Subtyping Adhd

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JAMA Psychiatry. Author manuscript; available in PMC 2014 December 29.
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JAMA Psychiatry. 2014 September ; 71(9): 10151024. doi:10.1001/jamapsychiatry.2014.763.
Subtyping attention-deficit/hyperactivity disorder using

temperament dimensions: toward biologically based nosologic
criteria
Sarah L. Karalunas, Ph.D.1,*, Damien Fair, Ph.D.1,2,3, Erica D. Musser, Ph.D.4, Kamari
Aykes, B.S.2, Swathi P. Iyer, M.S.5, and Joel T. Nigg, Ph.D.1,2
1Oregon
Health & Science University, Department of Psychiatry, Division of Psychology,

Portland, OR
2Oregon
Health& Science University, Department of Behavioral Neuroscience, Portland, OR
3Oregon
Health & Science University, Advanced Imaging Research Center, Portland OR
4Florida
International University, Department of Psychology, Division of Clinical Science, Miami,
FL
5Brigham
and Women's Hospital, Functional Neuroimaging Lab, Harvard Medical School, Boston,
MA
Abstract
ImportancePsychiatric nosology is limited by behavioral and biological heterogeneity within
existing disorder categories. The imprecise nature of current nosological distinctions limits both
mechanistic understanding and clinical prediction. Here, we demonstrate an approach consistent
with the NIMH Research Domain Criteria (RDoC) initiative to identifying superior,
neurobiologically-valid subgroups with better predictive capacity than existing psychiatric
categories for childhood Attention-Deficit Hyperactivity Disorder (ADHD).
ObjectiveRefine subtyping of childhood ADHD by using biologically-based behavioral

dimensions (i.e. temperament), novel classification algorithms, and multiple external validators. In
doing so, we demonstrate how refined nosology is capable of improving on current predictive
capacity of long-term outcomes relative to current DSM-based nosology.
Design, Setting, Participants437 clinically well-characterized, community-recruited
children with and without ADHD participated in an on-going longitudinal study. Baseline data
Corresponding Author may be reached at: ADHD Research Study UHN80R1, Oregon Health & Science University, 3181 SW Sam
Jackson Park Rd, Portland, OR 97239-9979, Phone: 503-494-5790, karaluna@ohsu.edu, Fax: 503-418-8416.
Author Contributions: Karalunas: community detection analysis, behavioral, and longitudinal analyses, writing and manuscript
preparation; Fair: functional connectivity analyses, community detection analysis, writing and manuscript preparation; Musser:
cardiac physiology analyses, writing and manuscript preparation; Aykes: functional connectivity analyses; Iyer: community detection
analysis; Nigg: theoretical conceptualization, hypotheses, project data collection and oversight, writing and manuscript preparation.
Conflicts of Interest: Dr. Karalunas reported no biomedical financial interests or potential conflicts of interest. Dr. Fair reported no
biomedical financial interests or potential conflicts of interest. Dr. Musser reported no biomedical financial interests or potential
conflicts of interest. Ms. Aykes reported no biomedical financial interests or potential conflicts of interest. Ms. Iyer reported no
biomedical financial interests or potential conflicts of interest. Dr. Nigg reported no biomedical financial interests or potential
conflicts of interest.
Karalunas et al.
Page 2
were used to classify children into subgroups based on temperament dimensions and to examine
external validators including physiological and MRI measures. One-year longitudinal follow-up
data are reported for a subgroup of the ADHD sample to address stability and clinical prediction.
Main Outcome MeasuresParent/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 three widely-accepted external validators: peripheral
physiology (cardiac measures of respiratory sinus arrhythmia and pre-ejection period), central
nervous system functioning (via resting-state functional connectivity MRI), and clinical outcomes
(at one-year longitudinal follow-up).
ResultsThe community detection algorithm suggested three novel types of ADHD, labeled as
Mild (normative emotion regulation); Surgent (extreme levels of positive approachmotivation); 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 outcome one year later.
Conclusions and RelevanceResults suggest that a biologically-informed temperamentbased typology, developed with a discovery-based community detection algorithm, provided a
superior description of heterogeneity in the ADHD population than any current clinical nosology.
This demonstration sets the stage for more aggressive attempts at a tractable, biologically-based
nosology.
Introduction
Psychiatric nosology remains exclusively syndromic, depending on clusters of signs and

