Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Mechanical pain sensitivity is associated with hippocampal structural integrity.

ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.

Peripheral magnetic stimulation for chronic peripheral neuropathic pain: A systematic review and meta-analysis.

OBJECTIVES: To provide a systematic review of the literature on the effects of peripheral magnetic stimulation (PMS) in the treatment of chronic peripheral neuropathic pain. METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, CINHAL, Web of Science, and ProQuest was conducted from inception to July 2023 to identify studies of any design published in English language that enrolled adult patients (≥18 years) that received PMS for treatment of a chronic peripheral neuropathic pain disorder (pain > 3 months). RESULTS: Twenty-three studies were identified which included 15 randomized controlled trials (RCTs), five case series, two case reports, and one non-randomized trial. PMS regimens varied across studies and ranged from 5 to 240 min per session over 1 day to 1 year of treatment. Results across included studies were mixed, with some studies suggesting benefits while others showing no significant differences. Of nine placebo-controlled RCTs, four reported statistically significant findings in favor of PMS use. In the meta-analysis, PMS significantly reduced pain scores compared to control within 0-1 month of use (mean difference -1.64 on a 0-10 numeric rating scale, 95% confidence interval -2.73 to -0.56, p = 0.003, I2 = 94%, 7 studies [264 participants], very low quality of evidence), but not at the 1-3 months and >3 months of PMS use (very low and low quality of evidence, respectively). Minimal to no adverse effects were reported with PMS use. DISCUSSION: There is limited and low-quality evidence to make definitive recommendations on PMS usage, however, the available data is encouraging, especially for short-term applications of this novel modality. Large high-quality randomized controlled trials are required to establish definitive efficacy and safety effects of PMS.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Insula-cingulate structural and functional connectivity: an ultra-high field MRI study.

The insula and the cingulate are key brain regions with many heterogenous functions. Both regions are consistently shown to play integral roles in the processing of affective, cognitive, and interoceptive stimuli. The anterior insula (aINS) and the anterior mid-cingulate cortex (aMCC) are two key hubs of the salience network (SN). Beyond the aINS and aMCC, previous 3 Tesla (T) magnetic resonance imaging studies have suggested both structural connectivity (SC) and functional connectivity (FC) between other insular and cingulate subregions. Here, we investigate the SC and FC between insula and cingulate subregions using ultra-high field 7T diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). DTI revealed strong SC between posterior INS (pINS) and posterior MCC (pMCC), and rs-fMRI revealed strong FC between the aINS and aMCC that was not supported by SC, indicating the likelihood of a mediating structure. Finally, the insular pole had the strongest SC to all cingulate subregions, with a slight preference for the pMCC, indicative of a potential relay node of the insula. Together these finding shed new light on the understanding of insula-cingulate functioning, both within the SN and other cortical processes, through a lens of its SC and FC.

Effect of Peripheral Magnetic Stimulation on Acute and Chronic Pain After Surgery: A Systematic Review and Meta-Analysis.

Peripheral magnetic stimulation (PMS) is a potentially promising modality to help manage postoperative pain. We systematically reviewed the effect of PMS on acute and chronic postoperative pain. MEDLINE, Cochrane CENTRAL, EMBASE, ProQuest Dissertations, and clinical trials.gov were searched from inception until May 2021. We included studies of any study design that included patients ≥18 years of age undergoing any type of surgery that administered PMS within the perioperative period and evaluated postoperative pain. Seventeen randomized controlled trials and 1 nonrandomized clinical trial were included into the review. Thirteen out of the 18 studies found a positive effect with PMS on postoperative pain scores. In our meta-analysis, peripheral magnetic stimulation was more efficacious than sham or no intervention within the first 7 postoperative days (mean difference [MD] -1.64 on a 0 to 10 numerical rating score, 95% confidence interval [CI] -2.08 to -1.20, I2 = 77%, 6 studies, 231 patients). This was also true at 1 and 2 months after surgery (MD -1.82, 95% CI -2.48 to -1.17, I2 = 0%, 3 studies, 104 patients; and MD -1.96, 95% CI -3.67 to -.26, I2 = 84%, 3 studies, 104 patients, respectively). A difference was not seen with persistent pain at 6 and 12-months after surgery, acute postoperative opioid consumption, or adverse events between groups. Results are limited by heterogeneity and generally low-quality studies, as well as low or very low quality of evidence. High-quality and adequately blinded trials are needed to definitively confirm the benefits of peripheral magnetic stimulation administered in the perioperative period. PERSPECTIVE: This review evaluates the efficacy and safety of PMS on postoperative pain. The results help elucidate PMS' role in postoperative pain management and identify gaps where more research is required.

