Introduction Theory of mind (ToM) difficulties have been reported in individuals at clinical high risk for psychosis (CHR). ToM have been associated with white-matter microstructure in patients with manifest psychosis, but whether such associations differ in CHR individuals relative to controls remains unclear. We investigated whether associations between regional fractional anisotropy (FA) and ToM differed in CHR individuals compared to controls. Methods Using a discovery-replication design, we included 110 CHRDisc and 57 controlsDisc, and further 33 CHRRepl and 13 controlsRepl as an independent replication cohort. ToM was assessed with The Awareness of Social Inference Test (Short Form), yielding total, sincere, simple sarcasm, and paradoxical sarcasm scores. Group differences were tested with adjusted covariance models. Primary analyses tested whether specific associations between superior longitudinal fasciculus (SLF) FA and ToM differed by group using hierarchical regression. Secondary linear mixed-effects models tested whether group differences in regional FA and ToM associations varied across all white-matter regions. Results CHRDisc participants showed lower ToM total scores (F = 5.76, p = 0.018), simple sarcasm scores (F = 7.98, p = 0.005) and lower left SLF FA (F = 6.68, p = 0.011); right SLF FA was lower in CHR at the sample mean age (F = 8.47, p = 0.004; Group × Age p = 0.014). No significant SLF FA × ToM group interactions were observed across both cohorts. Secondary analyses identified group differences in associations between ToM and right cingulum hippocampal, (F = 10.83, p = 0.001), and fornix, (F = 22.77, p < 0.001). Neither finding was observed in CHRRepl. Conclusion ToM differences in CHR were modest and cohort-dependent. No support for a single-tract explanation was provided, although secondary findings suggested additional candidate regions warranting confirmation in larger samples.
Ketamine exerts rapid antidepressant effects in treatment-resistant depression (TRD), but its impact on working memory and neural circuitry remains unclear. This secondary analysis investigated behavioral and neural changes during a working memory task post-ketamine infusion in TRD participants versus healthy volunteers (HVs). Data were previously collected from a randomized, double-blind, placebo-controlled, crossover trial of 22 unmedicated TRD participants (14F/8 M) and 19 matched HVs (12F/7 M). Participants received ketamine (0.5mg/kg) and placebo two weeks apart. 3T fMRI was acquired during an N-back task at baseline and two days post-ketamine. Accuracy, reaction time, and differential neural activation during 3-back versus 1-back contrasts were analyzed. Ketamine significantly reduced Montgomery-Asberg Depression Rating Scale scores compared to placebo (p < 0.01). N-back task performance did not significantly differ between drug conditions. In region of interest (ROI) analyses, TRD participants showed reduced activation in the superior temporal gyrus versus HVs (p < 0.01) after both infusions, and both groups demonstrated decreased parieto-occipital junction activation post-ketamine versus post-placebo (p = 0.01). Baseline dorsolateral prefrontal cortex activity significantly predicted post-infusion activity (p < 0.01). Ketamine’s antidepressant effects occurred without significant changes in working memory performance, though region-specific task-related brain changes were observed. Interpretation is limited by modest sample size and the exploratory nature of the ROI analyses. Clinical Trial Registration www.clinicaltrials.gov, NCT00088699.
Prenatal alcohol exposure (PAE) can alter neurodevelopment and cause health and behavioral effects. Mental health challenges disproportionately affect individuals with PAE and are related to brain alterations. Cortical folding (gyrification) is associated with mental health in clinical populations and may help understand mental health difficulties in individuals with PAE. 161 datasets from 125 youth (57 PAE, 59 females) aged 7–21 years were included. T1-weighted magnetic resonance imaging and the caregiver-report Behavior Assessment System for Children were collected at baseline and 2-year follow-up. Images were processed to extract local gyrification index (LGI) from 20 mental health-related regions. Linear mixed-effects models were used to test the effect of PAE on associations between LGI and mental health symptoms. Youth with PAE had more Externalizing Problems (60.7 ± 15.5) than unexposed youth (54.8 ± 11.1; p < 0.001). PAE moderated the relationship between Internalizing Problems and LGI in the left posterior orbital gyrus and the left subcallosal area, and between Externalizing Problems and LGI in the right frontal pole and left subcallosal area. Higher LGI was associated with higher Internalizing and Externalizing Problems in participants with PAE; this association was weaker or absent in unexposed youth. This indicates a potential neurobiological basis for mental health challenges in individuals with PAE.
Brain entropy (BEN) reflects temporal complexity of spontaneous neural activity, quantified using sample entropy of fMRI signals. The neural mechanisms underlying nonpharmacological treatments for depression remain incompletely understood. We used BEN to characterize treatment-related changes in neural complexity in mild-to-moderate depression. Resting-state fMRI data from 29 medication-free patients and 20 matched healthy controls (HCs) were analyzed from two public datasets (ds003007, ds002748). Among patients, 14 received cognitive-behavioral therapy (CBT, n = 8) or real-time fMRI neurofeedback (NFB, n = 6), while 15 remained untreated. Baseline BEN differences between patients and HCs were identified using two-sample t-tests, and significant regions served as regions of interest (ROIs). Repeated-measures ANOVA examined longitudinal BEN changes. Compared with HCs, patients showed higher baseline BEN in left dorsomedial prefrontal cortex (DMPFC), left amygdala/putamen, and right hippocampus/parahippocampal cortex. Following treatment, the treated group showed reduced BEN across all ROIs and decreased Beck Depression Inventory scores, whereas untreated patients showed no significant changes. Post-treatment BEN in the left DMPFC and left amygdala/putamen was no longer significantly different from HCs. These findings suggest CBT and NFB are associated with altered neural complexity within prefrontal-limbic network; BEN may represent an exploratory neuroimaging marker for tracking treatment-related neural changes in depression.
Major depressive disorder (MDD) is increasingly characterized as a disorder of brain dynamics, but the temporal scale on which resting-state activity differs from healthy controls remains unclear. We analyzed resting-state fMRI data from 71 participants (51 MDD, 20 controls; OpenNeuro ds002748) using bilateral grid-extracted left–right difference signals projected into a control-defined latent space. Across 30 analysis configurations spanning five denoising pipelines, three latent dimensionalities, and two left–right correction settings, MDD showed reduced mean lag-1 autocorrelation in 24 of 30 configurations (integrated β = −0.0321, p = 0.036) and reduced AR(1) gain φ in 24 of 30 (β = −0.0316, p = 0.037), both robust to adjustment for pipeline, age, sex, and head motion. The broader autocorrelation area under lags 1–10 was not significantly reduced (β = −0.0099, p = 0.22), and lag-by-lag analysis localized the group difference specifically to lag 1. A model-comparison analysis identified AR-gain reduction as one of three competing candidate generative transformations rather than the unique winner. MDD is thus associated with a focal short-lag autoregressive carry-over reduction, a candidate latent-dynamical phenotype rather than a fully identified mechanism.
