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Chopra, S.

Publications and source records attributed to Chopra, S..

At least 19 recordsLinked to original sources
bioRxiv2026

Extracellular GPX3 drives insulin receptor expression in adipose tissue independent of its peroxidase activity

Obesity-associated insulin resistance is driven in part by adipose tissue dysfunction and oxidative stress, yet the role of extracellular mechanisms in modulating insulin signaling remains poorly understood. Here, we show that extracellular Glutathione Peroxidase 3 (GPX3) enhances adipocyte insulin sensitivity and functionalities independent of its canonical peroxidase function. GPX3, a secreted selenoprotein highly expressed in white adipose tissue (WAT), is suppressed in obesity, but whether it actively regulates insulin sensitivity had not been established. We find that WAT GPX3 expression closely mirrors insulin receptor (InsR) expression across a broad range of metabolic parameters in humans and increases dynamically following weight loss. Prolonged therapeutic selenium supplementation in diet-induced obese mice selectively suppressed epididymal WAT oxidative damage, restored GPX3 and InsR expression, and enhanced insulin-stimulated AKT phosphorylation, improving oral glucose tolerance. Mechanistically, recombinant GPX3 extracellularly administered at physiological concentrations induced InsR expression across multiple adipocyte models, including pre-adipocytes, epididymal WAT explants, and adipocyte organoids, by promoting binding of the transcription factor Specificity Protein 1 (SP1) to the Insr promoter, while knockdown of GPX3 completely blocks SVF adipogenesis. These effects rely on the structural integrity, rather than selenocysteine-dependent activity. Thus, we identify a GPX3-SP1-InsR signaling axis in adipose tissue insulin sensitivity, suggesting GPX3 is a novel paracrine mediator of metabolic health and a potential therapeutic target to reinstate WAT insulin sensitivity in obesity and type 2 diabetes.

physiology↗
bioRxiv2026

Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation

Phagocytosis, a central process in innate immunity, depends on dynamic lipid remodelling, yet how cholesterol accumulates on late phagosomes remains unresolved. Here, we identify lysosomal acid lipase (LIPA) as a key cholesterol ester (CE) hydrolase driving cholesterol mobilization during phagosomal maturation. Using integrated lipidomics, chemoproteomics, and biochemical assays, we show that LIPA exhibits acidic CE hydrolase activity enriched on late phagosomes, generating free cholesterol essential for lipid raft formation. Pharmacologically inhibiting LIPA disrupts cholesterol-rich lipid raft assembly, impairs phagosomal trafficking, and alters pathogen fate - enhancing Staphylococcus aureus persistence, while restricting Mycobacterium tuberculosis survival. These findings reveal that LIPA couples cholesterol metabolism to phagocytosis, defining a mechanistic link between lipid catabolism and antimicrobial defence. By positioning CE hydrolysis as a critical determinant of phagosomal dynamics, our work uncovers a metabolic checkpoint in innate immunity and identifies LIPA as a potential therapeutic node in infection and inflammation.

biochemistry↗
bioRxiv2026

The Gp78 ubiquitin E3 ligase drives mitophagy by regulating omegasome formation

Autophagy is initiated at endoplasmic reticulum (ER)-associated omegasomes, yet how the ER contributes to mitochondrial cargo degradation during early autophagosome formation remains unclear. Gp78 is an ER-resident RING E3 ubiquitin ligase involved in ER-associated degradation (ERAD) that also promotes Parkin-independent mitophagy. However, the spatial relationship between Gp78 ubiquitin ligase activity, omegasome formation, and mitochondrial degradation has yet to be defined. Combining targeted mitochondria labeling and super-resolution STED microscopy, we show that the Gp78 ubiquitin ligase is localized to and regulates DFCP1-positive omegasome formation, where it drives mitochondrial protein breakdown. Using fluorescent mitophagy reporters and acute ivermectin-induced mitophagy, generation of mitophagy intermediates lacking mitochondrial outer membrane (TOMM20) was found to be dependent on the Gp78 RING finger as well as the BAG6-UBL4A-USP13 ubiquitin-ligase module, and independent of PINK1 and Parkin. Object-based analysis of 3D STED images further showed that both DFCP1- and LC3-positive structures associate primarily with intact mitochondrial fragments which show progressive degradation of mitochondrial content. Gp78 localizes to and promotes, via BAG6, the formation of DFCP1-positive omegasomes and mitochondrial protein degradation in these early autophagic structures. ER-derived omegasome biogenesis is therefore coupled to Gp78-dependent ubiquitin ligase activity and local degradation of mitochondrial cargo during mitophagy.

