Brain Imaging and Behavior

BackgroundLarge-scale T1-weighted MRI studies have established grey-matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white-matter pathways, yet prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretic metrics. MethodsCross-sectional structural and diffusion MRI scans from 449 individuals with BD (35.7{+/-}12.6 years) and 510 controls (33.3{+/-}12.6 years), aged 18-65, were analyzed across 16 ENIGMA-BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretic metrics of global and subnetwork organization were related to symptom severity and medications. ResultsBD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default-mode/salience/fronto-limbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater fronto-limbic connectivity. Antidepressant (particularly SSRI), anticonvulsant, and antipsychotic use related to poorer global and fronto-limbic connectivity; no clear lithium effects emerged. ConclusionsAs the largest structural connectivity study in BD, we reveal widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

ObjectiveFinding indicators of early response to antidepressant treatment in EEG signals recorded from patients suffering from major depressive disorder. MethodsFunctional brain connectivity networks based on weighted imaginary coherence and weighted imaginary mean phase coherence were computed for 176 patients for 6 different EEG frequency bands. Cross-hemispheric connectivity (CH) and lateral asymmetry (LA) were estimated from these networks based on EEG signals recorded before the beginning of treatment (V is1) and one week after the start of the treatment (V is2). Repeated measures ANOVA was used to check for statistically significant changes in connectivity based on these measures at V is2 w.r.t. V is1. Post-hoc analysis was performed with multiple pairwise comparison tests to determine which group means were significantly different. ResultsIt was found that CHV is2 was significantly reduced w.r.t. CHV is1 in the {beta}1 [12.5 - 17.5 Hz] frequency band for the responders to treatment. Also, LAV is2 was significantly increased w.r.t. LAV is1 in the {beta}1 frequency band for the responders. No such significant changes were observed for the non-responders. Brain networks constructed using both weighted imaginary coherence and weighted imaginary mean phase coherence were found to exhibit these results. For the CH connectivity changes, binarized networks and for the LA connectivity changes, weighted networks were found to be more reliable. ConclusionsResponders were found to show a reduction in cross-hemispheric connectivity and an increase in lateral asymmetry, both in the {beta}1 band while no such change was observed for the non-responders. SignificanceDecrease in cross-hemispheric connectivity and increase in lateral asymmetry in the {beta}1 band may represent candidate neurophysiological indicators of early treatment response, but they require independent replication before any clinical application can be considered.

BackgroundDepression is associated with social dysfunction, but the mechanisms linking affective symptoms to disrupted close relationships remain poorly understood. One possibility is that depression alters how people experience rewards shared with close others and how they interpret partners actions. It remains unclear whether neural sensitivity to shared reward predicts social valuation during more complex interactions such as reciprocated trust. MethodsIn this preregistered fMRI study, participants completed a reward-sharing task and a Trust Game with a close friend, a stranger, and a computer. We measured striatal shared reward sensitivity (SRS; friend > computer) and tested whether it related to subsequent investment behavior and brain responses to trust reciprocation. Depressive symptoms and perceived closeness were assessed via self-report. ResultsIn a final sample of n = 123, participants reporting more depressive symptoms invested more in their friend than in the computer. Striatal SRS predicted temporoparietal junction responses to reciprocated trust, but this association depended jointly on social closeness and depression -- with depression reversing the expected pattern among individuals reporting closer relationships. Striatal SRS was also inversely associated with connectivity between the default mode network and cerebellum during reciprocity. ConclusionsThese findings suggest that closeness calibrates the striatal SRS link to regional activity and network-level responses during social exchange, while depression alters how striatal SRS relates to regional activity, potentially disrupting how individuals interpret and respond to close others.

Introduction. There is consistent evidence of a disadvantage in bilinguals' speech production compared to monolinguals in healthy individuals, but studies investigating this phenomenon in clinical populations such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) are scarce. Given that both clinical groups are characterized by wordfinding difficulties, understanding how bilingualism influences speech production in these populations is essential. Methods. Early and highly proficient Catalan-Spanish bilinguals (active bilinguals) were compared to Spanish-dominant speakers with low proficiency in Catalan (passive bilinguals) using a picture-naming task. The study included 58 older adults, 66 patients with AD, and 124 individuals with MCI. Reaction times, accuracy, and error types were collected in the naming task in each individual's dominant language. Results. First, active bilinguals demonstrated faster naming latencies than passive bilinguals, particularly for low-frequency words. Second, active bilinguals with MCI exhibited more naming errors than passive bilinguals with MCI, including a higher incidence of crosslanguage intrusions and anomia. Third, passive bilinguals with MCI and AD showed more semantic errors than active bilinguals. Discussion. These findings underscore the impact of second language use on naming performance in MCI and AD. Moreover, they provide insight into the potential mechanisms underlying lexical retrieval differences in bilinguals, including lexico-semantic processing and language control.

BackgroundThe brains glymphatic system plays a vital role in maintaining neural health. However, little is known about whether second language (L2) immersion can influence this clearance pathway. Methods50 high-proficiency L2 English speakers (mean age: 32.6 years; 78% female) were assessed for glymphatic function using three multimodal MRI markers: BOLD-CSF coupling strength (fMRI), choroid plexus ratio (structural MRI), and DTI-ALPS index (diffusion MRI). Analyses examined relationships between glymphatic markers and L2 immersion duration, age of acquisition (AOA), and active use environment, controlling for age, education, and sex. ResultsL2 immersion duration correlated significantly with better glymphatic function. Longer immersion related to better BOLD-CSF coupling strength (r = -0.315, p < 0.05) and decreased choroid plexus ratios (r = -0.39, p < 0.05), suggesting enhanced brain-CSF coordination and fewer pathological CSF production structures. Mediation analyses demonstrated that immersion influenced ALPS indirectly through effects on choroid plexus morphology and BOLD-CSF coupling. L2 AOA moderated the immersion-coupling relationship: individuals who began learning after age 9.53 showed stronger associations between immersion and BOLD-CSF coupling, though AOA did not moderate choroid plexus effects. As for L2 immersive active is associated with better glymphatic function, while L2 immersive passive and L2 non-immersive active are both unrelated. ConclusionsL2 immersion associates with better glymphatic system function through multiple pathways, including improved brain-CSF coordination, optimized choroid plexus structure, and increased perivascular flow. These findings provide novel neurobiological evidence that bilingual experience may confer neuroprotective benefits through brain waste clearance mechanisms.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases. METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity. RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; ps < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior. DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.

Background Cognitive impairment is a core feature of schizophrenia and a major determinant of functional disability. Executive deficits affect approximately 85% of patients and are associated with reduced activity in the prefrontal cortex (hypofrontality). Current pharmacological treatments show limited efficacy in improving cognition, highlighting the need for alternative therapeutic approaches. Combining non-invasive brain stimulation with cognitive remediation may enhance neuroplasticity and improve cognitive outcomes. Methods This prospective, randomized, double-blind, sham-controlled, parallel-group superiority clinical trial. A total of 120 adults aged 18-65 years with clinically stable schizophrenia diagnosed according to DSM-5 criteria will be enrolled at a single clinical center. Participants will be randomly assigned in a 1:1 ratio to receive either active transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex followed by cognitive remediation therapy (CRT) using the RehaCom system, or sham stimulation followed by the same cognitive training. Assessments will be conducted at three time points: prior to the intervention (V1), immediately after the intervention (V2), and during the follow-up visit 8 weeks after the intervention (V3). The primary outcome is change in cognitive performance measured with the CANTAB battery. Secondary outcomes include symptom severity assessed with the PANSS, global clinical status (CGI-S), and neurophysiological changes measured by EEG. Written informed consent will be obtained from all participants, and the study has received ethics committee approval. Discussion This trial will evaluate whether tDCS administered prior to cognitive training enhances cognitive improvement compared with cognitive training alone. The findings may inform the development of more effective interventions targeting cognitive deficits in schizophrenia. Trial registration ClinicalTrials.gov Identifier: NCT07273175. Registered on 25 November 2025.

