Jurnal Psikiatri Anak

N EW R E S E A R C H
Face Emotion Processing in Pediatric Irritability: Neural

Mechanisms in a Sample Enriched for Irritability With
Autism Spectrum Disorder
Maria Kryza-Lacombe, MS, Natalia Iturri, BS, Christopher S. Monk, PhD, Jillian Lee Wiggins, PhD
Objective: Characterizing the pathophysiology of irritability symptoms from a dimensional perspective above and beyond diagnostic boundaries is
key to developing mechanism-based interventions that can be applied broadly. Face emotion processing deficits are present in youths with elevated levels
of irritability. The present study aimed to identify the neural mechanisms of face emotion processing in a sample enriched for irritability by including
youths with high-functioning autism spectrum disorder (HF-ASD).
Method: Youths (N ¼ 120, age ¼ 8.319.2 years) completed an implicit face emotion task during functional magnetic resonance imaging. We
evaluated how irritability, measured dimensionally, above and beyond diagnostic group, relates to whole-brain neural activation and amygdala con-
nectivity in response to face emotions.
Results: Both neural activation and amygdala connectivity differed as a function of irritability level and face emotion in the prefrontal cortex. Youths
with higher irritability levels had decreased activation in response to both fearful and happy faces in the left middle frontal gyrus and to happy faces in
the left inferior frontal gyrus. Furthermore, increased irritability levels were associated with altered right amygdala connectivity to the left superior frontal
gyrus when viewing fearful and sad faces.
Conclusion: The neural mechanisms of face emotion processing differ in youths with higher irritability compared to their less irritable peers. The
findings suggest that these irritability mechanisms may be common to both typically developing and HF-ASD youths. Understanding the neural
mechanisms of pediatric irritability symptoms that cut across diagnostic boundaries may be leveraged for future intervention development.
Key words: irritability, face emotion, fMRI, children, autism spectrum disorder
J Am Acad Child Adolesc Psychiatry 2020;59(12):1380–1391.
rritability symptoms, conceptualized as a rela- irritability dimension’s neural basis may point to common
I tively lower threshold for anger,1 are among the
most common self- and parent-reported mood
symptoms in youth,2 and are prevalent across multiple
pathophysiology and potential treatment targets that could
be applied across diagnostic boundaries.
In line with this, Research Domain Criteria (RDoC)
diagnostic categories, including depressive, anxiety, and efforts have promoted a dimensional perspective to evaluate
disruptive behavior disorders,3 as well as autism spectrum the neural underpinnings of symptom dimensions, such as
disorder (ASD)4 and typical development.5 Elevated irrita- irritability, across diagnostic boundaries.13 The present
bility levels are associated with severe, pervasive impairment work aims to answer RDoC-based calls for research14 to
in childhood6 and moreover predict poorer mental health7-9 investigate the neural correlates of irritability symptoms
and socioeconomic10 outcomes in adulthood. Thus, from a dimensional perspective in a sample enriched for
addressing pediatric irritability is crucial,1 not only to irritability by including youth with high-functioning ASD
improve the child’s well-being, but also to prevent poor (HF-ASD), a diagnostic category with high prevalence of
outcomes in adulthood. However, treatment options, both irritability.4 Irritability symptoms are common among
pharmacological and non-pharmacological, are lacking for youths without a psychiatric diagnosis15 as well as youths
irritability symptoms. Indeed, the only Food and Drug with HF-ASD,4 yet potential shared pathophysiology of the
Administration (FDA)approved medication for irritability irritability dimension is largely unexplored.