cell biology↗
bioRxiv2026

A cuffed CRISPR guide RNA for microRNA activity-dependent genome editing

Cells in multicellular eukaryotic systems are diverse biological units, with characteristics and functions determined by their molecular profiles. CRISPR-Cas9 genome editing has been widely used across biology to modulate gene expression and study gene function. However, there is currently no versatile and scalable method for editing a cells genome in response to endogenous cellular signals. Here, we report the engineering of a CRISPR guide RNA that efficiently confers genome editing in response to the catalytic activity of a target microRNA (miRNA) within a cell. miRNAs are short non-coding RNAs that are widely conserved across eukaryotes and can cleave their target RNA through almost perfect base pairing. In mammals, miRNAs are largely involved in development and homeostasis as well as disease progression and developmental disorders. To leverage these properties for genome editing, we developed a cuffed guide RNA (cgRNA) which is composed of a permutated order of sequence domains from the commonly used single guide RNA (sgRNA). These permutated domains were then concatenated with a miRNA target sequence, yielding a warped guide RNA that is inactive until cleaved by a complementary miRNA. We demonstrated that cgRNA enabled efficient miRNA activity-dependent genome editing in human and mouse cell lines. Biochemical and structural analyses revealed three stages of inhibition of the CRISPR genome-editing pathway for unprocessed cgRNA. Utilizing a lentiviral library of cgRNAs containing miRNA targets covering mouse genome-wide miRNAs, we identified miRNA cleavage activities and their sequence specificities in mouse embryonic stem cells and during smooth muscle cell differentiation. Furthermore, we showed that endogenous mRNA expression could be irreversibly recorded into a DNA sequence using a cgRNA targeted by a synthetic miRNA repeat. cgRNA is a simple, robust, miRNA activity-gated genome editing system that could facilitate the development of cell state-specific genome editing, the mapping of miRNA activity and gene expression landscapes, and the recording of molecularly determined cell states during the long-term progression of multicellular systems.

bioengineering↗
bioRxiv2026

Population-scale transcriptomics reveals host genetic control of phyllosphere fungal communities

The composition of plant-associated microbial communities plays a central role in host health and agricultural productivity, yet the genetic basis of plant-fungal interactions in the phyllosphere remains poorly understood. Progress has been limited in part by technical challenges in profiling low-abundance fungal communities and linking their variation to host genetics. Here we show that standard polyA-enriched RNA sequencing of plant leaf tissue, without targeted microbial enrichment, captures sufficient fungal transcripts to enable quantitative profiling of metabolically active mycobiomes at scale. Although fungal transcripts represented only 0.03-0.4% of classified reads in standard polyA-enriched leaf RNA-seq datasets, this still yielded >79 million fungal reads across 2,194 field-collected samples (median = 5,260-59,746 reads per sample), enabling robust quantification of several hundred fungal taxa. Leveraging these data, we perform genome-wide association and transcriptome-wide association analyses of fungal relative abundance and identify widespread host genetic control of phyllosphere fungal communities. We detect extensive and biologically structured associations between host genetic variation, gene expression, and fungal abundance across all three crops, including numerous loci with multi-taxon effects and strong colocalization between GWAS and expression quantitative trait loci. Network and module-level analyses further reveal coordinated host transcriptional programs linked to fungal community variation, while integration of orthologous gene sets indicates partial conservation but substantial species specificity in underlying genetic architecture. Together, these results demonstrate that standard RNA-seq datasets contain sufficient ecological signal to enable high-resolution microbiome genetic mapping and reveal that host genetic control of phyllosphere fungal communities is more pervasive than previously appreciated. This framework provides a scalable approach for reusing existing transcriptomic datasets to study plant-microbe interactions across diverse species and environments.

