Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms.
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ABSTRACT:
SUBMITTER: Satterthwaite TD
PROVIDER: S-EPMC4651819 | biostudies-other | 2015 Dec
REPOSITORIES: biostudies-other
Publications
Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms.
Satterthwaite T D TD Vandekar S N SN Wolf D H DH Bassett D S DS Ruparel K K Shehzad Z Z Craddock R C RC Shinohara R T RT Moore T M TM Gennatas E D ED Jackson C C Roalf D R DR Milham M P MP Calkins M E ME Hakonarson H H Gur R C RC Gur R E RE
Molecular psychiatry 20150602 12
Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8-22 years with psychosis-spectrum (PS) symptoms and 204 typ ...[more]
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Project description:IMPORTANCE:Structural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth. OBJECTIVE:To investigate the presence of structural brain abnormalities in youth with PS symptoms. DESIGN, SETTING, AND PARTICIPANTS:The Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011. MAIN OUTCOMES AND MEASURES:Measures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally. RESULTS:Following exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume (P?=?1.8?×?10-10) and expanded white matter volume (P?=?2.8?×?10-11). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score?=?5.2 and cluster size of 1225 for the right and maximum z score?=?4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity. CONCLUSIONS AND RELEVANCE:Structural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions.
| S-EPMC5048443 | biostudies-literature
Project description:The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype.To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing.The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220).Two functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces.In the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster-corrected P <?.05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r =?.32, P <?.001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P <?.05). The response in the amygdala correlated with positive symptom severity (r =?.16, P =?.01) but not with cognitive deficits.The pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help-seeking risk samples. Specific circuit dysfunction during cognitive and emotion-processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms.
| S-EPMC4581844 | biostudies-literature
Project description:Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Dynamic functional dysconnectivity has been described in patients with schizophrenia and in help-seeking individuals at clinical high risk for psychosis. Less is known, about developmental aspects of dynamic functional network connectivity (dFNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state functional magnetic resonance imaging data using established dFNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22 years), including 129 participants experiencing PS and 452 participants without PS (non-PS). Functional networks were identified using group spatial independent component analysis. A sliding window approach and k-means clustering were applied to covariance matrices of all functional networks to identify recurring whole-brain connectivity states. PS-associated dysconnectivity of default mode, salience, and executive networks occurred only in a few states, whereas dysconnectivity in the sensorimotor and visual systems in PS youth was more pervasive, observed across multiple states. This study provides new evidence that disruptions of dFNC are present even at the less severe end of the psychosis continuum in youth, complementing previous work on help-seeking and clinically diagnosed cohorts that represent the more severe end of this spectrum.
| S-EPMC7442416 | biostudies-literature
Project description:OBJECTIVE:Adults with established diagnoses of serious mental illness (bipolar disorder and schizophrenia) exhibit structural brain abnormalities, yet less is known about how such abnormalities manifest earlier in development. METHOD:Cross-sectional data publicly available from the Philadelphia Neurodevelopmental Cohort (PNC) were analyzed. Structural magnetic resonance neuroimaging data were collected on a subset of the PNC (N = 989; 9-22 years old). Cortical thickness, surface area (SA), and subcortical volumes were calculated. Study participants were assessed for psychiatric symptomatology using a structured interview and the following groups were created: typically developing (n = 376), psychosis spectrum (PS; n = 113), bipolar spectrum (BP; n = 117), and BP + PS (n = 109). Group and developmental differences in structural magnetic resonance neuroimaging measures were examined. In addition, the extent to which any structural aberration was related to neurocognition, global functioning, and clinical symptomatology was examined. RESULTS:Compared with other groups, PS youth exhibited significantly decreased SA in the orbitofrontal, cingulate, precentral, and postcentral regions. PS youth also exhibited deceased thalamic volume compared with all other groups. The strongest effects for precentral and posterior cingulate SA decreases were seen during early adolescence (13-15 years old) in PS youth. The strongest effects for decreases in thalamic volume and orbitofrontal and postcentral SA were observed in mid-adolescence (16-18 years) in PS youth. Across groups, better overall functioning was associated with increased lateral orbitofrontal SA. Increased postcentral SA was associated with better executive cognition and less severe negative symptoms in the entire sample. CONCLUSION:In a community-based sample, decreased cortical SA and thalamic volume were present early in adolescent development in youth with PS symptoms, but not in youth with BP symptoms or with BP and PS symptoms. These findings point to potential biological distinctions between PS and BP conditions, which could suggest additional biomarkers relevant to early identification.
| S-EPMC7110691 | biostudies-literature
Project description:Little is known about the impact of family history of psychosis on youth from community samples. To fill this gap, we compared youth with a first-degree relative with psychosis spectrum symptoms (i.e. family history of psychosis spectrum symptoms, FHPS) to youth without FHPS in a cross-sectional analysis of the Philadelphia Neurodevelopmental Cohort (PNC). The PNC is a racially diverse community sample of 9498 youth ages 8-21 years old, of whom 8928 completed the Family Interview for Genetic Studies to determine FHPS status. Polygenic risk score for schizophrenia (PRSS) was available for a subsample of 4433 European Americans. FHPS youth (n = 489) constituted 5.5% of the analytic sample. After adjusting for environmental risk factors (sociodemographic variables and traumatic stressful events), FHPS youth had lower functioning on the Children's Global Assessment Scale and elevated psychosis spectrum, mood, externalizing, and fear symptoms compared to non-FHPS youth (all p < .001). In the European-American subsample, FHPS status was associated with poorer functioning and greater symptom burden in all four psychopathology domains (all p < .001), even after covarying for PRSS. Thus, ascertaining FHPS is important because it is uniquely associated with symptoms and functional impairment in community youth beyond PRS-S and the environmental risk factors we investigated. Future research identifying environmental causes of FHPS-associated impairment could inform the development of interventions for the broad array of symptoms observed in FHPS youth.
| S-EPMC7239716 | biostudies-literature
Project description:BackgroundResting-state functional neuroimaging captures large-scale network organization; whether this organization is intact or disrupted during adolescent development across the psychosis spectrum is unresolved. We investigated the integrity of network organization in psychosis spectrum youth and those with first episode psychosis (FEP) from late childhood through adulthood.MethodsWe analyzed data from Philadelphia Neurodevelopmental Cohort (PNC; typically developing = 450, psychosis spectrum = 273, 8-22 years), a longitudinal cohort of typically developing youth (LUNA; N = 208, 1-3 visits, 10-25 years), and a sample of FEP (N = 39) and matched controls (N = 34). We extracted individual time series and calculated correlations from brain regions and averaged them for 4 age groups: late childhood, early adolescence, late adolescence, adulthood. Using multiple analytic approaches, we assessed network stability across 4 age groups, compared stability between controls and psychosis spectrum youth, and compared group-level network organization of FEP to controls. We explored whether variability in cognition or clinical symptomatology was related to network organization.ResultsNetwork organization was stable across the 4 age groups in the PNC and LUNA typically developing youth and PNC psychosis spectrum youth. Psychosis spectrum and typically developing youth had similar functional network organization during all age ranges. Network organization was intact in PNC youth who met full criteria for psychosis and in FEP. Variability in cognitive functioning or clinical symptomatology was not related to network organization in psychosis spectrum youth or FEP.DiscussionThese findings provide rigorous evidence supporting intact functional network organization in psychosis risk and psychosis from late childhood through adulthood.
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Project description:A multivariate analytical strategy may pinpoint the structural connectivity patterns associated with Alzheimer's disease (AD) pathology in connectome-wide association studies. Diffusion magnetic resonance imaging data from 161 participants including subjects with healthy controls, AD, stable and converting mild cognitive impairment, were selected for group-wise comparisons. A multivariate distance matrix regression (MDMR) analysis was performed to detect abnormality in brain structural network along with disease progression. Based on the seed regions returned by the MDMR analysis, supervised learning was applied to evaluate the disease predictive performance. Nine brain regions, including the left orbital part of superior and middle frontal gyrus, the bilateral supplementary motor area, the bilateral insula, the left hippocampus, the left putamen, and the left thalamus demonstrated extremely significant structural pattern changes along with the progression of AD. The disease classification was more efficient when based on the key connectivity related to these seed regions than when based on whole-brain structural connectivity. MDMR analysis reveals brain network reorganization caused by AD pathology. The key structural connectivity detected in this study exhibits promising distinguishing capability to predict prodromal AD patients.
| S-EPMC6396432 | biostudies-literature
Project description:Psychotic symptoms are not only 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 multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using 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. The 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 driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10-7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. 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). Our 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.
| S-EPMC7844241 | biostudies-literature
Project description:IntroductionDynamic relationships between the symptoms of psychosis can be shown in individual networks of psychopathology. In a single patient, data collected with the Experience Sampling Method (ESM-a method to construct intensive time series of experience and context) can be used to study lagged associations between symptoms in relation to illness severity and pharmacological treatment.MethodThe patient completed, over the course of 1 year, for 4 days per week, 10 daily assessments scheduled randomly between 10 minutes and 3 hours apart. Five a priori selected symptoms were analysed: 'hearing voices', 'down', 'relaxed', 'paranoia' and 'loss of control'. Regression analysis was performed including current level of one symptom as the dependent variable and all symptoms at the previous assessment (lag) as the independent variables. Resulting regression coefficients were printed in graphs representing a network of symptoms. Network graphs were generated for different levels of severity: stable, impending relapse and full relapse.ResultsESM data showed that symptoms varied intensely from moment to moment. Network representations showed meaningful relations between symptoms, e.g. 'down' and 'paranoia' fuelling each other, and 'paranoia' negatively impacting 'relaxed'. During relapse, symptom levels as well as the level of clustering between symptoms markedly increased, indicating qualitative changes in the network. While 'hearing voices' was the most prominent symptom subjectively, the data suggested that a strategic focus on 'paranoia', as the most central symptom, had the potential to bring about changes affecting the whole network.ConclusionConstruction of intensive ESM time series in a single patient is feasible and informative, particularly if represented as a network, showing both quantitative and qualitative changes as a function of relapse.
| S-EPMC5028060 | biostudies-literature
Project description:The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.
| S-EPMC6813871 | biostudies-literature