Neuroscience & Biobehavioral Reviews

1.Attention Deficit Hyperactivity Disorder (ADHD) affects over 400 million individuals worldwide, yet reliable biomarkers for diagnosis remain elusive. Recent studies have suggested elevated homocysteine levels may serve as a potential biomarker, given its role in one-carbon metabolism and neurotransmitter synthesis. Objective is to conduct a comprehensive systematic review and meta-analysis examining homocysteine levels in ADHD patients compared to healthy controls, and to identify shared molecular pathways through protein-protein interaction network analysis. A systematic search was conducted across PubMed, Scopus, Web of Science, and Embase databases from inception to June 2025. Studies comparing plasma/serum homocysteine levels between ADHD patients and healthy controls were included. Meta-analysis was performed using random-effects models with standardized mean differences (SMD). Protein-protein interaction networks were constructed using STRING database for genes common to ADHD and hyperhomocysteinemia, with hub gene identification through CytoHubba analysis. Six studies comprising 796 ADHD patients and 488 controls from three countries were included. Meta-analysis revealed no statistically significant difference in homocysteine levels between groups (SMD = -0.38, 95% CI [-1.24, 0.48], p = 0.386), with substantial heterogeneity (I{superscript 2} = 85.4%). Results showed a biphasic distribution, with three studies demonstrating lower homocysteine in ADHD and two showing higher levels. Network analysis identified 485 common genes between ADHD and hyperhomocysteinemia, revealing 25 hub genes enriched in inflammatory pathways (TNF signaling), growth factor signaling (FGF family), and MAPK cascades. In conclusion homocysteine levels do not serve as a reliable standalone biomarker for ADHD diagnosis due to significant inter-study variability and population-specific factors. However, shared molecular networks suggest complex mechanistic relationships involving neuroinflammation, one-carbon metabolism, and neurotransmitter regulation. Future diagnostic approaches should consider multidimensional biomarker panels incorporating genetic, metabolic, and inflammatory markers rather than single metabolites.

Very preterm (VPT) adolescents are at high risk of impaired sustained attention processes, as well as behavioral and socio-emotional problems. Previous studies have highlighted altered attentional patterns of brain activation in this population, but results are inconsistent. The current study aims to explore brain activity related to sustained attention in VPT and full-term adolescents aged 11-18, as well as its associations with attentional capacities and socio-emotional competences. Event-related functional MRI (fMRI) was used to assess sustained attention performance and associated brain activations by comparing VPT (n = 34) and their age-matched full-term (FT, n = 28) peers from a previously validated continuous performance task with gradual onset (gradCPT) paradigm, using two different modality versions (i.e., face and scene). In both groups, linear regression analyses were performed to examine associations between attentional and socio-emotional difficulties and brain activations related to sustained attention. Results show preserved sustained attention processes in VPT adolescents, indicated by comparable behavioral attentional performance and cerebral patterns of activations in both groups across the two modalities of the gradCPT. In addition, VPT adolescents showed over-recruitments in posterior occipital areas compared to FT adolescents. Moreover, higher socio-emotional difficulties (i.e., higher anxiety and social difficulties) in VPT were linked to altered activations specifically in the right middle frontal gyrus, occipito-temporal gyri and bilateral cerebellum, but exclusively observed during the face modality of the gradCPT. Overall, these results suggest that despite preserved sustained attention competences, VPT adolescents present a less mature sustained attention cerebral network, particularly during a task with a social context.

Adverse childhood experiences (ACEs) are common, altering behaviour and stress reactivity, with persistent structural and functional brain changes. ACEs are associated with a greater risk of physical and mental health morbidities, including depression and chronic pain (CP), which often co-exist. While changes in the reward system have been implicated in each condition, it remains unclear whether there are common neural mechanisms. Using brain scans from a large community sample, we examined how ACEs, depression, and CP affected the reward system. Individuals reporting both ACEs and CP exhibited reduced volume in the nucleus accumbens, a brain region associated with motivation and pleasure, particularly among women. Blunted reward-related activity in the basal ganglia was linked to higher depression scores, CP severity, and experiences of childhood sexual abuse. Importantly, these functional changes remained significant even after accounting for structural brain differences. Interestingly, brain structural-functional associations were weak, suggesting distinct underlying mechanisms. Structural brain alterations likely represent cumulative, enduring consequences of ACEs and CP, whereas altered reward activity appears more closely tied to current symptom severity. These findings reveal separable but converging neurobiological signatures of early adversity, pain, and depression within the brains reward system.

