Faculty Bibliography

The examination of functional connectivity in fMRI data collected during task-free "rest" has provided a powerful tool for studying functional brain organization. Limitations of this approach include susceptibility to head motion artifacts and participant drowsiness or sleep. These issues are especially relevant when studying young children or clinical populations. Here we introduce a movie paradigm, Inscapes, that features abstract shapes without a narrative or scene-cuts. The movie was designed to provide enough stimulation to improve compliance related to motion and wakefulness while minimizing cognitive load during the collection of functional imaging data. We compare Inscapes to eyes-open rest and to age-appropriate movie clips in healthy adults (Ocean's Eleven, n=22) and a pilot sample of typically developing children ages 3-7 (Fantasia, n=13). Head motion was significantly lower during both movies relative to rest for both groups. In adults, movies decreased the number of participants who self-reported sleep. Intersubject correlations, used to quantify synchronized, task-evoked activity across movie and rest conditions in adults, involved less cortex during Inscapes than Ocean's Eleven. To evaluate the effect of movie-watching on intrinsic functional connectivity networks, we examined mean functional connectivity using both whole-brain functional parcellation and network-based approaches. Both inter- and intra-network metrics were more similar between Inscapes and Rest than between Ocean's Eleven and Rest, particularly in comparisons involving the default network. When comparing movies to Rest, the mean functional connectivity of somatomotor, visual and ventral attention networks differed significantly across various analyses. We conclude that low-demand movies like Inscapes may represent a useful intermediate condition between task-free rest and typical narrative movies while still improving participant compliance. Inscapes is publicly available for download at headspacestudios.org/inscapes.

Working memory (WM) is central to the acquisition of knowledge and skills throughout childhood and adolescence. While numerous behavioral and task-based functional magnetic resonance imaging (fMRI) studies have examined WM development, few have used resting-state fMRI (R-fMRI). Here, we present a systematic R-fMRI examination of age-related differences in the neural indices of verbal WM performance in a cross-sectional pediatric sample (ages: 7-17; n=68), using data-driven approaches. Verbal WM capacity was measured with the digit span task, a commonly used educational and clinical assessment. We found distinct neural indices of digit span forward (DSF) and backward (DSB) performance, reflecting their unique neuropsychological demands. Regardless of age, DSB performance was related to intrinsic properties of brain areas previously implicated in attention and cognitive control, while DSF performance was related to areas less commonly implicated in verbal WM storage (precuneus, lateral visual areas). From a developmental perspective, DSF exhibited more robust age-related differences in brain-behavior relationships than DSB, and implicated a broader range of networks (ventral attention, default, somatomotor, limbic networks) - including a number of regions not commonly associated with verbal WM (angular gyrus, subcallosum). These results highlight the importance of examining the neurodevelopment of verbal WM and of considering regions beyond the "usual suspects".

To date, only one study has examined test-retest reliability of resting state fMRI (R-fMRI) in children, none in clinical developing groups. Here, we assessed short-term test-retest reliability in a sample of 46 children (11-17.9 years) with attention-deficit/hyperactivity disorder (ADHD) and 57 typically developing children (TDC). Our primary test-retest reliability measure was the intraclass correlation coefficient (ICC), quantified for a range of R-fMRI metrics. We aimed to (1) survey reliability within and across diagnostic groups, and (2) compare voxel-wise ICC between groups. We found moderate-to-high ICC across all children and within groups, with higher-order functional networks showing greater ICC. Nearly all R-fMRI metrics exhibited significantly higher ICC in TDC than in children with ADHD for one or more regions. In particular, posterior cingulate and ventral precuneus exhibited group differences in ICC across multiple measures. In the context of overall moderate-to-high test-retest reliability in children, regional differences in ICC related to diagnostic groups likely reflect the underlying pathophysiology for ADHD. Our currently limited understanding of the factors contributing to inter- and intra-subject variability in ADHD underscores the need for large initiatives aimed at examining their impact on test-retest reliability in both clinical and developing populations.

