Brain Research Bulletin

IntroductionThe auditory phantom sound perception tinnitus is accompanied by maladaptive neurophysiological changes. In tinnitus treatment, repetitive transcranial magnetic stimulation (rTMS) is applied to counteract these pathological alterations. Previous work showed that single-session rTMS can reduce tinnitus loudness and modulate tinnitus-associated oscillatory brain activity. This study aimed to contribute to this research branch by addressing previous methodological shortcomings, including the absence of neuronavigation and adequate sham control. The objective was to assess tinnitus loudness and ongoing brain activity changes following various rTMS protocols, and to characterize modulations related to patient-specific most effective protocols, potentially uncovering electrophysiological markers of tinnitus suppression. MethodsThree active protocols (1,10,20 Hz; 200 pulses) and one sham protocol (0.1 Hz; 20 pulses) were delivered to the left and right temporo-parietal junction of 22 chronic subjective tinnitus patients using e-field-guided neuronavigation. Resting state EEG was recorded before and after each stimulation, along with tinnitus loudness ratings. Patient-specific protocols eliciting maximal suppression were identified via significant pre-to-post loudness reductions exceeding sham. ResultsRight 10 Hz rTMS induced strongest loudness suppressions. Significant and sham-superior EEG modulations were observed after right 10 Hz, right 20 Hz and left 20 Hz. Power increases in the Delta, Theta, Alpha and Gamma frequency bands were mainly observed in frontal and temporal areas but did not correlate with reported tinnitus suppression. In 16 patients it was feasible to identify a protocol inducing significant loudness reduction exceeding sham. Here suppression was associated with increased Alpha activity in the frontal cortex. ConclusionsOur findings demonstrate that brief rTMS protocols can transiently suppress tinnitus and modulate tinnitus-related oscillatory brain activity dynamics. Frontal Alpha power increases might reflect local enhanced inhibitory processes and reduced tinnitus percept processing, emphasizing frontal Alpha as a candidate marker for effective tinnitus suppression.

Chronic pain is increasingly conceptualized within a stress-related framework. However, it remains unclear whether chronic pain and prototypical stress-related conditions--such as post-traumatic stress disorder (PTSD)--share common neurobiological substrates. To this end, we conducted a pre-registered transdiagnostic meta-analytic study of gray matter volume alterations in chronic pain (60 studies) and PTSD (20 studies). Disorder-specific meta-analyses revealed that chronic pain was associated with distributed volume reductions across ventromedial prefrontal, middle cingulate, and insular cortices, whereas PTSD exhibited a single cluster of reduced volume in the anterior cingulate/dorsomedial prefrontal cortices. A conjunction analysis revealed that both conditions converged onto an overlapping cluster of reduced volume in the bilateral medial orbitofrontal/anterior cingulate area. Using normative resting-state fMRI data (HCP 7T dataset), we found that chronic pain neuroanatomical abnormalities were embedded within a distributed architecture of large-scale circuits encompassing mesocorticolimbic/reward, default mode, salience, frontoparietal, dorsal attention, and somatosensory networks. On the other hand, the PTSD focal neuroanatomical alteration was embedded in a single large-scale circuit mapping onto the mesocorticolimbic/reward, default mode, salience, and visual networks. In both conditions, the mesocorticolimbic/reward circuit emerged as the most robustly involved large-scale network. Notably, the shared cluster of reduced volume showed functional integration within the mesocorticolimbic/reward and default mode networks, with neurochemical fingerprinting revealing robust spatial correspondence with dopaminergic, serotonergic, opioid, and endocannabinoid receptor/transporter maps. Overall, these findings suggest that chronic pain and PTSD, beyond disorder-specific alterations, converge on a shared large-scale network organization. The overlap between chronic pain and a prototypical stress-related disorder at the network level provides neurobiological support for conceptualizing chronic pain within a stress-related framework.