ObjectiveTo evaluate the functional changes of the dorsal attention network (DAN) in perimenopausal women using functional magnetic resonance imaging (fMRI) and explore the relationship between sex hormones and cognitive function. MethodsA total of 25 perimenopausal women and 25 premenopausal women underwent sex hormone level measurements, scale - based assessments, cognition evaluations, and magnetic resonance imaging (MRI) scans. Resting - state fMRI data were acquired using a 3.0 Tesla magnetic resonance scanner. Independent component analysis (ICA) was employed to assess the differences in DAN functional connections between the two groups. Gray matter volume (GMV) values of brain regions with differences in DAN functional connections were extracted, and the GMV differences between the two groups were compared. Correlation analyses were performed between the connection strengths of DAN functional connections, GMV values of regions of interest (ROIs), sex hormone levels, and clinical and neuropsychological assessment results in both groups. Additionally, sensitivity and exploratory analyses were conducted on the existing data, and the results were compared with those of existing studies. ResultsCompared with the premenopausal group, the perimenopausal group showed enhanced functional connections in the right inferior parietal lobule (IPL) and the right angular gyrus (AG) within the DAN. There were no significant differences in GMV values between the two groups. Correlation analysis indicated that in perimenopausal women, the connection strength of the right IPL negatively correlated with the estradiol level and positively correlated with the reaction time of the STROOP color - word test. Sensitivity analysis showed that the main results were robust to the influence of extreme values. Exploratory analysis identified potential subgroups within perimenopausal women. Comparison with existing studies confirmed the consistency of some findings while also revealing differences. ConclusionsICA results suggest that DAN functional changes in perimenopausal women may trigger the brains compensatory mechanisms to cope with physiological and psychological challenges during the reproductive transition. These findings contribute to a better understanding of the brain function changes in perimenopausal women. However, limitations such as a small sample size still exist, and future research directions are proposed.

BackgroundSeveral adolescent health behaviors have been hypothesized to improve academic performance via their beneficial impact on cognitive control and functional aspects of the prefrontal cortex (PFC). Specifically, exercise, restorative sleep, and proper diet are thought to improve PFC function, while substance abuse is thought to reduce it. Few studies have examined the relationships among all of these in the same sample, while quantifying downstream impacts on academic performance. ObjectiveThe primary objective of this study is to examine the association between lifestyle behaviors and academic performance in a sample of adolescents, and to examine the extent to which activity within the PFC and behavioural indices of inhibition may mediate this relationship. MethodsSixty-seven adolescents underwent two study sessions five days apart. Sleep and physical activity were measured using wrist-mounted accelerometry; eating habits, substance use and academic achievement were measured by self-report. Prefrontal function was quantified by performance on the Multi-Source Interference Task (MSIT), and task-related brain activity via functional near-infrared spectroscopy (fNIRS). ResultsHigher levels of accelerometer-assessed physical activity predicted higher MSIT accuracy scores (= .321,{rho} = 0.019) as well as greater task-related increases in activation within the right dlPFC (=.008, SE= .004,{rho} =.0322). Frequency of fast-food consumption and substance use were both negatively associated with MSIT accuracy scores (= -.307,{rho} = .023) and Math grades ({beta}= -3.702, SE= 1.563,{rho} = .022) respectively. However, these effects were not mediated by indicators of PFC function. ConclusionPhysical activity and eating behaviors predicted better interference task performance in adolescents, with the former mediated by greater task-related increases in right dlPFC activation. Substance use predicted worse Math grades, however, no other reliable effects of health behaviors on academic outcomes were evident.

