Aug 2026· Asian Journal of Psychiatry· Vol 123, pp.
105112
· 0 citations· 60 references
Medicine
TL;DR
The findings show that first-episode drug-naïve or minimally treated schizophrenia patients are characterized by disrupted intrinsic neural timescales with distinct cortical-subcortical alterations, which may represent a candidate neurobiological marker of early-stage schizophrenia.
Abstract
Background
The neuropathological mechanisms of schizophrenia remain unclear. Intrinsic neural timescale (INT) reflects the temporal organization of neural activity. This study aimed to characterize INT alterations in patients with first-episode schizophrenia who were drug-naïve or minimally treated, while minimizing confounding effects of chronic illness and medication exposure.
Methods
Resting-state fMRI data were collected from 123 first-episode, drug-naïve or minimally treated schizophrenia patients and 102 matched healthy controls. INT values were derived from the autocorrelation function of the fMRI signal. Group differences in INT were assessed using analysis of covariance (ANCOVA), controlling for age, gender and scanner site. Additional analyses included correlation analyses, gene annotation and enrichment analyses, and spatial correlation analyses.
Results
Patients exhibited a divergent cortical-subcortical pattern, characterized by reduced cortical INT and prolonged subcortical INT. Compared with healthy controls, patients showed significant INT alterations in 13 regions of interest (p-fdr < 0.05), predominantly involving the default mode network (5 regions) and subcortical network (4 regions), as well as the sensorimotor network, memory retrieval network, salience network, and ventral attention network. Regions with altered INT were enriched for synapse-related genes, and their spatial distribution was correlated with cerebral blood flow.
Conclusions
Our findings show that first-episode drug-naïve or minimally treated schizophrenia patients are characterized by disrupted intrinsic neural timescales with distinct cortical-subcortical alterations. These abnormalities may be related to cerebral perfusion, synaptic function and symptom severity. The distinct cortical-subcortical alterations of INTs may represent a candidate neurobiological marker of early-stage schizophrenia.
BACKGROUND
Subcortical regions are widely implicated in the pathological mechanisms and treatment of schizophrenia, and accumulating evidence, including our prior findings, suggests that subcortical functional dysconnectivity is closely associated with treatment response. Accordingly, the present study aimed to examine the relationship between the subcortical functional connectivity (FC) and treatment outcomes in schizophrenia using multivariate analytical approaches and machine learning algorithms.
METHODS
One hundred and nineteen individuals with first-episode schizophrenia were recruited for this study. All patients underwent MRI scanning and completed assessments with the Positive and Negative Syndrome Scale (PANSS) at baseline and at follow-up after 12 weeks of antipsychotic medication. We employed partial least squares analysis to explore the multivariate associations between changes in subcortical FC (∆FC) and changes in symptom severity (∆PANSS). In addition, a machine learning algorithm was used to predict the antipsychotic treatment outcome based on the distinctive subcortical FC pattern at baseline.
RESULTS
We identified a distinctive subcortical FC pattern dominated by the striatum that was associated with overall treatment outcomes in first-episode schizophrenia. Furthermore, the reduction in PANSS total scores predicted using baseline subcortical FC patterns was positively correlated with the actual reduction in PANSS total scores following antipsychotic treatment.
CONCLUSION
These results indicate that the distinctive subcortical FC pattern holds promise as a biomarker for schizophrenia, supporting individualized treatment approaches and facilitating early intervention to improve clinical outcomes.
C. Hou, Huan Huang, Sisi Jiang et al.· Schizophrenia Research· 0 citations
Abstract Background While abnormal spontaneous neural activity within cortico-striatal circuits is a hallmark feature of schizophrenia, a significant subset of patients presents with treatment-resistant schizophrenia (TRS), characterized by persistent severe symptoms despite multiple standard treatments. Clozapine remains the only effective pharmacological option for TRS, yet its unique mechanism of action on brain function is not fully understood. Although functional and structural abnormalities within these circuits have been frequently noted in TRS patients, longitudinal neurobiological studies assessing the impact of clozapine initiation on intrinsic brain activity and its correlation with clinical improvement are scarce. Aims & Objectives We aimed to investigate the divergent longitudinal trajectory of spontaneous brain activity by comparing TRS patients commencing clozapine with non-treatment-resistant schizophrenia (NTRS) patients maintained on standard medication over the same period, thereby seeking neural substrates specifically related to clozapine treatment efficacy and associated symptomatic changes. Method Both the TRS and NTRS groups (30 patients each) were included in this longitudinal investigation. Resting-state functional magnetic resonance imaging scans were acquired at baseline and after an 18-week follow-up. Changes in the fractional amplitude of low-frequency fluctuations (fALFF), a metric of spontaneous neural activity, were quantified. Clinical symptoms were evaluated concurrently using the positive and negative syndrome scale (PANSS). We assessed the group × time interaction on fALFF and examined correlations between fALFF alterations and PANSS score changes within the interacting region. Results No significant demographic differences (gender or age) were observed between the groups. A significant group × time interaction effect on fALFF was identified in the left inferior parietal cortex (IPC), indicating that the pattern of change in spontaneous brain activity over 18 weeks was significantly different between the two groups. Specifically, fALFF values in the IPC increased in the TRS group following clozapine commencement, whereas they decreased in the NTRS group over the follow-up period. Analysis of both groups combined revealed a negative trend between changes in IPC fALFF value and changes in total PANSS. Discussion & Conclusions The initiation of clozapine treatment in TRS is linked to a divergent longitudinal trajectory of spontaneous brain activity within the inferior parietal cortex (IPC). This differential fALFF change suggests that pharmacological factors unique to clozapine may critically influence IPC function, a region pivotal for attention and reality monitoring. Our findings provide novel neurobiological evidence specifically concerning the longitudinal effect of clozapine in TRS and highlight the IPC as a key region associated with therapeutic outcomes. Further studies are required to fully elucidate the mechanism by which clozapine modulates IPC activity and its long-term functional implications.
