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ABSTRACT: Memory biases for pain-related information may contribute to the development and maintenance of chronic pain; however, evidence for when (and for whom) these biases occur is mixed. Therefore, we examined neural, stress, and psychological factors that could influence memory bias, focusing on memories that motivate disabling behaviors: pain perception, conditioned responses to threat-and-safety cues, and responses to aversive nonnoxious stimuli. Two studies were conducted with adolescents with and without chronic pain. Data from 58 participants were included in study 1 (chronic pain n = 34, pain free n = 24, mean age = 16 years), and 39 participants were included in study 2 (chronic pain n = 26, pain free n = 13, mean age = 16 years). Both studies used a threat-safety learning paradigm with memory recall (≈1 month later). Participants completed structural and functional (resting-state) magnetic resonance imaging, salivary cortisol measurements, and self-report measures. Adolescents with pain and pain-free peers consistently recalled being more afraid of safety cues (CS-) and, during heightened stress at encoding (higher cortisol levels), also reported being more afraid of threat cues (CS+). However, no memory bias was present for the emotional response to an aversive stimulus (US; loud scream) or for the recall of pain intensity. Functional connectivity of the amygdala and hippocampus with memory circuits related to the degree of memory bias, but the specific connections varied between the studies, and we observed no relationship between memory bias and brain morphology. Our findings highlight the value of considering the interaction between implicit and explicit memory systems, contributing to a more comprehensive understanding of emotional memory biases in the context of chronic pain.
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OBJECTIVES: Acute orthopedic traumatic musculoskeletal injuries are prevalent, costly, and often lead to persistent pain and functional limitations. Psychological risk factors (eg, pain catastrophizing and anxiety) exacerbate these outcomes but are often overlooked in acute orthopedic care. Addressing gaps in current treatment approaches, this mixed-methods pilot study explored the use of a therapeutic virtual reality (VR; RelieVRx ), integrating principles of mindfulness and cognitive-behavioral therapy, for pain self-management at home following orthopedic injury. METHODS: We enrolled 10 adults with acute orthopedic injuries and elevated pain catastrophizing or pain anxiety from Level 1 Trauma Clinics within the Mass General Brigham health care system. Participants completed daily RelieVRx sessions at home for 8 weeks, which included pain education, relaxation, mindfulness, games, and dynamic breathing biofeedback. Primary outcomes were a priori feasibility, appropriateness, acceptability, satisfaction, and safety. Secondary outcomes were pre-post measures of pain, physical function, sleep, depression, and hypothesized mechanisms (pain self-efficacy, mindfulness, and coping). RESULTS: The VR and study procedures met or exceeded all benchmarks. We observed preliminary improvements in pain, physical functioning, sleep, depression, and mechanisms. Qualitative exit interviews confirmed high satisfaction with RelieVRx and yielded recommendations for promoting VR-based trials with orthopedic patients. DISCUSSION: The results support a larger randomized clinical trial of RelieVRx versus a sham placebo control to replicate the findings and explore mechanisms. There is potential for self-guided VR to promote evidence-based pain management strategies and address the critical mental health care gap for patients following acute orthopedic injuries.
