Faculty Bibliography

Evidence of comparing neural network differences between anxiety disorder subtypes is limited, while it is crucial to reveal the pathogenesis of anxiety disorders. The present study aimed to investigate specific and common resting-state functional connectivity (FC) networks in generalized anxiety disorder (GAD), panic disorder (PD), and healthy controls (HC). We employed the gRAICAR algorithm to decompose the resting-state fMRI into independent components and align the components across 61 subjects (22 GAD, 18 PD and 21 HC). The default mode network and precuneus network exhibited GAD-specific aberrance, the anterior default mode network showed atypicality specific to PD, and the right fronto-parietal network showed aberrance common to GAD and PD. Between GAD-specific networks, FC between bilateral dorsolateral prefrontal cortex (DLPFC) was positively correlated with interoceptive sensitivity. In the common network, altered FCs between DLPFC and angular gyrus, and between orbitofrontal cortex and precuneus, were positively correlated with anxiety severity and interoceptive sensitivity. The pathological mechanism of PD could closely relate to the dysfunction of prefrontal cortex, while GAD could involve more extensive brain areas, which may be related to fear generalization.

Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N = 369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

New large neuroimaging studies, such as the Adolescent Brain Cognitive Development study (ABCD) and Human Connectome Project (HCP) Development studies are adopting a new T1-weighted imaging sequence with prospective motion correction (PMC) in favor of the more traditional 3-Dimensional Magnetization-Prepared Rapid Gradient-Echo Imaging (MPRAGE) sequence. Here, we used a developmental dataset (ages 5-21, N = 348) from the Healthy Brain Network (HBN) Initiative to directly compare two widely used MRI structural sequences: one based on the Human Connectome Project (MPRAGE) and another based on the ABCD study (MPRAGE+PMC). We aimed to determine if the morphometric measurements obtained from both protocols are equivalent or if one sequence has a clear advantage over the other. The sequences were also compared through quality control measurements. Inter- and intra-sequence reliability were assessed with another set of participants (N = 71) from HBN that performed two MPRAGE and two MPRAGE+PMC sequences within the same imaging session, with one MPRAGE (MPRAGE1) and MPRAGE+PMC (MPRAGE+PMC1) pair at the beginning of the session and another pair (MPRAGE2 and MPRAGE+PMC2) at the end of the session. Intraclass correlation coefficients (ICC) scores for morphometric measurements such as volume and cortical thickness showed that intra-sequence reliability is the highest with the two MPRAGE+PMC sequences and lowest with the two MPRAGE sequences. Regarding inter-sequence reliability, ICC scores were higher for the MPRAGE1 - MPRAGE+PMC1 pair at the beginning of the session than the MPRAGE1 - MPRAGE2 pair, possibly due to the higher motion artifacts in the MPRAGE2 run. Results also indicated that the MPRAGE+PMC sequence is robust, but not impervious, to high head motion. For quality control metrics, the traditional MPRAGE yielded better results than MPRAGE+PMC in 5 of the 8 measurements. In conclusion, morphometric measurements evaluated here showed high inter-sequence reliability between the MPRAGE and MPRAGE+PMC sequences, especially in images with low head motion. We suggest that studies targeting hyperkinetic populations use the MPRAGE+PMC sequence, given its robustness to head motion and higher reliability scores. However, neuroimaging researchers studying non-hyperkinetic participants can choose either MPRAGE or MPRAGE+PMC sequences, but should carefully consider the apparent tradeoff between relatively increased reliability, but reduced quality control metrics when using the MPRAGE+PMC sequence.

Multilayer network models have been proposed as an effective means of capturing the dynamic configuration of distributed neural circuits and quantitatively describing how communities vary over time. Beyond general insights into brain function, a growing number of studies have begun to employ these methods for the study of individual differences. However, test-retest reliabilities for multilayer network measures have yet to be fully quantified or optimized, potentially limiting their utility for individual difference studies. Here, we systematically evaluated the impact of multilayer community detection algorithms, selection of network parameters, scan duration, and task condition on test-retest reliabilities of multilayer network measures (i.e., flexibility, integration, and recruitment). A key finding was that the default method used for community detection by the popular generalized Louvain algorithm can generate erroneous results. Although available, an updated algorithm addressing this issue is yet to be broadly adopted in the neuroimaging literature. Beyond the algorithm, the present work identified parameter selection as a key determinant of test-retest reliability; however, optimization of these parameters and expected reliabilities appeared to be dataset-specific. Once parameters were optimized, consistent with findings from the static functional connectivity literature, scan duration was a much stronger determinant of reliability than scan condition. When the parameters were optimized and scan duration was sufficient, both passive (i.e., resting state, Inscapes, and movie) and active (i.e., flanker) tasks were reliable, although reliability in the movie watching condition was significantly higher than in the other three tasks. The minimal data requirement for achieving reliable measures for the movie watching condition was 20 min, and 30 min for the other three tasks. Our results caution the field against the use of default parameters without optimization based on the specific datasets to be employed - a process likely to be limited for most due to the lack of test-retest samples to enable parameter optimization.

