Sarah L. Karalunas

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.

Annual Research Review: Reaction time variability in ADHD and autism spectrum disorders: measurement and mechanisms of a proposed trans-diagnostic phenotype

BACKGROUND Intraindividual variability in reaction time (RT) has received extensive discussion as an indicator of cognitive performance, a putative intermediate phenotype of many clinical disorders, and a possible trans-diagnostic phenotype that may elucidate shared risk factors for mechanisms of psychiatric illnesses. SCOPE AND METHODOLOGY Using the examples of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), we discuss RT variability. We first present a new meta-analysis of RT variability in ASD with and without comorbid ADHD. We then discuss potential mechanisms that may account for RT variability and statistical models that disentangle the cognitive processes affecting RTs. We then report a second meta-analysis comparing ADHD and non-ADHD children on diffusion model parameters. We consider how findings inform the search for neural correlates of RT variability. FINDINGS Results suggest that RT variability is increased in ASD only when children with comorbid ADHD are included in the sample. Furthermore, RT variability in ADHD is explained by moderate to large increases (d = 0.63-0.99) in the ex-Gaussian parameter τ and the diffusion parameter drift rate, as well as by smaller differences (d = 0.32) in the diffusion parameter of nondecision time. The former may suggest problems in state regulation or arousal and difficulty detecting signal from noise, whereas the latter may reflect contributions from deficits in motor organization or output. The neuroimaging literature converges with this multicomponent interpretation and also highlights the role of top-down control circuits. CONCLUSION We underscore the importance of considering the interactions between top-down control, state regulation (e.g., arousal), and motor preparation when interpreting RT variability and conclude that decomposition of the RT signal provides superior interpretive power and suggests mechanisms convergent with those implicated using other cognitive paradigms. We conclude with specific recommendations for the field for next steps in the study of RT variability in neurodevelopmental disorders.

Structural and functional connectivity of the human brain in autism spectrum disorders and attention-deficit/hyperactivity disorder: A rich club-organization study

Attention‐deficit/hyperactive disorder (ADHD) and autism spectrum disorders (ASD) are two of the most common and vexing neurodevelopmental disorders among children. Although the two disorders share many behavioral and neuropsychological characteristics, most MRI studies examine only one of the disorders at a time. Using graph theory combined with structural and functional connectivity, we examined the large‐scale network organization among three groups of children: a group with ADHD (8–12 years, n = 20), a group with ASD (7–13 years, n = 16), and typically developing controls (TD) (8–12 years, n = 20). We apply the concept of the rich‐club organization, whereby central, highly connected hub regions are also highly connected to themselves. We examine the brain into two different network domains: (1) inside a rich‐club network phenomena and (2) outside a rich‐club network phenomena. The ASD and ADHD groups had markedly different patterns of rich club and non rich‐club connections in both functional and structural data. The ASD group exhibited higher connectivity in structural and functional networks but only inside the rich‐club networks. These findings were replicated using the autism brain imaging data exchange dataset with ASD (n = 85) and TD (n = 101). The ADHD group exhibited a lower generalized fractional anisotropy and functional connectivity inside the rich‐club networks, but a higher number of axonal fibers and correlation coefficient values outside the rich club. Despite some shared biological features and frequent comorbity, these data suggest ADHD and ASD exhibit distinct large‐scale connectivity patterns in middle childhood. Hum Brain Mapp 35:6032–6048, 2014.

Development of Implicit and Explicit Category Learning.

We present two studies that examined developmental differences in the implicit and explicit acquisition of category knowledge. College-attending adults consistently outperformed school-age children on two separate information-integration paradigms due to childrens more frequent use of an explicit rule-based strategy. Accuracy rates were also higher for adults on a unidimensional rule-based task due to childrens more frequent use of the irrelevant dimension to guide their behavior. Results across these two studies suggest that the ability to learn categorization structures may be dependent on a childs ability to inhibit output from the explicit system.

Decomposing attention-deficit/hyperactivity disorder (ADHD)-related effects in response speed and variability.

OBJECTIVE Slow and variable reaction times (RTs) on fast tasks are such a prominent feature of attention-deficit/hyperactivity disorder (ADHD) that any theory must account for them. However, this has proven difficult because the cognitive mechanisms responsible for this effect remain unexplained. Although speed and variability are typically correlated, it is unclear whether single or multiple mechanisms are responsible for group differences in each. RTs are a result of several semi-independent processes, including stimulus encoding, rate of information processing, speed-accuracy trade-offs, and motor response, which have not been previously well characterized. METHOD A diffusion model was applied to RTs from a forced-choice RT paradigm in two large, independent case-control samples (NCohort 1 = 214 and NCohort 2 = 172). The decomposition measured three validated parameters that account for the full RT distribution and assessed reproducibility of ADHD effects. RESULTS In both samples, group differences in traditional RT variables were explained by slow information processing speed, and unrelated to speed-accuracy trade-offs or nondecisional processes (e.g., encoding, motor response). CONCLUSIONS RT speed and variability in ADHD may be explained by a single information processing parameter, potentially simplifying explanations that assume different mechanisms are required to account for group differences in the mean and variability of RTs.

