Revisiting the link between childhood adversity and stress-sensitive brain regions in psychosis and bipolar disorder: A systematic review and meta-analysis

Exploring Psychological and Biological mediators between Childhood Adversity and Psychosis: An updated Systematic Review and Meta-Analysis

Hippocampal Structural Changes and Antipsychotic Medication in Schizophrenia Spectrum Disorder: A Systematic Review and Meta-Analysis of Longitudinal MRI Studies Highlighting Current Evidence Gaps.

INTRODUCTION The hippocampus is among the most affected brain structures in schizophrenia and plays a central role in the core pathology of psychotic disorders. Despite observations that hippocampal structural deficits emerge from the early stages of schizophrenia, it remains unclear how these changes progress over the disease course and how antipsychotic medication influences them. METHODS We conducted a systematic review of longitudinal, volumetric MRI studies of patients with First-Episode Psychosis (FEP) and those at the Chronic stage (CH), and extracted data on hippocampal volume and antipsychotic medication exposure for meta-analysis. Both the review and the analysis conformed to PRISMA 2020 guidelines. RESULTS Eighteen reports were included. Longitudinal analysis of the FEP group revealed no significant change in hippocampal volume over time (scan interval), likely due to substantial heterogeneity across studies. By contrast, the CH group exhibited a significantly faster, albeit subtle, reduction in hippocampal volume compared with Healthy Controls (HC). The meta-regression analysis revealed no significant associations between hippocampal volume reduction and any examined factors, including antipsychotic medication exposure, likely reflecting the small number of studies and the paucity of medication-related data. DISCUSSION The pace of hippocampal volume change appears to differ between the early and chronic stages. CONCLUSIONS Substantial heterogeneity and insufficient available data in the current literature limit the ability to draw firm conclusions regarding hippocampal volume changes across disease stages or their relationship with antipsychotic medication. The pace of these changes may differ between the FEP and CH stages, but this observation should be interpreted cautiously. Further longitudinal MRI studies with more detailed and consistent reporting of medication-related variables are needed to clarify these relationships.

Amygdala Functional Hyperconnectivity: A Multiple Symptom Subdomain Marker of the Bipolar Risk to Disorder Spectrum.

BACKGROUND Identifying reproducible neural markers of bipolar disorder(BD) risk is critical for early detection and differentiation from unipolar/major depression. We previously demonstrated that inter-amygdala functional connectivity(FC) and bilateral-ventrolateral-right-dorsolateral-prefrontal-cortex(vlPFC-dlPFC)-FC were positively associated with both mania/hypomania and depression risk and mania/hypomania risk, respectively, as measured by the Mood Spectrum Self-Report(MOODS-SR) 'mood' subdomains, replicated in three independent samples. We tested whether these neural markers also generalized to the MOODS-SR 'cognition' and 'energy' subdomains and whether they are elevated in individuals with BD versus those at-risk. METHODS Three independent young adult samples without BD(n=299/ages 18-30) completed an fMRI approach emotion-processing task(Discovery n=114/age=21.60±1.91; Test sample-1 n=103/21.57±2.09; Test sample-2 n=82/23.43±2.86), and a fourth sample with BD(n=32/25.11±3.73) completed the same protocol. Poisson loglinear models tested whether previously identified neural markers of MOODS-SR mood subdomains were also associated with manic and depressive cognition and energy subdomains. One-way ANOVAs compared neural variables showing significant relationships with subdomain scores between low-risk, high-risk, and BD groups. RESULTS Across all risk samples, inter-amygdala-FC was positively associated with manic and depressive mood and cognition subdomains(qFDRs<0.001-0.01); vlPFC-dlPFC-FC was positively associated with manic mood and cognition subdomains(qFDRs<0.001-0.048). Inter-amygdala-FC differed significantly across groups(F2,328=3.56, P=0.03) and was higher in BD versus low-risk and in high-risk versus low-risk groups(Ps=0.033). CONCLUSIONS Inter-amygdala-FC emerged as a robust, cross-dimensional correlate of BD risk, linking subsyndromal risk to syndromal BD, whereas vlPFC-dlPFC-FC was specific to mania risk. Findings support a multidimensional, circuit-based model of BD risk supporting early identification and prevention.

How psychosis shapes the impact of childhood trauma on social cognition in bipolar disorder: the role of Theory of Mind.