symptoms rather than biologically-based measures. This dependence introduces
fundamentally confounding factors limiting a better understanding of mental illness [14].
For these reasons, the National Institute of Mental Health, under the Research Domain
Criteria (RDoC) initiative [2], has emphasized broad neurobiologically-based dimensions
(e.g. positive/negative valence, cognitive control) to refine existing nosology. The long-term
goal for this initiative, and the field in general, is to improve neurobiological validity,
clinical prediction, and treatment matching [2]. While it is clear that eventually the nosology
will need to be revised, a tractable approach to advance the current classification system is
not agreed upon. For example, no study of alternative nosology has demonstrated both
biological validity and clinical prediction within the same sample.
We address this problem for the case of Attention Deficit Hyperactivity Disorder (ADHD).
Like other psychiatric categories, ADHD is suspected of identifying children with diverse
etiologies [5, 6] but DSM-IV subtypes (and thus DSM-5 presentations) fail to elucidate clear
differences in pathophysiology or clinical course, in part due to their own instability over
time [5, 79]. To better parse heterogeneity some experts have advised looking beyond
existing symptom lists toward phenotypic measures that can be represented dimensionally
and have well-theorized relationships to neurobiological systems [2, 1012], which is the
core of the RDoC approach. At the same time, phenotype measures that retain clinical
Karalunas et al.
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applicability are desirable. ADHD is a good starting point for achieving RDoC aims because
children with the disorder can be characterized in terms of several features that are best
represented as dimensions and have well-theorized relationships to biological systems.
How are novel types to be empirically identified and validated? Clustering algorithms can be
expected to yield varying results depending on the algorithm used and features selected as
input [13] and therefore are, in themselves, exploratory [14]; the main question concerns
whether clusters are clinically useful. Our key considerations were (a) input features, (b)
choice of clustering method, and (c) multiple external validators.
Phenotypic features
For the features, we used a well-accepted, low-cost, parent-rated measure of child

temperament. Temperament traits can be described as a set of biologically-based behavioral
and emotional tendencies. While not the only approach available, these traits extend beyond
single disorder clinical symptoms to expand coverage of positive and negative emotion
systems, as well as attentional capacities [1517]. These in turn are directly related to the
RDoC domains of negative valence systems, positive valence systems/approach motivation,
and cognitive control, respectively. They also are related to, although not identical with,
personality traits in adults, and are relatively easily assessed via parent-report
questionnaires, which can be easily translated into clinical applications. Temperament traits
also have distinct neurobiological correlates with a substantial literature in humans and
animals [1820]. In humans, temperament domains are differentially related to peripheral
nervous system indicators [2125], as well to specific neural circuitry [e.g. amygdala,
hippocampus, insula, and striatum, anterior cingulate cortex, and prefrontal cortex, 26, 27].
The amygdala, in particular, plays a key role in emotion and motivation, and so is one
important brain correlate of temperament domains [17, 28, 29].
Clustering methods
In the current report we follow up on our earlier work [10] that utilizes a clustering method
known as community detection, which stems from the mathematical discipline of graph
theory [30]. Graph theory concerns the study of networks, where networks are sets of nodes
or vertices joined in pairs by lines or edges. Community structure in networks refers to the
existence of densely connected groups of nodes, with only sparse connections between the
groups. In our case, individuals with ADHD who share similar temperament traits may
cluster to form specific subtypes of the disorder. Community detection is a widely used
optimization clustering method (another well-known optimization clustering method is
mixture modeling). As a clustering approach it has the attractive features of being datadriven (in that the number of communities does not have to be pre-specified in the model)
and provides a quantitative measure of group robustness to chance variations in the data
structure.
External Validation
For external validation, we consider (a) peripheral physiology, (b) central nervous system
physiology (MRI), and (c) clinical outcome.
Karalunas et al.
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Methods
Participants and Diagnostic Procedures

Data are reported for 437 children: NControl=190 (46.3% male); NADHD=247 (71.6% male)
between the ages of 711. Participants were drawn from the Oregon ADHD Program, a
child cohort for which the community-based recruitment and enrollment procedures and
multi-informant assessment procedures for ADHD diagnosis are published elsewhere [31
33] and described in the Supplement. Sample characteristics for the ADHD and control
groups are presented in eTable 1 in the Supplement for background. Ethics approval was
obtained from the Institutional Review Board at Oregon Health & Science University. A
parent/legal guardian provided written informed consent, and children provided written
assent.
Temperament Ratings
A parent/guardian completed the widely used Temperament in Middle Childhood

