Corrigendum: Deep brain stimulation neuromodulation for the treatment of mood disorders: obsessive compulsive disorder and treatment resistant depression.

[This corrects the article DOI: 10.3389/fpsyt.2021.764776.].

Amygdala and hippocampus dialogue with neocortex during human sleep and wakefulness.

ABSTRACT: Previous studies have described synchronic electroencephalographic (EEG) patterns of the background activity that is characteristic of several vigilance states. STUDY OBJECTIVES: To explore whether the background synchronous activity of the amygdala-hippocampal-neocortical circuit is modified during sleep in the delta, theta, alpha, sigma, beta, and gamma bands characteristic of each sleep state. METHODS: By simultaneously recording intracranial and noninvasive scalp EEG (10-20 system) in epileptic patients who were candidates for neurosurgery, we explored synchronous activity among the amygdala, hippocampus, and neocortex during wakefulness (W), Non-Rapid Eye Movement (NREM), and Rapid-Eye Movement (REM) sleep. RESULTS: Our findings reveal that hippocampal-cortical synchrony in the sleep spindle frequencies was spread across the cortex and was higher during NREM versus W and REM, whereas the amygdala showed punctual higher synchronization with the temporal lobe. Contrary to expectations, delta synchrony between the amygdala and frontal lobe and between the hippocampus and temporal lobe was higher during REM than NREM. Gamma and alpha showed higher synchrony between limbic structures and the neocortex during wakefulness versus sleep, while synchrony among deep structures showed a mixed pattern. On the one hand, amygdala-hippocampal synchrony resembled cortical activity (i.e. higher gamma and alpha synchrony in W); on the other, it showed its own pattern in slow frequency oscillations. CONCLUSIONS: This is the first study to depict diverse patterns of synchronic interaction among the frequency bands during distinct vigilance states in a broad human brain circuit with direct anatomical and functional connections that play a crucial role in emotional processes and memory.

Importancia del estigma en epilepsia / Importance of Stigma in Epilepsy

Resumen El estigma es un fenómeno caracterizado por una respuesta negativa hacia una persona poseedora de un atributo diferente dentro del grupo social en el que se desarrolla. Se han descrito dos tipos de estigma: el percibido (sentido o interiorizado) y el promovido (social o promulgado). Dentro de las enfermedades con más carga asociada a estigma se encuentra la epilepsia, una de las enfermedades neurológicas más prevalentes a nivel mundial y de curso crónico. En los últimos años, se ha mostrado mayor interés en el estudio de este fenómeno, ya que afecta de manera directa la calidad de vida de las personas con epilepsia, influyendo en su desarrollo personal, escolar, laboral y pronóstico.

Abstract Stigma is a phenomenon characterized by a negative response to a person possessing a different attribute within the social group it develops. Two types of stigmas have been described: perceived (felt) and promoted (enacted). Among the diseases with the greatest burden associated with stigma is epilepsy, one of the most prevalent neurological diseases worldwide and with a chronic course. In recent years, greater interest has been shown in the study of this phenomenon since it directly affects the quality of life of people with epilepsy, influencing their personal, academic and work development and prognosis.

Deep Brain Stimulation for Refractory Temporal Lobe Epilepsy. Current Status and Future Trends.

A comparative analysis of the targets for deep brain stimulation (DBS) to treat refractory temporal lobe epilepsy and the rationale for its use is presented, with an emphasis on the latency to obtain the significant antiepileptic effect and the long-term seizure control. The analysis includes consideration of surgical techniques currently used to optimize antiseizure effects and decrease surgical risks. Seizure control is similar for programed DBS and DBS responsive to abnormal cortical or subcortical electroencephalogram (EEG) activity. There is no difference in the long-term seizure control between programmed and responsive and intermittent or continuous DBS. However, intermittent programed DBS may have a significant antiseizure effect starting in the first month when applied to a non-sclerotic tissue such as the parahippocampal cortex. DBS induces no neuropsychological deterioration.

Centromedian Nucleus and Epilepsy.

