Biology subjects

Bearden, C. E.

Publications and source records attributed to Bearden, C. E..

29 records · Page 2Linked to original sources

bioRxiv2022

Variability in cognitive task performance in early adolescence is associated with stronger between-network anticorrelation and future attention problems

BackgroundIntra-individual variability (IIV) during cognitive task performance is a key behavioral index of attention and consistent marker of ADHD. In adults, lower IIV has been associated with anticorrelation between the default mode network (DMN) and dorsal attention network (DAN) - thought to underlie effective allocation of attention. However, whether these behavioral and neural markers of attention are (i) associated with each other and (ii) can predict future attention-related deficits has not been examined in a developmental, population-based cohort. MethodsWe examined relationships at the baseline visit between IIV on three cognitive tasks, DMN-DAN anticorrelation, and parent-reported attention problems using the Adolescent Brain and Cognitive Development Study (n=11,878 participants, aged 9-10, female=47.8%). We also investigated whether behavioral and neural markers of attention at baseline predicted attention problems, 1, 2, and 3 years later. ResultsAt baseline, greater DMN-DAN anticorrelation was associated with lower IIV across all three cognitive tasks (unstandardized {beta}: 0.22-0.25). Older age at baseline was associated with stronger DMN-DAN anticorrelation and lower IIV ({beta}: -0.005--0.0004). Weaker DMN-DAN anticorrelation and IIV were cross-sectionally associated with attention problems ({beta}: 1.41-7.63). Longitudinally, lower IIV at baseline was associated with less severe attention problems, 1-3 years later, after accounting for baseline attention problems ({beta}: 0.288-0.77). ConclusionsThe results suggest that IIV in early adolescence is associated with worsening attention problems in a representative cohort of US youth. Attention deficits in early adolescence may be important for understanding and predicting future cognitive and clinical outcomes.

neuroscience↗

bioRxiv2022

Rare CNVs and phenome-wide profiling: a tale of brain-structural divergence and phenotypical convergence

Copy number variations (CNVs) are rare genomic deletions and duplications that can exert profound effects on brain and behavior. Previous reports of pleiotropy in CNVs imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, studies to date have primarily examined single CNV loci in small clinical cohorts. It remains unknown how distinct CNVs escalate the risk for the same developmental and psychiatric disorders. Here, we quantitatively dissect the impact on brain organization and behavioral differentiation across eight key CNVs. In 534 clinical CNV carriers from multiple sites, we explored CNV-specific brain morphology patterns. We extensively annotated these CNV-associated patterns with deep phenotyping assays through the UK Biobank resource. Although the eight CNVs cause disparate brain changes, they are tied to similar phenotypic profiles across [~]1000 lifestyle indicators. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

genetics↗

bioRxiv2022

Molecular and connectomic vulnerability shape cross-disorder cortical abnormalities

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21 000 patients and N = 26 000 controls, collected using a harmonized processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find that regional molecular vulnerability and macroscale brain network architecture interact to drive the spatial patterning of cortical abnormalities in multiple disorders. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, medial temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local biological attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

neuroscience↗

bioRxiv2020

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in this microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial protein translation and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a novel pathogenic mechanism for neurodevelopmental disorders.

neuroscience↗

bioRxiv2019

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

neuroscience↗

bioRxiv2019

Genetic and clinical analyses of psychosis spectrum symptoms in a large multi-ethnic youth cohort reveal significant link with ADHD.

ObjectivePsychotic symptoms are an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multi-ethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7,225, 20% PS).\n\nMethodsUsing an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects.\n\nResultsThe multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is: i) driven by subjects of European ancestry (OR=1.23 (1.14, 1.34), P=4.15x10-7) but is not observed in African American subjects (P=0.65) and ii) independent of phenotypic overlap. We also find a significant interaction with age (P=0.01), with a stronger association in younger children. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P= 0.02).\n\nConclusionsOur findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

genetics↗

bioRxiv2019

Reliability of Mismatch Negativity Event-Related Potentials in a Multisite, Traveling Subjects Study