The gut-brain axis has received considerable attention in recent years, and the "psychobiotics" concept indicates that probiotics have a potential positive effect on cognitive function. Therefore, the aim of this study was to quantitatively evaluate the influence of probiotics on cognitive function. We conducted a random-e?ects meta-analysis of 7 controlled clinical trials and 11 animals studies to evaluate the e?ects of probiotics on cognitive function. Probiotics supplementation enhanced cognitive function in both human (0.24 [0.05-0.42]; I2 = 0%) and animal studies (0.90 [0.47-1.34]; I2 = 74%). Subgroup analyses indicated that the effects of probiotics on cognitively impaired individuals (0.25 [0.05-0.45]; I2 = 0%) were greater than those on healthy ones (0.15 [-0.30 to 0.60]; I2 = 0%). Furthermore, compared with a multiple-probiotic supplement, one strain of probiotic was more effective in humans. The meta-analysis provided some suggestions for probiotics intervention and tended to support a customized approach for different individuals to ameliorate cognitive disorders. Future additional clinical trials are necessary to evaluate therapeutic effect and influencing factors.

Over the past two decades, numerous pharmaco-imaging studies have explored the neural basis of oxytocin (OT) on human cognition and behavior, yet findings are heterogenous and the links between the macroscopic neurofunctional effects and microscopic organization of the brain remain unclear. Here, we systematically explored the general neuromodulatory effects of OT across behavioral domains and populations by combining neuroimaging meta-analysis, meta-analytic connectivity modeling, behavioral decoding, and transcriptomic analysis. The primary meta-analysis based on data from 75 experiments and n = 2,247 participants revealed consistent domain-general neural effects of OT on the left thalamus, pallidum, caudate, and insula. Meta-analytic connectivity analyses revealed that these regions constituted a functionally integrated thalamus-striatum-insula circuit, directly influenced by OT, embedded within a larger secondary network, and associated with reward, motivation, and emotion, potentially mediating the complex effects of OT. Transcriptomic analyses revealed that the expression of three core OT pathway genes (CD38, OXT, and OXTR) is enriched in these subcortical regions and associated with the observed neural effects. Moreover, OTs effects were linked with the distribution of acetylcholinergic, dopaminergic, opioidergic, and vasopressinergic gene expressions, potentially reflecting functionally relevant interactions with these systems. Together, these findings delineate a robust effect of OT on human brain function that can help to inform effective pharmacotherapeutic targets, and highlight a core circuitry via which OT exerts its complex regulatory role. HighlightsMeta-analytic evidence for robust effects of exogenous OT on brain activity A thalamus-striatum-insula circuitry showed domain-general OT effects OT effects mediated by OT pathway gene expression (OXT, OXTR, CD38) OT effects interact with multiple neurotransmitter systems Decoding links OT targets to reward, emotion, social behavior

Despite the hardships of major depressive disorder (MDD), biomarkers for the diagnosis and pharmacological management of this condition are lacking. MicroRNAs are epigenetic mechanisms that could provide promising MDD biomarkers. Our aim was to summarize the findings and provide validation for the selection and use of specific microRNAs as biomarkers in the diagnosis and treatment of MDD. A systematic review was conducted using the PubMed/MEDLINE, Cochrane, PsycINFO, Embase, and LILACS databases from March to May 2022, with clusters of terms based on "microRNA" and "antidepressant". Studies involving human subjects, animal models, and cell cultures were included, whereas those that evaluated herbal medicines, non-pharmacological therapies, or epigenetic mechanisms other than miRNA were excluded. The review revealed differences in the expression of various microRNAs when considering the time of assessment (before or after antidepressant treatment) and the population studied. However, due to the heterogeneity of the microRNAs investigated, the limited size of the samples, and the wide variety of antidepressants used, few conclusions could be made. Despite the observed heterogeneity, the following microRNAs were determined to be important factors in MDD and the antidepressant response: mir-1202, mir-135, mir-124, and mir-16. The findings indicate the potential for the use of microRNAs as biomarkers for the diagnosis and treatment of MDD; however, more homogeneous studies are needed.