is in the context of ASD.11 Because irritability symptoms Face emotion processing deficits have been suggested as
occur across multiple diagnostic contexts,12 studying the one of the mechanisms underlying irritability symptoms1,16
1380 www.jaacap.org Journal of the American Academy of Child & Adolescent Psychiatry
Volume 59 / Number 12 / December 2020
Downloaded for Fakultas Kedokteran Universitas Hasanuddin (meetingresidenpsikiatriunhas@gmail.com) at Hasanuddin University from ClinicalKey.com
by Elsevier on February 09, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
FACE EMOTION PROCESSING IN PEDIATRIC IRRITABILITY
and have been documented in irritable youths,17-22 as well sample increases the variance of irritability in the sample,
as in HF-ASD.16,21,22 Irritability-related face emotion pro- leading to more robust statistical analyses.17,24
cessing deficits manifest in difficulties accurately labeling The current study examines the neural mechanisms of
emotions16,20 and in neural differences, both when explic- face emotion processing in a sample enriched for irritability
itly labeling face emotions18,19 and during implicit pro- by including youth with HF-ASD, addressing the afore-
cessing (eg, gender identification of emotional faces).17,21,22 mentioned gaps in the literature. Youths completed an
For example, irritable youths may interpret ambiguous faces implicit face emotion task during fMRI acquisition, probing
as more hostile23 or may need more intense emotional in- bottom-up processing of face emotions, which has been
formation to accurately label an emotion.16 Difficulties suggested to contribute to irritability.17,25 During the task,
understanding the facial expressions of others can have a participants labeled the gender of actors displaying fearful,
negative impact on social interactions, leading to confusion, sad, happy, or neutral facial expressions. We evaluated how
frustration, and ultimately to irritability symptoms. The irritability, measured dimensionally, above and beyond
extant irritability literature has focused on threatening, diagnostic group and core autism symptoms, relates to
happy, and neutral faces19,24,25; yet, other emotional ex- whole-brain neural activation and amygdala connectivity
pressions, such as sadness and fear, may also be perceived as and interacts with differing face emotions. Based on previ-
ambiguous in youth with emotion processing diffi- ous research of the neural mechanisms of implicit emotion
culties.18,21,26 The associated neural mechanisms may be processing in irritable youths,17,19,24,25 we hypothesized
informative for capturing the pathophysiology of irritability. that irritability would be associated with aberrant activation
Few studies have examined the neural mechanisms of in the amygdala and PFC as well as amygdalaprefrontal
face processing across the irritability dimension in youths, connectivity in response to viewing differing face emotions.
but findings primarily examining highly irritable diagnostic
groups point to aberrant neural patterns in the amyg- METHOD
dala18,19,25 and prefrontal cortex (PFC),24 as well as Participants
amygdala connectivity with the PFC17 during both explicit Data from 120 youths, aged 8.3 to 19.2 years (mean age
(ie, labeling face emotions)18,19 and implicit17,24,25 face [SD] ¼ 14.22[2.7]), were included. Additional participants
emotion functional magnetic resonance imaging (fMRI) were excluded due to missing key measures (n ¼ 11),
paradigms. Therefore, aberrant amygdala and prefrontal movement-related fMRI data quality (n ¼ 7), or poor ac-
engagement may be related to aberrant face emotion pro- curacy (<80%) on the gender identification task (n ¼ 6).
cessing among irritable youth. Neural activation has thus far The age range in the present sample (ie, late childhood
been the predominant means of identifying the neural through adolescence) encompasses important develop-
mechanisms of emotion processing in irritability,19,25 but mental periods during which irritability is a primary
identifying how brain areas interact (ie, functional connec- concern for parents seeking psychiatric care for their chil-
tivity), may provide a more comprehensive picture of dren.8,28 Irritability during this age range is predictive of
aberrant brain function in irritability. serious mental health, academic, social, and financial
Despite the recent focus on the importance of identi- problems across the lifespan.5,8 Therefore, understanding
fying transdiagnostic neural mechanisms of symptom di- the mechanisms of irritability across this developmental
mensions,27 few studies have included multiple diagnostic range is important groundwork for preventing short- and
groups to examine neural mechanisms of irritability levels. long-term effects of irritability.
To our knowledge, there are only three such studies17,18,24 ; Irritability is common among typically developing
however, those studies were not focused on the irritability youths,2 but variability in the higher ranges is sparse. To
dimension itself but rather on disentangling irritability from examine irritability dimensionally, beyond diagnostic
anxiety17,24 or bipolar disorder from disruptive mood dys- boundaries, youths with HF-ASD were included because
regulation disorder.18 Furthermore, pediatric irritability has irritability is prevalent in this population.4 Mean between-
not yet been evaluated in a sample that includes youths with group irritability levels differed, as expected, but covered
ASD, despite the high prevalence of irritability in this an overlapping range (Table 1). The final sample included
population.4 Examining irritability beyond diagnostic 73 youths recruited from the community and 47 youths
boundaries using a dimensional approach is important with ASD recruited through the University of Michigan
because it is more likely to identify underlying mechanisms Autism and Communication Disorders Center (UMACC),
that are common across diagnoses.14 Moreover, an enriched who had been diagnosed based on the Autism Diagnostic
Journal of the American Academy of Child & Adolescent Psychiatry www.jaacap.org 1381
KRYZA-LACOMBE et al.
