Network Effects of Brain Lesions Causing Central Poststroke Pain.

OBJECTIVE: This study was undertaken to test whether lesions causing central poststroke pain (CPSP) are associated with a specific connectivity profile, whether these connections are associated with metabolic changes, and whether this network aligns with neuromodulation targets for pain. METHODS: Two independent lesion datasets were utilized: (1) subcortical lesions from published case reports and (2) thalamic lesions with metabolic imaging using 18F- fluorodeoxyglucose positron emission tomography-computed tomography. Functional connectivity between each lesion location and the rest of the brain was assessed using a normative connectome (n = 1,000), and connections specific to CPSP were identified. Metabolic changes specific to CPSP were also identified and related to differences in lesion connectivity. Therapeutic relevance of the network was explored by testing for alignment with existing brain stimulation data and by prospectively targeting the network with repetitive transcranial magnetic stimulation (rTMS) in 7 patients with CPSP. RESULTS: Lesion locations causing CPSP showed a specific pattern of brain connectivity that was consistent across two independent lesion datasets (spatial r = 0.82, p < 0.0001). Connectivity differences were correlated with postlesion metabolism (r = -0.48, p < 0.001). The topography of this lesion-based pain network aligned with variability in pain improvement across 12 prior neuromodulation targets and across 32 patients who received rTMS to primary motor cortex (p < 0.05). Prospectively targeting this network with rTMS improved CPSP in 6 of 7 patients. INTERPRETATION: Lesions causing pain are connected to a specific brain network that shows metabolic abnormalities and promise as a neuromodulation target. ANN NEUROL 2022;92:834-845.

Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

Robot-Guided Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Central Neuropathic Pain.

OBJECTIVES: To confirm and extend previous results involving repetitive transcranial magnetic stimulation (rTMS) aimed at alleviating refractory central neuropathic pain (CNP). To evaluate pain relief in detail and to assess ongoing benefits after one year of treatment. DESIGN: Prospective observational study. SETTING: University hospital. Outpatient settings. PARTICIPANTS: Patients (N=80) with chronic central pain after brain or spinal cord injuries. INTERVENTIONS: High-frequency (20Hz) neuronavigated-rTMS sessions were applied on the primary motor cortex using a figure-of-eight coil positioned by a robotized arm. Patients received a minimum of 4 consecutive sessions, each separated by 3-4 weeks. MAIN OUTCOME MEASURES: Percentage of pain relief (%R), duration of pain relief (DPR), numeric rating scale (NRS), neuropathic pain symptom inventory (NPSI), and pain relief score (PRS). RESULTS: Seventy-one patients completed the study. On average, after the first 4 sessions, %R was 28% and DPR was 11 days. Fifty-four patients (76%) were responders with a permissive threshold of ≥10%R and 61% (43 patients) with a stringent threshold ≥30%R. After 12 months of treatment (15 sessions) we observed a cumulative effect on %R (48%), DPR (20d), and on the prevailing NPSI sub-score (-28%). This effect reached significance after 4 sessions and was further maintained over 12 months. Across participants, more than 1000 rTMS sessions were delivered over 6 years without any adverse effect. CONCLUSION: These results confirm that multiple rTMS sessions are both safe and have potential as a treatment for CNP. An ongoing randomized controlled trial will allow teasing out of this effect from placebo analgesia.

Field recordings of transcranial magnetic stimulation in human brain postmortem models.

Introduction: The ability of repetitive transcranial magnetic stimulation (rTMS) to deliver a magnetic field (MF) in deep brain targets is debated and poorly documented. Objective: To quantify the decay of MF in the human brain. Methods: Magnetic field was generated by single pulses of TMS delivered at maximum intensity using a flat or angulated coil. Magnetic field was recorded by a 3D-magnetic probe. Decay was measured in the air using both coils and in the head of 10 postmortem human heads with the flat coil being positioned tangential to the scalp. Magnetic field decay was interpreted as a function of distance to the coil for 6 potential brain targets of noninvasive brain stimulation: the primary motor cortex (M1, mean depth: 28.5 mm), dorsolateral prefrontal cortex (DLPFC: 28 mm), secondary somatosensory cortex (S2: 35.5 mm), posterior and anterior insulae (PI: 38.5 mm; AI: 43.5 mm), and midcingulate cortex (MCC: 57.5 mm). Results: In air, the maximal MF intensities at coil center were 0.88 and 0.77 T for the flat and angulated coils, respectively. The maximal intracranial MF intensity in the cadaver model was 0.34 T, with a ∼50% decay at 15 mm and a ∼75% MF decay at 30 mm. The decay of the MF in air was similar for the flat coil and significantly less attenuated with the angulated coil (a ∼50% decay at 20 mm and a ∼75% MF decay at 45 mm). Conclusions: Transcranial magnetic stimulation coil MFs decay in brain structures similarly as in air, attenuation with distance being significantly lower with angulated coils. Reaching brain targets deeper than 20 mm such as the insula or Antérior Cingulate Cortex seems feasible only when using angulated coils. The abacus of MF attenuation provided here can be used to adjust modalities of deep brain stimulation with rTMS in future research protocols.

