Compulsivity and emotional impulsivity (negative urgency) are considered transdiagnostic risk factors for compulsive-impulsive psychopathology that is linked to a neural imbalance between executive and motivational-emotional systems. However, existing evidence does not derive from within-subjects designs, leaving it unclear whether imbalance occurs with high expressions in compulsivity and negative urgency. To address this gap, we conducted a preregistered analysis to examine how feedback sensitivity and motor inhibition interact as a function of compulsivity and negative urgency.Participants (n = 205; collected 2018–2019) expressing a wide range in compulsivity and impulsivity performed two motor inhibition and two feedback tasks during electroencephalography. We examined how the relationship between neural correlates of motor inhibition (nogo/stop>go) and feedback sensitivity (loss>gain) was moderated by compulsivity and negative urgency. Compulsivity emerged as the most robust moderator. Across multiple tasks, feedback sensitivity was associated with motor inhibitory activity in participants with mild, but not severe, compulsivity. A similar effect was observed in low versus high negative urgency. The moderation by compulsivity remained when controlling for negative urgency, and vice versa. These results suggest a neural imbalance between systems tied to motor inhibition and feedback sensitivity in transdiagnostic risk. This imbalance manifests such that strong motivational-emotional sensitivity is insufficiently compensated by motor inhibitory resources. It could drive repetitive or rash behaviors in response to distress in compulsivity and negative urgency, respectively. Whereas shared mechanisms may underlie compulsivity and negative urgency, the current interactions appear to also reflect processes unique to each construct.

Preclinical studies indicate that volatile anesthetics such as sevoflurane induce neuroinflammation and oxidative stress-mechanisms implicated in the pathophysiology of depression-whereas propofol exhibits neuroprotective properties. However, whether these pharmacological differences translate into distinct long-term psychiatric outcomes in humans remains unclear. We conducted a multinational propensity score-matched cohort study using the TriNetX Global Federated Network (2005-2024) to determine whether sevoflurane anesthesia is associated with a higher risk of long-term depression compared with propofol. To isolate the effect of anesthetic choice, we applied a new-user design with a one-year latency washout, excluding patients with preexisting depression or antidepressant use. The primary outcome was new-onset depression diagnosed more than one year after anesthesia. The matched cohort included 37,936 patients balanced across more than 100 covariates. Sevoflurane exposure was associated with a higher risk of new-onset depression compared with propofol (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.41-1.61). The association remained consistent across severity strata (aHR, 1.51 for moderate-to-severe depression) and surgical subgroups. Notably, we observed a graded dose-response relationship, where repeated sevoflurane exposures conferred progressively higher risk (aHR, 1.75 for ≥2 exposures), consistent with a biologic gradient. In this large multinational cohort, sevoflurane use was associated with a higher long-term risk of incident depression compared with propofol. These findings align with preclinical evidence of anesthetic-related neuroinflammatory mechanisms and indicate that anesthetic selection may have implications for long-term neuropsychiatric risk. Further mechanistic and prospective studies are warranted.

Positive treatment expectations are known to enhance antidepressant efficacy. Experimental placebo studies aim to provide mechanistic insights into this association, yet their findings have not been clearly linked to clinical expectation effects within individual patients. In a randomized crossover trial, 61 participants with major depressive disorder (31 women, 30 men) completed an emotion classification task and mood assessments after administration of a saline nasal spray labeled as either oxytocin (sham oxytocin treatment, deceptive placebo) or saline (control). Forty-five participants subsequently underwent antidepressant treatment and were monitored weekly for treatment expectations and depressive symptoms, with follow-ups extending to three months. Using linear mixed-effect models, we examined trajectories of clinical expectation effects and their prediction by experimental placebo-induced changes in emotional processing. Sham oxytocin treatment acutely induced positive expectations, improved mood, and shifted emotional processing toward positivity. Longitudinal modeling revealed that weekly reductions in depressive symptoms were predicted by higher treatment expectations reported the preceding week. These clinical expectation effects were most pronounced in individuals exhibiting strong acute placebo responses in emotional processing. Overall, our findings indicate that positive treatment expectations facilitate critical aspects of emotional processing in depression and that individual responsiveness generalizes across different treatments and time windows. Experimental placebo assessments offer an ecologically valid model for elucidating mechanisms and predictors of clinical expectation effects and highlight expectation sensitivity as a promising target for treatment optimization.