Questionnaire [TMCQ, 34]. Items form 16 subscales and three higher order factors that are
hypothesized to be influenced by underlying neurobehavioral systems. List of scales and
reliabilities in the current sample (which were all satisfactory) are provided in the
Supplement.
Community Detection Analyses
Community detection [30, 35] is an optimization clustering method. As used here, a matrix
of child-by-child correlations was created based on the 16 TMCQ subscales, standardized to
the sample mean and standard deviation. Community detection was applied to the child
matrix using Rubinov and Sporns [35] weight-conserving modularity algorithm [36]. This
algorithm starts with each node (i.e. child) being the sole member of a community and
iteratively produces partitions whose conjunction produces the largest increase in the quality
index (Q) until Q reaches a maximum. In our case, Q is a weighted combination of the
modularity for positive relationships (Q+) and negative relationships (Q) introduced by
Rubinov and Sporns [35]. We provide the formal definition in the Supplement.
Conceptually, Q represents the overall segregation between identified communities, with
higher values indicating stronger separation of communities. Importantly, this and other
modularity algorithms are not deterministic, and thus can yield slightly different solutions on
different runs. To generate a single, stable depiction of structure, final group assignments for
each child were based on the modal group assignment across 10 runs of the modularity
algorithm. A secondary validation method [Variation of Information Algorithm (VOI), 37]
was also used to evaluate internal validity (group robustness to chance data variation).
External Validation
Physiological RecordingPhysiological response data were available for 178 children
with ADHD and 128 control children. Temperament traits are conceptually related to
positive and negative emotion domains, and so recording was completed during an emotion
induction/suppression task with positive and negative emotion conditions, as well as during
an emotionally-neutral baseline condition, exactly as described in prior publications [31].
Karalunas et al.
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Respiratory sinus arrhythmia (RSA), a measure of heart rate variability strongly influenced
by parasympathetic regulation and hypothesized to be related to emotion regulation [38],
was derived from the electrocardiogram (ECG) signal using MindWare Heart Rate
Variability software V.2.6 [39] and was quantified as the high frequency component (>0.15
Hz) of the R-R peak time series (in 60 second epochs). Standard methods for artifact
detection were followed as published in our prior work [40] and are also provided in the
Supplement.
Cardiac pre-ejection period (PEP) was derived from ECG and impedance cardiography in 60
second epochs using MindWare V.2.6 [41]. It was calculated as the time interval in
milliseconds from the onset of the Q-wave to the B-point of the dZ/dt wave using published
methods [42]. PEP reactivity is a generally agreed upon measure of sympathetic influence
on the heart, while the interpretation of tonic PEP is more complex.
Neural FunctioningResting-state functional connectivity data (rs fcMRI; 420600
seconds) are reported for 39 ADHD (NMild=18, NSurgent=11, NIrritable=10) and 15 typicallydeveloping children. Participants were scanned using a 3.0 Tesla Siemens Magnetom Tim
Trio scanner with a twelve-channel head-coil using methods we have published [4547].
Functional images were processed to reduce artifacts and connectivity was processed
following published methods [48] and are reproduced in the Supplement. Motion, a known
confound in functional MRI studies, was corrected and quantified several ways [46, 49] (for
details see the Supplement).
As noted earlier, one major candidate for neural involvement in temperament is the
amygdala, so it was chosen as our single seed region for this demonstration analysis. Left
and right amygdala regions of interest (ROIs) were obtained for subjects using FMRIB's
Integrated Registration and Segmentation Tool (FIRST), distributed with FMRIB Software
Library (FSL) [50, 51]. The ROIs were created in MNI atlas space and then converted to
Talairach atlas space. All subsequent operations were performed on the Talairach atlastransformed ROIs.
For all subjects, resting BOLD time series for each region of interest was correlated with all
other voxels in the brain, generating voxelwise functional connectivity maps. We performed
two-sample, two-tailed t-tests on all potential connections (Fischer transformed r-values)
between community-defined subgroups groups (assuming unequal variance; p0.05), as well
as between each community-defined subgroup and controls. One-sample tests were run for
within- group connectivity maps. To account for multiple comparisons, thresholding based
on Monte Carlo simulation was implemented [52]. To obtain multiple comparisons
corrected, p<0.05 voxel clusters, a threshold of 53 contiguous voxels with a Z-value >2.25
was used.
Longitudinal Follow-upOne-year longitudinal follow-up data on clinical features and
TMCQ ratings are reported for 101 children with ADHD (98% of those currently due for
follow up in this ongoing study).
Karalunas et al.
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Results
Community Detection Analyses