genomics↗
bioRxiv2026

Widespread use of invalid statistical tests in biomedical machine learning

Cross-validation is routinely used to compare performance in biomedical artificial intelligence. Standard tests ignore correlation across cross-validation folds, inflating false-positive rates. In a PRISMA-guided meta-analysis of 184 studies (impact factor [≥] 15) across 30 biomedical fields, 97% use invalid tests. Among studies with abstract-level claims supported by invalid tests, 59% rely on a spurious comparison: one that loses significance after correcting for this correlation. On average, regaining significance requires a 43% larger effect. Extending these findings to the broader literature, we estimate that spurious comparisons occur in nearly two in three studies and support abstract-level claims in nearly one in three studies. Simulations confirm false-positive rates paradoxically approach 100% when cross-validation is repeated to improve stability. We introduce SHARP, a redesign of cross-validation, which best balances false-positive control and power among 13 benchmarked tests. These results reveal widespread fragility in biomedical artificial intelligence and offer a practical route to valid comparisons.

bioinformatics↗
bioRxiv2025

Grey matter embedding of the cholinergic system

Integrity of acetylcholine-producing basal forebrain nuclei Ch1-4 is crucial for neurocognitive functioning and grey matter decline represents a hallmark of neuropsychiatric disorders, including Alzheimers disease, Parkinsons disease and schizophrenia. Approaches that link brain-wide grey matter atrophy with diminished cholinergic innervation from Ch1-4 projections are required for neuroimaging of disease stages and pharmacological decisions addressing cholinergic deficits. The current study assessed human magnetic resonance imaging-based markers for cholinergic nucleus subregions and synaptic targets in healthy exploration (HCP, n = 1113) and replication (IXI, n = 587) cohorts. Ch1-3 and Ch4 were delineated at 50% cytoarchitectonic probability to determine their grey matter coupling patterns using structural covariance analyses. Spatial colocalization with vesicular acetylcholine transporter, M1-muscarinic and 4{beta}2-nicotinic receptor density quantified the correspondence with synaptic cholinergic markers. All individual-level cholinergic nucleus and target region indices showed good test-retest reliability (R [≥] 0.80) when restricted to voxels with at least 10% grey matter probability. Spatial colocalization with presynaptic acetylcholine transporters emphasized a cholinergic nature of Ch1-4 grey matter and its coupling with corticopetal projections such as amygdala, insula and cingulate cortices. Subcortical gradients of M1-muscarinic receptor density and the Ch1-3 structural covariance map, however, dominated in locations of striatal cholinergic interneurons, such as nucleus accumbens, caudate nucleus and putamen. Ch4 covaried with medial thalamus and hippocampus, while both subregions structural covariance networks converged in a posterolateral Ch4 extensions, potentially resembling subputaminal nucleus of Ayala. The results emphasize Ch1-4 morphometry as marker for acetylcholine-driven brain regions and describe neuroimaging strategies to indicate synaptic cholinergic involvement. Significance StatementPrevious studies have suggested that grey matter alterations in basal forebrain Ch1-4 nuclei indicate cholinergic deficits in neurodegenerative and psychiatric pathologies. However, the use of Ch1-4 volume as a marker of cholinergic system integrity has yet to be validated. Additionally, there is a lack of non-invasive procedures to quantify integrity of regions innervated by its cholinergic projections. Our results suggest that grey matter coupling with Ch1-4 is a sensitive cholinergic system marker, mimicking the density distribution of synaptic cholinergic innervation. Furthermore, we introduce grey matter-based target region indices, evaluate their robustness in individual participants and describe regional contributions to M1-muscarinic, 4{beta}2-nicotinic and vesicular acetylcholine transporter gradients. The study advances our understanding of cholinergic circuits in vivo using magnetic resonance imaging.