W. Jung, E. Kim· International Journal of Neu...· 0 citations
A multiscale pathophysiological framework involving brain connectivity dynamics, molecular architecture, and neurochemical regulation in patients with MDD is supported, suggesting a role for inhibitory neurotransmission in temporal integration deficits.
Xiang Liu, Yuanzhi He, Li-Feng Li et al.· BMC Psychiatry· 0 citations
Schizophrenia is a severe psychiatric disorder marked by widespread brain abnormalities. Recent studies suggest that pathological changes may originate from focal 'epicenter' regions and subsequently spread to other brain areas strongly connected to them. Investigating drug-naïve first-episode schizophrenia (dn-FES) patients may help characterize early-stage regional functional abnormalities and their potential neurochemical underpinnings. Resting-state functional magnetic resonance imaging data were acquired from 50 dn-FES patients and 50 age- and sex-matched healthy controls (HCs). Static regional homogeneity (sReHo) and dynamic ReHo (dReHo) were compared between groups, and correlations with psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We further used the JuSpace toolbox to test whether spatial patterns of ReHo alterations were associated with specific neurotransmitter receptor/transporter densities. Compared with HCs, dn-FES patients showed reduced sReHo in the bilateral postcentral/precentral gyri, bilateral paracentral lobules and right supplementary motor area, and increased dReHo in the left lingual gyrus. sReHo in the right postcentral gyrus was inversely correlated with PANSS positive scores, whereas dReHo in the left lingual gyrus was negatively correlated with PANSS general scores. Schizophrenia-related sReHo alterations showed significant spatial associations with serotonergic, dopaminergic, noradrenergic and cholinergic systems, whereas dReHo alterations were associated with serotonergic, dopaminergic, cannabinoid and opioid systems. Taken together, this study identifies abnormal static and dynamic local functional connectivity in sensorimotor and visual regions in drug-naïve first-episode schizophrenia, and the spatial correspondence between these alterations and receptor/transporter distributions may offer insight into the molecular substrates associated with these functional abnormalities.
Ziyu Wang, Kangkang Xue, Yan Zhang et al.· Progress in Neuro-psychophar...· 0 citations
Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.
K. A. Mignondje, J. Connolly, A. Beermann et al.· medRxiv· 0 citations
Patients with psychosis and depression show widespread alterations in brain resting-state functional connectivity (rs-FC), affecting both sensory and higher-order brain regions. In this study, we investigate disruptions in the hierarchical organization of brain functional networks in patients with psychotic and affective disorders. We derived functional brain gradients, low dimensional representations of rs-FC that capture cortical hierarchy, in a large patient sample including clinical high-risk for psychosis (CHR-P) patients, recent-onset psychosis (ROP) patients, recent-onset depression (ROD) patients, and healthy controls (HC). We examined regional alterations, network-level alterations and functional differentiation and their relationship to clinical symptoms. In addition, we linked case-control differences to receptor expression maps to explore underlying neurobiological mechanisms. All patient groups exhibited alterations in the visual-to-sensorimotor gradient, while only ROP patients showed alterations in the association-to-sensory gradient. CHR-P and ROP patients exhibited lower values in the ventral attention network. Additionally, patients combined showed higher values in the somatomotor network, a reduced gradient range and altered between-network dispersion. ROD showed reduced within-network dispersion in the attentional networks and a reduced range. Correlational analysis revealed weak associations of gradient measures with functioning, visual dysfunctions and cognition. Furthermore case-control differences showed associations to receptor expression maps, suggesting the involvement of neurotransmitter systems in these disruptions. Our findings reveal transdiagnostic and disease-specific alterations of hierarchical brain organization. These alterations indicate deficits in functional integration across psychiatric diseases, highlighting the role of attentional and sensory networks in disease processes.
Hannah Hacker, L. Hoheisel, M. Buciuman et al.· Research Square· 0 citations
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