Ultrasound-guided repetitive pulsed peripheral magnetic stimulation provides pain relief in refractory glossopharyngeal neuralgia: A case report.

Aims: Repetitive peripheral magnetic stimulation (rPMS) is a novel nonpharmacological treatment modality. This noninvasive approach can stimulate peripheral nerves to provide analgesia through neuromodulation. We report the first case of ultrasound-guided rPMS to treat a case of severe refractory glossopharyngeal neuralgia. Methods: A 70-year-old female with an 8-year history of glossopharyngeal neuralgia reported refractory pain unresponsive to pharmacological and interventional treatments. After consenting to treatment, the patient received high-frequency rPMS in three different sessions using intermittent theta burst stimulation below motor thresholds. rPMS was applied over the skin directed at the glossopharyngeal nerve identified using ultrasound guidance. Session 1 included 20 min of continuous treatment, session 2 included 40 min of treatment (two 20-min treatments separated by a 10-min break), session 3 included 40 min of treatment (similar to Session 2) repeated daily for 5 days. Pre- and postintervention pain levels were collected with a daily 1-week pain diary and pain questionnaires. Results: Session 1 led to an immediate 30% decrease in pain after treatment. Session 2 led to a 75% decrease in pain immediately after treatment that remained reduced for approximately 2 days. Session 3 produced complete pain relief immediately after treatment and remained lower for 5 days after treatment and returned to baseline levels at 1 week. Conclusion: rPMS provided immense but temporary relief in a severe case of refractory glossopharyngeal neuralgia. Further work is needed to determine the most effective regimen to treat complex pain disorders in the head and neck.

La stimulation magnétique périphérique répétitive (SPMr) est une nouvelle modalité de traitement non pharmacologique. Cette approche non invasive peut stimuler les nerfs périphériques pour fournir une analgésie par le truchement de la neuromodulation. Nous rapportons le premier cas de SPMR guidée par ultrasons pour traiter un cas de névralgie glossopharyngée réfractaire sévère.Méthodes: Une femme de 70 ans avec une histoire de huit ans de névralgie glossopharyngée a fait état d'une douleur réfractaire ne répondant pas aux traitements interventionnels pharmacologiques. Après avoir consenti au traitement, la patiente a reçu une SMPr à haute fréquence au cours de trois séances différentes en utilisant la stimulation thêta-burst intermittente en-deçà des seuils moteurs. La SMPr a été appliquée sur la peau en ciblant le nerf glossopharyngé identifié à l'aide d'un guidage par ultrasons. La séance 1 comprenait 20 minutes de traitement continu, la séance 2 comprenait 40 minutes de traitement (deux traitements de 20 minutes séparés par une pause de 10 minutes), la séance 3 comprenait 40 minutes de traitement (similaire à la séance 2) répétées quotidiennement pendant cinq jours. Les niveaux de douleur pré et post-intervention ont été collectés à l'aide de questionnaires sur la douleur et consignés dans un journal quotidien de la douleur échelonné sur une semaine.Résultats: La séance 1 a entraîné une diminution immédiate de 30 % de la douleur après le traitement. La séance 2 a conduit à une diminution de 75 % de la douleur immédiatement après le traitement et cette diminution s'est maintenue pendant environ deux jours. La séance 3 a donné lieu à un soulagement complet de la douleur immédiatement après le traitement; la douleur est ensuite restée plus faible pendant cinq jours après et est revenue aux niveaux de départ au bout d'une semaine.Conclusion: La SMPr a procuré un soulagement immense mais temporaire dans un cas grave de névralgie glossopharyngée réfractaire. Des travaux supplémentaires sont nécessaires pour déterminer le régime de traitement le plus efficace pour traiter les troubles douloureux complexes de la tête et du cou.