Subject(s)
Mindfulness , Virtual Reality , Humans , Pilot Projects , Male , Female , Adult , Middle Aged , Catastrophization/psychology , Cognitive Behavioral Therapy/methods , Pain Management/methods , Virtual Reality Exposure Therapy/methods , Musculoskeletal Pain/therapy , Musculoskeletal Pain/etiology , Musculoskeletal Pain/psychology , Anxiety/etiology , Anxiety/therapy , Self-Management , Pain MeasurementABSTRACT
ABSTRACT: Chronic pain is common in young people and can have a major life impact. Despite the burden of chronic pain, mechanisms underlying chronic pain development and persistence are still poorly understood. Specifically, white matter (WM) connectivity has remained largely unexplored in pediatric chronic pain. Using diffusion-weighted imaging, this study examined WM microstructure in adolescents (age M = 15.8 years, SD = 2.8 years) with chronic pain (n = 44) compared with healthy controls (n = 24). Neurite orientation dispersion and density imaging modeling was applied, and voxel-based whole-white-matter analyses were used to obtain an overview of potential alterations in youth with chronic pain and tract-specific profile analyses to evaluate microstructural profiles of tracts of interest more closely. Our main findings are that (1) youth with chronic pain showed widespread elevated orientation dispersion compared with controls in several tracts, indicative of less coherence; (2) signs of neurite density tract-profile alterations were observed in several tracts of interest, with mainly higher density levels in patients; and (3) several WM microstructural alterations were associated with pain catastrophizing in the patient group. Implicated tracts include both those connecting cortical and limbic structures (uncinate fasciculus, cingulum, anterior thalamic radiation), which were associated with pain catastrophizing, as well as sensorimotor tracts (corticospinal tract). By identifying alterations in the biologically informative WM microstructural metrics orientation dispersion and neurite density, our findings provide important and novel mechanistic insights for understanding the pathophysiology underlying chronic pain. Taken together, the data support alterations in fiber organization as a meaningful characteristic, contributing process to the chronic pain state.
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Immersive virtual reality (iVR) employs head-mounted displays or cave-like environments to create a sensory-rich virtual experience that simulates the physical presence of a user in a digital space. The technology holds immense promise in neuroscience research and therapy. In particular, virtual reality (VR) technologies facilitate the development of diverse tasks and scenarios closely mirroring real-life situations to stimulate the brain within a controlled and secure setting. It also offers a cost-effective solution in providing a similar sense of interaction to users when conventional stimulation methods are limited or unfeasible. Although combining iVR with traditional brain imaging techniques may be difficult due to signal interference or instrumental issues, recent work has proposed the use of functional near infrared spectroscopy (fNIRS) in conjunction with iVR for versatile brain stimulation paradigms and flexible examination of brain responses. We present a comprehensive review of current research studies employing an iVR-fNIRS setup, covering device types, stimulation approaches, data analysis methods, and major scientific findings. The literature demonstrates a high potential for iVR-fNIRS to explore various types of cognitive, behavioral, and motor functions in a fully immersive VR (iVR) environment. Such studies should set a foundation for adaptive iVR programs for both training (e.g., in novel environments) and clinical therapeutics (e.g., pain, motor and sensory disorders and other psychiatric conditions).
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The brain-based assessments under anesthesia have provided the ability to evaluate pain/nociception during surgery and the potential to prevent long-term evolution of chronic pain. Prior studies have shown that the functional near-infrared spectroscopy (fNIRS)-measured changes in cortical regions such as the primary somatosensory and the polar frontal cortices show consistent response to evoked and ongoing pain in awake, sedated, and anesthetized patients. We take this basic approach and integrate it into a potential framework that could provide real-time measures of pain/nociception during the peri-surgical period. This application could have significant implications for providing analgesia during surgery, a practice that currently lacks quantitative evidence to guide patient tailored pain management. Through a simple readout of "pain" or "no pain," the proposed system could diminish or eliminate levels of intraoperative, early post-operative, and potentially, the transition to chronic post-surgical pain. The system, when validated, could also be applied to measures of analgesic efficacy in the clinic.
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Different stress models are employed to enhance our understanding of the underlying mechanisms and explore potential interventions. However, the utility of these models remains a critical concern, as their validities may be limited by the complexity of stress processes. Literature review revealed that both mental and physical stress models possess reasonable construct and criterion validities, respectively reflected in psychometrically assessed stress ratings and in activation of the sympathoadrenal system and the hypothalamic-pituitary-adrenal axis. The findings are less robust, though, in the pharmacological perturbations' domain, including such agents as adenosine or dobutamine. Likewise, stress models' convergent- and discriminant validity vary depending on the stressors' nature. Stress models share similarities, but also have important differences regarding their validities. Specific traits defined by the nature of the stressor stimulus should be taken into consideration when selecting stress models. Doing so can personalize prevention and treatment of stress-related antecedents, its acute processing, and chronic sequelae. Further work is warranted to refine stress models' validity and customize them so they commensurate diverse populations and circumstances.
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Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Humans , Hypothalamo-Hypophyseal System/physiology , Pituitary-Adrenal System/physiology , Stress, Physiological , Disease Progression , Stress, PsychologicalABSTRACT
Brain-related plasticity can occur at a significant rate varying on the developmental period. Adolescence in particular has been identified as a period of growth and change across the structure and function of the nervous system. Notably, research has identified migraines as common in both pediatric and adult populations, but evidence suggests that the phenotype for migraines may differ in these cohorts due to the unique needs of each developmental period. Accordingly, primary aims of this study were to define hippocampal structure in females (7-27 years of age) with and without migraine, and to determine whether this differs across developmental stages (i.e., childhood, adolescence, and young adulthood). Hippocampal volume was quantified based on high-resolution structural MRI using FMRIB's Integrated Registration and Segmentation Tool. Results indicated that migraine and age may have an interactional relationship with hippocampal volume, such that, while hippocampal volumes were lower in female migraineurs (compared to age-matched controls) during childhood and adolescence, this contrast differed during young adulthood whereby hippocampal volumes were higher in migraineurs (compared to age-matched controls). Subsequent vertex analysis localized this interaction effect in hippocampal volume to displacement of the anterior hippocampus. The transition of hippocampal volume during adolescent development in migraineurs suggests that hippocampal plasticity may dynamically reflect components of migraine that change over the lifespan, exerting possible altered responsivity to stress related to migraine attacks thus having physiological expression and psychosocial impact.
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Introduction: Neuropathic pain (NP) arises from nerve damage or disease, and when not defined, it can impair function and quality of life. Early detection allows for interventions that can enhance outcomes. Diagnosis of NP can be difficult if not properly evaluated. PainDETECT is a NP screening tool developed and successfully used in adults. Objectives: We evaluated the validity of painDETECT in a pediatric population. Methods: Adolescents and young adults (10-19 years old) completed painDETECT and quantitative sensory testing (QST), which assessed mechanical allodynia and hyperalgesia, common symptoms of NP. Pain diagnoses, including neuropathic pain (n = 10), were collected through documentation in the medical chart. Descriptive statistics were used to examine age, gender, pain diagnoses, and painDETECT scores. Kruskal-Wallis H tests were conducted to examine differences in QST results across painDETECT categorizations. Results: Youth with chronic pain (N = 110, Mage = 15.08 ± 2.4 years, Nfemale = 88) and peers without pain (N = 55, Mage = 15.84 ± 3.9 years, Nfemale = 39) completed the painDETECT. The painDETECT scores for youth with pain (M = 12.7 ± 6.76) were significantly higher than those for peers without pain (M = 2.05 ± 2.41). PainDETECT demonstrated 80% sensitivity and 33% specificity in a pediatric population. Individuals who screened positively on the PainDETECT had significantly higher mechanical allodynia (M = 0.640 ± 0.994) compared with those who screened negatively (M = 0.186 ± 0.499; P = 0.016). Conclusion: PainDETECT demonstrated the ability to screen for NP, and QST mechanical allodynia results were consistent with a positive NP screen. Results of the study offer preliminary support for the ongoing assessment of the painDETECT as a brief, inexpensive, and simple-to-use screening tool for pediatric patients with primary pain complaints.
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Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, attention/arousal and sleep spindle generation. We report that the TRN played an important role in CSD-induced hyperalgesia in mice, through its projections to the ventroposterior region of the thalamus. Metabolomics revealed that the level of N-arachidonoyl dopamine (NADA), an endocannabinoid, was decreased in the TRN after CSD. Using a recently developed CB1 receptor (cannabinoid receptor 1) activity sensor with spatiotemporal resolution, CB1 receptor activity in the TRN was found to be decreased after CSD. Moreover, CSD-induced hyperalgesia was attenuated by local NADA administration to the TRN. Taken together, these results suggest that TRN NADA signaling is critical for CSD-induced hyperalgesia.