ObjectiveThe goal of this pilot MRI study was to understand how focal transcranial direct current stimulation (tDCS) targeting auditory cortex changes brain function in chronic tinnitus. MethodsPeople with chronic tinnitus were randomized to active or sham tDCS on five consecutive days in this pilot mechanistic trial (n=10/group). Focal 4x1 tDCS (central anode, surround cathodes) targeted left auditory cortex, with single-blind 2mA current during twenty-minute sessions. Arterial spin-labeled and blood oxygenation level dependent MRI occurred immediately before and after the first tDCS session, and tinnitus symptoms were measured starting one week before the first tDCS session and through four weeks after the final session. ResultsAcute increases in cerebral blood flow and functional connectivity were noted in auditory cortex after the first active tDCS session. Reduced tinnitus loudness ratings after the final tDCS session correlated with acute change in functional connectivity between an auditory network and mediodorsal thalamus and prefrontal cortex. Reduced tinnitus intrusiveness also correlated with acute change in connectivity between precuneus and an auditory network. ConclusionsFocal auditory-cortex tDCS can influence function in thalamus, auditory, and prefrontal cortex, which may associate with improved tinnitus. SignificanceWith future refinement, noninvasive brain stimulation targeting auditory cortex could become a viable intervention for tinnitus. HIGHLIGHTSO_LIFocal transcranial direct current stimulation (tDCS) of auditory cortex changes cerebral blood flow and connectivity in tinnitus C_LIO_LITinnitus loudness ratings decreased on average after five sessions of active focal tDCS C_LIO_LIAcute changes in auditory, thalamic, and prefrontal function may predict quieter tinnitus after five sessions C_LI

Background Chronic pain is associated with structural and functional brain alterations, particularly within prefrontal, insular, and cingulate cortices. The dorsolateral prefrontal cortex (DLPFC) shows consistent structural abnormalities across chronic pain conditions, whereas findings on intrinsic functional connectivity (FC) remains inconsistent. Anchoring FC analyses to structural alterations may help identify consistent patterns across chronic pain conditions. Methods We employed a voxel-based morphometry (VBM)-guided, seed-based resting-state FC approach. Structural and functional MRI data were obtained from patients with chronic neck pain (CNP; n=21) and healthy controls (HC; n=25). Regions showing significant gray matter volume (GMV) differences were used as seeds for whole-brain FC analysis. Associations with pain intensity and pain-related fear were examined. Findings were further evaluated in an independent cohort with chronic primary pain (CPP; n=38). Results VBM revealed reduced GMV in the left DLPFC in CNP compared with HC, replicated in CPP. Seed-based FC analysis demonstrated reduced connectivity between the left DLPFC and the right hippocampus in CNP, with a similar pattern in CPP. In CNP, GMV in the DLPFC was positively associated with DLPFC-hippocampal connectivity (r = 0.45, 95% CI 0.02 to 0.74, p = 0.043). Reduced DLPFC-hippocampal connectivity was associated with higher activity avoidance (r = -0.50, 95% CI -0.77 to -0.09, p = 0.021), whereas no associations were observed with pain intensity. Conclusions These findings indicate consistent structural and functional alterations across chronic pain cohorts. Reduced DLPFC-hippocampal connectivity may reflect altered interactions between prefrontal and hippocampal circuits involved in pain-related cognitive and affective processes.

Fibromyalgia (FM) is a chronic condition marked by widespread pain, fatigue, sleep problems, cognitive decline, and other symptoms. Despite extensive research, the pathophysiology of FM remains poorly understood, complicating diagnosis and treatment, which often relies on self-report questionnaires. This study explored structural and functional brain changes in women with FM, identified potential biomarkers, and examined their relationship with FM severity. MRI data from 33 female FM patients and 33 matched healthy controls were utilized, focusing on T1-weighted MRI and resting-state fMRI scans. Functional connectivity (FC) analysis was performed using a machine learning framework to differentiate FM patients from healthy controls and predict FM symptom severity. No significant differences were found in brain structural features, such as gray matter volume, white matter volume, deformation-based morphometry, and cortical thickness. However, significant differences in FC were observed between FM patients and healthy controls, particularly in the default mode network (DMN), somatomotor network (SMN), visual network (VIS), and dorsal attention network (DAN). The FC metrics were significantly associated with FM severity. Our prediction model differentiated FM patients from healthy controls with an area under the curve of 0.65. FC measures accurately estimated FM symptom severities with a significant correlation (r = 0.45, p = 0.007). Functional connections in the DMN, VIS, and DAN were crucial in determining FM severity. These findings suggest that integrating brain FC measurements could serve as valuable biomarkers for early detection of FM and predicting FM symptom severity, improving diagnostic accuracy and facilitating the development of targeted therapeutic strategies.

