High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study.

BACKGROUND: We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. METHODS: Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. RESULTS: The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. CONCLUSIONS: Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Resting-state electroencephalography (EEG) biomarkers of chronic neuropathic pain. A systematic review.

Diagnosis and management of chronic neuropathic pain are challenging, leading to current efforts to characterize 'objective' biomarkers of pain using imaging or neurophysiological techniques, such as electroencephalography (EEG). A systematic literature review was conducted in PubMed-Medline and Web-of-Science until October 2021 to identify EEG biomarkers of chronic neuropathic pain in humans. The risk of bias was assessed by the Newcastle-Ottawa-Scale. Experimental, provoked, or chronic non-neuropathic pain studies were excluded. We identified 14 studies, in which resting-state EEG spectral analysis was compared between patients with pain related to a neurological disease and patients with the same disease but without pain or healthy controls. From these heterogeneous exploratory studies, some conclusions can be drawn, even if they must be weighted by the fact that confounding factors, such as medication and association with anxio-depressive disorders, are generally not taken into account. Overall, EEG signal power was increased in the θ band (4-7Hz) and possibly in the high-ß band (20-30Hz), but decreased in the high-α-low-ß band (10-20Hz) in the presence of ongoing neuropathic pain, while increased γ band oscillations were not evidenced, unlike in experimental pain. Consequently, the dominant peak frequency was decreased in the θ-α band and increased in the whole-ß band in neuropathic pain patients. Disappointingly, pain intensity correlated with various EEG changes across studies, with no consistent trend. This review also discusses the location of regional pain-related EEG changes in the pain connectome, as the perspectives offered by advanced techniques of EEG signal analysis (source location, connectivity, or classification methods based on artificial intelligence). The biomarkers provided by resting-state EEG are of particular interest for optimizing the treatment of chronic neuropathic pain by neuromodulation techniques, such as transcranial alternating current stimulation or neurofeedback procedures.

Additional Benefit of Intraoperative Electroacupuncture in Improving Tolerance of Deep Brain Stimulation Surgical Procedure in Parkinsonian Patients.

BACKGROUND: Deep brain stimulation (DBS) is an effective technique to treat patients with advanced Parkinson's disease. The surgical procedure of DBS implantation is generally performed under local anesthesia due to the need for intraoperative clinical testing. However, this procedure is long (5-7 h on average) and, therefore, the objective that the patient remains co-operative and tolerates the intervention well is a real challenge. OBJECTIVE: To evaluate the additional benefit of electroacupuncture (EA) performed intraoperatively to improve the comfort of parkinsonian patients during surgical DBS implantation. METHODS: This single-center randomized study compared two groups of patients. In the first group, DBS implantation was performed under local anesthesia alone, while the second group received EA in addition. The patients were evaluated preoperatively, during the different stages of the surgery, and 2 days after surgery, using the 9-item Edmonton Symptom Assessment System (ESAS), including a total sum score and physical and emotional subscores. RESULTS: The data of nine patients were analyzed in each group. Although pain and tiredness increased in both groups after placement of the stereotactic frame, the ESAS item "lack of appetite", as well as the ESAS total score and physical subscore increased after completion of the first burr hole until the end of the surgical procedure in the control group only. ESAS total score and physical subscore were significantly higher at the end of the intervention in the control group compared to the EA group. After the surgical intervention (D2), anxiety and ESAS emotional subscore were improved in both groups, but the feeling of wellbeing improved in the EA group only. Finally, one patient developed delirium during the intervention and none in the EA group. DISCUSSION: This study shows that intraoperative electroacupuncture significantly improves the tolerance of DBS surgery in parkinsonian patients. This easy-to-perform procedure could be fruitfully added in clinical practice.

Neurofeedback therapy for the management of multiple sclerosis symptoms: current knowledge and future perspectives.

Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Affective manifestations are also of high prevalence in this population and can drastically impact the patients' functioning. A considerable proportion of patients with MS suffer from cognitive deficits affecting general and social cognitive domains. In addition, pain in MS is commonly observed in neurology wards, could be of different types, and may result from or be exacerbated by other MS comorbidities. These complaints tend to cluster together in some patients and seem to have a complex pathophysiology and a challenging management. Exploring the effects of new interventions could improve these outcomes and ameliorate the patients' quality of life. Neurofeedback (NFB) might have its place in this context by enhancing or reducing the activity of some regions in specific electroencephalographic bands (i.e., theta, alpha, beta, sensorimotor rhythm). This work briefly revisits the principles of NFB and its application. The published data are scarce and heterogeneous yet suggest preliminary evidence on the potential utility of NFB in patients with MS (i.e., depression, fatigue, cognitive deficits and pain). NFB is simple to adapt and easy to coach, and its place in the management of MS symptoms merits further investigations. Comparing different NFB protocols (i.e., cortical target, specific rhythm, session duration and number) and performing a comprehensive evaluation could help developing and optimizing interventions targeting specific symptoms. These aspects could also open the way for the association of this technique with other approaches (i.e., brain stimulation, cognitive rehabilitation, exercise training, psychotherapies) that have proved their worth in some MS domains.

Phosphorus magnetic resonance spectroscopy and fatigue in multiple sclerosis.

Fatigue stands among the most debilitating multiple sclerosis (MS) manifestations. Several pathophysiological mechanisms have been proposed at its origin. However, unmet needs still exist, and further investigations are required to better understand and manage this complaint. A new imaging modality-the phosphorous magnetic resonance spectroscopy (31P-MRS)-might help studying fatigue by allowing the measurement of energy metabolites of various cerebral regions. Therefore, this work aimed to explore the association between fatigue and brain energy status. Thirty MS patients with progressive disease forms completed the study. Their sociodemographic and clinical data including fatigue and disability scores [i.e., Fatigue Severity Scale (FSS) and Expanded Disability Status Scale (EDSS)] were collected. 31P-MRS spectra of (1) bilateral frontoparietal area and (2) centrum semiovale normal appearing white matter (NAWM) were obtained. Percentages of phosphocratine and ß-adenosine triphosphate (ß-ATP) were calculated. FSS scores were found to be directly correlated with the frontoparietal ß-ATP % (p < 0.05). However, there were no significant correlations between FSS scores and NAWM energy metabolites or clinical data (i.e., age, EDSS scores or disease duration). These findings point toward the existence of a link between fatigue severity and the amount of cerebral ATP metabolites. Such a link might reflect either a high production or low utilization of ATP, both of which were paralleled with increased fatigue perception. While the former would be due to a redistribution of ion channels along demyelinated axons and subsequent changes in mitochondrial activity; the latter could be interpreted in the light of neuronal loss which would lead to a decrease in ATP utilization and accumulation of its metabolites.

Corticospinal inhibition and alexithymia in multiple sclerosis patients-An exploratory study.

OBJECTIVES: Alexithymia is a multicomponent personality construct that could occur in up to 53% of patients with multiple sclerosis (MS), with recent works proposing higher rates of alexithymia in progressive MS. Among the available models of alexithymia, some propose a deficient interhemispheric communication and an aberrant GABAergic transmission at its origin. However, no single study has addressed the underlying physiological mechanisms of alexithymia in MS. The aim of this work was to assess the relationship between GABAergic neurotransmission and alexithymia in progressive MS by means of transcranial magnetic stimulation (TMS). METHODS: Twelve patients with high alexithymia and fifteen patients with low alexithymia were included based on Toronto Alexithymia Scale (TAS). Sociodemographic, clinical and neuropsychological data were recorded. The following corticospinal excitability measures were obtained: resting motor threshold, cortical silent period (CSP which reflects cortical GABAergic function), and interhemispheric inhibition (i.e., GABAergic function mediated by interhemispheric fibers). RESULTS: No significant group differences were observed regarding sociodemographic, clinical or neuropsychological variables. Patients with high alexithymia scores exhibited shorter CSP than those with low alexithymia scores (81.87 ± 45.72 ms vs. 145.27 ± 77.26 ms, respectively, p < 0.05). A significant inverse correlation was also found between TAS scores and CSP duration (r = -0.59, p < 0.05). CONCLUSION: This study offers insights into the neurophysiological mechanisms of alexithymia in MS. Reduced GABAergic transmission, as reflected by short CSP, seems to be associated with alexithymia in this population. Future studies would benefit from a more comprehensive evaluation of cortical and interhemispheric mechanisms in MS patients with alexithymia.

Relieving peripheral neuropathic pain by increasing the power-ratio of low-ß over high-ß activities in the central cortical region with EEG-based neurofeedback: Study protocol for a controlled pilot trial (SMRPain study).

