Article
Neural Mechanisms of Frustration in
Chronically Irritable Children
Christen M. Deveney, Ph.D.
Megan E. Connolly, B.A.
Catherine T. Haring, B.A.
Brian L. Bones, B.A.
Richard C. Reynolds, M.S.
Pilyoung Kim, Ph.D.
Daniel S. Pine, M.D.
Ellen Leibenluft, M.D.
Objective: Irritability is common in children and adolescents and is the cardinal
symptom of disruptive mood dysregulation disorder, a new DSM-5 disorder, yet its
neural correlates remain largely unexplored. The authors conducted a functional
MRI study to examine neural responses to
frustration in children with severe mood
dysregulation.
Method: The authors compared emotional responses, behavior, and neural
activity between 19 severely irritable
children (operationalized using criteria
for severe mood dysregulation) and 23
healthy comparison children during a
cued-attention task completed under nonfrustrating and frustrating conditions.
Results: Children in both the severe
mood dysregulation and the healthy comparison groups reported increased frustration and exhibited decreased ability to
shift spatial attention during the frustration condition relative to the nonfrustration condition. However, these effects of
frustration were more marked in the
severe mood dysregulation group than
in the comparison group. During the
frustration condition, participants in
the severe mood dysregulation group
exhibited deactivation of the left amygdala, the left and right striatum, the
parietal cortex, and the posterior cingulate
on negative feedback trials, relative to the
comparison group (i.e., between-group
effect) and to the severe mood dysregulation group’s responses on positive feedback trials (i.e., within-group effect). In
contrast, neural response to positive feedback during the frustration condition did
not differ between groups.
Conclusions: In response to negative
feedback received in the context of frustration, children with severe, chronic irritability showed abnormally reduced
activation in regions implicated in emotion, attention, and reward processing.
Frustration appears to reduce attention
flexibility, particularly in severely irritable
children, which may contribute to emotion regulation deficits in this population.
Further research is needed to relate these
findings to irritability specifically, rather
than to other clinical features of severe
mood dysregulation.
(Am J Psychiatry 2013; 170:1186–1194)
I
rritability can be defined as a low threshold for
experiencing negative affect in response to frustration, with
frustration being the emotional response to blocked goal
attainment (1, 2). Irritability is both common and impairing
in child and adult psychiatric disorders (3), and its
importance is recognized in DSM-5 with the adoption of
disruptive mood dysregulation disorder, a disorder whose
defining feature is excessive and impairing irritability. Given
the importance and pervasiveness of irritability, it is notable
that few neuroimaging studies have been conducted to
examine its pathophysiology. Since irritability can be viewed
as a decreased threshold for experiencing frustration, one
approach to studying its pathophysiology is by evoking
frustration in the scanner. In this study, we compared the
neural correlates of frustration in healthy children and
children with chronic and impairing irritability.
Frustration is typically induced in the laboratory by
using paradigms that increase task difficulty or deceive
participants into believing that because their performance
is substandard, they cannot earn a reward (4–10). The few
functional MRI (fMRI) studies that have investigated the
circuitry mediating frustration have implicated the amygdala, parietal attentional networks, and the dorsal and
ventromedial prefrontal cortex. Healthy adults exhibit
increased amygdala activation with increased frustration
(11), consistent with the amygdala’s role in detecting
emotional salience (12). Healthy children demonstrate an
increase in a parietally mediated attentional event-related
brain potential (9, 10) and greater dorsal and ventromedial
prefrontal cortex recruitment during frustration (4), perhaps reflecting the engagement of attentional or cognitive
resources to facilitate task performance or emotion regulation. Finally, frustration tasks may activate the ventral
striatum, given its ability to signal when an expected reward
is not received (negative prediction error) (13, 14).
Whether children and adolescents with clinically significant irritability display dysfunction in these regions has
been largely unexplored, yet some evidence indicates that
This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. 1194),
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Am J Psychiatry 170:10, October 2013
DEVENEY, CONNOLLY, HARING, ET AL.
this may be the case. In nonfrustrating contexts, irritable
children display amygdala and electrocortical dysfunction
(9, 15). During frustration, they exhibit abnormal selective
attention and anterior cingulate dysfunction (7, 9). Finally,
during reward tasks, they display dysfunctional striatal
activation (16).