neuroscience↗
bioRxiv2025

Serum exosome miR-150-5p in rheumatic heart disease-associated angiogenesis

The focus of this study is on Rheumatic heart disease (RHD), an autoimmune consequence of rheumatic fever leading to mitral valve damage. Aim is to explore the role of exosomes derived from RHD patients in promoting angiogenesis during RHD pathogenesis. Exosomes were isolated via column chromatography from the pericardial fluid (PF) and serum of RHD patients, pericardial fluid from non-RHD patients undergoing coronary artery bypass grafting (CABG) surgery, and serum of healthy individuals. These exosomes were characterized by transmission electron microscopy (TEM) and western blotting. Human umbilical vein endothelial cells (HUVECs) cultured from umbilical cord(s), were treated with purified exosomes from RHD, CABG patients or healthy individuals. Exosome treatment induced morphological changes in HUVECs, including elongation and tube-like structure formation. The qRT-PCR gene expression analysis revealed significant upregulation of angiogenic markers (VEGF-A 2.7-fold, MMP2 1.5-fold) and inflammatory cytokine (IL-4 15.17-fold), in HUVECs stimulated with RHD serum exosomes. Conversely, there was downregulation of anti- angiogenic genes (RASA-1 0.65-fold and endostatin 0.4-fold). Notably, elevated levels of miR- 150-5p (34.29 + 9.524-fold mean difference; p= 0.0007) were detected in serum-derived exosomes from RHD patients compared to healthy controls. Stimulation of HUVECs with RHD serum exosomes resulted in reduction in the expression of TP53 (0.227-fold; p= 0.006), a known target of miR-150-5p. Furthermore, transfection of HUVECs with miR-150-5p mimics induced the formation of angiogenic endothelial tubes, underscoring the role of miR-150-5p in promoting angiogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/659484v1_ufig1.gif" ALT="Figure 1000"> View larger version (27K): org.highwire.dtl.DTLVardef@1520e92org.highwire.dtl.DTLVardef@3aa03aorg.highwire.dtl.DTLVardef@ed6e1dorg.highwire.dtl.DTLVardef@1d85231_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗
bioRxiv2025

A Platinum Butterfly Effect: Small Changes Turn an Anticancer Drug into a Non-toxic Metalloantibiotic with In Vivo Efficacy

Widespread resistance to all clinically used antibiotics has sparked investigations into alternative sources for novel and effective antimicrobial agents. Metal-based compounds (metalloantibiotics) have emerged as a promising class of potential antibiotics exhibiting high hit rates against critical bacterial pathogens while not displaying higher toxicity than organic compounds. Here, we describe the exploration of a novel class of non-toxic, Gram-positive acting platinum-based antibacterial agents with micro to nanomolar activity against a range of methicillin and vancomycin-resistant Staphylococcus aureus strains. Structure-activity relationship (SAR) studies revealed that modifications of the core scaffold result in reduced antibacterial activity. Mode of action studies investigations showed that lead compound Pt1 did not impair cell division, RNA, protein, or cell wall synthesis, nor did it affect membrane integrity or potential. Instead, akin to the structurally similar anticancer drug cisplatin (CisPt), Pt1 treatment resulted in reduced DNA staining, visible nucleoid compaction, and activation of DNA damage repair responses. Importantly, we could show that Pt1 is able to interact with and damage DNA directly, resulting in DNA strand breaks and fragmentation. Pt1 activity can be reduced significantly by high amounts of a hydroxyl radical scavenger. Derivative Pt8, which retained DNA-damaging activity but was less potent in terms of antibacterial activity, was not affected by the presence of radical scavengers, suggesting that Pt1 possesses a multimodal mechanism. In line with this observation, no resistance development to Pt1 was observed over the course of 36 passages. Finally, we could demonstrate the in vivo activity of Pt1, which significantly reduced the bacterial load in a murine S. aureus skin infection model. Altogether, these findings shed light on the SAR and antibacterial mode of action of a novel class of platinum metalloantibiotics, validate its in vivo efficacy, and pave the way for further exploration of platinum compounds as novel drug candidates with a highly attractive activity profile.