The collection of eye gaze information during functional magnetic resonance imaging (fMRI) is important for monitoring variations in attention and task compliance, particularly for naturalistic viewing paradigms (e.g., movies). However, the complexity and setup requirements of current in-scanner eye tracking solutions can preclude many researchers from accessing such information. Predictive eye estimation regression (PEER) is a previously developed support vector regression-based method for retrospectively estimating eye gaze from the fMRI signal in the eye's orbit using a 1.5-min calibration scan. Here, we provide confirmatory validation of the PEER method's ability to infer eye gaze on a TR-by-TR basis during movie viewing, using simultaneously acquired eye tracking data in five individuals (median angular deviation < 2°). Then, we examine variations in the predictive validity of PEER models across individuals in a subset of data (n = 448) from the Child Mind Institute Healthy Brain Network Biobank, identifying head motion as a primary determinant. Finally, we accurately classify which of the two movies is being watched based on the predicted eye gaze patterns (area under the curve = 0.90 ± 0.02) and map the neural correlates of eye movements derived from PEER. PEER is a freely available and easy-to-use tool for determining eye fixations during naturalistic viewing.

Background: Transcranial Direct Current Stimulation (TDCS)is a brain stimulation technique which some studies have suggested may improve cognition and decrease auditory hallucinations in patients with schizophrenia. We conducted a study of a study of effects of tDCS on cognition, symptoms, and brain connectivity in inpatients with relatively stable chronic schizophrenics in China who had substantial cognitive deficits but were not chosen for prominent auditory hallucinations. Method(s): Patients participated in a double blind study of 10 sessions of active or sham tDCS and followed up lasting up to 1 month. Patient were evaluated for cognitive changes by MATRICS, PASAT and COGSTATE, for symptoms on the PANSS scale, and for brain changes with fMRI for resting state and during active n-back task. Result(s): There were no significant (P<.05) changes in cognitive scores in active vs sham patients after 10 tDCS sessions compared to baseline, but MATRICS Speed of Processing scores and 1 back memory improved over testing times in the active tDCS group over several weeks (P<.05) and there were trends for improvement in other measures. The were no significant change in psychiatric symptoms. fMRI scans showed significant increases in brain activation in R and L middle frontal gurus and differences in activation on a n-back task after 10 sessions of active vs sham tDCS. Conclusion(s): Effects of tDCS in this Chinese sample did not replicate the marked cognitive improvement seen in our earlier U.S. study, but there were selective improvements in speed of processing and n-back. 10 sessions of tDCS produced significant effects on increasing brain activation in selected areas differentially in active vs sham treated subjects in resting state and during an active n-back task. 2 Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique which has shown cognitive and clinical effects in patients with schizophrenia and depression as well as controls, and there is preliminary evidence it may also effect brain networks. Its comparatively lower cost, low-side effects, and ease of administration may make it a more easily administered therapy to a wide population of patients, if efficacy can be consistently demonstrated. In an earlier study (Smith et al. 2015), in schizophrenic outpatients in the United States, we presented evidence from a double-blind study that 5 sessions of active 2 ma tDCS compared to Sham, produced statistically significant improvement in MATRICS battery scores. 3 Methods: We now report results from a larger double-blind study of active vs sham tDCS stimulation in 45 relatively stable inpatients with schizophrenia studied at the Shanghai Mental Health Center in China. Active and sham tDCS administration followed the procedures with placement of electrodes, current and other procedures described in detail in our previous published research (Smith et al. 2015). Placement of electrodes for tDCS had the anode placed over LDLPFC (F3) and the cathode over the contralateral supraorbital ridge (Fp2). The active tDCS group was stimulated with a 2 mA current for 20minutes. The sham group had stimulation with 2 mA lasting only 45 seconds, though the electrodes remained in place for 20 minutes. The main cognitive outcome measures were the composite and domain scores on the Chinese version of the MATRIC (MCCB) battery (Nuechterlein et al. 2008), which