TABLE 1 Demographic and Clinical Characteristics of Study Participants
Full sample HF-ASD Non-ASD Independent-samples

Characteristic (N ¼ 120) (n ¼ 47) (n ¼ 73) t test
Sex, % female 23.30% 17.00% 27.40% c2(1) [ 1.72, p > .05
Age, years 14.22 (2.70) 13.94 (2.35) 14.40 (2.90) t(111.88) [ 0.96, p > .05
Verbal cognitive functioning 114.17 (15.94) 112.83 (19.23) 115.03 (13.49) t(74.94) [ 68, p > .05
Nonverbal cognitive 103.22 (16.26) 106 (20.36) 101.39 (12.69) t(67.96) [ L1.37, p > .05
functioning
Gender ID accuracy, % 95.70% (3.94) 94.56% (3.81) 96.44% (3.89) t(118) [ 2.6, p ¼ .01
Irritabilitya 1.17 (1.49) 2.02 (1.73) 0.62 (0.98) t(65.32) [ L5.08, p < .001
Range 0L6 0L6 0L5
Social communication 47.78 (40.92) 90.53 (28.57) 19.88 (15.95) t(64.89) [ L15.46, p < .001
impairmentb
Range 0L163 21L163 0L82
Anxietyc 18.91 (11.78) 24.89 (14.02) 15 (8.00) t(65.71) [ L4.39, p < .001
Range 1L61 3L61 1L41
Depressiond 6.28 (5.54) 8.36 (6.08) 4.93 (4.74) t(81.20) [ L3.28, p < .01
Range 0L28 0L24 0L28
Note: Values indicate mean (SD) unless otherwise noted. Boldface type indicates statistically significant group differences based on independent-
samples t test. ASD ¼ autism spectrum disorder; HF ¼ high functioning; ID ¼ identification.
a
Irritability: sum of Child Behavior Checklist Items 86, 87, and 95.
b
Social communication impairment: score on Social Responsiveness Scale.
c
Anxiety: score on Spence Children’s Anxiety Scale.
d
Depression: score on Children’s Depression Inventory.
Observation Schedule (ADOS)29 and the Autism Diag- the Aberrant Behavior Checklist (ABC), which is specifically
nostic InterviewRevised (ADI-R).30 Exclusion criteria geared toward ASD. Second, the CBCL irritability scale is
included cognitive functioning scores <85, co-occurring particularly useful in the dimensional measurement of irri-
neurological disorders, or MRI contraindications. The tability in typical youths because it provides more variability
Institutional Review Board of the University of Michigan in the lower ranges compared to other irritability mea-
approved all procedures, and all participants provided con- sures.18,33 This is an important consideration, given that the
sent/assent. Parental permission was obtained for majority of youths included in the present study were
participants <18 years of age. Data from a subset of par- recruited from the community.
ticipants were included in previous studies,21,22,26,31 Supplement 1 and Table S1, available online, provide
including three on diagnostic group differences of neural details on participant screening, additional symptom mea-
face emotion processing.21,22,26 sures, psychotropic medication use, and fMRI acquisition.
