Alterations in static and dynamic intrinsic brain local connectivity and associated molecular analysis in drug-naïve first-episode schizophrenia: Insights from resting-state functional magnetic resonance imaging.
Jul 2026· Progress in Neuro-psychopharmacology and Biological Psychiatry· pp.
111863
· 0 citations· 121 references
Medicine
Abstract
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.
OBJECTIVE
Idiopathic REM sleep behavior disorder (iRBD) is a well-established prodromal manifestation of α-synucleinopathies, and patients without hyposmia may represent an early stage of the "body-first" Parkinson's disease (PD) subtype. This study aimed to investigate brain functional network alterations in hyposmia-free iRBD patients and validate the hypothesis of early cortical compensatory mechanisms.
METHODS
Data were retrieved from the Parkinson's Progression Markers Initiative (PPMI) database. Thirty-seven hyposmia-free iRBD patients and 37 demographically matched healthy controls (HCs) were included. Degree centrality (DC) analysis to identify functional hub alterations, and seed-based functional connectivity (FC) analysis using differentially expressed DC regions as regions of interest.
RESULTS
Compared with HCs, iRBD patients exhibited significantly increased DC values in the left superior frontal gyrus. Seed-based FC analysis revealed enhanced connectivity between the Frontal_Sup_2_L and multiple cortical regions, including prefrontal subregions, temporal gyri, and sensorimotor areas. Within the iRBD group, the mean FC strength between the Frontal_Sup_2_L and its differentially connected brain regions was negatively correlated with RBDSQ scores (r = -0.360, p = 0.029).
CONCLUSIONS
Our findings suggest that hyposmia-free iRBD patients exhibit compensatory reorganization of brain functional networks centered on the left superior frontal gyrus, supporting the early cortical compensation hypothesis in the "body-first" α-synucleinopathy subtype. Stratification by both the presence and timing of hyposmia relative to RBD onset is critical for reconciling inconsistent rs-fMRI findings in iRBD.The DC value of the left Frontal_Sup_2_L and its FC with extensive cortical regions represent candidate imaging indicators for prodromal α-synucleinopathies, whose clinical utility requires prospective validation in larger independent cohorts with longitudinal designs.
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
Disruptions in the hierarchical organization of brain functional networks in individuals with psychotic and affective disorders 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.· Translational Psychiatry· 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
The clinical high-risk (CHR) state identifies individuals at elevated risk for psychosis, yet neurobiological markers of vulnerability remain incompletely characterized, particularly in African populations. Functional Network Area and Topography Analysis (FUNCATA) quantifies individualized network size and spatial organization, addressing limitations of group-average parcellations. Prior studies in schizophrenia identified dorsal attention network (DAN) enlargement and topographic abnormalities. We applied FUNCATA to a Kenyan CHR cohort to examine whether similar alterations are detectable. Twenty-four healthy controls and 63 CHR participants (ages 18-26) underwent resting-state fMRI in Nairobi. Individualized functional networks were derived using template matching. Network size and Topographic Abnormality Index (TAI) were compared between groups using ANCOVA. Associations with symptom dimensions (BPRS-derived principal components), global functioning, cognition, and longitudinal symptom trajectories were examined. CHR participants demonstrated modest left-lateralized DAN enlargement (d = 0.61) and reduced salience network (SAL) size (d = 0.50). More robust effects emerged for TAI, with significantly elevated spatial abnormalities across multiple networks, most prominently the DAN (d = 1.18), default mode network (d = 0.91) and cingulo-opercular network (d = 0.80). Larger left DAN size was associated with longitudinal worsening of general psychopathology, while SAL size was associated with unusual thought processing and role functioning. TAI measures showed limited associations with clinical outcomes after correction. These results suggest that functional network enlargement and spatial reorganization are detectable in CHR individuals within a non-Western cohort. DAN enlargement and widespread topographic abnormalities may represent early neurobiological features of psychosis vulnerability. TAI appears particularly sensitive to spatial deviations and may serve as a promising biomarker for risk stratification and longitudinal monitoring.
D. Mamah, ShingShiun Chen, Michael P. Harms et al.· NeuroImage: Clinical· 0 citations
Dopaminergic signalling is critical for regulating large-scale brain network dynamics and is implicated in the pathophysiology of psychotic disorders. 22q11.2 deletion syndrome (22q11DS), a high-penetrance genetic risk factor for schizophrenia, is associated with both dopaminergic alterations and disruptions in functional connectivity (FC), yet the degree to which these separate people with 22q11DS from healthy controls and their inter-relationship remains unclear. Eighteen individuals with 22q11DS (no history of psychosis or antipsychotic use) and 22 controls underwent [18F]-DOPA PET imaging to assess striatal dopamine synthesis (indexed by Kicer values) and resting-state fMRI to examine FC. Classification performance using FC, dopamine measures, and their combination was assessed via repeated 10-fold cross-validation. Associations between Kicer, connectivity, and psychotic symptoms were evaluated using linear regression. FC alone classified 22q11DS with 68% balanced accuracy (p = 0.004), Kicer alone with 77% (p < 0.001), and combined measures with 85% balanced accuracy (p < 0.001), indicating additive value. The somatomotor and auditory networks contributed most to group discrimination. Across individuals, higher Kicer was significantly associated with more control-like connectivity profiles (p = 0.011), with significant effects in all striatal subdivisions. No association was found between FC and subclinical psychotic symptoms. This multimodal study demonstrates a significant association between striatal dopamine synthesis capacity and functional brain network architecture in 22q11DS. Higher dopamine synthesis was linked to more normative FC, potentially suggesting FC differences reflect a compensatory, rather than pathogenic role. These findings bridge genetic risk at the 22q11.2 locus with dopamine dysfunction and large-scale networks, offering novel insights into the neurobiology of 22q11DS and related neuropsychiatric risk.
V. Mancini, M. Rogdaki, S. Jauhar et al.· Molecular Psychiatry· 0 citations
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