Adverse Childhood Experiences (ACEs) increase vulnerability to chronic pain and mood disorders, yet the neural mechanisms linking early adversity to pain persistence remain poorly understood. We investigated whether ACEs are associated with altered effective connectivity within the salience network, a system critical for integrating emotionally and physiologically salient information and strongly implicated in chronic pain. Using neuroimaging data from a well-characterised, longitudinal cohort, participants performed an emotion-processing task (fearful vs. neutral faces) during fMRI. Region-of-interest analyses and dynamic causal modelling (DCM) were applied to examine directional connectivity among the anterior cingulate cortex (ACC), insula, and thalamus in relation to self-reported ACEs and chronic pain. Chronic pain and childhood emotional neglect were associated with reduced ACC-to-insula connectivity, suggesting impaired top-down regulation of interoceptive and affective signals. In contrast, individuals with chronic pain and a history of emotional neglect or abuse showed increased thalamus-to-insula and thalamus-to-ACC connectivity, consistent with heightened salience of sensory and emotional inputs. These findings demonstrate that ACEs influence salience network dynamics, establishing a mechanistic link between early adversity and chronic pain. They suggest that ACEs modify brain network activity, potentially contributing to the persistence of chronic pain and emphasising the roles of the ACC, insula, and thalamus.

ObjectiveLong-term opioid use is associated with diminished pain relief, hyperalgesia, and addiction which is not well understood. This study aimed to characterise opioid-related brain network alterations in chronic pain, focused on the right amygdala, and left mediodorsal thalamic nuclei that play key roles in affective pain processing, and are particularly rich in mu opioid receptors (MOR). SubjectsParticipants on opioid prescriptions with painful knee osteoarthritis and matched non-opioid using control pain participants. Methods and designSeed-based functional connectivity (FC) maps from resting-state fMRI data were compared between groups. ResultsWe found right amygdala hyperconnectivity with the posterior default mode network (pDMN) and the dorsomedial prefrontal cortex in opioid users in contrast to anti-correlations in controls. Conversely, opioid users showed predominant hypoconnectivity of the left dorsomedial thalamic seed with the cingulate cortex except for the subgenual part displaying an anti-correlation in opioid users and no association in non-users. Opioid users also showed higher negative affect in exploratory post-hoc tests suggesting a potential contribution of trait anxiety to amygdala-pDMN FC alteration. ConclusionOpioid use related hyperconnectivity of the right amygdalar network likely reflects maladaptive mechanisms involving negative affect and network plasticity. Hypoconnectivity of the mediodorsal thalamic nuclei with the anterior and mid cingulate on the other hand may reflect impaired resilience in line with previously reported compensatory MOR upregulation. In conclusion, this study provides new insight into possible brain mechanisms underlying adverse effects of prolonged opioids in chronic pain and offer candidate network targets for novel interventions.

Previous research has demonstrated the importance of the corticostriatal circuit in chronic pain. By focusing on nucleus accumbens (NAcc) circuits related to reward, we aimed to clarify how altered brain reward systems contribute to chronic pain. Using resting-state functional magnetic resonance imaging, we compared NAcc-medial prefrontal cortex (MPFC) functional connectivity in patients with fibromyalgia vs. healthy controls. Among patients, we analyzed the extent to which functional connectivity correlated with clinical measures. We also examined NAcc functional connectivity to subcortical regions. Lastly, we compared our results to a separate dataset of patients with chronic back pain. We identified robust NAcc-MPFC functional connectivity among patients with fibromyalgia and healthy controls, with no significant group differences. We found a positive correlational trend between NAcc-MPFC functional connectivity and total mood disturbance. Notably, patients with fibromyalgia showed significantly reduced functional connectivity of the right NAcc with mesolimbic circuit regions compared to controls. These results were largely similar to the results from the separate dataset. Our results provide novel evidence of intact corticostriatal but altered subcortical functional connectivity of the NAcc during resting-state in chronic pain and suggest that measured connectivity may relate to changes in mood and the level of cognitive demand during fMRI-based measurement. PerspectiveThis article indicates complex brain valuation system alterations associated with chronic pain. Our findings expand our understanding of the valuation system and its relationship to clinical presentation in patients with fibromyalgia.

BackgroundUnderstanding the associations among biopsychosocial factors is essential for improving research and treatment of chronic low back pain (CLBP). Here we characterized interrelations among biopsychosocial domains using network analysis and identified the most influential features in CLBP. MethodsData came from Quebec Low Back Pain Study, comprising 4,489 CLBP participants. We modeled relationships among baseline biopsychosocial features as networks, where nodes represent features and edges encode statistical or causal dependencies among them. Undirected network was inferred using distance correlation. Directed network was constructed using the Linear Non-Gaussian Acyclic Model, which estimates plausible causal directions. Influence maximization was performed using the Independent Cascade (IC) model to identify the most influential features in each network. ResultsIn the undirected network, physical function and pain interference were the most central nodes, followed by depression. In the directed network, fear of movement, catastrophizing, and widespread pain emerged as key downstream hubs receiving multiple causal inputs, whereas pain interference, physical function, and depression acted as major upstream drivers exerting broad causal influence. IC diffusion simulations further identified pain interference and physical function as the most influential features in the undirected and directed networks, respectively. ConclusionsPain interference, physical function, and depression consistently emerged as key components of the CLBP biopsychosocial network. These features exert causal effects on fear of movement, catastrophizing, and widespread pain, with diffusion analyses confirming their roles as system-wide drivers. Interventions targeting functionality and pain interference, rather than pain intensity alone, may yield broader benefits across psychological and functional domains.

Subjective tinnitus is the perception of sound in the absence of an external source, with a neurobiological basis that remains poorly understood. Importantly, tinni-tus prevalence increases with aging, reaching up to 25 % in adults aged above 65 years. This study examines white matter tract alterations in older adults with tinnitus using diffusion magnetic resonance imaging. The research involved 96 individuals from the Chilean ANDES cohort, including 56 patients with tinnitus and 40 controls. Thirty-six deep white matter (DWM) and 84 superficial white matter (SWM) bundles were segmented. For each bundle, we extracted four diffu-sion tensor imaging metrics: axial diffusivity (AD), mean diffusivity (MD), radial diffusivity (RD), and fractional anisotropy (FA). With these features, we trained an Extreme Gradient Boosting classifier to predict tinnitus, achieving an AUC of 0.93, highlighting the relevance of AD. Key DWM bundles included the ante-rior arcuate fasciculus, inferior longitudinal fasciculus, and cingulum short fibers (right hemisphere), and the superior motor thalamic radiation (left hemisphere). Significant SWM bundles in the left hemisphere included the superior parietal, cuneus, lingual, superior temporal, caudal middle frontal, precentral, fusiform, postcentral, supramarginal, rostral middle frontal, and superior frontal regions. Tinnitus patients showed decreased AD, MD, and RD, and increased FA, sug-gesting microstructural reorganization. These changes may reflect adaptive or maladaptive plasticity. Increased FA could signal compensatory responses, while decreased AD might indicate axonal damage. Meanwhile, the decrease in MD and RD could indicate an increase in myelin integrity. This is the first study to investigate SWM bundle alterations in tinnitus patients.

