Faculty Bibliography

For this Debate article, we asked two experts in the field, Prof. James Swanson (University of California at Irvine) and Prof. David Coghill (University of Melbourne), to argue for "against" and "for," respectively, in relation to the motion "Are stimulant medications for ADHD effective in the long-term"?

Brain function is characterized by a convolution of various biochemical and physiological processes, raising the interest whether resting-state functional connectivity derived from hemodynamic scales shows underlying metabolic synchronies. Increasing evidence suggests that metabolic connectivity based on glucose consumption associated PET recordings may serve as a marker of cognitive functions and neuropathologies. However, to what extent fMRI-derived resting-state brain connectivity can also be characterized based on dynamic fluctuations of glucose metabolism and how metabolic connectivity is influenced by [¹⁸F]FDG pharmacokinetics remains unsolved. Simultaneous PET/MRI measurements were performed in a total of 26 healthy male Lewis rats. Simultaneously to resting-state fMRI scans, one cohort (n = 15) received classical bolus [¹⁸F]FDG injections and dynamic PET images were recorded. In a second cohort (n = 11) [¹⁸F]FDG was constantly infused over the entire functional PET/MRI scans. Resting-state fMRI and [¹⁸F]FDG-PET connectivity was evaluated using a graph-theory based correlation approach and compared on whole-brain level and for a default-mode network-like structure. Further, pharmacokinetic and tracer uptake influences on [¹⁸F]FDG-PET connectivity results were investigated based on the different PET protocols. By integrating simultaneous resting-state fMRI and dynamic [¹⁸F]FDG-PET measurements in the rat brain, we identified homotopic correlations between both modalities, suggesting an underlying synchrony between hemodynamic processes and glucose consumption. Furthermore, the presence of the prominent resting-state default-mode network-like structure was not only depicted on a functional scale but also from dynamic fluctuations of [¹⁸F]FDG. In addition, the present findings demonstrated strong pharmacokinetic and tracer uptake dependencies of [¹⁸F]FDG-PET connectivity outcomes. This study highlights the application of dynamic [¹⁸F]FDG-PET to study cognitive brain functions and to decode underlying brain networks in the resting-state. Thereby, PET-derived connectivity outcomes indicated strong dependencies on tracer application regimens and subsequent time-varying tracer pharmacokinetics.

Poststroke aphasia (PSA) results from direct effect of focal lesions and dysfunction of distributed language networks. However, how flexible the activity at specific nodes control global dynamics is currently unknown. In this study, we demonstrate that alterations in the regional activity may cause imbalances between segregation and integration in temporo-spatial pattern, and the transient dynamics are disrupted in PSA patients. Specifically, we applied dynamic framework to eyes-closed resting-state functional MRI data from PSA patients (n = 17), and age-, gender-, and education-matched healthy controls (HCs, n = 20). Subsequently, we calculated two basis brain organizational principles: "dynamic segregation," obtained from dynamic amplitude of low-frequency fluctuations (dALFF), which represent the specialized processing within interconnected brain regions; and "dynamic integration," obtained from dynamic functional connectivity, which measures the efficient communication between interconnected brain regions. We found that both measures were decreased in the PSA patients within the left frontal and temporal subregions compared to the HCs. PSA patients displayed increased flexibility of interaction between left temporo-frontal subregions and right temporo-parieto-frontal subnetworks. Furthermore, we found that dALFF in the pars triangularis of left inferior frontal gyrus was associated with aphasia quotient. These findings suggest that the reduced temporal flexibility of regional activity in language-relevant cortical regions in PSA is related to the disrupted organization of intrahemispheric networks, leading to a loss of the corresponding functions. By using dynamic framework, our results offer valuable information about the alterations in segregation and integration of spatiotemporal information across networks and illuminate how dysfunction in flexible activity may underlie language deficits in PSA.