Subgrouping was done in a multi-step fashion using community detection. At the first step,
including all 437 children in the sample, community detection identified three profiles of
children (Q=.55) with sizes of 192, 181, 64. Profile 1 included 82% of the control children
and only 13% of the ADHD children. Profiles 2 and 3 together included 87% of the ADHD
children and only 18% of non-ADHD controls. Separation of the ADHD and non-ADHD
samples was not attributable to sample differences in age or gender (see Supplement). We
concluded that our initial clustering analysis recovered a primarily control profile and 2
ADHD profiles. Thus, at the second step, the analysis was conducted on the ADHD and
control samples separately with the aim of better characterizing variation within those two
populations. Results from the controls revealed weakly divided, marginal subgroups and
therefore were not subjected to further validation (see Supplement).
Community detection using the 247 children with ADHD identified as the modal solution
three profiles (referred to herein as types) with n= 64 (25.9%), 85 (34.4%), and 98
(39.7%) based on modal type assignments. The quality quotient suggested strong separation
of the groups (Q=.50). VOI analyses indicated that types were robust to modest random
perturbations in the data (see eFigure 1 in Supplement). Types reproduced with similar
quality scores after a random split replication of the ADHD population (Q=.46, Q=.50).
Clinically, Type 1 was more impulsive and inattentive (all p<.01) than controls, as well as
less affiliative (all p<.05), but otherwise did not differ from controls on any temperament
domain. Type 1 had milder impulsivity, inhibition, and attentional dyscontrol than the other
two ADHD types (all p<.001). We labeled Type 1 Mild ADHD. Type 2 had more severe
impulsivity than Type 1, and also less shyness and more assertiveness/dominance, highintensity pleasure seeking, and activity level than either of the other two types or than
controls (all p<.001); we labeled this type Surgent ADHD. Type 3, in addition to greater
impulsivity and attentional dyscontrol than the Mild type, also had more negative
emotionality than the other two types or the controls (all p<.001). This included higher
levels of anger, discomfort, fear, and sadness, and lower levels of soothability (all p<.001),
suggesting this is a group of children prone to anger, tantrums, and irritable behavior as
described in recent literature [53]. Type 3 was thus labeled Irritable ADHD. Figure 1
provides a spring-embedding graph for depiction of degree of group separation in terms of
the distance between subjects. Figure 2 depicts the profile for each group on the 16
temperament scales.
The DSM-5-based presentations of ADHD were split across the types suggesting the
temperament types did not reduce to DSM presentations. Additional clinical and
demographic description can be found in eTable 2 in the Supplement.
External Validity: I. Peripheral Physiology
Physiological measurements of peripheral nervous system response were recorded for 53
Mild, 61 Surgent, and 64 Irritable children with ADHD and 128 controls. Group differences
were examined in 2(Valence: Positive/Negative)2(Condition: Induction/Suppression)
Karalunas et al.
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4(Group) repeated-measures ANOVAs with gender covaried [54]. The ANOVA matrix
was decomposed following procedures recommended by Keppel [55] with embedded
correction for Type I error using a Fisherian decomposition strategy and an LSD test for
simple comparisons.
Pre-Ejection PeriodThere were baseline differences in PEP between groups (F[1,
305]=2.73, p=.044, 2=0.03). Post-hoc tests indicated that the Surgent group had
significantly shorter PEP values than typically-developing children or the other ADHD
types. Similarly, tonic PEP scores in each of the four emotion task conditions were
compared. Only the group main effect was significant (F[3, 303]=3.95, p=.009, 2=0.05).
Post-hoc tests again confirmed that the Surgent type had shorter PEP values than the
typically-developing controls, Irritable, and Mild ADHD types. None of the groups showed
significant change in PEP from baseline to task (i.e. PEP reactivity scores did not differ from
zero, all p>.05), and there were no significant main or interaction effects when PEP