Major depressive disorder (MDD) is characterized by disrupted functional network connectivity (FNC), with unclear underlying dynamics. We investigated both static FNC (sFNC) and dynamic FNC (dFNC) on resting-state fMRI data from drug-naive first-episode MDD patients and healthy controls (HC). MDD patients exhibited lower sFNC within and between sensory and motor networks than HC. Four dFNC states were identified, including a globally-weakly-connected state, a cognitive-control-dominated state, a globally-positively-connected state, and an antagonistic state. The antagonistic state was marked by strong positive connections within the sensorimotor domain and their anti-correlations with the executive-motor control domain. Notably, MDD patients exhibited significantly longer time dwelling in the globally-weakly-connected state, at the cost of significantly shorter time dwelling in the antagonistic state. Further, only the mean dwell time of this antagonistic state was significantly anticorrelated to disease severity measures. Our study highlights the altered dynamics of the antagonistic state as a fundamental aspect of disrupted FNC in early MDD.

BackgroundTranscranial Direct Current Stimulation (tDCS) aims to induce cortical plasticity by modulating the activity of brain structures. The broad stimulation pattern, which is one of the main limitations of tDCS, can be overcome with the recently developed technique called High-Definition tDCS (HD-TDCS). ObjectiveInvestigation of the effect of HD-tDCS on tinnitus in a large patient cohort. MethodsThis prospective study included 117 patients with chronic, subjective, non-pulsatile tinnitus who received six sessions of anodal HD-tDCS of the right Dorsolateral Prefrontal Cortex (DLPFC). Therapy effects were assessed by use of a set of standardized tinnitus questionnaires filled out at the pre-therapy (Tpre), post-therapy (T3w) and follow-up visit (T10w). Besides collecting the questionnaire data, the perceived effect (i.e. self-report) was also documented at T10w. ResultsThe Tinnitus Functional Index (TFI) and Tinnitus Questionnaire (TQ) total scores improved significantly over time (pTFI < .01; pTQ < .01), with the following significant post-hoc comparisons: Tpre vs. T10w (pTFI < .05; pTQ < .05) and T3w vs. T10w (pTFI < .01 ; pTQ < .01). The percentage of patients reporting an improvement of their tinnitus at T10w was 47%. Further analysis revealed a significant effect of gender with female patients showing a larger improvement on the TFI and TQ (pTFI < .01; pTQ < .05). ConclusionsThe current study reported the effects of HD-tDCS in a large tinnitus population. HD-tDCS of the right DLPFC resulted in a significant improvement of the tinnitus perception, with a larger improvement for the female tinnitus patients.

The pathophysiology of many chronic pain disorders is far from evident. MR imaging studies provided initial data indicating chronic pain might lead to changes in brain structure and function. These changes may contribute to cognitive and emotional impairment and maybe even to the chronification of pain. However, the evidence for pain-related changes in gray and white matter is inconclusive so far. Hence we investigated potential changes of white matter microstructure in 34 adults with chronic noncancer pain (> 1 year) and 34 sex- and age-matched healthy individuals using diffusion tensor imaging (DTI). Whole-brain tract-based spatial statistics (TBSS) analyses of fractional anisotropy, mode of diffusivity, mean diffusivity, axial diffusivity, and radial diffusivity did not show significant differences after correction for multiple comparisons. The volumes of subdivisons of the corpus callosum were not significantly different either. We also performed a systematic review of the existing literature on white matter microstructure in patients with chronic pain following PRISMA guidelines. We identified 53 eligible studies on DTI in chronic pain. These studies demonstrated conflicting results regarding the direction and location of white matter changes across all diagnoses and within major diagnostic subcategories. We propose that two factors primarily contribute to this low reproducibility, small sample size and the use of potentially unreliable DTI parameters derived from the single-tensor model.