BACKGROUND: Chronic neuropathic pain associated with peripheral neuropathies cannot be attributed solely to lesions of peripheral sensory axons and likely involves alteration in the processing of nociceptive information in the central nervous system in most patients. Few data are available regarding EEG correlates of chronic neuropathic pain. The fact is that effective cortical neuromodulation strategies to treat neuropathic pain target the precentral cortical region, i.e. a cortical area corresponding to the motor cortex. It is not known how these strategies might modulate brain rhythms in the central cortical region, but it can be speculated that sensorimotor rhythms (SMRs) are modified. Another potent way of modulating cortical rhythms is to use EEG-based neurofeedback (NFB). Rare studies previously aimed at relieving neuropathic pain using EEG-NFB training. METHODS/DESIGN: The objective of this single-centre, single-blinded, randomized controlled pilot study is to assess the value of an EEG-NFB procedure to relieve chronic neuropathic pain in patients with painful peripheral neuropathy. A series of 32 patients will be randomly assigned to one of the two following EEG-NFB protocols, aimed at increasing either the low-ß(SMR)/high-ß ratio (n=16) or the α(µ)/θ ratio (n=16) at central (rolandic) cortical level. Various clinical outcome measures will be collected before and one week after 12 EEG-NFB sessions performed over 4weeks. Resting-state EEG will also be recorded immediately before and after each NFB session. The primary endpoint will be the change in the impact of pain on patient's daily functioning, as assessed on the Interference Scale of the short form of the Brief Pain Inventory. DISCUSSION: The value of EEG-NFB procedures to relieve neuropathic pain has been rarely studied. This pilot study will attempt to show the value of endogenous modulation of brain rhythms in the central (rolandic) region in the frequency band corresponding to the frequency of stimulation currently used by therapeutic motor cortex stimulation. In the case of significant clinical benefit produced by the low-ß(SMR)/high-ß ratio increasing strategy, this work could pave the way for using EEG-NFB training within the armamentarium of neuropathic pain therapy.

Treatment of refractory headache secondary to intracranial endovascular procedure by transcutaneous electrical nerve stimulation of the occipital nerve.

This pilot study aimed at assessing the effect of transcutaneous electrical nerve stimulation (TENS) of the occipital nerve (ON) to treat chronic refractory headache secondary to intracranial endovascular procedures (iEVP) in 4 patients. The duration of ON-TENS therapy was only 1 month (n=2) or longer than 4 months (n=2). Overall, pain intensity decreased from 7.8 (on a 0-10 scale) at baseline to 0.8 at 6 months after ON-TENS therapy initiation (-90%), while drug treatment was reduced from 34.3 to 0.8 (-98%) on the medication quantification scale. ON-TENS is a simple technique that may benefit patients with post-iEVP refractory headache.

A reappraisal of the mechanisms of action of ketamine to treat complex regional pain syndrome in the light of cortical excitability changes.

OBJECTIVE: To evaluate the changes in glutamate/GABA balance of intracortical excitability produced by ketamine, delivered at subanaesthetic dose to treat patients with complex regional pain syndrome (CRPS). METHODS: In 19 patients with CRPS, we assessed the effect of a 5-day ketamine protocol on various clinical aspects, including pain and depression, and on cortical excitability parameters provided by transcranial magnetic stimulation testing. RESULTS: The rest motor threshold (RMT) and the amplitude of the motor evoked potentials at 120% of RMT were not modified after ketamine therapy. In contrast, ketamine reduced intracortical facilitation (ICF) in both hemispheres and increased short-interval intracortical inhibition (SICI), which was defective at baseline only in the hemisphere corresponding to the painful side. These changes positively correlated with pain relief. CONCLUSION: This study shows for the first time that the remarkable analgesic effects produced by ketamine in CRPS patients is associated with cortical excitability changes in favour of an enhanced GABAergic transmission in the hemisphere corresponding to the painful side and an overall reduction of excitability in the contralateral hemisphere. SIGNIFICANCE: Analgesic effects of ketamine cannot be resumed to its classical antigutamatergic action related to N-methyl-d-aspartate receptor blockade.

A good preoperative response to transcutaneous electrical nerve stimulation predicts a better therapeutic effect of implanted occipital nerve stimulation in pharmacologically intractable headaches.