microbiology↗
bioRxiv2025

Brain network dynamics reflect psychiatric illness status and transdiagnostic symptom profiles across health and disease

The network organization of the human brain dynamically reconfigures in response to changing environmental demands, an adaptive process that may be disrupted in a symptom-relevant manner across psychiatric illnesses. Here, in a transdiagnostic sample of participants with (n=134) and without (n=85) psychiatric diagnoses, functional connectomes from intrinsic (resting-state) and task-evoked fMRI were decomposed to identify constraints on brain network dynamics across six cognitive states. Hierarchical clustering of 110 clinical, behavioral, and cognitive measures identified participant-specific symptom profiles, revealing four core dimensions of functioning: internalizing, externalizing, cognitive, and social/reward. Brain network dynamics were flattened across cognitive states in individuals with psychiatric illness and could be used to accurately separate dimensional symptom profiles more robustly than both case-control status and primary diagnostic grouping. A key role of inhibitory cognitive control and frontoparietal network interactions was uncovered through systematic model comparison. We provide novel evidence that brain network dynamics can accurately differentiate the extent that psychiatrically-relevant dimensions of functioning are exhibited across health and disease.

neuroscience↗
bioRxiv2025

Mechanisms of long term non-reinforced preference change: functional connectivity changes in a longitudinal functional MRI study

Behavioral change studies mostly focus on external reinforcements to modify preferences. Cue-approach training (CAT) is a paradigm that influences preferences by the mere association of stimuli, sensory cues, and a rapid motor response, without external reinforcements. The behavioral effect has been shown to last for months after less than one hour of training. Here, we used a modified version of CAT by changing the neutral-cue to a number that represented a monetary amount of reward that the participants accumulate (i.e. incentive-cue). After a single training session, we compared behavioral performance and functional connectivity (FC), as measured using functional magnetic resonance imaging, between two groups, one receiving a neutral-cue and the other receiving an incentive-cue, at 5 time points across one year. We replicated the maintenance of behavioral changes after 6-months for the non-reinforced neutral-cue participants, but not for the reinforced group. The reinforced training group showed higher FC within the limbic system, whereas the non-externally reinforced group showed higher functional connectivity within and between default-mode and dorsal-attention networks. Our findings offer putative neural correlates for both reinforced and non-reinforced preference changes that are maintained over time and which could be implemented in future behavioral change interventions. Significance StatementThe current work examines the neural mechanisms of non-externally reinforced preference change and its maintenance over time, using both a neutral cue and a modified version of the cue-approach training paradigm. While both groups initially exhibited preference shifts, only the non-reinforced group maintained preference changes over one year, suggesting an enduring internal reinforcement mechanism. We identified distinct patterns in functional connectivity related to behavioral maintenance, find that non-external reinforcement increases the connectivity of the default mode network while external reinforcement elevates connectivity between limbic areas. These findings enhance our understanding of sustainable behavior change and advocate for non-external reinforcement in behavioral interventions.

neuroscience↗
bioRxiv2025

PsiConnect: A Multimodal Neuroimaging Study of Psilocybin-Induced Changes in Brain and Behaviour