Optimizing effective dose and image quality in cone beam CT sialography.

OBJECTIVES: The purpose of this study was to develop protocols that optimize patient radiation dose and image quality for cone beam computed tomographic (CBCT) sialography for the major salivary glands. STUDY DESIGN: Radiation absorbed dose measurements were repeated in triplicate using 25 sites in the head and neck of a Radiation ANalog DOsimetry system (RANDO) phantom, and effective doses were calculated across a range of peak kilovoltage (kVp) and milliamperage (mA) settings using an 8 cm (diameter) by 5 cm (height) field of view (FOV) for submandibular imaging and an 8 cm (diameter) by 8 cm (height) FOV for parotid imaging. Image signal difference-to-noise ratio (SDNR) was determined, and the figure-of-merit (FOM), a measure of image quality, was calculated. RESULTS: For submandibular sialography, 85 kVp and 6 mA were chosen as the optimal exposure parameters, resulting in a mean effective dose of 82.47 µSv and a mean SDNR of 13.86, with a mean FOM of 2.33 µSv-1. For parotid sialography, 70 kVp and 6 mA were chosen, and these settings resulted in a mean effective dose of 39.99 µSv, a mean SDNR of 17.43, and a mean FOM of 7.60 µSv-1. CONCLUSIONS: Low-dose 3-dimensional sialography with high image quality and minimal effective dose can be delivered using CBCT with localized, small FOVs.

Identification of central amygdala and trigeminal motor nucleus connectivity in humans: An ultra-high field diffusion MRI study.

The neuroanatomical circuitry of jaw muscles has been mostly explored in non-human animals. A recent rodent study revealed a novel circuit from the central amygdala (CeA) to the trigeminal motor nucleus (5M), which controls biting attacks. This circuit has yet to be delineated in humans. Ultra-high diffusion-weighted imaging data from the Human Connectome Project (HCP) allow in vivo delineation of circuits identified in other species-for example, the CeA-5M pathway-in humans. We hypothesized that the CeA-5M circuit could be resolved in humans at both 7 and 3 T. We performed probabilistic tractography between the CeA and 5M in 30 healthy young adults from the HCP database. As a negative control, we performed tractography between the basolateral amygdala (BLAT) and 5M, as CeA is the only amygdalar nucleus with extensive projections to the brainstem. Connectivity strength was operationalized as the number of streamlines between each region of interest. Connectivity strength between CeA-5M and BLAT-5M within each hemisphere was compared, and CeA-5M circuit had significantly stronger connectivity than the BLAT-5M circuit, bilaterally at both 7 T (all p < .001) and 3 T (all p < .001). This study is the first to delineate the CeA-5M circuit in humans.

Age-related effects on the anterior and posterior hippocampal volumes in 6-21 year olds: A model selection approach.

Although recent studies support significant differences in intrinsic structure, function, and connectivity along the longitudinal axis of the hippocampus, few studies have investigated the normative development of this dimension. In addition, factors known to influence hippocampal structure, such as sex or puberty, have yet to be characterized when assessing age-related effects on its subregions. This study addresses this gap by investigating the relationship of the anterior (antHC) and posterior (postHC) hippocampus volumes with age, and how these are moderated by sex or puberty, in structural magnetic resonance imaging scans from 183 typically developing participants aged 6-21 years. Based on previous literature, we first anticipated that non-linear models would best represent the relationship between age and the antHC and postHC volumes. We found that age-related effects are region-specific, such that the antHC volume remains stable with increasing age, while the postHC shows a cubic function characterized by overall volume increase with age but a slower rate during adolescence. Second, we hypothesized that models, which include biological sex or pubertal status would best describe these relationships. Contrary to expectation, models comprising either biological sex or pubertal status did not significantly improve model performance. Further longitudinal research is needed to evaluate their effects on the antHC and postHC development.

Amygdalar Functional Connectivity Differences Associated With Reduced Pain Intensity in Pediatric Peripheral Neuropathic Pain.

