was limited to Level-3/Class-C for heroin (10/20 subjects received active rTMS, effective in 1 study), methamphetamine (33/48 subjects received active rTMS, effective in 2 studies), cannabis (18/18 subjects received active rTMS, effective in 1 study), and pathological gambling (31/31 subjects received active rTMS, effective in 2 studies). The authors concluded that rTMS may serve as an emerging therapeutic option for addiction and related disorders. The major voids in this field include important methodological limitations and dearth of knowledge about precise mechanism of action that need to be addressed in the future studies.

Torres-Castano and colleagues (2021) noted that long-term cocaine use is associated with cognitive deficits and neuro-psychiatric pathologies; and rTMS is an emerging therapeutic strategy relating to changes in brain activity. It stimulates the prefrontal cortex and is involved in inhibitory cognitive control, decision-making and care. In a systematic review, these investigators examined the evidence on the safety, effectiveness, and cost-effectiveness of rTMS for the treatment of cocaine addiction. They carried out a systematic review of the literature. The following electronic databases were consulted from inception to October 2020: Medline, Embase, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Web of Science; RCTs, non-RCTs and case-series and full economic evaluations were included. A total of 12 studies were included. No identified study reported data on cost-effectiveness. Significant results of the effectiveness of TMS have been observed in terms of the reduction of craving to consume and the number of doses consumed. No serious adverse effects have been observed. The authors concluded that despite the low quality of the studies, the first results were observed in terms of reduction of cocaine use and craving. In any case, this effect was considered moderate. Since not all studies were RCTs, and the fact that the included studies had small sample sizes and a short follow-up, the evidence obtained did not allow conclusive statements. Moreover, these researchers stated that in order to consider TMS as a procedure likely to be recommended for the treatment of cocaine addiction, controlled clinical trials are needed to be performed under rigorous standards with respect, for example, to the characterization of the participants, the randomization and the blinding procedures. In this regard, there are a number of variables specific to the technique that make it difficult to obtain the “perfect” protocol for each subject and to obtain the best possible results. In the future, it will be necessary to conduct comparative studies to evaluate these key variables, among which it is necessary to mention the target region to be stimulated, the methods to locate the target and the type of coil to be used, the number and frequency of the pulses and the number of sessions.

Congenital Hemiparesis

In a phase I randomized, double-blinded, placebo-controlled pre-test/post-test trial, Gillick et al (2015) investigated the safety of combining a 6-Hz primed low-frequency rTMS intervention in the contralesional hemisphere with a modified constraint-induced movement therapy (mCIMT) program in children with congenital hemiparesis. Subjects (n = 19; age range of 8 to 17years) with congenital hemiparesis caused by ischemic stroke or peri-ventricular leukomalacia. No subject withdrew because of adverse events. All subjects included completed the study. Subjects were randomized to 1 of 2 groups:

either real rTMS plus mCIMT (n = 10) or
sham rTMS plus mCIMT (n = 9).

Main outcome measures included adverse events, physician assessment, ipsilateral hand function, stereognosis, cognitive function, subject report of symptoms assessment, and subject questionnaire. No major adverse events occurred. Minor adverse events were found in both groups. The most common events were headaches (real: 50 %, sham: 89 %; p = 0.14) and cast irritation (real: 30 %, sham: 44 %; p = 0.65). No differences between groups in secondary cognitive and unaffected hand motor measures were found. The authors concluded that primed rTMS can be used safely with mCIMT in congenital hemiparesis. They provided new information on the use of rTMS in combination with mCIMT in children. They stated that these findings could be useful in research and future clinical applications in advancing function in congenital hemiparesis.

Communication and Swallowing Disorders

Gadenz et al (2015) systematically review RCTs that evaluated the effects of rTMS on rehabilitation aspects related to communication and swallowing functions. A search was conducted on PubMed, Clinical Trials, Cochrane Library, and ASHA electronic databases. Studies were judged according to the eligibility criteria and analyzed by 2 independent and blinded researchers. These researchers analyzed 9 studies: 4 about aphasia, 3 about dysphagia, 1 about dysarthria in Parkinson's disease and 1 about linguistic deficits in Alzheimer's disease. All aphasia studies used low-frequency rTMS to stimulate Broca's homologous area. High-frequency rTMS was applied over the pharyngo-esophageal cortex from the left and/or right hemisphere in the dysphagia studies and over the left dorso-lateral prefrontal cortex in the Parkinson's and Alzheimer's studies. Two aphasia and all dysphagia studies showed a significant improvement of the disorder, compared to the sham group. The other 2 studies related to aphasia found a benefit restricted to subgroups with a severe case or injury on the anterior portion of the language cortical area, respectively, whereas the Alzheimer's study demonstrated positive effects specific to auditory comprehension. There were no changes for vocal function in the Parkinson's study. The authors concluded that the benefits of the technique and its applicability in neurogenic disorders related to communication and deglutition are still uncertain; other RCTs are needed to clarify the optimal stimulation protocol for each disorder studied and its real effects.

Epilepsy

Zeiler et al (2015) performed a systematic review on the use of rTMS in the treatment of status epilepticus (SE) and refractory status epilepticus (RSE). MEDLINE, BIOSIS, EMBASE, Global Health, Healthstar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to August 2015), and gray literature were searched. The strength of evidence was adjudicated using Oxford and GRADE methodology. These investigators identified 11 original articles; 21 patients were described, with 13 adult and 8 pediatric. All studies were retrospective. Seizure reduction/control with rTMS occurred in 15 of the 21 patients (71.4 %), with 5 (23.8 %) and 10 (47.6 %) displaying partial and complete responses, respectively. Seizures recurred after rTMS in 73.3 % of the patients who had initially responded. All studies were an Oxford level 4, GRADE D level of evidence. The authors concluded that Oxford level 4, GRADE D evidence exists to suggest a potential impact on seizure control with the use of rTMS for FSE and FRSE, though durability of the therapy is short-lived. They stated t routine use of rTMS in this context cannot be recommended at this time; and further prospective study of this intervention is needed.

Pereira et al (2016) noted that about 1/3 of patients with epilepsy remain with pharmacologically intractable seizures. An emerging therapeutic modality for seizure suppression is rTMS. Despite being considered a safe technique, rTMS carries the risk of inducing seizures, among other milder adverse events, and thus, its safety in the population with epilepsy should be continuously assessed. These researchers performed an updated systematic review on the safety and tolerability of rTMS in patients with epilepsy, similar to a previous report published in 2007, and estimated the risk of seizures and other adverse events during or shortly after rTMS application. They searched the literature for reports of rTMS being applied on patients with epilepsy, with no time or language restrictions, and obtained studies published from January 1990 to August 2015. A total of 46 publications were identified, of which 16 were new studies published after the previous safety review of 2007. Thee investigators noted the total number of subjects with epilepsy undergoing rTMS, medication usage, incidence of adverse events, and rTMS protocol parameters: frequency, intensity, total number of stimuli, train duration, inter-train intervals, coil type, and stimulation site. Their main data analysis included separate calculations for crude per subject risk of seizure and other adverse events, as well as risk per 1,000 stimuli. They also performed an exploratory, secondary analysis on the risk of seizure and other adverse events according to the type of coil used (figure-of-8 or circular), stimulation frequency (less than or equal to 1Hz or greater than 1Hz), pulse intensity in terms of motor threshold (less than 100 % or greater than or equal to 100 %), and number of stimuli per session (less than 500 or greater than or equal to 500). Presence or absence of adverse events was reported in 40 studies (n = 426 subjects). A total of 78 (18.3 %) subjects reported adverse events, of which 85 % were mild. Headache or dizziness was the most common one, occurring in 8.9 %. These researchers found a crude per subject seizure risk of 2.9 % (95 % CI: 1.3 to 4.5), given that 12 subjects reported seizures out of 410 subjects included in the analysis after data of patients with epilepsia partialis continua or status epilepticus were excluded from the estimate. Only 1 of the reported seizures was considered atypical in terms of the clinical characteristics of the patients' baseline seizures. The atypical seizure happened during high-frequency rTMS with maximum stimulator output for speech arrest, clinically arising from the region of stimulation. Although these investigators estimated a larger crude per subject seizure risk compared with the previous safety review, the corresponding CIs contained both risks. Furthermore, the exclusive case of atypical seizure was the same as reported in the previous report. The authors concluded that the risk of seizure induction in patients with epilepsy undergoing rTMS was small and that the risk of other adverse events was similar to that of rTMS applied to other conditions and to healthy subjects. They stated that these findings should be interpreted with caution, given the need for adjusted analysis controlling for potential confounders, such as baseline seizure frequency. Moreover, they noted that the similarity between the safety profiles of rTMS applied to the population with epilepsy and to individuals without epilepsy supports further investigation of rTMS as a therapy for seizure suppression.

In a Cochrane review, Chen and colleagues (2016) evaluated the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. The authors judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.

Navigated Transcranial Magnetic Stimulation

Navigated TMS is being studied as a diagnostic tool to stimulate functional cortical areas at precise anatomical locations to induce measurable responses. This technology is being investigated to map functionally essential motor areas for diagnostic purposes and for treatment planning.

Navigated TMS is a novel tool for pre-operative functional mapping. It has been used for motor mapping in the vicinity of rolandic brain lesions as well as for mapping human language areas.

Rossini and Rossi (2007) stated that TMS is widely used in clinical neurophysiology, including rehabilitation and intra-operative monitoring. Single-pulse TMS and other more recent versions (e.g., paired-pulse TMS, rTMS, integration with structural and functional MRI, and neuro-navigation) allow motor output to be mapped precisely to a given body district. Moreover, TMS can be used to assess excitatory/inhibitory intra-cortical circuits and to provide information on brain physiology and pathophysiology of various neuropsychiatric diseases as well as on the mechanisms of brain plasticity and of neuroactive drugs. Transcranial magnetic stimulation applied over non-motor areas made it possible to extend research applications in several fields of psychophysiology. Being able to induce relatively long-lasting excitability changes, rTMS has made the treatment of neuropsychiatric diseases linked with brain excitability dysfunctions possible. The authors noted that these uses, however, warrant further large-scale studies. In emerging fields of research, TMS-EEG co-registration is considered a promising approach to evaluate cortico-cortical connectivity and brain reactivity with high temporal resolution. However, safety and ethical limitations of TMS technique need a high level of vigilance.

Picht et al (2011) compared the accuracy of a 3-dimensional MRI-navigated TMS system with the gold standard of direct cortical stimulation. The primary motor areas of 20 patients with rolandic tumors were mapped pre-operatively with navigated TMS at 110 % of the individual resting motor threshold. Intra-operative direct cortical stimulation was available from 17 patients. The stimulus locations eliciting the largest electromyographic response in the target muscles ("hotspots") were determined for both methods. The navigated TMS and direct cortical stimulation hotspots were located on the same gyrus in all cases. The mean +/- SEM distance between the navigated TMS and direct cortical stimulation hotspots was 7.83 +/- 1.18 mm for the abductor pollicis brevis (APB) muscle (n = 15) and 7.07 +/- 0.88 mm for the tibialis anterior (TA) muscle (n = 8). When a low number of direct cortical stimulations was performed, the distance between the navigated TMS and direct cortical stimulation hotspots increased substantially (r = -0.86 for APB). After exclusion of the cases with less than 15 direct cortical stimulation APB responses, the mean +/- SEM distance between the hotspots was only 4.70 +/- 1.09 mm for APB (n = 8). The authors concluded that peri-tumoral mapping of the motor cortex by navigated TMS agreed well with the gold standard of direct cortical stimulation. Thus, navigated TMS is a reliable tool for pre-operative mapping of motor function. These preliminary findings need to be validated by well-designed studies with larger number of participants.

Picht et al (2012) evaluated how much influence, benefit, and impact navigated TMS has on the surgical planning for tumors near the motor cortex. This study reviewed the records of 73 patients with brain tumors in or near the motor cortex, mapped pre-operatively with navigated TMS. The surgical team prospectively classified how much influence the navigated TMS results had on the surgical planning. Step-wise regression analysis was used to explore which factors predict the amount of influence, benefit, and impact navigated TMS has on the surgical planning. The influence of navigated TMS on the surgical planning was as follows: it confirmed the expected anatomy in 22 % of patients, added knowledge that was not used in 23 %, added awareness of high-risk areas in 27 %, modified the approach in 16 %, changed the planned extent of resection in 8 %, and changed the surgical indication in 3 %. The authors concluded that navigated TMS had an objective benefit on the surgical planning in 25 % of the patients and a subjective benefit in an additional 50 % of the patients. It had an impact on the surgery itself in just more than 50 % of the patients.