The present study is, to our knowledge, the first fMRI
study to examine neural responses to frustration in healthy
children and children with severe, chronic, and impairing
levels of irritability (operationalized as severe mood
dysregulation [1, 2]). Although this study predated the
definition of disruptive mood dysregulation disorder, all of
the children with severe mood dysregulation in this study
would meet criteria for this disorder. Children with severe
mood dysregulation and healthy children completed an
adaptation of the Posner spatial cuing task that included
monetary rewards (7–10). Frustration was induced by
telling participants that they were responding too slowly
and therefore losing money. We hypothesized that during
frustration, children with severe mood dysregulation
would exhibit, relative to healthy children, increased amygdala activation, decreased activation in prefrontal regions
responsible for cognitive and emotion regulation, decreased parietal activation, and abnormal activation in the
ventral striatum reflecting aberrant prediction errors.
Method
Participants
The participants were children 8–17 years of age enrolled in
a study at the National Institute of Mental Health (NIMH).
Children received $105 for participation plus task winnings
during the nonfrustration blocks (up to $25). Participants included 19 patients who met criteria for severe mood dysregulation
and 23 healthy comparison children. The diagnostic and clinical
assessment methods we used have been described elsewhere (1,
15, 16). The study was approved by the NIMH Institutional Review
Board.
Participants in the severe mood dysregulation group met
published criteria (1), including excessive reactivity to negative
emotional stimuli, negatively valenced mood between outbursts,
and three hyperarousal symptoms. Symptoms began before age
12, were present for at least 1 year, and caused impairment in at
least two of three settings (home, school, and with peers). Hypomanic or manic episodes of 1 day or longer were considered
exclusionary, so none of the participants met criteria for bipolar
disorder. As noted, all children with severe mood dysregulation
in the present study meet criteria for disruptive mood dysregulation disorder. Both severe mood dysregulation and disruptive
mood dysregulation disorder are characterized by severe, recurrent, excessive, and developmentally inappropriate temper
outbursts and persistent negative mood between outbursts.
Severe mood dysregulation, but not disruptive mood dysregulation disorder, requires the presence of hyperarousal symptoms.
In addition, the required age at onset (10 years) is earlier and the
maximum acceptable asymptomatic period is longer (3 months)
in disruptive mood dysregulation disorder than in severe mood
dysregulation (age 12 and a period of 2 months, respectively).
Healthy children had no current or past psychiatric illness and
no first-degree relatives with a mood or anxiety disorder.
Exclusion criteria for all groups included IQ ,70, pervasive
Am J Psychiatry 170:10, October 2013
developmental disorder, a neurological disorder, an unstable or
chronic medical illness, or substance abuse within the past 2
months.
After receiving a complete description of the study, including
a statement that participants might receive misleading information, parents and participants provided informed consent or
assent.
Affective Posner Task
Participants completed an adapted affective Posner task (7–10).
Trials consisted of 1) a fixation cross, 2) a symbol indicating trial
type (i.e., money or no money), 3) two white squares, 4) a blue cue
appearing in one of the white squares, 5) a target appearing in one
of the white squares, and 6) feedback (Figure 1). Participants
identified the target’s location as quickly and accurately as
possible using a response button box. The blue cue predicted
target location on 75% of trials (valid trials) and was in the
opposite location on 25% of trials (invalid trials).
Participants completed the task as three “games.” During
game 1 (50 trials), participants received accurate performance
feedback and did not win or lose money. During game 2 (100
trials), participants received accurate feedback and won or lost
50¢ a trial, depending on performance. The frustration manipulation occurred during game 3 (260 trials). During game 3,
participants were told that they must respond both quickly and
accurately to win money, and that adequate speed was based
on a complicated formula that considered performance on
prior trials. Frustration was induced by giving participants the
feedback that they were “too slow” on 60% of accurate trials,
irrespective of the subject’s reaction time (referred to here as
“negative feedback trials”).