SUMMARY: Centromedian thalamic nucleus is an intralaminar nucleus with vast connectivity to cerebral cortex and basal ganglia. It receives afferents from the brain stem through the central tegmental tract and is part of the diffuse thalamic projection system. Because the reticulothalamic system has been related to initiation and propagation of epileptic activity (centroencephalic theory of epilepsy), deep brain stimulation has been proposed to interfere with seizure genesis or propagation. Centromedian thalamic nucleus is a large nucleus laying nearby the anatomical references for stereotaxis and therefore a convenient surgical target to approach. Electrodes are implanted in the anterior ventral lateral part of the nucleus (parvocellular area), guided by intraoperative recruiting responses elicited by unilateral 6 to 8 Hz electrical stimulation delivered through the deep brain stimulation electrode. Therapeutic stimulation is delivered with the following parameters: 60 Hz, 450 µs, 3.0 V. Seizure control runs between 69% and 83% in different reports, decreasing mainly generalized seizures from the start, with significant improvement in neuropsychological performance. Significant decrease in seizure occurs from hours to days after the onset of deep brain stimulation. Some reports refer that seizure improvement may occur by the simple insertion of the deep brain stimulation electrodes, and therefore, it was used to treat refractory epileptic status.

Electrical Stimulation of Subiculum for the Treatment of Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A 2-Year Follow-Up Study.

INTRODUCTION: Evidence has been provided that the subiculum may play an important role in the generation of seizures. Electrical stimulation at this target has been reported to have anticonvulsive effects in kindling and pilocarpine rat models, while in a clinical study of hippocampal deep brain stimulation (DBS), contacts closest to the subiculum were associated with a better anticonvulsive effect. OBJECTIVES: To evaluate the effect of electrical stimulation of the subiculum in patients with refractory mesial temporal lobe epilepsy (MTLE) who have hippocampal sclerosis (HS). METHODS: Six patients with refractory MTLE and HS, who had focal impaired awareness seizures (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS), had DBS electrodes implanted in the subiculum. During the first month after implantation, all patients were OFF stimulation, then they all completed an open-label follow-up of 24 months ON stimulation. DBS parameters were set at 3 V, 450 µs, 130 Hz, cycling stimulation 1 min ON, 4 min OFF. RESULTS: There was a mean reduction of 49.16% (±SD 41.65) in total seizure number (FIAS + FBTCS) and a mean reduction of 67.93% (±SD 33.33) in FBTCS at 24 months. FBTCS decreased significantly with respect to baseline, starting from month 2 ON stimulation. CONCLUSIONS: Subiculum stimulation is effective for FBTCS reduction in patients with MTLE and HS, suggesting that the subiculum mediates the generalization rather than the genesis of mesial temporal lobe seizures. Better results are observed at longer follow-up times.

Radiofrequency ablation of the centromedian thalamic nucleus in the treatment of drug-resistant epilepsy.

OBJECTIVE: To determine the usefulness and efficacy of radiofrequency ablations (RFA) of the Centromedian thalamic nucleus (CMN) to control primarily generalized or multifocal seizures in refractory epilepsy. METHODS: Six patients with clinical diagnosis of multifocal or primarily generalized drug-resistant epilepsy were included. Bilateral RFA of the CMN was performed through a monopolar 1.8 mm. tip electrode with a temperature of 80 °C during 90 seconds. Patients were followed in every 3 months visit for 20 to 36 months and kept a monthly seizure count calendar. We also compared maximal paroxysmal electroencephalogram (EEG) activity and neuropsychological evaluation pre and 6 months postoperatively. RESULTS: A significant reduction in the number of generalized seizures was observed in all subjects in the range of 79-98%, starting the first post-operative month. Although focal aware seizures remained unchanged throughout follow-up, there was an important reduction on paroxysmal activity between the pre and postoperative EEG. No major changes on cognitive status were detected. There was post-operative dysphagia and odynophagia lasting one week and there was no mortality in this group of patients. CONCLUSION: Preliminary results of CMN RFA suggest safety and a trend toward reduction of some seizure types, it may reduce the seizure frequency like other palliative procedures since the first post-operative month, but a larger, controlled study would be needed to establish the value of this therapy.

Familial mesial temporal lobe epilepsy in Mexico: Inheritance pattern and clinical features.