Background and ObjectivesAs the medical community seeks alternative pain management strategies, cannabinoids have emerged as a potential option. This review discusses the role of cannabinoids in chronic pain management and their potential as an alternative treatment in pain medicine, focusing on efficacy, safety, and possible opioid reduction. The objectives are to evaluate the efficacy and safety of cannabinoids in chronic pain management, explore their potential to reduce opioid use, and identify the mechanisms by which cannabinoids exert their analgesic effects. Additionally, the review seeks to highlight the clinical implications and limitations of using cannabinoids as an alternative to opioids. MethodsA comprehensive literature review and meta-analysis were conducted, focusing on studies from PubMed, MEDLINE, and Cochrane, focusing on various types of studies. Data were extracted and analyzed to assess the efficacy, safety, and potential opioid-sparing effects of cannabinoids. Mechanistic insights were also explored to understand how cannabinoids modulate pain. ResultsCannabinoids have shown efficacy in managing chronic pain, with evidence indicating their ability to reduce pain and improve quality of life. Studies suggest that cannabinoids can provide significant analgesic effects, although there is variability in efficacy across trials. Findings also show that Cannabinoids modulate pain through the endocannabinoid system, which plays a crucial role in pain perception and inflammation. LimitationsThe variability in efficacy across studies suggests a need for standardized formulations and dosing regimens. Long-term effects of cannabinoid use are not fully understood, necessitating further research. More high-quality trials are needed to confirm findings and address potential biases. ConclusionCannabinoids offer a promising alternative for chronic pain management, with the potential to mitigate the opioid epidemic. Integrating cannabinoids into clinical practice, guided by evidence-based protocols, can provide a safer and effective approach to chronic pain management.

BackgroundCurrent models on functional neurological disorders (FND) propose a multifactorial origin. Recent studies identified potential biological vulnerability factors - such as a reduced limbic volume or an altered stress response. These findings highlight the need to investigate a potential genetic contribution to the biological vulnerability to FND. MethodEighty-five mixed FND patients and seventy-six healthy controls (HC) were genotyped for ten single nucleotide polymorphisms within seven genes associated with the stress system. For the genetic variant that was found to be associated with FND, further associations to structural brain alterations were investigated using a region-of-interest approach. Regions were previously selected based on their biological involvement and as a vulnerability for FND. ResultsA significant association between the diagnosis of FND and the rs53576 of the oxytocin receptor (OXTR) gene was found. A significant association between decreased right insular volumes and rs53576 (OXTR) was identified in FND patients. In female patients, the rs53576 (OXTR) was associated with a reduced bilateral amygdalar volume. ConclusionThese preliminary results suggest a genetic contribution to the biological vulnerability for FND involving the oxytocinergic system, and (sex-specific) structural changes in insula and amygdala.

ObjectivesAttention-Deficit/Hyperactivity Disorder (ADHD) is emerging as a major neurodevelopmental disorder on a global scale, affecting both children and increasingly adult population. Its aetiology is unclear but seems to involve genetic and environmental factors, particularly diets and nutrients. However, most studies so far only focused on specific nutrients or dietary patterns, lacking systematic perspectives of their potential interactions, and also neglecting other confounding factors like socioeconomic status. Thus, we aim to systematically interrogate the association between nutrient supply, reflecting the food exposure and environment, socioeconomic status and ADHD disease burden at a global level over time. MethodsADHD disease burden, macronutrient supply and gross domestic product (GDP) were collated from more than 150 countries from 1990 to 2018 and analyzed with nutritional geometry generalized additive mixed models (GAMMs). ResultsModelling results suggested the interactive effects of nutrients and socioeconomic status on ADHD. Fat, especially plant-based fat supply, is associated with decreased ADHD disease burden. These associations were conserved across sexes and ages and were not confounded by the total energy supply. ConclusionsGlobally, far, particularly plant-based fat supply seemed to drive the reduction of ADHD disease burden, which is supported by previous reports about the amelioration of ADHD by ketogenic diets. Further in-depth studies are needed to elucidate the underlying mechanistic and may inform future targeted dietary interventions for ADHD prevention and/or treatment.