Irritability Gender Identification Task

Three items previously identified and validated as During fMRI, participants completed an event-related
comprising an irritability factor32,33 from the Child gender identification task with emotional (happy, sad,
Behavior Checklist (CBCL; version for 6- to 18-year-olds)34 fearful, or neutral) faces.21,22 Threatening faces were
were used to assess level of irritability symptoms (“temper excluded from the paradigm to limit the number of con-
tantrums or hot temper,” “stubborn, sullen, or irritable,” trasts. Faces came from the NimStim set35 and included an
and “sudden changes in mood or feelings”), rated on a scale equal number of male and female faces. One trial consisted
of 0 to 2. Items were summed and then used as a contin- of a fixation cross (500 milliseconds), a face (250 millisec-
uous variable as in prior studies.32,33 This subscale has onds), and a black screen (1,500 milliseconds), during
acceptable psychometric properties (a ¼ 0.73),32,33 and is which participants indicated the gender of the face by
sensitive to variation along the irritability spectrum.18,33 pressing the thumb button of a button box for male gender,
This subscale was selected for two reasons. First, and the index finger button for female gender. Participants
because it can be used across diagnostic categories, unlike thus viewed the faces without making explicit judgments on
the face emotion (and thus either “tamping down” on the Neural Activation. In this analysis, the 4 emotion condi-
emotion and/or probing a particular labeling process related tions were modeled as regressors convolved with AFNI’s
to language). All participants used the right hand to GAM basis function over 250 milliseconds of face presen-
respond. Unlike emotional face task paradigms in other tation for each trial. The resulting b-coefficient maps
studies17 that present faces for multiple seconds and cannot represent the magnitude of average neural activation for
control for attention, our implicit face processing task each emotion compared to implicit baseline.
minimized cross-subject differences in attention by having a
Amygdala Functional Connectivity. Given the extensive
very quick (250-millisecond) presentation of the face (ie,
literature on the role of the amygdala in emotion pro-
enough for one saccade but not enough for multiple sac-
cessing (eg, see Dannlowski et al.36), we completed
cades around the screen) and a task (identifying gender) that
generalized psychophysiological interaction (gPPI) analyses
required attention. Only trials in which gender was correctly
using right and left amygdala seeds. The amygdala masks
identified were included in the analyses. Intertrial intervals
(right amygdala ¼ 972 mm3; left amygdala ¼ 756 mm3)
were jittered, ranging from 0 to 6,000 milliseconds at in-
were created using the Talairach atlas in AFNI. gPPI an-
tervals of 2,000 milliseconds. Each of the two runs consisted
alyses calculated the change in correlations between the
of 60 trials, 15 of each emotion, randomized for each
amygdala seeds and each voxel in the brain, for each
participant.
condition compared to implicit baseline. The analyses
result in a set of voxelwise images that represent connec-
Participant Characteristics
tivity between the seed region and the rest of the brain for
Because our sample consisted of individuals with and
each face condition.
without the HF-ASD diagnosis, we conducted
independent-samples t tests and c2 tests to assess whether Addressing Head Motion. Excessive head motion was
the diagnostic groups differed on variables that could be addressed with multiple methods: realigning functional
relevant to irritability and potentially confound our results, images, scrubbing TR pairs with framewise displacement
namely, gender, age, verbal and nonverbal cognitive func- >1 mm, and including nuisance covariates for motion pa-
tioning, core ASD symptoms (social communication rameters in the individual level models.
impairment), anxiety, and depression. In the absence of
statistical significance, potentially clinically meaningful dif-
fMRI Data Analysis: Second-Level Models
ferences were also considered.
Addressing the Potential Confound of Diagnostic
Group. The aim of the present study was to evaluate the
Behavioral Data Analysis neural mechanisms of irritability from an RDoC-based
To examine potential differences in accuracy of labeling dimensional perspective, and the present sample of youths
gender in relation to irritability, we conducted a univariate was enriched for irritability by including youths with HF-
analysis of variance with percent accuracy as the dependent ASD, a diagnostic category with characteristic social
variable and irritability level as the independent variable. communication impairment.37 We controlled for potential
We also examined potential group (HF-ASD versus non- effects of autism as follows. Across all second-level models,
ASD) differences in task accuracy. diagnostic group (HF-ASD versus non-ASD) was included
as a binary covariate. In addition, we examined the impact
fMRI Preprocessing
of social communication impairment (Social Responsiveness
Preprocessing of fMRI data was done in AFNI. Supplement
Scale scores; see Supplement 1, available online) on our
1, available online, provides additional details.