PURPOSE: The objectives of this study were to determine the inheritance pattern by which familial mesial temporal lobe epilepsy (FMTLE) is segregated in Mexican families, and to identify if there was an association between the clinical characteristics and the inheritance pattern. METHOD: We included a total of 25 families with two or more members affected with MTLE during two years and elaborated a family pedigree for each family. The inheritance pattern was classified as autosomal dominant (AD) or autosomal recessive (AR), considering the affected members. We used statistical analysis association and differences between clinical characteristics and inheritance patterns. RESULTS: The affected families with the AD pattern were 15.7 fold times more likely to start seizures at 5 years of age or earlier than families with AR pattern, OR = 15.7 (IC 95% = 1.9-128.9). We observed a predominance and greater déjà vu association (64.4% vs 31.3%; p = 0.021), OR = 3.9 (CI 95% = 1.1-13.5) in patients with AD versus AR pattern. Finally, we identified that patients with AD pattern had a likelihood of presenting emotional alterations 5.6 times higher than AR (OR = 5.6, IC = 1.1-27.5). CONCLUSION: FMTLE is a heterogeneous syndrome, both phenotypically and genotypically; thus, our findings may be helpful for clinical use to perform an early diagnosis, to provide timely treatment, and to prevent comorbidities associated to this disease. However, in order to identify the possible genetic causes underlying these inheritance patterns, the use of molecular studies is necessary.

Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy.

Experimental evidence indicates that cannabidiol (CBD) induces anxiolytic and antiepileptic effects through the activation of 5-HT1A receptors. These receptors are coupled to Gi/o proteins and induce inhibitory effects. At present, the interaction of CBD with 5-HT1A receptors in the human brain is unknown. The aim of this study focused on evaluating the interaction between CBD and 5-HT1A receptors in cell membranes obtained from the hippocampus and temporal neocortex of autopsies and patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). Cell membranes were isolated from the hippocampus and temporal neocortex of a group of patients with DR-MTLE who were submitted to epilepsy surgery (n = 11) and from a group of autopsies (n = 11). The [3H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT1A receptors. The [35S]-GTPγS assay was used to investigate the CBD-induced activation of Gi/o proteins through its action on 5-HT1A receptors.The CBD affinity (pK i) for 5-HT1A receptors was similar for autopsies and patients with DR-MTLE (hippocampus: 4.29 and 4.47, respectively; temporal neocortex: 4.67 and 4.74, respectively). Concerning the [35S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (p > 0.05) at low CBD concentrations (1 pM to 10 µM). In contrast, at high concentrations (100 µM), CBD reduced the constitutive activity of Gi/o proteins of autopsies and DR-MTLE patients (hippocampus: 39.2% and 39.6%, respectively; temporal neocortex: 35.2% and 24.4%, respectively). These changes were partially reversed in the presence of WAY-100635, an antagonist of 5-HT1A receptors, in the autopsy group (hippocampus, 59.8%, p < 0.0001; temporal neocortex, 71.5%, p < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, p < 0.0001; temporal neocortex, 68.5%, p < 0.001). Our results show that CBD interacts with human 5-HT1A receptors of the hippocampus and temporal neocortex. At low concentrations, the effect of CBD upon Gi/o protein activation is limited. However, at high concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. This effect could modify neuronal excitation and epileptic seizures in patients with DR-MTLE.

Quantitative Analysis of [18F]FFMZ and [18F]FDG PET Studies in the Localization of Seizure Onset Zone in Drug-Resistant Temporal Lobe Epilepsy.

BACKGROUND: Positron emission tomography (PET) imaging in epilepsy is an in vivo technique that allows the localization of a possible seizure onset zone (SOZ) during the interictal period. Stereo-electro-encephalography (SEEG) is the gold standard to define the SOZ. The objective of this research was to evaluate the accuracy of PET imaging in localizing the site of SOZ compared with SEEG. METHODS: Seven patients with refractory temporal lobe epilepsy (Ep) and 2 healthy controls (HC) underwent 2 PET scans, one with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and another with 2'-[18F]fluoroflumazenil (FFMZ), acquired 1 day apart. FDG was acquired for 10 min (static scan) 1 h after administration. An FFMZ scan was acquired for 60 min from radiopharmaceutical administration in a dynamic mode. Each brain PET image was segmented using a standard template implemented in PMOD 3.8. The pons was used as the reference region for modeling of the nondisplaceable binding potential (BPND)for FFMZ, and to obtain uptake ratios for FDG. SEEG studies of patients were performed as a part of their surgical evaluation to define the SOZ. RESULTS: Well-defined differences between HC and Ep were found with both radiopharmaceuticals, showing the utility to identify abnormal brain regions using quantitative PET imaging. Lateralization of the SOZ findings by PET (lower uptake/binding in a specific brain hemisphere) matched in 86% for FFMZ and 71% for FDG with SEEG data. CONCLUSION: Quantitative PET imaging is an excellent complementary tool that matches reasonably well with SEEG to define SOZ in presurgical evaluation.