Krieg et al (2012) stated that navigated TMS is a newly evolving technique. Despite its supposed purpose (e.g., pre-operative central region mapping), little is known about its accuracy compared with established modalities like direct cortical stimulation and functional MR imaging (fMRI). These researchers compared the accuracy of navigated TMS with direct cortical stimulation and fMRI. Fourteen patients with tumors in or close to the pre-central gyrus were examined using navigated TMS for motor cortex mapping, as were 12 patients with lesions in the subcortical white matter motor tract. Moreover, pre-operative fMRI and intra-operative mapping of the motor cortex were performed via direct cortical stimulation, and the outlining of the motor cortex was compared. In the 14 cases of lesions affecting the pre-central gyrus, the primary motor cortex as outlined by navigated TMS correlated well with that delineated by intra-operative direct cortical stimulation mapping, with a deviation of 4.4 +/- 3.4 mm between the 2 methods. In comparing navigated TMS with fMRI, the deviation between the 2 methods was much larger: 9.8 +/- 8.5 mm for the upper extremity and 14.7 +/- 12.4 mm for the lower extremity. In 13 of 14 cases, the surgeon admitted easier identification of the central region because of navigated TMS. The procedure had a subjectively positive influence on the operative results in 5 cases and was responsible for a changed resection strategy in 2 cases. One of 26 patients experienced navigated TMS as unpleasant; none found it painful. The authors concluded that navigated TMS correlates well with direct cortical stimulation as a gold standard despite factors that are supposed to contribute to the inaccuracy of navigated TMS. Moreover, surgeons have found navigated TMS to be an additional and helpful modality during the resection of tumors affecting eloquent motor areas, as well as during pre-operative planning. These findings need to be confirmed.

Frey et al (2012) established a novel approach for fiber tracking based on navigated TMS mapping of the primary motor cortex and proposed a new algorithm for determination of an individualized fractional anisotropy value for reliable and objective fiber tracking. A total of 50 patients (22 females, 28 males; median age of 58 years, range of 20 to 80) with brain tumors compromising the primary motor cortex and the cortico-spinal tract underwent pre-operative MRI and navigated TMS mapping. Stimulation spots evoking muscle potentials (MEP) closest to the tumor were imported into the fiber tracking software and set as seed points for tractography. Next the individual FA threshold, namely, the highest FA value leading to visualization of tracts at a pre-defined minimum fiber length of 110 mm, was determined. Fiber tracking was then performed at a fractional anisotropy value of 75 % and 50 % of the individual FA threshold. In addition, fiber tracking according to the conventional knowledge-based approach was performed. Results of tractography of either method were presented to the surgeon for pre-operative planning and integrated into the navigation system and its impact was rated using a questionnaire. Mapping of the motor cortex was successful in all patients. A fractional anisotropy threshold for cortico-spinal tract reconstruction could be obtained in every case. TMS-based results changed or modified surgical strategy in 23 of 50 patients (46 %), whereas knowledge-based results would have changed surgical strategy in 11 of 50 patients (22 %). Tractography results facilitated intra-operative orientation and electrical stimulation in 28 of 50 (56 %) patients. Tracking at 75 % of the individual FA thresholds was considered most beneficial by the respective surgeons. The authors concluded that fiber tracking based on navigated TMS by the proposed standardized algorithm represents an objective visualization method based on functional data and provides a valuable instrument for pre-operative planning and intra-operative orientation and monitoring. This was a small study and it did not validate navigated TMS findings with improved health outcomes.

Tarapore et al (2012) noted that direct cortical stimulation is the gold-standard technique for motor mapping during craniotomy. However, pre-operative non-invasive motor mapping is becoming increasingly accurate. Two such non-invasive modalities are navigated TMS and magnetoencephalography (MEG) imaging. These investigators compared the accuracy of TMS to both direct cortical stimulation and MEG imaging. Patients with tumors in proximity to primary motor cortex underwent pre-operative TMS and MEG imaging for motor mapping. The patients subsequently underwent motor mapping via intra-operative direct cortical stimulation. The loci of maximal response were recorded from each modality and compared. Motor strength was assessed at 3 months post-operatively. Transcranial magnetic stimulation and MEG imaging were performed on 24 patients. Intra-operative direct cortical stimulation yielded 8 positive motor sites in 5 patients. The median distance +/- SEM between TMS and direct cortical stimulation motor sites was 2.13 +/- 0.29 mm, and between TMS and MEG imaging motor sites was 4.71 +/- 1.08 mm. In no patients did direct cortical stimulation motor mapping reveal a motor site that was unrecognized by TMS. Three of 24 patients developed new, early neurological deficit in the form of upper-extremity paresis. At the 3-month follow-up evaluation, 2 of these patients were significantly improved, experiencing difficulty only with fine motor tasks; the remaining patient had improvement to 4/5 strength. There were no deaths over the course of the study. The authors concluded that maps of the motor system generated with TMS correlate well with those generated by both MEG imaging and direct cortical stimulation. Negative TMS mapping also correlates with negative direct cortical stimulation mapping.

In a feasibility study, Forster et al (2012) examined cortical motor representation after resection of peri-rolandic World Health Organization grade II and III gliomas using navigated TMS. A total of 5 patients were examined before neurosurgery and after a follow-up period of 17.7 +/- 6.8 months. As a control, 5 healthy age-matched subjects were equally studied by navigated TMS in 2 sessions spaced 12.6 (range of 2 to 35) days apart. Resting motor thresholds (RMT), hotspots and centers of gravity (CoG) were identified for the first dorsal interosseous (FDI), APB, extensor digitorum (EXT), TA and abductor hallucis (AH) muscles. Euclidian distances, coefficients of variance and intra-class correlation coefficients (ICC) were calculated. Healthy subjects showed moderate-to-excellent reliability measurement of RMT (ICC = 0.69 to 0.94). Average displacement of CoGs across sessions was 0.68 +/- 0.34 cm in the dominant and 0.76 +/- 0.38 cm in the non-dominant hemisphere; hotspots moved 0.87 +/- 0.51 cm and 0.83 +/- 0.45 cm, respectively. In 1 patient these parameters differed significantly from the control group (p < 0.05 for both CoGs and hotspots). Overall, all patients' CoGs moved 1.12 +/- 0.93 cm, and hotspots were 1.06 +/- 0.7 cm apart. In both patients and healthy subjects, movement of assessed parameters was more important along the X- than the Y-axis. The authors concluded that navigated TMS allows evaluating cortical re-organization after brain tumor surgery. It may contribute to the understanding of neurofunctional dynamics, thus influencing therapeutic strategy.

Makela et al (2013) stated that navigated TMS has been suggested to be useful in pre-operative functional localization of motor cortex in patients having tumors close to the somato-motor cortex. These researchers described functional plasticity of motor cortex indicated by navigated TMS in 2 patients with epilepsy. Navigated TMS, fMRI, diffusion-tensor (DT)-tractography and MEG were utilized to pre-operatively localize motor cortical areas in the work-up for epilepsy surgery. The localizations were compared with each other, with the cortical anatomical landmarks, and in 1 patient with invasive electrical cortical stimulation (ECS). In 2 out of 19 studied patients, navigated TMS identified motor cortical sites that differed from those indicated by anatomical landmarks. In 1 patient, navigated TMS activated preferentially premotor cortex rather than pathways originating from the pre-central gyrus. Functional MRI and MEG localizations conformed with navigated TMS whereas ECS localized finger motor function into the pre-central gyrus. Resection of the area producing motor responses in biphasic navigated TMS did not produce a motor deficit. In the other patient, navigated TMS indicated abnormal ipsilateral hand motor cortex localization and confirmed the functionality of aberrant motor cortical representations of the left foot also indicated by fMRI and DT-tractography. The authors concluded that navigated TMS may reveal the functional plasticity and shifts of motor cortical function. Epileptic foci may modify cortical inhibition and the navigated TMS results. Thus, the authors noted that in some patients with epilepsy, the navigated TMS results need to be interpreted with caution with regard to surgical planning.

Raffa and colleagues (2019) stated that navigated TMS (nTMS) is an emerging tool for surgery of motor-eloquent intrinsic brain tumors; however, a critical re-appraisal of the literature evidence has never been performed. These researchers carried out a systematic review and meta-analysis using PubMed/Medline, and the Cochrane Central Register of Controlled Trials for studies that analyzed the impact of nTMS-based motor mapping on surgery of patients affected by motor-eloquent intrinsic brain tumors, in comparison with series of patients operated without using nTMS. The impact of nTMS mapping was assessed analyzing the occurrence of post-operative new permanent motor deficits, the gross total resection rate (GTR), the size of craniotomy and the length of surgery. A total of 8 studies were included in the quantitative review and meta-analysis. The pooled analysis showed that nTMS motor mapping significantly reduced the risk of post-operative new permanent motor deficits (OR = 0.54, p = 0.001, data available from 8 studies) and increased the GTR rate (OR = 2.32, p < 0.001, data from 7 studies). Moreover, results from 4 studies documented the craniotomy size was reduced in the nTMS group (-6.24 cm2, p < 0.001), whereas a trend towards a reduction, even if non-significant, was observed for the length of surgery (-10.30 mins, p = 0.38; in 3 studies). The authors concluded that available literature provided data in favor of the use of nTMS motor mapping: its use appeared to be associated with a reduced occurrence of post-operative permanent motor deficits, an increased GTR rate, and a tailored surgical approach compared to standard surgery without using pre-operative nTMS mapping. Nonetheless, a growing need of high-level evidence regarding the use of nTMS motor mapping in brain tumor surgery is perceived. These researchers stated that well-designed RCTs from multiple Institutions are needed to continue to shed a light on this emerging topic.

Sollmann and associates (2019) stated that nTMS in combination with diffusion tensor imaging fiber tracking (DTI FT) is increasingly used to locate subcortical language-related pathways. These researchers attempted to establish nTMS-based DTI FT for pre-operative risk stratification by evaluating associations between lesion-to-tract distances (LTDs) and aphasia and by determining a cut-off LTD value to prevent surgery-related permanent aphasia. A total of 50 patients with left-hemispheric, language-eloquent brain tumors underwent pre-operative nTMS language mapping and nTMS-based DTI FT, followed by tumor resection. nTMS-based DTI FT was performed with a pre-defined fractional anisotropy (FA) of 0.10, 0.15, 50 % of the individual FA threshold (FAT), and 75 % FAT (minimum fiber length [FL]: 100 mm). The arcuate fascicle (AF), superior longitudinal fascicle (SLF), inferior longitudinal fascicle (ILF), uncinate fascicle (UC), and fronto-occipital fascicle (FoF) were identified in nTMS-based tractography, and minimum LTDs were measured between the lesion and the AF and between the lesion and the closest other subcortical language-related pathway (SLF, ILF, UC, or FoF). LTDs were then associated with the level of aphasia (no/transient or permanent surgery-related aphasia, according to follow-up examinations). A significant difference in LTDs was observed between patients with no or only surgery-related transient impairment and those who developed surgery-related permanent aphasia with regard to the AF (FA = 0.10, p = 0.0321; FA = 0.15, p = 0.0143; FA = 50 % FAT, p = 0.0106) as well as the closest other subcortical language-related pathway (FA = 0.10, p = 0.0182; FA = 0.15, p = 0.0200; FA = 50 % FAT, p = 0.0077). Patients with surgery-related permanent aphasia showed the lowest LTDs in relation to these tracts. Thus, LTDs of greater than or equal to 8 mm (AF) and greater than or equal to 11 mm (SLF, ILF, UC, or FoF) were determined as cut-off values for surgery-related permanent aphasia. The authors concluded that nTMS-based DTI FT of subcortical language-related pathways appeared suitable for risk stratification and prediction in patients suffering from language-eloquent brain tumors. Therefore, the current role of nTMS-based DTI FT might be expanded, going beyond the level of being a mere tool for surgical planning and resection guidance.

In summary, there is insufficient evidence from peer-reviewed medical literature that navigated TMS is an effective clinical diagnostic test. Most published studies entailed small number of subjects; well-designed studies with larger sample sizes are needed to ascertain how this test can reduce clinical diagnostic uncertainty or impact treatment planning.

Obsessive-Compulsive Disorder

Trevizol and colleagues (2016) stated that TMS is a promising non-invasive brain stimulation intervention; it has been proposed for OCD with auspicious results. These investigators assessed the effectiveness of TMS for OCD in RCTs. They performed a systematic review using Medline and Embase from the first RCT available until March 11, 2016. The main outcome was the Hedges g for continuous scores for Yale-Brown Obsessive Compulsive Scale in a random-effects model. Heterogeneity was evaluated with the I and the χ test. Publication bias was evaluated using the Begg funnel plot. Meta-regression was performed using the random-effects model modified by Knapp and Hartung. These researchers included 15 RCTs (n = 483), most had small-to-modest sample sizes. Comparing active versus sham TMS, active stimulation was significantly superior for OCD symptoms (Hedges g = 0.45; 95 % CI: 0.2 to 0.71). The funnel plot showed that the risk of publication bias was low and between-study heterogeneity was low (I = 43 %, p = 0.039 for the χ test). Meta-regression showed no particular influence of any variable on the results. The authors concluded that TMS was superior to sham stimulation for the amelioration of OCD symptoms; trials had moderate heterogeneity results, despite different protocols of stimulation used. They stated that further RCTs with larger sample sizes are needed to clarify the precise impact of TMS in OCD symptoms.

