Clas Linnman

Meta-analyses are a valuable tool in evidence-based research and have contributed to our understanding of structural brain changes in chronic pain. Meta-analyses are also limited by published summary statistics and quality/completeness of underlying studies. To address these limitations, we conducted the first individual participant data (IPD) meta-analysis of brain structure alterations in chronic pain. Using traditional morphometric measures (i.e., volume, cortical thickness, and surface area) and differential-geometric shape metrics (i.e., intrinsic and extrinsic curvature), we aimed to reveal alterations in brain structure convergent across chronic pain conditions. Eight publicly available datasets spanning five conditions and 401 individuals with chronic pain were analyzed: 1) knee osteoarthritis, 2) chronic low back pain, 3) fibromyalgia, 4) migraine, and 5) primary trigeminal neuralgia. FreeSurfer was used to parcellate T1-weighted anatomical images, and metrics for cortical and subcortical structures were extracted. Meta-analysis of study-level comparisons revealed a range of structural changes in the brain associated with chronic pain. Cortical thinning and volume loss were small and localized to the temporo-occipital regions, including bilateral volumetric reductions in the entorhinal cortex. Increases in intrinsic curvature were widespread, involving 49 out of 68 cortical regions. No significant alterations were detected in subcortical volumes. Intrinsic curvature and subcortical volumetric estimates had higher levels of inter-study heterogeneity compared to other metrics, reflecting potential condition and sample specific variability. Leveraging harmonized processing across a large sample size, our novel IPD meta-analysis highlights both widespread and region-specific structural remodeling of chronic pain-related neuroanatomy.

Objective: Assess feasibility, safety, and tolerability of 3 months of oral brivaracetam for severe (9–10/10) spinal cord injury–related neuropathic pain. Methods: We conducted a multisite pilot study where adults were randomized to 3 months of brivaracetam (100 mg BID) or placebo. Pain was assessed via the Brief Pain Inventory, the International Spinal Cord Injury Pain Basic Dataset (version 2.0), and a daily pain diary. Results: We enrolled 24 participants across 2 sites and 14 participants were included in the final analysis (n = 8 placebo, n = 6 brivaracetam). The drug was tolerated with expected, nonserious side effects (nausea if taken on an empty stomach, fatigue that improved after 2–3 days). Side effects were more common in the brivaracetam group (73%, n = 8 vs 33%, n = 3). We observed a mean 2.7-point reduction in daily worst pain in the brivaracetam group compared to a 1.0-point reduction in the placebo group. The percentage of participants experiencing 30% (100% vs 60%) and 50% (60% vs 12.5%) pain reduction was greater in the brivaracetam group. Conclusions: These findings suggest safety, tolerability, and feasibility of brivaracetam for treating neuropathic pain in spinal cord injury. These pilot findings will be used to power future efficacy clinical trials.

Migraine is a multifaceted primary headache disorder. In neuroimaging of migraine, fMRI has been used to elucidate pathophysiology or monitor treatment effects. The current literature, however, is highly heterogeneous regarding reported variables and methodologies. This begets a lack of comparability and complicates synthesis of results across studies. We developed a framework for standardized reporting of fMRI studies in migraine. Experts on fMRI in migraine were identified from the literature and subjected to structured questionnaires in 2 iterations of 3 rounds according to the DELPHI method. A total of 157 statements across 17 reporting domains were rated on 5-point Likert scales (strong support to strong opposition). The first iteration covered demographic data, migraine-specific factors, medication, scan timing, healthy controls (HCs), participant sampling/recruiting, standardized forms, study preregistration, region of interest (ROI) analyses, validation data sets, data sharing, preprocessing documentation, and analysis software. The second iteration of the questionnaire covered scanner-related factors, sequence-related factors, physiology monitoring, and stimulation-related factors. Items showing strong consensus/consensus (≥90%/≥75% of participants indicating scores 4 or 5) were included as standard reporting items. All 3 rounds of the first/second iteration were completed by 29 and 26 researchers (age 46 ± 11 years; 38% female/age 46 ± 12 years; 44% female) from 23 and 21 institutions. Across both iterations, strong consensus and consensus was achieved for 34 (3 scanner-related factors, 9 sequence-related factors, 1 stimulation-related factor, 2 demographic factors, 7 migraine-specific factors, 2 medication-factors, 2 scan timing factors, 4 HC factors, 1 preregistration factor, 1 analysis software factor, and 2 ROI analyses factors) and 33 (1 scanner-related factors, 4 sequence related factors, 1 factor related to physiology monitoring, 1 stimulation-related factor, 3 demographic factors, 6 migraine-specific factors, 4 medication factors, 3 HC factors, 2 sampling factors, 1 standardized form, 1 preregistration factor, 1 data sharing factor, 2 analysis software factors, and 3 ROI analyses factors) items, respectively. From these, a checklist covering 63 items from 14 reporting domains was created. We present an expert-based framework for reporting standards in fMRI studies of migraine, which can be used for future studies to homogenize cohort characterization, fMRI acquisitions, and analysis protocols.