INTRODUCTION: Bilingualism may confer resilience via enhanced neural integrity. However, evidence for bilingualism's neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are scarce. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA). METHODS: In 136 amnestic AD and 88 lvPPA participants with neuropsychological assessments and structural MRI, we analyzed differences between monolinguals and bilinguals within each variant, controlling for demographic covariates. RESULTS: Amnestic AD bilinguals exhibited less GMV in hippocampal, fusiform, and occipital regions compared to monolinguals. LvPPA bilinguals had less temporal and occipital volumes, but they had greater volumes in inferior parietal regions, which are considered a disease epicenter in lvPPA. Cognitive performance in monolinguals and bilinguals was comparable within variants. DISCUSSION: Bilingualism may support cognitive reserve (preserved cognition despite reduced GMV) in both AD variants, with additional brain reserve in lvPPA.

Importance: Conventional repetitive transcranial magnetic stimulation (rTMS) can be ineffective in individuals who have previously failed brain stimulation, ketamine and/or multiple lines of therapies. Modern accelerated rTMS protocols using image-guided targets have not been systematically investigated in these individuals. The goal of this study was to assess the feasibility and efficacy of personalized, connectivity-guided, accelerated intermittent theta-burst stimulation (iTBS) in patients with treatment-resistant depression (TRD) of varying refractoriness. Objective: To assess whether connectivity-guided, accelerated iTBS produces significant reductions in depression severity, and to what extent this benefit extends to ultra treatment-resistant depression (UTRD). Design: This was an open-label feasibility trial of connectivity-guided, accelerated iTBS in patients with TRD. Two distinct groups of participants were recruited from a neurosurgical-psychiatry clinic with UTRD and an interventional psychiatry clinic with TRD. Patients were stratified into a priori treatment-resistance subgroups. Patients received five days of open-label treatment. Outcome measures were collected immediately prior to and after treatment, as well as at 4- and 12-weeks post-treatment. Setting: This trial (NCT05813093) was conducted between November 2023 and July 2025 at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Participants: Patients with major depressive disorder. A total of 96 participants were screened, with 73 meeting eligibility criteria (UTRD=30, TRD=43). One withdrew due to inability to tolerate the baseline MRI, and the other withdrew voluntarily prior to treatment. Intervention: Participants underwent a neuronavigated accelerated iTBS (600 pulses) protocol using personalized left dorsolateral prefrontal cortex (dlPFC) targets derived from functional magnetic resonance imaging (fMRI), comprising eight daily treatments, repeated over five days. Main Outcomes: Primary outcomes were i) change in Hamilton Depression Rating Scale (HAM-D17) from baseline to the end of the fifth day of treatment, and ii) the difference in change in HAM-D17 between UTRD and TRD subgroups. Results: Connectivity-guided fMRI targeting yielded personalized targets clustered around the anterolateral dlPFC. Accelerated iTBS elicited rapid antidepressant effects ({Delta}HAM-D17 -9.01 [SD 6.06], t = -12.45, p < 0.001) regardless of treatment-resistance group ({Delta}HAM-D17 -9.64 [SD 5.94] vs -8.10 [SD 6.12], t = -1.05, p = 0.299), which were sustained up to 12 weeks after treatment. Overall response and remission rates at the end of treatment were 40.8% and 16.9%. Self-report scales revealed broad symptomatic relief outside of core depressive symptoms. Conclusions & Relevance: This study demonstrated that fMRI connectivity-guided, accelerated iTBS induces sustained antidepressant effects and broader psychiatric benefits in patients across the spectrum of TRD. In a cohort unlikely to respond to most antidepressant therapies, connectivity-guided, accelerated iTBS offers a safe, well-tolerated option that can achieve benefit, or when ineffective, allow patients to expeditiously proceed with subsequent therapies than conventional rTMS. Trial Registration: This clinical trial was registered at clinicaltrials.gov with NCT05813093.

