Motor Cortex Stimulation

Number: 0755

Table Of Contents

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

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses motor cortex stimulation.

Experimental and Investigational

Aetna considers the following the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

1. Motor cortex stimulation for the treatment of the following indications (not an all-inclusive list) because its effectiveness has not been established:
   1. Amyotrophic lateral sclerosis;
   2. Autism spectrum disorder;
   3. Cerebral palsy;
   4. Chronic refractory pain (e.g., central pain syndromes, complex regional pain syndrome, neuropathic orofacial pain syndromes, peripheral neuropathic pain, phantom limb pain, thalamic pain, and trigeminal neuropathic pain);
   5. Dysphagia;
   6. Dystonia secondary to a focal basal ganglia lesion;
   7. Movement disorders;
   8. Muscle re-innervation;
   9. Nerve regeneration;
   10. Obsessive compulsive disorder;
   11. Parkinson's disease;
   12. Post-stroke aphasia;
   13. Post-stroke hemiparesis;
   14. Traumatic brain injury.
2. The use of motor cortex stimulation during implantation of a deep brain stimulator. 

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes not covered for indications listed in the CPB:
61850	Twist drill or burr hole(s) for implantation of neurostimulator electrodes, cortical
61860	Craniectomy or craniotomy for implantation of neurostimulator electrodes, cerebral, cortical
61885	Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
61886	with connection to two or more electrode arrays
64568	Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator
95961	Functional cortical and subcortical mapping by stimulation and/or recording of electrodes on brain surface, or of depth electrodes, to provoke seizures or identify vital brain structures; initial hour of physician attendance
+ 95962	each additional hour of physician attendance (List separately in addition to code for primary procedure)
95970	Electronic analysis of implanted neurostimulator pulse generator system (e.g., rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (i.e., cranial nerve, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming
Other CPT codes related to the CPB:
+61781	Stereotactic computer-assisted (navigational) procedure; cranial, intradural (list separately in addition to code for primary procedure)
+61782	cranial, extradural (list separately in addition to code for primary procedure)
61863	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
+61864	each additional array (List separately in addition to primary procedure)
61867	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
+61868	each additional array (List separately in addition to primary procedure)
61880	Revision or removal of intracranial neurostimulator electrodes
61888	Revision or removal of cranial neurostimulator pulse generator or receiver
70551 - 70553	Magnetic resonance (e.g., proton) imaging, brain (including brain stem)
70554 - 70555	Magnetic resonance imaging, brain, functional MRI
95927	Short-latency somatosensory evoked potential study, stimulation of any/all peripheral nerves or skin sites, recording from the central nervous system; in the trunk or head
95965 - 95967	Magnetoencephalography (MEG), recording and analysis
96020	Neurofunctional testing selection and administration during noninvasive imaging functional brain mapping, with test administered entirely by a physician or psychologist, with review of test results and report
HCPCS codes not covered for indications listed in the CPB:
C1767	Generator, neurostimulator (implantable), nonrechargeable
C1778	Lead, neurostimulator (implantable)
C1787	Patient programmer, neurostimulator
C1816	Receiver and/or transmitter, neurostimulator (implantable)
C1820	Generator, neurostimulator (implantable), non high-frequency with rechargeable battery and charging system
C1883	Adaptor/extension, pacing lead or neurostimulator lead (implantable)
C1897	Lead, neurostimulator test kit (implantable)
E0745	Neuromuscular stimulator, electronic shock unit
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
L8695	External recharging system for battery (external) for use with implantable neurostimulator
Other HCPCS codes related to the CPB:
C1770	Imaging coil, magnetic resonance (insertable)
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
F42.2 - F42.9	Obsessive-compulsive disorder
F51.8	Other sleep disorders not due to a substance or known physiological condition
F84.0	Autistic disorder
F98.4	Stereotyped movement disorders
G10	Huntington's disease
G12.21	Amyotrophic lateral sclerosis
G20, G21.0 - G21.9	Parkinson's disease and secondary parkinsonism
G23.0 - G23.9	Other degenerative diseases of basal ganglia
G24.01 - G24.9	Dystonia
G25.0 - G26	Extrapyramidal and movement disorders
G47.61	Periodic limb movement disorder
G47.69	Other sleep related movement disorders
G50.0	Trigeminal neuralgia
G50.1	Atypical facial pain [chronic neuropathic orofacial pain syndrome]
G54.6 - G54.7	Phantom limb syndrome
G60.0 - G60.9	Hereditary and idiopathic neuropathy
G80.0 - G80.9	Cerebral palsy
G89.0	Central pain syndrome
G89.21 - G89.29	Chronic pain, not elsewhere classified
G89.3	Neoplasm related pain (acute) (chronic)
G89.4	Chronic pain syndrome
G90.3	Multi-system degeneration of the autonomic nervous system
G90.50 - G90.59	Complex regional pain syndrome I (CRPS I)
I69.051 - I69.059, I69.151 - I69.159 I69.251 - I69.259, I69.351 - I69.359 I69.851 - I69.859, I69.951 - I69.959	Hemiplegia and hemiparesis, sequelae of cerebrovascular disease
I69.320	Aphasia following cerebral infarction
R13.0, R13.10	Aphagia and unspecified dysphagia
R25.0 - R25.9	Abnormal involuntary movements
S06.0X0A - S06.A1XS	Intracranial injury

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Background

While MCS has been employed in the treatment of a variety of chronic refractory pain conditions, there is only limited evidence regarding its effectiveness.  Available evidence is largely derived from small, uncontrolled, case studies.

Ebel et al (1996) reported the results of MCS in treating severe trigeminal neuropathic pain (TNP) (n = 7).  In all but one case the impulse-generator was implanted after a successful period of test stimulation.  "Successful" means a pain reduction of more than 50 % as assessed with a visual analog scale (VAS).  Excluding one case, in which a prolonged focal seizure resulting in a post-ictal speech arrest occurred during test stimulation, there have been no operative complications and the post-operative course was uneventful.  In all the other patients the pain inhibition appeared below the threshold for producing motor effects.  Initially these patients reported a good-to-excellent pain relief.  In 3 of 6 patients a good-to-excellent pain control was maintained for a follow-up period of 5 months to 2 years.  In the remaining 3 patients the positive effect decreased over several months.

Nguyen et al (2000) studied the use of MCS in the treatment of central pain (n = 32).  The mean follow-up was 27.3 months.  Ten of the 13 patients (77 %) with central pain and 10 of the 12 patients (83.3 %) with neuropathic facial pain experienced substantial pain relief.  One of the 3 patients with post-paraplegia pain was clearly improved.  A satisfactory result was obtained in 1 patient with pain related to plexus avulsion and in 1 patient with pain related to intercostal herpes zoster.  None of the patients developed epileptic seizures.  The authors concluded that chronic MCS is an effective method in treating certain forms of refractory pain.

Mogilner and Rezai (2001) noted that chronic epidural MCS has been shown to have promise in the treatment of patients with refractory deafferentation pain.  A total of 5 patients underwent MCS in which functional imaging guidance was used.  Prior to surgery, patients underwent MRI with skin fiducial markers placed on standard anatomical reference prints, followed by magneto-encephalography mapping of the sensory and motor cortices.  In 2 patients, functional MRI was also performed using a motor task paradigm.  The functional imaging data were integrated into a frameless stereotactic database by using a 3-dimensional co-registration algorithm.  Subsequently, a frameless stereotactic craniotomy was performed using the integrated anatomical and functional imaging data for surgical planning.  Intra-operative somato-sensory evoked potentials (SSEPs) and direct stimulation were used to confirm the target and final placement of the electrode.  Direct stimulation and SSEPs performed intra-operatively confirmed the accuracy of the functional imaging data.  Trial periods of stimulation successfully reduced pain in 3 of the 5 patients who then underwent permanent internal placement of the system.  At a mean 6-month follow-up, these patients reported an average reduction in pain of 55 % on a VAS.