The American Psychiatric Association (APA)’s practice guideline on “The treatment of patients with obsessive-compulsive disorder” (Koran et al, 2007) stated that “Transcranial magnetic stimulation (TMS) is associated with less potential for side effects, but evidence for its efficacy is limited … Findings of the 4 published trials of repetitive TMS (rTMS) are inconsistent, perhaps because the studies differed in design, stimulation sites, duration, and stimulation parameters. The available results and the technique’s non-invasiveness and good tolerability should encourage future research, but the need for daily treatment may limit the use of TMS in practice”.

Koran and Simpson (2013) summarized new evidence and developments since the 2007 publication of the APA’s practice guideline on “The Treatment of Patients With Obsessive-Compulsive Disorder”. The authors stated that “New studies are available on repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), and other somatic treatments, but the overall strength of evidence for these treatments remains low”.

On August 17, 2018, the FDA permitted marketing of the Brainsway Deep Transcranial Magnetic Stimulation System for treatment of OCD. Dr. Carlos Pena, director of the Division of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health stated that “With today’s marketing authorization, patients with OCD who have not responded to traditional treatments now have another option”. The FDA reviewed data from a randomized, multi-center study of 100 patients, of which 49 patients received treatment with the Brainsway device and 51 received treatment with a non-working (sham) device. Patients already receiving OCD treatments (medical management) were maintained at their current dosages throughout the study. The study evaluated the reduction in patients’ YBOCS score. The results indicated that 38 % of patients responded to the Brainsway device (i.e., greater than 30 % reduction in YBOCS score), whereas 11 % of patients responded when using the sham device. The Brainsway device is contraindicated for patients with metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, other implanted electrodes or stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry and hair barrettes. During treatment with the device, the patient must use earplugs to reduce exposure to the loud sounds produced by the device. Patients with a history of seizures should discuss their history with their health care provider before receiving the device. The FDA reviewed the Brainsway device through the de-novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no legally marketed predicate device to which the device can claim substantial equivalence.

In a retrospective, open study, Kumar and colleagues (2018) evaluated the safety and effectiveness of low-frequency rTMS (LF-rTMS) over left-orbitofrontal cortex (Lt-OFC) as a potential augmentation strategy in treatment of patients with medication-refractory OCD in real-world clinical setting. This study also examined the factors affecting response to rTMS and the durability of effects produced by rTMS over 1 month of follow-up period. This was a retrospective review and analysis of clinical case files of 25 patients with medication-refractory OCD, all of whom had received 20 sessions of LF-rTMS over Lt-OFC as part of routine clinical care. A reduction of 25 % and 35 % in YBOCS scores was used to determine the proportion of partial and complete responders, respectively. There was a significant decrease in mean YBOCS score at the end of 20 sessions of rTMS compared with baseline (7.04 ± 5.07; p < 0.001), with no further significant change during the subsequent 1-month follow-up period (0.20 ± 1.38; p = 0.47); 13 patients (52 %) met criteria for partial response (PR), 11 patients (44 %) showed complete response (CR). Furthermore, higher number of failed medication trials was found to be significantly associated with greater chances of non-response to rTMS treatment. The authors concluded that there is a role of applying LF-rTMS over Lt-OFC as an augmentation strategy in ameliorating clinical symptoms among patients with medication-refractory OCD. This was a small study (n = 25) with short-term follow-up.

In a randomized, double-blinded, sham-controlled trial, Arumugham and associates (2018) examined the efficacy of LF-rTMS over bilateral pre-supplementary motor area (pre-SMA) in patients suffering from OCD with partial response/poor response to pharmacotherapy. A total of 40 subjects with OCD, who were on stable medications with PR/poor response to pharmacotherapy were randomly divided into 2 groups (n = 20 in each group), to receive either active or sham LF-rTMS over bilateral pre-SMA; 36 patients were eligible for ITT analysis. There was no significant difference in relevant demographic and clinical variables between the 2 groups at baseline. There were no statistically significant differences between the 2 groups after 3 weeks of treatment in the YBOCS score (time*group interaction, F2.48,84.16 = 0.80, p = 0.40) and other secondary outcome measures including responder rates and depressive and anxiety symptoms. The authors concluded that LF-rTMS over pre-SMA may not be effective as an augmenting agent in partial/poor responders to SRIs. They stated that the findings of this study underlined the need to explore alternate rTMS protocols in OCD.

In a double-blinded, pilot study, Carmi and colleagues (2018) examined if modulation of medial prefrontal cortex (mPFC)- anterior cingulate cortex (ACC) activity by dTMS affects OCD symptoms. Treatment resistant OCD subjects were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), or sham dTMS of the mPFC and ACC for 5 weeks. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the YBOCS. Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least 1 month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that was attributed to ACC activity. The authors concluded that HF-dTMS over the mPFC-ACC alleviated OCD symptoms and may be used as a novel therapeutic intervention. Moreover, they stated that larger studies should examine if this promising technique may become an established treatment for OCD, while considering the option of an additional maintenance phase, as done for the treatment of major depression.

The authors stated that this study had several drawbacks. First, the study was considered as a pilot study and the sample size was relatively small (n = 23). As such, further studies should be conducted in order to establish this intervention for the treatment of OCD. Second, the effect of provocation was not controlled, and relevant brain activity was not recorded during the provocation. Furthermore, the extent to which the ACC and the mPFC were adequately stimulated needs to be further investigated. Consequently, the above discussion in this matter should be regarded as speculative. Finally, the total number of pulses (over the 5 weeks of treatment) that was administered, was different between the LF group (22,500 pulses) and the HF group (50,000 pulses), which may stand as an alternative explanation for the superior efficacy of the HF treatment.

Lusicic and associates (2018) stated that evidence for rTMS use in OCD is accumulating and informing further developments in the neuro-stimulation field, the latest being dTMS, which allows direct stimulation of deeper subcortical structures and larger brain volume than conventional rTMS. Underlying neurobiological mechanisms related to TMS are still under evaluation, but appear to offer a novel "3rd" way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. This systematic review focused on the effects of rTMS and dTMS stimulation on different brain targets in OCD. Brain areas included are the dorsolateral prefrontal cortex, supplementary motor area, orbitofrontal cortex/medial prefrontal cortex, and anterior cingulate cortex (ACC). The authors concluded that as a new neuro-stimulation technique, rTMS showed promise as part of a toolbox of current psychiatric treatment options for OCD. Its non-invasiveness with good tolerability and side-effect profile made it an appealing treatment consideration. Underlying neurobiological mechanisms related to TMS are still under evaluation, but appeared to offer a novel “3rd” way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. Recent studies have considered rTMS as an adjunct treatment in TR patients with long duration of illness. In the future, apart from managing design and methodology issues encountered in previous studies, it will be of interest to address rTMS as an augmentation strategy earlier in the course of treatment and consider parallel stimulation of a few cortical regions. Also, rTMS could be evaluated as an option in medication-naïve patients who cannot tolerate pharmacological treatment and have limited benefits from psychotherapy approaches. Advances in targeted brain stimulation via development of dTMS H coils paired with functional neuroimaging are offering a step further in understanding and management of OCD. However, it is yet to be determined how one can best optimize the approach via rTMS or dTMS to achieve clinically relevant results.

Rehn and co-workers (2018) stated that randomized and sham-controlled trials (RCTs) of rTMS in the treatment of OCD have yielded conflicting results, which may be due to the variability in rTMS parameters used. These researchers performed an updated systematic review and meta-analysis on the effectiveness of rTMS for the treatment of OCD and examined if certain rTMS parameters, such as cortical target, may be associated with higher treatment effectiveness. After conducting a systematic literature review for RCTs on rTMS for OCD through to December 1, 2016 using Medline, PubMed, Web of Science, PsycINFO, Google, and Google Scholar, these investigators performed a random-effects meta-analysis with the outcome measure as pre-post changes in YBOCS scores. To determine whether rTMS parameters may have influenced treatment effectiveness, studies were further analyzed according to cortical target, stimulation frequency, and length of follow-up. Data were obtained from 18 RCTs on rTMS in the treatment of OCD. Overall, rTMS yielded a modest effect in reducing YBOCS scores with Hedge's g of 0.79 (95 % CI: 0.43 to 1.15, p < 0.001). Stimulation of the supplementary motor area yielded the greatest reductions in YBOCS scores relative to other cortical targets. Sub-group analyses suggested that LF-rTMS was more effective than HF-rTMS. The effectiveness of rTMS was also greater at 12 weeks follow-up than at 4 weeks follow-up. The authors concluded that the findings of this meta-analysis implied that LF-rTMS applied over the supplementary motor area may offer the greatest effectiveness in the treatment of OCD. The therapeutic effects of rTMS also appeared to persist post-treatment and may offer beneficial long-term effectiveness. They stated that with these findings, it is suggested that future large-scale studies focus on the supplementary motor area and include follow-up periods of 12 weeks or more.

Singh and co-workers (2019) examined the effectiveness of rTMS treatment targeting either SMA or orbitofrontal cortex (OFC) among patients with OCD in real-world clinical practice settings. These researchers also examined for potential predictors of response to rTMS treatment. Retrospective review and analysis of records of 79 patients with medication-refractory OCD, all of whom had received 20 sessions of 1-Hz rTMS as part of routine clinical care. Of 79 patients, 46 received rTMS over the bilateral SMA and 33 over the left OFC. A reduction of 25 % and 35 % in YBOCS scores was used to classify outcome as PR and CR, respectively. Statistical analysis was done using SPSS version 23.0. There was a significant decrease in mean YBOCS score from baseline to end of treatment (7.68 ± 5.62; t = 12.14, p < 0.001); 45 patients (57 %) met criteria for PR, of which 32 patients (40.5 %) showed CR. There was no significant difference in outcomes between patients receiving rTMS over SMA or OFC. Binary logistic regression analysis revealed presence of co-morbid depression and higher baseline YBOCS score to be associated with lesser likelihood of response to rTMS. The authors concluded that this study provided evidence for overall effectiveness of adjunctive 1-Hz rTMS treatment over either SMA or OFC in patients with medication-refractory OCD, and reported co-morbid depression and higher pretreatment YBOCS scores as potential predictors of poor response to rTMS. There may be overlapping of patients between this study and that of the afore-mentioned study by Kumar et al (2018).

Carmi et al (2019) noted that OCD is a chronic and disabling disorder that often unsatisfactorily responds to pharmacological and psychological treatments. Converging evidence suggested a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD and a prior feasibility study indicated beneficial effects of dTMS targeting the medial-prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) components. In a large, multi-center, double-blind, FDA-regulated, sham-controlled study, these researchers examined the therapeutic effect of dTMS. At 11 centers, a total of 99 OCD patients were randomly allocated to either high-frequency (20-Hz) or sham dTMS, and were treated daily for 6 weeks following individualized symptom provocation. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive-Scale (Y-BOCS) and the primary efficacy end-point was the change in this scale from baseline to post-treatment. Additional measures were response rates (defined as reduction of 30 % of Y-BOCS score) at post-treatment and following another month of follow-up; 98 % of the active group and 92 % of the sham group completed the study. Reduction in Y-BOCS scores in patients who received active dTMS treatment was significantly greater than that of patients who received sham treatment (-6.0 versus -3.3, p = 0.01), with response rates of 38.1 % and 11.1 %, respectively. The response rate at 1 month follow-up was 45.2 % in the active versus 17.8 % in the sham group. Significant differences between the groups were maintained at follow-up. The authors concluded that high-frequency dTMS over the mPFC and ACC significantly improved OCD symptoms and represented a potential intervention for patients who did not respond adequately to pharmacological and psychological interventions. These researchers noted that the intriguing finding of an additional benefit for OCD patients who did not respond adequately to pharmacological or psychological treatment suggested that this technology may involve a different mechanism. Accordingly, these researchers recommend considering, at a relatively early stage, the option of adding dTMS to treatment when the response to a proper psychological or pharmacological intervention is inadequate. (This recommendation takes into consideration that the benefit to risk ratio of this treatment is favorable).

The authors stated that this study had several drawbacks. First, the effect of provocation was not controlled, and relevant brain activity was not recorded; hence, the exact contribution of the exposure procedure was not fully known. In addition, the extent to which the ACC and the mPFC were stimulated needs to be further examined in future functional brain imaging studies. Moreover, although the patients were asked about their past treatment history, this was not validated with source documentation such as filled prescriptions or other objective information. These investigators stated that It would be optimal if clinicians could predict the patients who are likely to respond to treatment. For example, in the pilot study (Carmi et al, 2018) the amplitude of the theta frequency band (4 to 8 Hz) in response to a Stroop task correlated with the amplitude of the change in the Y-BOCS. The possibility of corroborating such measures at baseline, following a validation study in a large sample of patients, could help predict the response and selection of the appropriate population for this 6-week treatment course. Further refinements of the stimulation and provocation parameters, treatment during a maintenance phase, and the combination of dTMS treatment with CBT intervention should be investigated. Studies that combine a precise behavioral challenge with neuromodulation and neuroimaging, and that attempt to identify potential responders should also be considered.