BackgroundSchizophrenia is a neurodevelopmental disorder shaped by immune-related mechanisms, particularly dysregulated complement-mediated synaptic pruning. Genome-wide association studies have identified CSMD1 as a major schizophrenia risk gene, an association robustly replicated across populations of diverse ancestries. As a complement regulator, CSMD1 further links genetic vulnerability to synaptic refinement processes. However, the transcriptional status of CSMD1 and its homolog CSMD2 in individuals with schizophrenia (SZ individuals) remains poorly characterized. We conducted a meta-analysis of gene-expression datasets to determine whether CSMD1 and CSMD2 are differentially expressed in brain and peripheral tissues, and to assess the concordance between central and peripheral transcriptional signals. MethodsTranscriptional data were obtained from gene expression omnibus. Random-effects meta-analyses were performed on CSMD1 and CSMD2 expression data from 854 postmortem brain samples derived from 348 SZ individuals and 346 healthy controls (HC), and 295 peripheral blood samples from 162 SZ individuals and 133 HC. Sex-stratified analyses and meta-regressions evaluated potential moderators. ResultsIn brain tissues, CSMD2 expression was significantly increased in SZ individuals vs. HC (SMD: 0.22 [0.05; 0.39], adj-p=0.026), whereas CSMD1 showed no differential expression. The female-only meta-analysis revealed nominal CSMD2 overexpression (p=0.037) in brain tissues, not surviving correction. No significant transcriptional differences were detected in peripheral blood. ConclusionIn schizophrenia, our findings point to a dissociation between genetic vulnerability and transcriptional activity within the CSMD gene family. Schizophrenia is associated with selective brain CSMD2 overexpression, contrasting with unchanged CSMD1 transcription and absent peripheral blood alterations. These findings support complement-related dysregulation as a central pathway in schizophrenia.

BackgroundCognitive-behavioral therapy (CBT) is a widely used treatment for mental disorders, yet the biological mechanisms underlying its effects, and the factors contributing to response, remain poorly understood. DNA methylation, an epigenetic mechanism shaped by both genetic and environmental factors, may offer insights into individual differences in psychotherapy outcomes. MethodsSaliva samples were collected before treatment, after treatment, and three months post-treatment from individuals with OCD undergoing the Bergen 4-Day Treatment (n = 889). DNA methylation was measured using the Illumina EPIC v02 array, followed by epigenome-wide DNA methylation analyses of CBT response. ResultsWe identified ten differentially methylated regions (DMRs) associated with treatment response at baseline, 23 DMRs showing consistent associations with response across multiple time points, and three DMRs displaying longitudinal methylation changes associated with response. These loci were annotated to genes with roles in neuroplasticity, stress response, immune function, mitochondrial processes, and gene regulation. Baseline and stable methylation signals were largely influenced by genetic variation, whereas all longitudinal associations appeared to be confounded by psychoactive medication use and psychiatric comorbidities. In addition, changes in monocyte and CD4+T cell proportions were associated with treatment response. ConclusionsWe identified DNA methylation markers associated with CBT response in OCD at baseline. Stable methylation patterns associated with treatment response are likely driven by genetic factors. Longitudinal methylation analyses should be interpreted cautiously, as medication and comorbidities can exert substantial effects - even when they remain unchanged over time. Baseline methylation profiles may ultimately help predict treatment outcomes, thereby advancing precision psychiatry.