Game 3 consisted of three trial types: money trials (N=100),
no-money trials (N=100), and fixation trials (N=60), randomly
presented across three runs (Figure 1). Money trials were identified by three green dollar signs (trial type symbol), indicating that participants could win or lose 50¢ a trial. Feedback
consisted of a coin image with green text on positive feedback
trials and red text on negative feedback or error trials; the
participant’s cumulative winnings were displayed at the bottom
of the screen. No-money trials were identified by three yellow
circles, and participants did not win or lose money. Thus, on
each money or no-money trial, participants received one of three
kinds of feedback: error (“wrong” on inaccurate or missed trials),
negative (“too slow” on 60% of accurate trials), or positive (“you
win” [money trials] or “good job” [no-money trials] on 40% of
accurate trials). Fixation trials (N=60) consisted of a fixation cross
centrally presented. All trials were followed by a variable intertrial interval (range=850–1150 ms, mean=1000 ms).
Procedure
Participants completed game 1 and 60 trials of game 2 outside
the scanner. Next, participants completed 40 trials of game 2 in
the scanner while anatomical brain images were collected. This
allowed us to determine whether behavioral or affective changes
were related to the scanning environment as opposed to the
frustration manipulation. Participants then completed three
blocks of game 3 during functional imaging. Thus, scanning
time was focused on the frustration condition.
Participants self-reported valence, arousal, and frustration at
six time points (after game 1 and after each block of games 2
and 3) using 9-point Likert scales (17). After scanning, participants’ deception was assessed via self-report questionnaire and
follow-up interview. Participants who knew that the feedback
had been manipulated were excluded. No participant reported
marked distress associated with the frustration manipulation or
deception.
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FIGURE 1. Schematic of Trial Structure During the Frustration Condition (Game 3)a
YOU WIN!
A. Money Trials
TOTAL: $5.00
TOO SLOW!
+
$$$
750 ms
1000 ms
TOTAL: $4.00
300 ms
200 ms
1260 ms
WRONG!
TOTAL: $4.00
2000 ms
B. No-Money Trials
GOOD JOB!
+
000
750 ms
1000 ms
TOO SLOW!
300 ms
200 ms
1260 ms
WRONG!
2000 ms
a
The blue cue and the black target could appear in either the left or the right box. On valid trials, the cue and target were in the same location.
On invalid trials, the cue and target were in opposite locations. Participants were instructed to press a button corresponding to the target
location. During game 3, which was the frustration condition, participants viewed money trials and no-money trials that were distinguished
by different trial type indicators (green “$$$” versus yellow “000”) and the possibility of winning and losing money. During money trials,
participants won or lost money depending on performance. During no-money trials, no money was won or lost. For both money and nomoney trials in the frustration condition, 40% of correct responses were followed by positive feedback (either “You win” or “Good job”), and
60% of correct responses were followed by negative feedback (“Too slow”). All incorrect responses received negative feedback (“Wrong”).
Data Analysis
Demographic characteristics. Unpaired t tests or chi-square
tests were used to compare age, IQ, and sex distribution between
groups. Sex distribution differed between groups and was included as a covariate in all analyses.
Self-reported valence, arousal, and frustration ratings.
Group differences on valence, arousal, and frustration were assessed using a time-by-group repeated-measures analysis of
covariance (ANCOVA) in which time had six categories: game 1,
game 2–out of scanner, game 2–in scanner, game 3–run 1, game
3–run 2, and game 3–run 3.
Behavioral data. Group differences in response time and accuracy were evaluated using two repeated-measures ANCOVAs.
First, we conducted a group-by-time-by-validity (valid, invalid)
ANCOVA. Next, to examine whether trial type (money or nomoney) influenced group differences in response time, we
conducted a group-by-validity-by-trial type ANCOVA that included response time averaged across the three runs of game 3.
Two separate ANOVAs were required because game 3, but not
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games 1 and 2, contained both money and no-money trials.
Feedback was not included as a factor in either ANOVA because
responses were made before feedback was received. We report
interactions and main effects not qualified by interactions (for all
findings, see Table S1 in the data supplement that accompanies
the online edition of this article).
Imaging data. Neuroimaging data were acquired on a 1.5-T GE
scanner using an eight-channel head coil and including a highresolution anatomical scan (1.5-mm slices, three-dimensional
fast spoiled gradient echo, 20° flip angle, 2563192 matrix, 24 cm
field of view). Gradient echo-planar imaging images were collected during game 3 (TR=2900 ms, TE=27 ms, field of view=24 cm,
flip angle=90°, voxel size=2.533.7533.75 mm).
Data were analyzed using AFNI (Analysis of Functional
Neuroimages) (18). Preprocessing included temporal alignment
to the first acquired slice, coregistration, smoothing (kernel full
width at half maximum=6), masking, intensity scaling, and transformation into Talairach space. Repetitions with motion .2 mm
or .2 degrees relative to the preceding repetition were removed
from the analysis.
Am J Psychiatry 170:10, October 2013
DEVENEY, CONNOLLY, HARING, ET AL.
Event types included three categories: trial type (money, nomoney), validity (valid, invalid), and feedback (positive, negative,
error). All combinations of these three factors were modeled
using individual linear regression with a fixed-shape, gammavariate response function, convolved with a boxcar function of
the stimulus duration. The model included each of the event
type regressors, the six motion parameters, and baseline drift
for each of the three runs. Beta coefficients and t-statistics were
calculated for each voxel and regressor. Because of an insufficient number of invalid and error trials, group analyses focused
on the remaining four event types: money–valid–positive feedback; money–valid–negative feedback; no-money–valid–positive
feedback; and no-money–valid–negative feedback.
Group-level analyses occurred on two levels. Region-ofinterest analyses were conducted on the left and right amygdala
and striatum (caudate, putamen, and nucleus accumbens), as
defined by the Talairach-Tournoux Daemon. Mean signal intensity was extracted from each region of interest for each of the
four event types. Amygdala values were submitted to a group-bytrial type-by-feedback-by hemisphere ANCOVA in SPSS. Striatum
values were submitted to a group-by-trial type-by-feedback-byhemisphere-by-region (regions were caudate, putamen, and
nucleus accumbens) ANCOVA in SPSS.
Next, we computed a whole-brain analysis using a group-bytrial type-by-feedback ANCOVA with participant as a randomeffects factor. 3dClustSim using group blur estimates indicated
that a cluster-extent threshold of k$37 at p,0.001 resulted in
a whole-brain false positive probability of p,0.05. Average signal
change values were extracted and post hoc ANCOVAs were
performed in SPSS for clusters meeting identified thresholds.
Because our primary interest was in group differences in response to positive and negative feedback, we only discuss the
group-by-feedback interaction (for all findings, see Table S2 in
the online data supplement). Greenhouse-Geisser correction was
used when analyses violated sphericity assumptions.
Post hoc analyses examined the effects of medication,
comorbid attention deficit hyperactivity disorder (ADHD), and
affect ratings (i.e., self-reported frustration during game 3 and
irritability over a 6-month period) on neural activation patterns.
Exploratory post hoc t tests compared neural activation on
negative feedback trials between unmedicated children with
severe mood dysregulation (N=7) and healthy comparison
children, and between children with severe mood dysregulation
without comorbid ADHD (N=4) and healthy comparison children
in the brain regions identified in the primary analysis. Pearson
correlations conducted separately for each group examined associations between affect measures, behavioral variables, and neural response to negative feedback.
Results
Participants
A total of 61 children enrolled, 19 of whom were
excluded for various reasons (inability to complete the
task because of frustration or anxiety, five children with
severe mood dysregulation; not deceived, two healthy
children; technical difficulties, one child with severe mood
dysregulation and one healthy child; structural brain
abnormality, one healthy child; insufficient numbers of
trials/condition (,35% of trials) because of poor behavioral performance or motion .2 mm, five children with
severe mood dysregulation and three healthy children;
and poor coregistration, one healthy child). The final
Am J Psychiatry 170:10, October 2013
TABLE 1. Demographic and Clinical Characteristics of Children With Severe Mood Dysregulation and Healthy Comparison Children
Severe Mood
Dysregulation
Group (N=19)
Characteristic
Age (years)
IQa
Children’s Depression
Rating Scale score
Number of medications
Number of
comorbid diagnoses
Maleb
Comorbid diagnoses
ADHDc
Major depression
Oppositional
defiant disorder
Anxiety
Conduct disorder
Medication
Unmedicated
Atypical antipsychotic
Lithium
Antiepileptic
Antidepressant
Stimulant
a
b
c
Mean
13.6
104.3
26.1
SD
2.2
13.8
5.1
1.7
3.3
1.6
1.5
N
15
%
78.9
15
4
16
78.9
21.1
84.2
12
1
63.2
5.3
7
7
1
5
7
7
36.8
36.8
5.3
26.3
36.8
36.8
Healthy
Comparison
Group (N=23)
Mean
14.3
110.4
SD
2.2
12.2
N
11
%
47.8
Wechsler Abbreviated Scale of Intelligence (two-scale IQ).