Furthermore an UpToDate review on “Treatment of obsessive-compulsive disorder in children and adolescents” (Rosenberg, 2019) does not mention transcranial magnetic stimulation as a therapeutic option.

In a “Letter to the Editor” regarding the study by Carmi et al (2019), Harmelech et al (2020) stated that although further research is needed to elucidate the mechanism that mediates clinical improvement with deep transcranial magnetic stimulation (dTMS) and target selection for individuals with major depressive disorder (MDD), these researchers recommended, based on the available evidence, to treat co-morbid obsessive-compulsive disorder (OCD)-MDD patients with just the OCD protocol (H7 to the dorso-medial prefrontal cortex [dmPFC] / anterior cingulate cortex [ACC]).

In a “Letter to the Editor” regarding the study by Carmi et al (2018), Alyagon et al (2021) stated that this study included limitations of relative medium sample sizes and the analysis method of post-correct (PC) and post-error (PE), which may be subject to potential drift bias (although alternative methods suffer from other pitfalls). Nevertheless, this behavioral analysis of objective measures derived from a computerized cognitive task, further supports the clinical improvements observed and suggested that dTMS of the mPFC and ACC could induce long-term modifications to cognitive functioning associated with error monitoring.

Roth et al (2020) stated that OCD is a chronic and disabling disease with a lifetime prevalence of 2 % to 3 %; approximately 40 % to 60 % of these patients do not adequately respond to pharmacotherapy and cognitive behavioral therapy (CBT). Deep transcranial magnetic stimulation (dTMS) was shown to be safe and effective as a treatment alternative for OCD and recently received regulatory approvals. Yet, it is unclear whether patients who failed numerous medications and/or CBT can still benefit from dTMS. These investigators analyzed recent data from a double-blind, multi-center dTMS study; they stated that the present analysis suggested that dTMS is beneficial for OCD patients with different treatment history, including those with unsatisfactory response to multiple medications and CBT.

The authors stated that drawbacks of this analysis, other than the reduction of sample size to smaller cohorts, included the lack of controlled monitoring of prior pharmacological treatments and regimens. Since OCD is a chronic disorder and patients are prescribed medications from different providers over the course of their lifetime, the medication history gathered was generally an under-estimation of medication exposure. Furthermore, patients who were recalling benefits from medications at a time when they were doing poorly, might be under-estimating those prior benefits as those medications could have been discontinued after the patient responded and plateaued but lost perspective. There is no simple solution for this, as pharmacy records were only available for 2 years, and clinician records for 7 years. These researchers also found that the patient and therapist reported on CBT for OCD did not necessarily correlate with exposure and response prevention (ERP) for OCD. In several cases, patients were receiving re-assurance or relaxation techniques on a weekly basis; or were instructed to do brief exposures without the time for habituation. A formal test on the components of ERP is needed to determine that someone truly did not respond to CBT/ERP for OCD.

Roth et al (2021) noted that dTMS with the H7-coil was FDA-cleared (not PMA-approved) for OCD in August 2018 based on multi-center sham-controlled studies. These researchers examined the efficacy of dTMS for OCD in real world practices. All dTMS clinics were asked to supply their data on treatment details and outcome measures. The primary outcome measure was response, defined by at least a 30 % reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline to endpoint. Secondary outcome measures included 1st response, defined as the 1st time the YBOCS score has met response criteria, and at least 1-month sustained response. Analyses included response rate at the endpoint (after 29 dTMS sessions), number of sessions and days needed to reach 1st response and sustained response. A total of 22 clinical sites with H7-coils provided data on details of treatment and outcome (YBOCS) measures from a total of 219 patients; 167 patients who had at least 1 post-baseline YBOCS measure were included in the main analyses. Overall 1st and sustained response rates were 72.6 % and 52.4 %, respectively. The response rate was 57.9 % in patients who had YBOCS scores after 29 dTMS sessions. First response was achieved in average after 18.5 sessions (SD = 9.4) or 31.6 days (SD = 25.2). Onset of sustained 1-month response was achieved in average after 20 sessions (SD = 9.8) or 32.1 days (SD = 20.5). Average YBOCS scores demonstrated continuous reduction with increasing numbers of dTMS sessions. The authors concluded that in real-world clinical practice, the majority of OCD patients benefitted from dTMS, and the onset of improvement usually occurred within 20 sessions. Extending the treatment course beyond 29 sessions resulted in continued reduction of OCD symptoms, raising the prospect of value for extended treatment protocols in non-responders.

The authors stated that this real-world analysis was primarily limited by the amount of information that sites were able to submit for analysis. A minority of the sites did not fill out demographic information and only shared the number of treatments and YBOCS scores. The main drawback was that only a small percentage of the sites took the time to participate, even though these investigators knew the utilization patterns from many more sites that were treating OCD patients with anecdotal reports of very high success rates. Their focus was on treating patients and not consistent detailed documentation or research. Potential solutions to the deficiencies in real-world evidence data collection require interoperable technologies to enable consensual effortless sharing between electronic health records, patient mobile health applications or wearables and surveys. These researchers hope to use these in the future in order to gain information from a larger cohort of patients in a naturalistic setting, such as in the present study. Moreover, the naturalistic data is by its nature incomplete and may lead to bias. For example, the data on response after 29 sessions may be biased by the patients who dropped-out at an earlier stage; 57.8% of those earlier quitters reached response. Hence it was possible that the drop-out led to decreased measured response rates after 29 sessions. Likewise, data of 1-month follow-up after response or 1-month without response was available for only 63 patients. Yet, the vast majority of patients who reached response at any time-point (92 of 113, 81.4 %) were responders in their last YBOCS assessment. Hence, it was possible that sustained response was attained by much more than 52.4 % found in this study among the patients who had 1-month follow-up data. Another drawback was that dTMS treatment for OCD is currently not reimbursed by insurance. Hence the patients payed out-of-pocket for the treatment. This may introduce a bias towards increased response rates due to cognitive dissonance.

Storch et al (2021) stated that dTMS has emerged as a therapeutic option for adults with OCD who continue to exhibit impairing symptoms following an adequate response to 1s- line interventions. Currently, little is known about the predictors or moderators of dTMS outcome for OCD. These researchers examined if several theoretically relevant variables may predict and moderate treatment effects including OCD symptom severity, functional impairment, co-occurring depressive symptoms, age, gender, age of OCD onset, and family history of OCD. As part of a previously reported study, 100 patients received 29 dTMS or sham stimulation treatments over 6 weeks. dTMS was administered using a Magstim Rapid2 TMS stimulator equipped with a H-shaped coil design, which was specifically designed to stimulate the dmPFC-ACC bilaterally. Findings suggested older subjects and those with lower OCD severity and disability responded faster to both dTMS and sham stimulation. dTMS of the dmPFC/ACC appeared to have larger benefits for individuals with greater OCD severity, whereas the difference between treatment arms was minimal in those with lower severity.

The authors stated that this study had several drawbacks. First, the sample was mostly White and non-Hispanic and no information was collected on the socioeconomic status (SES), which limited the ability to generalize findings. Second, brain activity in the target brain regions was not recorded; this prevented the authors from determining the extent to which the mPFC and ACC were stimulated as well as the association of changes in brain activity with the different predictors and moderator of outcome. Finally, some factors significantly associated with outcomes of other treatment forms, such as OCD symptom dimensions and family accommodation, were not measured in this study; thus, it was impossible to determine their association with dTMS outcomes. These investigators stated that future studies should include measures of brain activity before and after treatment, to examine potential treatment-related changes and their associations with the different predictors and moderators of outcome.

Harmelech et al (2022) shed some light on the potential durability of dTMS for the treatment of OCD, clinical sites that participated in the OCD multi-center trial as well as those that contributed the post-marketing data were contacted (n = 16). All sites were provided with a list of their patients who met response criteria at their last Y-BOCS evaluation following the dTMS treatment course (overall n = 108) and were compensated for contacting these patients and reporting whether each of them had, since the end of their treatment, any medication change/CBT/hospitalization/dTMS re-treatment. If so, on what date did the change in treatment occur and was it due to an exacerbation of the patient's OCD or due to a desire for greater improvement. Sites were also requested to inquire about functional disability, days lost and days unproductive per week. The patient populations were previously described. Moreover, these researchers stated that as with any registry-based study, the primary limitations to this study were incomplete data due to a lack of follow-up or continued care with the dTMS provider following the treatment course. Many patients only went to the dTMS center for the treatment and not their ongoing psychiatric care, which limited the analysis set to 60/108 (55.6 %) responders and 7/16 (43.8 %) centers. Furthermore, as the Y-BOCS is not used in routine clinical practice, this resulted in a “durability” definition as elapsed time from the last dTMS session until any change in treatment was necessary. Ideally, this would be corroborated by Y-BOCS scores, a more standardized metric administered every few months. The authors concluded that confirmatory and mechanistic studies examining the response “durability” of dTMS therapy for OCD with standardized measures are needed.

Gregory et al (2022) examined the cost-effectiveness of dTMS for the treatment refractory OCD relative to other established therapeutic options, including anti-depressant medication (ADM), ADM + anti-psychotic augmentation, real-world cognitive-behavioral therapy (ADM + CBT Effectiveness), clinical trial CBT (ADM + CBT), intensive outpatient program (IOP), partial hospitalization program (PHP), and PHP to IOP step-down. A decision analytic model was developed to evaluate the cost-effectiveness of dTMS relative to other established treatment alternatives for adults (18 to 64 years old) with refractory OCD. Building on Gregory et al (2018), the model was parameterized with probabilistic and deterministic parameters from the literature and an outcomes database to perform a Monte Carlo simulation of a hypothetical cohort of 100,000 adults with OCD to estimate costs, and incremental cost-effectiveness ratio (ICER) for dTMS relative to each treatment strategy. Encounters took place from 2012 to 2015. Data for dTMS were taken from a recent multi-site study. Although dTMS fit between ADM and ADM + CBT in overall costs, ADM + CBT had the lowest ICER and thus would be chosen before dTMS. dTMS was determined to be more cost-effective relative to PHP/IOP stepdown, PHP, and IOP. The authors concluded that these findings suggested that dTMS was cost-effective, along the treatment trajectory from outpatient medication management and CBT to more intensive, facilities-based approaches, and may afford an incremental strategy to employ when higher intensity strategies are either not available, not financially feasible, or while on extended waits for admission to these higher levels of care. In the latter scenario, dTMS may be appropriate for those with significant obsessive-compulsive symptomology to potentially receive benefit while they wait. These researchers stated that future studies should incorporate robust naturalistic data into dTMS estimates to confirm placement on the treatment continuum.

The authors stated that this study had several drawbacks. First, cost-effectiveness results were included from a broad array of studies characterized by differences in treatment history, period of time sampled, and OCD symptom severity. For example, there may be differences in clinical severity between individuals who participated in clinical trials versus receiving naturalistic intensive treatment. Alternatively, estimates from naturalistic open-label treatment may be greater than those from clinical research studies given the flexibility in treatment of the former (e.g., duration, con-commitment interventions). Second, these investigators were unable to include additional adjustments for health status for individuals receiving anti-psychotic treatments, which have documented weight-gain and other metabolic issues. On balance, some of the individuals across clinical trials and higher levels of care would be on conjoint anti-psychotic treatment; thus, balancing out additional effects. Third, these researchers only had short-term estimates for cost and treatment response; and could not parameterize estimates over longer durations. Fourth, these investigators sourced cost-estimates from a variety of sources. Rates within the specialty IOP/PHP programs likely reflected proportionally higher rates than cost estimates derived from Truven, which reflected non-specialty care; this may have resulted in cost-effectiveness estimates being biased against the specialty IOP/PHP programs. Fifth, published data examining real-world effectiveness of CBT (relative to that provided in clinical trials) may represent lower estimates of potential effects. Sixth, data on age, race/ethnicity, and other potentially important demographic variables were not consistently available for analysis. Finally, the outcomes database relied on consensus diagnostic procedures (versus through structured interviews) and used self-reported Y-BOCS versus the clinician-rated Y-BOCS used in research studies.

Restless Legs Syndrome

The American Academy of Neurology (AAN)’s practice guideline on “Treatment of restless legs syndrome” (Winkelman et al, 2016) stated that “rTMS is possibly effective in the treatment of primary moderate to severe RLS …. Cathodal and anodal transcranial direct current stimulation are probably ineffective for improving RLS symptoms in women with RLS who were drug-naive”. It stated that “When non-pharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C)”.

