Brain Stimulation For Neuropathic Pain Research Articles

The deep and the deeper: Spinal cord and deep brain stimulation for neuropathic pain

Neuropathic pain occurs in people experiencing lesion or disease affecting the somatosensorial system. It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases. Neuromodulation approaches are often proposed for those not tolerating or not responding to usual pharmacological management. These approaches can be delivered surgically (invasively) or non-invasively. Invasive neuromodulation techniques were the first to be employed in neuropathic pain. Among them is spinal cord stimulation (SCS), which consists of the implantation of epidural electrodes over the spinal cord. It is recommended in some guidelines for peripheral neuropathic pain. While recent studies have called into question its efficacy, others have provided promising data, driven by advances in techniques, battery capabilities, programming algorithms and software developments. Deep brain stimulation (DBS) is another well-stablished neuromodulation therapy routinely used for movement disorders; however, its role in pain management remains limited to specific research centers. This is not only due to variable results in the literature contesting its efficacy, but also because several different brain targets have been explored in small trials, compromising comparisons between these studies. Structures such as the periaqueductal grey, posterior thalamus, anterior cingulate cortex, ventral striatum/anterior limb of the internal capsule and the insula are the main targets described to date in literature. SCS and DBS present diverse rationales for use, mechanistic backgrounds, and varying levels of support from experimental studies. The present review aims to present their methodological details, main mechanisms of action for analgesia and their place in the current body of evidence in the management of patients with neuropathic pain, as well their particularities, effectiveness, safety and limitations.

Somatotopic organization of the ventral nuclear group of the dorsal thalamus: deep brain stimulation for neuropathic pain reveals new insights into the facial homunculus.

Deep Brain Stimulation (DBS) is an experimental treatment for medication-refractory neuropathic pain. The ventral posteromedial (VPM) and ventral posterolateral (VPL) nuclei of the thalamus are popular targets for the treatment of facial and limb pain, respectively. While intraoperative testing is used to adjust targeting of patient-specific pain locations, a better understanding of thalamic somatotopy may improve targeting of specific body regions including the individual trigeminal territories, face, arm, and leg. To elucidate the somatotopic organization of the ventral nuclear group of the dorsal thalamus using in vivo macrostimulation data from patients undergoing DBS for refractory neuropathic pain. In vivo macrostimulation data was retrospectively collected for 14 patients who underwent DBS implantation for neuropathic pain syndromes at our institution. 56 contacts from 14 electrodes reconstructed with LeadDBS were assigned to macrostimulation-related body regions: tongue, face, arm, or leg. 33 contacts from 9 electrodes were similarly assigned to one of three trigeminal territories: V1, V2, or V3. MNI coordinates in the x, y, and z axes were compared by using MANOVA. Across the horizontal plane of the ventral nuclear group of the dorsal thalamus, the tongue was represented significantly medially, followed by the face, arm, and leg most laterally (p < 0.001). The trigeminal territories displayed significant mediolateral distribution, proceeding from V1 and V2 most medial to V3 most lateral (p < 0.001). Along the y-axis, V2 was also significantly anterior to V3 (p = 0.014). While our results showed that the ventral nuclear group of the dorsal thalamus displayed mediolateral somatotopy of the tongue, face, arm, and leg mirroring the cortical homunculus, the mediolateral distribution of trigeminal territories did not mirror the established cortical homunculus. This finding suggests that the facial homunculus may be inverted in the ventral nuclear group of the dorsal thalamus.

Noninvasive Brain Stimulation Does Not Improve Neuropathic Pain in Individuals With Spinal Cord Injury

