Treatment of Thalamic Pain by Chronic Motor Cortex Stimulation

All forms of therapy, including chronic stimulation of the thalamic relay nucleus, can provide satisfactory pain control in only 20%-30% of cases of thalamic pain syndrome. In order to develop a more effective treatment for thalamic pain syndrome, we investigated the effects of stimulation of various brain regions on the burst hyperactivity of thalamic neurons recorded in cats after deafferentiation of the spinothalamic pathway. Complete, long-term inhibition of the burst hyperactivity was induced by stimulation of the motor cortex. Based on this experimental finding, we treated seven cases of thalamic pain syndrome by chronic motor cortex stimulation employing epidural plate electrodes. Excellent or good pain control was obtained in all cases without any complications or side effects. During the stimulation, an increase in regional blood flow of the cerebral cortex and thalamus, a marked rise in temperature of the painful skin regions, and improved movements of the painful limbs were observed. These results suggest that thalamic pain syndrome can be most effectively treated by chronic motor cortex stimulation.     

Spinal Cord Stimulation (SCS) in Deafferentation Pain

Spinal cord stimulation is considered to be ineffective in relieving deafferentation pain. We have retrospectively analyzed the results obtained in a series of 41 patients. Sixteen suffered from pain associated with an incomplete traumatic spinaJ lesion, 15 from a posttherapeutic neuralgia, and 10 from pain due to root and/or nerve damage. At the end of the test period, 43.7% of the patients with paraplegic pain, (40% of those with peripheral deafferentation pain and 66.6% of the ones with postherapeutic neuralgia), reported satisfactory pain relief and were connected to a chronic stimulation system. At mean follow-up (15 months), only 20% of the patients of the first two groups reported sufficient pain relief In the postherapeutic group the figure of responders was unchanged. The mean analgesia achieved was 70%. From this analysis we conclude that the results achieved in the postherapeutic pain patients, although positive in only 66% of them, are remarkably stable with time. Therefore, we recommend a percutaneous test trial of SCS in every case of postherapeutic pain resistant to medical treatment.     

Deep Brain Stimulation and Motor Cortical Stimulation for Neuropathic Pain

Deep brain stimulation (DBS) is an important treatment option for neuropathic pain. DBS has a considerable history, and it can be used successfully for a wide number of pain syndromes. Epidural motor cortex stimulation (MCS) also is a treatment option for neuropathic pain. Less invasive than DBS, MCS has been rapidly adopted and studied since first described in 1991. A growing body of literature supports the use of MCS for facial pain, though further study to better define the mechanism of action and the most appropriate patient populations is ongoing.     

Anodal Transcranial Direct Current Stimulation of the Motor Cortex Ameliorates Chronic Pain and Reduces Short Intracortical Inhibition

ContextConsecutive sessions of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) may be a suitable therapy to treat chronic pain, as it can modulate neural activities in the stimulated and interconnected regions.ObjectivesThe present study investigated the analgesic effect of five consecutive days of anodal/sham tDCS using subjective (visual analog scale [VAS]) and objective (cortical excitability measured by transcranial magnetic stimulation [TMS]) measurements.MethodsPatients with therapy-resistant chronic pain syndromes (trigeminal neuralgia, poststroke pain syndrome, back pain, fibromyalgia) participated. As this clinical trial was an exploratory study, statistical analyses implemented exploratory methods. Twelve patients, who underwent both anodal and sham tDCS, were analyzed using a crossover design. An additional nine patients had only anodal or sham stimulation. tDCS was applied over the hand area of the M1 for 20 minutes, at 1 mA for five consecutive days, using a randomized, double-blind design. Pain was assessed daily using a VAS rating for one month before, during, and one month post-stimulation. M1 excitability was determined using paired-pulse TMS.ResultsAnodal tDCS led to a greater improvement in VAS ratings than sham tDCS, evident even three to four weeks post-treatment. Decreased intracortical inhibition was demonstrated after anodal stimulation, indicating changes in cortico-cortical excitability. No patient experienced severe adverse effects; seven patients suffered from light headache after anodal and six after sham stimulation.ConclusionResults confirm that five daily sessions of tDCS over the hand area of the M1 can produce long-lasting pain relief in patients with chronic pain.     