Background: There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation. Objective: To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP. Methods: This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11-18 years with clinical features of chronic peripheral NeuP (n = 17), recruited from a tertiary clinic, relative to healthy adolescents (n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences. Results: Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (P FDR <0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males (r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females (r = -0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory. Conclusions: Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible.

Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain.

INTRODUCTION: Current treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches. METHODS AND ANALYSIS: Here we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function. ETHICS AND DISSEMINATION: The study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children's Hospital Medical Center Review Board as the reviewing IRB. Stanford's IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories. TRIAL REGISTRATION NUMBER: NCT04285112.

Hippocampal volume, FKBP5 genetic risk alleles, and childhood trauma interact to increase vulnerability to chronic multisite musculoskeletal pain.

Chronic multisite musculoskeletal pain (CMP) is common and highly morbid. However, vulnerability factors for CMP are poorly understood. Previous studies have independently shown that both small hippocampal brain volume and genetic risk alleles in a key stress system gene, FKBP5, increase vulnerability for chronic pain. However, little is known regarding the relationship between these factors and CMP. Here we tested the hypothesis that both small hippocampal brain volume and FKBP5 genetic risk, assessed using the tagging risk variant, FKBP5rs3800373, increase vulnerability for CMP. We used participant data from 36,822 individuals with available genetic, neuroimaging, and chronic pain data in the UK Biobank study. Although no main effects were observed, the interaction between FKBP5 genetic risk and right hippocampal volume was associated with CMP severity (ß = -0.020, praw = 0.002, padj = 0.01). In secondary analyses, severity of childhood trauma further moderated the relationship between FKBP5 genetic risk, right hippocampal brain volume, and CMP (ß = -0.081, p = 0.016). This study provides novel evidence that both FKBP5 genetic risk and childhood trauma moderate the relationship between right hippocampal brain volume and CMP. The data increases our understanding of vulnerability factors for CMP and builds a foundation for further work assessing causal relationships that might drive CMP development.

Pain Relief Reverses Hippocampal Abnormalities in Trigeminal Neuralgia.

Chronic pain patients frequently report memory and concentration difficulties. Objective testing in this population points to poor performance on memory and cognitive tests, and increased comorbid anxiety and depression. Recent evidence has suggested convergence between chronic pain and memory deficits onto the hippocampus. The hippocampus consists of heterogenous subfields involved in memory consolidation, behavior regulation, and stress modulation. Despite significant studies outlining hippocampal changes in human and chronic pain animal models, the effect of pain relief on hippocampal abnormalities remains unknown. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder which is highly amenable to surgical interventions, providing a unique opportunity to investigate the effect of pain relief. This study investigates the effect of pain relief on hippocampal subfields in TN. Anatomical MR images of 61 TN patients were examined before and 6 months after surgery. Treatment responders (n = 47) reported 95% pain relief, whereas non-responders (n = 14) reported 40% change in pain on average. At baseline, patients had smaller hippocampal volumes, compared to controls. After surgery, responders' hippocampal volumes normalized, largely driven by CA2/3, CA4, and dentate gyrus, which are involved in memory consolidation and neurogenesis. We propose that hippocampal atrophy in TN is pain-driven and successful treatment normalizes such abnormalities. PERSPECTIVE: Chronic pain patients have structural abnormalities in the hippocampus and its subfields. Pain relief normalizes these structural abnormalities and impacts patients in a sex-dependent manner.

Baseline resting-state functional connectivity determines subsequent pain ratings to a tonic ecologically valid experimental model of orofacial pain.

ABSTRACT: Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure-the insertion of an elastomeric separator between teeth-which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional MRI scanning before the placement of a separator between the first molar and second premolar, which was kept in place for 5 days. Participants recorded pain ratings 3 times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve or gray matter volume of any brain region. Peak pain did, however, positively correlate with baseline resting-state functional connectivity between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, preinterventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

The structural and functional connectivity neural underpinnings of body image.

How we perceive our bodies is fundamental to our self-consciousness and our experience in the world. There are two types of interrelated internal body representations-a subjective experience of the position of a limb in space (body schema) and the subjective experience of the shape and size of the limb (body image). Body schema has been extensively studied, but there is no evidence of the brain structure and network dynamics underpinning body image. Here, we provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger-stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants' susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances.