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Abstract Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Background/Objectives: Acupuncture is an efficacious integrative therapy for treating pain, fatigue, and sleep disturbance (the psychoneurological symptom cluster) in breast cancer survivors. However, the mechanisms underlying its effects remain unclear, and related metabolomics studies are limited. This study aimed to examine serum metabolite changes after acupuncture and their relationships to symptom improvement. Methods: Forty-two breast cancer survivors experiencing pain, fatigue, and sleep disturbance participated in a single-arm acupuncture trial. They received a 10-session acupuncture intervention over 5 weeks. Fasting blood samples and symptom surveys were collected before and after the acupuncture intervention, and untargeted metabolomics profiling was conducted on serum samples. Mixed-effects models adjusting for covariates (age, race, body mass index, and antidepressant use) were applied for analysis. Results: After acupuncture, there was a significant reduction in the psychoneurological symptom cluster (mean reduction = −6.2, p < 0.001).Bonferroni correction was applied to 40 independent metabolite clusters (α = 0.00125); cysteine-glutathione disulfide (p = 0.0006) significantly increased, and retinal (p = 0.0002) and cis-urocanate (p = 0.0005) were significantly decreased. Dimethyl sulfone (p = 0.00139) showed a trend towards reduction after acupuncture and its change (p = 0.04, β =1.97) was positively associated with reduction in the psychoneurological symptom cluster. Also, increased lauroylcarnitine (p = 0.0009) and decreased cytosine (p = 0.0008) can modulate the therapeutic effects of acupuncture. Conclusions: Acupuncture demonstrates beneficial effects on the psychoneurological symptom cluster in breast cancer survivors. Dimethyl sulfone may be a promising mediator in the relationship between acupuncture and psychoneurological symptoms, while acylcarnitine metabolism may modulate the therapeutic effect of acupuncture.

Abstract Despite the longstanding use of nitrous oxide and descriptions of its psychological effects more than a century ago, there is a paucity of neurobiological investigation of associated psychedelic experiences. We measure the brain’s functional geometry (through analysis of cortical gradients) and temporal dynamics (through analysis of co-activation patterns) using human resting-state functional magnetic resonance imaging data acquired before and during administration of 35% nitrous oxide. Both analyses demonstrate that nitrous oxide reduces functional differentiation in frontoparietal and somatomotor networks. Importantly, the subjective psychedelic experience induced by nitrous oxide is inversely correlated with the degree of functional differentiation. Thus, like classical psychedelics acting on serotonin receptors, nitrous oxide flattens the functional geometry of the cortex and disrupts temporal dynamics in association with psychoactive effects.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients’ well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies.Clinical Trial RegistrationClinicalTrials.gov, Identifier: NCT05045820.

BackgroundPain is a common, debilitating, and poorly understood complication of sickle cell disease (SCD). The need for clinical pain management of SCD is largely unmet and relies on opioids as the main therapeutic option, which leads to a decreased quality of life (QoL). According to the literature, acupuncture has shown certain therapeutic effects for pain management in SCD. However, these clinical studies lack the guidance of Traditional Chinese Medicine (TCM) Syndrome Differentiation principles for treatment.AimTo characterize differences in clinical presentation amongst TCM diagnosed Syndromes in SCD patients.MethodFifty-two patients with SCD and 28 age- and sex-matched healthy controls (HCs) were enrolled in an ongoing trial of acupuncture. Each participant completed a series of questionnaires on pain, physical function, fatigue, sleep, anxiety, depression and QoL and underwent cold- and pressure-based quantitative sensory testing at baseline. Data on prescription opioid use over the 12 months prior to study enrollment was used to calculate mean daily morphine milligram equivalents (MME). Differences among the three TCM Syndromes were analyzed by one-way ANOVA followed by Tukey post hoc testing. Two-sample t-tests were used to compare SCD and HC groups.ResultsTCM diagnosis criteria classified SCD patients into one of three TCM Syndromes: (a) Equal; (b) Deficiency; and (c) Stagnation. The Stagnation group exhibited higher pain interference, physical dysfunction, nociplastic pain, fatigue, anxiety, depression, MME consumption and lower sleep quality and QoL compared to the Equal group. Few differences were observed between HCs and the Equal SCD group across outcomes. Deficiency and Stagnation groups were differentiated with observed- and patient-reported clinical manifestations.ConclusionThese findings suggest that TCM diagnosed Syndromes in SCD can be differentially characterized using validated objective and patient-reported outcomes. Because characteristics of pain and co-morbidities in each SCD patient are unique, targeting specific TCM “Syndromes” may facilitate treatment effectiveness with a Syndrome-based personalized treatment plan that conforms to TCM principles. These findings lay the foundation for the development of tailored acupuncture interventions based on TCM Syndromes for managing pain in SCD. Larger samples are required to further refine and validate TCM diagnostic criteria for SCD.

The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical “hot zone,” posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.

Abstract Background and Purpose Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain‐free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. Methods This pilot study included 16 subjects, 10 with TMD and 6 pain‐free controls. Clinical pain was characterized using self‐reported questionnaires. Visual task‐based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. Results Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. Conclusions The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or “omics,” quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.

Fibromyalgia (FM) is a chronic pain condition that is characterized by hypersensitivity to multimodal sensory stimuli, widespread pain, and fatigue. We have previously proposed explosive synchronization (ES), a phenomenon wherein a small perturbation to a network can lead to an abrupt state transition, as a potential mechanism of the hypersensitive FM brain. Therefore, we hypothesized that converting a brain network from ES to general synchronization (GS) may reduce the hypersensitivity of FM brain. To find an effective brain network modulation to convert ES into GS, we constructed a large-scale brain network model near criticality (i.e., an optimally balanced state between order and disorders), which reflects brain dynamics in conscious wakefulness, and adjusted two parameters: local structural connectivity and signal randomness of target brain regions. The network sensitivity to global stimuli was compared between the brain networks before and after the modulation. We found that only increasing the local connectivity of hubs (nodes with intense connections) changes ES to GS, reducing the sensitivity, whereas other types of modulation such as decreasing local connectivity, increasing and decreasing signal randomness are not effective. This study would help to develop a network mechanism-based brain modulation method to reduce the hypersensitivity in FM.

Psychedelics have been recognized as model interventions for studying altered states of consciousness. However, few empirical studies of the shamanic state of consciousness, which is anecdotally similar to the psychedelic state, exist. We investigated the neural correlates of shamanic trance using high-density electroencephalography (EEG) in 24 shamanic practitioners and 24 healthy controls during rest, shamanic drumming, and classical music listening, followed by an assessment of altered states of consciousness. EEG data were used to assess changes in absolute power, connectivity, signal diversity, and criticality, which were correlated with assessment measures. We also compared assessment scores to those of individuals in a previous study under the influence of psychedelics. Shamanic practitioners were significantly different from controls in several domains of altered states of consciousness, with scores comparable to or exceeding that of healthy volunteers under the influence of psychedelics. Practitioners also displayed increased gamma power during drumming that positively correlated with elementary visual alterations. Furthermore, shamanic practitioners had decreased low alpha and increased low beta connectivity during drumming and classical music and decreased neural signal diversity in the gamma band during drumming that inversely correlated with insightfulness. Finally, criticality in practitioners was increased during drumming in the low and high beta and gamma bands, with increases in the low beta band correlating with complex imagery and elementary visual alterations. These findings suggest that psychedelic drug-induced and non-pharmacologic alterations in consciousness have overlapping phenomenal traits but are distinct states of consciousness, as reflected by the unique brain-related changes during shamanic trance compared to previous literature investigating the psychedelic state.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

Many diseases, such as rheumatoid arthritis, are characterized by a chronic inflammatory state, but it is not clear whether or how this affects the brain. Here, the authors show that the severity of on-going inflammation predicts altered functional brain connectivity in people with rheumatoid arthritis.

Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p=0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p=0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome. Keywords: Proton magnetic resonance spectroscopy, Interstitial cystitis, Choline, Gamma aminobutyric acid (GABA), Centralized pain, MAPP

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.

Persistent fatigue is a pernicious symptom in many cancer survivors. Existing treatments are limited or ineffective and often lack any underlying biologic rationale. Acupressure is emerging as a promising new intervention for persistent cancer-related fatigue; however, the underlying mechanisms of action are unknown. Our previous investigations suggested that fatigued breast cancer survivors have alterations in brain neurochemistry within the posterior insula and disturbed functional connectivity to the default mode network (DMN), as compared to non-fatigued breast cancer survivors. Here, we investigated if insula and DMN connectivity were modulated by self-administered acupressure by randomizing breast cancer survivors (n = 19) to two distinct treatments: relaxing acupressure or stimulating acupressure. All participants underwent proton magnetic resonance spectroscopy of the posterior insula and functional connectivity magnetic resonance imaging at baseline and immediately following 6 weeks of acupressure self-treatment. As compared to baseline measures, relaxing acupressure decreased posterior insula to dorsolateral prefrontal cortex connectivity, whereas stimulating acupressure enhanced this connectivity (p

Purpose: In this prospective study, we used 2D chemical shift imaging (CSI), a multi-voxel proton spectroscopy technique, to evaluate the brain metabolites on conventional magnetic resonance imaging (MRI) in normal-appearing white and grey matter in systemic lupus erythematosus (SLE) patients with neuropsychiatric symptoms (NPSLE); without neuropsychiatric symptoms (non-NPSLE); and healthy controls (HCs). Our objective was to find metabolites that discriminated NPSLE patients from the non-NPSLE and HC cohorts. Materials and methods: The study included 23 NPSLE patients, 20 non-NPSLE patients, and 21 HCs. A clinical assessment including the SLE disease activity index (SLEDAI) and systemic lupus international collaborating clinics (SLICC) scores was conducted. All patients underwent conventional MRI and 2D CSI technique to acquire the following metabolic ratios: NAA/Cr, Cho/Cr, and Cho/NAA in the anterior and posterior insula, anterior frontal and parietal white and grey matter, thalamus, basal ganglia, and occipital grey matter. Results: In terms of metabolic differences, the NPSLE patients had significant differences compared with the non-NPSLE and HC groups in the: left posterior insula (increased Cho/NAA; p = 0.008), right internal capsule (increased Cho/Cr; p < 0.05), left thalamus (increased NAA/Cr; p = 0.011), anterior grey matter (increased NAA/Cr; p = 0.004), posterior grey matter (increased Cho/NAA; p = 0.016), anterior white matter (increased NAA/Cr; p = 0.012), and left posterior white matter (increased Cho/NAA; p = 0.022). The NPSLE patients showed significantly higher SLEDAI scores (p < 0.001). Conclusion: We found several significant distinct metabolic differences between NPSLE and non-NPSLE/HC patients in various brain locations. Keywords: systemic lupus erythematosus; SLE; neuropsychiatric systemic lupus erythematosus; NPSLE; spectroscopy