Significant difference between groups, p,0.04.
ADHD=attention deficit hyperactivity disorder.
sample included 19 children with severe mood dysregulation (seven of them unmedicated) and 23 healthy
comparison children (Table 1). The groups did not differ
significantly in age or full-scale IQ. The severe mood
dysregulation group had a greater proportion of boys than
the healthy comparison group (x2=4.27, p,0.04), so sex
was a covariate in all analyses.
Affect Ratings
A group-by-time interaction (F=3.42, df=5, 190, p,0.05)
revealed that children with severe mood dysregulation
reported more frustration than healthy children after the
last two runs of game 3, but not at earlier assessment
points. All participants felt more unhappy during the
frustration condition (game 3) than during nonfrustration
conditions (games 1 and 2) (time, F=12.76, df=5, 190,
p,0.001), but there were no main effects of group or interactions. No findings emerged from the arousal ratings.
Behavioral Results
The first behavioral analysis (group-by-time-by-validity)
revealed a time-by-validity interaction for response time
(F=7.67, df=5, 195, p,0.001) and accuracy (F=30.05, df=5,
195, p,0.001). In general, participants were faster but less
accurate during frustration relative to nonfrustration trials, with no differences between groups.
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NEURAL MECHANISMS OF FRUSTRATION IN CHRONICALLY IRRITABLE CHILDREN
FIGURE 2. Reaction Time to Identify a Target on Valid and
Invalid Trials During the Frustration Condition (Game 3)a
500
Reaction Time (ms)
400
300
200
100
0
Severe Mood
Dysregulation
Group
Valid trials
a
Healthy
Comparison
Group
Invalid trials
All participants responded more slowly on invalid compared with
valid trials; however, children with severe mood dysregulation
were slower on invalid trials than were healthy comparison
children (p,0.05).
The second behavioral analysis (group-by-validity-bytrial type), was restricted to the frustration condition
(game 3), since only game 3 included money and nomoney trials. On response time, there was a group-byvalidity interaction (F=5.41, df=1, 39, p,0.03). During
frustration, all participants responded more slowly during
invalid than valid trials; however, children with severe
mood dysregulation were slower than healthy children
only on invalid trials (Figure 2). A main effect of trial type
also emerged (F=8.24, df=1, 39, p,0.01), indicating that
participants responded more quickly during money
than no-money trials. No group differences emerged for
accuracy.
fMRI Activation Results
The amygdala region-of-interest analysis revealed
a group-by-feedback-by-hemisphere interaction (F=4.70,
df=1, 39, p,0.04). Compared with healthy children, children
with severe mood dysregulation exhibited less activation in
the left amygdala on negative feedback trials (betweengroup difference). There was also a within-group difference
in the severe mood dysregulation group only, with participants exhibiting less activation in the left amygdala on
negative relative to positive feedback trials. Activation in
healthy children did not differ between positive and
negative feedback trials, and activation did not differ between groups on positive feedback trials.
In the striatum, the group-by-trial type-by-feedback-byhemisphere-by-region ANCOVA revealed a group-byfeedback interaction (F=5.54, df=1, 39, p,0.03) but no
higher-order interactions. The pattern in the striatum was
similar to that in the amygdala: children with severe mood
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dysregulation exhibited less activation in the left and right
striatum than healthy children during negative feedback
trials (between-group difference). Children with severe
mood dysregulation also exhibited less activation in the
striatum during negative relative to positive feedback
trials. This within-group difference was present in the
severe mood dysregulation group only; in healthy children, striatal activation did not differ between positive and
negative feedback trials. As in the amygdala, children with
severe mood dysregulation did not differ from healthy
children on striatal activation during positive feedback
trials.
In the whole-brain analysis, no regions showed a groupby-trial type-by-feedback interaction. However, there was
a group-by-feedback interaction in 11 regions (Table 2;
Figure 3). Activation patterns were identical in each region
and similar to the region-of-interest results—that is, we
observed a between-group difference during negative
feedback trials, no group differences during positive
feedback trials, and, in the severe mood dysregulation
group only, a within-group difference on negative relative
to positive-feedback trials. Specifically, relative to healthy
children, children with severe mood dysregulation exhibited less activation in response to negative feedback in
parietal, parahippocampal, and thalamic/cingulate/
striatal regions (F values, .10.00, p values, ,0.005). Activation did not differ between groups on positive feedback trials. In these same regions, children with severe
mood dysregulation exhibited less activation in response
to negative relative to positive feedback (F values, .7.50,
p values, ,0.02), whereas healthy children did not show
a within-group difference.
