Psychiatry - Research Publications
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ItemPublisher Correction: Brain charts for the human lifespan.(Springer Science and Business Media LLC, 2022-10)
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ItemBrain charts for the human lifespan(NATURE PORTFOLIO, 2022-04-06)Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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ItemCell type-specific manifestations of cortical thickness heterogeneity in schizophrenia(SPRINGERNATURE, 2022-02-10)Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
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ItemWhite Matter Alterations Between Brain Network Hubs Underlie Processing Speed Impairment in Patients With Schizophrenia.(Oxford University Press (OUP), 2021-01)Processing speed (PS) impairment is one of the most severe and common cognitive deficits in schizophrenia. Previous studies have reported correlations between PS and white matter diffusion properties, including fractional anisotropy (FA), in several fiber bundles in schizophrenia, suggesting that white matter alterations could underpin decreased PS. In schizophrenia, white matter alterations are most prevalent within inter-hub connections of the rich club. However, the spatial and topological characteristics of this association between PS and FA have not been investigated in patients. In this context, we tested whether structural connections comprising the rich club network would underlie PS impairment in 298 patients with schizophrenia or schizoaffective disorder and 190 healthy controls from the Australian Schizophrenia Research Bank. PS, measured using the digit symbol coding task, was largely (Cohen's d = 1.33) and significantly (P < .001) reduced in the patient group when compared with healthy controls. Significant associations between PS and FA were widespread in the patient group, involving all cerebral lobes. FA was not associated with other cognitive measures of phonological fluency and verbal working memory in patients, suggesting specificity to PS. A topological analysis revealed that despite being spatially widespread, associations between PS and FA were over-represented among connections forming the rich club network. These findings highlight the need to consider brain network topology when investigating high-order cognitive functions that may be spatially distributed among several brain regions. They also reinforce the evidence that brain hubs and their interconnections may be particularly vulnerable parts of the brain in schizophrenia.
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ItemO2.3. ABNORMAL BRAIN AGING IN YOUTH WITH SUBCLINICAL PSYCHOSIS AND OBSESSIVE-COMPULSIVE SYMPTOMS(Oxford University Press (OUP), 2020-05-18)Abstract Background Psychiatric symptoms in childhood and adolescence have been associated with both delayed and accelerated patterns of grey matter development. This suggests that deviation in brain structure from a normative range of variation for a given age might be important in the emergence of psychopathology. Distinct from chronological age, brain age refers to the age of an individual that is inferred from a normative model of brain structure for individuals of the same age and sex. We predicted brain age from a common set of grey matter features and examined whether the difference between an individual’s chronological and brain age was associated with the severity of psychopathology in children and adolescents. Methods Participants included 1313 youths (49.8% male) aged 8–21 who underwent structural imaging as part of the Philadelphia Neurodevelopmental Cohort. Independent Component Analysis was used to obtain 7 psychopathology dimensions representing Conduct, Anxiety, Obsessive-Compulsive, Attention, Depression, Bipolar, and Psychosis symptoms and an overall measure of severity (General Psychopathology). Using 10-fold cross-validation, support vector machine regression was trained in 402 typically developing youth to predict individual age based on a feature space comprising 111 grey matter regions. This yielded a brain age prediction for each individual. Brain age gap was calculated for each individual by subtracting chronological age from predicted brain age. The general linear model was used to test for an association between brain age gap and each of the 8 dimensions of psychopathology in a test sample of 911 youth. The regional specificity and spatial pattern of brain age gap was also investigated. Error control across the 8 models was achieved with a false discovery rate of 5%. Results Brain age gap was significantly associated with dimensions characterizing obsessive-compulsive (t=2.5, p=0.01), psychosis (t=3.16, p=0.0016) and general psychopathology (t=4.08, p<0.0001). For all three dimensions, brain age gap was positively associated with symptom severity, indicating that individuals with a brain that was predicted to be ‘older’ than expectations set by youth of the same chronological age and sex tended to have higher symptom scores. Findings were confirmed with a categorical approach, whereby higher brain age gap was observed in youth with a lifetime endorsement of psychosis (t=2.35, p=0.02) and obsessive-compulsive (t=2.35, p=0.021) symptoms, in comparison to typically developing individuals. Supplementary analyses revealed that frontal grey matter was the most important feature mediating the association between brain age gap and psychosis symptoms, whereas subcortical volumes were most important for the association between brain age gap and obsessive-compulsive and general symptoms. Discussion We found that the brain was ‘older’ in youth experiencing higher subclinical symptoms of psychosis, obsession-compulsion, and general psychopathology, compared to normally developing youth of the same chronological age. Our results suggest that deviations in normative brain age patterns in youth may contribute to the manifestation of specific psychiatric symptoms of subclinical severity that cut across psychopathology dimensions.