Research suggests that irritability and defiance are distinct dimensions of youth oppositionality that are differentially associated with internalizing and conduct problems, respectively. Because much of this evidence has emerged with limited psychometric evaluation, we conducted the first multi-informant examination of selected Child Behavior Checklist (CBCL) and Youth Self Report (YSR) items for measuring irritability and defiance in a large clinical sample. Clinically referred youths (N = 1,030; ages 6-15; 43% female, 42% ethnic minority) were assessed prior to treatment using multi-informant rating scales and diagnostic interviews. Analyses examined factor structure, invariance, internal consistency, multi-informant patterns, and convergent, discriminant, and criterion validity with internalizing and externalizing problems/disorders. A correlated 2-factor model of irritability (stubborn/sullen/irritable, mood, temper) and defiance (argues, disobeys-home, disobeys-school) fit well for both informants. Adequate measurement invariance and scale consistency was consistently found for parent-report but not youth-report. With both informants, all hypothesized convergent and discriminant validity associations were supported: irritability and defiance with internalizing and conduct scales, respectively. However, hypothesized criterion validity associations were largely found only by parent-report: irritability with anxiety and depressive disorders, defiance with conduct disorder, and both with oppositional defiant disorder. Results consistently supported the reliability and validity of the CBCL irritability and defiance scales, with somewhat less consistent support for the YSR scales. Thus, CBCL items may provide psychometrically sound assessment of irritability and defiance, whereas further research is needed to advance youth-report and multi-informant strategies. Results also provide further support for a two subdimension model of oppositional defiant disorder symptoms that includes irritability and defiance.

The delay aversion hypothesis argues that the tendency for impulsive choice (preference for smaller sooner over larger later rewards) is motivated by the escape of negative affective states associated with delay. This model predicts that individuals with ADHD find the imposition of delay before an outcome or event especially aversive and its escape reinforcing. Consistent with this, fMRI studies show that ADHD is associated with amygdala hyper-sensitivity to cues of delay. However, evidence that delay escape is reinforcing is lacking. Here we extend fMRI research by using electrophysiological methods to study the reinforcing properties of delay-escape in ADHD. Thirty controls and 25 adolescents with ADHD aged 10-15 years performed the Escape Delay Incentive (EDI) task- in which pre-target cues indicated three conditions: i) CERTAIN DELAY: delay would follow a response irrespective of response speed ii) CONDITIONAL DELAY: delay would only follow if the response was too slow and iii) NO DELAY: delay would follow the response whatever the speed. We focused on the Contingent Negative Variation (CNV), a cue-evoked marker of motivated response preparation, across two time windows (CNV1 and CNV2). We took measures of parent, teacher and self-rated ADHD symptoms, task performance (RT) and self-rated delay aversion. We isolated CNV components and compared these between ADHD and controls. Adolescents with ADHD displayed a larger CNV2 to the CONDITIONAL DELAY than the CERTAIN DELAY cues compared to controls. However, this effect was not mirrored at the performance level and was unrelated to self-reported delay aversion. Our study provides the first ERP evidence that delay escape differentially reinforcers neural activation of attention preparation in ADHD cases. Future studies should examine the impact of varying cognitive load on task EDI performance.

BACKGROUND:Identifying risk factors of individuals in a clinical-high-risk state for psychosis are vital to prevention and early intervention efforts. Among prodromal abnormalities, cognitive functioning has shown intermediate levels of impairment in CHR relative to first-episode psychosis and healthy controls, highlighting a potential role as a risk factor for transition to psychosis and other negative clinical outcomes. The current study used the AX-CPT, a brief 15-min computerized task, to determine whether cognitive control impairments in CHR at baseline could predict clinical status at 12-month follow-up. METHODS:Baseline AX-CPT data were obtained from 117 CHR individuals participating in two studies, the Early Detection, Intervention, and Prevention of Psychosis Program (EDIPPP) and the Understanding Early Psychosis Programs (EP) and used to predict clinical status at 12-month follow-up. At 12 months, 19 individuals converted to a first episode of psychosis (CHR-C), 52 remitted (CHR-R), and 46 had persistent sub-threshold symptoms (CHR-P). Binary logistic regression and multinomial logistic regression were used to test prediction models. RESULTS:Baseline AX-CPT performance (d-prime context) was less impaired in CHR-R compared to CHR-P and CHR-C patient groups. AX-CPT predictive validity was robust (0.723) for discriminating converters v. non-converters, and even greater (0.771) when predicting CHR three subgroups. CONCLUSIONS:These longitudinal outcome data indicate that cognitive control deficits as measured by AX-CPT d-prime context are a strong predictor of clinical outcome in CHR individuals. The AX-CPT is brief, easily implemented and cost-effective measure that may be valuable for large-scale prediction efforts.