Exploratory Analyses
Post hoc analyses (see Table S3 in the online data
supplement) indicated that unmedicated children with
severe irritability, as well as children with severe mood
dysregulation without comorbid ADHD, exhibited hypoactivation relative to healthy children in the left amygdala,
in the left and right striatum, and in 10 of the 11 regions
identified by the whole-brain analyses (F values, .4.10,
p values, ,0.05).
In both children with severe mood dysregulation and
healthy children, greater self-reported frustration during
the task was associated with reduced activation in response to negative feedback trials in several regions
identified in primary analyses (severe mood dysregulation:
left inferior parietal lobule/supramarginal gyrus; right
supramarginal gyrus; and left parahippocampal gyrus
[r values, ,20.47, p values, ,0.05]; healthy comparison
children: left insula, left parahippocampal gyrus, left pre-/
postcentral gyrus, right precuneus, and left cingulate/
thalamus/caudate; left amygdala [r values, .20.42, p
values, ,0.05]).
In healthy children, greater parent-reported irritability
was associated with decreased accuracy on valid trials
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DEVENEY, CONNOLLY, HARING, ET AL.
TABLE 2. Significant Findings From the Group-by-Feedback Interaction Observed in the Whole-Brain fMRI Analysis
Talairach Coordinatesb
a
Analysisc
Area of Activation
Side
Cluster Size
x
y
z
Brodmann’s Area
F
p
Posterior cingulate cortex
Posterior cingulate cortex
Postcentral gyrus and inferior parietal lobule
Supramarginal gyrus and inferior parietal lobule
Insula
Supramarginal gyrus
Insula
Parahippocampal gyrus
Post-/precentral gyrus
Precuneus
Cingulate/thalamus/caudate
Right
Left
Right
Left
Left
Right
Left
Left
Left
Right
Left
296
137
83
82
74
65
60
49
45
39
38
17
–19
62
–37
–28
47
–40
–13
–40
14
–13
–40
–55
–25
–31
–22
–52
5
–13
–16
–58
–28
14
32
35
26
20
29
2
–13
23
38
23
29
17/31
2
13
13
39
13
28/34
6
7
20.52
14.62
10.02
12.07
16.61
10.05
21.46
20.72
14.70
10.42
16.01
,0.001
,0.001
,0.005
,0.002
,0.001
,0.005
,0.001
,0.001
,0.002
,0.005
,0.001
a
b
c
Cluster size was determined using a significance threshold of p,0.05, corrected for the number of comparisons.
Coordinates refer to the voxel with maximum signal intensity.
Statistics refer to the analysis of the extracted clusters in SPSS; df=1, 39.
during frustration (r=20.46, p,0.05), and greater selfreported irritability was negatively associated with activation to negative feedback trials in the left parahippocampal
gyrus (r=20.78, p,0.001). Self-reported irritability was not
associated with any behavioral or neural measure in children
with severe mood dysregulation.
Discussion
To our knowledge, this is the first fMRI study to compare
the affective, behavioral, and neural correlates of frustration in children with severe and chronic irritability and
healthy subjects. During the frustrating game, chronically
irritable children exhibited behavioral deficits relative to
healthy comparison children, in that children with severe
mood dysregulation responded more slowly than healthy
comparison children on invalid trials. Also during the
frustrating game, irritable children differed from healthy
children by showing marked deactivation of neural regions
associated with spatial attention, reward processing, and
emotional salience on the contrast of negative versus positive feedback trials. Groups did not differ in their neural
response to positive feedback trials.