was administered at baseline, after 10 sessions of tDCS, and 2 and 4 weeks after completion of the 10^th session. Because the Chinese version of the MCCB does not contain the verbal working memory test (LNS), we used an additional task to test for verbal working memory, the Paced Auditory Serial Addition Task (PASAT)(Gronwall 1977), using the 3 second presentation module, which was evaluated at the same time points as the MATRICS battery. Additionally, we used components of the CogState battery (CS) using CS tasks - identification task, n-back (1-back/2-back). Patients were evaluated for changes in psychopathology with the PANSS scale at baseline and after completion of 10 tDCS sessions and 2 weeks and 4 weeks later. Changes in brain activation were evaluated with fMRI Brain Scans at baseline and after 10 sessions using a Siemens Trio 3.0 Tesla MRI scanner with a standard 32-channel head coil. fMRI data was evaluated for: a) Changes on resting state intensity activation, and b) Before and after 10 sessions of tDCS, participants perform 0 back and 2 back tasks while scanned in fMRI. Cortical activation during 0 back and 2 back tasks were analyzed to check the difference between low and high load tasks. For (a) resting state fMRI data were preprocessed by Configurable Pipeline for the Analysis of Connectomes. Group analysis was conducted by FMRIB's Software Library (FSL) proprietary mixed effects analysis (FLAMEO). Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. For (b) fMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.00, part of FSL. Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. 1 Results: Behavioral measures: There were no significant differences (P<=.05) in effect of Active vs. Sham tDCS on any cognitive measure tested shortly after completion of 10 sessions of stimulation. However, the active tDCS group showed trends for better improvement vs. sham group, on testing done at two and/or 4 weeks after 10 tDCS session. At the two-week time point the difference from baseline improvement scores of the MATRICS Overall Composite Score and Speed of Processing Domain score, as well as a measure of accuracy on CogState 1-back was significantly better in active than sham groups at uncorrected significance levels (P<.05). Brain Activation: In testing with the n-back during fMRI scans, in active tDCS group, we found significant improvement in accuracy of 0 back condition after 10 sessions of tDCS (p<0.01). In the active tDCS vs. sham group task activation decreased in right middle frontal gyrus after 10 sessions of tDCS for the 0 back condition. No changes were found under the 2 back condition. Comparing the 2 back and 0 back conditions, increased activation in bilateral middle frontal gyrus was evident after 10 sessions of active tDCS vs sham. In resting state brain scans, the active tDCS group vs sham showed significantly increased activation in the R middle frontal and superior gyrus and L middle frontal gyrus. [Figure presented] N=45, Active tDcs-24, sham tDCS=2. Analysis is result of mixed-model analysis including all subjects who had value for in the at baseline and after 10 sessions tDCS. Significance of difference between the active vs sham values at specific time point by t-test from mixed-model output: *P<=05 **P<=01. Benjamini-Hochberg corrected significance levels taking into account the three time-point comparisons: ^Asignificant at (a=.05) [Figure presented] 2 Discussion and Conclusion(s): The results of this study in Chinese schizophrenics did not replicate the immediate pro-cognitive effects directly after a series to tDCS sessions that we found in the U.S. sample but suggest possible pro-cognitive effects 2 or 4 weeks after treatment. The long term effects to tDCS on cognitive function reported in this and some other studies suggest that some of the positive effects of tDCS may require a consolidation period to improve some aspects of cognitive functions. The fMRI data show that the tDCS treatment had significant effects on brain activation, and the changes in n-back performance in the active tDCS group during fMRI scans suggest increased capacity for working memory performance. References: Gronwall DM (1977) Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 44: 367-73. Nuechterlein K, Green M, Kern R, Baade L, Barch D, Cohen J, Essock S, Fenton W, Frese F, Gold J, Goldberg T, Heaton R, Keefe R, Kraemer H, Seidman L, Stover E, Weinberger D, Young A, Zalcan S, Mardder S (2008) The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. The American journal of psychiatry. Smith RC, Boules S, Mattiuz S, Youssef M, Tobe RH, Sershen H, Lajtha A, Nolan K, Amiaz R, Davis JM (2015) Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study. Schizophrenia research 168: 260-266.