Devulder and colleagues (2002) noted that amitriptyline and sodium channel blockers are the drugs of first-choice for the treatment of central pain.  If oral or transdermal drug delivery is not indicated or ineffective, the intra-thecal administration route can be attempted with baclofen, clonidine, opioids and midazolam.  Invasive electro-stimulation is the last treatment option.  Thalamic stimulation can be tried in spinal cord injuries, and MCS is sometimes the last resort.  Rainov and Heidecke (2003) reported long-term follow-up of 2 patients with unilateral facial neuropathic pain due to idiopathic trigeminal neuropathy and surgical trauma to the glosso-pharyngeal nerve, respectively.  These patients failed other modalities for pain relief.  Electrical stimulation of the motor cortex with a quadripolar electrode contralateral to the painful area of the face was tried and resulted in immediate analgesia with more than 50 % pain reduction.  During a follow-up period of 72 months, a sufficient (greater than 50 %) and stable analgesic effect of MCS was observed.

Henderson et al (2004) stated that MCS may serve as an adjunct in managing neuropathic pain after other conservative and interventional methods have failed.  However, the magnitude and duration of the benefit are highly variable, with a significant percentage of patients losing pain relief over time.  These researchers examined if intensive re-programming could re-capture the beneficial effects of MCS (n = 6).  Patients' average age was 50 years (range of 26 to 71).  The diagnoses were TNP (n = 2), complex regional pain syndrome (CRPS) I (n = 2), phantom limb pain (n = 1) and PSP (n = 1).  The mean duration of pain was 6 years.  The MCS benefit had initially lasted for a mean of 7.16 months (range of 2 to 18 months).  After re-programming, 5 of 6 patients experienced improvement in pain.  Average VAS scores decreased from 7.44 to 2.28 (p < 0.001) in those patients who responded to re-programming.  Three patients experienced seizures during re-programming.  No patient experienced seizures at their therapeutic settings.  Pain control was maintained after discharge.  These resesrchers found that intensive re-programming can re-capture the benefit of MCS in patients who have lost pain control.

Tirakotai et al (2004) noted that MCS is an alternative treatment for central pain syndromes.  A total of 5 patients suffering from central pain underwent MCS with the guidance of a frameless stereotactic system.  The neuro-navigation was used for identification of the pre-central gyrus and accurate planning of the single burr hole.  The exact location was re-confirmed by an intra-operative stimulation test.  Post-operative clinical and neuro-radiological evaluations were performed in each patient.  The navigation system worked properly in all 5 cases.  Determination of the placement of stimulating electrode was possible in every case.  All patients obtained post-operative pain relief.  No surgical complication occurred, and the post-operative course was uneventful in all patients. 

In a prospective study (n = 10), Brown and Pilitsis (2005) used the McGill Pain Questionnaire, VAS, and an inventory of drug consumption to review the results of treating patients with TNP by means of MCS.  Implantation of electrodes was performed via intra-operative neuro-navigation and cortical mapping for stimulation site targeting.  Nine patients had TNP from post-herpetic neuralgia, surgical injury, or unknown cause, and 1 patient had pain of central origin.  Patients were evaluated with multi-modality scales before, immediately after, and at designated intervals after surgery.  Eight patients underwent permanent implantation after a trial evaluation.  In 2 patients, the stimulating electrodes were removed after an unsuccessful trial: 1 had a lateral medullary infarct leading to central pain, and in the other patient, there was no explanation for the pain.  The average duration of pain before surgery was 6 years.  Post-operatively, there was an 88 % rate of immediate pain relief (greater than 50 % on VAS score) and a 75 % rate of pain relief at mean follow-up of 10 months (range of 3 to 24 months).  Mean pre-operative McGill Pain Questionnaire total pain rating index was 57 (higher than that observed in causalgia) for patients who did not undergo implantation and 53 for those who underwent implantation.  Mean McGill Pain Questionnaire pain rating index at mean follow-up of 10 months was 24 (55 % decrease).  Mean VAS score pre-operatively was 9 in patients with stimulator implants and 8 in those whose stimulator was removed after the trial.  Immediate post-operative mean VAS score was 1.  This score stabilized 3 months after surgery.  Patients with implanted stimulators reduced their pain medication dose by a mean of more than 50 %.  Three patients with facial weakness and sensory loss regained both strength and discriminative sensation during stimulation.  In another patient, dysarthria improved.  In a review of the literature, 29 (76 %) of 38 patients with neuropathic facial pain treated with MCS achieved greater than 50 % pain relief.  The authors concluded that these results provided support for the use of MCS in facial neuropathic pain and document pain improvement as measured by multi-dimensional scales.

Rasche et al (2006) analyzed retrospectively 17 patients with chronic neuropathic pain who were treated with contralateral epidural stimulation electrodes; TNP was diagnosed in 10 cases and PSP in 7 cases.  The placement of the electrodes was performed in local anesthesia using neuro-navigation and intra-operative neuro-monitoring.  A test trial of minimum 1 week including double-blind testing was conducted and pain intensity was measured using a VAS.  Correct placement of the electrode was achieved in all patients using intra-operative neurophysiological monitoring.  Double-blind testing was able to identify 6 (35%) non-responders.  In 5 of 10 (50 %) with TNP and 3 of 7 (43%) with PSP, a positive effect with pain reduction greater than or equal to  50% was observed.  The mean follow-up period was 3.6 years (range of 1 to 10 years) and included 1 patient with 10 years of positive stimulation effect.  The authors concluded that MCS is a treatment option for patients with chronic neuropathic pain localized in the face or upper extremity. 

In a review on neuro-stimulation for chronic non-cancer pain, Coffey and Lozano (2006) noted that neurostimulation to treat chronic pain includes approved and investigational therapies directed at the spinal cord, thalamus, peri-aqueductal or peri-ventricular gray matter, motor cortex, as well as peripheral nerves.  Persistent pain following surgery and work-related or neural injuries are common indications for such treatments.  In light of the risks, efforts, costs, and expectations associated with neuro-stimulating therapies, a careful re-examination of the methods used to gather evidence for this treatment’s long-term effectiveness is in order.  The authors concluded that future analyses of emerging neuro-stimulating modalities for pain should require unambiguous diagnoses as an entry criterion and should involve the use of randomization, parallel control groups that receive sham stimulation, as well as blinding of patients, investigators, and device programmers.  Given the chronicity of patient symptoms and stimulation therapies, effectiveness should be studied for 1 year or longer following implantation of the device.  Meticulous methods are especially important to evaluate new therapies such as MCS.  Henderson and Lad (2006) noted that MCS is a relatively new technique that has shown some promise in the treatment of TNP.  This technique has the potential to revolutionize the treatment of chronic pain.  The authors stated that it is important to evaluate MCS critically in a prospective, controlled fashion.