Both groups showed approximately 30% lower accuracy
on invalid trials in the frustration versus nonfrustration
condition. Therefore, frustration decreased spatial attention flexibility in both groups, perhaps by inhibiting
disengagement from the cue. Whereas the groups did
not differ on accuracy during frustration, there were
between-group differences on reaction time. Specifically,
children with severe mood dysregulation were slower than
healthy comparison children on invalid trials during frustration, suggesting they had particular difficulty shifting
spatial attention away from the cue. Such behavioral
deficits may be associated with the parietal hypoactivation
observed in children with severe mood dysregulation in
response to negative feedback, given the prominent role of
parietal regions in mediating spatial attention processes
Am J Psychiatry 170:10, October 2013
(19). Attention allocation skills are important for successful emotion regulation (20), and deficits in attention
control have been associated with increased negative
affect and aggression in children (21–24). When frustrated
and confronted with a negative event, children with severe
mood dysregulation may have difficulty disengaging attention from the blocked goal and attending instead to
stimuli that might serve as helpful distractors and improve
their emotional state (20). Alternatively, an inability to
shift attention flexibly may reduce the number of emotion regulation strategies that can be identified and employed. Either mechanism might contribute to the irritable
outbursts characteristic of children with severe mood
dysregulation.
Alternatively, the behavioral impairments and frustration
experienced by children with severe mood dysregulation
may stem from deficits in bottom-up processes mediated
by the amygdala/insula or striatum. Our observation of left
amygdala hypoactivation in children with severe mood
dysregulation during negative feedback is surprising, given
the amygdala’s role in responding to emotionally salient
stimuli (12) and prior evidence of amygdala hyperactivation
to frustrating stimuli in adults with high trait anger (25, 26).
However, an independent sample of children with severe
mood dysregulation exhibited amygdala hypoactivation in
response to emotional stimuli on another task (15), perhaps
reflecting generalized amygdala dysregulation, with a tendency toward hypoactivation, in chronically irritable children. Additional studies are needed to replicate and clarify
these findings.
Decreased striatal response in children with severe mood
dysregulation during negative feedback trials may reflect
abnormalities in regions supporting reward processing. For
example, negative prediction errors, which occur when an
outcome is worse than expected, are associated with ventral
striatal deactivation (13, 14). Therefore, our striatal finding
in children with severe mood dysregulation may indicate
that these children experienced the frustrating event as
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FIGURE 3. Brain Activation in Children With Severe Mood Dysregulation and Healthy Comparison Children on Positive and
Negative Feedback Trialsa
R
L
R
L
A.
0.2
b
% BOLD Signal Change
b
0.1
0
–0.1
–0.2
–0.3
Severe Mood
Dysregulation
Group
Positive feedback
Healthy
Comparison
Group
Negative feedback
B.
0.2
b
% BOLD Signal Change
b
0.1
0
–0.1
–0.2
–0.3
Severe Mood
Dysregulation
Group
Positive feedback
Healthy
Comparison
Group
Negative feedback
a
Panel A shows activation in the left posterior cingulate and precuneus (Talairach coordinates, x=219, y=255, z=32). Panel B shows activation
in the left insula (Talairach coordinates, x=228, y=222, z=20). Images are displayed according to radiologic convention (left=right).
BOLD=blood-oxygen-level-dependent.
b
Significantly different (p,0.05).
more unexpected and aversive than did healthy children.
This response may contribute to their exaggerated and inappropriate responses to frustrating events.
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In contrast to two adult studies using similar frustration
tasks (25, 26), we did not observe group differences in
prefrontal regions. Null findings are difficult to interpret,
Am J Psychiatry 170:10, October 2013
DEVENEY, CONNOLLY, HARING, ET AL.
as they may reflect type II error. Indeed, children with
severe mood dysregulation have been found to exhibit
abnormal anterior cingulate activation (measured by magnetoencephalography) in response to frustrating feedback
(7) and inferior frontal gyrus activation deficits during an
fMRI reward study (16). Thus, deficits in prefrontal regions
supporting top-down processing in response to frustration
may exist in this population even though they were not
observed in this study.
In interpreting the deactivation that we observed,
frustration tasks probably induce longer-lasting emotional
responses than those elicited by the presentation of, for
example, emotional faces or pictures. Thus, it is possible
that feelings of frustration remained “on” throughout all of
game 3, in which case fixation trials may not have been
cognitively or affectively neutral. This may complicate the
interpretation of neural responses to task-related activity,
since these are calculated relative to fixation trials. However, neural response to both positive and negative feedback trials were calculated with respect to fixation trials,
and deactivation occurred only during negative trials. We
are currently comparing neural responses to feedback under nonfrustration and frustration conditions to examine
whether participants’ “baseline” activation changes during frustration.