A major challenge in neuroscience is understanding how brain function emerges from the connectome. Most current methods have focused on quantifying functional connectomes in gray-matter (GM) signals obtained from functional magnetic resonance imaging (fMRI), while signals from white-matter (WM) have generally been excluded as noise. In this study, we derived a functional connectome from WM resting-state blood-oxygen-level-dependent (BOLD)-fMRI signals from a large cohort (n = 488). The WM functional connectome exhibited weak small-world topology and nonrandom modularity. We also found a long-term (i.e., over 10 months) topological reliability, with topological reproducibility within different brain parcellation strategies, spatial distance effect, global and cerebrospinal fluid signals regression or not. Furthermore, the small-worldness was positively correlated with individuals' intelligence values (r = .17, p_corrected = .0009). The current findings offer initial evidence using WM connectome and present additional measures by which to uncover WM functional information in both healthy individuals and in cases of clinical disease.

BACKGROUND:Youth involved in the juvenile justice system (YIJJ) have high rates of substance use problems; however, rates of YIJJ engagement in substance use services is low. Barriers to service engagement include lack of appropriate screening and connection to services by the juvenile justice system, as well as lack of resources for delivering evidence-based treatment in community-based settings. To address these barriers, this paper describes a protocol for a type 1 hybrid design to (1) implement universal substance use screening for YIJJ; (2) implement and evaluate the feasibility and effectiveness of a brief, three-session substance use interventions based in motivational interviewing for youth with mild/moderate substance use: Teen Intervene (an individual-based intervention); (3) implement ENCOMPASS, an evidence-based substance use intervention based in motivational enhancement and cognitive behavioral therapy for youth with severe substance use; and (4) evaluate facilitators and barriers to implementing these interventions for mild to severe substance use among YIJJ in community mental health centers (CMHC). METHODS/DESIGN/METHODS:Using a hybrid type 1 clinical effectiveness-implementation design, we will collaborate with CMHCs and juvenile justice in two rural Indiana counties. Guided by the EPIS (exploration, preparation, implementation, sustainability) framework, we will measure factors that affect implementation of substance use screening in juvenile justice and implementation of substance use interventions in CMHCs utilizing self-reports and qualitative interviews with juvenile justice and CMHC staff pre- and post-implementation. YIJJ with mild/moderate substance use will receive a brief interventions and YIJJ with severe substance use will receive ENCOMPASS. We will measure the effectiveness of a brief and comprehensive intervention by assessing changes in substance use across treatment. We anticipate recruiting 160 YIJJ and their caregivers into the study. We will assess intervention outcomes utilizing baseline, 3-, and 6-month assessments. DISCUSSION/CONCLUSIONS:Findings have the potential to improve screening and intervention services for YIJJ.

A critical task in psychotherapy research is identifying the conditions within which treatment benefits can be replicated and outside of which those benefits are reduced. We tested the robustness of beneficial effects found in two previous trials of the modular Child STEPs treatment program for youth anxiety, depression, trauma, and conduct problems. We conducted a randomized trial, with two significant methodological changes from previous trials: (a) shifting from cluster- to person-level randomization, and (b) shifting from individual to more clinically feasible group-based consultation with STEPs therapists. Fifty community clinicians from multiple outpatient clinics were randomly assigned to receive training and consultation in STEPs (n = 25) or to provide usual care (UC; n = 25). There were 156 referred youths-ages 6-16 (M = 10.52, SD = 2.53); 48.1% male; 79.5% Caucasian, 12.8% multiracial, 4.5% Black, 1.9% Latino, 1.3% Other-who were randomized to STEPs (n = 77) or UC (n = 79). Following previous STEPs trials, outcome measures included parent- and youth-reported internalizing, externalizing, total, and idiographic top problems, with repeated measures collected weekly during treatment and longer term over 2 years. Participants in both groups showed statistically significant improvement on all measures, leading to clinically meaningful problem reductions. However, in contrast to previous trials, STEPs was not superior to UC on any measure. As with virtually all treatments, the benefits of STEPs may depend on the conditions-for example, of study design and implementation support-in which it is tested. Identifying those conditions may help guide appropriate use of STEPs, and other treatments, in the future.

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.