Occipital nerve stimulation (ONS) is a surgical approach to treat patients with medically intractable chronic headache disorders. However, no preoperative test has been yet validated to allow candidates to be selected for implantation. In this study, the analgesic efficacy of transcutaneous electrical nerve stimulation (TENS) was tested for 1 to 3 months in 41 patients with pharmacologically intractable headache disorders of various origins, using a new technique of electrode placement over the occipital nerve. ONS electrodes were subsequently implanted in 33 patients (occipital neuralgia [n=15], cervicogenic headache [n=7], cluster headache [n=6], chronic migraine [n=5]) who had responded at least moderately to TENS. Assessment was performed up to five years after implantation (three years on average), based on the mean and maximum daily pain intensity scored on a 0-10 visual analogue scale and the number of headache days per month. Both TENS and chronic ONS therapy were found to be efficacious (57-76% improvement compared to baseline on the various clinical variables). The efficacy of ONS was better in cases of good or very good preoperative response to TENS than in cases of moderate response to TENS. Implanted ONS may be a valuable therapeutic option in the long term for patients with pharmacologically intractable chronic headache. Although we cannot conclude in patients with poor or no response to TENS, a good or very good response to TENS can support the indication of ONS therapy. This preoperative test could particularly be useful in patients with chronic migraine, in whom it may be difficult to indicate an invasive technique of cranial neurostimulation.

Motor cortex stimulation does not improve dystonia secondary to a focal basal ganglia lesion.

OBJECTIVE: To assess the efficacy of epidural motor cortex stimulation (MCS) on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion. METHODS: In this double-blind, crossover, multicenter study, 5 patients with dystonia secondary to a focal BG lesion were included. Two quadripolar leads were implanted epidurally over the primary motor (M1) and premotor cortices, 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 postoperatively, 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 (visual analog scale), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation. RESULTS: Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS. CONCLUSIONS: Bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bipolar epidural MCS with the anode placed over the motor representation of the most affected limb failed to improve any clinical feature in dystonia secondary to a focal BG lesion.

Reappraisal of the anatomical landmarks of motor and premotor cortical regions for image-guided brain navigation in TMS practice.

Image-guided navigation systems dedicated to transcranial magnetic stimulation (TMS) have been recently developed and offer the possibility to visualize directly the anatomical structure to be stimulated. Performing navigated TMS requires a perfect knowledge of cortical anatomy, which is very variable between subjects. This study aimed at providing a detailed description of sulcal and gyral anatomy of motor cortical regions with special interest to the inter-individual variability of sulci. We attempted to identify the most stable structures, which can serve as anatomical landmarks for motor cortex mapping in navigated TMS practice. We analyzed the 3D reconstruction of 50 consecutive healthy adult brains (100 hemispheres). Different variants were identified regarding sulcal morphology, but several anatomical structures were found to be remarkably stable (four on dorsoventral axis and five on rostrocaudal axis). These landmarks were used to define a grid of 12 squares, which covered motor cortical regions. This grid was used to perform motor cortical mapping with navigated TMS in 12 healthy subjects from our cohort. The stereotactic coordinates (x-y-z) of the center of each of the 12 squares of the mapping grid were expressed into the standard Talairach space to determine the corresponding functional areas. We found that the regions whose stimulation produced almost constantly motor evoked potentials mainly correspond to the primary motor cortex, with rostral extension to premotor cortex and caudal extension to posterior parietal cortex. Our anatomy-based approach should facilitate the expression and the comparison of the results obtained in motor mapping studies using navigated TMS.

Pain.

Invasive stimulation of the motor (precentral) cortex using surgically implanted epidural electrodes is indicated for the treatment of neuropathic pain that is refractory to medical treatment. Controlled trials have demonstrated the efficacy of epidural motor cortex stimulation (MCS), but MCS outcome remains variable and validated criteria for selecting good candidates for implantation are lacking. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach that could be used as a preoperative tool to predict MCS outcome and also could serve as a therapeutic procedure in itself to treat pain disorders. This requires repeated rTMS sessions and a maintenance protocol. Other studies have also demonstrated the efficacy of transcranial direct current stimulation (tDCS) in relieving chronic pain syndromes. The most studied target is the precentral cortex, but other targets, such as the prefrontal and parietal cortices, could be of interest. The analgesic effects of cortical stimulation relate to the activation of various circuits modulating neural activities in remote structures, such as the thalamus, limbic cortex, insula, or descending inhibitory controls. In addition to the treatment of refractory neuropathic pain by epidural MCS, new developments of this type of strategy are ongoing, for other types of pain syndrome and stimulation techniques.

Stroke rehabilitation using noninvasive cortical stimulation: motor deficit.