BackgroundChronic low back pain (CLBP) poses a significant challenge, contributing significantly to the ongoing opioid crisis while also being a leading cause of disability. Although spinal cord stimulation (SCS) stands as the primary FDA-endorsed method for neuromodulatory therapy in CLBP, there remains a subset of patients unresponsive to SCS and others who experience insufficient pain relief over time. In view of the evidence suggesting the critical role of subcallosal cingulate cortex (SCC) connectivity in pain processing, in the current study we investigated the role of the baseline SCC structural as a potential neuroimaging predictive biomarker to identify patients that are likely to benefit from SCS. MethodsDiffusion magnetic resonance imaging scans were acquired in 8 patients with CLBP (mean (SD) age = 70 (10) years; 6 female/2 male, 6 UCLA site, 2 UTSW) before their initial SCS trial. Probabilistic tractography from subject-specific anatomically defined SCC seed regions to the ventral striatum (VS), anterior cingulate cortex (ACC), uncinate fasciculus (UCF) and bilateral medial prefrontal cortex (mPFC) was used to calculate FSL structural probabilistic connectivity in the target network. To explore cross-sectional variations in SCC connectivity related to SCS trial response, we employed a general linear model (GLM) using the SCC probability of connectivity as dependent variable, and the response to the SCS trial as independent variable. We used Pearson correlation to evaluate further the relationships between the critical SCC probability of connectivity and the change in VAS score after the SCS trial. Finally, the role of depression in the treatment outcome was evaluated. ResultsResponders to SCS had significantly lower ipsilateral SCC connectivity to mPFC (F1,8 =8.19, p = 0.03) and VS (F1,8 =17.48, p=0.01) on the left hemisphere compared to non-responders. Pearson correlation analysis showed that decreased ipsilateral SCC baseline connectivity to left mPFC (p=0.03) and VS (p=0.01) was correlated with higher improvement in VAS scores. The baseline depression severity did not significantly influence the change in VAS score following the SCS trial. On the other hand, baseline SCC-VS connectivity on the left hemisphere was a significant predictor of change in VAS score (p=0.02). ConclusionsOur study highlights the important role of SCC connectivity that can serve as a potential biomarker for CLBP stratification and prediction to SCS treatment. These results can reshape our perspective on CLBP management and can serve as early indicator of response to the treatment providing a personalized approach based on the individuals underlying SCC connectivity.

The extent of white matter (WM) and Grey matter (GM) structural neuroplasticity following cognitive behavioral therapy for chronic pain management remains undetermined. In the current study, we investigated structural alterations in GM morphometry, as well as WM complexity and connectivity, before and after an 11-week group CBT for the treatment of chronic musculoskeletal pain. We hypothesized that effective pain management would influence WM structural metrics indicative of brain plasticity, particularly within cognitive and limbic circuitry as well as GM volume within pain matrix structures. To determine this, patients were randomized into two groups: 1) CBT group that received CBT once-weekly for 11-weeks, or 2) EDU group consisting of an active patient control group that received educational materials by mail. All subjects completed behavioral assessments and underwent neuroimaging at: baseline prior to any intervention (TP1), 11-weeks following either CBT or EDU (TP2), and four months following completion of the intervention (TP3). CBT resulted in significant clinical improvements, assessed via behavioral self-reports, compared to EDU. Compared to EDU, region of interest WM analysis revealed several fiber tracts that had significantly increased WM complexity following CBT intervention, including the bilateral posterior internal capsule and the left cingulum within the temporal lobe. Conversely, several tracts exhibited a decrease in WM complexity including the right external capsule, the left posterior internal capsule, and the right cingulum within the temporal lobe. Changes in clinical outcomes were predictive of alterations in WM complexity metrics immediately following intervention and at long-term follow-up. No between-group differences were observed in either WM connectivity or GM volume. In conclusion, psychotherapeutic interventions such as group CBT influence coping strategies for effective pain relief that influence WM microstructure, however, the mechanisms of these changes remain undetermined. Future studies will be required to uncover the biological underpinnings of these alterations in pain populations. ClinicaltrialsgovCan Therapy Alter CNS Processing of Chronic Pain: A Longitudinal Study (https://clinicaltrials.gov/ct2/show/NCT01794988?term=naylor&cntry=US&state=US%3AVT&draw=2&rank=1;NCT01794988). The study protocol was registered in the Clinical Trials Database.