Catechol-O-methyl transferase (COMT) enzyme catalyzes the metabolism of dopamine and other catechols in the brain. Several articles investigated catechol-O-methyltransferase (COMT) Val158Met polymorphism as risk factor for alcohol dependence (AD) but the results were inconclusive. The aim of present meta-analysis was to evaluate the association of Val158Met (COMT) polymorphism with AD. Authors performed keyword search of the four electronic databases-Pubmed, Google Scholar, Springer Link and Science Direct databases up to December 31,2019. Total eighteen studies that investigated the association of Val158Met polymorphism with AD were retrieved. The pooled results from the meta-analysis (2,278 AD cases and 3717 healthy controls) did not show association with AD using all five genetic models (allele contrast model: OR = 1.02, 95% CI= 0.90-1.14, p= 0.03; homozygote model: OR = 1.06, 95% CI= 0.81-1.38, p= 0.69; dominant model: OR = 0.99, 95% CI= 0.85-1.14, p= 0.87; co-dominant model: OR = 0.97, 95% CI= 0.86-1.11, p= 0.71; recessive model: OR = 1.05;95% CI= 0.85-1.29, p=0.61). Results of subgroup analysis showed that Val158Met is not risk for AD in Asian and Caucasian population. In conclusion, COMT Val158Met is not a risk factor for alcohol dependence.

Electroencephalography (EEG) has emerged as a key method for investigating the neural mechanisms through which oxytocin influences cognition and behaviour. EEG is cost-effective, has excellent temporal precision, and may elucidate neural correlates of emotional and cognitive processes. EEG studies evaluating oxytocins electrophysiological effects have, however, yielded mixed results, which is likely driven by heterogeneity in EEG measures, study designs, dosages, and samples. To investigate the effect of oxytocin administration on EEG measures, we performed two multilevel random effects meta-analyses: The first meta-analysis synthesized studies investigating the effects of oxytocin administration on different neural correlates of social and cognitive processing; the second meta-analysis synthesized studies evaluating effects of oxytocin administration on exploratory, less task-specific neural activity measures, such as the modulation of microstates. Across both meta-analyses, we synthesized 161 effect sizes from 28 randomised controlled trials with a total of 1361 participants from different population groups. These multilevel meta-analyses yielded small effect sizes of oxytocin administration across different EEG measures reflecting social and cognitive processes (Hedges g = 0.14), and exploratory neural activity (Hedges g = 0.28) with significant heterogeneity estimates (p < 0.01 and p < 0.001, respectively). Moderator analyses revealed that the different EEG measurements of interest (e.g., event-related potentials) and the proportion of female participants were found to significantly moderate the effect of oxytocin on neural EEG activity. Altogether, these meta-analyses present tentative evidence for oxytocin administration modulating a wide range of neural activity. We observed substantial heterogeneity across studies - in terms of study designs, experimental paradigms and EEG measurements, and participant characteristics. More research is warranted to map out the context-specific effects of oxytocin administration on different neural markers, to better understand the neurobiological mechanisms of oxytocin.