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Dopamine , Endocannabinoids , Mice , Animals , Dopamine/pharmacology , Hyperalgesia , Receptor, Cannabinoid, CB1 , Thalamic Nuclei , SleepABSTRACT
Migraine is underpinned by central nervous system neuroplastic alterations thought to be caused by the repetitive peripheral afferent barrage the brain receives during the headache phase (cortical hyperexcitability). Calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) are highly effective migraine preventative treatments. Their ability to alter brain morphometry in treatment-responders vs. non-responders is not well understood. Our aim was to determine the effects of the anti-CGRP-mAb galcanezumab on cortical thickness after 3-month treatment of patients with high-frequency episodic or chronic migraine. High-resolution magnetic resonance imaging was performed pre- and post-treatment in 36 migraine patients. In this group, 19 patients were classified responders (≥50 % reduction in monthly migraine days) and 17 were considered non-responders (<50 % reduction in monthly migraine days). Following cross-sectional processing to analyze the baseline differences in cortical thickness, two-stage longitudinal processing and symmetrized percent change were conducted to investigate treatment-related brain changes. At baseline, no significant differences were found between the responders and non-responders. After 3-month treatment, decreased cortical thickness (compared to baseline) was observed in the responders in regions of the somatosensory cortex, anterior cingulate cortex, medial frontal cortex, superior frontal gyrus, and supramarginal gyrus. Non-responders demonstrated decreased cortical thickness in the left dorsomedial cortex and superior frontal gyrus. We interpret the cortical thinning seen in the responder group as suggesting that reduction in head pain could lead to changes in neural swelling and dendritic complexity and that such changes reflect the recovery process from maladaptive neural activity. This conclusion is further supported by our recent study showing that 3 months after treatment initiation, the incidence of premonitory symptoms and prodromes that are followed by headache decreases but not the incidence of the premonitory symptoms or prodromes themselves (that is, cortical thinning relates to reductions in the nociceptive signals in the responders). We speculate that a much longer recovery period is required to allow the brain to return to a more 'normal' functioning state whereby prodromes and premonitory symptoms no longer occur.
Subject(s)
Antibodies, Monoclonal , Migraine Disorders , Humans , Antibodies, Monoclonal/adverse effects , Cerebral Cortical Thinning , Cross-Sectional Studies , Gray Matter/diagnostic imaging , Prospective Studies , Migraine Disorders/diagnostic imaging , Migraine Disorders/drug therapy , Headache/chemically induced , Treatment OutcomeABSTRACT
Ehlers-Danlos Syndrome (EDS) is a rare disease affecting the skin, joints, vasculature, and internal organs. Approximately 85% of those affected are categorized as the hypermobile type (hEDS), which is associated with numerous medical and psychiatric comorbidities, including chronic pain. Additionally, approximately 71% of patients with hEDS undergo at least one surgical procedure; however, indicators for surgery and pain outcomes after surgery are poorly understood. This preliminary study used a medical chart review to identify the frequency and nature of comorbidities in a cohort of adolescents and young adult patients with hEDS and a surgical history compared to those without a surgical history. Results showed that patients diagnosed with hEDS who underwent surgery reported significantly more comorbidities (e.g., CRPS, IBS, Fibromyalgia, POTS, hypothyroidism, etc.) than those who did not have surgery. Seventy percent of individuals who presented for surgery fell within the categories of orthopedic, gastrointestinal, or laparoscopic/endometriosis-related surgeries. Identifying patients with hEDS who are at risk for needing surgery will help identify the mechanisms contributing to risk factors for poor surgical outcomes. The results of this study may be instructive in the management and care of hEDS patients undergoing surgery.