Cheshire (2007) noted that MCS, although having shown initial promise for TNP, seemed to be ineffective for classical TN.  Lazorthes et al (2007) reported that the results of MCS on phantom limb pain are promising; and the conclusions of ongoing multi-center randomized clinical trials (RCTs) will be very useful and are likely to promote further research and clinical applications in this field.  Cioni and Meglio (2007) stated that the indications for MCS included TNP and other types of central/peripheral deafferentation pain.  The results reported in the literature were quite good; the mean long-term success rate was 80 % in facial pain and 53 % in non-facial pain.  However, results from these researchers were less impressive; 4 of 14 (28 %) patients with chronic non-malignant pain experienced a greater than 40 % pain relief, but in 2 of them the effect faded with time.  These investigators stated that it is time for a large, multi-center, prospective, randomized, double-blind study evaluating not only the effect of MCS on pain, but also the optimal electrode placement and stimulation parameters.

Available guidelines indicate that RCTs are needed to ascertain the effectivness of MCS in the treatment of chronic pain.  The Reflex Sympathetic Dystrophy Syndrome Association's treatment guidelines on CRPS (2006) listed MCS as an experimental procedure in the treatment algorithm of this condition.  Furthermore, the guideline on assessment and management of chronic pain by the Institute for Clinical Systems Improvement (2007) stated that neurosurgical techniques for chronic pain resistant to an adequate conservative approach hold promise, but have limited scientific evidence.  These invasive approaches include ablative techniques such as cingulotomy and mesencephalotomy, as well as stimulation techniques such as deep brain stimulation and MCS.  In addition, the European Federation of Neurological Societies' guidelines on neurostimulation therapy for neuropathic pain (Cruccu et al, 2007) stated that there is level C evidence (possibly effective, ineffective, or harmful) that MCS is useful in 50 to 60 % of patients with central PSP as well as central or peripheral facial neuropathic pain, with small risk of medical complications.  The evidence about any other condition remains insufficient.  The authors stated that further controlled trials are needed for spinal cord stimulation in conditions other than failed back surgery syndrome and CRPS; and for MCS and deep brain stimulation in general.  An assessment by the Institute for Clinical Effectiveness and Health Policy (Pichon-Riviere et al, 2007) concluded that MCS for central and neuropathic pain is an investigational technique.

More recently, MCS is also being studied for the treatment of other diseases.  Several studies have specifically examined the use of MCS in treating Parkinson's disease (Cioni et al, 2007).  Arle and Shils (2008) performed a literature search between 1991 and 2007 and found 512 cases using MCS.  Although most of these addressed the treatment of pain (n = 422), 84 of them involved movement disorders.  Moreover, Priori and Lefaucheur (2007) noted that the therapeutic effects of MCS in the treatment of movement disorders still need to be assessed in controlled studies.  Arle and colleagues (2008) stated that although there have been some positive findings using MCS for Parkinson's disease, a larger study may be needed to better determine if it should be pursued as an alternative surgical treatment to deep brain stimulation.

Lima and Fregni (2008) conduct a systematic review and meta-analysis to quantify the efficacy of invasive and non-invasive MCS for the treatment of chronic pain.  Medline and other databases were searched as data sources.  Reference lists and conference abstracts were examined for further relevant articles.  A total of 11 studies using non-invasive brain stimulation and 22 studies using invasive brain stimulation met the inclusion criteria.  The results showed that weighted responder rate was 72.6 % (95 % confidence interval [CI]: 67.7 to 77.4) for the invasive stimulation studies and 45.3 % (95 % CI: 39.2 to 51.4) for the non-invasive stimulation studies.  This difference was significant.  For the non-invasive stimulation studies, the random effects model revealed that the number of responders in the active group was significantly higher as compared with sham stimulation group (risk ratio of 2.64) (95 % CI: 1.63 to 4.30).  The authors concluded that this meta-analysis shows that two different techniques of brain stimulation of motor cortex -- invasive and non-invasive -- can exert a significant effect on pain in patients with chronic pain.  They discussed potential reasons that invasive brain stimulation showed a larger effect in this meta-analysis; these findings encourage continuation of research in this area and highlight the need for well-designed clinical trials to define the role of brain stimulation in pain management.  These investigators stated that future studies should address several questions (e.g., the duration of the effects, parameters of stimulation, and the use of medications).  More importantly, sham-controlled trials on invasive brain stimulation for pain treatment should be carried out.  This is in agreement with the observations of Fontaine et al (2009) who stated that studies with a better design are mandatory to confirm the effectiveness of MCS for the treatment of chronic neuropathic pain.

Lefaucheur et al (2009) presented the results of the first RCT using chronic MCS for the treatment of refractory peripheral neuropathic pain.  A total of 16 patients were included with pain origin as follows: trigeminal neuralgia (n = 4), brachial plexus lesion (n = 4), neurofibromatosis type-1 (n = 3), upper limb amputation (n = 2), herpes zoster ophthalmicus (n = 1), atypical orofacial pain secondary to dental extraction (n = 1) and traumatic nerve trunk transection in a lower limb (n = 1).  A quadripolar lead was implanted, under radiological and electrophysiological guidance, for epidural cortical stimulation.  A randomized cross-over trial was performed between 1 and 3 months post-operative, during which the stimulator was alternatively switched "on" and "off" for 1 month, followed by an open phase during which the stimulator was switched "on" in all patients.  Clinical assessment was performed up to 1 year after implantation and was based on the following evaluations: VAS, brief pain inventory, McGill Pain questionnaire, sickness impact profile and medication quantification scale.  The cross-over trial included 13 patients and showed a reduction of the McGill Pain questionnaire-pain rating index (p = 0.0166, Wilcoxon test) and McGill Pain questionnaire sensory subscore (p = 0.01) when the stimulator was switched "on" compared to the "off-stimulation" condition.  However, these differences did not persist after adjustment for multiple comparisons.  In the 12 patients who completed the open study, the VAS and sickness impact profile scores varied significantly in the follow-up and were reduced at 9 to 12 months post-operative, compared to the pre-operative baseline.  At final examination, the mean rate of pain relief on VAS scores was 48 % (individual results ranging from 0 % to 95 %) and MCS efficacy was considered as good or satisfactory in 60 % of the patients.  Pain relief after 1 year tended to correlate with pain scores at 1 month post-operative, but not with age, pain duration or location, pre-operative pain scores or sensory-motor status.  Although the results of the cross-over trial were slightly negative, which may have been due to carry-over effects from the operative and immediate post-operative phases, observations made during the open trial were in favor of a real efficacy of MCS in peripheral neuropathic pain.  Analgesic effects were obtained on the sensory-discriminative rather than on the affective aspect of pain.  The authors concluded that these findings suggested that the indication of MCS might be extended to various types of refractory, chronic peripheral pain beyond TNP.  The resutls of this small study needs to be validated by well-designed studies.

Anderson et al (2009) reported on a patient with a neuropathic facial pain syndrome, including elements of trigeminal neuralgia, glossopharyngeal neuralgia, and dysphagia.  After failing medical and surgical decompressive treatments, the patient underwent implantation of a MCS system. The patient was a 54-year old woman who had a 14-year history of left-sided facial pain, throat pain, and associated nausea and vomiting.  She failed several open surgical and percutaneous procedures for her facial pain syndrome.  Additionally, several medication trial attempts were unsuccessful.  Imaging studies were normal.  The patient underwent placement of a right-sided MCS system for treatment of her neuropathic facial pain syndrome.  The procedure was well-tolerated, and the trial stimulator provided promising results.  The permanent MCS generator needed to be re-programmed at the time of the 5-week follow-up visit to optimize symptom relief.  The patient demonstrated dramatic improvements in her neuropathic facial and oral pain, including improvements in swallowing toleration, after the 5-week follow-up examination with sub-threshold MCS.  A decline in treatment efficacy also occurred 2 years after implantation due to generator depletion.  Symptom improvement returned with stimulation after the generator was replaced.  The authors concluded that a novel implantable MCS system was used to treat this patient's neuropathic facial pain.  Durable improvements were noted not only in her facial pain, but also in swallowing toleration.  The ultimate role of MCS in the treatment of pain conditions is still not well-defined but might play a part in refractory cases and, as in this case, might improve other functional issues, including dysphagia.

