Erica D. Musser

Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria

IMPORTANCE Psychiatric nosology is limited by behavioral and biological heterogeneity within existing disorder categories. The imprecise nature of current nosologic distinctions limits both mechanistic understanding and clinical prediction. We demonstrate an approach consistent with the National Institute of Mental Health Research Domain Criteria initiative to identify superior, neurobiologically valid subgroups with better predictive capacity than existing psychiatric categories for childhood attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE To refine subtyping of childhood ADHD by using biologically based behavioral dimensions (i.e., temperament), novel classification algorithms, and multiple external validators. DESIGN, SETTING, AND PARTICIPANTS A total of 437 clinically well-characterized, community-recruited children, with and without ADHD, participated in an ongoing longitudinal study. Baseline data were used to classify children into subgroups based on temperament dimensions and examine external validators including physiological and magnetic resonance imaging measures. One-year longitudinal follow-up data are reported for a subgroup of the ADHD sample to address stability and clinical prediction. MAIN OUTCOMES AND MEASURES Parent/guardian ratings of children on a measure of temperament were used as input features in novel community detection analyses to identify subgroups within the sample. Groups were validated using 3 widely accepted external validators: peripheral physiological characteristics (cardiac measures of respiratory sinus arrhythmia and pre-ejection period), central nervous system functioning (via resting-state functional connectivity magnetic resonance imaging), and clinical outcomes (at 1-year longitudinal follow-up). RESULTS The community detection algorithm suggested 3 novel types of ADHD, labeled as mild (normative emotion regulation), surgent (extreme levels of positive approach-motivation), and irritable (extreme levels of negative emotionality, anger, and poor soothability). Types were independent of existing clinical demarcations including DSM-5 presentations or symptom severity. These types showed stability over time and were distinguished by unique patterns of cardiac physiological response, resting-state functional brain connectivity, and clinical outcomes 1 year later. CONCLUSIONS AND RELEVANCE Results suggest that a biologically informed temperament-based typology, developed with a discovery-based community detection algorithm, provides a superior description of heterogeneity in the ADHD population than does any current clinical nosologic criteria. This demonstration sets the stage for more aggressive attempts at a tractable, biologically based nosology.

Emotion Regulation via the Autonomic Nervous System in Children with Attention-Deficit/Hyperactivity Disorder (ADHD)

Despite growing interest in conceptualizing ADHD as involving disrupted emotion regulation, few studies have examined the physiological mechanisms related to emotion regulation in children with this disorder. This study examined parasympathetic and sympathetic nervous system reactivity via measures of respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP) in children with ADHD (n = 32) and typically developing controls (n = 34), using a novel emotion task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. Both groups showed strong task-response effects in RSA. However, typically developing children showed systematic variation in parasympathetic activity (RSA) depending on both emotion valence (more activation for negative emotion, reduced activation for positive emotion) and task demand (more activation for suppression than induction). In contrast, children with ADHD displayed a stable pattern of elevated parasympathetic activity (RSA) across all task conditions compared to baseline. No group differences in sympathetic activity (PEP) were observed. It is concluded ADHD in childhood is associated with abnormal parasympathetic mechanisms involved in emotion regulation.

Reward circuit connectivity relates to delay discounting in children with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior.

Delay discounting of reward in ADHD: application in young children

BACKGROUND A key underlying process that may contribute to attention-deficit/hyperactivity disorder (ADHD) involves alterations in reward evaluation, including assessing the relative value of immediate over delayed rewards. This study examines whether children with ADHD discount the value of delayed rewards to a greater degree than typically developing children using a delay discounting task. METHODS Children aged 7-9 years diagnosed with ADHD and controls completed a task in which they chose between a hypothetical

Emotion Regulation and Heterogeneity in Attention-Deficit/Hyperactivity Disorder

10 available after a delay (7, 30, 90 and 180 days) versus various amounts available immediately. RESULTS ADHD participants discounted more steeply than controls. However, this effect did not survive covarying of IQ. CONCLUSIONS ADHD is associated with a steeper delay gradient when contemplating hypothetical later rewards, but not independently of IQ. The interplay of cognitive processing and IQ with reward evaluation in ADHD requires further exploration.

Altered Cortico-Striatal–Thalamic Connectivity in Relation to Spatial Working Memory Capacity in Children with ADHD

OBJECTIVE How best to capture heterogeneity in attention-deficit/hyperactivity disorder (ADHD) using biomarkers has been elusive. This study evaluated whether emotion reactivity and regulation provide a means to achieve this. METHOD Participants were classified into three groups: children with ADHD plus low prosocial behavior (hypothesized to be high in callous/unemotional traits; n = 21); children with ADHD with age-appropriate prosocial behavior (n = 54); and typically developing children (n = 75). Children completed a task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. The task required children to view an emotion-laden film clip, while either facially mimicking (induction) or masking (suppression) the emotion of the main character. Parasympathetic and sympathetic nervous system activity were assessed via respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP), respectively. Symptoms of anxiety, conduct, and oppositional defiant disorders were treated as covariates. RESULTS The ADHD-typical-prosocial group displayed atypically elevated parasympathetic reactivity (emotion dysregulation) during positive induction, along with increased sympathetic activity (elevated arousal) across conditions. In contrast, the ADHD-low-prosocial group displayed reduced parasympathetic reactivity and reduced sympathetic activity (low emotional arousal) across baseline and task conditions. Thus, both ADHD groups had altered patterns of autonomic functioning, but in two distinct forms. CONCLUSION Although ADHD is heterogeneous clinically, results suggest that ADHD is also heterogeneous with regard to physiological indices of emotion and regulation. Future studies of emotion, regulation, and ADHD should take this into account. Further study of physiological responding in ADHD may yield clinically and etiologically distinct domains or groups.

