Motor cortex stimulation for phantom limb pain: comprehensive therapy with spinal cord and thalamic stimulation

The effects of spinal cord stimulation (SCS), deep brain stimulation (DBS) of the thalamic nucleus ventralis caudalis (VC) and motor cortex stimulation (MCS) were analyzed in 19 patients with phantom limb pain. All of the patients underwent SCS and, if the SCS failed to reduce the pain, the patients were considered for DBS and/or MCS. Satisfactory pain control for the long-term was achieved in 6 of 19 (32%) by SCS, 6 of 10 (60%) by DBS and 1 (20%) of 5 by MCS. SCS and DBS of the VC sometimes produced a dramatic effect on the pain, leading to a long pain-free interval and infrequent use of stimulation. The effects of both DBS of the VC and MCS were tested in four. One patient of them reported better pain control by MCS than by DBS, whereas two reported the opposite results. There is no evidence at present for an advantage of MCS over SCS and DBS of the VC in controlling phantom limb pain.     

Invasive and non-invasive brain stimulation for treatment of neuropathic pain in patients with spinal cord injury: A review

Context

Past evidence has shown that invasive and non-invasive brain stimulation may be effective for relieving central pain.

Objective

To perform a topical review of the literature on brain neurostimulation techniques in patients with chronic neuropathic pain due to traumatic spinal cord injury (SCI) and to assess the current evidence for their therapeutic efficacy.

Methods

A MEDLINE search was performed using following terms: “Spinal cord injury”, “Neuropathic pain”, “Brain stimulation”, “Deep brain stimulation” (DBS), “Motor cortex stimulation” (MCS), “Transcranial magnetic stimulation” (TMS), “Transcranial direct current stimulation” (tDCS), “Cranial electrotherapy stimulation” (CES).

Results

Invasive neurostimulation therapies, in particular DBS and epidural MCS, have shown promise as treatments for neuropathic and phantom limb pain. However, the long-term efficacy of DBS is low, while MCS has a relatively higher potential with lesser complications that DBS. Among the non-invasive techniques, there is accumulating evidence that repetitive TMS can produce analgesic effects in healthy subjects undergoing laboratory-induced pain and in chronic pain conditions of various etiologies, at least partially and transiently. Another very safe technique of non-invasive brain stimulation – tDCS – applied over the sensory-motor cortex has been reported to decrease pain sensation and increase pain threshold in healthy subjects. CES has also proved to be effective in managing some types of pain, including neuropathic pain in subjects with SCI.

Conclusion

A number of studies have begun to use non-invasive neuromodulatory techniques therapeutically to relieve neuropathic pain and phantom phenomena in patients with SCI. However, further studies are warranted to corroborate the early findings and confirm different targets and stimulation paradigms. The utility of these protocols in combination with pharmacological approaches should also be explored.     

Motor cortex stimulation in patients with Parkinson disease: 12-month follow-up in 4 patients

OBJECT: Since the initial 1991 report by Tsubokawa et al., stimulation of the M1 region of cortex has been used to treat chronic pain conditions and a variety of movement disorders. METHODS: A Medline search of the literature published between 1991 and the beginning of 2007 revealed 459 cases in which motor cortex stimulation (MCS) was used. Of these, 72 were related to a movement disorder. More recently, up to 16 patients specifically with Parkinson disease were treated with MCS, and a variety of results were reported. In this report the authors describe 4 patients who were treated with extradural MCS. RESULTS: Although there were benefits seen within the first 6 months in Unified Parkinson's Disease Rating Scale Part III scores (decreased by 60%), tremor was only modestly managed with MCS in this group, and most benefits seen initially were lost by the end of 12 months. CONCLUSIONS: Although there have been some positive findings using MCS for Parkinson disease, a larger study may be needed to better determine if it should be pursued as an alternative surgical treatment to DBS.     

Efficacy of motor cortex stimulation for intractable central neuropathic pain: comparison of stimulation parameters between post-stroke pain and other central pain

