Faculty Bibliography

Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5-21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n=664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis).

Psychiatric disorders are amongst the most prevalent and impairing conditions in childhood and adolescence. Unfortunately, it is well known that general practitioners (GPs) and other frontline health providers (i.e., child protection workers, public health nurses, and pediatricians) are not adequately trained to address these ubiquitous problems (Braddick et al. Child and Adolescent mental health in Europe: infrastructures, policy and programmes, European Communities, 2009; Levav et al. Eur Child Adolesc Psychiatry 13:395-401, 2004). Advances in technology may offer a solution to this problem with clinical decision support systems (CDSS) that are designed to help professionals make sound clinical decisions in real time. This paper offers a systematic review of currently available CDSS for child and adolescent mental health disorders prepared according to the PRISMA-Protocols (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols). Applying strict eligibility criteria, the identified studies (n = 5048) were screened. Ten studies, describing eight original clinical decision support systems for child and adolescent psychiatric disorders, fulfilled inclusion criteria. Based on this systematic review, there appears to be a need for a new, readily available CDSS for child neuropsychiatric disorder which promotes evidence-based, best practices, while enabling consideration of national variation in practices by leveraging data-reuse to generate predictions regarding treatment outcome, addressing a broader cluster of clinical disorders, and targeting frontline practice environments.

Reports an error in "Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: A cross-sectional mega-analysis" by Martine Hoogman, Janita Bralten, Derrek P. Hibar, Maarten Mennes, Marcel P. Zwiers, Lizanne S. J. Schweren, Kimm J. E. van Hulzen, Sarah E. Medland, Elena Shumskaya, Neda Jahanshad, Patrick de Zeeuw, Eszter Szekely, Gustavo Sudre, Thomas Wolfers, Alberdingk M. H. Onnink, Janneke T. Dammers, Jeanette C. Mostert, Yolanda Vives-Gilabert, Gregor Kohls, Eileen Oberwelland, Jochen Seitz, Martin Schulte-Ruther, Sara Ambrosino, Alysa E. Doyle, Marie F. Hovik, Margaretha Dramsdahl, Leanne Tamm, Theo G. M. van Erp, Anders Dale, Andrew Schork, Annette Conzelmann, Kathrin Zierhut, Ramona Baur, Hazel McCarthy, Yuliya N. Yoncheva, Ana Cubillo, Kaylita Chantiluke, Mitul A. Mehta, Yannis Paloyelis, Sarah Hohmann, Sarah Baumeister, Ivanei Bramati, Paulo Mattos, Fernanda Tovar-Moll, Pamela Douglas, Tobias Banaschewski, Daniel Brandeis, Jonna Kuntsi, Philip Asherson, Katya Rubia, Clare Kelly, Adriana Di Martino, Michael P. Milham, Francisco X. Castellanos, Thomas Frodl, Mariam Zentis, Klaus-Peter Lesch, Andreas Reif, Paul Pauli, Terry L. Jernigan, Jan Haavik, Kerstin J. Plessen, Astri J. Lundervold, Kenneth Hugdahl, Larry J. Seidman, Joseph Biederman, Nanda Rommelse, Dirk J. Heslenfeld, Catharina A. Hartman, Pieter J. Hoekstra, Jaap Oosterlaan, Georg von Polier, Kerstin Konrad, Oscar Vilarroya, Josep Antoni Ramos-Quiroga, Joan Carles Soliva, Sarah Durston, Jan K. Buitelaar, Stephen V. Faraone, Philip Shaw, Paul M. Thompson and Barbara Franke (The Lancet Psychiatry, 2017[Apr], Vol 4[4], 310-319). In the original article, there were some errors. Corrections are present in the erratum. (The abstract of the original article appeared in record 2017-14573-025).

