Neurofeedback Training without Explicit Phantom Hand Movements and Hand-Like Visual Feedback to Modulate Pain: A Randomized Crossover Feasibility Trial.

Phantom limb pain is attributed to abnormal sensorimotor cortical representations, although the causal relationship between phantom limb pain and sensorimotor cortical representations suffers from the potentially confounding effects of phantom hand movements. We developed neurofeedback training to change sensorimotor cortical representations without explicit phantom hand movements or hand-like visual feedback. We tested the feasibility of neurofeedback training in fourteen patients with phantom limb pain. Neurofeedback training was performed in a single-blind, randomized, crossover trial using two decoders constructed using motor cortical currents measured during phantom hand movements; the motor cortical currents contralateral or ipsilateral to the phantom hand (contralateral and ipsilateral training) were estimated from magnetoencephalograms. Patients were instructed to control the size of a disk, which was proportional to the decoding results, but to not move their phantom hands or other body parts. The pain assessed by the visual analogue scale was significantly greater after contralateral training than after ipsilateral training. Classification accuracy of phantom hand movements significantly increased only after contralateral training. These results suggested that the proposed neurofeedback training changed phantom hand representation and modulated pain without explicit phantom hand movements or hand-like visual feedback, thus showing the relation between the phantom hand representations and pain. PERSPECTIVE: Our work demonstrates the feasibility of using neurofeedback training to change phantom hand representation and modulate pain perception without explicit phantom hand movements and hand-like visual feedback. The results enhance the mechanistic understanding of certain treatments, such as mirror therapy, that change the sensorimotor cortical representation.

Induced sensorimotor brain plasticity controls pain in phantom limb patients.

The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback.

Validation and the future of stimulation therapy of the primary motor cortex.

The use of electrical motor cortex stimulation (EMCS) for post-stroke pain was established in Japan and has spread globally. EMCS has been used for the treatment of neuropathic pain, Parkinson's syndrome, and recovery of motor paresis. Since 2000, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of various neurological disorders. rTMS is a non-invasive method with almost no adverse effects. In the USA, rTMS of the left dorsolateral prefrontal cortex was approved for the treatment of major depression in 2008. rTMS of the primary motor cortex (M1) has been studied worldwide for the treatment of neuropathic pain, Parkinson's disease, motor paresis after stroke, and other neurological problems. New methods and devices for rTMS therapy are under development, and rTMS of the M1 is likely to be established as an effective therapy for some neurological disorders. The present review discusses EMCS and rTMS of the M1 concisely.

Spinal cord stimulation for central poststroke pain.

BACKGROUND: Although spinal cord stimulation (SCS) has been shown to be effective for treating neuropathic pain of peripheral origin, its effectiveness for central poststroke pain (CPSP) is not well established. OBJECTIVE: We report our experience with SCS in 30 consecutive patients with intractable CPSP. METHODS: All patients underwent a percutaneous SCS trial. When patients decided to proceed, they received a permanent SCS system. Pain intensity was evaluated by a visual analogue scale (VAS). The Patient Global Impression of Change (PGIC) scale was also assessed at the latest follow-up visit as an indicator of overall improvement. RESULTS: During trial stimulation, pain relief was good (> or =50% VAS score reduction) in 9 patients (30%), fair (30%-49% reduction) in 6 patients (20%), and poor (<30% reduction) in 15 patients (50%). Ten patients elected to receive a permanent SCS system. Nine of these 10 patients were followed long-term (mean, 28 months; range, 6-62 months). Seven patients reported significant pain relief on the VAS (5 = good and 2 = fair). On the PGIC scale, 6 of these 7 patients reported a rating of 2 (much improved) and 1 reported a rating of 3 (minimally improved). Of the remaining 2 patients, 1 reported a rating of 4 (no change) and 1 reported a rating of 5 (minimally worse). The median VAS score in the 9 patients decreased significantly from 8.6 (range, 6.0-10.0) to 4.5 (range, 3.0-8.0; P = .008). There were no significant reported complications. CONCLUSION: SCS may provide improved pain control in a group of patients with intractable CPSP and may have therapeutic potential for intractable CPSP.