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Significance: Quantitative measurement of perisurgical brain function may provide insights into the processes contributing to acute and chronic postsurgical pain. Aim: We evaluate the hemodynamic changes in the prefrontal cortex (medial frontopolar cortex/mFPC and lateral prefrontal cortex) and the primary somatosensory cortex/S1 using functional near-infrared spectroscopy (fNIRS) in 18 patients (18.2±3.3 years, 11 females) undergoing knee arthroscopy. Approach: We examined the (a) hemodynamic response to surgery and (b) the relationship between surgery-modulated cortical connectivity (using beta-series correlation) and acute postoperative pain levels using Pearson's r correlation with 10,000 permutations. Results: We show a functional dissociation between mFPC and S1 in response to surgery, where mFPC deactivates, and S1 activates following a procedure. Furthermore, the connectivity between (a) left mFPC and right S1 (original r=-0.683, ppermutation=0.001), (b) right mFPC and right S1 (original r=-0.633, ppermutation=0.002), and (c) left mFPC and right S1 (original r=-0.695, ppermutation=0.0002) during surgery were negatively associated with acute postoperative pain levels. Conclusions: Our findings suggest that greater functional dissociation between mFPC and S1 is likely the result of inadequately controlled nociceptive barrage during surgery leading to more significant postoperative pain. It also supports the utility of fNIRS during the perioperative state for pain monitoring and patient risk assessment for chronic pain.
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OBJECTIVE: Placebo responses are significantly higher in children than in adults, suggesting a potential underused treatment option in pediatric care. To facilitate the clinical translation of these beneficial effects, we explored physicians' current practice, opinions, knowledge, and likelihood of recommending placebos in the future. METHODS: A cross-sectional web-based survey administered by REDCap was conducted at Boston Children's Hospital between October 2021 and March 2022. Physicians (n = 1157) were invited to participate through an email containing a link to a 23-item survey designed to assess physicians' attitudes and perceptions towards the clinical use of placebo in pediatrics. RESULTS: From 207 (18%) returned surveys, 109 (9%) were fully completed. Most respondents (79%) believed that enhancing the therapeutic components that contribute to the placebo response may be a way of improving pediatric care. However, whereas most (62%) found placebo treatments permissible, only one-third reported recommending them. In pediatrics, placebos are typically introduced as a medicine that "might help" (43%). The most common treatments recommended to enhance placebo effects are physical therapy, vitamins, and over-the-counter analgesics. Physicians most frequently recommend placebos for occasional pain, headaches, and anxiety disorders. Finally, the great majority of physicians (87%) stated they would be more likely to recommend placebo treatments if there were safety and ethical guidelines for open-label placebos. CONCLUSIONS: Placebo treatments seem permissible to physicians in pediatric care, but the development of safety and ethical guidelines may be necessary before physicians systematically incorporate the benefits of the placebo effect in pediatrics.
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Pediatrics , Physicians , Child , Humans , Attitude of Health Personnel , Cross-Sectional Studies , Practice Patterns, Physicians' , Surveys and QuestionnairesABSTRACT
BACKGROUND: The goal of this observational, open-label, cohort study was to determine whether prophylactic migraine treatment with galcanezumab, a peripherally acting drug, alters the incidence of premonitory symptoms, and/or occurrence of headache after exposure to triggers or aura episodes in treatment-responders (≥ 50% reduction in monthly migraine days [MMD]), super-responders (≥ 70%), non-responders (< 50%) and super non-responders (< 30%). METHODS: Participants were administered electronic daily headache diaries to document migraine days and associated symptoms one month before and during the three months of treatment. Questionnaires were used to identify conscious prodromal and trigger events that were followed by headache prior to vs. after 3 months of treatment. RESULTS: After 3 months of galcanezumab treatment, (a) the incidence of premonitory symptoms that were followed by headache decreased by 48% in the 27 responders vs. 28% in the 19 non-responders, and by 50% in the 11 super-responders vs. 12% in the 8 super non-responders; (b) the incidence of visual and sensory aura that were followed by headache was reduced in responders, non-responders, and super-responders, but not in super non-responders; (c) the number of triggers followed by headache decreased by 38% in responders vs. 13% in non-responders, and by 31% in super-responders vs. 4% in super non-responders; and (d) some premonitory symptoms (e.g., cognitive impairment, irritability, fatigue) and triggers (e.g., stress, sleeping too little, bright light, aura) were followed by headache only in super non-responders. CONCLUSIONS: Mechanistically, these findings suggest that even a mild decrease in migraine frequency is sufficient to partially reverse the excitability and responsivity of neurons involved in the generation of certain triggers and potentially premonitory symptoms of migraine. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04271202. Registration date: February 10, 2020.