Recent evidence suggests that psychosis involves glutamatergic dysfunction and altered activity/connectivity within corticolimbic circuitry. While altered relationships between corticolimbic glutamatergic metabolite levels and resting-state functional connectivity (FC) have been described in schizophrenia and first-episode psychosis (FEP), whether these disruptions are also present prior to psychosis onset remains unclear. We measured Glx (glutamate + glutamine) levels in the anterior cingulate cortex (ACC) and hippocampus with magnetic resonance spectroscopy (MRS), and resting-state FC between corticolimbic regions of interest (ACC, hippocampus, amygdala and nucleus accumbens (NAc)) in antipsychotic-naive participants at clinical high-risk for psychosis (CHR-P, n=22), compared to healthy controls (HC, n=23) and FEP participants (n=10). Primary analyses compared corticolimbic Glx-FC interactions between CHR-P and HC groups. FEP individuals were included in secondary Glx comparisons but were excluded from FC analyses due to insufficient sample size after quality control. There was a significant interaction between group and ACC Glx for FC between the NAc and the bilateral amygdala and hippocampus (p-FDR=0.021), which was driven by a significant negative association in the CHR-P group (p-FDR=0.005). Complementary seed-to-whole-brain analyses revealed additional negative associations between ACC Glx and FC with the left middle temporal gyrus, and between hippocampal Glx and FC with the parahippocampal and temporal fusiform cortices in CHR-P individuals, which were absent in HC. FEP showed higher Glx than HC across both regions (p=0.015), but there were no significant Glx differences between CHR-P and HC. These data suggest that increased risk for psychosis is associated with altered relationships between corticolimbic connectivity and glutamatergic function.

Background: The highly influential predictive processing theory of psychosis posits that symptoms arise from imbalances in the weighting of predictions (priors) and sensory evidence. Despite this theory's increasing prominence, studies often present conflicting results. This is particularly problematic as findings from single tasks with modest sample sizes are frequently used to advance a theory for a generalised altered reliance on priors in psychosis. Methods: This study presents a random-effects, multi-level meta-analysis (PROSPERO CRD42024574379) evaluating evidence for aberrant reliance on priors in psychosis across perceptual tasks. The search identified articles in Embase, MEDLINE, APA PsycINFO, and APA PsycArticles published between 1st January 2005 and 31st October 2024, with risk of bias assessed using the Newcastle-Ottawa Scale. Included articles (34 results from 27 studies) compared adults with schizophrenia-spectrum psychosis (SZ; n = 904) to healthy controls (n = 1,039) on behavioural measures representing reliance on priors. Results: Results provided no evidence for atypical reliance on priors in psychosis (g = .03, 95% CI [-0.27, 0.34]; p = .818) or associations with delusions (6 results; SZ = 183; r = -.16, 95% CI [-0.51, 0.19]; p = .293) or hallucinations (10 results; SZ = 370; r = .04, 95% CI [-0.28, 0.36]; p = .780). In contrast with the theory that psychosis may differentially affect priors at different levels of the cognitive hierarchy, a sub-group analysis indicated that a two-level hierarchical model of priors did not account for conflicting results (F(1,32) = 0.1, p = .758). Conclusion: These findings do not suggest that psychosis is associated with a generalised predictive processing deficit spanning multiple aspects of perception. Key words: psychosis, schizophrenia, predictive processing, prior expectations, perception

Previous studies exploring the connection between early language development and brain anatomy have shown that cortical areas relating to individual differences in language skills are diverse and vary depending on the age of child. However, due to lack of large longitudinal samples, current literature is limited in answering the extent to which individual differences in language development prior to school age are reflected in areas of the cortex. To fill this gap, we compared gray matter density between participants that belonged to different longitudinally defined language profiles from 14 months to five years of age in a large population-based sample. Participants were 166 children from the FinnBrain Birth Cohort Study who had longitudinal language data from 14 months to five years of age and magnetic resonance imaging data at five years of age. Three groups of language development were used as per our prior study: persistent low, stable average, and stable high. Voxel-based morphometry metrics were calculated using SPM12 and the three language profile groups were compared to one another. Covariates included sex and age at brain scan. The statistics were thresholded at p < 0.01 and false discovery rate corrected at the cluster level. Of the three longitudinal language profiles, the stable high group had higher gray matter density than the persistent low group in the right superior frontal gyrus. No differences were found between the stable average and stable high groups, nor persistent low and stable average groups. The identified superior frontal cortical area belongs to executive functions neural network. This finding adds to the cumulating evidence that individual differences in language development are reflected in growth of gray matter supporting general processing ability rather than specialized language regions. The results suggest that cognitive development and early language development are linked through shared principles of neural growth, identifiable already at age five. Key pointsO_LIAn association between early language development from 14 months to five years of age and gray matter density differences of the right superior frontal gyrus was found at the age of five years. Children following the strongest language trajectory were more likely to exhibit higher gray matter density of the right superior frontal gyrus than children following the weakest trajectory. C_LIO_LIAs the superior frontal gyrus is part of executive functions network, we propose that individual differences in early language development are more defined by general learning mechanisms supported by those networks, rather than language specific pathways. C_LI