reactivity scores were examined for the emotion task (all p>.05). These results are
summarized in Figure 2 and in eTable 3 in the Supplement.
RSARSA change from baseline to task was assessed, with positive scores (increases)
interpreted as increased parasympathetic activity and negative scores (decreases) as reduced
parasympathetic activity [56]. A main effect of group (F[3, 303]=3.97, p=.047, 2=0.03)
was qualified by a 3-way interaction of ValenceCondition Group (F[3, 303]=4.09, p=.
018, 2=0.03). The follow up simple comparisons revealed that the Irritable type had a
smaller increase in RSA than both the control and Mild groups during the two negative
emotion conditions (all p<.05).
The Surgent Type differed from the other three groups during the negative suppression
condition (p=.036, 2=0.04) because they showed no change in RSA in this condition from
baseline. In the positive emotion conditions, the Surgent group also significantly differed
from the other ADHD types and non-ADHD controls (p=.012, 2=0.05). Where other
ADHD types and typically-developing children increased RSA, the Surgent group decreased
RSA (p=.012, 2=0.05), consistent with withdrawal of parasympathetic activity (see Figure
2 and eTable 3).
Thus, data suggest that the Surgent and Irritable types have distinct peripheral physiological
profiles as compared to each other and to typically-developing children. The Mild types, in
contrast, showed a physiological profile similar to that of typically-developing children.
External Validation: II. Neural Connectivity
We examined functional connectivity of the amygdala. Findings related to each group were
distributed throughout the cortex. We highlight a few of these differences here and they are
reported fully in Table 1 and shown in Figure 4.
The Irritable group displayed weaker connectivity (in the form of reduced negative
relationships) from the amygdala to the anterior insula relative to all other groups (including
non-ADHD controls) and weaker connectivity to the posterior cingulate (a key hub in the
default network) relative to typically-developing and the Surgent children. The Mild type
Karalunas et al.
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showed the reduced connectivity profile of the posterior cingulate/precuneus versus the
typically-developing and Surgent groups. The Surgent type evidenced increased
connectivity from the amygdala to cingulate/precuneus compared to the Mild and Irritable
groups, but was similar relative to control populations. All groups had differential patterns
of connectivity to unique dorsolateral prefrontal cortex regions compared to at least one
other group (see Table 1). Overall, each ADHD type had a distinct central nervous system
physiology.
External validation: III. Longitudinal Stability and Clinical Outcome
Community detection was repeated using Time 2 data. Again, the modal solution suggested
three ADHD profiles (Q=.51), which could be characterized as Mild (n=18), Surgent (n=42),
and Irritable (n=41).
Multinomial logistic regression [57] indicated that temperament types were more stable than
expected by chance (2[4]=71.84, p<.001). In both the Surgent and Irritable types, over 70%
of children were assigned to the same type at follow-up. In contrast, the Mild type often
changed profile: 43.6% remained Mild type at Time 2; 41% became Surgent type and 15.4%
became Irritable type (see eVideo 1 in Supplement for depiction of stability of types over
time).
With regard to clinical outcomes, children in the Irritable type at Time 1 were more likely
than those in the other two types to develop a new comorbid disorder over the course of
longitudinal follow-up (2[2]=10.11, p=.006), with more than double the rate of onsets as
compared to either of the other types or non-ADHD controls (11.1%, 18.2%, 11.1%, and
39.5% in controls, Mild, Surgent, and Irritable types, respectively). This prediction was
superior to other nosological designations at baseline that may be related to prognosis:
neither DSM-5 presentations nor groups based on the presence/absence of ODD symptoms
(i.e. 0 symptoms versus 1+ symptoms) differed in their rates of new comorbid disorder
onsets at Time 2 (2[1]=0.68, p=.409 and 2[1]=2.54, p=.111, respectively).
Furthermore, when temperament types, DSM-5 presentations, and oppositional defiant

