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Original Investigation |

Subtyping Attention-Deficit/Hyperactivity Disorder Using Temperament Dimensions :  Toward Biologically Based Nosologic Criteria ONLINE FIRST

Sarah L. Karalunas, PhD1; Damien Fair, PhD1,2,3; Erica D. Musser, PhD4; Kamari Aykes, BS2; Swathi P. Iyer, MS5; Joel T. Nigg, PhD1,2
[+] Author Affiliations
1Division of Psychology, Department of Psychiatry, Oregon Health and Science University, Portland
2Department of Behavioral Neuroscience, Oregon Health and Science University, Portland
3Advanced Imaging Research Center, Oregon Health and Science University, Portland
4Division of Clinical Science, Department of Psychology, Florida International University, Miami
5Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. Published online July 09, 2014. doi:10.1001/jamapsychiatry.2014.763
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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 (ie, 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.

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Figure 1.
Spring-Embedded Visualization of Temperament Groups

Graphical representation of the community detection results in the attention-deficit/hyperactivity disorder (ADHD) sample, which shows many strong correlations among individuals in the same temperament type and fewer between-type connections. Nodes represent individuals in each temperament group and connecting edges indicate correlations between individuals. Blue indicates the mild; red, surgent; and green, irritable types of ADHD. Correlations are thresholded at .50 for purposes of visual representation.

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Figure 2.
Temperament Type Profiles

Temperament in Middle Childhood Questionnaire scores for each of the 3 temperament types identified in the attention-deficit/hyperactivity disorder sample: cognitive control (A), surgency domains (B), and negative emotion domains (C). Scores are shown as z scores relative to the control sample mean (0 on the y-axis is the mean of the typically developing sample). Limit lines indicate SEs. Scores were reversed for some scales as follows: for inhibition, high scores indicate less inhibitory control; for attentional focus, high scores mean poorer focus; for shyness, high scores mean less shy; for soothability, high scores indicate less soothability. Three scales that only weakly differentiate groups (openness, perceptual sensitivity, and low-intensity pleasure) are not shown, but scores for these scales are reported in eTable 2 in the Supplement. HIP indicates high-intensity pleasure.

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Figure 3.
Cardiac Physiological Response

Raw pre-ejection period (PEP) (A) and mean respiratory sinus arrhythmia (RSA) change from baseline (B) for each of the emotion task epochs: negative induction (NI), negative suppression (NS), positive induction (PI), and positive suppression (PS), shown by temperament type. Limit lines indicate SE.

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Figure 4.
Resting-State Functional Connectivity Data Magnetic Resonance Imaging Conjunction Maps

Amygdala connectivity maps for each temperament type were directly compared with the 2 other types and a matched control population. Results from each of these comparisons are provided in the Table. The figure is a conjunction map for the comparisons. For each comparison (eg, mild vs surgent, mild vs irritable), a voxel was coded as either 0 (not significantly different between groups) or 1 (significantly different between groups). Maps were summed such that voxels that never differ between groups have a value of No. = 0.0 and voxels that differ in all comparisons for that group have a value of No. = 3.0. A, Mild type differed from other types in areas in the posterior cingulate/precuneus (black arrow). B, As with the mild type, the surgent type showed areas in the posterior cingulate and precuneus (black arrow) where it was distinct from at least 2 other groups. C, The irritable type was distinct from the mild, surgent, and control populations in the anterior insula (black arrows)—a region important for emotional regulation and task level control. No. indicates the number of comparisons in which the voxel significantly differed between groups. The colors range from 0.0 (never different) to 3.0 (different in all comparisons).

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Temperament Types

Video provides graphical representation of the temperament types identified at each time point, as well as the stability of groups from Time 1 to Time 2. Nodes (colored dots) represent children and connecting edges indicate correlations between individuals (shorter lines indicate stronger correlation). Colors of nodes are based on Time 1 groupings (Red: Uncomplicated, Green: Surgent, Blue: Irritable). In the first half of the video, the grouping of the individuals at Time 1 is displayed. After a pause, the transition to the Time 2 correlations are added and the movement of individuals between groups is depicted. Both the Surgent and Irritable types are highly stable and remain tightly clustered, whereas the Uncomplicated type is less so and disperses somewhat at Time 2.

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