Our findings in children with severe mood dysregulation
are likely to be informative about neural dysfunction in
children with disruptive mood dysregulation disorder
during frustration. Like those with severe mood dysregulation, children meeting criteria for disruptive mood
dysregulation disorder experience recurrent, excessive,
and developmentally inappropriate temper outbursts, as
well as chronic negative affect between outbursts. Unlike
in severe mood dysregulation, the diagnostic criteria for
disruptive mood dysregulation disorder do not include
hyperarousal symptoms. Therefore, severe mood dysregulation can be viewed as a subset of disruptive mood
dysregulation disorder. Since we do not know the degree
to which irritability, rather than hyperarousal, is responsible for the abnormalities observed in children with
severe mood dysregulation, it is unclear whether our
findings would generalize to those with disruptive mood
dysregulation disorder who do not have hyperarousal or
ADHD symptoms.
Indeed, given high rates of co-occurring ADHD in
children with severe mood dysregulation, behavioral and
neural deficits related to attention are not surprising and
may be related to ADHD symptoms rather than irritability.
Post hoc analyses of the deactivation patterns observed in
the irritable children in this study suggest that this is not
the case. However, a stricter test would involve comparing
children with severe mood dysregulation to nonirritable
children with ADHD. We are currently conducting such
a study. Similar research is necessary to evaluate the
contribution of other clinical factors related to severe
mood dysregulation (e.g., other co-occurring disorders,
Am J Psychiatry 170:10, October 2013
psychotropic medications) to confirm the specific effects
of irritability. In addition, whether the chronic irritability
of children with severe mood dysregulation affects neural
and behavioral responses to frustration differently than
the episodic irritability characteristic of children with
bipolar disorder is unknown and deserves further study.
Our study has some limitation. First, previous studies
using the affective Posner paradigm employed methods
that isolated neural responses to feedback. In this study,
the paradigm modeled the entire trial and thus limited our
ability to detect neural activation specific to feedback.
Second, behavioral findings, collected across all three
games, suggest that attention flexibility differed between
nonfrustration and frustration conditions. However, because of time constraints, fMRI data were collected only
during the frustration condition (i.e., game 3). An ongoing
study includes scanning during frustration and nonfrustration conditions. Third, high rates of psychotropic medication use and of comorbid diagnoses in children with
severe mood dysregulation complicate attributions of
study findings to irritability specifically. Exploratory post
hoc analyses suggest that deficits in irritable children were
not attributable to co-occurring ADHD or to psychotropic
medications, but additional research is needed to identify
the role of irritability independent of other clinical factors.
Similarly, an important question for further research is
the degree to which state frustration and trait irritability
influence behavioral and neural responses to frustration.
Finally, the task we used assessed only participants’ ability
to shift spatial attention. Frustration likely influences other
types of attention and perhaps cognitive control more
broadly, and these are important issues to pursue in future
research.
Conclusions
Given that irritability is both common and impairing in
psychiatric patients, a better understanding of its pathophysiology could inform the broad psychiatric literature.
Our findings suggest that frustration impairs attention
flexibility and reduces activation in neural regions supporting spatial attention, emotion salience, and reward
processing in response to negative feedback in severely
irritable children. Research utilizing such paradigms and
populations may facilitate the development of novel
interventions.
Received July 14, 2012; revision received Jan. 11, 2013; accepted
Feb. 14, 2013 (doi: 10.1176/appi.ajp.2013.12070917). From the
Emotion and Development Branch and the Scientific and Statistical
Computing Core, NIMH, Bethesda, Md. Address correspondence to
Dr. Deveney ([email protected]).
The authors report no financial relationships with commercial
interests.
Supported by the NIMH Intramural Research Program.
The authors gratefully acknowledge the efforts of members of the
Emotion and Development Branch and suggestions by R.J.R. Blair.
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Clinical Guidance: Severe Irritability in Children
The behavioral responses to frustration in children with severe, chronic irritability
are mirrored by abnormal neural responses. Deveney et al. report that brain regions
implicated in emotion, spatial attention, and reward processing show less activation
after negative feedback in frustrating situations among children with severe mood
dysregulation than among healthy children. Children with severe mood dysregulation
also exhibit difficulty in shifting attention. Ryan points out in an editorial (p. 1093) that
the findings may apply to other disorders, since irritability spans multiple diagnoses.
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