OBJECTIVE Childhood trauma and psychotic symptoms are prevalent in bipolar disorder (BD) and independently linked to social cognition impairments, particularly Theory of Mind (ToM). However, it remains unclear whether trauma and psychosis exert cumulative effects on ToM performance in BD. METHODS We conducted a cross-sectional study involving 54 euthymic individuals with BD reporting at least moderate childhood trauma (Childhood Trauma Questionnaire; CTQ). Participants completed the Reading the Mind in the Eyes Test (RMET) to assess ToM. Clinical and sociodemographic data were collected. Participants were stratified by lifetime psychotic symptoms for between-group comparisons. RESULTS Individuals with a history of psychotic symptoms (n=18) reported significantly higher total CTQ scores (Mean=61.0, SD=15.7) than those without psychotic symptoms (Mean=44.5, SD=13.1; p=0.028) and exhibited significantly lower ToM accuracy (Mean RMET=23.0, SD=4.5 vs. 25.4, SD=3.4; p<0.001, d=0.58). CONCLUSIONS In BD, the co-occurrence of childhood trauma and lifetime psychosis is associated with more pronounced ToM deficits. These results highlight the need for trauma-informed approaches and early cognitive interventions targeting social cognition in individuals with BD and psychosis history.

Right hippocampal volume and attenuated psychotic symptoms distinguish subgroups of youth with common patterns of temporoparietal effective connectivity

Associations between patterns of brain connectivity and brain structural features have transdiagnostic relevance to psychopathology. There is considerable evidence for disruptions to the hippocampus and temporoparietal brain systems in psychotic disorders. The present study examines structure–function relationships—specifically, the relation of hippocampal volume with patterns of temporoparietal effective connectivity—in youth at clinical high-risk for psychosis (CHR-P) and healthy controls (HCs). Participants at CHR-P and HCs completed clinical symptom measures and magnetic resonance imaging at baseline (n = 388, 42.5% female, age = 19.8 ± 4.2) in the second cohort of the North American Prodrome Longitudinal Study. Group Iterative Multiple Model Estimation established a common functional network of temporoparietal effective connectivity in the full sample. Next, supervised (assuming the CHR-P and HC groups represent classes) and unsupervised (data-driven) clustering procedures interrogated effective connectivity parameters relevant to subsamples. Mean difference tests by unsupervised cluster membership determined whether clusters formed based on temporoparietal effective connectivity differed in hippocampal volume. Clusters were also compared on representation of CHR-P and positive and negative symptom totals to determine whether unsupervised clustering recovered clinical features. Unsupervised clustering generated two clusters that differed significantly in right hippocampal volume and attenuated positive and negative symptoms with small-to-medium effect sizes. The cluster demonstrating reduced right hippocampal volume reported greater symptoms. Unsupervised clustering did not recover diagnostic groups. Findings are consistent with literature indicating the transdiagnostic relevance of hippocampal volume to organizational properties of brain functional networks and patterns of temporoparietal connectivity.

Childhood emotional maltreatment and trauma-related outcomes: a systematic review and multilevel meta-analysis

ABSTRACT Background: Estimating the association between childhood emotional maltreatment (CEM) and trauma-related outcomes is important for prevention and intervention. Objective: We synthesised the evidence by differentiating between emotional abuse and emotional neglect, examining post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD) and exploring moderators and mediators. Method: Following PRISMA guidelines, seven databases were searched up to 19/03/2026 (PROSPERO-CRD42024598358) for studies on the association between CEM and PTSD/CPTSD. Study quality was assessed using an adapted Newcastle-Ottawa Scale (NOS), and certainty of evidence was evaluated using the GRADE framework. Results: Of 11,479 records, 62 were included in the review, of which 57 studies provided 132 effect sizes for a random-effects multilevel meta-analysis (N = 323,776). Study quality was overall fair (Mean NOS = 5.8). A positive association between CEM and PTSD/CPTSD (k = 132, r = .27, 95% CI [.23, .30]) 95% PI [−.04, .53] with substantial heterogeneity (I² = 86.5%). Higher estimates were identified for emotional abuse (k = 71, r = .29, 95% CI [.25, .33]) compared to emotional neglect (k = 55, r = .24, 95% CI [.19, .28]). Effect sizes were similar for CPTSD (k = 29, r = .29, 95% CI [.24, .35]) and PTSD (k = 103, r = .26, 95% CI [.22, .30]). No differences were observed by sex, age, or population type (clinical vs. non-clinical). However, higher estimates were identified in high-income settings and more developed contexts. Narrative synthesis identified cognitive, affective, physiological and interpersonal mechanisms as potential mediators. The certainty of the evidence was generally low. Limitations include the predominance of cross-sectional designs, reliance on self-report measures of CEM and variability across outcome measures. Conclusions: These findings underscore the importance of CEM in trauma-related symptomatology and support the need for its systematic assessment in clinical and research settings, particularly by highlighting differences between emotional abuse and emotional neglect.