Motor cortex stimulation (MCS) has now become the preferred option for neurosurgical management of intractable central neuropathic pain such as post-stroke pain and trigeminal neuropathic pain. However, the efficacy of MCS for other central neuropathic pain such as pain resulting from spinal cord or brainstem lesions is unclear. We retrospectively reviewed 11 consecutive patients with intractable central neuropathic pain who underwent MCS in our institution. Eight patients had poststroke pain caused by thalamic hemorrhage (n = 5) or infarction (n = 3) (thalamic group). Two patients had postoperative neuropathic pain caused by spinal cord lesions, and one patient had facial pain caused by a brainstem lesion associated with multiple sclerosis (brainstem-spinal group). Visual analog scale and stimulation parameters were evaluated at 1 and 6 months postoperatively. MCS was effective for six of eight patients in the thalamic group, and all three patients in the brainstem-spinal group. These efficacies continued for 6 months after surgery without significant change in the stimulation parameters compared with the parameters at 1 month in both groups. The mean amplitude at 1 month and frequency at 6 months after surgery were significantly higher in the brainstem-spinal group than the thalamic group, although the patient number was small. MCS is effective for other central neuropathic pain, but higher intensity stimulation parameters may be necessary to gain adequate pain reduction.     

Motor cortex stimulation in a patient with intractable complex regional pain syndrome type II with hemibody involvement. Case report

The authors describe the effectiveness of motor cortex stimulation (MCS) in a patient with complex regional pain syndrome (CRPS) Type II, formerly known as causalgia, with hemibody allodynia. During MCS, a subjective sensation of warm paresthesia developed in the painful hand and forearm and spread toward the trunk. Pain and allodynia in the areas associated with this sensation were alleviated significantly. The analgesic effect of stimulation proved to be long lasting and was still present at the 12-month follow up. The authors speculate that MCS might exert its effect through the modulation of thalamic activity in this particular case of CRPS with hemisensory deficit. A central mechanism associated with functional disturbance in noxious-event processing in the thalamus might have an important role in the pathogenesis of the condition.     

Spinal cord stimulation for treatment of patients in the minimally conscious state

Minimally conscious state (MCS) is characterized by inconsistent but clearly discernible behavioral evidence of consciousness, and can be distinguished from coma and the vegetative state (VS). Ten MCS patients were evaluated neurologically and electrophysiologically over 3 months after the onset of brain injury, and were treated by spinal cord stimulation (SCS). A flexible four-contact, cylinder electrode was inserted into the epidural space of the cervical vertebrae, and placed at the C2-C4 levels. Stimulation was applied for 5 minutes every 30 minutes during the daytime at an intensity that produced motor twitches of the upper extremities. We used 5 Hz for SCS, considering that the induced muscle twitches can be a useful functional neurorehabilitation for MCS patients. Eight of the 10 MCS patients satisfied the electrophysiological inclusion criteria, which we proposed on the basis of the results of deep brain stimulation for the treatment of patients in the VS. Seven patients recovered from MCS following SCS therapy, and were able to carry out functional interactive communication and/or demonstrate the functional use of two different objects. Cervical SCS increased cerebral blood flow (CBF) diffusely in the brain, and CBF increased by 22.2% during the stimulation period compared with CBF before stimulation in MCS patients (p < 0.0001, paired t-test). Five-Hz cervical SCS could increase CBF and induce muscle twitches of the upper extremities. This SCS therapy method may be suitable for treating MCS.     

A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder

OBJECT: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial. METHODS: Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus. CONCLUSIONS: Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.     

Translational research for neurostimulation

The effects of electrical stimulation on the nervous system have been known for many years. Electrical stimulation has been employed as a treatment of functional diseases of the nervous system and has been mainly developed on the basis of deep brain stimulation (DBS), motor cortex stimulation (MCS), and spinal cord stimulation (SCS). Over the past two decades, DBS has replaced lesioning techniques as a treatment for movement disorders, and DBS has been shown to be safe and efficacious. The field of application for DBS is becoming wider, currently encompassing dystonias, epilepsy, and psychiatric disease. On the other hand, MCS has been employed as a therapy for intractable pain for more than ten years. Recently, this therapy has been used as a treatment for involuntary movements and motor palsy caused by stroke. Although the effects of electrical stimulation are distinct and the therapeutic benefits are well recognized, the exact mechanisms of these therapies have not yet been fully clarified. Animal experiments, either in vitro or in vivo, show complex patterns roughly suggesting inhibitory effects. More recent data from in vitro biological research studies show that electrical stimulation affects cellular functions, particularly protein synthesis, suggesting that it could alter synaptic transmission and reorganize neural networks. Research for the understanding of the effects of electrical stimulation at the neuronal level is still in progress, and knowledge from these research will eventually improve the effectiveness of this therapy. Moreover, these basic research and preliminary clinical studies will call for the re-examination of the basic effects of electricity on living tissues because it is now clear that electrical stimulation has a wider application. In this review, we summarizes the history and rationale behind electrical neurostimulation therapy and the recent applications of this technique for various functional diseases of the nervous system.     