The aim of the study was to examine the effectiveness of noninvasive brain stimulation on neuropathic pain in individuals with spinal cord injury. A meta-analysis on pain intensity, depression, and anxiety levels was conducted to evaluate the effect of noninvasive brain stimulation on neuropathic pain in individuals with spinal cord injury. The authors searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase (OvidSP), PsycINFO (OvidSP), and Physiotherapy Evidence Database (PEDro). Randomized controlled trials comparing noninvasive brain stimulation with sham stimulation were included. Eleven studies were selected. The pooled analysis demonstrated no significant effect of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, or cranial electrotherapy stimulation on neuropathic pain reduction after spinal cord injury. In addition, noninvasive brain stimulation showed no beneficial effect over sham stimulation on the improvement of depression, while it yielded a significant reduction of anxiety levels immediately after treatment. Subgroup analysis showed that only cranial electrotherapy stimulation had a significant effect on the reduction of anxiety levels among the three types of noninvasive brain stimulation. In individuals with spinal cord injury, no significant effects of noninvasive brain stimulation on neuropathic pain and depression were observed. Cranial electrotherapy stimulation may be beneficial for the management of anxiety. These findings do not support the routine use of noninvasive brain stimulation for neuropathic pain in individuals with spinal cord injury.

Functional dynamics of thalamic local field potentials correlate with modulation of neuropathic pain.

Understanding the functional dynamics of neural oscillations in the sensory thalamus is essential for elucidating the perception and modulation of neuropathic pain. Local field potentials were recorded from the sensory thalamus of twelve neuropathic pain patients. Single and combinational neural states were defined by the activity state of a single or paired oscillations. Relationships between the duration or occurrence rate of neural state and pre-operative pain level or pain relief induced by deep brain stimulation were evaluated. Results showed that the occurrence rate of the single neural state of low-beta oscillation was significantly correlated with pain relief. The duration and occurrence rate of combinational neural states of the paired low-beta with delta, theta, alpha, high-beta or low-gamma oscillations were more significantly correlated with pain relief than the single neural states. Moreover, these significant combinational neural states formed a local oscillatory network with low-beta oscillation as a key node. The results also showed correlations between measures of combinational neural states and subjective pain level as well. The duration of combinational neural states of paired alpha with delta or theta oscillations and the occurrence rate of neural states of the paired delta with low-beta or low-gamma oscillations were significantly correlated with pre-operative pain level. In conclusion, this study revealed that the integration of oscillations and the functional dynamics of neural states were differentially involved in modulation and perception of neuropathic pain. The functional dynamics could be biomarkers for developing neural state-dependent deep brain stimulation for neuropathic pain.

Thalamic Deep Brain Stimulation for Neuropathic Pain: Efficacy at Three Years’ Follow-Up

Chronic neuropathic pain is estimated to affect 3-4.5% of the worldwide population, posing a serious burden to society. Deep Brain Stimulation (DBS) is already established for movement disorders and also used to treat some "off-label" conditions. However, DBS for the treatment of chronic, drug refractory, neuropathic pain, has shown variable outcomes with few studies performed in the last decade. Thus, this procedure has consensus approval in parts of Europe but not the USA. This study prospectively evaluated the efficacy at three years of DBS for neuropathic pain. Sixteen consecutive patients received 36 months post-surgical follow-up in a single-center. Six had phantom limb pain after amputation and ten deafferentation pain after brachial plexus injury, all due to traumas. To evaluate the efficacy of DBS, patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, University of Washington Neuropathic Pain Score (UWNPS), Brief Pain Inventory (BPI), and 36-Item Short-Form Health Survey (SF-36). Contralateral, ventroposterolateral sensory thalamic DBS was performed in sixteen patients with chronic neuropathic pain over 29 months. A postoperative trial of externalized DBS failed in one patient with brachial plexus injury. Fifteen patients proceeded to implantation but one patient with phantom limb pain after amputation was lost for follow-up after 12 months. No surgical complications or stimulation side effects were noted. After 36 months, mean pain relief was sustained, and the median (and interquartile range) of the improvement of VAS score was 52.8% (45.4%) (p = 0.00021), UWNPS was 30.7% (49.2%) (p = 0.0590), BPI was 55.0% (32.0%) (p = 0.00737), and SF-36 was 16.3% (30.3%) (p = 0.4754). DBS demonstrated efficacy at three years for chronic neuropathic pain after traumatic amputation and brachial plexus injury, with benefits sustained across all pain outcomes measures and slightly greater improvement in phantom limb pain.

Thalamic deep brain stimulation for neuropathic pain after amputation or brachial plexus avulsion

Fifteen hundred patients have received deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy over the last half-century, but few during the last decade. Deep brain stimulation for neuropathic pain has shown variable outcomes and gained consensus approval in Europe but not the US. This study prospectively evaluated the efficacy at 1 year of DBS for phantom limb pain after amputation, and deafferentation pain after brachial plexus avulsion (BPA), in a single-center case series. Patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, 36-Item Short-Form Health Survey (SF-36), Brief Pain Inventory (BPI), and University of Washington Neuropathic Pain Score (UWNPS). Twelve patients were treated over 29 months, receiving contralateral, ventroposterolateral sensory thalamic DBS. Five patients were amputees and 7 had BPAs, all from traumas. A postoperative trial of externalized DBS failed in 1 patient with BPA. Eleven patients proceeded to implantation and gained improvement in pain scores at 12 months. No surgical complications or stimulation side effects were noted. In the amputation group, after 12 months the mean VAS score improved by 90.0% ± 10.0% (p = 0.001), SF-36 by 57.5% ± 97.9% (p = 0.127), UWNPS by 80.4% ± 12.7% (p < 0.001), and BPI by 79.9% ± 14.7% (p < 0.001). In the BPA group, after 12 months the mean VAS score improved by 52.7% ± 30.2% (p < 0.001), SF-36 by 15.6% ± 30.5% (p = 1.000), UWNPS by 26.2% ± 40.8% (p = 0.399), and BPI by 38.4% ± 41.7% (p = 0.018). Mean DBS parameters were 2.5 V, 213 microseconds, and 25 Hz. Deep brain stimulation demonstrated efficacy at 1 year for chronic neuropathic pain after traumatic amputation and BPA. Clinical trials that retain patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.

Long-term Outcomes of Deep Brain Stimulation for Neuropathic Pain

Deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy has reported variable outcomes and has gained United Kingdom but not USA regulatory approval. To prospectively assess long-term efficacy of DBS for chronic neuropathic pain in a single-center case series. Patient reported outcome measures were collated before and after surgery, using a visual analog score, short-form 36-question quality-of-life survey, McGill pain questionnaire, and EuroQol-5D questionnaires (EQ-5D and health state). One hundred ninety-seven patients were referred over 12 years, of whom 85 received DBS for various etiologies: 9 amputees, 7 brachial plexus injuries, 31 after stroke, 13 with spinal pathology, 15 with head and face pain, and 10 miscellaneous. Mean age at surgery was 52 years, and mean follow-up was 19.6 months. Contralateral DBS targeted the periventricular gray area (n = 33), the ventral posterior nuclei of the thalamus (n = 15), or both targets (n = 37). Almost 70% (69.4%) of patients retained implants 6 months after surgery. Thirty-nine of 59 (66%) of those implanted gained benefit and efficacy varied by etiology, improving outcomes in 89% after amputation and 70% after stroke. In this cohort, >30% improvements sustained in visual analog score, McGill pain questionnaire, short-form 36-question quality-of-life survey, and EuroQol-5D questionnaire were observed in 15 patients with >42 months of follow-up, with several outcome measures improving from those assessed at 1 year. DBS for pain has long-term efficacy for select etiologies. Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.

N-of-1 Trials for Assessing the Efficacy of Deep Brain Stimulation in Neuropathic Pain

The objective of this study is to determine the usefulness of single-patient, randomised, controlled trials (N-of-1 trials) in assessing the efficacy of deep brain stimulation (DBS) in neuropathic pain. Seven patients with various causes of intractable neuropathic pain underwent insertion of deep brain stimulating electrodes into the periventricular gray area or ventroposterolateral nucleus of the thalamus. Preoperatively, pain was measured using Visual Analog Scales (VAS) and the McGill Pain Questionnaire (MPQ). At 6months, these pain assessments were repeated. At this point all patients were entered into a N-of-1 trial with the DBS on and off. Data were analyzed using the Wilcoxon and Student t-tests. Following placement of the deep brain stimulator, VAS scores were significantly reduced in six of seven patients. McGill Pain Scores (MPS) showed pain reduction in four of seven. The results of the N-of-1 trials were most similar to the MPQ scores and showed that three of seven patients could accurately predict whether the DBS was on or off. In the N-of-1 trials, the time between changing the DBS from on to off (or vice versa) had an effect on the results and probably underestimated the efficacy. We conclude that N-of-1 trials are a useful tool for assessing DBS efficacy.