results in post hoc analyses. Between-group effects of irri-
tability are also of interest but are outside the scope of the
fMRI Data Analysis: First-Level Models
present study. Nevertheless, for the interested reader, we
Three models were used for individual level analyses: one
completed these additional analyses (ie, Irritability
for neural activation, and one each for right and left
Diagnosis Face Emotion). Results are listed in
amygdala functional connectivity. Face emotion regressors
Supplement 1 and Table S2, available online. However, the
(ie, happy, fearful, sad, and neutral) were included as
results should be interpreted with caution, as the variability
described below. All models also included incorrect trials as
of irritability is limited among the non-ASD sample.
a nuisance regressor, as well as motion parameters (esti-
mated in the x, y, z, roll, pitch, and yaw directions), and Whole-Brain Analyses. AFNI’s 3dMVM was used to
fourth-degree polynomials modeling low-frequency drift in conduct second-level, repeated- measures ANOVAs with
the baseline model. the individual-level b coefficients as the dependent variable,
face emotion (neutral, happy, sad, and fearful) as a as an additional covariate (see Supplement S1, available
within-subject factor, and irritability as the between-subject online).
quantitative variable. Diagnosis (HF-ASD versus non-ASD)
was included as a covariate to examine neural mechanisms RESULTS
of irritability above and beyond potential diagnosis effects. Participant characteristics for the overall sample as well as
Three whole-brain analysis of variance models were con- each participant pool separately are listed in Table 1. There
ducted, one each for activation, and right and left amygdala were no significant diagnostic group differences in gender,
to whole-brain functional connectivity. These models age, or verbal and nonverbal cognitive functioning
generated the contrast of primary interest, Irritability (Table 1). Overall accuracy to label gender (mean ¼
Emotion, which examines neural correlates of face emotion 95.70%, SD ¼ 3.9%) was well above chance (50%). Irri-
processing depending on irritability level, in addition to tability was not significantly associated with task accuracy
lower-order terms (eg, Emotion, Irritability, Diagnosis main (r ¼ 0.10, p ¼ .26), and did not significantly predict overall
effects). task accuracy controlling for diagnostic group (F1,117 ¼
A whole-brain cluster corrected threshold of a ¼ 0.003, p ¼ .95). There was a significant between-group
0.05 was used, calculated via AFNI’s 3dClustsim program difference in gender identification accuracy (t118 ¼ 2.6,
using a mixed-model spatial autocorrelation function p ¼ .01); thus, we subsequently evaluated whether our re-
(-acf) and the NN1 2-sided option, per recent recom- sults would remain after controlling for accuracy (see
mendations.38 The cluster extent threshold resulting from Additional Analyses).
the 3dClustsim analysis was k 28 voxels for all second-
level analyses. In addition, a height threshold of p < .005
Associations of Irritability With Neural Activation
was used.
We found that the Irritability Emotion interaction was
Amygdala Region-of-Interest Analyses. Given the previ- associated with activation in the left middle frontal gyrus
ously documented role that the amygdala may play in irri- (MFG; F3,351 ¼ 10.23, xyz ¼ 35, 32, 33, k ¼ 98, p <
tability (eg, see Dannlowski et al.36), we additionally used .05 corrected) (Figure 1A), and left inferior frontal gyrus
region-of-interest (ROI) analyses to specifically probe po- (IFG; F3,351 ¼ 8.26, xyz ¼ 44, 8, 9, k ¼ 38, p < .05
tential neural mechanisms of irritability related to amygdala corrected) (Figure 1B). Post hoc analyses indicated that in
activation. We extracted average activation for each condi- the left MFG, there was a significant negative association
tion in each individual based on the right and left amygdala between irritability and activation in response to fearful
masks from the Talairach Daemon atlas in AFNI. Analysis (r ¼ 0.26, p < .05, corrected) and happy (r ¼ 0.25, p <
of covariance in SPSS v. 24 (IBM Corp., Armonk, NY) was .05, corrected) faces, and in the left IFG there was a sig-
used to assess the Irritability Emotion interaction co- nificant negative association between irritability and acti-
varying for Diagnostic Group. vation to happy faces (r ¼ 0.39, p < .001, corrected). In
other words, greater levels of irritability are associated with
Post Hoc Analyses less activation to fearful and happy faces in the left MFG,
To evaluate significant omnibus findings for the and to happy faces in the left IFG. Post hoc partial corre-
Irritability Emotion interaction, values from resulting lations were not significant for any other face emotion
clusters in each analysis were extracted and partial correla- conditions. Clusters that emerged for other contrasts are
tions conducted in SPSS: irritability was correlated with listed in Table 2.
activation (or connectivity) for each face emotion condition
separately, controlling for diagnosis. False discovery rate Amygdala ROI Analysis
(FDR) was used to correct for multiple comparisons. Irritability Emotion was not significantly associated with
right or left amygdala activation.