Noninvasive cortical stimulation (NICS) has been used during the acute, postacute and chronic poststroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. This paper reviews the rationale for using the different NICS modalities to promote motor stroke rehabilitation. The changes in cortical excitability after stroke and the possible mechanisms of action of cortical stimulation in this context are outlined. A number of open and placebo-controlled trials have investigated the clinical effect of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (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 high-frequency rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via low-frequency 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 interhemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neurorehabilitation were found to be safe and equally effective at the short term on various aspects of poststroke motor abilities. However, 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.

Stroke rehabilitation using noninvasive cortical stimulation: aphasia.

Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca's aphasia) or in the semantic aspects of language comprehension (Wernicke's aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery.

Stroke rehabilitation using noninvasive cortical stimulation: hemispatial neglect.

The rehabilitation of neuropsychological sequels of cerebral stroke such as hemispatial neglect by noninvasive cortical stimulation (NICS) attracts increasing attention from the scientific community. The NICS techniques include primarily repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are based on the concept of either reactivating a hypoactive cortical region affected by the stroke (the right hemisphere in case of neglect) or reducing cortical hyperactivity of the corresponding cortical region in the contralateral hemisphere (the left hemisphere). In the studies published to date on the topic of neglect rehabilitation, rTMS was used to inhibit the left parietal cortex and tDCS to either activate the right or inhibit the left parietal cortex. Sham-controlled NICS studies assessed short-term effects, whereas long-term effects were only assessed in noncontrolled rTMS studies. Further controlled studies of large series of patients are necessary to determine the best parameters of stimulation (including the optimal cortical target location) according to each subtype of neglect presentation and to the time course of stroke recovery. To date, even if there are serious therapeutic perspectives based on imaging data and experimental studies, the evidence is not compelling enough to recommend any particular NICS protocol to treat this disabling condition in clinical practice.

Non-invasive stimulation therapies for the treatment of refractory pain.

Drug-refractory pain is an indication for neurostimulation therapy, which can be either non-invasive [mainly transcutaneous electrical nerve stimulation (TENS), repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial direct current stimulation (tDCS)] or invasive which requires the intervention of a surgeon to implant electrodes and a pulse generator [peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS)]. In this review, the respective mechanisms of action and efficacy of TENS, rTMS, and tDCS are discussed. The advantages of TENS include non-invasiveness and ease to use, so that the technique can be operated by the patient. TENS can be indicated as a first-line treatment in patients suffering from peripheral neuropathic pain if the painful area is limited and the sensory deficit moderate. The current best indications are chronic radiculopathies, mononeuropathies, and postherpetic pain. Test sessions allow to select suitable patients and to determine the site, frequency, and optimal intensity of stimulation. Three to four 30- to 60-minute sessions per day are usually recommended. With regard to rTMS, published randomized controlled studies in chronic neuropathic and non-neuropathic pain (fibromyalgia) reached a sufficient level of evidence to recommend this technique for the indication of implanted motor cortex stimulation for the treatment of refractory neuropathic pain or as a long-term treatment for pain syndromes, in which surgery is not indicated, such as fibromyalgia. Other indications, concerning either chronic or acute pain syndromes, such as postoperative pain, should be developed in parallel with the optimization of stimulation parameters. This also includes the availability of new coils and magnetic field waveforms and progress in neuronavigation techniques, especially by the integration of functional imaging and high-resolution EEG data.

Noninvasive cortical modulation of experimental pain.

Noninvasive cortical stimulation (NICS) can produce analgesic effects by means of repetitive transcranial magnetic stimulation or transcranial direct current stimulation (tDCS). Such effects have been demonstrated on chronic ongoing pain, as in acute provoked pain. The investigation of induced changes in the perception of experimental pain by NICS could help clinicians and researchers to better understand the mechanisms of action involved with these techniques and the role played by the cortex in the integration of nociceptive information. This review presents current literature data on the modulation of experimental pain perception by cortical stimulation. The observations found that NICS analgesic effects depend on the method used to provoke pain (referring to the type of nerve fibers and neural circuits that are recruited to mediate pain) and the parameters of cortical stimulation (especially the nature of the cortical target). The motor cortex (precentral cortical area) is the most widely used target for pain modulation. However, other targets, such as the dorsolateral prefrontal cortex, could be of particular interest to modulate various components of pain. Further developments in NICS techniques, such as image-guided navigated brain stimulation, might lead to improvement in the beneficial effects of NICS on pain. Finally, we discuss whether the results obtained in experimental pain can be transposed to the problem of chronic pain and whether they can be used to optimize cortical stimulation therapy for pain disorders.