Biology subjects

Amir, C. M.

Publications and source records attributed to Amir, C. M..

3 recordsLinked to original sources

bioRxiv2026

Symptom Dimension-Specific Neurotransmitter Correlates of Psychopathology and Cognition in Early Psychosis

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; {rho}=.40, q=.030) and vesicular acetylcholine transporter (VAChT; {rho}=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT ({rho}=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

neuroscience↗

bioRxiv2025

Convergent and Divergent Cerebellar Alterations in 22q11.2 Copy Number Variants

BackgroundIndividuals with copy number variants (CNVs) at 22q11.2 are at elevated risk for neurodevelopmental and psychiatric disorders, including autism spectrum disorder and intellectual disability. For psychosis, effects diverge, with 22q11.2 deletion (22qDel) conferring one of the highest known risks for schizophrenia, while duplication (22qDup) may be protective. Prior investigations of neurobiological mechanisms in 22q11.2 CNVs have predominantly focused on the cerebrum, whereas the cerebellum--a region increasingly recognized for its contributions to cognitive, affective, and social processes--remains underexplored and represents a promising target for investigation. Although alterations in cerebellar structure have been reported in 22qDel, they remain largely unexplored in 22qDup. This study provides the first characterization of regional cerebellar volumes in 22qDup and the first direct comparison of cerebellar structure across 22q11.2 CNVs, offering a unique opportunity to identify shared and distinct neurobiological mechanisms with implications for understanding cerebellar contributions to brain-behavior relationships in CNV carriers. MethodsWe analyzed 514 longitudinally collected structural Magnetic Resonance Imaging (MRI) scans of 111 individuals with 22qDel, 37 individuals with 22qDup, and 167 typically developing (TD) controls. Total and regional cerebellar volumes were quantified using ACAPULCO, a deep-learning-based parcellation method that segments the cerebellum into 28 subregions. Group differences in cerebellar volumes, as well as their associations with cognition, autism-related traits, and psychosis-risk symptoms, were examined using linear mixed-effects models. False discovery rate (FDR) correction was applied to control for multiple comparisons where appropriate. ResultsIn relation to TD controls, cerebellar volumes were broadly reduced in 22qDel, whereas cerebellar alterations in 22qDup were more modest and variable. Regional analyses revealed both linear (22qDel < TD < 22qDup) and nonlinear (22qDel {approx} 22qDup < TD; 22qDel < 22qDup < TD) gene-dosage patterns, though not all reached significance. Vermis VII was significantly reduced in both CNVs but showed no relationship to behavioral differences. In contrast, reduction of Right Lobule VIIIA was associated with greater social impairment in 22qDup. Unlike TD controls, this region was not associated with IQ in 22qDup, suggesting CNV-specific alterations in cerebellar-behavior relationships. ConclusionThese findings indicate that reciprocal CNVs at the 22q11.2 locus both affect cerebellar structure, yet their functional consequences diverge, suggesting overlapping but distinct pathways to clinical risk. They underscore the cerebellums multifaceted role in neurodevelopment and highlight the need for studies examining broader cognitive and socio-affective domains, as well as cerebellar-cortical connectivity, to clarify links to clinical outcomes.

neuroscience↗

bioRxiv2024

Unique functional neuroimaging signatures of genetic versus clinical high risk for psychosis

Background22q11.2 Deletion Syndrome (22qDel) is a copy number variant (CNV) associated with psychosis and other neurodevelopmental disorders. Adolescents at clinical high risk for psychosis (CHR) have subthreshold psychosis symptoms without known genetic risk factors. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped results to biological pathways. MethodsWe analyzed two large multi-site cohorts with resting-state functional MRI (rs-fMRI): 1) 22qDel (n=164, 47% female) and typically developing (TD) controls (n=134, 56% female); 2) CHR individuals (n=244, 41% female) and TD controls (n=151, 46% female) from the North American Prodrome Longitudinal Study-2. We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions, testing case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation. ResultsBSV, LC, and GBC are significantly disrupted in 22qDel compared with TD controls (False Discovery Rate q<0.05). Spatial maps of BSV and LC differences are highly correlated with each other, unlike GBC. In CHR, only LC is significantly altered versus controls, with a different spatial pattern compared to 22qDel. Group differences map onto biological gradients, with 22qDel effects strongest in regions with high predicted blood flow and metabolism. Conclusion22qDel and CHR exhibit divergent effects on fMRI temporal variability and multi-scale functional connectivity. In 22qDel, strong and convergent disruptions in BSV and LC not seen in CHR individuals suggest distinct functional brain alterations.

neuroscience↗