Additional Analyses Evaluating Potential Confounds
Extracted values were also used to conduct post hoc Associations of Irritability With Right Amygdala
analyses of covariance using SPSS to assess the potential Functional Connectivity
influence of confounding variables, including age, We detected that the Irritability Emotion interaction was
gender, anxiety and depression symptoms, core ASD associated with right amygdala connectivity with the left
symptoms (social communication impairment), task superior frontal gyrus (SFG; F3,351 ¼ 8.27,
accuracy, and use of psychotropic medications. In xyz ¼ 20,14,48, k ¼ 56) (Figure 2). Post hoc analyses
addition, whole-brain models were repeated with gender indicated a significant negative association between
FIGURE 1 Irritability Emotion Interaction Is Associated With Prefrontal Cortex Activation
A
Mean Acvaon Fearful Sad Le Middle Frontal Gyrus
r = -.26* r = .12
Happy Neutral
Peak xyz = -35 32 33
k = 98
Mean Acvaon
F3,351 = 10.25
HF-ASD
r = -.25* r = .19 Non-ASD
B Fearful Sad
Le Inferior Frontal Gyrus
Mean Acvaon
r = -.04 r = .05
Happy Neutral
Peak xyz = -44 8 9

Mean Acvaon
k = 38
F3,351 = 8.26
HF-ASD
r = -.39*** r = .06 Non-ASD
Note: (A) Left middle frontal gyrus. (B) Left inferior frontal gyrus. Partial correlation coefficients are shown. For this and all figures, brain images represent axial sections
(left ¼ left) with threshold set at whole-braincorrected p < .05. ASD ¼ autism spectrum disorder; HF ¼ high functioning.
*p < .05, corrected; ***p < .001, corrected.
TABLE 2 Significant Clusters Resulting From Whole-Brain Analyses
Activation
Irritability 3 emotiona
k F3,351 x y z BA Region
98 10.25 e35 32 33 9,32 Left middle frontal gyrus
38 8.26 e44 8 9 44,45 Left inferior frontal gyrus
Irritability
36 17.61 e8 e62 39 7 Left precuneus
Diagnostic group
46 18.91 e41 e80 9 19 Left middle occipital gyrus
28 19.04 38 e80 6 19 Right middle occipital gyrus
Emotion
35 7.56 e44 e56 9 39,22 Left middle temporal gyrus, left superior temporal
gyrus
31 9.60 60 e47 9 22,21 Right superior temporal gyrus, right middle
temporal gyrus
Right amygdala connectivity
127b 11.60 20 e23 33 31 Bilateral cingulate gyrus
56 8.27 e20 14 48 8 Left superior frontal gyrus
Diagnostic group 3 emotion
37 7.90 8 59 18 10 Right medial frontal gyrus, left medial frontal gyrus
Left amygdala connectivity
1294 11.30 e5 38 24 32 Bilateral anterior cingulate cortex and medial frontal
gyrus
30 9.15 62 14 21 44 Right inferior frontal gyrus
29 8.41 50 e2 40 6 Right precentral gyrus
Diagnostic group 3 emotion
k F3,351 X y z BA Region
37 7.46 38 14 42 6,9 Right middle frontal gyrus, right precentral gyrus
Emotion
49 10.71 e11 e68 12 30,18,31 Left cuneus, left posterior cingulate, left lingual
gyrus
36 9.25 e5 e53 e23 e Bilateral nodule
33 9.50 29 e83 21 19 Right middle occipital gyrus
29 6.85 e8 e8 60 6 Bilateral medial frontal gyrus, left middle frontal
gyrus
Note: BA ¼ Brodmann area.

a
Contrast of interest in this study: extracted values for boldface type clusters are presented in Figures 1 and 2; for any contrasts not listed, no significant
clusters emerged in the analyses.
b
Of this cluster’s voxels, 85% were situated in the hemispheric white matter and most likely represent noise. We therefore focused our post hoc
analyses on the left superior frontal gyrus cluster for the contrast of interest among right amygdala functional connectivity results.
FIGURE 2 Irritability Emotion Interaction Is Associated With Right Amygdala Connectivity With Left Superior Frontal Gyrus
Fearful Sad
Mean Right Amygdala Connecvity
Le Superior Frontal Gyrus
r = -.33*** r = .25*
Happy Neutral
Mean Right Amygdala Connecvity
Peak xyz = -20 14 48

k = 56
F3,351 = 8.27
HF-ASD
r < -.01 r = .05 Non-ASD
Note: Partial correlation coefficients are shown. ASD ¼ autism spectrum disorder; HF ¼ high functioning.
*p < .01, corrected; ***p < .001, corrected.
irritability and right amygdala connectivity in response to Supplement 1, available online, for details). Overall, left
fearful faces (r ¼ 0.33, p < .001, corrected) and a sig- amygdala connectivity results are therefore less robust and
nificant positive association between irritability and right are not further discussed in the main article. Clusters that
amygdala connectivity with sad faces (r ¼ 0.25, p < .05, emerged for other contrasts are listed in Table 2.
corrected). Post hoc partial correlations were not significant
for other face emotion conditions. Clusters that emerged for Additional Analyses
other contrasts are listed in Table 2. After taking the potential impact of age, gender, anxiety,
depression, core ASD symptoms (social communication
Associations of Irritability With Left Amygdala impairment), task accuracy, and psychotropic medication
Functional Connectivity use into account, main results for neural activation and right
The Irritability Emotion interaction was associated with amygdala connectivity remain significant (see Supplement 1
left amygdala connectivity with the bilateral anterior and Table S3, available online, for additional details).
cingulate cortex (ACC)/MFG (F3,351 ¼ 11.30,
xyz ¼ 5,38,24, k ¼ 1,294), the right IFG (F3,351 ¼ 9.15, DISCUSSION
xyz ¼ 62,14,21, k ¼ 30; Figure S1, available online), and The present study focused on examining the neural mech-
the right precentral gyrus (F3,351 ¼ 8.14, xyz ¼ 50, 2,40, anisms of implicit emotion processing in youth across the
k ¼ 29; Table 2). Inspection of the extracted mean con- irritability spectrum by adopting an RDoC-based dimen-
nectivity values for these clusters revealed that the results sional perspective on irritability in a sample of youths
were outlier driven (ie, driven by connectivity values >3 enriched for irritability by including youths with HF-ASD.
SDs from the mean; see Supplement 1, available online, for As hypothesized, we found that both neural activation and
outlier analyses). In addition, follow-up analyses (see section amygdala connectivity differed as a function of irritability
below) revealed that the bilateral ACC/MFG and right level and face emotion in the prefrontal areas, suggesting
precentral gyrus clusters are no longer significant when that the underlying neural mechanisms of face emotion
controlling for potential confounding variables (see processing vary with level of irritability. These findings are
largely consistent with the literature,24,25 as outlined below, environment40 and may thus elicit high-arousal, hostile
and are significant above and beyond diagnostic category as responses in those prone to irritability.
well as core ASD symptoms (ie, social communication Overall, the regions that emerged as significant in the
impairment), indicating that these irritability mechanisms present study have been linked to brain circuits associated
may be common to both typically developing and HF-ASD with executive functions41 and emotion regulation, such as
youths. reappraisal of negative emotions.42 Irritability symptoms
Our whole-brain activation analyses revealed that have likewise been linked to deficits in executive functioning
youths with higher irritability levels have decreased activa- in childhood.43 In the present study, youths with higher
tion in response to both fearful and happy faces in the left irritability levels demonstrated decreased recruitment of
middle frontal gyrus and to happy faces in the left inferior these regions when viewing happy and fearful faces, which
frontal gyrus. These findings are consistent with previous could be a marker for weaker engagement of the self-
studies investigating the neural mechanisms of face emotion regulation circuit in response to the faces.