Cortical stimulation for chronic pain: from anecdote to evidence.

Epidural stimulation of the motor cortex (eMCS) was devised in the 1990's, and has now largely supplanted thalamic stimulation for neuropathic pain relief. Its mechanisms of action involve activation of multiple cortico-subcortical areas initiated in the thalamus, with involvement of endogenous opioids and descending inhibition toward the spinal cord. Evidence for clinical efficacy is now supported by at least seven RCTs; benefits may persist up to 10 years, and can be reasonably predicted by preoperative use of non-invasive repetitive magnetic stimulation (rTMS). rTMS first developed as a means of predicting the efficacy of epidural procedures, then as an analgesic method on its own right. Reasonable evidence from at least six well-conducted RCTs favors a significant analgesic effect of high-frequency rTMS of the motor cortex in neuropathic pain (NP), and less consistently in widespread/fibromyalgic pain. Stimulation of the dorsolateral frontal cortex (DLPFC) has not proven efficacious for pain, so far. The posterior operculo-insular cortex is a new and attractive target but evidence remains inconsistent. Transcranial direct current stimulation (tDCS) is applied upon similar targets as rTMS and eMCS; it does not elicit action potentials but modulates the neuronal resting membrane state. tDCS presents practical advantages including low cost, few safety issues, and possibility of home-based protocols; however, the limited quality of most published reports entails a low level of evidence. Patients responsive to tDCS may differ from those improved by rTMS, and in both cases repeated sessions over a long time may be required to achieve clinically significant relief. Both invasive and non-invasive procedures exert their effects through multiple distributed brain networks influencing the sensory, affective and cognitive aspects of chronic pain. Their effects are mainly exerted upon abnormally sensitized pathways, rather than on acute physiological pain. Extending the duration of long-term benefits remains a challenge, for which different strategies are discussed in this review.

Human surrogate models of central sensitization: A critical review and practical guide.

BACKGROUND: As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. DATA TREATMENT: We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. RESULTS: From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low- or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. CONCLUSIONS: While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. SIGNIFICANCE: Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.

Is the analgesic effect of motor cortex stimulation somatotopically driven or not?

OBJECTIVES: Mechanisms of analgesic efficacy related to motor cortex stimulation (MCS) remain poorly understood. Specifically, it is unclear whether pain relief is somatotopically driven or not. We present three illustrative case-reports of MCS in which unintentional stimulation setting errors occurred, leading to differential (and reversible) pain relief outcomes across the hemi-body. METHODS: After successful preoperative rTMS trials, three patients suffering from post-stroke pain were selected for MCS. Stimulation was set with the aim of activating two epidural electrodes over the somatotopic representation of the lower and upper limbs. Data regarding pain relief were prospectively collected. RESULTS: At the first follow-up, all three patients complained of a lack of pain relief in the lower limb, contrasting with good outcome in the upper limb. In fact, for each of them we diagnosed the same stimulation setting error, to which they were "blinded", i.e., the parasagittal electrode over the somatotopic representation of the lower limb was inadvertently turned off. Subsequently, six months after having the electrode turned on (still in a "blinded" fashion), all three patients described substantial pain relief in the lower limb, with a median improvement of 50% (range: 40-70%). DISCUSSION: These incidental case reports argue in favor of a genuine and at least partly somatotopically-driven analgesic efficacy of MCS. Therefore, the parasagittal electrode seems crucial when treating lower limb pain with MCS.

New procedure of high-frequency repetitive transcranial magnetic stimulation for central neuropathic pain: a placebo-controlled randomized crossover study.