PsiConnect is a large-scale neuroimaging study designed to investigate the neural and subjective effects of psilocybin using multimodal neuroimaging. It combines functional, structural, and diffusion-weighted MRI with EEG to examine brain activity in 62 participants before and after a 19 mg dose of psilocybin. The design includes resting-state scans and three naturalistic conditions: guided meditation, music listening, and movie watching. Half of the cohort underwent an 8-week meditation training program, enabling the exploration of interactions among meditation, psilocybin, and brain function. The fMRI data was obtained through multi-echo fMRI, which enhances the signal-to-noise ratio and reduces susceptibility artifacts, thereby improving the reliability of the analyses. A comprehensive battery of behavioural and self-report measures captured both acute and longitudinal cognitive and subjective effects, with follow-ups extending to one year post-administration. The large sample size, multimodal neuroimaging, diversity of contexts, and longitudinal behavioural follow-ups enable the study of psilocybin-induced changes in brain and behaviour with an unprecedented level of detail and reliability. Furthermore, the data is curated according to open science principles to ensure accessibility and interoperability with established neuroimaging processing pipelines. These factors make PsiConnect a valuable and highly reusable resource for researchers in cognitive and computational neuroscience.

neuroscience↗
bioRxiv2025

The molecular and cellular underpinnings of human brain lateralization

Hemispheric specialization is a fundamental characteristic of human brain organization, where most individuals exhibit left-hemisphere dominance for language and right-hemisphere dominance for visuospatial attention. While some lateralized functions are evident in other species, the human brain displays a strong, species-wide bias. Despite the evolutionary and functional significance of these asymmetries, their molecular and cellular foundations remain poorly understood. Here, we identify key neurochemical and cellular asymmetries that underpin cortical lateralization. Specifically, we demonstrate lateralized gradients in neurotransmitter receptor densities, particularly along the multimodal monoaminergic-cholinergic axis, as well as asymmetries in mitochondrial distribution and the spatial prevalence of microglia and glutamatergic excitatory neurons. Using a multimodal approach that integrates in vivo functional MRI, PET imaging, and post-mortem transcriptomic and cellular data, we delineate two distinct cortical clusters: a left-lateralized network centered on language processing and a right-lateralized network supporting visuospatial attention. These results highlight a biologically embedded substrate for lateralized cognition that may inform both evolutionary theory and our mechanistic understanding of neuropsychiatric illnesses characterized by disrupted lateralization.

neuroscience↗
bioRxiv2025

In vitro and in vivo synergy of Vancomycin and β-lactams against drug-resistant Mycobacterium tuberculosis and Non-tuberculous mycobacteria

The unabated increase in antimicrobial resistance has underlined the importance of identifying novel drug combinations which eliminate infections more potently and likely reduce the emergence of resistance. In this context, we have identified Vancomycin and many {beta}-lactams as being potently active against drug-resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria including M. abscessus, emerging as pathogens of concern owing to their inherent drug resistance profile. In this study, we have identified combinations of Vancomycin, a glycopeptide and {beta}-lactams, especially Ceftriaxone, Ceftazidime and Meropenem, in the presence or absence of Sulbactam, a {beta}- lactamase inhibitor, as possessing potent antimicrobial activity against several drug-resistant mycobacterial strains. The combination of Vancomycin and {beta}-lactams exhibited potent bactericidal activity and reduced the bacterial load better than either drug alone. The molecular basis of synergy was mediated by increase in permeability of mycobacterial cell as demonstrated by ethidium bromide assay. In the murine model of mycobacterial infection, synergistic combination of Vancomycin and {beta}-lactams outperformed clinically utilized drugs including Isoniazid, Rifampicin and Ethambutol against M. tuberculosis and Amikacin, Clarithromycin against M. abscessus. The combinations caused a significant reduction in bacterial load in various organs in M. tuberculosis and M. abscessus infected mice. Thus, the synergistic combination of Vancomycin and {beta}-lactams could potentially be utilized for treatment of recalcitrant mycobacterial infection especially those caused due to drug-resistant pathogens.

