Emotion regulation relies on the interplay between prefrontal and limbic brain regions, with prefrontal regions implicated in the top-down modulation of the amygdala. In social anxiety disorder, disruptions in these networks have been reported, but most studies used undirected functional connectivity.

Dynamic causal modelling (DCM) was used to assess effective (i.e. directed) connectivity differences during emotion processing and regulation in individuals with social anxiety disorder compared with healthy controls.

A total of 102 participants (61 with social anxiety disorder, 41 healthy controls) performed a functional magnetic resonance imaging emotion regulation task under two conditions: viewing neutral/negative faces, and downregulating emotions using a self-chosen strategy. DCM was applied to model effective connectivity among the amygdala and key prefrontal regions. Connectivity patterns were characterised in healthy controls, and group comparisons tested how social anxiety disorder differed from this baseline model using parametric empirical Bayes. Leave-one-out cross-validation (LOOCV) evaluated whether connectivity differences predicted diagnostic group, symptom severity and emotion regulation difficulties.

In healthy controls, observation of negative faces was characterised by reciprocal influences between the amygdala and prefrontal cortex (PFC), including increased amygdala-to-ventromedial PFC (vmPFC) connectivity and inhibitory vmPFC-to-amygdala connectivity. During emotion regulation, healthy controls showed negative modulation from the amygdala to all prefrontal regions. Patients with social anxiety disorder did not differ from controls in amygdala–prefrontal connectivity; their alterations were confined to prefrontal circuits, with inhibitory connectivity from the pre-supplementary motor area (preSMA) to dorsolateral PFC during observation and bidirectional excitatory connectivity between the preSMA and vmPFC during regulation. LOOCV indicated that connectivity differences predicted diagnostic group.

The results support the idea that emotion processing and regulation influence connectivity between prefrontal areas and the amygdala in a complex, feedback-driven manner. Our findings suggest that aberrant emotion regulation in social anxiety disorder appears to be more closely linked to differences in intra-prefrontal circuits than deficits in amygdala–prefrontal connectivity.

We need to identify novel, tractable therapeutic targets for anxiety disorders. Converging evidence suggests the endogenous opioid system plays a role in modulating affective processing, but its contribution to regulation of threat processing in humans remains unclear.

We investigated the neural correlates of non-specific opioid antagonism on explicit and implicit regulation of threatening stimuli in healthy volunteers, using functional magnetic resonance imaging (fMRI).

In a randomised, double-blind, placebo-controlled, crossover design, 38 healthy participants received the opioid antagonist naltrexone (50 mg) or placebo before completing two tasks during fMRI: (a) a cognitive emotional reappraisal task probing explicit regulation and (b) a face-viewing task probing implicit processing.

Contrary to our hypothesis, we found naltrexone reduced distress ratings during the reappraisal task (p = 0.044) without impairing regulation success. Explicit regulation in the reappraisal task engaged lateral prefrontal regions similarly across drug conditions. However, naltrexone attenuated ventromedial prefrontal cortex, thalamus and caudate activation when viewing negative images. Naltrexone additionally altered ventromedial prefrontal cortex activity and in task-positive regions including right premotor area and frontal pole compared with placebo when viewing emotional faces. In particular, naltrexone increased left middle frontal gyrus activity when viewing fearful faces.

Our results support a role for opioid signalling in automatic emotional regulation, but not in explicit regulation. Furthermore, naltrexone appeared to diminish activity in task-positive regions in response to emotional faces. These findings are consistent with a model where endogenous opioids ‘fine-tune’ affective responses to both negative and positive stimuli. Future research should explore dose–response effects, kappa-opioid contributions and whether similar results are seen in clinical populations.

People with schizophrenia develop more chronic diseases at a younger age and die younger than people in the general population. It has been hypothesized that this excess morbidity and mortality could be partially due to accelerated aging in schizophrenia. If true, this would motivate the development of ‘gero-protective’ interventions to reduce chronic disease burden in schizophrenia. However, it has been difficult to test this hypothesis, in part, due to the limited ability to measure aging in samples of people with schizophrenia.