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Epilepsy , Migraine Disorders , Humans , Cohort Studies , Incidence , Headache , Migraine Disorders/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Migraine is a complex neurological disorder involving generalized abnormalities in processing sensory information. Adopting evidence that central sensitization imposes major hurdles in the treatment of migraine, we hypothesized that it is the non-ictal (rather than ictal) allodynia that may determine the outcome of migraine prevention with peripherally-acting drugs. METHODS: To test this hypothesis, we used Quantitative Sensory Testing to determine whether it is possible to identify a patient's response to prophylactic treatment with galcanezumab based on presence/absence of cephalic and/or extracephalic allodynia during the pre-treatment non-ictal phase of migraine. RESULTS: Using strict criteria for allodynia (heat 32-40°C, cold 32-20°C, mechanical <60 g), we report that (a) the incidence of pre-treatment non-ictal cephalic allodynia was 21% in the 24 responders (>50% decrease in monthly migraine days) and 85% in the 19 non-responders; (b) the incidence of non-ictal extracephalic allodynia distinguishes responders from non-responders less accurately; and that (c) the incidence of non-ictal cephalic allodynia was similar in the chronic migraine and high-frequency episodic migraine groups. CONCLUSIONS: Clinically, the findings suggest that presence/absence of non-ictal allodynia can be used to identify galcanezumab responders with nearly 80% accuracy and galcanezumab non-responders with nearly 85% accuracy. Mechanistically, the presence of non-ictal allodynia (reflecting a state of activity-independent central sensitization) in both chronic migraine and high-frequency episodic migraine patients raises the possibility that the state of non-ictal allodynia may be attributed to physiological properties of central trigeminovascular neurons that are due to the genetic load of the individual patient rather than their migraine frequency.
Subject(s)
Hyperalgesia , Migraine Disorders , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Double-Blind Method , Hyperalgesia/drug therapy , Hyperalgesia/prevention & control , Migraine Disorders/drug therapy , Migraine Disorders/prevention & control , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Endometriosis is the leading cause of chronic pelvic pain. Alterations in brain functional connectivity have been reported in adult women with endometriosis-associated pain (EAP), however, it is still unknown if similar patterns of changes exist in adolescents. METHODS: In this pilot study, resting-state fMRI scans were obtained from 11 adolescent and young women with EAP and 14 healthy female controls. Using a seed-to-voxel approach, we investigated functional connectivity between the anterior insula, medial prefrontal cortex, and the rest of the brain. Furthermore, we explored whether potential functional connectivity differences were correlated with clinical characteristics including disease duration, pain intensity, and different psychosocial factors (pain catastrophizing, fear of pain, functional disability, anxiety, and depression). RESULTS: Our findings revealed that patients with EAP demonstrated significantly decreased connectivity between the right anterior insula and two clusters: one in the right cerebellum, and one in the left middle frontal gyrus compared to controls. Additionally, functional connectivity between the right anterior insula and the right cerebellum was positively associated with pain intensity levels. In patients with EAP, brain changes were also correlated with state anxiety and fear of pain. CONCLUSIONS: Our results are relevant not only for understanding the brain characteristics underlying EAP at a younger age, but also in enhancing future pain treatment efforts by supporting the involvement of the central nervous system in endometriosis.
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Chronic Pain , Endometriosis , Adult , Humans , Adolescent , Female , Magnetic Resonance Imaging/methods , Pilot Projects , Endometriosis/complications , Endometriosis/diagnostic imaging , BrainABSTRACT
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.