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ItemNo Preview AvailableBrain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder(Elsevier, 2021)Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophrenia-spectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFNγ, IL4, IL5 and IL13 with frontal thickness, and of IFNγ and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFNγ, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFNγ and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.
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ItemNo Preview AvailableLarge-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals(Oxford University Press (OUP), 2021-03-01)INTRODUCTION: Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. METHODS: All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. RESULTS: Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = -3.56, P = .0004) and IL-12(p70) (t = -2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. CONCLUSIONS: We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.
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ItemNo Preview AvailableNetwork Analysis of Symptom Comorbidity in Schizophrenia: Relationship to Illness Course and Brain White Matter Microstructure(Oxford University Press (OUP), 2021-03-08)INTRODUCTION: Recent network-based analyses suggest that schizophrenia symptoms are intricately connected and interdependent, such that central symptoms can activate adjacent symptoms and increase global symptom burden. Here, we sought to identify key clinical and neurobiological factors that relate to symptom organization in established schizophrenia. METHODS: A symptom comorbidity network was mapped for a broad constellation of symptoms measured in 642 individuals with a schizophrenia-spectrum disorder. Centrality analyses were used to identify hub symptoms. The extent to which each patient's symptoms formed clusters in the comorbidity network was quantified with cluster analysis and used to predict (1) clinical features, including illness duration and psychosis (positive symptom) severity and (2) brain white matter microstructure, indexed by the fractional anisotropy (FA), in a subset (n = 296) of individuals with diffusion-weighted imaging (DWI) data. RESULTS: Global functioning, substance use, and blunted affect were the most central symptoms within the symptom comorbidity network. Symptom profiles for some patients formed highly interconnected clusters, whereas other patients displayed unrelated and disconnected symptoms. Stronger clustering among an individual's symptoms was significantly associated with shorter illness duration (t = 2.7; P = .0074), greater psychosis severity (ie, positive symptoms expression) (t = -5.5; P < 0.0001) and lower fractional anisotropy in fibers traversing the cortico-cerebellar-thalamic-cortical circuit (r = .59, P < 0.05). CONCLUSION: Symptom network structure varies over the course of schizophrenia: symptom interactions weaken with increasing illness duration and strengthen during periods of high positive symptom expression. Reduced white matter coherence relates to stronger symptom clustering, and thus, may underlie symptom cascades and global symptomatic burden in individuals with schizophrenia.
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ItemIndividual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort(SPRINGERNATURE, 2020-09-22)The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.
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ItemPredicting individual improvement in schizophrenia symptom severity at 1-year follow-up: Comparison of connectomic, structural, and clinical predictors(Wiley, 2020-08-15)In a machine learning setting, this study aims to compare the prognostic utility of connectomic, brain structural, and clinical/demographic predictors of individual change in symptom severity in individuals with schizophrenia. Symptom severity at baseline and 1‐year follow‐up was assessed in 30 individuals with a schizophrenia‐spectrum disorder using the Brief Psychiatric Rating Scale. Structural and functional neuroimaging was acquired in all individuals at baseline. Machine learning classifiers were trained to predict whether individuals improved or worsened with respect to positive, negative, and overall symptom severity. Classifiers were trained using various combinations of predictors, including regional cortical thickness and gray matter volume, static and dynamic resting‐state connectivity, and/or baseline clinical and demographic variables. Relative change in overall symptom severity between baseline and 1‐year follow‐up varied markedly among individuals (interquartile range: 55%). Dynamic resting‐state connectivity measured within the default‐mode network was the most accurate single predictor of change in positive (accuracy: 87%), negative (83%), and overall symptom severity (77%) at follow‐up. Incorporating predictors based on regional cortical thickness, gray matter volume, and baseline clinical variables did not markedly improve prediction accuracy and the prognostic utility of these predictors in isolation was moderate (<70%). Worsening negative symptoms at 1‐year follow‐up were predicted by hyper‐connectivity and hypo‐dynamism within the default‐mode network at baseline assessment, while hypo‐connectivity and hyper‐dynamism predicted worsening positive symptoms. Given the modest sample size investigated, we recommend giving precedence to the relative ranking of the predictors investigated in this study, rather than the prediction accuracy estimates.