Furthermore, an UpToDate review on “Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults” (Tarsy and Silber, 2017) does not mention transcranial magnetic stimulation and cranial direct electrical stimulation as therapeutic options.

Visual Hallucinations after Stroke

Rafique and colleagues (2016) examined the effectiveness of multi-day rTMS to the occipital cortex in a patient with continuous visual phosphene hallucinations for more than 2 years following occipital stroke. Low-frequency rTMS (1 Hz) was applied to the lesion site for 30 minutes daily over 5 consecutive days; fMRI was performed before and after rTMS treatment. Increased application of rTMS corresponded with a reduction in intensity of visual phosphene hallucinations and was reflected in altered blood oxygen level-dependent signal; fMRI revealed focal excitatory discharges at the border of the lesion, highlighting the origin of phosphenes. Post-rTMS, rTMS did not simply suppress activity in the patient but rather re-distributed the previously imbalanced cortical activity not only at the stimulation site but in remote cortical regions so that it more closely resembled that of controls. The authors concluded that this case was rare in its presentation of chronic continuous visual phosphene hallucinations following occipital stroke. They presented a case of multi-day application of rTMS to visual cortex and demonstrated that rTMS provided a valuable therapeutic intervention in modulating visual hallucinations following occipital damage. This study provided Class IV evidence in a single-case report that multi-day rTMS reduced intra-hemispheric and inter-hemispheric imbalance and associated visual phosphene hallucinations following occipital stroke. The main drawbacks of this study were: (i) single-case design, and (ii) the inability to refine stimulation intensity and duration to attain maximal phosphine suppression.

Differential Diagnosis of Alzheimer Disease from Frontotemporal Dementia

Benussi and colleagues (2017) examined if a TMS multi-paradigm approach can be used to distinguish AD from frontotemporal dementia (FTD). Paired-pulse TMS was used to investigate short-interval intra-cortical inhibition (SICI) and facilitation (ICF), long-interval intra-cortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intra-cortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis. A total of 175 participants met the inclusion criteria. These researchers diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. They found that while patients with AD were characterized by a specific impairment of SAI, FTD showed a remarkable dysfunction of SICI-ICF intra-cortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8 % and specificity of 88.6 %, AD from HC with a sensitivity of 84.8 % and specificity of 90.6 %, and FTD from HC with a sensitivity of 90.2 % and specificity of 78.1 %. These results were confirmed in patients with mild disease. The authors concluded that TMS is a non-invasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice. This study provided Class III evidence that TMS measures can distinguish patients with AD from those with FTD. These researchers stated that further studies should examine if the AD/FTD-specific pattern of cortical dysfunction, classified according to the SICI-ICF/SAI ratio identified here, could also provide relevant prognostic information. The SICI-ICF/SAI measure has been shown to provide the footprints of the specific underlying neurotransmitter deficit, having the potential to be used as an additional diagnostic instrument in clinical practice and eventually in clinical trials.

Treatment of Complex Regional Pain Syndrome

Nardone and colleagues (2018) noted that the sensory and motor cortical representation corresponding to the affected limb is altered in patients with complex regional pain syndrome (CRPS). In this review, these investigators performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and rTMS for the treatment of CRPS. Literature searches were conducted using PubMed and Embase. They identified 8 articles matching the inclusion criteria; 114 patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS-I patients. Sensory and motor hyper-excitability were in the most studies bilateral and likely involve corresponding regions within the central nervous system (CNS) rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS-I. TMS examinations also revealed that the nature of motor dysfunction in CRPS-I patients differed from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS-I patients; 2 studies have begun to therapeutically use rTMS. The authors concluded that this non-invasive brain stimulation approach could have therapeutic utility in CRPS, but further well-designed studies are needed to corroborate initial findings.

TMS for Phantom Pain

Nardone and colleagues (2019) noted that several studies have applied TMS to examine the pathophysiological mechanisms of phantom-limb pain (PLP) and non-painful phantom sensations (PS). These researchers performed a systematic review of available evidence of this emerging technology in this indication. They identified studies that reported a reduced intra-cortical inhibition and increased intra-cortical facilitation in the hemisphere contralateral to the PLP; TMS mapping revealed a significant lateralization of the center of gravity and an enlargement of the excitable area on the hemisphere contralateral to the amputation. N-methyl-d-aspartate-mediated mechanisms influence the changes of intra-cortical inhibition and facilitation occurring after limb amputation; however, these cortical excitability changes and PLP were independent of each other. TMS could also influence brain function if applied repetitively. A few studies have begun to therapeutically use rTMS to relief PLP and non-painful PS; rTMS of the contralateral parietal cortex resulted in a transient reduction in pain intensity; HF-rTMS applied over the contralateral motor cortex (M1) or LF- rTMS over the unaffected hemisphere might also induce significant clinical improvement in PLP. On the other hand, serum beta-endorphin increased significantly after real stimulation over contralateral M1. The authors concluded that the findings of this systematic review showed that TMS technique is an emerging tool to gain insights to pathophysiological aspects of PLP and non-painful PS. These researchers stated that TMS could support appropriate patient selection for different therapies and may also have therapeutic utility in subjects with PLP or PS, although the evidence is still very preliminary and well-designed studies in larger cohort of patients are needed.

TMS for Bipolar Disorder

Yang and colleagues (2019) noted that patients with bipolar disorder (BD) present wide-spread and significant neurocognitive impairments during all stages of the disorder; rTMS has been tried to improve clinical outcomes in common psychiatric diseases, such as depression, anxiety disorders, schizophrenia, and BD. Whether rTMS can improve cognitive function in BD patients remains unclear. These researchers examined the effects of rTMS on cognitive function in patients with BD. A total of 52 eligible subjects with BD were randomly assigned to receive active or sham rTMS via high-speed magnetic stimulator with a figure-of-eight coil for 10 consecutive days. In the active rTMS group, a total of 25,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110 % of the motor threshold. The sham group received corresponding sham stimulation. Clinical manifestations and cognitive functions were assessed using a modified 24-item HDRS, the Young Mania Rating Scale (YMRS), and the MATRICS Consensus Cognitive Battery (MCCB). These investigators found that 10 consecutive days of HF- rTMS improved scores on the Wechsler Memory Scale-III Spatial Span, and the MCCB Category Fluency subtest, without intolerable adverse effects. No significant differences in HDRS or YMRS scores were found between groups. The authors concluded that short-term rTMS could improve cognitive function in BD patients. The main drawbacks of this study were its relatively small sample size (n = 52), the lack of follow-up after the intervention, and the effect of the drug on cognitive function in subjects was not excluded.

In a triple-blinded, randomized, placebo-control, pilot study, McIntyre and colleagues (2021) examined if rTMS would improve cognitive function in adults with BD. Subjects (aged 18 to 60 years) with a diagnosis of DSM-5-defined BD (I or II) were recruited and randomized (n = 36) to receive either a sham treatment (n = 20) or an active rTMS treatment (n = 16). Patients completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at baseline and 1 to 2 weeks after the rTMS intervention. A significant group by time interaction was observed in the Hopkins Verbal Learning Test-Revised (HVLT-R), (F (1, 34) = 17.0, p < 0.001, partial η2 = 0.33). Post-hoc analysis revealed that although both groups did not significantly differ at baseline (p = 0.58), patients in the active rTMS group significantly improved following neurostimulation (p = 0.02) for HVLT-R. Moreover, within-subject analysis indicated that the active rTMS group significantly improved in score from pre-treatment to post-treatment (p < 0.001), while the sham group did not improve (p = 0.94) for HVLT-R. No significant differences were observed in the other cognitive measures. The authors concluded that this pilot study, which was intended to establish feasibility, suggested that rTMS may offer benefit in select domains of cognitive functioning in BD. None of the measures across sub-domains revealed a dyscognitive effect. Moreover, these investigators stated that this study had a small sample (n = 16 in the rTMS group); larger, rigorous studies are needed to replicate and extend results of this pilot study.

TMS for Multiple Sclerosis

Leon Ruiz and colleagues (2018) stated that a growing number of studies have examined the effects of TMS for the symptomatic treatment of multiple sclerosis (MS). These researchers performed a PubMed search for articles, recent books, and recommendations from the most relevant clinical practice guidelines and scientific societies regarding the use of TMS as symptomatic treatment in MS. The authors concluded that excitatory electromagnetic pulses applied to the affected cerebral hemisphere allow researchers to optimize functional brain activity, including the transmission of nerve impulses through the demyelinated cortico-spinal pathway. Various studies into TMS have shown statistically significant improvements in spasticity, fatigue, lower urinary tract dysfunction, manual dexterity, gait, and cognitive deficits related to working memory in patients with MS; however, the exact level of evidence has not been defined as the results have not been replicated in a sufficient number of controlled studies. These investigators stated that further well-designed RCTs involving a greater number of subjects are needed to attain a higher level of evidence in order to recommend the appropriate use of TMS in MS patients across the board. They noted that TMS acts as an adjuvant with other symptomatic and immunomodulatory treatments; additional studies should specifically examine the effect of conventional rTMS on fatigue in these patients, something that has yet to see the light of day.

In a review and meta-analysis, Chen and colleagues (2022) examined the effectiveness of rTMS in the treatment of patients with MS. The PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, CBM, CNKI and Wanfang databases were searched for RCTs from their inception through July 10, 2021. RCTs that met the inclusion were included in the study, and RevMan software was used for meta-analysis. Outcome indicators included scores on the fatigue severity scale (FSS), MAS and the H/M amplitude ratio of the Soleus H reflex. When p < 0.05, the difference was considered significant. A total of 10 articles were included in this study, with 8 of them in the quantitative synthesis. The meta-analysis showed that the short-term effect of rTMS treatment for the MAS was better than that of the control treatment (95 % CI: -1.27 to -0.25, p = 0.004); and compared with the control group, the effect of rTMS treatment for the H/M ratio showed a significant effect (95 % CI: -0.12 to -0.03, p = 0.002); while the treatment effect for the FSS was not significant (95 % CI: -4.87 to 1.28, p = 0.25). The authors concluded that since the quality of the evidence was limited by considerable heterogeneity, small sample size, and differences in parameters across these protocols, these findings were inadequate to support the use of rTMS to treat fatigue associated with MS; but do support its use in the management of spasticity in MS patients. These researchers stated that in the future, the maintenance of the positive effect on spasticity and the exact effect on fatigue require more large-scale RCTs with increased follow-up durations to verify.

TMS for Neurodevelopmental Disorders

Masuda and colleagues (2019) stated that neurodevelopmental disorders, including ASD, are common in children and adolescents, but treatment strategies remain limited. Although rTMS has been studied for neurodevelopmental disorders, there is no clear consensus on its therapeutic effects. In a systematic review, these investigators evaluated literature on rTMS for children and adolescents with neurodevelopmental disorders published up to 2018 using the PubMed database. The search identified 264 articles and 14 articles met eligibility criteria; 12 of these studies used conventional rTMS and 2 studies used theta burst stimulation. No severe AEs were reported in these studies. In patients with ASD, LF-rTMS and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors. In patients with attention deficit/hyperactivity disorder (ADHD), LF-rTMS applied to the left dorsolateral prefrontal cortex and HF-rTMS applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity. In patients with tic disorders, LF-rTMS applied to the bilateral supplementary motor area improved tic symptom severity. The authors concluded that the findings of this systematic review suggested that rTMS may be a promising intervention for children and adolescents with neurodevelopmental disorders. These researchers stated that these findings warrant further large RCTs of rTMS in children with neurodevelopmental disorders.

TMS for Substance Use Disorders

Kedzior and colleagues (2018) stated that deep TMS (DTMS) is a non-invasive method of stimulating widespread cortical areas and, presumably, deeper neural networks. In a systematic review, these researchers examined the effects of DTMS in the treatment of substance use disorders (SUD). Electronic literature search (PsycInfo, Medline until April 2017) identified k = 9 studies (k = 4 RCTs, with inactive sham and k = 5 open-label studies). DTMS was most commonly applied using HF/intensity (10 to 20 Hz/100 to 120 % of the resting motor threshold, MT) protocols for 10 to 20 daily sessions in cases with alcohol, nicotine or cocaine use disorders. The outcome measures were craving and dependence (according to standardized scales) or consumption (frequency, abstinence or results of biological assays) at the end of the daily treatment phases and at the last follow-up. Acute and longer-term (6 to 12 months) reductions in alcohol craving were observed after 20 sessions (20-Hz, 120 % MT) relative to baseline in k = 4 open-label studies with co-morbid SUD and MDD. In k = 2 RCTs without MDD, alcohol consumption acutely decreased after 10 to 12 sessions (10 to 20 Hz, 100 to 120 % MT) relative to baseline or to sham. Alcohol craving was reduced only after HF/intensity DTMS (20-Hz, 120 % MT) relative to sham in k = 1 RCT. Nicotine consumption was reduced and abstinence was increased after 13 sessions (10-Hz, 120 % MT) and at the 6-month follow-up relative to sham in k = 1 RCT. Cocaine craving was reduced after 12 sessions (15-Hz, 100 % MT) and at the 2-month follow-up relative to baseline in k = 1 open-label study while consumption was reduced after 12 sessions (10-Hz, 100 % MT) relative to baseline but not to sham in k = 1 RCT. The authors concluded that HF-DTMS may be effective at treating some SUD both acutely and in the longer-term. These researchers stated that large RCTs with inactive sham are needed to determine the efficacy and the optimal stimulation parameters of DTMS for the treatment of SUD.