Prelemniscal Lesion for Selective Improvement of Parkinson Disease Tremor.

BACKGROUND: Selective improvement of symptoms may be required when treating Parkinson disease (PD) patients with a predominantly monosymptomatic clinical picture. OBJECTIVE: To define a target in prelemniscal radiation fibers (Raprl) related to the physiopathology of tremor evidenced by tractography. CASE REPORT: We report a patient with predominant unilateral rest and postural tremor, diagnosed as PD based on 80% improvement induced by the administration of L-DOPA/carbidopa, subsequently complicated by motor fluctuations, L-DOPA dyskinesia, and a reduced ON period. A stereotactic radiofrequency lesion was made for tremor control, and postoperative diffusion-weighted imaging (DWI) demonstrated the precise location and extension of the lesioned tract. RESULTS: Perfect control of the tremor was achieved with the patient OFF medication; this has lasted for 5 years, without hypotonia in the treated extremities. DWI revealed a 3.0-mm lesion at the base of the nucleus ventralis intermedius (Vim) interrupting cerebellar-Vim fibers sparing the cerebellar ventralis oralis posterior nucleus component. CONCLUSION: Selective improvement of symptoms is feasible in patients with a predominantly monosymptomatic PD clinical presentation.

Association of white matter diffusion characteristics and cognitive deficits in temporal lobe epilepsy.

OBJECTIVE: The purpose of this study was to evaluate the relation between cognitive performance and white matter (WM) integrity in patients with temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS). METHODS: We included 26 patients with TLE (10 right, 16 left onset) as well as 24 healthy controls matched for age, gender, and years of education. In addition to quantitative hippocampal volume and transverse relaxation (T2) evaluation, whole-brain WM was analyzed using fractional anisotropy (FA) maps, derived from the diffusion tensor model. Average FA values were obtained from 38 regions of interest (ROI) of the main WM fascicles using an atlas-based approach. All subjects underwent extensive coFignitive assessments, Wechsler Adult Intelligence Scale (WAIS-IV) and Wechsler Memory Scale (WMS-IV). Fractional anisotropy was correlated with neuropsychological scores, and group effects were evaluated. Finally, patients were clustered based on their cognitive performance to evaluate if clinical and structural variables relate to specific cognitive profiles. RESULTS: Patients had differential alterations in the integrity of the WM dependent on seizure laterality and presence of hippocampal sclerosis. Patients with TLE showed, on average, lower scores in most of the cognitive assessments. Correlations between cognition and WM followed specific trajectories per group with TLE, particularly in Left-TLE, in which we found a marked association between cognitive abilities and WM abnormalities. Cluster analysis of cognitive performance revealed three cognitive profiles, which were associated with the degree and spread of WM abnormalities. SIGNIFICANCE: White matter diffusion characteristics differ between patients, particularly in relation to seizure laterality and hippocampal damage. Moreover, WM abnormalities are associated with cognitive performance. The extent of WM alterations leads to disrupted cerebral intercommunication and therefore negatively affects cognition.

Unilateral Stimulation of Prelemniscal Radiations for the Treatment of Acral Symptoms of Parkinson's Disease: Long-Term Results.

BACKGROUND: Prelemniscal radiations (Raprl) have been proposed as a target for the treatment of Parkinson's disease. We evaluated effectiveness of this target through UPDRS-III in patients treated with Raprl deep brain stimulation (Raprl-DBS) and followed from 24 to 48 months. METHODS: Nineteen patients in Hoehn-Yahr stages II-III were implanted with tetrapolar deep brain stimulation electrodes in Raprl contralateral to the extremities with more prominent symptoms. Placement was assisted by MRI/CT/anatomical atlas fusion, microelectrode recording, and micro- and macro-stimulation. The effect on motor symptoms was evaluated in an open label protocol through specific items of the UPDRS-III score, applied pre-operatively and 6, 12, 24, and 48 months after the onset of stimulation in an OFF-medication/ON-stimulation condition. Changes in scores with regard to pre-operative condition were obtained for each symptom in both sides and statistical significance determined through double-tail Wilcoxon test. Influence of demographic variables on outcome was analyzed using linear regression testing. RESULTS: A greater than 80% decrease in UPDRS score for contralateral symptoms (classified as excellent results) occurred in 14 patients (73.7%), while in the other 5 it decreased from 33 to 79% (considered suboptimal results). These changes remained statistically significant up to 48 months (p < 0.01), while ipsilateral symptoms progressively increased. Suboptimal results were associated with selective improvement of only one symptom. CONCLUSION: Raprl-DBS induces a long-term, significant improvement of contralateral acral symptoms of Parkinson's disease.