Naturalistic viewing paradigms such as movies have been shown to reduce participant head motion and improve arousal during fMRI scanning relative to task-free rest, and have been used to study both functional connectivity and stimulus-evoked BOLD-signal changes. These task-based hemodynamic changes are synchronized across subjects and involve large areas of the cortex, and it is unclear whether individual differences in functional connectivity are enhanced or diminished under such naturalistic conditions. This work first aims to characterize variability in BOLD-signal based functional connectivity (FC) across 2 distinct movie conditions and eyes-open rest (n=31 healthy adults, 2 scan sessions each). We found that movies have higher within- and between-subject correlations in cluster-wise FC relative to rest. The anatomical distribution of inter-individual variability was similar across conditions, with higher variability occurring at the lateral prefrontal lobes and temporoparietal junctions. Second, we used an unsupervised test-retest matching algorithm that identifies individual subjects from within a group based on FC patterns, quantifying the accuracy of the algorithm across the three conditions. The movies and resting state all enabled identification of individual subjects based on FC matrices, with accuracies between 61 and 100%. Overall, pairings involving movies outperformed rest, and the social, faster-paced movie attained 100% accuracy. When the parcellation resolution, scan duration, and number of edges used were increased, accuracies improved across conditions, and the pattern of movies>rest was preserved. These results suggest that using dynamic stimuli such as movies enhances the detection of FC patterns that are unique at the individual level.

In this pilot study, we examined training effects of a computerized working memory program on resting state functional magnetic resonance imaging (fMRI) measures in children with neurofibromatosis type 1 (NF1). We contrasted pre- with post-training resting state fMRI and cognitive measures from 16 participants (nine males; 11.1 +/- 2.3 years) with NF1 and documented working memory difficulties. Using non-parametric permutation test inference, we found significant regionally specific differences (family-wise error corrected) in two of four voxel-wise resting state measures: fractional amplitude of low frequency fluctuations (indexing peak-to-trough intensity of spontaneous oscillations) and regional homogeneity (indexing local intrinsic synchrony). Some cognitive task improvement was observed as well. These preliminary findings suggest that regionally specific changes in resting state fMRI indices may be associated with treatment-related cognitive amelioration in NF1. Nevertheless, current results must be interpreted with caution pending independent controlled replication.

Adolescents are generally characterized as impulsive. However, impulsivity is a multi-dimensional construct that involves multiple component processes. Which of these components contribute to adolescent impulsivity is currently unclear. This study focused on the neural mechanisms underlying individual differences in distinct components of temporal discounting (TD), i.e., the preference for smaller immediate rewards over larger delayed rewards. Participants were 58 adolescents (12-16 years-old) who performed an fMRI TD task with both monetary and snack rewards. Using mixed-effects modeling, we determined participants' average impatience, and further decomposed TD choices into: 1) amount sensitivity (unique contribution of the magnitude of the immediate reward); and 2) delay sensitivity (unique contribution of delay duration). Adolescents' average impatience was positively correlated with frontoparietal and ventral striatal activity during delayed reward choices, and with ventromedial prefrontal cortex activity during immediate reward choices. Adolescents' amount sensitivity was positively associated with ventral striatal and dorsal anterior cingulate cortex activity during immediate reward choices. Delay sensitivity was positively correlated with inferior parietal cortex activity during delayed reward choices. As expected, snacks were discounted more steeply than money, and TD of both reward types was associated with overlapping activation in the inferior parietal cortex. Exploring whether testosterone or estradiol were associated with TD and its neural correlates revealed no significant associations. These findings indicate that distinct components contribute uniquely to TD choice and that individual differences in amount sensitivity are uniquely associated with activation of reward valuation areas, while individual differences in delay sensitivity are uniquely associated with activation of cognitive control areas.

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60). R-fMRI sessions were conducted under light anesthesia at both ages. Offspring reared with insufficient bedding (that is, maltreated) displayed enduring negative affective behaviors. Amygdala-prefrontal cortex (PFC) functional connectivity increased significantly from adolescence to adulthood in controls, but not in maltreated animals. We computed the fractional amplitude of low-frequency fluctuations (fALFF), an index of intrinsic brain activity, and found that fALFF in medial prefrontal cortex and anterior cingulate cortex (MPFC/ACC) increased significantly with age in controls but remained unchanged in maltreated animals during adolescence and adulthood. We used a seed-based analysis to explore changes in functional connectivity between this region and the whole brain. Compared with controls, maltreated animals demonstrated reduced functional connectivity between MPFC/ACC and left caudate/putamen across both ages. Functional connectivity between MPFC/ACC and right caudate/putamen showed a group by age interaction: decreased in controls but increased in maltreated animals. These data suggest that maltreatment induces vulnerability to psychopathology and is associated with differential developmental trajectories of prefrontal and subcortical circuits underlying affect regulation.