The hippocampal CA1 subregion supports learning, memory formation, and spatial navigation. Although its three-layered architecture has been described in ex-vivo investigations, the in-vivo microstructural profile of CA1 and its relation to individual variations in memory performance remain poorly characterized. In this study, we used ultra-high field structural MRI at 7 Tesla to investigate the depth-dependent myelination patterns (measured by quantitative T1) of CA1 in younger adults, their relation to the local arterial architecture, and their association with individual differences in cognitive functions, specifically memory performance. Results show that left and right CA1 present depth-dependent patterns of myelination, with the outer and inner compartments showing higher myelination than the middle compartment. No significant relationship between layer-specific myelination of CA1 and distance to the nearest artery was observed. Right CA1 was found to be more myelinated than left CA1. Pairwise correlations and regression models showed that higher left CA1 myelination is linked to higher accuracy in object localization. Together, our data demonstrates the feasibility of describing the three layered myelin architecture of CA1 in vivo, and provides information on how alterations in the architecture of CA1 may relate to alterations in cognitive performance in younger adults.

BackgroundContemporary research indicates that psychedelics induce notable neurophysiological changes, some lasting weeks to months after a single dose. However, most evidence derives from acute administration studies and limited post-acute follow-ups. Long-term naturalistic psychedelic users remain critically underexamined, yet may exhibit distinct neurobiological profiles informing our understanding of persistent alterations following repeated exposure. MethodsWe recorded resting-state EEG in 57 long-term psychedelic users (abstinent [&ge;]30 days) and 49 matched non-users across two independent sites under eyes-open and eyes-closed conditions. We analyzed oscillatory power, signal complexity, and source-localized effective connectivity, focusing on five canonical frequency bands and regions of the Default Mode, Salience, and Central Executive Networks. Analyses included linear mixed-effects modeling for power spectra and complexity results and a rank-based approach combining ordinary least squares regression with randomization inference for effective connectivity. ResultsWe observed predominantly null findings. No significant between-group differences emerged for oscillatory power. Complexity comparison yielded results contrary to our hypothesis: psychedelic users exhibited lower complexity values in the eyes-open condition. Effective connectivity revealed no within- or between-network differences that would survive statistical corrections. Additionally, we report a few small-magnitude effects uncovered by exploratory analyses. Conclusions Long-term naturalistic psychedelic users showed largely non-significant differences in oscillatory power, complexity, and network connectivity compared to non-users -- across several measures commonly reported as altered in acute administration studies. These findings raise the question of whether psychedelics neurophysiological signatures persist during abstinence despite repeated prior use, or whether they reflect homeostatic receptor adaptation, individual variability, or contextual factors. Null, incongruous, or subtle effects contribute to the existing evidence base, yet underscore the need for replication in larger, more ecologically valid populations to advance the emerging field of psychedelic neuroscience.