TMS for Central Neuropathic Pain

In a randomized, double-blinded, sham-controlled, 3-arm parallel study, Galhardoni and colleagues (2019) compared the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) rTMS in patients with central neuropathic pain (CNP) following stroke or SCI. Subjects were randomly allocated into the active PSI-rTMS, ACC-rTMS, sham-PSI-rTMS, or sham-ACC-rTMS arms. Stimulations were carried out for 12 weeks, and a comprehensive clinical and pain assessment, psychophysics, and cortical excitability measurements were performed at baseline and during treatment. The main outcome measure was pain intensity (numeric rating scale [NRS]) after the last stimulation session. A total of 98 patients (age of 55.02 ± 12.13 years) completed the study; NRS score was not significantly different between groups at the end of the study. Active rTMS treatments had no significant effects on pain interference with daily activities, pain dimensions, neuropathic pain symptoms, mood, medication use, cortical excitability measurements, or QoL. Heat pain threshold was significantly increased after treatment in the PSI-dTMS group from baseline (1.58, 95 % CI: 0.09 to 3.06) compared to sham-dTMS (-1.02, 95 % CI: -2.10 to 0.04, p = 0.014), and ACC-dTMS caused a significant decrease in anxiety scores (-2.96, 95 % CI: -4.1 to -1.7) compared to sham-dTMS (-0.78, 95 % CI: -1.9 to 0.3; p = 0.018). The authors concluded that ACC- and PSI-dTMS were not different from sham-dTMS for pain relief in CNP despite a significant anti-nociceptive effect following insular stimulation and anxiolytic effects of ACC-dTMS. These findings showed that the different dimensions of pain can be modulated in humans non-invasively by directly stimulating deeper SNC cortical structures without necessarily affecting clinical pain per se. The main drawbacks of this study were that it was a single-center trial and the subjects varied in their CNP etiologies.

TMS for Concussion

Mollica and colleagues (2021) noted that post-concussive symptoms (PCSs) are common, disabling, and challenging to manage. Evolving models of concussion pathophysiology suggested evidence of brain network dysfunction that may be amenable to neuromodulation; and rTMS has emerged as a potential novel therapeutic option for PCSs. These researchers systematically examined rTMS trials for the treatment of symptoms following concussion/mild TBI (mTBI). They carried out a systematic review of PubMed/Medline, Embase, and PsychINFO databases up to May 19, 2020. Studies were included if they were prospective rTMS treatment studies of patients with mTBI/concussion. Variables including patient demographics, study design, rTMS protocol parameters, primary outcome measures, and efficacy data were extracted and qualitatively synthesized; rTMS methodology and study quality were also evaluated. Of the 342 studies identified, 11 met eligibility criteria and were included for synthesis. A total of 41 of patients were women, and age ranged from 18 to 65 (average age of 38.5 years). Post-concussive depression (7 studies) and headache (4 studies) were the most commonly investigated symptoms. The majority of trials were sham-controlled with RCT designs; however, all were small pilot samples (n less than 30). Methodological heterogeneity and a low number of identified trials precluded quantitative meta-analysis. Regarding rTMS for post-concussive depression, positive results were found in 2 out of 4 studies with depression as a primary outcome, and all 3 studies that evaluated depression as a secondary outcome. All 4 rTMS studies for post-concussive headache reported positive results. The authors concluded that rTMS for the treatment of concussion/mTBI showed promising preliminary results for post-concussive depression and headache, symptoms that otherwise have limited effective therapeutic options. Moreover, these researchers stated that more studies with larger sample sizes are needed to further establish potential efficacy.

TMS for Insomnia

Sun and colleagues (2021) noted that rTMS might be a promising approach in the treatment of insomnia. In a meta-analysis, these researchers examined the safety and efficacy of rTMS for the treatment of insomnia; either as monotherapy or as a complementary strategy. CENTRAL, PubMed, Embase, PsycINFO, CINAHL, PEDro, CBM, CNKI, WanFang, and VIP were searched from earliest record to August 2019; RCTs published in English and Chinese examining effects of rTMS on patients with insomnia were included. Two authors independently completed the article selection, data extraction and rating. Physiotherapy Evidence Database (PEDro) scale was used to examine the methodological quality of the included studies. The RevMan software was used for meta-analysis. The quality of the evidence was examined by the GRADE approach. A total of 36 trials from 28 eligible studies were included, involving a total of 2,357 adult participants (mean age of 48.80 years; 45.33 % men). Compared with sham rTMS, rTMS was associated with improved Pittsburgh sleep quality index (PSQI) total score (SMD -2.31, 95 % CI: -2.95 to -1.66; Z = 7.01, p < 0.00001) and scores of 7 subscales. Compared to other treatment, rTMS as an adjunct to other treatment was associated with improved PSQI total score (SMD -1.44, 95 % CI -2.00 to -0.88; Z = 5.01, p < 0.00001), and may have effects on scores of 7 subscales. Compared with other treatment, rTMS was associated with improved PSQI total score (SMD -0.63, 95 % CI: -1.22 to -0.04; Z = 2.08, p = 0.04), and may have a better score in sleep latency, sleep disturbance and hypnotic using of 7 subscales. In the 3 pair of comparisons, the results for polysomnography (PSG) outcomes were varied. In general, rTMS may improve sleep quality through increasing slow wave and rapid eye movement (REM) sleep. The rTMS group was more prone to headache than the sham or blank control group (relative risk [RR] 1.71, 95 % CI: 1.03 to 2.85; Z = 2.07, p = 0.04). No severe AEs were reported. Reporting biases and low and very-low grade of some evidences should be considered when interpreting the results of this meta-analysis. The authors concluded that these findings indicated that rTMS may be a safe and effective option for insomnia. Moreover, these researchers stated that further international, multi-center, high-quality RCTs with more objective, QOL related and follow-up assessments are needed.

TMS for Peri-Partum Depression

Cox and co-workers (2020) noted that post-partum depression (PPD) is a common and gravely disabling health concern; and rTMS is an FDA-approved treatment for major depression and may be a valuable tool in the treatment of PPD. In an exploratory study, a total of 6 women with PPD received 20 sessions of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) over a 4-week period. Psychiatric rating scales (BDI, EPDS, STATI), cognitive assessments (MMSE, Trails B, List Generation) and breast-feeding practices were surveyed at baseline and post rTMS treatment. BDI and EPDS were obtained weekly, as well as 3 months and 6 months post-study conclusion. Average BDI, EPDS, and STAI scores declined over the 4-week duration of rTMS treatment. Of the 6 patients, 4 achieved remission as evaluated by EPDS and 1 achieved remission and 2 responded as assessed by BDI. Mean BDI and EPDS scores at 3- and 6-month follow-ups remained below levels at study entry. No evidence of cognitive changes or breast-feeding disruptions. The authors concluded that rTMS was safe and well-tolerated among women with evidence of sustained improvements in depression and anxiety scores. This study supported rTMS as a promising non-pharmacologic treatment modality for perinatal depression. This was an exploratory study with small sample size (n = 6) with no sham control arm. Daily administration of rTMS provided potential for confounding of behavioral activation in the otherwise often isolative post-partum period.

Liu and associates (2020) systematically reviewed the safety and efficacy of rTMS for women with PPD. Several databases (WanFang, CNKI, VIP, CBM, PubMed, Embase, Cochrane Library, PsyINFO, Web of Science, and Clinical trial) were searched from inception until April 12, 2020. A total of 10 RCTs met the eligibility criteria and were included in this systematic review. These investigators calculated the combined effect size (SMD and odds ratio [OR]) for the corresponding effects models. The aggregated result of 10 trials indicated a significant benefit of rTMS on PPD, and the aggregated result of remission showed significantly positive effects of Test group VS. In terms of treatment adverse effects, the aggregated result showed no statistical significance of headache and dry mouth between the 2 groups. The results of the meta-analysis suggested that rTMS was a safe and effective intervention for PPD. Moreover, these researchers stated that owing to poor methodological quality among the included studies, high-quality multi-center RCTs are needed to further verify the effects of this treatment.

Lee and colleagues (2021) noted that PPD is a common disorder with very high potential hazards for both the patients and their babies. The typical therapeutic options include anti-depressants and ECT; however, these approaches do not ensure the safety of the fetus. Recently, rTMS has emerged as a promising treatment for neuropathies as well as depression. Nevertheless, many studies excluded pregnant women. In a systematic review and meta-analysis, these researchers examined if rTMS was a suitable therapeutic option for women with PPD. They carried out a systematic review that followed the PRISMA guidelines. These investigators searched for studies in the Medline, PsycINFO, Embase, and Cochrane library databases published until the end of September 2020. A total of 11 studies were selected for the systematic review, and 5 were selected for quantitative synthesis. Data analysis was performed using Comprehensive Meta-Analysis 3 software. The effect size was analyzed using the SMD, and the 95 % CI was determined by the generic inverse variance estimation method. The therapeutic effect size of rTMS for PPD was 1.394 (95 % CI: 0.944 to 1.843), and the sensitivity analysis effect size was 1.074 (95 % CI: 0.689 to 1.459), indicating a significant effect. The side effect size of rTMS for PPD was 0.346 (95 % CI: 0.214 to 0.506), a meaningful result. There were no severe side effects to the mothers or fetuses. The authors concluded that from various perspectives, rTMS could be considered an alternative treatment to treat PPD to avoid exposure of fetuses to drugs and the severe side effects of ECT. Moreover ,these researchers stated that further research is needed to increase confidence in these findings.

The authors stated that this meta-analysis had several drawbacks. The findings showed high heterogeneity, and the reason may be heterogeneity due to methodological diversity because the parameters of rTMS varied from study to study, or heterogeneity due to coincidence because the analysis was conducted with small sample-sized studies. However, because the parameters varied according to the patient’s situation (e.g., the stimulation site changes according to symptoms and the frequency changes according to the stimulation site), it should be judged as clinical heterogeneity. The lack of patients and studies might also constrain these findings; therefore, the effects of rTMS on PPD should be interpreted with caution. They noted that future research should focus on the effects in the prenatal and infancy periods and establish parameters for rTMS, such as the site stimulation or frequency.

Combined Transcranial Magnetic Stimulation and Electroencephalography for Evaluation of Unconscious State

Aria and colleagues (2021) noted that unconscious state has been examined in many studies so far; however, pathophysiology of this state is still unclear. Recently, combined electroencephalography (EEG) and TMS (TMS-EEG) and has been developed to allow for non-invasive evaluation of neurophysiology in the cerebral cortex. These researchers carried out a systematic literature search for TMS-EEG studies on human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including 1 article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. The authors concluded that this review demonstrated that TMS-EEG could represent a promising neuroscientific tool to examine various unconscious states. Moreover, these investigators stated that further TMS-EEG research may help elucidate the neural basis of unconscious state.

Porcaro and associates (2022) stated that when treating patients with a disorder of consciousness (DOC), it is important to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a vegetative state (VS)/UWS from those in a MCS. Upwards of approximately 40 % of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include PET, fMRI, EEG, and TMS. These investigators reviewed the different ways in which these techniques could improve diagnostic differentiation between VS/UWS and MCS patients. They did so by referring to studies that were carried out within the past decade, which were extracted from the PubMed database. A total of 55 studies met selection criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG and TMS- EEG tools) and were included in this review. These researchers noted that by summarizing the promising results achieved in understanding and diagnosing these conditions, they aimed to emphasize the need for more such tools to be incorporated in standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals. The authors stated that the TMS-EEG in a cognitive experiment allows for the observation of event-related potentials that follow cortical stimulation from TMS, known as TMS evoked potentials. Moreover, these researchers stated that despite these promising early results, TMS-EEG is not yet available for clinical purposes. However, further research and developments should be pursued for its eventual implementation in clinical settings.