In a double-blind, placebo-controlled trial, Di Lazzaro and colleagues (2009) tested the hypothesis that repetitive transcranial magnetic stimulation given as continuous theta burst stimulation (cTBS), repeated monthly for 1 year, would affect amyotrophic lateral sclerosis (ALS) progression.  A total of 20 patients with ALS were randomly allocated to blinded real or placebo stimulation.  Continuous theta burst stimulation of the motor cortex was performed for 5 consecutive days every month for 1 year.  Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R).  Treatment was well-tolerated.  There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation.  ALSFRS-R mean scores declined from 32.0 (standard deviation [SD] 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation.  Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease.

Central pain syndrome is a neurological condition caused by damage to or dysfunction of the central nervous system (CNS), which includes the brain, brainstem, and spinal cord.  This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or Parkinson's disease.

Moreno-Duarte et al (2014) reviewed initial efficacy, safety and potential predictors of response by assessing the effects of neural stimulation techniques to treat spinal cord injury (SCI) pain.  A literature search was performed using the PubMed database including studies using the following targeted stimulation strategies: transcranial direct current stimulation (tDCS), high-definition tDCS (HD-tDCS), repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcutaneous electrical nerve stimulation (TENS), spinal cord stimulation (SCS) and MCS, published prior to June of 2012.  These researchers included studies from 1998 to 2012.  A total of 8 clinical trials and 1 naturalistic observational study (9 studies in total) 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, these researchers found an important variability in these results across studies.  The authors concluded that there is a clear need for the development of methods to decrease treatment variability and increase response to neural stimulation for pain treatment. 

Moore et al (2014) noted that chronic neuropathic pain affects 8.2 % of adults, extrapolated to roughly 18 million people every year in the United States.  Patients who have pain that cannot be controlled with pharmacologic management or less invasive techniques can be considered for deep brain stimulation or MCS.  These techniques are not currently approved by the Food and Drug Administration for chronic pain and are, thus, considered off-label use of medical devices for this patient population.  The authors stated that conclusive effectiveness studies are still needed to demonstrate the best targets as well as the reliability of the results with these approaches.

In a double-blind, cross-over, multi-center, pilot study, Rieu et al (2014) evaluated the effectiveness of epidural MCS on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion.  A total of 5 patients with dystonia secondary to a focal BG lesion were included in this study.  Two quadri-polar leads were implanted epidurally over the M1 and the premotor cortex, contralateral to the most dystonic side.  The leads were placed parallel to the central sulcus.  Only the posterior lead over M1 was activated in this study.  The most lateral or medial contact of the lead (depending on whether the dystonia predominated in the upper or lower limb) was selected as the anode, and the other 3 as cathodes.  One month post-operatively, patients were randomly assigned to on- or off-stimulation for 3 months each, with a 1-month washout between the 2 conditions.  Voltage, frequency, and pulse width were fixed at 3.8 V, 40 Hz, and 60 μs, respectively.  Evaluations of dystonia (Burke-Fahn-Marsden Scale), spasticity (Ashworth score), pain intensity (VAS), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation.  Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS.  The authors concluded that bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion.

Slotty et al (2015) reported a retrospective long-term analysis of patients neuropathic pain treated with MCS over a median follow-up of 39.1 months. A total of 23 closely followed patients treated with MCS were retrospectively analyzed. Reduction in pain measured on a VAS was defined as the primary outcome parameter; VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. The mean VAS under best medical treatment was 7.8 (SD 1.2, range of 5 to 9) with escalation to 9.3 (SD 0.9, range of 6 to 10) when the patients' medications were missed or delayed. About 50 % of the patients experienced a satisfactory (greater than 50 %) reduction in pain during the first month of treatment. The best treatment results were seen at the 3-month follow-up (mean VAS of 4.8, SD 1.9, -37.2 % compared to baseline). A decline in the treatment effect was generally observed at the subsequent follow-up assessments; 6 patients had their devices explanted during the follow-up period due to loss of treatment effect. The authors concluded that MCS failed to provide long-term pain control for neuropathic pain. They noted that many aspects of MCS still remain unclear; and means must be developed to overcome the problems in this promising technique.

Ngernyam et al (2015) examined the effects of tDCS in patients with neuropathic pain from SCI. This study tested the hypothesis that pain reduction with tDCS is associated with an increase in the peak frequency spectrum density in the theta-alpha range. A total of 20 patients with SCI and bilateral neuropathic pain received single sessions of both sham and anodal tDCS (2 mA) over the left primary motor area (M1) for 20 minutes. Treatment order was randomly assigned. Pre- to post-procedure changes in pain intensity and peak frequency of electroencephalogram (EEG) spectral analysis were compared between treatment conditions. The active treatment condition (anodal tDCS over M1) but not sham treatment resulted in significant decreases in pain intensity. In addition, consistent with the study hypothesis, peak theta-alpha frequency (PTAF) assessed from an electrode placed over the site of stimulation increased more from pre- to post-session among participants in the active tDCS condition, relative to those in the sham tDCS condition. Moreover, these researchers found a significant association between a decrease in pain intensity and an increase in PTAF at the stimulation site. The authors concluded that these findings were consistent with the possibility that anodal tDCS over the left M1 may be effective, at least in part, because it results in an increase in M1 cortical excitability, perhaps due to a pain inhibitory effect of MCS that may influence the descending pain modulation system. They stated that future research is needed to determine if there is a causal association between increased left anterior activity and pain reduction.

Zanjani et al (2015) examined the effects of rTMS targeting the primary motor cortex (M1) in the treatment of motor signs in PD. Studies meeting inclusion criteria were analyzed using meta-analytic techniques and the Unified Parkinson's Disease Rating Scale (UPDRS) sections II and III were used as outcome measures. In order to determine the treatment effects of rTMS, the UPDRS II and III scores obtained at baseline, same day, to 1 day post-rTMS treatment (short-term follow-up) and 1-month post-stimulation (long-term follow-up) were compared between the active and sham rTMS groups. Additionally, the placebo effect was evaluated as the changes in UPDRS III scores in the sham rTMS groups. A placebo effect was not demonstrated, because sham rTMS did not improve motor signs as measured by UPDRS III. Compared with sham rTMS, active rTMS targeting the M1 significantly improved UPDRS III scores at the short-term follow-up (Cohen's d of 0.27, UPDRS III score improvement of 3.8 points). When the long-term follow-up UPDRS III scores were compared with baseline scores, the standardized effect size between active and sham rTMS did not reach significance. However, this translated into a significant non-standardized 6.3-point improvement on the UPDRS III. No significant improvement in the UPDRS II was found.  The authors concluded that rTMS over the M1 may improve motor signs; and further studies are needed to provide a definite conclusion.

Obsessive-Compulsive Disorder

Saba and colleagues (2015) stated that rTMS and tDCS are non-invasive brain stimulation methods that became widely used as therapeutic tools during the past 20 years especially in cases of depression and schizophrenia. Low frequency rTMS and cathodal effect of tDCS inhibits cortical functioning while high frequency and anodal effect of tDCS have the opposite effect. Prolonged and repetitive application of either methods leads to changes in excitability of the human cortex that outlast the period of stimulation. Both rTMS and tDCS induce functional changes in the brain-modulating neural activity at cortical level. These investigators reviewed rTMS and tDCS effects in clinical trials for obsessive-compulsive disorder (OCD). Low frequency rTMS, particularly targeting the supplementary motor area and the orbital frontal cortex, seems to be the most promising in terms of therapeutic efficacy while older studies targeting the prefrontal dorsal cortex were not as successful. The authors concluded that tDCS clearly needs to be investigated in large scale and sufficiently powered RCTs. They stated that from a general point of view, these non-invasive techniques hold promise as novel therapeutic tools for OCD patients.