SignificanceStress represents a key contributor to internalizing disorders and of rising global mental health challenges, particularly in young individuals. There is a critical need for accessible, brain-based interventions that can strengthen stress regulation and promote resilience. AimWe investigated whether a single session of real-time functional near-infrared spectroscopy (fNIRS)-informed neurofeedback training targeting the lateral prefrontal cortex (PFC) can enhance stress regulation under ecologically valid physiological and social stress conditions. ApproachIn a pre-registered double-blind, sham-controlled parallel-group trial, 60 young healthy adults underwent four neurofeedback, preceded and followed by baseline and maintenance runs without feedback. The training combined continuous feedback from individualized lateral PFC channels with reappraisal strategies to guide regulatory control. Stress regulation was assessed using the socially-evaluated cold pressor test (SECPT) that combines physiological and social stressors. ResultsNeurofeedback significantly increased lateral PFC activity across training runs. Participants in the neurofeedback group exhibited reduced stress - but not pain - experience in the SECPT and post-training anxiety, reflecting a successful domain-specific transfer of regulatory control. ConclusionsThis study demonstrates fNIRS-guided PFC neurofeedback facilitates adaptive learning of regulatory control and robustly enhances stress regulation and resilience under real-world stress. This scalable, non-invasive intervention offers a promising translational strategy for promoting resilience in vulnerable populations.

BackgroundFibromyalgia is a prevalent chronic pain condition characterized by widespread pain and sensory hypersensitivity. While much remains unknown about fibromyalgias neurobiological underpinnings, central nervous system alterations appear to be heavily implicated in its pathophysiology. Previous research examining brain structural abnormalities associated with fibromyalgia has yielded inconsistent findings. Thus, we followed previous methods to examine brain gray matter differences in fibromyalgia. We hypothesized that, relative to healthy controls, participants with fibromyalgia would exhibit lower gray matter volume in regions consistently implicated in fibromyalgia: the anterior cingulate cortex and medial prefrontal cortex. MethodsThis study used magnetic resonance imaging to evaluate regional and whole brain differences in gray matter among females with and without fibromyalgia. Group differences were analyzed with two-sample t-tests, controlling for total intracranial volume. ResultsNo significant differences in regional or whole brain gray matter volumes were detected between fibromyalgia and healthy controls. ConclusionsResults add to an existing body of disparate findings regarding brain gray matter volume differences in fibromyalgia, and suggest structural differences previously detected in fibromyalgia should be examined for reproducibility. Absent significant differences may also suggest that functional, but not structural, brain adaptations are primarily associated with fibromyalgia.

Widespread hyperalgesia, characterized by pain sensitivity beyond the primary pain site, is a common yet under-characterized feature across chronic pain conditions, including chronic pancreatitis (CP). In this exploratory study, we identified a candidate neural biosignature of widespread hyperalgesia using high-density electroencephalography (EEG) in patients with chronic low back pain (cLBP). Specifically, stimulus-evoked delta, theta, and alpha oscillatory activity in the bilateral medial orbitofrontal cortex (mOFC) differentiated cLBP patients with widespread hyperalgesia from healthy controls. To examine cross-condition generalizability and advance predictive biomarker development for CP, we applied this mOFC-derived EEG biosignature to an independent cohort of patients with CP. The biosignature distinguished CP patients with widespread hyperalgesia and predicted individual treatment responses to peripherally targeted endoscopic therapy. These preliminary findings provide early support for a shared cortical signature of central sensitization across pain conditions and offer translational potential for developing EEG-based predictive tools for treatment response in CP.