TMS for the Treatment of Functional Neurological Disorder and Somatic Symptom Disorder (Somatization Disorder)

Oriuwa and colleagues (2022) noted that functional neurological disorder and somatic symptom disorder (somatization disorder) are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. These researchers carried out a systematic review of Medline, Embase and PsycINFO up to March 4, 2021. Trials examining neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric co-morbidity, neurostimulation protocols, clinical outcome measures and results. A total of 404 studies were identified with 12 meeting inclusion criteria. A total of 221 patients were treated in the included studies with mean study sample size of 18 (4 to 70); 5 studies were randomized clinical trials. Functional motor symptoms (6 weakness, 4 movement disorders) were the most studied subpopulations; TMS was the most frequently used device (10 studies), followed by ECT (1 study) and direct-current stimulation (1 study). Treatment protocols varied in intended therapeutic mechanism(s): 8 studies aimed to modulate underlying network dysfunction, 5 aimed to demonstrate movement (1 also leveraged the former) and 3 boosted their primary mechanism with enhanced suggestion/expectation. All but 1 study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. The authors concluded that neuromodulation, especially TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. These researchers stated that larger, sham-controlled studies are needed to further establish effectiveness and better understand therapeutic mechanisms.

Transcranial Magnetic Stimulation / Transcranial Direct Current Stimulation for Dyslexia

Turker and Hartwigsen (2022) stated that non-invasive brain stimulation (NIBS) allows to actively and non-invasively modulate brain function. Aside from inhibiting specific processes, NIBS may also enhance cognitive functions, which might be employed for the prevention and intervention of learning disabilities such as dyslexia. However, despite the growing interest in modulating learning abilities, a comprehensive, up-to-date review synthesizing NIBS studies with dyslexics is missing. These investigators examined the potential of NIBS as a therapeutic option in dyslexia. Searches included the key words “dyslexia” in combination with “transcranial magnetic stimulation”, “transcranial direct current stimulation”, and “non‐invasive brain stimulation”. The findings of the 15 included studies suggested that repeated sessions of reading training combined with different NIBS protocols may induce long-lasting improvements of reading performance in child and adult dyslexics, opening promising avenues for future research. In particular, the "classical" reading areas appeared to be most successfully modulated through NIBS, and facilitatory protocols could improve various reading-related sub-processes. Moreover, these researchers emphasized the need to further examine the potential to modulate auditory cortex function as a pre-intervention and intervention approach for affected children (e.g., to avoid the development of auditory and phonological difficulties at the core of dyslexia). The authors outlined how future studies may increase the understanding of the neurobiological basis of NIBS-induced improvements in dyslexia. Transcranial direct current stimulation was one of the keywords of this systematic review.

Cranial Electrical Stimulation for Anxiety and Insomnia

Shekelle and colleagues (2018) noted that CES is increasingly popular as a treatment, yet its clinical benefit is unclear. These investigators reviewed evidence regarding the benefits and harms of CES for adult patients with chronic painful conditions, anxiety, depression, and insomnia. Data sources included several databases from inception to October 10, 2017 without language restrictions and references from experts, prior reviews, and manufacturers; RCTs of CES versus usual care or sham CES that reported pain, anxiety, depression, or sleep outcomes in any language were selected for analysis. Data extraction entailed single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. A total of 28 articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively; 14 trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results; 4 trials carried out more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES did not cause serious side effects. The authors concluded that evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggested modest benefit in patients with anxiety and depression. The authors stated that the main drawback of this study was that most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding.

Transcranial Direct Current Stimulation for Progressive Supranuclear Palsy

In a double-blinded, sham-controlled, cross-over study, Valero-Cabre and colleagues (2019) examined if tDCS over the dorsolateral prefrontal cortex (DLPFC) could improve language capacities in patients with progressive supranuclear palsy (PSP). These researchers examined the efficiency of tDCS over the DLPFC in a cohort of 12 patients with PSP. In 3 separate sessions, they assessed the ability to boost the left DLPFC via left-anodal (excitatory) and right-cathodal (inhibitory) tDCS, while comparing them to sham tDCS. Tasks evaluating lexical access (letter fluency task) and semantic access (category judgment task) were applied immediately before and after the tDCS sessions to provide a marker of potential language modulation. The comparison with healthy controls showed that patients with PSP were impaired on both tasks at baseline. Contrasting post-stimulation versus pre-stimulation performance across tDCS conditions revealed language improvement in the category judgment task following right-cathodal tDCS, and in the letter fluency task following left-anodal tDCS. A computational finite element model of current distribution corroborated the intended effect of left-anodal and right-cathodal tDCS on the targeted DLPFC. The authors concluded that these findings demonstrated tDCS-driven language improvement in PSP. Level of Evidence = III. This was a proof-of-concept study. Moreover, these researchers stated that double-blinded and sham-controlled trials with multi-day tDCS regimens engaging enduring plasticity phenomena are needed to confirm therapeutically meaningful long-lasting effects in large PSP cohorts, or in other prefrontal pathologies affecting language processing.

In an editorial that accompanied the afore-mentioned study by Valero-Cabre et al (2019), Vanacore and Canevelli (2019) noted that the study was carried out in a sample that was likely poorly representative of real-world populations of patients with PSP. In particular, subjects were excluded if they were taking psychotropic medications, or if they had major depression or cognitive impairment. These “ideal” conditions are hardly transferable to routine clinical practice and would limit the external validity of the findings. The generalizability of the study is also influenced by the marked heterogeneity of language profiles in the different PSP variants. In this regard, a detailed phenotyping of language abilities and disturbances in affected individuals could help to identify the best candidates for specific non-invasive brain stimulation protocols. Moreover, these editorialists noted that the study by Valero-Cabre et al reaffirmed the difficulty to combine, especially in this experimental field, the lenses of statistical significance (i.e., how likely that any apparent between-group difference in outcome is real and not due to chance) and clinical significance (i.e., how large such difference is in clinical practice) when interpreting the study findings. In fact, the clinical meaningfulness of the observed clinical benefits was not measured or discussed in the study and could only be inferred. In other words, was the 33 % average improvement at the adopted letter fluency task clinically evident and relevant besides being statistically significant (and apparently important)? Along the same lines, how could researchers clinically judge the observed average increase of 3.9 points at the category judgment test? These questions assume special relevance considering that language assessment was based on experimental tasks lacking a robust clinical validation. Vanacore and Canevelli were aware that investigators still faced with proof-of-concept (or pre-therapeutic) evidence and that more detailed information on the clinical relevance of these interventions will surely be provided by future studies enrolling large cohorts of patients and investigating longer protocols. Nevertheless, they were convinced that, despite these drawbacks, these exploratory studies will increase interest and lead to additional exciting discoveries.

TMS for the Treatment of Cerebellar Ataxia

In a systematic review and meta-analysis, Wang et al (2023) examined the effectiveness of TMS in improving cerebellar ataxia. PubMed, Embase, the Cochrane Library, Springer, Science Direct, the China National Knowledge Infrastructure (CNKI) and the China Science and Technology Journal Database (VIP) were searched until 2022. Trials with TMS on the effects on cerebellar ataxia were included, and the effect size was evaluated using the SMD or MD and a 95 % CI. A total of 8 studies comprising 272 participants, published between 2014 and 2022, were included. The results revealed that the effect of TMS on patients with cerebellar ataxia as assessed by the International Cooperative Ataxia Rating Scale (ICRAS), the Scale for the Assessment and Rating of Ataxia (SARA), the Berg Balance Scale (BBS), and the Timed Up and Go (TUG) test was statistically significant (p < 0.01) with low heterogeneity among the studies (I2 = 4, 27, 0, and 0 %, respectively). The authors concluded that the effects of TMS in improving cerebellar ataxia in the affected patients were significant. TMS targeting the cerebellar structures could induce changes in the excitability of the cerebellar-thalamus-cortical pathways; therefore, it is necessary to perform large-scale research with good design and high quality in the future.

TMS for the Treatment of Cerebral Palsy

In a systematic review and meta-analysis, Sun et al (2023) examined the quality of the evidence of effectiveness of rTMS in the treatment of motor and language ability of patients with cerebral palsy (CP). Medline, Cochrane library, Web of Science, Embase, PubMed, and CNKI databases were searched up to July 2021 by 2 independent reviewers; RCTs that were published in English and Chinese and met the following criteria were included. The population comprised patients who met the diagnostic criteria for CP. Intervention included the following: comparison about rTMS and sham rTMS or comparison about rTMS combined with other PT. Outcomes included motor function, as follows: gross motor function measure (GMFM), Gesell Development Diagnosis Scale, fine motor function measure (FMFM), Peabody developmental motor scale, and modified Ashworth scale. For language ability, sign-significant relation (S-S) was included. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. A total of 29 studies were included in the meta-analysis. Results of evaluation using the Cochrane Collaborative Network Bias Risk Assessment Scale showed that 19 studies specifically explained randomization, among which 2 studies described allocation concealment, 4 studies blinded participants and had low risk of bias, and 6 studies explained that the assessment of outcome measures was blinded. Significant improvements in motor function were observed. The GMFM of total score was determined by using the random-effect model (I2 = 88 %; MD = -1.03; 95 % CI: -1.35 to -0.71; p < 0.0001) and FMFM was determined by using the fixed-effect model (p = 0.40 and I2 = 3 %; SMDs = -0.48, 95 % CI: -0.65 to -0.30; p < 0.01). For language ability, the language improvement rate was determined using a fixed-effect model (p = 0.88 and I2 = 0 %; MD = 0.37, 95 % CI: 0.23 to 0.57; p < 0.01). According to the PEDro scale, 10 studies had low-quality, 4 studies had excellent quality, and the remaining studies had good quality. Using the GRADEpro GDT online tool, these researchers included a total of 31 outcome indicators, as follows: 22 for low quality, 7 for moderate quality, and 2 for very low quality. The authors concluded that rTMS could improve the motor function and language ability of patients with CP; however, rTMS prescriptions varied, and the studies had low sample sizes. These researchers stated that studies using rigorous and standard research designs about prescriptions and large samples are needed to collect sufficient evidence regarding the effectiveness of using rTMS for the treatment of patients with CP.

TMS for the Treatment of Schizo-Affective Disorder and Psychosis

Lajoie et al (2021) stated that individuals with a psychotic disorder suffer from major cognitive impairments that prevent their functional recovery. Source memory (SM) impairments have been shown to be associated with psychotic symptoms and even to precede their onset; thus, SM has been hypothesized as a cognitive precursor of psychosis. However, few interventions targeting SM are included in current therapeutic approaches for early psychosis. In a systematic review, these investigators examined non-pharmacological interventions for early psychosis that have impacted SM processes. Studies were selected from 9 databases when they included a non-pharmacological intervention involving a sample of patients with early-onset psychotic disorder or sub-clinical psychotic symptoms; and effects on SM processes, measured directly or inferred via an episodic memory task. A total of 13 studies were identified, including 2 cognitive remediation programs and 1 rTMS treatment that reported beneficial effects on SM. The authors concluded that relevant intervention strategies for SM impairments were identified. This review highlighted a need to further develop interventions targeting theoretically defined SM concepts and examine their effects with specific and valid tasks. Recommendations regarding underlying mechanisms that could have a beneficial impact on SM may provide guidance for the future advent of early psychosis interventions.

The authors described a single case study that examined the effect of rTMS on cerebral processes. The rTMS was used in conjunction with functional magnetic resonance imagery (fMRI) guidance in an 11-year-old with severe early-onset psychosis. The stimulation was applied to the temporo-parietal junction (TPJ), a brain structure previously shown to be associated with SM. The right TPJ was stimulated for 5 days followed by stimulation to the left TPJ for 5 additional days. Using 2 specific source monitoring tasks, the authors showed a significant decrease in internal and external source attribution errors following rTMS. In addition, a significant decrease in verbal hallucinations and normalization of neuronal activity level were observed after treatment. These researchers stated that cognitive remediation of episodic memory using retrieval and meta-memory strategies and rTMS to the TPJ showed promising effects on SM functioning and need further investigation in patients with early course of psychosis.

Hua et al (2022) stated that cerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. These researchers carried out an updated systematic review examining the literature on cerebellar stimulation effectiveness and tolerability for mitigating symptoms of schizophrenia. They discussed the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population. Two independent authors identified 20 published studies (7 RCTs, 7 open-label studies, 1 pilot study, 4 case reports, and 1 pre-clinical study) that described the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo. Most studies stimulating the cerebellum used TMS or tDCS, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, these investigators did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appeared tolerable for individuals with schizophrenia, with only mild and temporary side effects. The authors concluded that cerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlighted the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.

Moreover, these researchers stated that it has also been argued that research linking clinical symptoms to neurobiological measures is hampered by research design obstacles, many of which were present across these studies. Notably, larger sample sizes with greater power are needed to establish the reliability of cerebellar stimulation effects. Most studies to-date included fewer than 20 patients with schizophrenia. Alternatively, standardization across sites and studies would allow for the pooling of data. This point is made not only for the stimulation methods/parameters, but also for the assessments, especially cognitive batteries (as there is more consistency in the clinical symptom inventories used). In addition, pre-clinical models of psychosis are needed to test mechanistic hypotheses of cerebellar stimulation. Furthermore, these investigators stated that additional research is needed to understand who will likely benefit from cerebellar stimulation. Many studies recruited individuals who were treatment-resistant or who had at least moderate symptoms; however, it is unclear if these individuals were more likely to benefit from treatment than those with fewer symptoms. Evaluating patients across the psychosis spectrum could aid in elucidating if less symptomatic individuals or those earlier in the illness course could similarly benefit from cerebellar stimulation.