Wang et al (2023) noted that in OCD, glutamatergic neurotransmission dysfunction plays key roles in pathophysiology.  These researchers examined changes of neuro-metabolites in the bilateral striatum of OCD patients receiving low-frequency rTMS using 1H proton magnetic resonance spectroscopy (1H-MRS).  A total of 52 OCD patients were divided into rTMS treatment group (n = 29) and the control group (medication only) (n = 22).  The levels of neuro-metabolites in the bilateral striatum of patients with OCD were measured using MRS before and after treatment.  All participants were taking medication before the treatment and the process.  Following rTMS treatment, Yale-Brown Obsessive-Compulsive Scale (YBOCS) score was significantly decreased in the rTMS group compared with the control group.  Glutamate (Glu) and glutamate and glutamine complexes (Glx) in the bilateral striatum of the rTMS treatment response group increased significantly with the improvement of OCD.  Glu in the bilateral striatum and Glx in the right striatum were positively correlated with compulsion following the treatment.  The authors concluded that the physio-pathological mechanism of OCD may be related to the glutamatergic dysfunction, and the low-frequency rTMS applied to the supplementary motor area could improve OCD symptoms by modulating glutamatergic levels in the bilateral striatum of patients with OCD.  These findings need to be validated by well-designed studies.

Complex Regional Pain Syndrome

Lopez and colleagues (2016) described a case of a 30-year old woman who suffered a traumatic injury of the right brachial plexus, developing severe complex regional pain syndrome type II (CRPS-II). After clinical treatment failure, SCS was indicated with initial positive pain control.  However, after 2 years her pain progressively returned to almost baseline intensity before SCS.  Additional motor cortex electrode implant was then proposed as a rescue therapy and connected to the same pulse generator.  This method allowed simultaneous MCS and SCS in cycling mode with independent stimulation parameters in each site.  At 2 years follow-up, the patient reported sustained improvement in pain with dual stimulation, reduction of painful crises, and improvement in quality of life.  The authors concluded that the encouraging results in this case suggested that this can be an option as add-on therapy over SCS as a possible rescue therapy in the management of CRPS-II.  However, they stated that comparative studies must be performed in order to determine the effectiveness of this therapy.

Traumatic Brain Injury

Clayton and associates (2016) noted that there is growing evidence that electrical and magnetic brain stimulation can improve motor function and motor learning following brain damage. Rodent and primate studies have strongly demonstrated that combining cortical stimulation (CS) with skilled motor rehabilitative training enhances functional motor recovery following stroke.  Brain stimulation following traumatic brain injury (TBI) is less well studied, but early pre-clinical and human pilot studies suggested that it is a promising treatment for TBI-induced motor impairments as well.  These researchers discussed the evidence supporting brain stimulation efficacy derived from the stroke research field as proof of principle and then reviewed the few studies exploring neuromodulation in experimental TBI studies.

Cerebral Palsy

de Almeida Carvalho Duarte et al (2018) described the protocol of a study that evaluated the best electrode position of transcranial direct current stimulation combined with treadmill training in children with unilateral spastic cerebral palsy (CP).  A total of 30 children with CP will be randomly allocated to 3 groups:

1. Group I – treadmill training combined with anodal electrode positioned over the primary motor cortex in the region of the dominant hemisphere and the cathode positioned in the supraorbital region contralateral to anode;
2. Group II – sham anodal transcranial direct current stimulation over the primary motor cortex and sham cathode over the contralateral supraorbital region combined with treadmill training; and
3. Group III – treadmill training combined with the anodal electrode positioned over the primary motor cortex in the region of the injured hemisphere and the cathode positioned contralateral to anode over the primary motor cortex.  

Evaluations of gait, balance, quality of life (QOL), and electromyographic (EMG) activity were performed.  The authors concluded that this is the protocol for an intervention study investigating electrode position to achieve improved function.

Chronic Neuropathic Pain

Kurt and colleagues (2017) noted that MCS was introduced in the early 1990s by Tsubokawa and his group for patients diagnosed with drug-resistant, central neuropathic pain.  Inconsistencies concerning the details of this therapy and its outcomes and poor methodology of most clinical essays divide the neuromodulation society worldwide into "believers" and "nonbelievers".  A European expert meeting was organized in Brussels, Belgium by the Benelux Neuromodulation Society in order to develop uniform MCS protocols in the pre-operative, intra-operative, and post-operative courses.  An expert meeting was organized, and a questionnaire was sent out to all the invited participants before this expert meeting.  An extensive literature research was conducted in order to enrich the results.  Topics that were addressed during the expert meeting entailed inclusion and exclusion criteria, targeting and methods of stimulation, effects of MCS, and results from the questionnaire.  The authors concluded that substantial commonalities but also important methodologic divergences emerged from the discussion of MCS experts from 7 European Centers.  From this meeting and questionnaire, all participants concluded that there is a need for more homogenous standardized protocols for MCS regarding patient selection, implantation procedure, stimulation parameters, and follow-up-course.

Henssen and co-workers (2018) stated that MCS was introduced as a last-resort treatment for chronic neuropathic pain.  Over the years, MCS has been used for the treatment of various pain syndromes but long-term follow-up is unknown.  These investigators reported the results of MCS from 2005 until 2012 with a 3-year follow-up.  Patients who suffered from chronic neuropathic pain treated with MCS were studied.  The analgesic effect was determined as successful by decrease in pain-intensity on the VAS of at least 40 %.  The modifications in drug regimens were monitored with use of the medication quantification scale (MQS).  Stimulation parameters and complications were also noted.  Interference of pain with QOL, the QOL index (QLI), was determined with use of a specific subset of questions from the Dutch version of the McGill pain questionnaire (MPQ-DLV) score; 18 patients were included.  Mean pre-operative VAS changed from 89.4 ± 11.2 to 53.1 ± 25.0 after 3 years of follow-up (p < 0.0001).  A successful outcome was achieved in 7 responders (38.9 %).  All patients in the responder group suffered from pain caused by a central lesion.  With regard to all the patients with central pain lesions (n = 10) and peripheral lesions (n = 8), a significant difference in response to MCS was noticed (p = 0.002); MQS scores and QLI-scores diminished during the follow-up period (p = 0.210 and p = 0.007, respectively).  The authors concluded that MCS appeared to be a promising therapeutic option for patients with refractory pain syndromes of central origin. 

The authors stated that the main drawbacks of this study were its small sample size (n = 18) and the lack of a control group.  Also, these investigators noted that as over the years new insights in neurophysiological features of chronic pain and MCS were gained, important diagnostic steps were not included in this protocol.  In this regard, they noted that Rasche and Tronnier suggested that a double-blinded test trial with an external stimulation device could identify non-responders and placebo responders, hence improving the results of MCS.  They also performed a trial with an externalized epidural lead, although the authors thought the effects of MCS could take for months to occur, which made an externalized epidural lead hazardous due to high risk of infections.  Other studies suggested that the efficacy of MCS relied on the number of available opioid receptors in the brain.  As both the double-blinded test trial with transcranial stimulation and the pre-operative (11)C-diprenorphine positron emission tomography (PET) scan were not widely accessible exploration possibilities, possible non-responders were not recognized.  However, these sophisticated techniques are still not widely available.

