Progress in Neuro-Psychopharmacology and Biological Psychiatry

Electroencephalography (EEG) based biomarkers have been shown to correlated with the presence of psychotic disorders. Increased delta and decreased alpha power in psychosis indicate an abnormal arousal state. We investigated brain activity across the basic EEG frequencies and also dynamic functional connectivity of both intra and cross-frequency coupling that could reveal a neurophysiological biomarker linked to an aberrant modulating role of alpha frequency in adolescents with schizophrenia spectrum disorders (SSDs). A dynamic functional connectivity graph (DFCG) has been estimated using the imaginary part of phase lag value (iPLV) and correlation of the envelope (corrEnv). We analyzed DFCG profiles of electroencephalographic resting state (eyes closed) recordings of healthy controls (HC) (n=39) and SSDs subjects (n=45) in basic frequency bands {{delta},{theta},1,2,{beta}1,{beta}2,{gamma}}. In our analysis, we incorporated both intra and cross-frequency coupling modes. Adopting our recent Dominant Coupling Mode (DoCM) model leads to the construction of an integrated DFCG (iDFCG) that encapsulates the functional strength and the DoCM of every pair of brain areas. We revealed significantly higher ratios of delta/alpha1,2 power spectrum in SSDs subjects versus HC. The probability distribution (PD) of amplitude driven DoCM mediated by alpha frequency differentiated SSDs from HC with absolute accuracy (100%). The network Flexibility Index (FI) was significantly lower for subjects with SSDs compared to the HC group. Our analysis supports a central role of alpha frequency alterations in the neurophysiological mechanisms of SSDs. Currents findings open up new diagnostic pathways to clinical detection of SSDs and supports the design of rational neurofeedback training. HighlightsO_LIRatios of delta/alpha1,2 relative power spectrum were significant higher in SSDs subjects compared to HC C_LIO_LIProbability distribution (PD) of amplitude driven DoCM mediated by alpha frequency differentiated SSDs from HC with 100% C_LIO_LINetwork Flexibility index (FI) was significant lower for subjects with SSDs compared to HC group. C_LI

BackgroundPeople living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined transcranial magnetic stimulation (TMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored TMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke. MethodsEight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS. ResultsCompared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias. ConclusioniTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Amid the ongoing global repercussions of SARS-CoV-2, its crucial to comprehend its potential long-term psychiatric effects. Several recent studies have suggested a link between COVID-19 and subsequent mental health disorders. Our investigation joins this exploration, concentrating on Schizophrenia Spectrum and Psychotic Disorders (SSPD). Different from other studies, we took acute respiratory distress syndrome (ARDS) and COVID-19 lab negative cohorts as control groups to accurately gauge the impact of COVID-19 on SSPD. Data from 19,344,698 patients, sourced from the N3C Data Enclave platform, were methodically filtered to create propensity matched cohorts: ARDS (n = 222,337), COVID-positive (n = 219,264), and COVID-negative (n = 213,183). We systematically analyzed the hazard rate of new-onset SSPD across three distinct time intervals: 0-21 days, 22-90 days, and beyond 90 days post-infection. COVID-19 positive patients consistently exhibited a heightened hazard ratio (HR) across all intervals [0-21 days (HR: 4.6; CI: 3.7-5.7), 22-90 days (HR: 2.9; CI: 2.3 -3.8), beyond 90 days (HR: 1.7; CI: 1.5-1.)]. These are notably higher than both ARDS and COVID-19 lab-negative patients. Validations using various tests, including the Cochran Mantel Haenszel Test, Wald Test, and Log-rank Test confirmed these associations. Intriguingly, our data indicated that younger individuals face a heightened risk of SSPD after contracting COVID-19, a trend not observed in the ARDS and COVID-negative groups. These results, aligned with the known neurotropism of SARS-CoV-2 and earlier studies, accentuate the need for vigilant psychiatric assessment and support in the era of Long-COVID, especially among younger populations.