INTRODUCTION: Our aim was to assess differences in movement measures in attention-deficit/hyperactivity disorder (ADHD) vs. typically developing (TD) controls. METHODS: We performed meta-analyses of published studies on motion measures contrasting ADHD with controls. We also conducted a case-control study with children/adolescents (n=61 TD, n=62 ADHD) and adults (n=30 TD, n=19 ADHD) using the McLean motion activity test, semi-structured diagnostic interviews and the behavior rating inventory of executive function and Conners (parent, teacher; self) rating scales. RESULTS: Meta-analyses revealed medium-to-large effect sizes for actigraph (standardized mean difference [SMD]: 0.64, 95% confidence interval (CI): 0.43, 0.85) and motion tracking systems (SDM: 0.92, 95% CI: 0.65, 1.20) measures in differentiating individuals with ADHD from controls. Effects sizes were similar in studies of children/adolescents ([SMD]: 0.75, 95% CI: 0.50, 1.01) and of adults ([SMD]: 0.73, 95% CI: 0.46, 1.00). In our sample, ADHD groups differed significantly in number of head movements (p=0.02 in children; p=0.002 in adults), displacement (p=0.009/p<0.001), head area (p=0.03/p<0.001), spatial complexity (p=0.06/p=0.02) and temporal scaling (p=0.05/p=0.04). Mean effect sizes were non-significantly larger (d=0.83, 95% CI: 0.20, 1.45) in adults vs. children/adolescents with ADHD (d=0.45, 95% CI: 0.08, 0.82). In the concurrent go/no-go task, reaction time variability was significantly greater in ADHD (p<0.05 in both age groups) than controls. CONCLUSIONS: Locomotor hyperactivity remains core to the construct of ADHD even in adults. Our results suggest that objective locomotion measures may be particularly useful in evaluating adults with possible ADHD.

Psychostimulants such as methylphenidate and amphetamine are the first-line pharmacologic treatments for Attention-Deficit/Hyperactivity Disorder (ADHD). They are considered prototypical cognitive enhancers but their effects on standard laboratory indices of cognitive function are modest when administered acutely, and even less substantial chronically. However, large-scale observational studies in patients with ADHD have detected stimulant-associated decreases of criminal acts, transportation accidents, slightly improved academic performance, and possible protection against drug abuse. These effects likely reflect modulation of broader domains such as emotional regulation and motivation which have been under-examined. Efforts to clarify the ontological relations between cognitive tasks and their underlying constructs should be incorporated into the Research Domain Criteria project and similar harmonization initiatives.

We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naive children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. Hum Brain Mapp 36:2544-2557, 2015. (c) 2015 Wiley Periodicals, Inc.

Objective: To assess group-differences in movement measures in published studies contrasting Attention-Deficit/Hyperactivity Disorder (ADHD) vs. controls. Background: ADHD diagnoses continue to be completely based on clinical history, which is subjective and subject to recall bias. In response, investigators have proposed incorporating objective measures such as locomotor activity which can be measured with actigraphy or with a high spatial and temporal resolution infrared camera. In May 2014, the United States Food and Drug Administration cleared an example of the latter, the Qb-Test, as a device to be used in supporting the diagnosis of ADHD. A review of the literature did not reveal any prior meta-analyses of such data. Methods: We performed a systematic review and meta-analysis of published studies on motion measures contrasting individuals diagnosed with ADHD and healthy controls. Two authors reviewed a total of 89 abstracts culled from an initial search of 356. After applying inclusion and exclusion criteria, 13 papers were included in our analyses of actigraphy and five papers in analyses of motion tracking systems. Results: The combined sample sizes were 406 patients with ADHD versus 359 controls with actigraphy data and 164 patients with ADHD versus 156 controls with motion tracking system data. Meta-analyses revealed medium effect sizes for actigraphy (standardized mean difference [SMD]: 0.64, 95 % CI: 0.43, 0.85) and large effects for motion tracking systems (SMD: 0.92, 95 % CI: 0.65, 1.20) in differentiating individuals with ADHD from controls. Conclusions: When measured objectively, locomotor hyperactivity robustly differentiates groups of patients with ADHD from healthy controls. Inclusion of objective locomotion measures is likely to be useful in circumstances in which ancillary information is not available, such as when evaluating adults with possible ADHD. However, even the relatively large effect sizes reported to date are unlikely to yield clinically actionable information for individual patients on their own. How to best incorporate such objective data in the diagnostic process remains unclear

We propose a novel method for neurodevelopmental brain mapping that displays how an individual's values for a quantity of interest compare with age-specific norms. By estimating smoothly age-varying distributions at a set of brain regions of interest, we derive age-dependent region-wise quantile ranks for a given individual, which can be presented in the form of a brain map. Such quantile rank maps could potentially be used for clinical screening. Bootstrap-based confidence intervals are proposed for the quantile rank estimates. We also propose a recalibrated Kolmogorov-Smirnov test for detecting group differences in the age-varying distribution. This test is shown to be more robust to model misspecification than a linear regression-based test. The proposed methods are applied to brain imaging data from the Nathan Kline Institute Rockland Sample and from the Autism Brain Imaging Data Exchange (ABIDE) sample.