In a systematic literature-based analysis of effectiveness and case series experience, Mo and colleagues (2019) examined the clinical effectiveness of MCS in the treatment of refractory pain.  These investigators searched in database of Cochrane library, Embase and PubMed, using relevant strategies.  Data were extracted from eligible articles and pooled as mean with SD.  Comparative analysis was measured by non-parametric t-test and linear regression model.  The pooled effect estimate from 12 trials (n = 198) elucidated that MCS shown the positive effect on refractory pain, and the total percentage improvement was 35.2 % in post-stroke pain and 46.5 % in trigeminal neuropathic pain.  There is no statistical differences between stroke involved thalamus or non-thalamus.  The improvement of plexus avulsion (29.8 %) and phantom pain (34.1 %) was similar.  The highest improvement rate was observed in post-radicular plexopathy (65.1 %) and MCS may aggravate the pain induced by spinal cord injury, confirmed by small sample size.  Concurrently, both the duration of disease (r = 0.233, p = 0.019*) and the time of follow-up (r = 0.196, p = 0.016*) had small predicative value, while age (p = 0.125) had no correlation to post-operative pain relief.  The authors concluded that MCS was conducive to the patients with refractory pain.  The duration of disease and the time of follow-up could be regarded as predictive factor.  Moreover, these researchers stated that further studies are needed to reveal the mechanism of MCS and to re-evaluate the cost-benefit aspect with better-designed clinical trials.

The authors stated this analysis had several drawbacks.  Although these investigators tried to retrieve all published articles, establish strict included criteria, choose the optimal statistical methods, the small sample and the poor design studies still influenced the reliability of the chosen articles.  Well-designed studies, such as RCTs or randomized, double-blind, cross-over studies, were expected to further verify the effectiveness of MCS.  Also, these researchers failed to eliminate the negative effect brought by the different stimulation parameters across centers.  The individual stimulation parameters rendered the statistical work difficult.  They noted that despite the rapid development of the MCS, it was still unclear whether the therapy represents an advancing alternative treatment.  Besides, the specified mechanism and limitations await further refinement.  Lastly, the efficacy of MCS depends on the accurate electrode placement, individualized programming parameters, patient selections, and response to rTMS.  Future work is needed to further illustrate the advancing treatment and potential mechanism, such as endogenous pain control, the interaction between motor and pain system, and the involved neural circuits.  New generation of stimulators and electrode design worth paying enough attention to.  The optimal target should be evaluated pre-operatively via the usage of advanced neurological functional and structural imaging.  In general, specialized, quantitative and objective evaluation criterion should be developed and adopted to examine the pain relief in the clinical trials.  Even better would be to focus more on the QOL and capacity for work of patients.  Well-designed study can provide strong evidence to explain this question.  Future researches regarding the comparisons and contrasts between MCS and other neuro-modulatory techniques is expected.  Also, based on the principle of patient first, in order to minimize patient trauma, invasive treatments could be replaced by revolutionary and promising non-invasive therapies, if there is no statistically significant different in cost-benefit aspect.

Henssen and colleagues (2020) stated that invasive MCS (iMCS) was introduced in the 1990's for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful.  However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS.  In a systematic review and meta-analysis, these investigators examined if the effectiveness of iMCS is significantly different among different CNOP disorders; and if other confounding factors could be impacting iMCS results in CNOP.  They carried out a systematic review and meta-analysis using a linear mixed-model.  A total of 23 papers were included, entailing 140 CNOP patients.  Heterogeneity of the studies showed to be 55.8 %.  A VAS measured median pain relief of 66.5 % (ranging from 0 to 100 %) was found.  Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030).  Furthermore, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049).  No other confounding factors were elucidated.  The authors concluded that the overall analgesic effect of iMCS might be relevant for CNOP patients who do not respond to other treatments.  The best results of iMCS were achieved in patients with CNOP etiologies affecting the central portion of the trigeminal system.  No other factors were found to significantly influence the outcome of iMCS in CNOP disorders.  Moreover, these researchers stated that due to the small sample size, the relatively poor quality of the analyzed literature and the inconsistent use of diagnoses, this statement needs further exploration in future studies.

The authors stated that as the quality of the retrieved literature was considered to be moderate/low, the conclusions must be interpreted with caution.  The inconsistent use of the nomenclature of several diagnoses formed another limitation of this study as it complicated the analysis of groups of diagnoses.  In addition, the lack of psychometric properties of the VAS scores that were used as an outcome measurement in all the included studies formed another limitation of these studies and the present meta-analysis as it hampered the direct translation of these results to clinical decision-making.  For example, the included studies often did not report on modifications in QOL scores before and after iMCS.  The absence of a large RCT with regard to iMCS CNOP formed an important limitation of this meta-analysis.  The absence of such well-designed trials indicated a crucial shortage in the scientific literature with regard to iMCS and CNOP.  Furthermore, part of the scientific literature could not be included in this analysis due to the fact that these studies did not meet the strict, pre-defined inclusion criteria.  It is known that RCTs are well-suited to examine the influence of the placebo response and to assess the true treatment effect in an appropriate manner.  The relative absence of such well-designed trials indicated a crucial shortage in the scientific literature with regard to iMCS and CNOP.  Based on other invasive treatment studies, the placebo-effect was possibly stronger as compared to studies in which less invasive treatments were performed.  Thus, it was not possible to rule out or determine the placebo-effect in the included studies or the current review.  This limitation provoked a risk of bias that precluded the drawing of a sound conclusion.  Finally, it is for unethical to perform a sham operation to provide a control group.  Possibly a double-blinded on/off-phase trial could be a valuable addition with regard to the lack of a control group.

Volkers and associates (2020) noted that iMCS has been proposed as a treatment for intractable neuropathic pain syndromes.  Although the mechanisms underlying the analgesic effect of iMCS remain largely elusive, several studies found iMCS-related changes in regional cerebral blood flow (rCBF) in neuropathic pain patients.  In a meta-analyze, these researchers examined the findings of neuroimaging studies on rCBF changes to iMCS.  PubMed, Embase, Medline, Google Scholar, and the Cochrane Library were systematically searched for retrieval of relevant scientific papers.  After initial assessment of relevancy by screening title and abstract by 2 investigators, independently, pre-defined inclusion and exclusion criteria were used for final inclusion of papers.  Descriptive results were statistically assessed, whereas coordinates were pooled and meta-analyzed in accordance with the activation likelihood estimation (ALE) methodology.  A total of 6 studies were included in the systematic narrative analysis, suggesting rCBF increases in the cingulate gyrus, thalamus, insula, and putamen after switching the MCS device "ON" as compared to the "OFF" situation.  Decreases in rCBF were found in for example the pre-central gyrus and different occipital regions; 2 studies did not report stereotactic coordinates and were excluded from further analysis.  ALE meta-analysis showed that, after switching the iMCS electrode "ON," increased rCBF occurred in the anterior cingulate gyrus; putamen; cerebral peduncle; pre-central gyrus; superior frontal gyrus; red nucleus; internal part of the globus pallidus; ventral lateral nucleus of the thalamus; medial frontal gyrus; inferior frontal gyrus; and claustrum, as compared to the "OFF" situation.  Reductions in rCBF were found in the posterior cingulate gyrus when the iMCS electrode was turned "OFF".  The authors concluded that the findings of this ALE meta‐analysis suggested that rCBF changes were induced by active iMCS in key nodes of the default mode network (posterior cingulate cortex and prefrontal cortex), the salience network ([mid]cingulate cortex) and sensorimotor network (thalamus, primary motor cortex, corticospinal tract/cerebral peduncle).  Whether these iMCS‐induced rCBF changes in principal components of the pain matrix form the neurophysiological foundation for pain relief in patients with neuropathic pain remains largely elusive and needs data from complementary methods.

The authors stated that the ALE methodology has several drawbacks including the absence of null‐findings when weighing the results and the fact that the weighing of the data was mainly based on sample size.  Another drawback was that other sophisticated neuroimaging methods, including various MRI techniques, were not included in this meta‐analysis.  However, this drawback could be explained by the fact that the neuromodulation devices used in iMCS were not MR conditional.  Another possible limitation concerned that several factors (e.g., variability in pain relief induced by iMCS, variability in included pain syndromes, variability in duration of pain, differences in acquisition protocols and timing) might have introduced heterogeneity in the included studies.  However, the authors were unable to find an appropriate method to control for these factors.  However, results from the included publications were rather homogeneous.  Another possible limitation of this paper was that the selected studies came from only 2 research groups: Peyron and Garcia‐Larrea from France, and Saitoh and colleagues from Japan.  Nevertheless, this ALE meta‐analysis was not necessarily hindered by this limitation as this is goal-dependent.  The objective of the present ALE meta‐analysis was to provide insight into the most important theories of iMCS on a meta‐level.  By examining this theory using a method that has never been carried out before in iMCS imaging studies, this study contributed to the existing literature.  Furthermore, it also showed the lack neuroimaging studies that could help investigators to elucidate the mechanisms of action in iMCS in humans.

Garcia-Pallero and colleagues (2022) noted that PLP is a chronic pain syndrome that is difficult to cope with.  Despite neurostimulation treatment is indicated for refractory neuropathic pain, there is scant evidence from RCTs to recommend it as the treatment choice.  In a systematic review, these researchers examined the efficacy of CNS stimulation therapies as a strategy for pain management in patients with PLP.  They carried out a literature search for studies conducted between 1970 and September 2020 using the Medline and Embase databases.  Principles of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline were followed.  A total of 10 full-text articles were retrieved and included in this review.  Deep brain stimulation (DBS), rTMS, tDCS, and MCS were the treatment strategies used in the selected clinical trials; rTMS and tDCS were effective therapies to reduce pain perception, as well as to relieve anxiety and depression symptoms in patients with PLP.  Conversely, invasive approaches were considered the last therapeutic option as evidence in DBS and MCS suggested that the value of PLP treatment remains controversial.  The authors concluded that non-invasive treatments to stimulate the CNS (e.g., rTMS and tDCS) may be beneficial to reduce pain sensation in PLP.   Invasive treatments also need further investigation, as these treatments tend to have positive outcomes in both PLP and other forms of neuropathic pain.

The author stated that the main drawback of this study, was that, based on the Jadad Scale for reporting RCTs, only 4 of the clinical trials included were rated as high-quality.  Another drawback was that these trials entailed a very small number of subjects, with 5 subjects in the smallest sample.  In addition, most of the studies did not only study PLP syndrome.  Other types of pain, such as post-stroke or SCI were included, especially in trials involving tDCS, DBS and MCS treatments.  Thus, conclusions should be taken with caution.  Finally, because of the limited number of reviews of clinical trials, observational research may be considered to complete the overall literature review.

Muscle Re-Innervation and Nerve Regeneration

Nicolas and associates (2018) noted that immediate microsurgical nerve suture remains the gold standard after peripheral nerve injuries.  However, functional recovery is delayed, and it is satisfactory in only 2/3 of cases.  Peripheral electrical nerve stimulation proximal to the lesion enhances nerve regeneration and muscle re-innervation.  In an experimental rat model, these researchers evaluated the effects of MCS on peripheral nerve regeneration after injury.  A total of 80 rats underwent right sciatic nerve section, followed by immediate microsurgical epineural sutures.  Rats were divided into 4 groups: Group 1 (control, n = 20): no electrical stimulation; group 2 (n = 20): immediate stimulation of the sciatic nerve just proximal to the lesion; Group 3 (n = 20): motor cortex stimulation (MCS) for 15 minutes after nerve section and suture (MCSa); group 4 (n = 20): MCS performed over the course of 2 weeks after nerve suture (MCSc).  Assessment included electrophysiology and motor functional score at day 0 (baseline value before nerve section), and at weeks 4, 8, and 12.  Rats were euthanized for histological study at week 12.  Results showed that MCS enhanced functional recovery, nerve regeneration, and muscle re-innervation starting week 4 compared with the control group (p < 0.05).  The MCS induced higher re-innervation rates even compared with peripheral stimulation, with better results in the MCSa group (p < 0.05), especially in terms of functional recovery.  The authors concluded that MCS appeared to have a beneficial effect after peripheral nerve injury and repair in terms of nerve regeneration and muscle re-innervation, especially when acute mode was used.  These preliminary findings from an animal model study needs to be further investigated.

Phantom Limb Pain

Bolognini et al (2013) stated that limb amputation may lead to chronic painful sensations referred to the absent limb, i.e., phantom limb pain (PLP), which is likely subtended by maladaptive plasticity.  These researchers examined if tDCS, a non-invasive technique of brain stimulation that can modulate neuroplasticity, can reduce PLP.  In 2 double-blind, sham-controlled experiments in subjects with unilateral lower or upper limb amputation, they measured the effects of a single session of tDCS (2 mA, 15 mins) of the primary motor cortex (M1) and of the posterior parietal cortex (PPC) on PLP, stump pain, non-painful phantom limb sensations and telescoping.  Anodal tDCS of M1 induced a selective short-lasting decrease of PLP, whereas cathodal tDCS of PPC induced a selective short-lasting decrease of non-painful phantom sensations; stump pain and telescoping were not affected by parietal or by motor tDCS.  These findings demonstrated that painful and non-painful phantom limb sensations are dissociable phenomena.  Phantom limb pain is associated primarily with cortical excitability shifts in the sensorimotor network; increasing excitability in this system by anodal tDCS has an antalgic effect on PLP.  Conversely, non-painful phantom sensations are associated to a hyper-excitation of PPC that can be normalized by cathodal tDCS.  The authors concluded that this evidence highlighted the relationship between the level of excitability of different cortical areas, which underpins maladaptive plasticity following limb amputation and the phenomenology of phantom limb, and it opens up new opportunities for the use of tDCS in the treatment of PLP.  Well-designed studies are needed to ascertain the effectiveness of MCS in the treatment of PLP.

In a cross-over, double-blind, sham-controlled study, Bolognini et al (2015) examined the analgesic effects of tDCS over the motor cortex on post-amputation PLP. A total of 8 subjects with unilateral lower or upper limb amputation and chronic PLP were included in this study. For 5 consecutive days, anodal (active or sham) tDCS was applied over the motor cortex for 15 minutes at an intensity of 1.5 mA. The 5-day treatment with active, but not sham, tDCS induced a sustained decrease in background PLP and in the frequency of PLP paroxysms, which lasted for 1 week after the end of treatment. Moreover, on each day of active tDCS, patients reported an immediate PLP relief, along with an increased ability to move their phantom limb. Patients' immediate responses to sham tDCS, on the contrary, were variable, marked by an increase or decrease of PLP levels from baseline. The authors concluded that these results showed that a 5-day treatment of MCS with tDCS can induce stable relief from PLP in amputees. They stated that neuromodulation targeting the motor cortex appears to be a promising option for the management of this debilitating neuropathic pain condition, which is often refractory to classic pharmacologic and surgical treatments.