Systematic Review and Neural Network Analysis to Define Predictive Variables in Implantable Motor Cortex Stimulation to Treat Chronic Intractable Pain

Implantable motor cortex stimulation (iMCS) has been performed for >25 years to treat various intractable pain syndromes. Its effectiveness is highly variable and, although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment for intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief of >40% as measured by a numerical rating scale (NRS) score. NNA was carried out to predict the outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as the mean accuracy, sensitivity, and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0 and 100%. A total of 358 patients were included (202 males [56.4%]; mean age, 54.2 ±13.3 years), 201 of whom were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified 6 predictive variables that had a relatively high M: 1) the sex of the patient (M = 19.7%); 2) the origin of the lesion (M = 15.1%); 3) the preoperative numerical rating scale score (M = 9.2%); 4) preoperative use of repetitive transcranial magnetic stimulation (M = 7.3%); 5) preoperative intake of opioids (M = 7.1%); and 6) the follow-up period (M = 13.1%). The results from the present study show that these 6 predictive variables influence the outcome of iMCS and that, based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery.PerspectiveThe presented NNA analyzed the functioning of computational models and modeled nonlinear statistical data. Based on this NNA, 6 predictive variables were identified that are suggested to be of importance in the improvement of future iMCS to treat chronic pain.     

The Effect of Theta Burst Stimulation Over the Primary Motor Cortex on Experimental Hamstring Pain: A Randomized,Controlled Study

Theta burst stimulation (TBS) over the primary motor cortex (M1) is an emerging technique that may have utility in the treatment of musculoskeletal pain. However, previous work exploring the analgesic effects of noninvasive brain stimulation has been limited largely to the arm or hand, despite 80% of acute musculoskeletal injuries occurring in the lower limb. This is a pertinent point, given the functional and neurophysiological differences between upper and lower limb musculature, as well as evidence suggesting that reorganization of corticomotor pathways is region-specific. This study investigated the effect of excitatory TBS on pain, function, and corticomotor organization during experimentally induced lower limb pain. Twenty-eight healthy participants attended 2 experimental sessions. On Day 0, participants completed 10 sets of 10 maximal eccentric contractions of the right hamstring muscles to induce delayed onset muscle soreness. Four consecutive blocks of either active or sham TBS were delivered on Day 2. Measures of mechanical sensitivity, pain (muscle soreness, pain intensity, pain area) function (single-leg hop distance, maximum voluntary isometric contraction, lower extremity functional scale), and corticomotor organization were recorded before and after TBS on Day 2. Pain and function were also assessed daily from Days 2 to 10. Active TBS reduced mechanical sensitivity compared to sham stimulation (P = .01). Corticomotor organization did not differ between groups, suggesting that improvements in mechanical sensitivity were not mediated by changes in M1. Subjective reports of pain intensity and function did not change following active TBS, contrasting previous reports in studies of the upper limb.PerspectiveM1 TBS reduces mechanical sensitivity associated with experimentally induced hamstring pain. Though further work is needed, these findings may hold important implications for those seeking to expedite recovery or reduce muscle sensitivity following hamstring injury.     

Interactions between Pain and the Motor Cortex: Insights from Research on Phantom Limb Pain and Complex Regional Pain Syndrome

Purpose: Pain is a significantly disabling problem that often interacts with other deficits during the rehabilitation process. The aim of this paper is to review evidence of interactions between pain and the motor cortex in order to attempt to answer the following questions: (1) Does acute pain interfere with motor-cortex activity? (2) Does chronic pain interfere with motor-cortex activity, and, conversely, does motor-cortex plasticity contribute to chronic pain? (3) Can the induction of motor plasticity by means of motor-cortex stimulation decrease pain? (4) Can motor training result in both motor-cortex reorganization and pain relief?Summary of Key Points: Acute experimental pain has been clearly shown to exert an inhibitory influence over the motor cortex, which can interfere with motor learning capacities. Current evidence also suggests a relationship between chronic pain and motor-cortex reorganization, but it is still unclear whether one causes the other. However, there is growing evidence that interventions aimed at normalizing motor-cortex organization can lead to pain relief.Conclusions: Interactions between pain and the motor cortex are complex, and more studies are needed to understand these interactions in our patients, as well as to develop optimal rehabilitative strategies.     

Motor Cortex Stimulation Activates the Incertothalamic Pathway in an Animal Model of Spinal Cord Injury

We have shown previously that electrical stimulation of the motor cortex reduces spontaneous painlike behaviors in animals with spinal cord injury (SCI). Because SCI pain behaviors are associated with abnormal inhibition in the inhibitory nucleus zona incerta (ZI) and because inactivation of the ZI blocks motor cortex stimulation (MCS) effects, we hypothesized that the antinociceptive effects of MCS are due to enhanced inhibitory inputs from ZI to the posterior thalamus (Po)—an area heavily implicated in nociceptive processing. To test this hypothesis, we used a rodent model of SCI pain and performed in vivo extracellular electrophysiological recordings in single well-isolated neurons in anesthetized rats. We recorded spontaneous activity in ZI and Po from 48 rats before, during, and after MCS (50 μA, 50 Hz; 300-ms pulses). We found that MCS enhanced spontaneous activity in 35% of ZI neurons and suppressed spontaneous activity in 58% of Po neurons. The majority of MCS-enhanced ZI neurons (81%) were located in the ventrorateral subdivision of ZI—the area containing Po-projecting ZI neurons. In addition, we found that inactivation of ZI using muscimol (GABA_A receptor agonist) blocked the effects of MCS in 73% of Po neurons. Although we cannot eliminate the possibility that muscimol spread to areas adjacent to ZI, these findings support our hypothesis and suggest that MCS produces antinociception by activating the incertothalamic pathway.PerspectiveThis article describes a novel brain circuit that can be manipulated, in rats, to produce antinociception. These results have the potential to significantly impact the standard of care currently in place for the treatment of patients with intractable pain.     

Primary Motor Cortex Function in Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis

Dysfunction in the central nervous system is thought to underlie the movement disorders that commonly occur in complex regional pain syndrome (CRPS), with much of the literature focusing on reorganization of the primary motor cortex (M1). Presumed changes in the M1 representation of the CRPS-affected body part have contributed to new CRPS treatments, which are increasingly being integrated in the clinic. We systematically investigated the evidence for altered M1 function in CRPS. We adhered to rigorous systematic review procedure in our search strategy, risk-of-bias appraisal, and data extraction. Eighteen studies comprising 14 unique data sets were included. The included studies used several neuroimaging techniques, whose outcomes we grouped into M1 cortical excitability, spatial representation, reactivity, and glucose metabolism, and conducted meta-analyses where possible. Risk of bias across studies was high, mainly due to missing data and unblinded assessment of outcomes. No definitive conclusions can be drawn regarding M1 spatial representation, reactivity, or glucose metabolism in CRPS. There is limited evidence for bilateral M1 disinhibition in CRPS of the upper limb.     

Sessions of Prolonged Continuous Theta Burst Stimulation or High-frequency 10 Hz Stimulation to Left Dorsolateral Prefrontal Cortex for 3 Days Decreased Pain Sensitivity by Modulation of the Efficacy of Conditioned Pain Modulation

The 10 Hz repetitive transcranial magnetic stimulation (10 Hz-rTMS) to the left dorsolateral prefrontal cortex produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10 Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the left dorsolateral prefrontal cortex reduced pain sensitivity more efficiently compared with 10 Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intracortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10 Hz-rTMS. Pain thresholds to heat (HPT), cold, pressure (PPT), intracortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10 Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P = .007). Based on pooled data from pcTBS and 10 Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P = .008), while no correlations were found at Day4 or with the intracortical excitability.PerspectivePreliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10 Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intracortical excitability changes.     