The central mechanisms underlying fibromyalgia syndrome (FMS) remain undetermined. The dorsolateral prefrontal cortex (DLPFC) is particularly relevant to FMS because it is implicated in cognitive, affective, and top-down pain regulation. Imbalances in excitatory (Glutamate) and inhibitory (Gamma aminobutyric acid; GABA) neurochemicals may play a critical role in the pathophysiology of the condition and more generally in homeostatic function within cortical circuits. Although the balance of excitation and inhibition are intrinsically linked no investigations to date have investigated the E/I ratio in FMS. Thus, the primary objective of this study was to determine whether the E/I ratio in the DLPFC is altered in participants with FMS compared to healthy controls using magnetic resonance spectroscopy. Additionally, we examined the relationship between E/I ratio and pain metrics. We hypothesized that the E/I ratio within the DLPFC would be altered in participants with FMS compared to controls and, secondly, that E/I ratio would be associated with both clinical pain and thermal pain sensitivity. The Brief Pain Inventory (BPI) self-assessment was used to evaluate pain severity and impact on physical functioning and acute pain sensitivity was determined via quantitative sensory testing to define thermal (heat) pain threshold and tolerance. Our results revealed an elevation in the E/I ratio in FMS compared to controls. A positive relationship between E/I ratio and thermal pain sensitivity measures was identified in the FMS cohort. Collapsing across groups, there was a positive relationship between E/I ratio and BPI score. These findings suggest that dysfunction in the balance between excitation and inhibition within cognitive brain circuitry may play a role in pain processing in FMS.

PurposeReal-world evidence (RWE) is of practical significance as it enables the evaluation of whether findings observed in rigorously controlled clinical trial settings are generalizable to routine clinical practice. While Lenire, a bimodal neuromodulation tinnitus treatment device, has demonstrated efficacy and safety within controlled trials, further RWE from clinics is needed to reinforce these results. This is the first real-world study to assess the therapeutic effects of Lenire on tinnitus using the Tinnitus Functional Index (TFI), a multidimensional instrument designed to capture tinnitus severity and treatment responsiveness. The study correlates findings with the Tinnitus Handicap Inventory (THI), a well-established tool that assesses the perceived functional, emotional, and catastrophic impact of tinnitus that was used in previous clinical trials and real-world studies. The use of an alternative validated outcome measure in a real-world study may add more feasible, relevant and patient-centered research findings to the body of evidence for Lenire, while maintaining scientific credibility. MethodsA single-site, single-arm retrospective study examining patients fitted with the Lenire device was conducted. Ninety-seven patients with moderate or greater tinnitus severity used the Lenire device for 12 weeks, for up to 60 minutes a day. The primary outcome was change in tinnitus severity, assessed using the TFI at 6-week (FU1) and 12-week (FU2) follow-ups. The THI was included as a secondary outcome measure. Responder rates and mean score changes between initial assessment and FU1 and FU2 were compared using Z-tests for proportions and t-tests, respectively. Pearsons correlations were used to examine the relationship between the TFI and THI change scores. ResultsAfter just 12 weeks of treatment, 73.4% [95% CI: 62.6%, 84.3%] of patients achieved a clinically significant improvement, defined as a reduction of at least 13 points on the TFI. This improvement was strongly supported by results from the THI, where 84.1% [95% CI: 75.1%, 93.2%] of patients met the minimum clinically important difference of 7 points. Mean score reductions were-25.9 (2.4, SEM) for the TFI and - 28.0 (2.4, SEM) for the THI. Change scores from initial assessment to FU2 on the TFI and THI were highly correlated (r = 0.74, p < 0.001), indicating strong agreement between the two measures in capturing treatment related improvements. All eight TFI subdomains showed reductions ranging from 18.5 to 31.4 points at FU2. ConclusionsThis retrospective study demonstrates that 12 weeks of treatment with the Lenire device resulted in clinically meaningful improvements in tinnitus severity on the TFI which was strongly supported by the THI. The high correlation between TFI and THI change scores indicates strong correlation between the two questionnaires in capturing treatment effects. Furthermore, all eight TFI subdomains showed notable reductions, underscoring the multidimensional impact of the treatment. These findings support the clinical utility of both the TFI and THI as complementary tools for evaluating treatment outcomes and guiding tinnitus management in routine practice.