Neurobiological abnormalities associated with psychiatric disorders do not map well to existing diagnostic categories. High co-morbidity suggests dimensional circuit-level abnormalities that cross diagnoses. Here we seek to identify brain-based dimensions of psychopathology using sparse canonical correlation analysis in a sample of 663 youths. This analysis reveals correlated patterns of functional connectivity and psychiatric symptoms. We find that four dimensions of psychopathology – mood, psychosis, fear, and externalizing behavior – are associated (r = 0.68–0.71) with distinct patterns of connectivity. Loss of network segregation between the default mode network and executive networks emerges as a common feature across all dimensions. Connectivity linked to mood and psychosis becomes more prominent with development, and sex differences are present for connectivity related to mood and fear. Critically, findings largely replicate in an independent dataset (n = 336). These results delineate connectivity-guided dimensions of psychopathology that cross clinical diagnostic categories, which could serve as a foundation for developing network-based biomarkers in psychiatry.

Data quality is increasingly recognized as one of the most important confounding factors in brain imaging research. It is particularly important for studies of brain development, where age is systematically related to in-scanner motion and data quality. Prior work has demonstrated that in-scanner head motion biases estimates of structural neuroimaging measures. However, objective measures of data quality are not available for most structural brain images. Here we sought to identify quantitative measures of data quality for T1-weighted volumes, describe how these measures relate to cortical thickness, and delineate how this in turn may bias inference regarding associations with age in youth. Three highly-trained raters provided manual ratings of 1840 raw T1-weighted volumes. These images included a training set of 1065 images from Philadelphia Neurodevelopmental Cohort (PNC), a test set of 533 images from the PNC, as well as an external test set of 242 adults acquired on a different scanner. Manual ratings were compared to automated quality measures provided by the Preprocessed Connectomes Project's Quality Assurance Protocol (QAP), as well as FreeSurfer's Euler number, which summarizes the topological complexity of the reconstructed cortical surface. Results revealed that the Euler number was consistently correlated with manual ratings across samples. Furthermore, the Euler number could be used to identify images scored "unusable" by human raters with a high degree of accuracy (AUC: 0.98-0.99), and out-performed proxy measures from functional timeseries acquired in the same scanning session. The Euler number also was significantly related to cortical thickness in a regionally heterogeneous pattern that was consistent across datasets and replicated prior results. Finally, data quality both inflated and obscured associations with age during adolescence. Taken together, these results indicate that reliable measures of data quality can be automatically derived from T1-weighted volumes, and that failing to control for data quality can systematically bias the results of studies of brain maturation.

IMPORTANCE Because more than one-third of people making nonfatal suicide attempts do not receive mental health treatment, it is essential to extend suicide attempt risk factors beyond high-risk clinical populations to the general adult population.OBJECTIVE To identify future suicide attempt risk factors in the general population using a data-driven machine learning approach including more than 2500 questions from a large, nationally representative survey of US adults. DESIGN, SETTING, AND PARTICIPANTS Data came from wave 1 (2001 to 2002) and wave 2 (2004 to 2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). NESARC is a face-to-face longitudinal survey conducted with a national representative sample of noninstitutionalized civilian population 18 years and older in the US. The cumulative response rate across both waves was 70.2% resulting in 34 653 wave 2 interviews. A balanced random forest was trained using cross-validation to develop a suicide attempt risk model. Out-of-fold model prediction was used to assess model performance, including the area under the receiver operator curve, sensitivity, and specificity. Survey design and nonresponse weights allowed estimates to be representative of the US civilian population based on the 2000 census. Analyses were performed between May 15, 2019, and June 10, 2020.MAIN OUTCOMES AND MEASURES Attempted suicide in the 3 years between wave 1 and wave 2 interviews. RESULTSOf 34 653 participants, 20 089 were female (weighted proportion, 52.1%). The weighted mean (SD) age was 45.1 (17.3) years at wave 1 and 48.2 (17.3) years at wave 2. Attempted suicide during the 3 years between wave 1 and wave 2 interviews was self-reported by 222 of 34 653 participants (0.6%). Using survey questions measured at wave 1, the suicide attempt risk model yielded a cross-validated area under the receiver operator characteristic curve of 0.857 with a sensitivity of 85.3% (95% CI, 79.8-89.7) and a specificity of 73.3% (95% CI, 72.8-73.8) at an optimized threshold. The model identified 1.8% of the US population to be at a 10% or greater risk of suicide attempt. The most important risk factors were 3 questions about previous suicidal ideation or behavior; 3 items from the 12-Item Short Form Health Survey, namely feeling downhearted, doing activities less carefully, or accomplishing less because of emotional problems; younger age; lower educational achievement; and recent financial crisis. CONCLUSIONS AND RELEVANCEIn this study, after searching through more than 2500 survey questions, several well-known risk factors of suicide attempt were confirmed, such as previous suicidal behaviors and ideation, and new risks were identified, including functional impairment resulting from mental disorders and socioeconomic disadvantage. These results may help guide future clinical assessment and the development of new suicide risk scales.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with MRI and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1,042 youths (ages 11 to 23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF during a resting state was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis, and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state fMRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision-making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Taken together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence. Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision-making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence.