Invasive brain stimulation for the treatment of neuropathic pain.

Neurostimulation therapy is indicated for neuropathic pain that is refractory to medical treatment, and includes stimulation of the dorsal spinal cord, deep brain structures, and the precentral motor cortex. Spinal cord stimulation is validated in the treatment of selected types of chronic pain syndromes, such as failed back surgery syndrome. Deep brain stimulation (DBS) has shown promise as a treatment for peripheral neuropathic pain and phantom limb pain. Compared with DBS, motor cortex stimulation (MCS) is currently more frequently used, mainly because it is more easily performed, and has a wider range of indications (including central poststroke pain). Controlled trials have demonstrated the efficacy of MCS in the treatment of various types of neuropathic pain, although these trials included a limited number of patients and need to be confirmed by large, controlled, multicenter studies. Despite technical progress in neurosurgical navigation, results from studies of MCS are variable, and validated criteria for selecting good candidates for implantation are lacking. However, the evidence in favor of MCS is sufficient to include it in the range of therapeutic options for refractory neuropathic pain. In this Review, the respective efficacies and mechanisms of action of DBS and MCS are discussed.

Predictive value of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain.

UNLABELLED: This study was designed to assess the value of repetitive transcranial magnetic stimulation (rTMS) to predict the efficacy of epidural motor cortex stimulation (EMCS) to treat neuropathic pain. We have included 59 patients treated by EMCS for more than 1 year and in whom active and sham 10Hz-rTMS sessions were performed as preoperative tests, targeted over the cortical representation of the painful area. Analgesic effects were rated on a visual analogue scale. The real rTMS efficacy was determined by subtracting the effect of the sham stimulation on pain scores from that of the active stimulation (active-sham calculation). Pain scores were significantly reduced by active rTMS and EMCS, but not by sham rTMS. Twenty-six of the 33 patients (79%) who responded to active rTMS and all the 21 patients (100%) who responded for active-sham calculation also responded to EMCS. The response observed in active-sham calculation had a positive predictive value of 1.0, but a negative predictive value of .6 regarding EMCS outcome. The analgesic effect of rTMS or EMCS was not influenced by the side, origin, or duration of pain or by the presence of motor or sensory deficit in the painful area. Poorer results were observed in case of lower limb pain for rTMS and in older patients for EMCS. This study confirms that neuropathic pain can be significantly relieved by motor cortex rTMS or EMCS. A positive outcome of EMCS can be predicted by a real response to rTMS, but not on clinical grounds. PERSPECTIVE: Single sessions of sham-controlled preoperative rTMS tests can be used to confirm the indication of EMCS therapy but have no value to exclude patients from this therapy. New rTMS protocols remain to be assessed to improve the usefulness of preoperative rTMS in EMCS practice.

Treatment of poststroke pain by epidural motor cortex stimulation with a new octopolar lead.

BACKGROUND: Chronic, drug-resistant neuropathic pain can be treated by surgically implanted motor cortex stimulation (MCS). The leads used for MCS have not been specifically designed for this application. OBJECTIVE: To study the value of a new 8-contact lead for MCS therapy in a series of 6 patients with refractory central poststroke pain. METHODS: The study comprised a 1-month randomized phase, starting 1 month after implantation, during which the neurostimulator was switched on in one-half of the patients or remained off in the other half, followed by an open phase of 10 months, during which the stimulator was switched on in all patients. Clinical assessment was performed at baseline and 1, 2, 3, 6, and 12 months after implantation with the following scales: Visual Analog Scale, Verbal Rating Scale, Brief Pain Inventory, McGill Pain Questionnaire, Sickness Impact Profile, and Medication Quantification Scale. RESULTS: In the randomized phase, clinical scores were found to be globally reduced in the on- vs off-stimulation condition. In the open follow-up phase, all clinical scores improved significantly over time. The ratio between affective and sensory McGill Pain Questionnaire subscores decreased, suggesting a preferential effect of MCS on the affective component of pain. Compared with preoperative baseline, 2 patients were totally relieved of central poststroke pain, 3 patients were very much relieved, and 1 patient remained unchanged at the final examination. CONCLUSION: A good clinical outcome was observed in all patients except 1, suggesting that this new octopolar lead could be used for MCS therapy to treat refractory central poststroke pain.

Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome.

Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched 'ON' or 'OFF' for 1h. Significant changes in 'ON' condition were as follows: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, H-reflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing.

Descending volleys generated by efficacious epidural motor cortex stimulation in patients with chronic neuropathic pain.