Modulation of neuronal activity after spinal cord stimulation for neuropathic pain; H(2)15O PET study.

Spinal cord stimulation (SCS) is an effective therapy for chronic neuropathic pain. However, the detailed mechanisms underlying its effects are not well understood. Positron emission tomography (PET) with H(2)(15)O was applied to clarify these mechanisms. Nine patients with intractable neuropathic pain in the lower limbs were included in the study. All patients underwent SCS therapy for intractable pain, which was due to failed back surgery syndrome in three patients, complex regional pain syndrome in two, cerebral hemorrhage in two, spinal infarction in one, and spinal cord injury in one. Regional cerebral blood flow (rCBF) was measured by H(2)(15)O PET before and after SCS. The images were analyzed with statistical parametric mapping software (SPM2). SCS reduced pain; visual analog scale values for pain decreased from 76.1+/-25.2 before SCS to 40.6+/-4.5 after SCS (mean+/-SE). Significant rCBF increases were identified after SCS in the thalamus contralateral to the painful limb and in the bilateral parietal association area. The anterior cingulate cortex (ACC) and prefrontal areas were also activated after SCS. These results suggest that SCS modulates supraspinal neuronal activities. The contralateral thalamus and parietal association area would regulate the pain threshold. The ACC and prefrontal areas would control the emotional aspects of intractable pain, resulting in the reduction of neuropathic pain after SCS.

Diffusion tensor fiber tracking in patients with central post-stroke pain; correlation with efficacy of repetitive transcranial magnetic stimulation.

Central post-stroke pain (CPSP) is one of the most common types of intractable pain. We reported that repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex relieves pain for patients who were refractory to medical treatment. But the mechanism is unclear. In the present study, we investigated relations between the characteristics of CPSP and the results of fiber tracking, which is the only noninvasive method of evaluating the anatomical connectivity of white matter pathways. Fiber tracking of the corticospinal tract (CST) and thalamocortical tract (TCT) was investigated in 17 patients with CPSP. The stroke lesion was located in a supratentorial region in all cases (corona radiata, one case; thalamus, seven cases; putamen, nine cases). Relations between the delineation ratio (defined as the ratio of the cross section of the affected side to that of the unaffected side) of the CST and of the TCT, manual muscle test score, pain score, region of pain, and efficacy of rTMS were evaluated. Fiber tracking was successful in 13 patients with the stroke lesion involving the TCT. The rTMS-effective group had higher delineation ratio of the CST (p=0.02) and the TCT (p=0.005) than the rTMS-ineffective group. Previous studies suggested that an intact CST allows pain control but did not discuss the TCT. Our results suggest that the TCT also plays a role in pain reduction by rTMS of the primary motor cortex and that the efficacy of rTMS for patients with CPSP is predictable by fiber tracking.

Electrical stimulation of primary motor cortex within the central sulcus for intractable neuropathic pain.

OBJECTIVE: To assess the pain-relieving effects of motor cortex electrical stimulation (MCS) within the central sulcus and the predictive factors retrospectively. METHODS: Thirty-four patients with intractable neuropathic pain underwent MCS; 19 patients had cerebral lesions, and 15 had non-cerebral lesions. In selected 12 patients, test electrodes were implanted within the central sulcus and on the precentral gyrus. Twelve patients received both MCS and repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex. RESULTS: Pain reduction of > or =50% was observed in 12 of 32 (36%) patients with > or =12 months follow-ups (2 patients were excluded because of short follow-up). In 10 of the 12 patients who received test electrodes within the central sulcus and on the precentral gyrus, the optimal stimulation was MCS within the central sulcus. In 4 of these (40%) patients, positive effects were maintained at follow-ups. The pain reduction of rTMS significantly correlated with that of MCS during test stimulation. CONCLUSIONS: The test stimulation within the central sulcus was more effective than that of the precentral gyrus. In the selected patients, chronic stimulation within the central sulcus did not significantly improve long-term results. SIGNIFICANCE: The present findings suggest that an intra-central sulcus is one of the favorable targets for MCS.