Shared familial transmission of autism spectrum and attention-deficit/hyperactivity disorders

Introduction: Attention deficit hyperactivity disorder (ADHD) captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting-state functional connectivity MRI (rs-fcMRI) studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical–striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD. Methods: We correlated the rs-fcMRI of five thalamic regions of interest (ROIs) with spatial span working memory scores in a sample of 67 children aged 7–11 years [ADHD and typically developing children (TDC)]. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7–11 years) from the ADHD-200 dataset. Thalamic ROIs were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus. Results/Conclusion: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype.

Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2

BACKGROUND To determine whether familial transmission is shared between autism spectrum disorders and attention-deficit/hyperactivity disorder, we assessed the prevalence, rates of comorbidity, and familial transmission of both disorders in a large population-based sample of children during a recent 7 year period. METHODS Study participants included all children born to parents with the Kaiser Permanente Northwest (KPNW) Health Plan between 1 January 1998 and 31 December 2004 (n = 35,073). Children and mothers with physician-identified autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) were identified via electronic medical records maintained for all KPNW members. RESULTS Among children aged 6-12 years, prevalence was 2.0% for ADHD and 0.8% for ASD; within those groups, 0.2% of the full sample (19% of the ASD sample and 9.6% of the ADHD sample) had co-occurring ASD and ADHD, when all children were included. When mothers had a diagnosis of ADHD, first born offspring were at 6-fold risk of ADHD alone (OR = 5.02, p < .0001) and at 2.5-fold risk of ASD alone (OR = 2.52, p < .01). Results were not accounted for by maternal age, child gestational age, child gender, and child race. CONCLUSIONS Autism spectrum disorders shares familial transmission with ADHD. ADHD and ASD have a partially overlapping diathesis.

Attention-deficit/hyperactivity disorder (ADHD) and being overweight/obesity: New data and meta-analysis

BACKGROUND Peripheral epigenetic marks hold promise for understanding psychiatric illness and may represent fingerprints of gene-environment interactions. We conducted an initial examination of CpG methylation variation in children with or without attention-deficit/hyperactivity disorder (ADHD). METHODS Children age 7-12 were recruited, screened, evaluated and assigned to ADHD or non-ADHD groups by defined research criteria. Two independent age-matched samples were examined, a discovery set (n = 92, all boys, half control, half ADHD) and a confirmation set (n = 20, half ADHD, all boys). 5-methylcytosine levels were quantified in salivary DNA using the Illumina 450 K HumanMethylation array. Genes for which multiple probes were nominally significant and had a beta difference of at least 2% were evaluated for biological relevance and prioritized for confirmation and sequence validation. Gene pathways were explored and described. RESULTS Two genes met the criteria for confirmation testing, VIPR2 and MYT1L; both had multiple probes meeting cutoffs and strong biological relevance. Probes on VIPR2 passed FDR correction in the confirmation set and were confirmed through bisulfite sequencing. Enrichment analysis suggested involvement of gene sets or pathways related to inflammatory processes and modulation of monoamine and cholinergic neurotransmission. CONCLUSIONS Although it is unknown to what extent CpG methylation seen in peripheral tissue reflect transcriptomic changes in the brain, these initial results indicate that peripheral DNA methylation markers in ADHD may be promising and suggest targeted hypotheses for future study in larger samples.

Attention-deficit/hyperactivity disorder developmental trajectories related to parental expressed emotion.

BACKGROUND Literature has suggested that ADHD may be associated with increased risk of obesity. If so, this would have important clinical implications. OBJECTIVE To clarify the size of the association between ADHD and obesity and to evaluate key moderators of the association including medication, gender, age, and psychiatric comorbidity. METHOD Two preliminary studies are presented to supply critical additional data for the meta-analysis: a two-year longitudinal study of an ADHD case-control sample of 313 children aged 7-11, and a national survey study of 45,309 families in the United States using the 2012 National Survey of Childrens Health. Formal meta-analysis was then conducted. The identification procedure yielded 43 studies, reporting 225 comparisons or effect sizes, studying 703,937 participants An overall effect size was estimated with a random effects model (after pooling within study using a modified fixed effects model). Effect size was then examined in relation to medication, gender, age, and psychiatric comorbidity. RESULTS The new study of children revealed no reliable association of ADHD and body mass index at any age or time point. In the national survey, ADHD was associated with obesity only in adolescent girls but not in children or boys; this effect was statistically accounted for by covarying of depression and conduct disorder. In the meta-analysis, the composite effect size was OR=1.22 (95% CI=1.11-1.34); 22 studies provided effects with medication controlled, yielding a composite effect size of OR=1.30 (95% CI=1.12-1.50). Pooled across age the association without covariates was reliable in females (OR=1.19 [1.01-1.41]) but not males (OR=1.10 [0.95-1.23]) although males and females did not statistically differ. Pooled across gender, the association was significantly larger in adults (>18years) (OR=1.37 [1.19-1.58]) than in youth (OR=1.13 [1.00-1.27]), p=.04. CONCLUSIONS ADHD has a small overall association with obesity, but this effect is moderate in adults. The effect is likely to be of no clinical significance in children, possible clinical significance in adolescent girls with comorbid disorders, and of clinical relevance by adulthood.