disorder symptom status were entered into a logistic regression model, the temperament
types were the best predictor of comorbidity onsets (p=.019, Odds Ratio=2.46). Neither the
presence of Time 1 ODD symptoms (p=.563) nor ADHD DSM-5 presentation (p=.113)
uniquely predicted new onsets at Time 2. Future work can examine other clinical
designations that were less common in the sample.
Discussion
Here, we demonstrate an approach to revising psychiatric nosology that: (1) goes beyond
clinical symptoms, in this case choosing temperament measures that are closely related to
RDoC domains; (2) utilizes a novel, discovery-based clustering algorithm; (3) demonstrates
external validation concurrently using peripheral and central physiology; and (4) shows
superior clinical prediction versus existing clinical categories related to ADHD or ADHD
with comorbidity. Results suggest that revising the nosology in the case of ADHD is
tractable and will be biologically meaningful. The current results add to prior work in
Karalunas et al.
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schizophrenia [e.g. 58], suggesting that the use of biologically-influenced indicators,

optimization-based clustering techniques, and comparison on external validators is an
informative approach for understanding heterogeneity in psychiatric disorders.
We identify three distinct types of ADHD based on temperament profiles: a Mild type
whose members are characterized only by deficits in core ADHD symptom domains; a
Surgent type characterized by high levels of positive approach-motivated behaviors and
activity level, shorter PEP,, parasympathetic withdrawal in response to positive emotions,
and atypical amygdala connectivity to medial frontal areas; and an Irritable type
characterized by high levels of negative emotionality, weak parasympathetic response to
negative emotional stimuli, reduced amygdala-insula connectivity, and a doubling of risk for
onset of new behavioral or emotional disorders.
Crucially, we considered multiple validators, choosing a subset from the classic validators
suggested by Robins and Guze [59] and Cantwell [60], including biological correlates and
clinical course. We found promising results suggesting that these types outperform existing
nosology of ADHD. Here, the Surgent and Irritable types survived every test of validation,
including distinct physiology and functional connectivity, stability over time, and better
clinical prediction than DSM presentations or the most common comorbid grouping, ODD.
Thus, they emerge as promising, novel types of ADHD that support the promise in this
approach generally, and that warrant further validation.
Although the Mild type showed distinct patterns of functional connectivity compared to
other types, they showed normative peripheral physiology and assignment to this type was
not particularly stable over time. Thus, this type was not as well-validated as the others.
From the perspective of Wakefields [61] definition of mental disorder as including a
psychological or physiological dysfunction, these youth did not as clearly have a disorder
even though they just as clearly met DSM-5 ADHD criteria.
Cardiac physiology measures suggest that the neurobiology of the Irritable type is related to
weak parasympathetic response to negative emotionality. This pattern is consistent with high
levels of negative valence emotions and low soothability captured in the temperament
profile, as well as with high rates of comorbidity in this group. In contrast, the neurobiology
of the Surgent type is related to parasympathetic withdrawal to positive valence
emotionality, which is potentially consistent with high sensation-seeking and approachmotivated behaviors in this group. Although no differences were seen in PEP reactivity, the
Surgent type had shortened tonic PEP scores. Tonic PEP may be influenced by many
factors, including sympathetic nervous system activity, preload, afterload, peripheral
resistance, and biomechanical processes. It will be interesting in future studies to examine
whether the source of this effect can be described in terms of abnormal sympathetic arousal,
due to its historic interest in externalizing disorders, or whether these tonic PEP differences
reflect other factors.
The Irritable group, which had abnormal parasympathetic response to negative emotions,
also had prominent atypical connectivity between the amygdala and the anterior insula.
Although imaging results are based on a small subsample of participants and should be
Karalunas et al.
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considered preliminary, the insula is a region that has been long known to be important for
monitoring and adjusting sympathetic and parasympathetic tone. More recently, it has also
been shown to be heavily involved in higher order control processing [62, 63]. Together
these data may highlight the regions importance for emotional regulation and impulse
control.
Several of the neural regions (e.g. DLPFC, anterior insula) differentiating the ADHD
temperament types are also implicated in executive control of attention [67]. Thus, our
results, while preliminary due to the small sample size, are consistent with Petersen &
Posners [67] recent elaboration of their attention model suggesting a close relationship
between the anatomical correlates of executive attention and the broader constructs of
behavioral and emotional self-regulation [6769]. Additional work examining the cognitive
profiles of each temperament-based group, as well as to understand the relationships
between attention and self-regulation models [e.g. 70] will be an important areas for future
research.
Perhaps most encouraging here was that our new temperament types of ADHD predicted
clinical outcome. In this case, we focused on onset of new comorbid psychiatric disorder at
one year follow-up as an index of clinical deterioration. The new categories provided
improved prediction versus existing clinical indicators.
With regard to implications for ADHD itself, these findings are broadly consistent with, but
suggest some modifications to, prior theory of ADHD temperament variation that inspired
this work [64, 65], while being mostly consistent with and building on previous work
exploring temperament subgroups in ADHD in a different sample [66]. Although the
subgroups found here were largely stable over time, future work will need to address issues
related to family history, genetics, replicability in other samples, and treatment response [59,
60].
In addition, despite well-described limitations of parental-report measures [71], current