In a systematic review and meta-analysis, Pacheco-Barrios and colleagues (2020) examined the effects of neuromodulation techniques in adults with PLP.  These researchers carried out a systematic search, comprising RCTs and quasi-experimental (QE) studies that were published from data-base inception to February 2019 and that measured the effects of neuromodulation in adults with PLP.  Hedge's g effect size (ES) and 95 % CIs were calculated, and random-effects meta-analyses were performed.  A total of 14 studies (9 RCTs and 5 QE noncontrolled studies) were included.  The meta-analysis of RCTs showed significant effects for excitatory primary motor cortex (M1) stimulation in reducing pain after stimulation (ES = -1.36, 95 % CI: -2.26 to -0.45); anodal M1 transcranial direct current stimulation (tDCS) in lowering pain after stimulation (ES = -1.50, 95 % CI: -2.05 to 0.95), and 1-week follow-up (ES = -1.04, 95 % CI: -1.64 to 0.45).  The meta-analysis of non-controlled QE studies demonstrated a high rate of pain reduction after stimulation with TENS (rate = 67 %, 95 % CI: 60 % to 73 %) and at 1-year follow-up with deep brain stimulation (rate = 73 %, 95 % CI: 63 % to 82 %).  The authors concluded that the evidence from RCTs suggested that excitatory M1 stimulation -- specifically, anodal M1 tDCS -- had a significant short-term effect in reducing pain scale scores in PLP.  These researchers stated that various neuromodulation techniques appeared to have a significant and positive impact on PLP, however, due to the limited amount of data, it is not possible to draw more definite conclusions.

Garcia-Pallero and colleagues (2022) noted that PLP is a chronic pain syndrome that is difficult to cope with.  Despite neurostimulation treatment is indicated for refractory neuropathic pain, there is scant evidence from RCTs to recommend it as the treatment choice.  In a systematic review, these researchers examined the efficacy of CNS stimulation therapies as a strategy for pain management in patients with PLP.  They carried out a literature search for studies conducted between 1970 and September 2020 using the Medline and Embase databases.  Principles of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline were followed.  A total of 10 full-text articles were retrieved and included in this review.  Deep brain stimulation (DBS), rTMS, tDCS, and MCS were the treatment strategies used in the selected clinical trials; rTMS and tDCS were effective therapies to reduce pain perception, as well as to relieve anxiety and depression symptoms in patients with PLP.  Conversely, invasive approaches were considered the last therapeutic option as evidence in DBS and MCS suggested that the value of PLP treatment remains controversial.  The authors concluded that non-invasive treatments to stimulate the CNS (e.g., rTMS and tDCS) may be beneficial to reduce pain sensation in PLP.   Invasive treatments also need further investigation, as these treatments tend to have positive outcomes in both PLP and other forms of neuropathic pain.

The author stated that the main drawback of this study, was that, based on the Jadad Scale for reporting RCTs, only 4 of the clinical trials included were rated as high-quality.  Another drawback was that these trials entailed a very small number of subjects, with 5 subjects in the smallest sample.  In addition, most of the studies did not only study PLP syndrome.  Other types of pain, such as post-stroke or SCI were included, especially in trials involving tDCS, DBS and MCS treatments.  Thus, conclusions should be taken with caution.  Finally, because of the limited number of reviews of clinical trials, observational research may be considered to complete the overall literature review.

Post-Stroke Aphasia

Branscheidt and co-workers (2018) noted that 1/3 of stroke survivors worldwide suffer from aphasia.  Speech and language therapy (SLT) is considered effective in treating aphasia, but because of time constraints, improvements are often limited.  Non-invasive brain stimulation is a promising adjuvant strategy to facilitate SLT.  However, stroke might render "classical" language regions ineffective as stimulation sites.  Recent work showed the effectiveness of MCS together with intensive naming therapy to improve outcomes in aphasia.  In a sham-controlled, double-blind study, these researchers examined the role of motor cortex in language, investigating its functional involvement in access to specific lexico-semantic (object versus action relatedness) information in post-stroke aphasia.  They tested effects of anodal transcranial direct current stimulation (tDCS) to the left motor cortex on lexical retrieval in 16 patients with post-stroke aphasia.  Critical stimuli were action and object words, and pseudo-words.  Participants performed a lexical decision task, deciding whether stimuli were words or pseudo-words.  Anodal tDCS improved accuracy in lexical decision, especially for words with action-related content and for pseudo-words with an "action-like" ending (t15 = 2.65, p = 0.036), but not for words with object-related content and pseudo-words with "object-like" characteristics.  These investigators showed as a proof-of-principle that the motor cortex may play a specific role in access to lexico-semantic content.  Thus, MCS may strengthen content-specific word-to-semantic concept associations during language treatment in post-stroke aphasia.  The authors proposed that MCS may specifically strengthen word-to-semantic concept association in aphasia.  They stated that these findings potentially provide a way to tailor therapies for language rehabilitation.

Thalamic Pain

Lin and colleagues (2018) stated that thalamic pain is a severe pain that is often unresponsive to medical therapy.  Repetitive transcranial magnetic stimulation (rTMS) entirely non-invasively modulates neuronal plasticity to produce therapeutic benefit.  Since the rTMS stimulation parameters varied, it is difficult to determine which specific parameters are best for clinical use.  In an open-label study, these researchers evaluated the analgesic lasting effect of 10-Hz rTMS over the motor cortex (M1) for 10 consecutive days to treat thalamic pain.  Patients were treated with daily 10-Hz rTMS sessions for 1,000 pulses applied over the M1 for 10 consecutive days.  Pain severity and mood were assessed at baseline, immediately after, 2 weeks, 4 weeks, 6 weeks, 8 weeks after rTMS.  Pain severity was measured by the VAS and the percentage of pain relief on VAS score was calculated between baseline and final examination.  Mood was monitored using the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD).  A total of 7 patients with thalamic pain were enrolled; VAS score was significantly decreased after rTMS.  Mean VAS scores were 7 at baseline and decreased to 5.6 at 2 weeks after rTMS and then decreased to 3.9 at 8 weeks after rTMS.  The analgesic effect of rTMS can last up to 8 weeks.  The percentage of pain relief ranged from 25.0 % to 66.7 % at the 8th week; 4 patients (3 moderate pain and 1 severe pain) achieved satisfactory relief (pain relief greater than or equal to 40 to 69 %).  The authors concluded that although this was an open-label study without a control group, these findings showed that 10 Hz rTMS over the M1 for 10 consecutive days could produce satisfactory or partial antalgic effect on patients with thalamic pain.  The main drawbacks of this study were its open-label design, small sample size (n = 7), lack of a control group and short-term follow-up (8 weeks).  These preliminary findings need to be validated by well-designed studies.

Treatment of Autism Spectrum Disorder

Masuda and colleagues (2019) stated 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.  Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD.  These researchers carried out a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intra-cortical 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 reflected GABA(A) receptor-mediated function.  Conversely, other magnetic resonance spectroscopy (MRS) and post-mortem methodologies assess GABA levels.  The authors concluded that the present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD; and 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.  Targeting a wider range of brain areas outside of M1-- dorsolateral prefrontal cortex -- which would be more closely related to cognitive and/or sensory functions of the disorder is the next logical area of investigation.

Use of Motor Cortex Stimulation During Implantation of a Deep Brain Stimulator

An UpToDate review on “Device-assisted and surgical treatments for Parkinson disease” (Tarsy, 2019) does not mention the use of motor cortex stimulation during implantation of a deep brain stimulator.

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References