Working Memory Demands Impair Skill Acquisition in Children With ADHD

This study examined the process of cognitive skill acquisition under differential working memory (WM) load conditions in children with the primarily inattentive (n = 21) and the combined (n = 32) subtypes of childhood attention-deficit/hyperactivity disorder (ADHD) and compared the results with those of non-ADHD controls (n = 48). Children completed 2 tasks of cognitive skill acquisition: alphabet arithmetic and finger math. The tasks differed in the amount of WM required for execution (alphabet arithmetic required more) but were otherwise matched with respect to logical structure, design, and discriminatory power. As would be predicted if the WM of the to-be-learned task affected the ability of children with ADHD to develop automaticity for a complex cognitive skill, ADHD-related impairments in the development of automaticity were seen for alphabet arithmetic but not for finger math. Results not only are relevant to ongoing debate regarding the presence of effortful versus automatic cognitive deficits in ADHD but also have implications for the development of new psychoeducational interventions for children with ADHD.

Examining Relationships Between Executive Functioning and Delay Aversion in Attention Deficit Hyperactivity Disorder

Although motivation and cognition are often examined separately, recent theory suggests that a delay-averse motivational style may negatively impact development of executive functions (EFs), such as working memory (WM) and response inhibition (RI) for children with Attention Deficit Hyperactivity Disorder (ADHD; Sonuga-Barke, 2002). This model predicts that performance on delay aversion and EF tasks should be correlated for school-age children with ADHD. However, tests of these relationships remain sparse. Forty-five children ages 8 to 12 with ADHD and 46 non-ADHD controls completed tasks measuring EFs and delay aversion. Children with ADHD had poorer WM and RI than non-ADHD controls, as well as nonsignificantly worse delay aversion. Consistent with previous research, RI was not related to delay aversion. However, delay aversion did predict WM scores for children with and without ADHD. Implications for the dual-pathway hypothesis and future research on cognitive and motivational processing in ADHD are discussed.

Spatial summation in the tactile sensory system: Probability summation and neural integration

Psychophysical thresholds for the detection of a 300-Hz burst of vibration applied to the thenar eminence were measured for stimuli applied to the skin through 1.5 cm2 and through 0.05 cm2 contactors. Thresholds were approximately 13 dB lower when the area of the contactor was 1.5 cm2 than when it was 0.05 cm2. The difference between the thresholds measured with the large and small contactors was significantly reduced when only the lowest thresholds obtained in the testing sessions were considered. This result supports the hypothesis that one component of spatial summation in the P channel is probability summation. In addition, threshold measurements within a session were less variable when measured with the 1.5 cm2 contactor. We conclude that spatial summation in the P channel is a joint function of two processes that occur as the areal extent of the stimulus increases: probability summation in which the probability of exceeding the psychophysical detection threshold increases as the number of receptors of varying sensitivities increases, and neural integration in which neural activity originating from separate receptors is combined within the central nervous system rendering the channel more sensitive to the stimulus.

Is reaction time variability in ADHD mainly at low frequencies

BACKGROUND Intraindividual variability in reaction times (RT variability) has garnered increasing interest as an indicator of cognitive and neurobiological dysfunction in children with attention deficit hyperactivity disorder (ADHD). Recent theory and research has emphasized specific low-frequency patterns of RT variability. However, whether group differences are specific to low frequencies is not well examined. METHOD Two studies are presented. The first is a quantitative review of seven previously published studies that have examined patterns of RT variability in ADHD. The second provides new data from a substantially larger sample of children than in prior studies (N(Control) = 42; NADHD = 123). The children completed a choice RT task as part of a traditional go/stop task. Fast-Fourier transform analyses were applied to assess patterns of variability. RESULTS Quantitative review of previous studies indicated that children with ADHD demonstrate more low-frequency variability than non-ADHD controls (Hedges g = .39; 95% CI: .16-.62), but an equivalent excess variability in a faster frequency comparison band (g = .36; 95% CI: .03-.69), with a trivial and nonsignificant difference between ESs in each band. New data replicated results of the quantitative review with nearly identical effects in the low-frequency (g = .39; 95% CI: .05-.75) and faster frequency comparison bands (g = .40; 95% CI: .04-.74) and no evidence of diagnosis × frequency interaction (p = .954). CONCLUSIONS Results suggest that theories of RT variability in ADHD that focus on low-frequency variability will need to be modified to account for the presence of variability at a broader range of frequencies.

Implications of ongoing neural development for the measurement of the error-related negativity in childhood.

Event-related potentials (ERPs) have been proposed as biomarkers capable of reflecting individual differences in neural processing not necessarily detectable at the behavioral level. However, the role of ERPs in developmental research could be hampered by current methodological approaches to quantification. ERPs are extracted as an average waveform over many trials; however, actual amplitudes would be misrepresented by an average if there was high trial-to-trial variability in signal latency. Low signal temporal consistency is thought to be a characteristic of immature neural systems, although consistency is not routinely measured in ERP research. The present study examined the differential contributions of signal strength and temporal consistency across trials in the error-related negativity (ERN) in 6-year-old children, as well as the developmental changes that occur in these measures. The 234 children were assessed annually in kindergarten, 1st, and 2nd grade. At all assessments signal strength and temporal consistency were highly correlated with the average ERN amplitude, and were not correlated with each other. Consistent with previous findings, ERN deflections in the averaged waveform increased with age. This was found to be a function of developmental increases in signal temporal consistency, whereas signal strength showed a significant decline across this time period. In addition, average ERN amplitudes showed low-to-moderate stability across the three assessments whereas signal strength was highly stable. In contrast, signal temporal consistency did not evidence rank-order stability across these ages. Signal strength appears to reflect a stable individual trait whereas developmental changes in temporal consistency may be experientially influenced.