BackgroundNeuroplasticity describes the brains ability to adapt in response to alterations in the environment, and is fundamental to learning. Reduced neuroplasticity has been proposed to underlie several psychiatric symptoms and disorders. Advances in neuroimaging have provided new methods for examining or indexing the potential for neuroplastic changes in-vivo. The proposed systematic review and meta-analysis will synthesize research utilizing neuroimaging assessments to compare the potential for rapid brain changes between individuals with commonly-studied psychiatric disorders relative to healthy control peers (HC). MethodsThis systematic review will include studies comparing the potential for neuroplastic changes between individuals with commonly-studied psychiatric disorders (mood, anxiety, compulsive, trauma-related, eating, and schizophrenia and other psychotic disorders). Included studies will assess neuroplasticity using established or putative neuroimaging biomarkers. Longitudinal studies, studies using non-neuroimaging methods to assess neuroplastic potential, and animal studies will be excluded. PubMed, Web of Science, Embase, and PsycINFO will be searched using predefined terms. Two independent reviewers will screen titles, abstracts, and full texts using Rayyan, with conflicts resolved by a third reviewer. Data including study and participant characteristics will be extracted. Summary statistics will be combined and analyzed using random-effects meta-analyses to estimate the average difference in neuroplasticity between groups. In the event of heterogeneity, subgroup analyses and meta-regression will explore potential moderators of the between-group difference. The extent to which publication bias is likely to impact the findings of the review will be assessed using Eggers test. DiscussionThis review will summarize alterations in neuroplasticity, as indicated by momentary neuroimaging assessments, among individuals with major psychiatric disorders. As research increasingly links psychiatric conditions to neuroplasticity, this review will offer a valuable resource for understanding how neuroplasticity can be measured in-vivo to examine mechanisms of psychiatric illness. Systematic review registrationThis review is registered in PROSPERO (registration number: CRD42025630626)

IntroductionOne of the purported underlying causal mechanisms of attention deficit hyperactivity disorder (ADHD) is altered motivational processes. Questionnaires have been used to identify the characteristics of reward and punishment sensitivity in individuals with ADHD. However, these questionnaires were initially developed to measure individual traits related to anxiety (inhibitory) and impulsivity (approach) tendencies or differences in pleasure-seeking. These reward and punishment sensitivity questionnaires are useful but might not capture all relevant aspects of altered motivational processes in ADHD. The proposed scoping review aims to: 1) examine which aspects of hypothesized altered reward and punishment sensitivity correspond to constructs measured by existing questionnaires, 2) characterize the relationships between ADHD symptomatology and reward and punishment sensitivity as measured by existing questionnaires, and 3) evaluate the consistency between the altered reward and punishment sensitivity as measured by existing questionnaires and experimental task performance. Methods and analysisThis scoping review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews and the Joanna Briggs Methodology for Scoping Reviews. Published English language literature will be searched in three electronic databases, with no restriction on the year of publication. Two researchers will independently screen all identified titles/abstracts and review the method sections of the identified papers to confirm their eligibility before proceeding to full-text review and data extraction. Methods, results, and conclusions will be tabulated by research questions. A narrative review, and summary conclusions will be presented. The evidence will be summarized as descriptive data in the Excel table. Ethics and disseminationThis study reviews existing publications with ethical approval in place. Therefore, ethical approval is not required. Review results will be disseminated through academic conferences and peer-reviewed manuscripts. Scoping review results will also inform future research to measure and identify altered motivational processes in ADHD. Strengths and limitations of this studyO_LIThis scoping review is the first study to identify which aspects of ADHD reinforcement sensitivity have been measured by existing reward and punishment scales and comprehensively review studies reporting relationships between experimental task results and reward and punishment scales in ADHD. (strengths) C_LIO_LIThis study will be conducted according to PRISMA guidelines for systematic reviews. (strength) C_LIO_LIResults will be summarized separately for children/adolescents and adults. (strength) C_LIO_LIThis review includes only published peer-reviewed English language studies. (limitation) C_LI

BackgroundAutism spectrum disorder (ASD) is a neurodevelopment disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. In ASD, studies show activated immune-inflammatory and nitro-oxidative pathways which are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acids (CAAs) and activation of the TRP catabolite (TRYCAT) pathway. ObjectivesThis study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in blood and urine of ASD patients. MethodsAfter searching PubMed, Google Scholar, and SciFinder extensively, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3,557 people with ASD and 30,96 healthy controls). ResultsBlood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD= -0.227, 95% confidence interval, CI: -0.540; 0.085 and SMD= 0.158, 95%CI: -0.042; 0.359) respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD= 0.001, 95%CI: -0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. ConclusionsOur study demonstrates that there are no abnormalities in peripheral blood TRP metabolism, IDO activity, and TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASDs pathophysiology.

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.

BackgroundPain and sleep disturbances are primary reasons for medicinal cannabis use. Cannabis influences both pain and sleep through its modulation of the endocannabinoid system, which regulate pain pathways and sleep regulation. Despite their interconnected roles, the effects of cannabis and chronic pain on sleep architecture are studied mainly in isolation. An integrated understanding is needed to guide use and minimize risks in this population. ObjectiveOur primary aim was to examine the potential interactive effect of regular cannabis use on chronic pain and sleep. MethodsA total of 339 nights (2,273.43 hours) of in-home sleep electroencephalogram (EEG) recordings were collected from 60 adults (50% male; 32% chronic pain; 47% cannabis use; Mage= 25.25; SE= 1.05) over seven consecutive nights per participant. A mixed-model repeated-measures ANCOVA tested the main effects and interactions of chronic pain and regular cannabis use on total sleep time (TST), total slow-wave sleep (SWS%), total rapid-eye-movement (REM%), sleep onset latency (SOL), and number of awakenings. ResultsThere was a significant main effect of cannabis use on SWS, TST, SOL, and REM. There was a significant main effect of chronic pain on TST. Significant interactions emerged between cannabis use and chronic pain on SWS and REM. ConclusionsThese findings may reflect a dysregulated sleep response in individuals using cannabis to manage chronic pain, highlighting the need to consider both beneficial and detrimental effects of cannabis on specific sleep stages.

BackgroundFunctional magnetic resonance imaging (fMRI) is quickly becoming a significant outcome measure for clinical trials and as more than one thousand trials with fMRI as an outcome measure were registered in clinicaltrials.gov at the time of writing this article. However, 93% of these registered trials are still not completed with published results and there is no picture available about methodological dimensions of these ongoing trials with fMRI as an outcome measure. MethodsWe collected trials that use fMRI as an outcome measure by searching "fMRI" in the ClinicalTrials.gov registry on October 13 2018 and reviewing each trials record entry. Eligible trials characteristics were extracted and summarized. ResultsIn total, 1386 clinical trials were identified that reported fMRI in their outcome measures with fMRI as the only primary outcome in 33% of them. 82% of fMRI trials were started after 2011. The most frequent intervention was drug (29%). 57% of trials had parallel assignment design and 20% were designed for cross over assignment. For task-based fMRI, cognitive systems (46%) based on RDoC was the most frequent domain of tasks, followed by positive valence systems (19%), systems for social processing (10%) and sensorimotor systems (5%). Less than one-third of trials (28%) registered at least one region of interest for their analysis. Food cue reactivity task, pain perception task, n-back task and monetary incentive delay task were recruited in more than 25 registered trials. ConclusionThe number of fMRI trials (fMRI as an outcome measure) with both task and rest protocols is growing rapidly. Different RDoC domains are covered by various tasks in fMRI trials. However, our study suggests the need of greater harmony and better standardization for registration of fMRI details on both methods and analysis which would allow for more effective comparison across studies in systematic reviews and also help the validation of results towards having fMRI as a biomarker in the future.

IntroductionSpecific diseases such as Alzheimers, schizophrenia and multiple sclerosis have been associated with environmental changes, including changes in season. The relationship between changes in season or photoperiod and brain volume has been widely studied in animals. However, the relationship between changes in season and brain volume in humans is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging (MRI) studies examining the effects of changes in season or photoperiod on brain volume. MethodsWe used a systematic review approach to study reports on the relationship between changes in season or photoperiod and brain volume using MRI. PubMed database and Google Scholar search engines were used to locate appropriate. PRISMA was used in selection of appropriate studies on season or photoperiod and brain volume using MRI. ResultsFive studies were included in the current review: three examined the relationship between changes in photoperiod and brain volumes while two studies examined the relationship between changes in season and brain volume. ConclusionWhen studying other variables like changes in temperature and humidity on how they affect brain volume, no effect was observed. It was, however, observed from studies that hydration status changed brain volumes when measured using MRI. Overall, we found evidence demonstrating differences in human brain volumes across different seasons. We suggest future longitudinal research to prove changes in brain volume across different seasons.