Spinal cord injury (SCI) below-level neuropathic pain is a difficult condition to treat both pharmacologically and surgically. Successful treatment using surgically created lesions of the spinal cord dorsal root entry zone (DREZ), guided by intramedullary monitoring of neuronal electrical hyperactivity, has shown that DREZs both cephalad and caudal to the level of injury can be the primary generators of SCI below-level pain. Below-level pain perception follows a unique somatotopic map of DREZ pain generators, and neuronal transmission to brain pain centres can occur primarily through sympathetic nervous system (SNS) pathways. This study evaluated changes in brain resting-state and task-based functional magnetic resonance imaging responses before and after neuroelectrically guided DREZ microcoagulation surgery. Eight persons with clinically complete SCI who suffered chronic, severe and unrelenting below-level neuropathic pain refractory to all pharmacological management were investigated before and after the surgical intervention. Baseline differences between DREZ subjects, group-matched low pain SCI and healthy controls were observed in medial primary somatosensory and motor cortex connectivity to the hippocampus, amygdala and medial prefrontal cortex. The DREZ surgery led to short-term (12 days) almost complete pain relief in all participants and long-term (1+ year) pain relief in all participants receiving DREZ lesioning both cephalad and caudal to the level of injury (six out of eight participants). Follow-up 12 days post-operatively indicated that DREZ surgery normalized prior negative functional coupling between primary sensory (S1) and motor (M1) cortices to the hippocampus, amygdala and the medial prefrontal cortex, increased M1 to putamen and amygdala connectivity and decreased limbic to cerebellar connectivity. DREZ hyperactivity was found both cephalad and caudal to the level of injury. The regional distribution of hyperactive regions corresponded not to classical dermatomes but rather mapped on to intermediolateral (IML) cell column end organ innervation of body regions of below-level pain perception, consistent with a non-classical SNS-mediated somatotopic map of DREZ below-level pain generators. The results indicate that neuroelectrically guided DREZ microcoagulation alters a medial prefrontal–somatosensory–limbic network that is separate from classical pain pathways. This provides further evidence that below-level SCI pain originates in hyperactive DREZs and can be relayed to the brain via the SNS.

Spinal cord injuries (SCI) often lead to lifelong disability. Among the various types of injuries, incomplete and discomplete injuries, where some axons remain intact, offer potential for recovery. However, demyelination of these spared axons can worsen disability. Demyelination is a reversible phenomenon, and drugs like 4-aminopyridine (4AP), which target K ⁺ channels in demyelinated axons, show that conduction can be restored. Yet, accurately assessing and monitoring demyelination post-SCI remains challenging due to the lack of suitable imaging methods. In this study, we introduce a novel approach utilizing the positron emission tomography (PET) tracer, [ ¹⁸ F]3F4AP, specifically targeting K ⁺ channels in demyelinated axons for SCI imaging. Rats with incomplete contusion injuries were imaged up to one month post-injury, revealing [ ¹⁸ F]3F4AP’s exceptional sensitivity to injury and its ability to detect temporal changes. Further validation through autoradiography and immunohistochemistry confirmed [ ¹⁸ F]3F4AP’s targeting of demyelinated axons. In a proof-of-concept study involving human subjects, [ ¹⁸ F]3F4AP differentiated between a severe and a largely recovered incomplete injury, indicating axonal loss and demyelination, respectively. Moreover, alterations in tracer delivery were evident on dynamic PET images, suggestive of differences in spinal cord blood flow between the injuries. In conclusion, [ ¹⁸ F]3F4AP demonstrates efficacy in detecting incomplete SCI in both animal models and humans. The potential for monitoring post-SCI demyelination changes and response to therapy underscores the utility of [ ¹⁸ F]3F4AP in advancing our understanding and management of spinal cord injuries.

Humans commit more violent crimes when temperature and air pollution is higher. Here, we investigate if also the day-to-day rates of dogs biting humans is influenced by environmental factors. 69,525 reports of dogs biting humans, sourced from public records on animal control requests and from ER records, were analyzed. The impact of temperature and air pollutants were evaluated with a zero-inflated Poisson generalized additive model, while controlling for regional and calendar effects. Exposure–response curves were used to assess the association between outcome and major exposure variables. We find that the rates of dogs biting humans increases with increasing temperature and ozone, but not PM_2.5 exposure. We also observed that higher UV irradiation levels were related to higher rats of dog bites. We conclude that dogs, or the interactions between humans and dogs, are more hostile on hot, sunny, and smoggy days, indicating that the societal burden of extreme heat and air pollution also includes the costs of animal aggression.