ObjectiveMismatch negativity (MMN) is an auditory event-related potential (ERP) used to study schizophrenia and psychosis risk. MMN reliability from a multisite, traveling subjects study was compared using different ERP referencing, averaging, and scoring techniques.\n\nMethodsReliability of frequency, duration, and double (frequency+duration) MMN was determined from eight traveling subjects, tested on two occasions at eight EEG laboratory sites. Deviant-specific variance components were estimated for MMN peak amplitude and latency measures using different ERP processing methods. Generalizability (G) coefficients were calculated using two-facet (site, occasion), fully-crossed models and single-facet (occasion) models within each laboratory to assess MMN reliability.\n\nResultsG-coefficients calculated from two-facet models indicated fair (0.4 0.5). Reliability of MMN amplitude was greater than latency, and reliability with mastoid referencing significantly outperformed nose-referencing.\n\nConclusionsEEG preprocessing methods have a significant impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies.\n\nSignificanceWith standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizes within rare patient groups.

neuroscience↗

bioRxiv2019

Distinct and shared contributions of diagnosis and symptom domains to cognitive performance in severe mental illness

BackgroundSevere mental illness (SMI) diagnoses display overlapping symptomatology and shared genetic risk, motivating trans-diagnostic investigations of disease-relevant quantitative measures. We analyzed relationships between neurocognitive performance, symptom domains, and diagnoses, in a large sample of SMI cases (ascertained agnostic to diagnosis) and healthy controls from a single, homogeneous population. Methods2,406 participants (1,689 cases, 717 controls; mean age 39 years, 64% female) were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases carried structured-interview based diagnoses of schizophrenia (SCZ, n=160), bipolar-I (BP-I, n=519), bipolar-II (BP-II, n=204) and major depressive disorder (MDD, n=806). Linear mixed models, using CNB tests as repeated measures, modeled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses, in cases, included symptom factor scores obtained from exploratory factor analysis of symptom data, as main effects. FindingsBP-I and SCZ displayed nearly identical impairments in accuracy and speed, across cognitive domains. BP-II and MDD performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, while high depression scores were associated with increased social cognition accuracy. InterpretationTrans-diagnostic investigations demonstrated that neurocognitive function in SMI is characterized by two distinct profiles (BP-I/SCZ and BP-II/MDD), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating SMI causes and trajectories.

neuroscience↗

bioRxiv2019

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Background22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear. MethodsUsing a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder. ResultsPolygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ- and ASD-associated neurodevelopmental networks, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. ConclusionsThe current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD, and elucidate the mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.

systems biology↗

bioRxiv2018

Transient patterns of functional dysconnectivity in youth with psychosis spectrum symptoms

Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Both static and dynamic dysconnectivity have been described in patients with schizophrenia and, more recently, in help-seeking individuals at clinical high-risk for psychosis. Less is known, however, about developmental aspects of dynamic functional network connectivity (FNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state fMRI data using established dynamic FNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22), including 129 participants experiencing PS and 452 participants without PS (non-PS).\n\nApplying a sliding window approach and k-means clustering, 5 dynamic states with distinct whole-brain connectivity patterns were identified. PS-associated dysconnectivity was most prominent in states characterized by synchronization or antagonism of the default mode network (DMN) and cognitive control (CC) domains. Hyperconnectivity between DMN, salience, and CC domains in PS youth only occurred in a state characterized by synchronization of the DMN and CC domains, a state that also becomes less frequent with age. However, dysconnectivity of the sensorimotor and visual systems in PS youth was revealed in other transient states completing the picture of whole-brain dysconnectivity patterns associated with PS.\n\nOverall, state-dependent dysconnectivity was observed in PS youth, providing the first evidence that disruptions of dynamic functional connectivity are present across a broader psychosis continuum.

neuroscience↗

bioRxiv2017

Reciprocal Disruptions in Thalamic and Hippocampal Resting-State Functional Connectivity in Youth with 22q11.2 Deletions

22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional MRI (rs-fMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of young men and women with 22q11DS (n=42) and demographically matched healthy controls (n=39). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed reciprocal disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in sensorimotor cortex, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to sensory and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.\n\nSIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a reciprocal fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.

neuroscience↗