Faculty Bibliography

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.

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.

OBJECTIVES/OBJECTIVE:To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently under- or misdiagnosed, and under- or mistreated, often for years. METHODS:We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first-lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies. RESULTS:Cyclothymic features, a family history of BD, retrospectively reported attenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like [hypo]mania often appears to be long enough to encourage early identification and timely intervention. CONCLUSIONS:The predictive value of any risk factor identified remains largely unknown. Prospective controlled studies are urgently needed for prevention and effective treatment.

BACKGROUND:The cortisol awakening response (CAR) is characterised by an increase in cortisol in the 30 to 60 min after waking. Research has found significant associations between an atypical CAR and symptoms of stress and anxiety in typically developing (TD) children and adolescents. A number of studies have explored the CAR in autism spectrum disorder (ASD), but no evidence synthesis is available to date. OBJECTIVE AND METHODS/OBJECTIVE:Based on a preregistered protocol (PROSPERO: CRD42017051187), we carried out a systematic review (SR) and meta-analysis (MA) of CAR studies to explore potential significant differences between children and adolescents with ASD and TD controls. Web of Science, PubMed and PsychInfo were searched until January 2019. A random-effects model was used to pool studies and we used the Newcastle-Ottawa scale (NOS) to assess study quality and risk of bias. FINDINGS/RESULTS:DISCUSSION AND CLINICAL IMPLICATIONS: Given the relatively few studies and lack of appropriately matched TD controls, additional research is needed to further understand and recommend the utility of the CAR as a reliable marker to differentiate ASD and TD.

BACKGROUND:Substance use and unprotected sex are prevalent among adolescents. The link between substance use and unprotected sex is well-established. Research has also highlighted how adolescents' attitudes and risk perceptions regarding unprotected sex, including concerns about pregnancy ("Getting pregnant would force me to grow up too fast"), are associated with unprotected sex and unplanned pregnancy. However, less research has examined the potential relationship between pregnancy concerns and substance use among adolescents. OBJECTIVES/OBJECTIVE:The study prospectively examined (1) differences in pregnancy concerns across patterns of substance use and (2) whether pregnancy concerns mediate the relationship between substance use and later unprotected sex among a sample of middle and high school students. METHOD/METHODS:98 adolescents [M(SD) age = 14.28(1.68), 59.4% female, 59.4% black/African American] completed self-report measures of marijuana and alcohol use, pregnancy concerns, and unprotected sex across three time points over 6 months (T1-T3). RESULTS:Substance users (alcohol/marijuana) reported fewer pregnancy concerns compared to non-substance users (t = 2.99, p = .04). Pregnancy concerns at T2 mediated the relationship between T1 lifetime substance use and later unprotected sex (T3) (indirect effect: b = 0.10, CI[.01-.41]; direct effect: b = 0.15, p = .32), controlling for gender, age, and race. More frequent substance use (T1) was related to fewer pregnancy concerns at T2 (b = -0.10, p = .04); fewer pregnancy concerns were related to increased likelihood of later unprotected sex (b = -1.02, p = .02). CONCLUSIONS:Findings offer new insight into associations between substance use and unprotected sex and suggest that substance use and sexual health interventions should target pregnancy concerns.

Recent surveys demonstrate skyrocketing rates of adolescent vaping,¹ while the opioid epidemic, rightfully, is daily front page news. At the same time, the public perceives cannabis as a harmless source of recreation or even as cure-all therapy. Now more than ever, child and adolescent psychiatrists, politicians, policy leaders, and parents need empirical support to bolster the position that drugs of abuse should be avoided by young people. We have a robust literature connecting cannabis use to earlier and worse psychotic disorders,² as well as strong longitudinal data implicating cannabis in various neuropsychological deficits.³ What our field lacks, however, are brain imaging studies that definitively document the negative neurobiological impact of substance use on the developing human brain. The key to appreciating why this research literature is so limited has to do with one of the core tenets of substance use disorder (SUD) etiology: SUDs do not emerge de novo in adulthood or late adolescence when people typically present with impairing symptoms. Decades of research now suggests that certain latent childhood traits predispose some youth to initiate and then escalate drug and alcohol use more often than is typical.⁴ Children born into families with SUDs are more likely to express these highly heritable traits and are additionally subject to environmental risk factors and adversity. Therefore, children born into families with SUDs are disproportionately laden with genetic and environmental factors that shape brain structure and function. In other words, before exposure to drugs of abuse (which themselves may influence the brain), some children's brains already differ from those of typically developing youth. This observation limits the usefulness of cross-sectional neuroimaging studies that compare youth who have used drugs to those who have not, because of the nonrandom interaction of latent traits, environmental factors, and pre-existing brain differences. This interaction likely accelerates these adolescents' propensity to initiate and continue to use drugs of abuse.

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.

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.