Epidural motor cortex stimulation (EMCS) is a therapeutic option for chronic, drug-resistant neuropathic pain, but its mechanisms of action remain poorly understood. In two patients with refractory hand pain successfully treated by EMCS, the presence of implanted epidural cervical electrodes for spinal cord stimulation permitted to study the descending volleys generated by EMCS in order to better appraise the neural circuits involved in EMCS effects. Direct and indirect volleys (D- and I-waves) were produced depending on electrode polarity and montage and stimulus intensity. At low-intensity, anodal monopolar EMCS generated D-waves, suggesting direct activation of corticospinal fibers, whereas cathodal EMCS generated I2-waves, suggesting transsynaptic activation of corticospinal tract. The bipolar electrode configuration used in chronic EMCS to produce maximal pain relief generated mostly I3-waves. This result suggests that EMCS induces analgesia by activating top-down controls originating from intracortical horizontal fibers or interneurons but not by stimulating directly the pyramidal tract. The descending volleys elicited by bipolar EMCS are close to those elicited by transcranial magnetic stimulation using a coil with posteroanterior orientation. Different pathways are activated by EMCS according to stimulus intensity and electrode montage and polarity. Special attention should be paid to these parameters when programming EMCS for pain treatment.

Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain.

OBJECTIVE: To assess the modulation of acute provoked pain by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic neuropathic pain. METHODS: In 32 patients with chronic neuropathic pain affecting one upper limb, laser-evoked potentials (LEPs) (N2 and P2 components) were recorded in response to laser stimulation of the painful or painless hand, before and after active or sham rTMS applied at 10Hz over the motor cortex corresponding to the painful hand. Laser-induced pain was scored on a visual analogue scale. RESULTS: Both active and sham rTMS reduced N2-P2 amplitude of the LEPs in response to painful or painless hand stimulation, likely due to the decline of attention during the sessions. However, active rTMS, but not sham rTMS, specifically reduced N2 amplitude and N2/P2 amplitude ratio of the painful hand LEPs. Painful hand LEP attenuation correlated with the magnitude of pain relief produced by active rTMS. CONCLUSION: Motor cortex rTMS delivered at high frequency (10Hz) was able to reduce LEP amplitude in parallel with laser-induced pain scores in patients with chronic neuropathic pain. The preferential change in the N2 component suggested a modulation of the sensori-discriminative aspect of laser-induced pain. SIGNIFICANCE: Previous studies have shown that rTMS delivered to various cortical targets by different protocols could modulate experimental pain, primarily in healthy subjects. The present results demonstrate the ability of motor cortex rTMS to interfere with the processing of acute provoked pain, even if there is an underlying chronic neuropathic pain.

Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain.

Epidural motor cortex stimulation (MCS) has been proposed as a treatment for chronic, drug-resistant neuropathic pain of various origins. Regarding pain syndromes due to peripheral nerve lesion, only case series have previously been reported. We present the results of the first randomized controlled trial using chronic MCS in this indication. Sixteen 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 crossover trial was performed between 1 and 3 months postoperative, 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: visual analogue scale (VAS), brief pain inventory, McGill Pain questionnaire, sickness impact profile and medication quantification scale. The crossover 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 9-12 months postoperative, compared to the preoperative 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 postoperative, but not with age, pain duration or location, preoperative pain scores or sensory-motor status. Although the results of the crossover trial were slightly negative, which may have been due to carry-over effects from the operative and immediate postoperative phases, observations made during the open trial were in favour 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. These results suggest that the indication of MCS might be extended to various types of refractory, chronic peripheral pain beyond trigeminal neuropathic pain.

Outcome of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease: correlation with intra-operative multi-unit recordings but not with the type of anaesthesia.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) gained general acceptance in the treatment of Parkinson's disease (PD). OBJECTIVE: To study the clinical outcome and the predicting factors of efficacy of chronic STN stimulation, while DBS electrodes were implanted under local or general anaesthesia with intra-operative electrophysiological guidance based on multi-unit recordings. METHODS: We included a large single-centre cohort of 54 patients with advanced PD (mean age: 59 years; disease duration: 14 years). Clinical evaluation was performed by the Unified Parkinson's Disease Rating Scale (UPDRS) before and 1 year after surgical placement of DBS electrodes. RESULTS: In the on-stimulation and off-medication condition, the UPDRS part III score was reduced by 56% compared to the off-stimulation condition or pre-operative off-drug score. In the on-stimulation and on-medication condition, this score was reduced by 73%. The severity of motor fluctuations and dyskinesia (UPDRS part IV) and the activities of daily living (UPDRS part II) were reduced by 65 and 80%, respectively, in the on-stimulation/on-medication condition compared to the pre-operative baseline. The daily dose of antiparkinsonian treatment was diminished by 72%. Among the various pre- and intra-operative data, the most important predictive factor for clinical efficacy of STN stimulation was the length of hyperactivity along the best track observed in intra-operative multi-unit recordings. Other predictive factors included age, disease duration and pre-operative levodopa responsiveness or baseline off-drug values of the Hoehn and Yahr and UPDRS part III scores. In contrast, the type of anaesthesia (local vs. general) did not significantly influence the clinical outcome. CONCLUSION: The present results are in the average of previously published results, but they have been obtained from a large single-centre cohort of patients with important reductions in the daily dose of antiparkinsonian drugs. This study confirmed the efficacy of the STN-DBS technique and emphasized the value of an original intra-operative electrophysiological approach based on multi-unit and not single-unit quantified recordings. This method allows DBS electrode implantation to be safely performed under general anaesthesia without lessening the rate of efficacy of the procedure.

Treatment of chronic neuropathic pain by motor cortex stimulation: results of a bicentric controlled crossover trial.

BACKGROUND: Chronic motor cortex stimulation (MCS) with surgically implanted epidural electrodes has been proposed as a treatment for neuropathic pain refractory compared with medical treatment. However, no prospective controlled trial has been published to provide convincing evidence of MCS analgesic efficacy. OBJECTIVE: To compare MCS analgesic efficacy between "ON"- and "OFF"-stimulation conditions in a double-blinded crossover trial. METHODS: Ten patients with chronic neuropathic pain of either peripheral or central origin underwent MCS implantation in two centers (Créteil, France, and Mexico City, Mexico). At the end of the second postoperative month, patients were randomly assigned into two groups. In the first group, the stimulator was switched "OFF" for two weeks and then was switched "ON" for the next 2 weeks. The opposite sequence was applied in the second group. Preoperative and postoperative assessment (until 1 year after surgery) was performed using visual analogue scale (VAS), verbal scale (VS), Wisconsin brief pain questionnaire (WBPQ), McGill pain questionnaire (MPQ), McGill quality of life scale, and medication quantification scale. RESULTS: During the crossover trial, VAS, VS, WBPQ, and MPQ scores were significantly reduced in the"ON"- compared with the "OFF"-stimulation condition. One year after surgery, all clinical scores were significantly reduced compared with preoperative values. In particular, MCS decreased the affective MPQ subscore relative to the sensory MPQ subscore. Six of the 10 patients clearly benefited from MCS treatment. CONCLUSIONS: These results were in favor of real analgesic effects produced by MCS with no loss of benefit over time. The differential changes in MPQ subscores suggested that MCS relieved pain by acting predominantly on its affective aspect. The decrease in pain intensity was associated with improved daily living activities and quality of life and reduced consumption of analgesic medication.

Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation.

A concept in Parkinson's disease postulates that motor cortex may pattern abnormal rhythmic activities in the basal ganglia, underlying the genesis of observed motor symptoms. We conducted a preclinical study of electrical interference in the primary motor cortex using a chronic MPTP primate model in which dopamine depletion was progressive and regularly documented using 18F-DOPA positron tomography. High-frequency motor cortex stimulation significantly reduced akinesia and bradykinesia. This behavioral benefit was associated with an increased metabolic activity in the supplementary motor area as assessed with 18-F-deoxyglucose PET, a normalization of mean firing rate in the internal globus pallidus (GPi) and the subthalamic nucleus (STN), and a reduction of synchronized oscillatory neuronal activities in these two structures. Motor cortex stimulation is a simple and safe procedure to modulate subthalamo-pallido-cortical loop and alleviate parkinsonian symptoms without requiring deep brain stereotactic surgery.

Motor cortex stimulation in the treatment of deafferentation pain. I. Localization of the motor cortex.

MRI and electrophysiological techniques to localize the primary motor cortex (MC) were performed on patients considered for MC stimulation for the treatment of deafferentation pain. The representation and trajectory of the rolandic fissure (RF) were accurately localized by external cranial landmarks and radiopaque fiducials superimposed on oblique MRI sections. In addition, the scalp distribution of the corticocortical responses elicited by acute epidural stimulation [motor cortex (MC) in frontal and sensory cortex (SC) in parietal scalp regions], and analgesic responses at the topographical representation of the painful periphery elicited by subacute epidural stimulation were found to be simple and reliable procedures to localize MC, SC and RF.

Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data.

Thirty-two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27.3 months. The first 24 patients were operated according to the technique described by Tsubokawa. The last 13 cases (eight new patients and five reinterventions) were operated by a technique including localisation by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organisation of the motor cortex was established peroperatively by studying the motor responses at stimulation of the motor cortex through the dura. Ten of the 13 patients with central pain (77%) and ten of the 12 patients with neuropathic facial pain had experienced substantial pain relief (75%). One of the three patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zooster. None of the patients developed epileptic seizures. The position of the stimulating poles effective on pain corresponded to the somatotopic representation of the motor cortex. The neuronavigator localisation and guidance technique proved to be most useful identifying the appropriate portion of the motor gyrus. It also allowed the establishment of reliable correlations between electrophysiological-clinical and anatomical data which may be used to improve the clinical results and possibly to extend the indications of this technique.