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.     

Patient-controlled deep brain stimulation can overcome analgesic tolerance

We report a technique based on patient-controlled stimulation to restore analgesia after development of tolerance to deep brain stimulation (DBS). A 45-year-old female with neurogenic pain after cerebellar stroke underwent DBS implantation in the right ventralis caudalis (VC) thalamus with excellent stimulus-controlled analgesia for 29 months, followed by development of tolerance and loss of analgesia. Analgesia was restored when a stimulation module that allowed patient-controlled stimulation was implanted.     

Thalamic sensory relay nucleus stimulation for the treatment of peripheral deafferentation pain

We applied chronic deep brain stimulation (DBS) of the thalamic nucleus ventralis caudalis (Vc) for the treatment of peripheral deafferentation pain. The subjects included 11 cases of phantom limb pain and 7 of root or nerve injury pain without phantom sensation. In the phantom limb pain patients, the spike density markedly increased in the same area of the Vc where microstimulation induced paresthesia in the part with phantom sensation. Reorganization of the receptive field representation within the Vc was also demonstrated by microrecording and microstimulation. In the root or nerve injury pain patients with severe allodynia and without phantom sensation, oscillating neural hyperactivity appeared when the allodynia was induced during single-cell recording in the Vc. In both groups stimulation of these areas with the DBS electrode was useful for achieving pain reduction. Inhibition of spinothalamic tract neurons, restoration of the original receptive field representation and modulation of thalamocortical rhythmic oscillations are proposed to play important roles in a possible mechanism of Vc-DBS for the treatment of deafferentation pain.     

Appetite suppression and weight loss incidental to spinal cord stimulation for pain relief

Spinal cord stimulation (SCS) uses electrical stimulation of the dorsal columns of the spinal cord to prevent the perception of intractable neuropathic pain signals, but its mechanisms and consequences of use are poorly understood. Two overweight female patients who were implanted with SCS systems (Precision™; Advanced Bionics/Boston Scientific, Valencia, CA) reported better than 50% relief of their chronic back and leg pain. Unexpectedly, SCS stimulation was also associated with a tingling sensation in the viscera and a reduction in appetite. Both patients were thus able to reduce food intake at mealtimes and had lost about 9 kg in the first 4 months of SCS use, despite denying changes in exercise habits. The mechanism by which SCS can reduce the desire for food is unknown, but this and similar neuromodulation techniques may hold promise for weight loss in patients who fail other treatments or are not healthy enough for surgery. All data were collected in medical practice. Dr. Foster is an employee of Advanced Bionics/Boston Scientific.     

Regional cerebral perfusion differences between periventricular grey, thalamic and dual target deep brain stimulation for chronic neuropathic pain

Regional cerebral blood flow changes were evaluated in different subcortical brain targets following deep brain stimulation (DBS) for chronic pain. Three patients with intractable neuropathic pain were assessed; one had stimulating electrodes in the ventroposterolateral thalamic nucleus (VPL), one in the periventricular grey (PVG) area, and one had electrodes in both targets. Pain relief was achieved in all patients. Cerebral perfusion was measured by single-photon emission computed tomography to determine the effects of DBS. Comparison was made between individual scans using subtraction analysis. DBS consistently increased perfusion in the posterior subcortical region between VPL and PVG, regardless of the site of stimulation. Furthermore, thalamic and dual target DBS increased thalamic perfusion, yet PVG DBS decreased perfusion in the PVG-containing midbrain region and thalamus. Dual target stimulation decreased anterior cingulate and insular cortex perfusion. The study demonstrates regional differences in cerebral perfusion between three accepted and efficacious targets for analgesic DBS.     

Deep brain stimulation for the treatment of chronic, intractable pain

Deep brain stimulation (DBS) was first used for the treatment of pain in 1954. Since that time, remarkable advances have been made in the field of DBS, largely because of the resurgence of DBS for the treatment of movement disorders. Although DBS for pain has largely been supplanted by motor cortex and spinal cord stimulation during the last decade, no solid evidence exists that these alternative modalities truly offer improved outcomes. Furthermore, nuclei not yet fully explored are known to play a role in the transmission and modulation of pain. This article outlines the history of DBS for pain, pain classification, patient selection criteria, DBS target selection, surgical techniques, indications for DBS (versus ablative techniques), putative new DBS targets, complications, and the outcomes associated with DBS for pain.     