results suggest that parent-reported temperament characteristics (at least as measured in this
study) may be related to important individual differences in underlying physiology,
suggesting some validity and clinical applicability for these measures. Importantly,
temperament traits have been investigated in many other disorders [65] and further
exploration of temperament types in other DSM-defined disorders may be informative for
understanding shared and unique risk profiles and revising psychiatric nosology. Similarly,
detailed comparison and integration of results obtained using alternative clustering
algorithms or based on different input features will be important.
In terms of the proposed RDoC research framework, parent-report on the TMCQ broadly
captures RDoC domains of negative valence systems, positive valence systems/approach
motivation, and cognitive control. Additional studies examining sub-constructs within these
domains (e.g. frustrative non-reward, reward valuation, or response selection and inhibition,
respectively) may further refine the picture provided here. In addition, here we focus on
relationships between parent-report measures, reflecting the self-report unit of analysis in
the RDoC matrix, and peripheral and central nervous system indicators, reflecting the
Karalunas et al.
Page 11
physiology and circuit units of analysis, respectively. Additional work examining

relationships with other units of analysis, such cells or genes, will also be informative.
Overall, we conclude that progress toward a neurobiologically-based nosology, as

envisioned in the NIMH RDoC initiative [2], is tractable. In the illustration here,
temperament profiles in children with ADHD can be related to meaningful differences in
both central and peripheral nervous system and longitudinal course, setting the stage for
improving nosology.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Many special thanks to Colleen Schmitt, M.S. and Hilary Galloway-Long, B.A. for help with data and project
management. Funding was provided by R01 MH059105 (Nigg), R01 MH086654 (Nigg), R01 MH096773 (Fair),
R00 MH091238 (Fair), and F32 MH098632 (Karalunas).
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Figure 1. Spring-embedded visualization of temperament groups
Graphical representation of the community detection results in the 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 (Blue:
Mild, Red: Surgent, Green: Irritable) and connecting edges indicate correlations between
individuals. (Note: Correlations are thresholded at .50 for purposes of visual representation;
however, reported results are based on an unthresholded modularity algorithm as explained
in Methods.)
Karalunas et al.
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Figure 2. Temperament type profiles
TMCQ scores for each of the three temperament types identified in the ADHD sample.
Scores are shown as z-scores relative to the control sample mean (such that 0 on the Y axis
is the mean of the typically-developing sample). Standard errors are shown. 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 soothabtility. Panel A) shows
scores on temperament domains related to Cognitive Control; B) shows scores for Surgency
Karalunas et al.
Page 17
domains; and C) shows scores for Negative Emotion Domains. Two scales that did not
differentiate types (Openness and Perceptual Sensitivity) are not show, but scores for these
scales are reported in eTable 2 in the Supplement.

Karalunas et al.
Page 18

Figure 3. Cardiac physiological response
A) Mean RSA change from baseline and B) raw PEP for each of the emotion task epochs:
negative induction (NI), negative suppression (NS), positive induction (PI), and positive
suppression (PS), shown by temperament type.

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Page 19

Figure 4. rs fcMRI conjunction maps
Amygdala connectivity maps for each temperament type were directly compared to the two
other types and a matched control population. Results from each of these comparisons are
provided in Table 1. The figure is a conjunction map for the comparisons. For each
comparison (i.e. Mild vs Surgent, Mild vs Irritable, Mild vs Control and similar for each of
the two other subgroups), a voxel was coded as either 0 (not significantly different between
groups) or 1 (significantly different between groups). Maps based on this coding were
summed such that voxels that never differ between groups will have a value of 0 and voxels
Karalunas et al.
Page 20
that differ in all comparisons for that group have a value of 3. In A) the Mild type differed
from other types in areas in the posterior cingulate/precuneus (black arrow). B) As with the
Mild type, the Surgent type also 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
quite distinct from Mild, Surgent, and control populations in the anterior insula (black
arrows) a region important for emotional regulation and task level control.