Background and Objectives: Normal appearing white matter (NAWM) may already harbor subtle microstructural alterations not yet visible on conventional MRI. Quantitative Multi-Parametric Mapping (qMPM) such as Magnetization Transfer saturation (MTsat), longitudinal relaxation rate (R1), and Proton Density (PD) offer new possibilities for analyzing NAWM which are sensitive to demyelination, axonal loss, and edema. We aimed to characterize these alterations within white matter hyperintensities (WMH) and the perilesional NAWM (pNAWM), to gain insights into the underlying process of lesion progression. We also investigated their association with cerebrovascular risk factors (CVRF) and long-term cognitive performance. Methods: This investigation included the cerebral MRI data of 245 participants from the prospective Berlin Longterm Observation of Vascular Events (BeLOVE) study. Furthermore, 121 participants cognitive performance was evaluated at baseline and longitudinally at 2 years follow-up using Montreal Cognitive Assessment (MoCA). Regions of interest (ROIs) of WMH, pNAWM at 1, 2, 3 mm were assessed in comparison to the mirrored contralesional white matter (cWM). Linear mixed effects models were employed to demonstrate the pairwise comparisons between each region using estimated marginal means and the association of MPM metrics with CVRFs. Linear regression was used to assess the association with cognitive performance. Results: In 245 participants, (mean age 62 years, SD: 12 years; 29.8% females), MPM metrics demonstrated a clear spatial gradient of microstructural injury. MTsat and R1 values were lower in WMH compared to cWM (lower case Greek beta = -0.48 (-0.52 - -0.44) and lower case Greek beta = -0.07 (-0.08 - -0.06), p<0.001, respectively) and showed gradual recovery with increasing distance indicating a microstructural gradient in pNAWM. Conversely, PD values were higher in WMH and decreased peripherally (lower case Greek beta = 2.32 (2.05 - 2.61, p<0.001). No substantial associations were found between MPM parameters and CVRFs in our cohort. At baseline and 2-year follow-up, cognitive performance was associated with higher pNAWM R1 values, whereas MTsat were only moderately associated. Discussion: Quantitative MPM reliably detects microstructural alterations not only within WMH, but also in pNAWM, confirming the high sensitivity of qMPM to subtle tissue pathology and support its utility as a promising biomarker for longitudinal studies and monitoring therapeutic effects.

ObjectiveImpaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population. Materials and MethodsNeurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimers Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). ResultsSignificant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population. ConclusionOur findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.

BackgroundGrowing evidence suggests that sleep plays an important role in PTSD outcomes, potentially due to its influence on emotional memory consolidation, though these mechanisms remain unknown. This study sought to test the hypotheses that sleep neurophysiology, PTSD status, and sex moderates the degree to which the late positive potential (LPP) mediates memory accuracy for affective visual stimuli. MethodsN = 39 participants (18 female) viewed 75 negative and 75 neutral IAPS images while EEG was recorded. After viewing the images, participants took a two-hour long nap which was followed by a memory assessment. Memory accuracy was measured using d = Z(hit rate) - Z(false alarm rate), where hit rate refers to the proportion of images seen during the memory assessment that are correctly identified as being previously seen, false alarm rate refers to the proportion of images seen during the memory assessment that are incorrectly identified as being previously seen, and Z() is the inverse cumulative distribution function of the standard normal distribution function. ResultsThe early (300 - 1000 ms) and late (1000 - 1500 ms) LPP mediated enhanced discrimination accuracy for emotional compared to neural stimuli (d) (ps < 0.001). The association between the late LPP and d was moderated by sleep such that the association was stronger when participants spent proportionately more time in N3 and REM (p = 0.02). The differences in reactivity between emotional and neutral images for both the early and late LPP were attenuated in PTSD+ individuals vs. controls (ps < 0.001). Despite mediation results showing greater d for emotional compared to neutral stimuli, women showed overall worse memory accuracy for negative compared to neutral stimuli (p < 0.001) whereas men showed no difference (p = 0.64). ConclusionsN3 and REM sleep play a critical role for memory of stimuli that produce large and sustained neural responses. PTSD is marked by a diminished ability to distinguish between negative and neutral information. More research is critical to understand sex effects on emotional memory.