Trauma exposure can lead to posttraumatic stress disorder (PTSD) in a subset of vulnerable individuals. Circadian rhythm disturbances have emerged as a candidate pathway of vulnerability, yet mean circadian levels often show limited discriminability. We tested whether circadian instability at trauma aftermath prospectively predicts long-term PTSD risk, and what behavioral and physiological indices are most predictive. For that, 211 survivors of the Supernova music festival mass-trauma event and 113 matched comparison participants were monitored in real-world settings for one-month, two-to-six months post-event, using wearable sensors that tracked their heart rate (HR), activity, and sleep-wake cycles. PTSD symptoms were assessed before and after the recording period, as well as at follow-up eight-to-eleven months post-event. Linear regression models compared circadian metrics between trauma survivors and comparison participants, and tested associations between circadian measures two-to-six months post-event and PTSD status and severity at follow-up. Results revealed that trauma survivors exhibited reduced circadian stability relative to comparison participants, characterized by greater sleep interday instability and higher variability in daily HR acrophase, as well as elevated rhythm-adjusted mean HR (MESOR). Further, circadian instability at two-to-six months post-event was particularly elevated among survivors with PTSD at follow-up and predicted their symptom severity. Finally, hierarchical models highlighted sleep instability at trauma aftermath as the most significant circadian predictor of long-term PTSD risk, above and beyond initial PTSD severity. Together, specific behavioral and physiological metrics of circadian instability at trauma aftermath prospectively index PTSD risk, highlighting circadian regulation as a target for vulnerability monitoring and early intervention.

Ketamine has demonstrated rapid antidepressant efficacy in treatment-resistant depression (TRD), but clinical decision-making is challenging due to variability in individual response. Current trial-and-error prescribing practices may expose patients to ineffective treatment and avoidable adverse effects, underscoring the need for reliable predictive tools to optimize treatment selection and support personalized, evidence-based care. We developed a machine-learning model (support vector classifier) to predict antidepressant response to ketamine using pre-treatment structural MRI data. The model was trained on 99 adults with TRD given a single intravenous ketamine infusion (0.5 mg/kg). Clinical response was defined as a ≥50% reduction in MADRS scores 24 h post-infusion. Internal validation used repeated nested cross-validation, and generalizability was tested in two independent ketamine-treated cohorts (n = 51) and a saline-treated control group (n = 49). Among ketamine-treated participants, 52 (52.5%) responded to treatment. The model achieved a balanced accuracy of 72.2% (sensitivity = 72.3%, specificity = 73.1%, AUC = 0.72) in the discovery sample and 60.0% (p = 0.01, AUC = 0.65) in external validation. Greater gray matter volume in frontal regions predicted response, whereas greater cerebellar volume predicted non-response. Performance dropped to chance in the saline cohort (BAC = 41.1%, AUC = 0.45), supporting pharmacologic specificity. These findings present the first machine-learning model for the prediction of ketamine response in TRD using structural neuroimaging and highlight its potential utility for stratified treatment planning and biomarker-informed interventions while providing mechanistic insight into neuroanatomical predictors of antidepressant response.

Social communication deficits are common across mental-health disorders, yet little is known about how individuals perceive their own gesture behaviours. Gaining insight into this, particularly across different disorders, could enhance our understanding of social communicative impairments and disruptions in self-awareness. The current study included 274 participants: N = 113 with schizophrenia, N = 65 with depression and N = 96 healthy controls where we compared self-reported gesture behaviours in social and non-social contexts. These self-reports where further explored in relation to objective-measures of gesture performance and expert-rating scales of symptom severity and social functioning. Both patient groups self-reported impairments compared to controls, but with disorder-specific profiles. Specifically, people with schizophrenia uniquely reported reduced gesture perception and use, while both patient groups reported diminished social gesture production. The schizophrenia group also reported elevated social perception relative to the other groups. The depression group consistently rated themselves higher than the schizophrenia group across domains. Furthermore, only the schizophrenia group showed distinct associations: self-reported social perception was negatively associated with self-reported gesture perception, but positively associated with self-reported social production. Notably, only schizophrenia showed a significant link between self-reported difficulties in social gesture production and objective gesture performance deficits. These findings suggest that disruptions in self-awareness of gesture behaviours manifests differently across disorders and underscore the value of integrating self-report measures together with objective assessments to capture the complexity of social-communicative impairments. This will help in designing tailored interventions aimed at enhancing social communication and awareness in diverse mental-health disorder populations.