We utilized a novel neuroimaging biomarker of the longitudinal pace of aging, DunedinPACNI, to test for accelerated whole-body aging in schizophrenia across four neuroimaging datasets (total N = 2,096, 48% female) accessed through the Lieber Institute for Brain Development, the University of Bari Aldo Moro, and the North American Prodrome Longitudinal Study – 3.

We found consistent evidence of faster DunedinPACNI in schizophrenia compared with controls. In contrast, youth at clinical-high risk for psychosis did not have faster DunedinPACNI compared to controls. Unaffected siblings of patients also did not have faster DunedinPACNI than controls. Faster DunedinPACNI in schizophrenia was not explained by tobacco smoking or antipsychotic medication use.

The results support the hypothesis that schizophrenia is accompanied by accelerated aging. Results were inconsistent with some of the most obvious explanations for accelerated aging in schizophrenia (familial risk, smoking, and iatrogenic medication effects). Research should aim to uncover why people who have schizophrenia age rapidly, as well as the utility of early disease-risk monitoring and anti-aging interventions in schizophrenia.

Understanding the neuroanatomical correlates of treatment response in schizophrenia is crucial for improving clinical stratification and clarifying underlying pathophysiological mechanisms.

To examine subcortical volumetric differences across clinically defined schizophrenia treatment-response subgroups.

T1-weighted structural magnetic resonance imaging data were analysed from 109 participants, including 79 individuals with schizophrenia and 30 healthy controls. Patients were categorised into three distinct treatment response groups: ultra-treatment-resistant (UTR; n = 22), clozapine-responsive (n = 28) and first-line antipsychotic responsive (FLR; n = 29). Group differences were examined across 33 regions of interest, including subcortical, ventricular and hippocampal subfield regions.

The UTR group had higher antipsychotic dosages and exhibited greater symptom severity than other patient groups. Across all schizophrenia subgroups, hippocampal and amygdala volumes were smaller relative to controls. Treatment-resistant patients (UTR and clozapine-responsive) also showed reduced nucleus accumbens volumes, whereas FLR patients demonstrated larger pallidal volumes. In addition, the UTR subgroup exhibited enlarged lateral ventricles. Hippocampal subfield analyses revealed widespread reductions in treatment-resistant patients, most prominently in the CA4/dentate gyrus, subiculum and stratum, whereas FLR patients showed more focal reductions in the CA4/dentate gyrus and left subiculum.

These results suggest that smaller hippocampal and amygdala volumes represent a shared neuroanatomical signature of schizophrenia, whereas reduced accumbens and enlarged pallidal volumes may differentiate treatment-resistant and treatment-responsive profiles, respectively. The findings underscore the heterogeneity of schizophrenia and highlight the need for longitudinal research to disentangle illness-related pathology from medication effects.

Avoidant/restrictive food intake disorder (ARFID) leads to faltering growth and psychosocial impairment. Three phenotypes can co-occur: fear of aversive consequences of eating (ARFID-fear phenotype), sensory sensitivity, and lack of interest in eating/food. We hypothesized that youth with ARFID, especially ARFID-fear phenotype, would show hyperactivation of fear-related regions in response to ARFID-specific fear images, compared to healthy controls (HC), and activation of these regions would positively correlate with ARFID fear severity.

Youth (N=103: 76 ARFID, including 20 ARFID-fear phenotype; 27 HC) underwent functional MRI scanning while viewing ARFID-specific fear (e.g. vomiting, choking) versus neutral images. We compared blood-oxygen-level-dependent (BOLD) response in fear-related region of interests (ROI; e.g. amygdala, hippocampus, insula) between ARFID and ARFID-fear phenotype versus HC. We evaluated the association between brain response and ARFID fear severity in ARFID-fear phenotype.