Motor cortex stimulation in patients with deafferentation pain: activation of the posterior insula and thalamus.

OBJECT: The mechanisms underlying deafferentation pain are not well understood. Motor cortex stimulation (MCS) is useful in the treatment of this kind of chronic pain, but the detailed mechanisms underlying its effects are unknown. METHODS: Six patients with intractable deafferentation pain in the left hand were included in this study. All were righthanded and had a subdural electrode placed over the right precentral gyrus. The pain was associated with brainstem injury in one patient, cervical spine injury in one patient, thalamic hemorrhage in one patient, and brachial plexus avulsion in three patients. Treatment with MCS reduced pain; visual analog scale (VAS) values for pain were 82 +/- 20 before MCS and 39 +/- 20 after MCS (mean +/- standard error). Regional cerebral blood flow (rCBF) was measured by positron emission tomography with H2(15)O before and after MCS. The obtained images were analyzed with statistical parametric mapping software (SPM99). RESULTS: Significant rCBF increases were identified after MCS in the left posterior thalamus and left insula. In the early post-MCS phase, the left posterior insula and right orbitofrontal cortex showed significant rCBF increases, and the right precentral gyrus showed an rCBF decrease. In the late post-MCS phase, a significant rCBF increase was detected in the left caudal part of the anterior cingulate cortex (ACC). CONCLUSIONS: These results suggest that MCS modulates the pathways from the posterior insula and orbitofrontal cortex to the posterior thalamus to upregulate the pain threshold and pathways from the posterior insula to the caudal ACC to control emotional perception. This modulation results in decreased VAS scores for deafferentation pain.

Bilateral cortical stimulation for deafferentation pain after spinal cord injury. Case report.

The relief of intractable pain after spinal cord injury (SCI) is very difficult to obtain, even with dorsal root entry zone lesioning, spinal cord stimulation, and thalamic stimulation. Using bilateral motor cortex stimulation (MCS) the authors successfully treated a woman who experienced deafferentation pain 4 years after sustaining an SCI. To the authors' knowledge, this is the first report of bilateral MCS for pain relief after SCI. The success they achieved using this method indicates that MCS could be a new treatment option for deafferentation pain following SCI.

Increased regional cerebral blood flow in the contralateral thalamus after successful motor cortex stimulation in a patient with poststroke pain.

The mechanisms underlying poststroke pain have not been clearly identified. Although motor cortex stimulation (MCS) sometimes reduces poststroke pain successfully, the exact mechanism is not yet known. For further investigation of the neural pathways involved in the processing of poststroke pain and in pain reduction by MCS, the authors used positron emission tomography (PET) scanning to determine significant changes in regional cerebral blood flow (rCBF). This 58-year-old right-handed man suffered from right-sided poststroke pain for which he underwent implantation of a stimulation electrode in the right motor cortex. After 30 minutes of stimulation, his pain was remarkably reduced (Visual Analog Scale scores decreased 8 to 1) and he felt warmth in his left arm. The rCBF was studied using PET scanning with 15O-labeled water when the patient was in the following states: before MCS (painful condition, no stimulation) and after successful MCS (painless condition, no stimulation). The images were analyzed using statistical parametric mapping software. State-dependent differences in global blood flow were covaried using analysis of covariance. Comparisons of the patient's rCBF in the painful condition with that in the painless condition revealed significant rCBF increases in the left rectus gyrus (BA11), left superior frontal lobe (BA9), left anterior cingulate gyms (BA32), and the left thalamus (p < 0.05, corrected). On the other hand, there were significant decreases in rCBF in the right superior temporal gyrus (BA22, p < 0.01, corrected) and the left middle occipital gyrus (BA19, p < 0.05, corrected). The efficacy of MCS was mainly related to increased synaptic activity in the thalamus, whereas the activations in the rectus gyrus, anterior cingulate gyrus, and superior frontal cortex as well as the inactivation of the superior temporal lobe may be related to emotional processes. This is the first report in which the contralateral thalamus was significantly activated and pain relief was achieved using MCS.