Repetitive transcranial magnetic stimulation (rTMS) is a procedure increasingly used to treat patients with central neuropathic pain, but its efficacy is still under debate. Patients with medically refractory chronic central neuropathic pain were included in 2 randomized phases (active/sham), separated by a wash-out period of 8 weeks. Each phase consisted of 4 consecutive rTMS sessions and a final evaluation session, all separated from one another by 3 weeks. High-frequency (20 Hz) rTMS was delivered over the primary motor cortex (M1) contralateral to the patient's pain using a neuronavigated robotic system. Patients and clinicians assessing outcomes were blinded to treatment allocation during the trial. The primary outcome measured the percentage of pain relief (%R) from baseline. Secondary outcomes were VAS score, Neuropathic Pain Symptom Inventory, analgesic drug consumption, and quality of life (EQ-5D). Thirty-six patients performed the entire study with no adverse effects. The analgesic effect for the main criterion (%R) was significantly higher in the active (33.8% confidence interval [CI]: [23.88-43.74]) than in the sham phase (13.02% CI: [6.64-19.76]). This was also the case for the secondary outcome VAS (-19.34% CI: [14.31-25.27] vs -4.83% CI: [1.96-8.18]). No difference was observed for quality of life or analgesic drug consumption. Seventeen patients (47%) were identified as responders, but no significant interaction was found between clinical and technical factors considered here and the analgesic response. These results provide strong evidence that 3 weeks spaced high-frequency rTMS of M1 results in a sustained analgesic effect and support the clinical interest of this stimulation paradigm to treat refractory chronic pain.

Cingulate-mediated approaches to treating chronic pain.

Anterior midcingulate cortex (aMCC) has been shown to be involved in most of the functional imaging studies investigating acute pain. For 10-15 years, it has even been a main focus of interest for pain studies, considering that neurons in the aMCC could encode for pain intensity. This latter function is now presumed to occur in secondary somatosensory (SII) area and/or insular cortices, while anterior cingulate cortex (ACC) is supposed to sustain other functions such as pain-related attention, arousal, motor withdrawal reflex, pain modulations, and engagement of endogenous pain control system. The quantitative imaging studies have shown a rich density of opioid receptors in the ACC. Thus, the perigenual subdivision has been suggested to participate in top-down controls of pain, (including the placebo effects known to be opioid mediated), mainly (but not exclusively) through the connection between the orbitofrontal/subgenual ACC and the periaqueductal gray (PAG). From this rationale, this area may lead to neurosurgical targeting including electrical stimulation for intractable pain in the future. A number of imaging studies have also reported activity changes in the posterior cingulate cortex during pain and proposed its speculative involvement to modulate the conscious experience of pain according to elements from the context and awareness of the self and others.

Added value of multiple versus single sessions of repetitive transcranial magnetic stimulation in predicting motor cortex stimulation efficacy for refractory neuropathic pain.

OBJECTIVESelection criteria for offering patients motor cortex stimulation (MCS) for refractory neuropathic pain are a critical topic of research. A single session of repetitive transcranial magnetic stimulation (rTMS) has been advocated for selecting MCS candidates, but it has a low negative predictive value. Here the authors investigated whether multiple rTMS sessions would more accurately predict MCS efficacy.METHODSPatients included in this longitudinal study could access MCS after at least four rTMS sessions performed 3-4 weeks apart. The positive (PPV) and negative (NPV) predictive values of the four rTMS sessions and the correlation between the analgesic effects of the two treatments were assessed.RESULTSTwelve MCS patients underwent an average of 15.9 rTMS sessions prior to surgery; nine of the patients were rTMS responders. Postoperative follow-up was 57.8 ± 15.6 months (mean ± standard deviation). Mean percentage of pain relief (%R) was 21% and 40% after the first and fourth rTMS sessions, respectively. The corresponding mean durations of pain relief were respectively 2.4 and 12.9 days. A cumulative effect of the rTMS sessions was observed on both %R and duration of pain relief (p < 0.01). The %R value obtained with MCS was 35% after 6 months and 43% at the last follow-up. Both the PPV and NPV of rTMS were 100% after the fourth rTMS session (p = 0.0045). A significant correlation was found between %R or duration of pain relief after the fourth rTMS session and %R at the last MCS follow-up (R2 = 0.83, p = 0.0003).CONCLUSIONSFour rTMS sessions predicted MCS efficacy better than a single session in neuropathic pain patients. Taking into account the cumulative effects of rTMS, the authors found a high-level correlation between the analgesic effects of rTMS and MCS.