microbiology↗
bioRxiv2025

Psychedelics Align Brain Activity with Context

Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are context-sensitive. To understand how this reorganisation depends on context, we collected and comprehensively analysed the largest psychedelic neuroimaging dataset to date. Sixty-two adults were scanned with functional MRI and EEG during rest and naturalistic stimuli (meditation, music, and movie), before and after ingesting 19 mg of psilocybin (functional MRI {approx}80 min post-dose; EEG {approx}150 min post-dose). Half the participants ranked the experience among the most meaningful of their lives. Under psilocybin, functional MRI and EEG signals recorded during eyes-closed conditions became similar to those recorded during an eyes-open condition. Global functional connectivity increased in associative regions and decreased in sensory areas. Using machine learning to represent neural activity as low-dimensional trajectories, we found that psilocybin reorganised these into structured, context-sensitive patterns of brain activity that reflected both experimental condition and the quality of subjective experience, revealing an organisation that was missed by time-averaged connectivity measures. Under psilocybin, brain networks that ordinarily segregate internal and external processing coherently integrated and aligned neural dynamics with context. This context-alignment manifested as distinct and cohesive neural trajectories in participants reporting positively felt self- and boundary-dissolving effects, corresponding to the felt experience of being part of the environment, which we refer to as embeddedness--the subjective experience of being continuous with, rather than separate from, the surrounding environment. The strength of this context-alignment was associated with next-day mindset change, bridging the neural, experiential, and therapeutic dimensions of the psychedelic state. These findings show that the organisation of brain activity covaries with the experiential coherence of the psychedelic state, and provide a systems-level framework for how context-sensitive brain dynamics link neurobiology to subjective experience and behavioural change.

neuroscience↗
bioRxiv2024

Shared and unique lifetime stressor characteristics and brain networks predict adolescent anxiety and depression

BackgroundExposure to major life stressors and aberrant brain functioning have been related to anxiety and depression, especially during adolescence. However, whether these associations differ based on the specific characteristics of the stressors experienced, and/or the functional networks engaged, remains unclear. MethodsWe used baseline lifetime stressor exposure and resting-state functional magnetic resonance imaging data from a longitudinal sample of 150 adolescents enriched for anxiety and depressive disorders. We examined the cumulative lifetime stressor frequency and severity of five stressor characteristics: physical danger, interpersonal loss, humiliation, entrapment, and role change/disruption. Anxiety and depression symptoms were assessed at three time points: baseline, 6-month and 12-month follow-ups. Linear mixed-effect models tested if the lifetime frequency and severity of these stressor characteristics and functional connectivity within and between frontoparietal, default, and ventral attention networks at baseline predicted anxiety and depression symptoms at three time points. ResultsLifetime frequency and severity of humiliation and entrapment predicted both anxiety and depression symptoms. Lifetime frequency and severity of entrapment exposures predicted anxiety and depression symptoms after accounting for baseline depression and anxiety symptoms, respectively. Resting-state functional connectivity between default, frontoparietal and ventral attention networks did not predict either anxiety or depression symptoms after correcting for multiple comparisons. ConclusionsOur study highlights lifetime exposures to humiliation and entrapment stressors as central stressor characteristics predictive of prospective anxiety and depression symptoms in adolescence. Our results also suggest that resting-state functional connectivity within and between default, frontoparietal and ventral attention networks may be relatively weak predictors of prospective anxiety and depression symptoms in adolescence.

neuroscience↗
bioRxiv2024

Multiscale heterogeneity of white matter morphometry in psychiatric disorders

BackgroundInter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear. MethodsWe applied Warped Bayesian Linear Regression normative models to T1- weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter- regional connections, specific brain regions, and spatially extended brain networks. ResultsThe specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals. ConclusionsThe prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders.

neuroscience↗