Suicidal ideation (SI) in major depressive disorder (MDD) presents a serious clinical concern, yet its underlying biological mechanisms remain poorly understood. Using an exploratory, multimodal design, this study included 98 MDD patients with SI (MDD_SI), 61 without SI (MDD_nSI), and 233 healthy controls (HC), and collected functional MRI and peripheral blood transcriptomic data. Network-based statistics of resting-state functional connectivity (FC) identified brain network differences among the three groups, followed by graph-theoretical analysis of derived hub regions. Differential module connectivity (MDC) analyses of blood transcriptomic modules were performed to identify group-level differences, and exploratory correlation analyses were performed to examine associations between brain network topology and transcriptomic alterations. A functional network centered on the caudal temporal thalamus (cTtha) showed significant group differences (MDD_SI > MDD_nSI >HC; p < 0.001), with increased nodal efficiency of the left cTtha in both the MDD_SI (p = 0.043) and MDD_nSI (p < 0.001) groups compared with the HC group. Modules differentiating MDD_SI from MDD_nSI were enriched in antiviral immune responses and epigenetic regulation (darkred, MDC = 1.508, p = 0.04; yellow, MDC = 0.93, p = 0.01), while SI-specific alterations involved mitochondrial energy dysregulation and nSI-specific alterations involved vascular and translational pathways. Notably, one immune-related gene module was significantly correlated with left cTtha betweenness centrality (r = 0.274, p = 0.021), degree centrality (r = 0.262, p = 0.027), and nodal efficiency (r = 0.235, p = 0.048) in the MDD_SI group. This study indicates that MDD and SI are associated with cTtha-centered functional network alterations and peripheral transcriptomic dysregulation, and that, within MDD, SI may show a potential link between cTtha-centered brain network disruption and immune transcriptomic dysregulation. These results should be interpreted cautiously given the exploratory design, binary SI assessment, and modest effect sizes.

The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups-NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)-and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral-central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum-CSF GFAP correlation was found in the BC group (r = 0.446, P = 0.033), which became markedly stronger in the BMCI group (r = 0.753, P < 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, P < 0.001), IL-4 (r = 0.412, P = 0.003), IL-6 (r = 0.296, P = 0.035), and TNF-α (r = 0.352, P = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum-CSF IL-6 correlation reached significance (r = 0.469, P = 0.024). These findings suggest that BBB disruption markedly enhances peripheral-central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.

Extracurricular activities shape children's development, yet how the interaction between their modality (digital/physical) and social context (social/non-social) impact mental health and neurodevelopment remains unclear. This study examined these relationships and their bidirectionality, as well as mediation by brain structural changes. Using baseline and one-year follow-up data from 8230 children in the Adolescent Brain Cognitive Development Study, we analyzed self-reported screen time for six digital activities (three social, three non-social), caregiver-reported participation in 28 extracurricular activities (11 social, 17 non-social), mental health via the Child Behavior Checklist and Kiddie Schedule for Affective Disorders and Schizophrenia, and gray matter volume using T1-weighted MRI. Distinct interaction patterns between modality and social context emerged. Physical-social activities were linked to fewer psychiatric symptoms, particularly withdrawn/depressed behaviors, and increased frontoparietal gray matter. In contrast, digital non-social activities were associated with higher psychiatric risk, especially rule-breaking behaviors, and reduced temporal gray matter. Physical non-social and digital-social activities demonstrated mixed effects on developmental measures. Longitudinal analyses revealed bidirectional activity-mental health associations, with brain volume changes mediating 3.7-5.0% of these relationships. These findings highlight the interactive role of activity modality and social context in children's development and provide neurobiological evidence informing guidelines for beneficial developmental outcomes.

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia, and positron emission tomography (PET) studies demonstrate in vivo reductions in synaptic density across illness stages. Stress is a key modifiable risk factor, and while animal studies show it disrupts synaptic function, its effects on humans remain unclear. We examined the relationship between stress and synaptic density in individuals with first-episode psychosis (FEP) and those at clinical high risk (CHR). Seventy-eight participants, including 25 FEP, 32 CHR, and 21 healthy controls (HC), underwent 90-min [18F]SynVesT-1 PET scans to quantify synaptic density measured as SV2A binding across prioritized brain regions. Stress-related measures included the Hassles and Uplifts Scale and the Trier Inventory for Chronic Stress (TICS). Depressive symptoms were evaluated using the Hamilton Depression Rating Scale (HDRS). Across all participants, greater acute stress was associated with lower [18F]SynVesT-1 binding (F1449 = 12.0, p < 0.001), with no significant group interaction (F2449 = 2.44, p = 0.09). Group differences emerged for chronic stress and depressive symptoms (TICS × Group: F2431 = 3.87, p = 0.02; sqHDRS × Group: F2443 = 4.47, p = 0.01). Post hoc analyses revealed that higher chronic stress was associated with lower synaptic density in HC (F1119 = 7.07, p = 0.009) but not in clinical groups. Lower mood symptoms were associated with lower synaptic density in FEP (F(1141) = 5.19, p = 0.02) only. These findings indicate that the relationship between stress and synaptic density differs between clinical and healthy groups. The changes in the relationship between stress and synaptic density in FEP may reflect impaired adaptive neuroplasticity, providing a potential mechanism by which stress contributes to psychosis vulnerability.