BackgroundA common feature of Cannabis use disorder (CUD) is an intense reactivity to cannabis cues, which are becoming increasingly visible due to growth in the decriminalization, accessibility and marketing of cannabis products. The brains automatic reactivity to cannabis cues can trigger craving and subsequent use. This study aimed to test neural activity during cannabis cue-induced craving in non-treatment seeking individuals with moderate-to-severe CUD, with past attempts to cut down/quit. MethodsThe study examined 65 individuals with moderate-to-severe CUD and 43 controls, with a fMRI cannabis cue-induced craving task and assessment of mental health, substance use, and cognitive testing. Group differences in neural cue-induced craving were examined, adjusting for age and sex; correlations with cannabis use characteristics were assessed, accounting for recent substance use. ResultsIndividuals with a CUD relative to controls showed greater brain activity during cannabis cue-induced craving in the superior/middle occipital, medial/lateral OFC, anterior/posterior cingulate, cerebellar, hippocampus, middle temporal and lateral parietal cortices (p < .05; cluster k > 10, FWE-corrected). Greater occipital/cerebellar activity correlated with greater subjective arousal towards cannabis images and cannabis withdrawal scores, while anterior cingulate/inferior parietal activity negatively correlated with urinary level of 11-Nor-9-carboxy-{Delta}9-tetrahydrocannabinol:creatinine (ps<.05). ConclusionsExposure to cannabis cues can elicit greater activity within salience evaluation/attention, motivation and disinhibition pathways of addiction neurocircuitry in people with moderate-to-severe CUD, consistent with prominent neuroscientific theories of addiction and findings with other substances. Interventions which can suppress brain activity in salience and attention circuits during cannabis-induced craving may help reduce craving and subsequent use.

ObjectivesThis study characterizes the structural and metabolic cerebral correlates of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) in a preclinical setting that considers the lifestyle of young European men exposed to HIV, including recreational drugs. DesignProspective inclusion of participants. MethodsSimultaneous structural brain magnetic resonance imaging (MRI) and positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) were acquired on a hybrid PET-MRI system in 23 asymptomatic young men with HIV+ (mean age: 33.6 years, age range: 23-60 years; normal CD4+ cell count, undetectable viral load). Neuroimaging data were compared with that of a group of 26 young HIV-men, highly well matched for what concerns age, lifestyle, named pre-exposure prophylaxis users (HIV-PrEP), and to a group of 23 undifferentiated matched young men (i.e., healthy controls). A comprehensive neuropsychological assessment was also administered to the HIV+ and HIV-PrEP subjects. ResultsHIV+ subjects had lower performances in executive, attentional and working memory functions compared to HIV-PrEP subjects. No structural or metabolic differences were found between those two groups. Compared to healthy controls, HIV+ and HIV-PrEP exhibited a common frontal hypometabolism in the right prefrontal cortex that correlated with the level of recreational drug use. No structural brain abnormality was found. ConclusionA dynamic prevention of recreational drugs use in HIV+ and HIV-PrEP subjects is mandatory to cope with their negative impact on brain function and their neurocognitive consequences. A complex interplay between recreational drugs and HIV might be involved in the development of neurocognitive disorders in young men with HIV.

Electroencephalography (EEG) measures the neuronal activity at the scalp, while functional magnetic resonance imaging (fMRI) provides a sub-cortical view of blood supply in the human brain. Although fMRI is known for providing rich spatial information, it is expensive and of restricted use. EEG to fMRI synthesis is a cross modal research area that bridges the gap between the two and has recently received attention. Although these studies promise lower healthcare costs and ambulatory assessments, their utility in diagnostic settings is still largely untapped. Using simultaneous EEG and fMRI recordings, this study combines a state-of-the-art synthesis model with a modified contrastive loss, and subsequent prediction layering, to unprecedentedly assess its predictive power in schizophrenia diagnosis. In addition, we perform an exhaustive search for the (synthesized) hemodynamic brain patterns able to discriminate schizophrenia. Schizophrenia diagnosis using synthesized hemodynamics yield an area under the ROC curve of 0.77, confirming the validity of the undertaken neuroimaging synthesis. Experiments further revealed schizophrenia-related patterns in frontal, left temporal and cerebellum regions of the brain. Altogether, our results suggest that a synthesized fMRI view is able to discriminate this pathology, and it contains discriminative patterns of brain activity in accordance with related work on schizophrenia.

Cannabis use disorder (CUD) affects [~]22M people globally and is characterised by difficulties in cutting down and quitting use, but the underlying neurobiology remains unclear. We examined resting-state functional connectivity (rsFC) between regions-of-interest (ROIs) of the addiction neurocircuitry and the rest of the brain in 65 individuals with moderate-to-severe CUD who reported attempts to cut down or quit, compared to 42 controls, and explored the association between rsFC and cannabis exposure and related problems, to elucidate potential drivers of rsFC alterations. The CUD group showed greater rsFC than controls between ROIs implicated in reward processing and habitual substance use (i.e., nucleus accumbens, putamen, pallidum) and occipito/parietal areas implicated in salience processing and disinhibition. Putamen-occipital rsFC correlated with levels of problematic cannabis use and depression symptoms. CUD appears to show neuroadaptations of the addiction neurocircuitry, previously demonstrated in other substance use disorders.

Resting-state fMRI (rs-fMRI) captures brain activity at rest, it demonstrates information on how different regions interact without explicity task-based influences. This provides insights into both healthy and disordered brain states. However, clinical application of rs-fMRI remains challenging due to the wide variability in functional connectivity across individuals. Traditional data-driven methods like independent component analysis (ICA) struggle to balance these individual differences with broader patterns. Constrained methods, such as constrained ICA (cICA), have been introduced to address this by integrating templates from multiple external datasets to enhance accuracy and consistency. In our study, we analyzed rs-fMRI data from 100,517 individuals from diverse datasets, processed through a robust quality-control dynamic connectivity pipeline established in previous work. Using the resulting brain state templates as cICA priors, we examined the effectiveness of cICA for schizophrenia classification using a combined CNN and LSTM architecture. Results showed stable classification accuracy (87.6% to 86.43%) for the CNN model, while the LSTM model performed less optimally, likely due to sequence processing, yet still yielded comparable results. These findings underscore the potential of group-informed methods and prior data templates in constrained dynamic ICA, offering improved reliability and clinical relevance in rs-fMRI analysis and advancing our understanding of brain function.

ObjectiveMajor depressive disorder affects millions of people globally, which lacks dependable biomarkers for the early identification of treatment success. This study examines two treatment modalities, pharmacological and neurostimulation. The aim is to discern alterations in brain connection patterns and direction of influence among various regions during the initial phase of the two treatment approaches. ApproachWe perform an information theory-based causality analysis on instantaneous phase time series data derived from electroen-cephalography recordings of 176 patients who underwent the aforementioned treatments. Each patient was recorded twice: prior to the commencement of treatment (visit 1) and one week after the initiation of treatment (visit 2). Main resultsTwo independent outcomes were observed. Initially, we discovered that different treatment modalities have different impacts on the brains connectivity and the direction of influence during the course of one week of treatment. The cohort administered with pharmacological agents exhibited a notable increase in both global and local information transmission in the brain within the {beta}2 (18Hz - 25.5Hz) frequency range, whereas the group subjected to stimulation exhibited a notable increase within the {delta} (1.5Hz - 3.5Hz) band. Secondly, potential respondents and nonrespondents to pharmacological therapy had distinct baseline brain causality effects at the initial session, with individuals who reacted to pharmacological therapy having considerably reduced information flow strength in the (8Hz - 12Hz) band compared to those who did not respond to treatment. SignificanceCausality analysis is conducted on the phases of the data, yielding more accurate conclusions by minimising the possible noise introduced by the signal amplitude. Our study provides significant insights into the directional influence inside the brain during depression and subsequent treatment.

BackgroundCocaine use disorder (CUD) is a worldwide public health condition which is suggested to induce pathological changes in macro- and microstructure. Repetitive transcranial magnetic stimulation (rTMS) has gained attention to induce a reduction in CUD symptoms. Here, we sought to elucidate whether rTMS induces changes on white-matter (WM) microstructure in frontostriatal circuits after two weeks of therapy in patients with CUD, and to test whether baseline WM microstructure of the same circuits has an effect on clinical improvement. This study consisted of a 2-week, parallel group, double-blind, randomized controlled clinical trial (acute phase) (sham [n=23] and active [n=27]), in which patients received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (lDLPFC) as an add-on treatment. T1-weighted and HARDI-DWI at baseline and two weeks after served to evaluate WM microstructure. After active rTMS, results showed a significant increase in neurite density compared to sham rTMS in WM-tracts connecting left DLPFC with left and right vmPFC. Similarly, rTMS showed reduction in orientation dispersion in WM tracts connecting left DLPFC with left caudate nucleus, left thalamus and left vmPFC. Results also showed a greater reduction in craving VAS after rTMS when baseline ICVF was low in WM tracts connecting left caudate nucleus with substantia nigra, left pallidum, and left thalamus with substantia nigra and left pallidum. Our results evidence rTMS-induced WM microstructural changes in fronto-striato-thalamic circuits and support its efficacy as a therapeutic tool in the treatment of CUD. Further, individual clinical improvement may rely on the patients individual structural connectivity integrity. HighlightsO_LIWhite matter microstructural changes between fronto-striato-thalamic regions after 2 weeks of rTMS. C_LIO_LIWhether rTMS would induce microstructural changes may depend on the baseline integrity of the connections between the striatum, thalamus, and the substantia nigra. C_LIO_LIOur results highlight rTMS as a potential therapeutic tool in the treatment of CUD, due to its ability to modulate altered brain microstructure. C_LI

BACKGROUND Schizophrenia, characterized by cognitive impairments, arises from a disturbance of brain network. Pathological changes in white matter (WM) have been indicated as playing a role in disturbing neural connectivity in schizophrenia. However, deficits of functional connectivity (FC) in individual WM bundles in schizophrenia have never been explored; neither have cognitive correlates with those deficits. METHODS Resting-state and spatial working memory task fMRI images were acquired on 67 healthy subjects and 84 patients with schizophrenia. The correlations in blood-oxygenation-level-dependent (BOLD) signals between 46 WM and 82 gray matter regions were quantified, analyzed and compared between groups under three scenarios (i.e., resting state, retention period and entire time of a spatial working memory task). Associations of FC in WM with cognitive assessment scores were evaluated for three scenarios. RESULTSFC deficits were significant (p<.05) in external capsule, cingulum, uncinate fasciculus, genu and body of corpus callosum under all three scenarios. Deficits were also present in the anterior limb of the internal capsule and cerebral peduncle in task scenario. Decreased FCs in specific WM bundles associated significantly (p<.05) with cognitive impairments in working memory, processing speed and/or cognitive control. CONCLUSIONSDecreases in FC are evident in several WM bundles in patients with schizophrenia and are significantly associated with cognitive impairments during both rest and working memory tasks. Furthermore, working memory tasks expose FC deficits in more WM bundles and more cognitive associates in schizophrenia than resting state does.

Understanding the alterations in brain function across different episodes of bipolar disorder (BD), including manic (BipM), depressive (BipD), and remission states (rBD), poses a significant challenge. In our cross-sectional study, we collected resting-state functional magnetic resonance imaging data from 117 BD patients (BipM: 38, BipD: 42, rBD: 37) and 35 healthy controls. Our aim was to delineate functional connections associated with episode dynamics, delineate common and specific patterns, validate them as biomarkers, and elucidate their biological underpinnings. Initially, we identified a common altered pattern within the subregions of the ventral-attention network, alongside specific patterns observed in the default mode network for BipM, the prefrontal network for BipD, and the limbic network for rBD. Using large-sample data from the Human Connectome Project, we further identified that these connectivity patterns exhibit relatively high reliability and heritability. Also, these distinct patterns accurately characterized the diverse episodes of BD and effectively predicted the corresponding clinical symptoms linked with each episode type. Importantly, using out of sample data to decode possible neurobiological mechanisms underlying these patterns, we found that regions of particular interest were enriched in multiple receptors, including MOR, NMDA, and H3 for specific alterations, and A4B2, 5HTT, and 5HT1a for common alterations. Moreover, both episode-specific and common patterns demonstrated a high enrichment for cell types such as L5ET, Micro/PVM,oligodendrites and Chandelier. Our study offers novel insights concerning episode dynamics in BD, paving the way for personalized medicine approaches tailored to address the various episodes.

Despite antiretroviral treatment (cART), people living with HIV (PLWH) are more susceptible to neurocognitive impairment (NCI), probably due to synergistic/additive contribution of traditional cerebrovascular risk factors. Specifically, altered blood brain barrier (BBB) and transmigration of inflammatory monocytes are risk factors for developing cerebral small vessel disease (CSVD). In order to investigate if inflammatory monocytes exacerbate CSVD and cognitive impairment, 110 PLWH on cART and 110 age-, sex- and Reynolds cardiovascular risk score-matched uninfected individuals were enrolled. Neuropsychological testing, brain magnetic resonance imaging and whole blood analyses to measure platelet-monocyte interaction and monocyte, endothelial activation were performed. Results demonstrated that PLWH exhibited increased levels of platelet-monocyte complexes (PMCs) and higher expression of activation molecules on PMCs. PLWH with CSVD had the poorest cognitive performance and the highest circulating levels of non-classical monocytes which exhibited significant inverse correlation with each other. Furthermore, markers of monocyte and endothelium activation were significantly positively correlated indicating BBB impairment. Our results confirm that interaction with platelets activates and drives monocytes towards an inflammatory phenotype in PLWH. In particular, elevated levels of non-classical monocytes may represent a common pathway to neuroinflammation, CSVD and subsequent cognitive impairment, warranting further longitudinal studies to evaluate responsiveness of this potential biomarker.

ImportanceThe pathophysiology of ADHD is complicated by high rates of psychiatric comorbidities, thus delineating unique versus shared functional brain perturbations is critical in elucidating illness pathophysiology. ObjectiveTo investigate resting-state fMRI (rsfMRI)-complexity alterations among children with ADHD, oppositional defiant disorder (ODD), and obsessive-compulsive disorder (OCD), respectively, and comorbid ADHD, ODD, and OCD, within the cool and hot executive function (EF) networks. DesignWe leveraged baseline data (wave 0) from the Adolescent Brain and Cognitive Development (ABCD) Study. SettingThe data was collected between September 2016 and September 2019 from 21 sites in the USA. ParticipantsChildren who singularly met all DSM-5 behavioral criteria for ADHD (N = 61), ODD (N = 38), and OCD (N = 48), respectively, were extracted, alongside children with comorbid ADHD, ODD, OCD, and/or other psychiatric diagnoses (N = 833). A control sample of age-, sex-, and developmentally-matched children was also extracted (N = 269). Main Outcomes and MeasuresVoxel-wise sample entropy (SampEn) was computed using the LOFT Complexity Toolbox. Mean SampEn within all regions of the EF networks was calculated for each participant and hierarchical models with Generalized Estimating Equations compared SampEn of comorbid-free and comorbid ADHD, ODD, and OCD within the EF networks. ResultsSampEn was reduced in comorbid-free ADHD and ODD in overlapping regions of both EF networks, including the bilateral superior frontal gyrus, anterior/posterior cingulate gyrus, and bilateral caudate (Wald statistic = 5.682 to 10.798, p < 0.05 & BH corrected), with ADHD additionally affected in the right inferior/middle frontal gyrus and bilateral frontal orbital cortex (Wald statistic = 7.231 to 9.420, p < 0.05 & BH corrected). Among comorbid presentations, the additional presence of ADHD symptomatology was associated with significantly lower SampEn in every region of interest (z = -3.973 to -2.235, p < 0.05 & BH corrected). Conclusions and RelevanceADHD and ODD shared common impairments underlying the EF networks in the comorbid-free presentations, with ADHD showing more widespread complexity reduction. When ADHD co-occurred with other psychiatric disorders, the reduction in SampEn extended beyond the regions affected in comorbid-free ADHD, indicating that comorbidities amplify neural complexity deficits.

AimTo determine robust transdiagnostic brain structural markers for compulsivity by capitalizing on the increasing number of case-control studies examining gray matter alterations in substance use disorders (SUD) and obsessive-compulsive disorder (OCD). DesignPre-registered voxel-based meta-analysis of grey matter volume (GMV) changes through seed-based d Mapping (SDM), follow-up functional, and network-level characterization of the identified transdiagnostic regions by means of co-activation and Granger Causality (GCA) analysis. ParticipantsLiterature search resulted in 31 original VBM studies comparing SUD (n = 1191, mean-age = 40.03, SD = 10.87) and 30 original studies comparing OCD (n = 1293, mean-age = 29.18, SD = 10.34) patients with healthy controls (SUD: n = 1585, mean-age = 42.63, SD = 14.27, OCD: n = 1374, mean-age = 28.97, SD = 9.96). MeasurementsVoxel-based meta-analysis within the individual disorders as well as conjunction analysis were employed to reveal common GMV alterations between SUDs and OCD. Meta-analytic coordinates and signed brain volumetric maps determining directed (reduced or increased) brain volumetric alterations between the disorder groups and controls served as the primary outcome. Meta-analytic results employed statistical significance thresholding (FWE< 0.05). FindingsSeparate meta-analysis demonstrated that SUD (cocaine, alcohol, and nicotine) as well as OCD patients exhibited widespread GMV reductions in frontocortical regions including prefrontal, cingulate, and insular regions. Conjunction analysis revealed that the left inferior frontal gyrus (IFG) consistently exhibited decreased GMV across all disorders. Functional characterization suggests that the IFG represents a core hub in the cognitive control network and exhibits bidirectional (Granger) causal interactions with the striatum. Only OCD showed increased GMV in the dorsal striatum with higher changes being associated with more severe OCD symptomatology. ConclusionsFindings demonstrate robustly decreased GMV across the disorders in the left IFG, suggesting a transdiagnostic brain structural marker. The functional characterization as a key hub in the cognitive control network and casual interactions with the striatum suggest that deficits in inhibitory control mechanisms may promote compulsivity and loss of control that characterize both disorders.

Adaptive emotion regulation (ER) is essential for mental health. Reappraisal and acceptance are effective ER strategies that form the basis of therapeutic interventions, yet their common and distinct neural signatures - and the translational potential of these signatures - remain unclear. Here, we combined naturalistic fMRI with multivariate predictive modeling to develop neurofunctional signatures that accurately and comprehensively characterize negative affect and its regulation via acceptance and reappraisal in dynamic, immersive contexts (n=59). These signatures demonstrated process-specificity and generalization across cohorts, cultures, and modalities (n=33, n=358, n=33). ER strategies were encoded in distributed, distinguishable neural representations, with shared contributions from the default mode network and strategy-specific contributions from the amygdala, somatomotor and attention (acceptance), and the frontoparietal control (reappraisal) networks. The neuromarkers precisely identified strategy-specific ER impairments in cannabis users (nhealthy_controls=48, ncannabis_users=49), underscoring their translational relevance. We provide comprehensive, clinically-relevant brain models of emotion regulation and dysregulation in naturalistic contexts.

Major Depressive Disorder (MDD) is a prevalent, chronic, and multidimensional mental disorder characterized by widespread functional dysconnectivity in the whole brain. However, the potential molecular, cellular, and neural mechanisms, contributing to the diverse symptomatology and heterogeneity of MDD remain poorly understood. This study aims to elucidate the multi-scale pathophysiological mechanisms underlying MDD subtypes by integrating functional connectivity, transcriptomic, neurotransmitter, and cell-type analyses across two Asian cohorts: the Chinese REST-meta-MDD Consortium (Discovery) and the Japanese Decoded Neurofeedback Project (Validation). The discovery cohort identified distinct patterns of distance-dependent functional connectivity strength (FCS) alterations in MDD, revealing short- to medium-range hyperconnectivity in both total MDD and recurrent MDD (RMDD) patients, with long-range hyperconnectivity specifically observed in RMDD. In contrast, first-episode drug-naive (FEDN) patients did not exhibit significant distance-dependent alterations in FCS. Genes associated with the FCS differences between FEDN and RMDD were enriched in pathways related to chemical synaptic transmission, neuron projection, and synaptic signaling. Moreover, FCS alterations in MDD subtypes were correlated with neurotransmitter receptor densities, particularly in the monoaminergic (e.g., 5HT1a, 5HT2a, and KappaOp) and GABAergic (GABAa) systems. Distinctive cell-type associations were observed, with astrocytes, endothelial cells, and oligodendrocyte precursor cells (OPCs) linked to FCS changes in RMDD, while only OPCs were associated with alterations in FEDN. The validation cohort partially replicated the key findings regarding distance-dependent FCS alterations, transcriptomic signatures, neurotransmitter associations, and cell-type specific relationships. These findings provide novel insights into the neurobiological underpinnings of functional dysconnections in MDD subtypes.

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.

Exaggerated reactivity to drug-cues and emotional dysregulations represent key symptoms of early stages of substance use disorders. The diagnostic criteria for (Internet) Gaming Disorder strongly resemble symptoms for substance-related addictions. However, previous cross-sections studies revealed inconsistent results with respect to neural cue reactivity and emotional dysregulations in these populations. To this end the present fMRI study applied a combined cross-sectional and prospective longitudinal design in excessive online gamers (n=37) and gaming-naive controls (n=67). To separate gaming-associated changes from predisposing factors, gaming-naive subjects were randomly assigned to 6 weeks of daily Internet gaming or a non-gaming condition. At baseline and after the training subjects underwent an fMRI paradigm presenting gaming-related cues and non-gaming related emotional stimuli. Cross-sectional comparisons revealed gaming-cue specific enhanced valence attribution and neural reactivity in a parietal network, including the posterior cingulate/precuneus in excessive gamers as compared to gaming naive-controls. Prospective analysis revealed that six weeks of gaming elevated valence ratings as well as neural cue-reactivity in a similar parietal network, specifically the posterior cingulate/precuneus in previously gaming-naive controls. Together, the prospective longitudinal design did not reveal supporting evidence for altered emotional processing of non-gaming associated stimuli in excessive gamers while convergent evidence for increased emotional and neural reactivity to gaming-associated stimuli was observed. Findings suggest that exaggerated neural reactivity in posterior parietal regions engaged in self-referential processing already occur during early stages of regular gaming probably promoting continued engagement in gaming behavior.

IntroductionThe primary psychoactive component in marijuana is tetrahydrocannabinol (THC), which acts on receptors, such as cannabinoid 1 (CB1), that are distributed broadly throughout the brain. THC interferes with synaptic plasticity and neurogenesis and impacts the brains macrostructure, specifically white matter where CB1 receptors are abundant. The current study aims to investigate whether callosal morphology differs depending on how much experience individuals have with marijuana. MethodsThis is a quantitative between-group corpus callosum morphology analysis using cohort study data. The data for this study (n = 144) came from the S1200 Release from the Washington University - University of Minnesota Human Connectome Project Consortium (WU-Minn HCP). Marijuana use was quantified using self-reports and grouped as (1) no use, (2) low use, and (3) high use. T1-weighted MRI brain images were obtained and then processed using SPM12 and MATLAB. Each corpus callosum was manually traced and automatically separated into seven callosal areas according to the Witelson parcellation scheme. The resulting area measures were compared between the three groups, while covarying for total brain volume. ResultsOur ANCOVA analysis was significant (F(2, 145) = 4.38, p = .014), and posthoc tests revealed a significantly smaller anterior midbody in the high marijuana use group compared to the no marijuana use group (p = .012). ConclusionSmaller callosal areas in the high use marijuana group suggest that heavy cannabis may be related to weaker interhemispheric connectivity. Future research is required to replicate the current findings using well-powered designs.