Finger Somatotopy in Human Motor Cortex

Although qualitative reports about somatotopic representation of fingers in the human motor cortex exist, up to now no study could provide clear statistical evidence. The goal of the present study was to reinvestigate finger motor somatotopy by means of a thorough investigation of standardized movements of the index and little finger of the right hand. Using high resolution fMRI at 3 Tesla, blood oxygenation level-dependent (BOLD) responses in a group of 26 subjects were repeatedly measured to achieve reliable statistical results. The center of mass of all activated voxels within the primary motor cortex was calculated for each finger and each run. Results of all runs were averaged to yield an individual index and little finger representation for each subject. The mean center of mass localizations for all subjects were then submitted to a paired t test. Results show a highly significant though small scale somatotopy of fingerspecific activation patterns in the order indicated by Penfields motor homunculus. In addition, considerable overlap of finger specific BOLD responses was found. Comparing various methods of analysis, the mean center of mass distance for the two fingers was 2–3 mm with overlapping voxels included and 4–5 mm with overlapping voxels excluded. Our data may be best understood in the context of the work of Schieber (1999) who recently described overlapping somatotopic gradients in lesion studies with humans.     

Transcutaneous Electrical Nerve Stimulation for Phantom Pain and Stump Pain in Adult Amputees

Abstract Following amputation, 50% to 90% of individuals experience phantom and/or stump pain. Transcutaneous electrical nerve stimulation (TENS) may prove to be a useful adjunct analgesic intervention, although a recent systematic review was unable to judge effectiveness owing to lack of quality evidence. The aim of this pilot study was to gather data on the effect of TENS on phantom pain and stump pain at rest and on movement. Ten individuals with a transtibial amputation and persistent moderate‐to‐severe phantom and/or stump pain were recruited. Inclusion criteria was a baseline pain score of ≥3 using 0 to 10 numerical rating scale (NRS). TENS was applied for 60 minutes to generate a strong but comfortable TENS sensation at the site of stump pain or projected into the site of phantom pain. Outcomes at rest and on movement before and during TENS at 30 minutes and 60 minutes were changes in the intensities of pain, nonpainful phantom sensation, and prosthesis embodiment. Mean (SD) pain intensity scores were reduced by 1.8 (1.6) at rest (P < 0.05) and 3.9 (1.9) on movement (P < 0.05) after 60 minutes of TENS. For five participants, it was possible to project TENS sensation into the phantom limb by placing the electrodes over transected afferent nerves. Nonpainful phantom sensations and prosthesis embodiment remained unchanged. This study has demonstrated that TENS has potential for reducing phantom pain and stump pain at rest and on movement. Projecting TENS sensation into the phantom limb might facilitate perceptual embodiment of prosthetic limbs. The findings support the delivery of a feasibility trial.     

Altered Primary Motor Cortex Structure,Organization, and Function in Chronic Pain: A Systematic Review and Meta-Analysis

Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non-neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long-interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive.

Transcranial Magnetic Stimulation Can Be Used to Test Connections to Primary Motor Areas from Frontal and Medial Cortex in Humans

Surface EMG responses (MEPs) were recorded from the relaxed first dorsal interosseous (FDI) of 16 normal subjects following transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex. These test responses were conditioned by a subthreshold stimulus applied 2-15 ms beforehand over a range of anterior or medial sites. Stimuli applied 3-5 cm anterior to the hand motor area (site A) or 6 cm anterior to the vertex on the nasion-inion line (site B) inhibited the test responses at short latency. The largest effect was seen when the interstimulus interval was 6 ms and the intensity of the conditioning stimulus was equal to 0.9x active motor threshold (AMT) at the hand area. Increasing the intensity to 1.2x AMT produced facilitation. Suppression of surface EMG responses was mirrored in the behavior of single motor units. Conditioning stimuli had no effect on responses evoked in the active FDI muscle by transcranial electric stimulation of motor cortex nor on forearm flexor H reflexes even though MEPs in the same muscle were suppressed at appropriate interstimulus intervals. We conclude that low-intensity TMS over presumed premotor areas of frontal cortex can engage corticocortical connections to the primary motor hand area.     