Combination therapy of radiofrequency lumbar facet joint denervation and epidural spinal cord stimulation for failed back surgery syndrome

An 81-year-old woman with failed back surgery syndrome (FBSS) was treated using a combination of percutaneous radiofrequency (RF) lumbar zygapophysial joint denervation and epidural spinal cord stimulation (SCS). She had undergone a staged laminectomy for narrowing of the spinal canal from L1 to S1 and degenerative spondylolisthesis at the L3-4 level. Postoperatively, in addition to low back pain (LBP) induced by dynamic motion, she began to experience intractable leg pain with a burning sensation, presumably caused by damage to the cauda equina. She initially underwent RF lumbar zygapophysial joint denervation for the LBP and subsequently underwent SCS via dual electrode leads for the leg pain. This combination therapy of RF denervation and SCS relieved the LBP almost entirely and relieved the leg pain by approximately 50%. The combination of these two minimally invasive interventions is particularly effective for severe leg pain and LBP in elderly patients or medically compromised cases with contraindications against general anesthesia, as well as in patients with FBSS.     

Motor cortex stimulation for post-stroke pain using neuronavigation and evoked potentials: report of 3 cases

Although motor cortex stimulation (MCS) has been accepted as an effective therapeutic option for central pain, the efficacy of MCS widely varies among previous reports. In this report, we describe our recent trial for successful MCS in 3 patients with central pain due to cerebral stroke. Medical treatments were transiently effective, but gradually became ineffective in all of the cases. During surgery, the appropriate cortical target was determined by using neuronavigation, somatosensory evoked potential (SEP), and motor evoked potential (MEP). A flat, four-plate electrode was positioned on the dura mater parallel to the motor cortex. After surgery, pain almost resolved in 2 of 3 patients and markedly improved in another. The pain relief depended on their motor function. These findings strongly suggest that both patient selection and intraoperative monitoring for targeting the motor cortex are quite important for successful MCS, although further studies were essential.     

Impact of spinal cord stimulation on sensory characteristics in complex regional pain syndrome type I: a randomized trial

BACKGROUND: A randomized trial was performed to assess the effect of spinal cord stimulation (SCS) on detection and pain thresholds for pressure, warmth, and cold and on the extent of mechanical hyperalgesia in patients with chronic complex regional pain syndrome type I. METHODS: Fifty-four chronic complex regional pain syndrome type I patients were randomized to receive both SCS and physical therapy (SCS+PT; n = 36), or to receive only physical therapy (PT; n = 18). Twenty-four SCS+PT patients responded positively to trial stimulation and underwent SCS implantation. During a 12-month follow-up period, six quantitative sensory testing sessions were performed. The main analysis compared 24 SCS patients with 29 nonimplanted patients--one PT patient was excluded. RESULTS: SCS showed no effect on detection thresholds for warmth and cold or on pain thresholds for any sensation. The pressure detection threshold initially increased by SCS, but after 3 months, pressure detection thresholds returned to normal. Mechanical hyperalgesia, both dynamic and static, was reduced slightly with SCS. CONCLUSIONS: Although SCS has previously been shown to cause a significant pain reduction in complex regional pain syndrome type I, the treatment has no long-term effect on detection and pain thresholds for pressure, warmth, or cold. The treatment seems to have only minimal influence on mechanical hyperalgesia.     

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.     

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.     

Chronological changes in astrocytes induced by chronic electrical sensorimotor cortex stimulation in rats

Motor cortex stimulation (MCS) is a treatment option for various disorders such as medically refractory pain, poststroke hemiplegia, and movement disorders. However, the exact mechanisms underlying its effects remain unknown. In this study, the effects of long-term chronic MCS were investigated by observing changes in astrocytes. A quadripolar stimulation electrode was implanted on the dura over the sensorimotor cortex of adult rats, and the cortex was continuously stimulated for 3 hours, 1 week, 4 weeks, and 8 weeks. Immunohistochemical staining of microglia (ionized calcium-binding adaptor molecule 1 [Iba1] staining) and astrocytes (glial fibrillary acidic protein [GFAP] staining), and neuronal degeneration histochemistry (Fluoro-Jade B staining) were carried out to investigate the morphological changes following long-term chronic MCS. Iba1 staining and Fluoro-Jade B staining showed no evidence of Iba1-positive microglial changes or neurodegeneration. Following continuous MCS, GFAP-positive astrocytes were enlarged and their number increased in the cortex and the thalamus of the stimulated hemisphere. These findings indicate that chronic electrical stimulation can continuously activate astrocytes and result in morphological and quantitative changes. These changes may be involved in the mechanisms underlying the neuroplasticity effect induced by MCS.