Karalunas et al.
Page 21
Table 1
ROI table for between-group comparisons.

Surgent- Irritable Type Comparison
Region
Anterior Insula
Posterior Insula
Mid-/Post-Cingulate
Temporal Lobe- Anterior/Superior
Effect
36
21
Surgent < Irritable
44
15
Surgent < Irritable
36
17
Surgent < Irritable
36
18
Surgent < Irritable
36
24
11
Surgent > Irritable
38
59
Surgent > Irritable
42
65
Surgent > Irritable
58
Surgent > Irritable
47
15
Surgent > Irritable
Temporal Lobe- Inferior
40
35
Surgent > Irritable
Temporal Lobe- Medial
41
10
20
Surgent > Irritable
Temporal Lobe- Superior
61
53
Irritable > Surgent
Occipital Lobe
85
32
Irritable < Surgent
13
84
20
Irritable < Surgent
Parahippocampus
33
20
24
Surgent > Irritable
Parietal Lobe
20
36
56
Surgent > Irritable
Effect
29
20
Mild < Irritable
Mild- Irritable Type Comparison

Region
Anterior Insula
37
14
Mild < Irritable
Temporal Lobe- Inferior
65
20
16
Mild > Irritable
Occipital Lobe
90
Irritable < Mild
Occipital Lobe
13
87
13
Irritable < Mild
Region
Dorsal Medial Frontal
22
56
Surgent < Mild
Mid-/Post-Cingulate
40
56
Surgent > Mild
Mild- Surgent Type Comparison

Effect
10
44
59
Mild < Surgent
Precuneus/Posterior Cingulate
15
54
50
Mild < Surgent
Ventral Medial Prefrontal Cortex
34
Surgent < Mild
Effect
92
Control<Mild
19
81
Control<Mild
27
93
Control<Mild
18
99
Control>Mild
21
82
Control<Mild
26
94
Control<Mild
Control-Mild Type Comparison

Region
Occipital Lobe
Karalunas et al.
Page 22
Lateral Frontal
Precuneus/Posterior Cingulate
Inferior Parietal Lobe
24
100
Control<Mild
49
21
28
Control>Mild
52
52
Control<Mild
10
43
51
Control<Mild
55
30
39
Control<Mild
44
36
42
Control<Mild
Anterior Insula
22
18
Control<Mild
Cerebellum
22
79
28
Control>Mild
31
71
27
Control<Mild
19
17
22
Control<Mild
18
53
10
Control<Surgent
30
54
Control<Surgent
41
81
34
Control>Surgent
Caudate
Control-Surgent Comparison
Region
Medial Frontal
Cerebellum
Effect
Control-Irritable Comparison
Region
Anterior Insula
Effect
43
14
Control> Irritable
35
22
Control>Irritable
Precuneus
69
24
Control> Irritable
Medial Frontal
33
44
27
Control> Irritable


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Subtyping attention-deficit/hyperactivity disorder using

Health & Science University, Department of Psychiatry, Division of Psychology,

Health& Science University, Department of Behavioral Neuroscience, Portland, OR

Health & Science University, Advanced Imaging Research Center, Portland OR

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International University, Department of Psychology, Division of Clinical Science, Miami,

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ObjectiveRefine subtyping of childhood ADHD by using biologically-based behavioral

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Psychiatric nosology remains exclusively syndromic, depending on clusters of signs and

JAMA Psychiatry. Author manuscript; available in PMC 2014 December 29.

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For the features, we used a well-accepted, low-cost, parent-rated measure of child

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Participants and Diagnostic Procedures

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A parent/guardian completed the widely used Temperament in Middle Childhood

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Community Detection Analyses

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JAMA Psychiatry. Author manuscript; available in PMC 2014 December 29.

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Furthermore, when temperament types, DSM-5 presentations, and oppositional defiant

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schizophrenia [e.g. 58], suggesting that the use of biologically-influenced indicators,

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JAMA Psychiatry. Author manuscript; available in PMC 2014 December 29.

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In addition, despite well-described limitations of parental-report measures [71], current

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physiology and circuit units of analysis, respectively. Additional work examining

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Overall, we conclude that progress toward a neurobiologically-based nosology, as

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