Tang et al (2023) noted that cognitive deficits in visuo-spatial learning (VSL) are highly associated with an increased risk of developing psychosis among individuals with clinical high-risk (CHR) for psychosis. Early interventions targeting VSL enhancement are needed in CHR but remain rudimentary. These investigators examined if personalized TMS over the left parieto-hippocampal network could improve VSL performance in CHR patients and if it could reduce the risk of psychosis conversion within 1 year. A total of 65 CHR patients were randomized to receive active or sham TMS treatments using an accelerated TMS protocol, consisting of 10 sessions of 20-Hz TMS treatments within 2 days. TMS target was defined by individual parieto-hippocampal functional connectivity and precisely localized by individual structural magnetic resonance imaging (MRI). VSL performance was measured using Brief Visuospatial Memory Test-Revised included in measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery (MCCB); 58 CHR patients completed the TMS treatments and MCCB assessments and were included in the data analysis. These researchers observed significant VSL improvements in the active TMS subgroup (Cohen's d = 0.71, p < 0.001) but not in the sham TMS subgroup (Cohen's d = 0.07, p = 0.70). Furthermore, active TMS improved the precision of VSL performance. At a 1-year follow-up, CHR patients who received active TMS showed a lower psychosis conversion rate than those who received sham TMS (6.7 % versus 28.0 %, χ2 = 4.45, p = 0.03). The authors concluded that these findings showed that personalized TMS in the left parieto-hippocampal network may be a promising preventive intervention that improved VSL in CHR patients and reduced the risk of psychosis conversion at follow-up.

Furthermore, an UpToDate review on “Schizophrenia in adults: Maintenance therapy and side effect management” (Stroup and Marder, 2023) does not mention transcranial magnetic stimulation as a management / therapeutic option.

Appendix

Antidepressant medication classes include:

aminoketones (Wellbutrin/SR/XL [bupropion]);
monoamine oxidase inhibitors (MAOIs) (e.g., Marplan, Nardil, Parnate, phenelzine, tranylcypromine);
noradrenaline and specific serotoninergic antidepressants (NASSAs) (e.g., amoxapine, maprotiline, mirtazapine/ODT, Oleptro ER, Remeron/Solutab, trazodone);
selective serotonin reuptake inhibitors (SSRIs) (e.g., Celexa, citalopram, escitalopram, fluoxetine, fluvoxamine, Lexapro, Luvox/CR, paroxetine, Paxil/CR, Pexeva, Prozac/Weekly, sertraline, Zoloft);
serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., Cymbalta, desvenlafaxine/ER, duloxetine, Effexor/XR, Fetzima, Irenka, Khedezla, Pristiq, venlafaxine/ER); and
tricyclic antidepressants (TCAs) (e.g., amitriptyline, desipramine, doxepin, Elavil, imipramine, Norpramin, nortriptyline, Pamelor, Surmontil, Tofranil, trimipramine).

Augmentation therapy is defined as any of the following:

two FDA-approved antidepressants with different mechanisms of action used concomitantly,
an FDA-approved antidepressant and a second-generation antipsychotic used concomitantly that is FDA approved for augmenting depression treatment,
an FDA-approved antidepressant and lithium used concomitantly,
an FDA-approved antidepressant and thyroid hormone T₃ used concomitantly.

Table: Antidepressants
Brand Name	Generic Name	Dose	Frequency
Ascendin	Amoxapine	100-600 mg	1x/day
Anafranil	Clomipramine	100-250 mg	1x/day
Aplenzin	Bupropion HBr	174 mg to 348 mg	1x/day
Auvelity	Dextromethorphan HBr and Bupropion HCl	45 mg/105 mg	2 x a day
Celexa	Citalopram	20-40 mg	1x/day
Cymbalta	Duloxetine	60-120 mg	1x/day
Desyrel	Trazadone	150-400 mg	divided dose
Effexor XR	Venlafaxine	75-225 mg	1x/day
Elavil	Amitriptyline	50-150 mg	1x/day
Emsam	Selegiline	6-9 mg	1x/day
Fetzima	Levomilnacipran	40-120 mg	1x/day
Lexapro	Escitalopram	10-20 mg	1x/day
Ludiomil	Maprotiline	75-225 mg	1x/day
Luvox	Fluvoxamine	50-150 mg	1x/day
Nardil	Phenlyzine	30-90 mg	1x/day
Norpramin	Desipramine	100-300 mg	1x/day
Pamelor	Nortriptyline	50-150 mg	1x/day or therapeutic blood level
Parnate	Tranylcypromine	30-60 mg	1x/day
Paxil CR	Paroxetine CR	25-75 mg	1x/day
Paxil	Paroxetine	20-60 mg	1x/day
Pristiq	Desvenlafaxine	50-150 mg	1x/day
Prozac	Fluoxetine	20-80 mg	1x/day
Remeron	Mirtazapine	30-60 mg	1x/day
Seroquel XR	Quetiapine XR	50 mg- to 300 mg	1x/day
Sinequan	Doxepin	75-150 mg	1x/day
Surmontil	Trimipramine	75-200 mg	1x/day
Symbax	Fluoxetine/Olanzapine	3/25-12/50 mg	1x/day
Trintellix	Vortioxetine	10-20 mg	1x/day
Tofranil	Imipramine	100-300 mg	1x/day
Viibryd	Vilazodone HCl	20-40 mg	1x/day
Vivactil	Protriptyline	15-60 mg	1x/day
Wellbutrin	Buproprion	300-450 mg	3 x a day
Wellbutrin SR	Buproprion	200-400 mg	2 x a day
Wellbutrin XL	Buproprion	150 to 450 mg	1x/day
Zoloft	Sertraline	50-200 mg	1x/day

Table: Augmenting Agents
Brand Name	Generic Name	Dose	Frequency
Abilify	Aripiprazole	2-15 mg	1x/day
Rexulti	Brexpiprazole	0.5-3 mg	1x/day
Seroquel XR	Quetiapine XR	150-300 mg	1x/day
Spravato	Esketamine	54 mg or 84 mg nasal spray	REMS protocol: 2 x a week for 4 weeks then 1 x a week for 4 weeks then as clinically indicated
Vraylar	Cariprazine	1.5-3 mg	1x/day
Zyprexa	Olanzapine	only in combination with fluoxetine within dosage range Olanzapine 6-18 mg and Fluoxetine 25-50 mg	1x/day

Source: Prescribing Information

Note: Trials of medications that have no FDA approval (i.e., drugs that are not approved for use in the United States) do not qualify as adequate trials of antidepressants/augmenting agents.

References

The above policy is based on the following references:

Cranial Electrical Stimulation

Angelakis E, Liouta E, Andreadis N, et al. Transcranial direct current stimulation effects in disorders of consciousness. Arch Phys Med Rehabil. 2014;95(2):283-289.
Benninger DH, Lomarev M, Lopez G, et al. Transcranial direct current stimulation for the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010;81(10):1105-1111.
Boldt I, Eriks-Hoogland I, Brinkhof MW, et al. Non-pharmacological interventions for chronic pain in people with spinal cord injury. Cochrane Database Syst Rev. 2014;11:CD009177.
Bronfort G, Nilsson N, Haas M, et al. Non-invasive physical treatments for chronic/recurrent headache. Cochrane Database Syst Rev. 2004;(3):CD001878.
Cameron M, Lonergan E, Lee H. Transcutaneous electrical nerve stimulation (TENS) for dementia. Cochrane Database Syst Rev. 2003;(3):CD004032.
Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Electrosleep Therapy (30.4). Medicare Coverage Database. Baltimore, MD: CMS; undated.
Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database Syst Rev. 2013b;11:CD009645.
Elsner B1, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving aphasia in patients after stroke. Cochrane Database Syst Rev. 2013a;6:CD009760..
Hordacre B, McCambridge AB, Ridding MC, Bradnam LV. Can transcranial direct current stimulation enhance poststroke motor recovery? Development of a theoretical patient-tailored model. Neurology. 2021;97(4):170-180.
Kavirajan HC, Lueck K, Chuang K. Alternating current cranial electrotherapy stimulation (CES) for depression. Cochrane Database Syst Rev. 2014;7:CD010521.
Kirton A, Ciechanski P, Zewdie E, et al. Transcranial direct current stimulation for children with perinatal stroke and hemiparesis. Neurology. 2017;88(3):259-267.
Klawansky S, Yeung A, Berkey C, et al. Meta-analysis of randomized controlled trials of cranial electrostimulation: Efficacy in treating selected psychological and physiological conditions. J Nervous Mental Dis. 1995;183(7):478-484.
Pickworth WB, Fant RV, Butschky MF, et al. Evaluation of cranial electrostimulation therapy on short-term smoking cessation. Biol Psychiatry. 1997;42(2):116-121.
Plow EB, Obretenova SN, Halko MA, et al. Combining visual rehabilitative training and noninvasive brain stimulation to enhance visual function in patients with hemianopia: A comparative case study. PM R. 2011;3(9):825-835.
Rose KM, Taylor AG, Bourguignon C, et al. Cranial electrical stimulation: Potential use in reducing sleep and mood disturbances in persons with dementia and their family caregivers. Fam Community Health. 2008;31(3):240-246.
Rose KM, Taylor AG, Bourguignon C. Effects of cranial electrical stimulation on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with Alzheimer's disease. Appl Nurs Res. 2009;22(2):119-125.
Shekelle PG, Cook IA, Miake-Lye IM, et al. Benefits and harms of cranial electrical stimulation for chronic painful conditions, depression, anxiety, and insomnia: A systematic review. Ann Intern Med. 2018 168(6):414-421.
Solomon S, Elkind A, Freitag F, et al. Safety and effectiveness of cranial electrotherapy in the treatment of tension headache. Headache. 1989;29(7):445-450.
Solomon S, Guglielmo KM. Treatment of headache by transcutaneous electrical stimulation. Headache. 1985;25(1):12-15.
Thibaut A, Bruno MA, Ledoux D, et al. tDCS in patients with disorders of consciousness: Sham-controlled randomized double-blind study. Neurology. 2014;82(13):1112-1118.
Valero-Cabre A, Sanches C, Godard J, et al. Language boosting by transcranial stimulation in progressive supranuclear palsy. Neurology. 2019;93(6):e537-e547.
Vanacore N, Canevelli M. Transcranial direct current stimulation as a therapeutic opportunity in PSP. Neurology. 2019;93(6):235-236.
Whyte J. Disorders of consciousness: The changing landscape of treatment. Neurology. 2014;82(13):1106-1107.
Winkelmann A, Hauser W, Friedel E, et al; Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. Physiotherapy and physical therapies for fibromyalgia syndrome. Systematic review, meta-analysis and guideline. Schmerz. 2012;26(3):276-286.

Navigated Transcranial Magnetic Stimulation

Chervyakov AV, Bakulin IS, Savitskaya NG, et al. Navigated transcranial magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve. 2015;51(1):125-131.
Forster MT, Senft C, Hattingen E, et al. Motor cortex evaluation by nTMS after surgery of central region tumors: A feasibility study. Acta Neurochir (Wien). 2012;154(8):1351-1359.
Frey D, Strack V, Wiener E, et al. A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values. Neuroimage. 2012;62(3):1600-1609.
Krieg SM, Shiban E, Buchmann N, et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas. J Neurosurg. 2012;116(5):994-1001.
Makela JP, Vitikainen AM, Lioumis P, et al. Functional plasticity of the motor cortical structures demonstrated by navigated TMS in two patients with epilepsy. Brain Stimul. 2013;6(3):286-291.
Picht T, Schmidt S, Brandt S, et al. Preoperative functional mapping for rolandic brain tumor surgery: Comparison of navigated transcranial magnetic stimulation to direct cortical stimulation. Neurosurgery. 2011;69(3):581-588.
Picht T, Schulz J, Hanna M, et al. Assessment of the influence of navigated transcranial magnetic stimulation on surgical planning for tumors in or near the motor cortex. Neurosurgery. 2012;70(5):1248-1256.
Raffa G, Scibilia A, Conti A, et al. The role of navigated transcranial magnetic stimulation for surgery of motor-eloquent brain tumors: A systematic review and meta-analysis. Clin Neurol Neurosurg. 2019;180:7-17.
Sollmann N, Fratini A, Zhang H, et al. Associations between clinical outcome and tractography based on navigated transcranial magnetic stimulation in patients with language-eloquent brain lesions. J Neurosurg. 2019;132(4):1033-1042.
Tarapore PE, Tate MC, Findlay AM, et al. Preoperative multimodal motor mapping: A comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation. J Neurosurg. 2012;117(2):354-362.