Faculty Bibliography

OBJECTIVE:To determine normative values for heart rate patterns in healthy fetuses. METHODS:This research is from the Safe Passage Study conducted by the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network. A standardized protocol assessed fetal heart rate (FHR), heart rate variability (HRV), and movement from 1655 fetuses at three-time points during gestation (20-24 weeks, 28-32 weeks, 34-38 weeks gestation). RESULTS:FHR decreased while HRV increased over gestation. At the latter two ages, males had significantly lower FHR than females while there were no sex differences in FHR at 20-24 weeks. When accounting for the fetal state during late gestation (34-28 weeks), we found that males had significantly lower FHR than females in the active fetal state only. CONCLUSION:Results demonstrate significant state, gestational age, and sex-related changes in cardiac activity, somatic activity, and autonomic function as the fetus approaches birth.

Increasing numbers of gender-nonconforming children are socially transitioning-changing pronouns to live as their identified genders. We studied a cohort of gender-nonconforming children ( n = 85) and contacted them again approximately 2 years later. When recontacted, 36 of the children had socially transitioned. We found that stronger cross-sex identification and preferences expressed by gender-nonconforming children at initial testing predicted whether they later socially transitioned. We then compared the gender-nonconforming children with groups of transitioned transgender children ( n = 84) and gender-conforming controls ( n = 85). Children from our longitudinal cohort who would later transition were highly similar to transgender children (children who had already socially transitioned) and to control children of the gender to which they would eventually transition. Gender-nonconforming children who would not go on to transition were different from these groups. These results suggest that (a) social transitions may be predictable from gender identification and preferences and (b) gender identification and preferences may not meaningfully differ before and after social transitions.

Electronic shared-decision making programs may provide an assistive technology to support physician-patient communication. This mixed methods study examined use of a web-based shared decision-making program (MyCHOIS-CommonGround) by individuals receiving specialty mental health services, and identified qualitative factors influencing adoption during the first 18 months of implementation in two Medicaid mental health clinics. T-tests and χ² analyses were conducted to assess differences in patient use between sites. Approximately 80% of patients in both clinics created a MyCHOIS-CommonGround user profile, but marked differences emerged between clinics in patients completing shared decision-making reports (79% vs. 28%, χ²₍₁₎ = 109.92, p < .01) and average number of reports (7.20 vs. 3.60, t = - 3.64, p < .01). Results suggest high penetration of computer-based programs in specialty mental health services is possible, but clinic implementation factors can influence patient use including leadership commitment, peer staff funding to support the program, and implementation strategy, most notably integration of the program within routine clinical workflow.

Over the past decade, our field has observed rapidly rising rates of mental illness in children and adolescents. The numbers are sobering. Nearly 50% of teens 13 to 18 years of age meet DSM criteria for at least 1 disorder and 27.6% meet criteria for a "severe disorder."¹ Adverse childhood experiences affect more than 50% of children and predispose these individuals to not only academic and behavioral problems throughout their youth, but also future physical disability, such as obesity, hypertension, and diabetes, as adults.² By 14 years of age, accidents, suicide, and homicide assert themselves as the leading causes of death among our youth, accounting for more than 85% of the mortality among teens and young adults and holding fast to that ranking until 35 years of age.³ Most addictive behavior starts in adolescence, accounting for the 3 greatest causes of preventable death-smoking, obesity, and alcohol abuse-that take the lives of approximately 1 million adults in the United States annually.⁴ In addition, if there were ever a statistic to be held on the tip of every psychiatrist's tongue, it would be that 50% of all mental illnesses begin by 14 years of age and 75% begin by 24 years.⁵.

Depression is the most common perinatal psychiatric disorder, but little is known about how it may impact offspring neurodevelopment, as well as the mechanisms by which it may confer transgenerational psychiatric risk. This review presents imaging studies conducted to evaluate the relationship between perinatal depression (PND) and infant and child neurodevelopment. Altered structural and functional connectivity is implicated in children exposed to PND and anxiety. Overall, there are changes in connectivity between amygdala and the prefrontal cortex. Studies suggest decreased hippocampal growth in the first 6 months after birth, decreased cortical thickness in children, and increased amygdala volumes, that are more pronounced in female offspring. Future research is needed to understand the impact of PND on development so that early interventions which promote mother-infant bonding and cognitive development may improve developmental outcomes in children exposed to PND, reducing later risk of psychopathology.

OBJECTIVE:We tested mediation of birth weight and ADHD symptoms by multiple biologically plausible neurocognitive functions and evaluated familiality of observed indirect effects. METHOD/METHODS:647 youth from 284 multiplex families with ADHD completed the Arithmetic, Digit Span, Vocabulary, and Block Design subtests of the Wechsler Intelligence Scale for Children (WISC). Multiple mediation tested WISC subtests as mediators of birth weight and multi-informant ADHD symptoms. Familiality of indirect effects was estimated via moderated mediation comparing conditional indirect effects across siblings concordant and discordant for ADHD. RESULTS:Controlling for IQ and demographic factors, Arithmetic uniquely mediated birth weight and ADHD symptoms. Conditional indirect effects through Arithmetic did not differ across ADHD concordant and discordant siblings. CONCLUSION/CONCLUSIONS:These cross-sectional findings support previous prospective longitudinal research implicating Arithmetic (i.e., fluid reasoning) as a preliminary causal mediator of birth weight and ADHD symptoms, and suggest that this pathway is independent of genetic influences on ADHD.

OBJECTIVE:Sleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors. DATA SOURCES/METHODS:Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017. STUDY SELECTION/METHODS:Included were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients. DATA EXTRACTION/METHODS:Two PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author. RESULTS:Increased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate. CONCLUSIONS:Several types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.

Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

Precise timing makes the difference between harmony and cacophony, but how the brain achieves precision during timing is unknown. In this study, human participants (7 females, 5 males) generated a time interval while being recorded with magnetoencephalography. Building on the proposal that the coupling of neural oscillations provides a temporal code for information processing in the brain, we tested whether the strength of oscillatory coupling was sensitive to self-generated temporal precision. On a per individual basis, we show the presence of alpha-beta phase-amplitude coupling whose strength was associated with the temporal precision of self-generated time intervals, not with their absolute duration. Our results provide evidence that active oscillatory coupling engages α oscillations in maintaining the precision of an endogenous temporal motor goal encoded in β power; the when of self-timed actions. We propose that oscillatory coupling indexes the variance of neuronal computations, which translates into the precision of an individual's behavioral performance.SIGNIFICANCE STATEMENT Which neural mechanisms enable precise volitional timing in the brain is unknown, yet accurate and precise timing is essential in every realm of life. In this study, we build on the hypothesis that neural oscillations, and their coupling across time scales, are essential for the coding and for the transmission of information in the brain. We show the presence of alpha-beta phase-amplitude coupling (α-β PAC) whose strength was associated with the temporal precision of self-generated time intervals, not with their absolute duration. α-β PAC indexes the temporal precision with which information is represented in an individual's brain. Our results link large-scale neuronal variability on the one hand, and individuals' timing precision, on the other.

OBJECTIVE/UNASSIGNED:Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS/UNASSIGNED:Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS/UNASSIGNED:In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS/UNASSIGNED:Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.