Spinal Cord Stimulation and Motor Disorders

Spinal cord stimulation has been investigated by us during the past 10 years in the treatment of various disorders of the motor system. The effectiveness was studied in 735 cases, including cerebral palsy (212), dystonia (129), torticollis (66), spinal cord injury (169), and degenerative diseases (159). Our resuits indicate that in properly selected patients, stimulating the spinal neural axis is therapeutically effective in the majority of the cases treated. Our data demonstrate that the level stimulated, the pattern and the polarity of the applied field, and the frequency of the stimulation are critical to achieve a satisfactory therapeutic result and must be individualized in each patient.     

Repetitive Transcranial Magnetic Stimulation of the Left Premotor/Dorsolateral Prefrontal Cortex Does Not Have Analgesic Effect on Central Poststroke Pain

Central poststroke pain (CPSP) is caused by an encephalic vascular lesion of the somatosensory pathways and is commonly refractory to current pharmacologic treatments. Repetitive transcranial magnetic stimulation (rTMS) of the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC) can change thermal pain threshold toward analgesia in healthy subjects and has analgesic effects in acute postoperative pain as well as in fibromyalgia patients. However, its effect on neuropathic pain and in CPSP, in particular, has not been assessed. The aim of this prospective, double-blind, placebo-controlled study was to evaluate the analgesic effect of PMC/DLPFC rTMS in CPSP patients. Patients were randomized into 2 groups, active (a-) rTMS and sham (s-) rTMS, and were treated with 10 daily sessions of rTMS over the left PMC/DLPFC (10 Hz, 1,250 pulses/d). Outcomes were assessed at baseline, during the stimulation phase, and at 1, 2, and 4 weeks after the last stimulation. The main outcome was pain intensity changes measured by the visual analog scale on the last stimulation day compared to baseline. Interim analysis was scheduled when the first half of the patients completed the study. The study was terminated because of a significant lack of efficacy of the active arm after 21 patients completed the whole treatment and follow-up phases. rTMS of the left PMC/DLPFC did not improve pain in CPSP.PerspectiveThe aim of this double-blind, placebo-controlled study was to evaluate the analgesic effects of rTMS to the PMC/DLPFC in CPSP patients. An interim analysis showed a consistent lack of analgesic effect, and the study was terminated. rTMS of the PMC/DLPFC is not effective in relieving CPSP.     

On Somatotopic Representation Centers for Finger Movements in Human Primary Motor Cortex and Supplementary Motor Area

We usedfunctional magnetic resonance imaging to examine the representation pattern for repetitive voluntary finger movements in the primary motor cortex (M1) and the supplementary motor area (SMA) of humans. Healthy right-handed participants performed repetitive individuated flexion-extension movements of digits 1, 2, and 3 using the dominant hand. Contralateral functional labeling for the group indicated a largely overlapping activation pattern in M1 and SMA for the three digits. Consistent with recent findings, the geographic activation center in M1 for each finger differed, and we found some evidence of a homunculus organization pattern in M1 and SMA, but only for the central location of the representations. However, the statistical power for the homunculus pattern was weak, and the distance separating the digit geographical centers was typically less than 15% of the entire extent of digit representations in M1 or SMA. While separations for digit representations occurred, the entire data set provided more support for the concept of distributed, overlapping representations than for a classic homunculus organization for voluntary finger movements.     

Asymmetry in the Human Motor Cortex and Handedness

Handedness is one of the most obvious functional asymmetries, but its relation to an anatomical asymmetry of the hand representation area in the motor cortex has not been demonstrated. This would be a crucial test for the hypothesis of structure–function correlation in cortical motor organization. Using magnetic resonance morphometry, we show for the first time that the depth of the central sulcus is related to handedness. In right-handers, the left central sulcus is deeper than the right, and vice versa in left-handers. Macrostructural asymmetry is complemented by a microstructural left-larger-than-right asymmetry in neuropil volume (i.e., tissue compartment containing dendrites, axons, and synapses) in Brodmann's area 4. These asymmetries suggest that hand preference is associated with increased connectivity (demonstrated by an increased neuropil compartment in left area 4) and an increased intrasulcal surface of the precentral gyrus in the dominant hemisphere.