Pharmacoresistant temporal lobe epilepsy modifies histamine turnover and H3 receptor function in the human hippocampus and temporal neocortex.

Experiments were designed to evaluate the tissue content of tele-methylhistamine (t-MeHA) and histamine as well as H3 receptor (H3 Rs) binding and activation of the heterotrimeric guanine nucleotide binding αi/o proteins (Gαi/o) coupled to these receptors in the hippocampus and temporal neocortex of patients (n = 10) with pharmacoresistant mesial temporal lobe epilepsy (MTLE). Patients with MTLE showed elevated tissue content of t-MeHA in the hippocampus. Analyses revealed that a younger age at seizure onset was correlated with a higher tissue content of t-MeHA, lower H3 R binding, and lower efficacy of Gαi/o protein activation in the hippocampus. We conclude that the hippocampus shows a reduction in the H3 R function associated with enhanced histamine. In contrast, the temporal neocortex displayed a high efficacy of H3 Rs Gαi/o protein activation that was associated with low tissue contents of histamine and t-MeHA. These results indicate an overactivation of H3 Rs leading to decreased histamine in the temporal neocortex. However, this situation was lessened in circumstances such as a longer duration of epilepsy or higher seizure frequency. It is concluded that decrease in H3 Rs function and enhanced levels of histamine may contribute to the epileptic activity in the hippocampus and temporal neocortex of patients with pharmacoresistant MTLE.

Optimizing Prelemniscal Radiations as a Target for Motor Symptoms in Parkinson's Disease Treatment.

OBJECTIVE: To better define prelemniscal radiations (Raprl) as a target for the control of tremor and rigidity in Parkinson's disease (PD). METHODS: A total of 36 deep brain stimulation (DBS) electrodes were stereotactically implanted in Raprl contralateral to the extremities to be treated. Effects on symptoms were evaluated using UPDRS-III before and after DBS, and significance was determined using the Wilcoxon test. The location of DBS contacts in cases with optimum versus suboptimum results was evaluated using Student's t test and percentage improvement correlated through a bivariable Pearson test. The power and percentage of spike components for microelectrode recordings were statistically compared between the target point and structures located above and below. RESULTS: Raprl-DBS improved tremor and rigidity (p < 0.01). The potency of microelectrode recordings indicated that the target was formed by fibers. There was no correlation between demographic characteristics and clinical outcome, and there were no significant differences in stereotactic placement between cases with optimum and suboptimum results. Tremor and rigidity were selectively improved in cases with suboptimum results. CONCLUSION: Raprl-DBS is an effective treatment for the motor symptoms of PD. Selective improvement of symptoms suggests that the target has different fiber components related to either tremor or rigidity, and variations in improvement between cases may derive from individual variations of the location of these fibers.

Mu opioid receptor mRNA expression, binding, and functional coupling to G-proteins in human epileptic hippocampus.

Mu opioid receptors (MOR) are known to be involved in seizure activity. The main goal of the present study was to characterize the MOR mRNA expression, binding, as well as G protein activation mediated by these receptors in epileptic hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (TLE). In contrast with autopsy samples, hippocampus obtained from patients with mesial TLE demonstrated enhanced MOR mRNA expression (116%). Saturation binding experiments revealed significantly higher (60%) B(max) values for the mesial TLE group, whereas the K(d) values were not statistically different. Although mesial TLE group demonstrated high levels of basal binding for the G proteins (136%), DAMGO-stimulated [(35)S]GTPγS binding did not demonstrate significant alterations. In conclusion, our present data provide strong evidence that the epileptic hippocampus of patients with pharmacoresistant mesial TLE presents significant alterations in MOR. Such changes may represent adaptive mechanisms to compensate for other as yet unknown alterations.

Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle.

OBJECTIVE: Deep brain stimulation has been used in the treatment of refractory obsessive-compulsive disorder (OCD). Our principal objective was to determine the safety and effectiveness of deep brain stimulation of the inferior thalamic peduncle in the treatment of refractory OCD. METHODS: An open protocol was performed from March 2003 to April 2007 in 5 patients with OCD refractory to conventional treatments. Bilateral stereotactic implantation of tetrapolar electrodes was aimed at the inferior thalamic peduncle and corroborated by electrophysiological responses and magnetic resonance imaging. All patients were off stimulation for 1 month after implantation. In the on-stimulation period, parameters were set at 5 V, 450 microseconds, 130 Hz in bipolar and continuous mode. Clinical changes were evaluated every 3 months for 12 months by means of the Yale-Brown Obsessive Compulsive Scale and the Global Assessment of Functioning scale. Statistical significance was assessed by the Friedman and Wilcoxon tests. RESULTS: The mean Yale-Brown Obsessive Compulsive Scale score decreased from 35 to 17.8 (P < 0.001), and the mean Global Assessment of Functioning scale score improved from 20% to 70% (P < 0.0001). The neuropsychological battery did not show significant changes, and there were no side effects related to electrical stimulation in the chronic period. CONCLUSION: We conclude that inferior thalamic peduncle stimulation is a safe procedure and may be an effective alternative in the treatment of those OCD cases refractory to conventional treatments.

[Brain activity associated with a nouns-reading task]. / Activación cerebral asociada a una tarea de lectura de sustantivos.

BACKGROUND: Word reading involves several steps, from the visual perception of each of its constitutent elements to its recognition as an entity with a specific meaning. Various brain structures participate in these processes, depending of the linguistic and cognitive characteristics of the stimulus. Our objective was to characterize brain activity through the use of functional magnetic resonance imaging (FMRI) associated with the process of noun reading. METHODS: Eleven healthy right-handed volunteers participated in a lexical decision task involving 58 written nouns. An equal number of letter sequences were used as control stimuli. Reaction times were also recorded. RESULTS: There was a difference (p < 0.05) in reaction time between nouns and letter sequences in the lexical decision task. FMRI contrasted between conditions revealed significant activations in several areas involved in reading. CONCLUSIONS: The brain activation may reflect the different perceptual demands associated with the initial processing of nouns, as compared to meaningless letter sequences. We attribute the difference between our results and those previously reported to the particular characteristics of the pronunciation rules of written Spanish.

Efficacy of motor cortex stimulation in the treatment of neuropathic pain: a randomized double-blind trial.

OBJECT: In this study the authors used a double-blind protocol to assess the efficacy of motor cortex stimulation (MCS) for treating neuropathic pain. METHODS: Eleven patients with unilateral neuropathic pain (visual analog scale [VAS] score 8-10) of different origins and topography were selected for MCS. A 20-contact grid was implanted through a craniotomy centered over the motor cortex contralateral to the painful area. The motor cortex strip was identified using neuroimages, somatosensory evoked potentials, acute electrical stimulation, and corticocortical evoked potentials. Subacute therapeutic stimulation trials allowed the authors to determine the most efficient pair of contacts to use for long-term MCS. The grid was replaced with a 4-contact electrode connected to an internalized stimulator. Bipolar stimulation at a 40-Hz frequency, 90-micro sec pulse width, amplitude 2-7 V, and 1 hour in "ON" and 4 hours in "OFF" mode was used. Pain was evaluated using the VAS, Bourhis, and McGill pain scales applied each month for 1 year. At Day 60 or 90, the stimulators were turned to OFF mode for 30 days in a randomized, double-blind fashion. The statistical tool used was the Wilcoxon test. RESULTS: Three patients did not report improvement in the subacute trial and were excluded from long-term MCS; the remaining patients underwent long-term stimulation. Significant improvement of pain was induced by MCS (p < 0.01); this persisted during the follow-up period. Turning stimulation to OFF mode increased pain significantly (p < 0.05). Improvement at 1 year was >or= 40% (40-86%) in all cases. CONCLUSIONS: Motor cortex stimulation is an efficient treatment for neuropathic pain, according to an evaluation facilitated by a double-blind maneuver. Subacute stimulation trials are recommended to determine the optimum motor cortex area to be stimulated and to identify nonresponders.