Across individuals, there was a robust bilateral amygdala response to ARFID-specific fear versus neutral images. Compared to HC, ARFID-fear phenotype showed a greater insula response to ARFID-specific fear versus neutral images (p=0.049). There were no other group differences and no significant relationships between BOLD response and ARFID fear severity in ARFID-fear phenotype.

ARFID-specific fear images elicit amygdala responses across individuals, with greater activation in the insula only in ARFID-fear phenotype versus HC. These findings validate the ARFID-specific fear paradigm and highlight the intriguing possibility that, in the ARFID-fear phenotype, universally feared experiences such as choking and vomiting serve as the unconditioned stimulus in developing ARFID and may partially be mediated by the insular cortex.

The dysconnection hypothesis of schizophrenia posits that widespread synaptic inefficiencies lead to altered macroscale brain connectivity, contributing to symptom severity and cognitive deficits in individuals with schizophrenia spectrum disorders (SSD). Emerging evidence suggests that physical exercise may help to ameliorate these connectivity abnormalities and associated clinical impairments.

This study investigated whether reductions in functional dysconnectivity following exercise therapy were associated with clinical improvements in individuals with SSD. In addition, it explored the genetic underpinnings of these changes using imaging transcriptomics.

Using data from the ESPRIT C3 trial, we analysed 23 SSD patients (seven female) undergoing aerobic exercise or flexibility, strengthening and balance training over 6 months. Functional dysconnectivity, assessed at baseline and post-intervention relative to a healthy reference sample (n = 200), was evaluated at the whole-brain, network and regional levels. Linear mixed effect models and voxel-wise Pearson’s correlations were used to assess exercise-induced changes and clinical relevance.

Functional dysconnectivity significantly decreased (d = −2.73, P < 0.001), and this decrease was primarily linked to enhanced oligodendrocyte-related gene expression. Reductions in the default-mode network were correlated with improved global functioning, whereas changes in insular regions were associated with symptom severity and functioning. Dysconnectivity reductions in somatomotor and frontoparietal networks were correlated with total symptom improvements, and changes in language-related regions (e.g. Broca’s area) were linked to cognitive benefits.

Our findings support the role of oligodendrocyte pathology in SSD and suggest that targeting dysconnectivity in the default-mode, salience and language networks may enhance global functioning, symptom severity and cognitive impairments.

Structural abnormalities in cortical and subcortical brain regions are consistently observed in schizophrenia; however, substantial inter-individual variability complicates identifying clear neurobiological biomarkers. The Person-Based Similarity Index (PBSI) quantifies individual structural variability; however, its applicability across schizophrenia stages remains unclear. This study aimed to compare cortical and subcortical structural variability in recent-onset and chronic schizophrenia and explore associations with clinical measures.

Neuroimaging data from 41 patients with recent-onset schizophrenia, 32 with chronic schizophrenia, and 59 healthy controls were analysed. The PBSI scores were calculated for cortical thickness, surface area, cortical grey matter volume, and subcortical volumes. Group differences in PBSI scores were assessed using linear regression and analysis of variance. Correlations between the PBSI scores and clinical measures were also examined.

Both patients with recent-onset and chronic schizophrenia exhibited significantly lower PBSI scores than healthy controls, indicating greater morphometric heterogeneity. However, significant differences between the recent-onset and chronic patient groups were limited to subcortical and cortical thickness PBSI scores. Correlations between PBSI scores and clinical symptoms are sparse and primarily restricted to surface area variability and symptom severity in patients with recent-onset schizophrenia.

Patients with schizophrenia show marked structural brain heterogeneity compared with healthy controls, which is detectable even in the early stages of the illness. Although there were few differences in PBSI scores between the recent-onset and chronic schizophrenia groups and limited correlations between PBSI scores and clinical measures, the PBSI may still provide valuable insights into individual differences contributing to clinical heterogeneity in schizophrenia.