processing in irritable youths. For example, deactivation of Amygdalaprefrontal connectivity has been shown to be
prefrontal areas in response to implicit processing of fearful related to successful emotion regulation, with increased
faces was demonstrated in youths with severe mood dysre- connectivity between the amygdala and the inferior frontal
gulation compared to nonirritable youths.25 Another study gyrus related to down-regulation of emotions.44 The dys-
evaluating how neural mechanisms of threat bias differ regulation of amygdala connectivity with the inferior frontal
based on severity of irritability symptoms found that higher gyrus among youths with higher irritability symptoms may
irritability was associated with aberrant activation in the represent deficits in emotion regulation in response to fearful
prefrontal cortex when youths were to attend away from a and sad faces. Recent evidence that mindful attention to
threatening face.24 Aberrant activation in frontal areas in breath regulates emotions via increased amygdalaprefrontal
response to emotional faces may therefore represent deficits cortex connectivity45 suggests that this may not only be a
in face emotion interpretation, which may underlie mechanism of irritability, but also a potential intervention
irritability. route for irritable youths. In addition, our findings that
Our amygdala connectivity findings implicated amygdala prefrontal recruitment relates to irritability symptoms sug-
prefrontal cortex connectivity, not amygdalaventral visual gests that youths with increased irritability may have diffi-
area connectivity as in a prior study.17 Moreover, we did culty recruiting prefrontal areas to appropriately interpret
not find amygdala activation differences with varying levels social stimuli. Indeed, the inferior frontal gyrus and medial
of irritability, unlike other findings in irritable youths.19,25,39 prefrontal cortex have also been implicated in social
This may be due to differences in task stimuli/design. cognition46 and are likely related to interpretation of social
Unlike our gender identification face paradigm, tasks in information. As youths with irritability have difficulty la-
studies that found amygdala activation effects varied in- beling emotional faces,20 this may lead to difficulty and
tensity of emotional faces19,25 or had participants judge frustration in interpreting social cues, and thus lead to
nose width, which did not require attention to the entire irritability.47
face.39 In our study, the inclusion of a HF-ASD group not
Although more research is needed to consolidate dif- only enriched the sample for irritability, but also aligns with
ferential findings, the fact that similar brain regions (ie, Research Domain Criteria efforts to redefine categorical
prefrontal cortex, prefrontalamygdala connectivity) diagnostic categories based on dimensionally measured
emerged in our two orthogonal whole-brain analyses (acti- symptom manifestations by evaluating the neural un-
vation and amygdala connectivity) is corroborating evidence derpinnings of the irritability dimension across diagnostic
that these regions are involved in irritability. That is, altered categories.13 Of note, such dimensional conceptualizations
activation in the prefrontal cortex to fearful and happy faces may be more sensitive than traditional diagnostic group-
as well as altered amygdalaprefrontal connectivity to based comparisons. For example, other studies comparing
fearful and sad faces, all in relation to irritability, suggest highly irritable to nonirritable diagnostic groups generally
that the amygdala and the prefrontal cortex play an failed to detect neural alterations in response to happy faces
important role in face emotion mechanisms of irritability. during implicit face tasks25; by contrast, we found differ-
Moreover, it is interesting to note that across both ences in relation to happy faces when irritability is captured
orthogonal analyses, prefrontal circuitry was implicated in dimensionally in the model. This dimensional approach of
response to fearful faces (ie, decreased activation and conceptualizing psychopathology may be promising, as
amygdala connectivity with greater levels of irritability). characterization of mechanisms can reach beyond what are
Fearful faces, like angry faces, can signal a threat in the often arbitrary diagnostic boundaries and thus be more
accurate. Moreover, understanding the dimensional features studies have looked at responses to angry faces exclusively.
of irritability that expand across diagnostic boundaries may Finally, we did not use eye-tracking during fMRI acquisition
aid in intervention and prevention efforts that can be and cannot rule out that eye fixation patterns differed be-
applied across a wide range of diagnoses. tween samples and influenced our results.48 However, these
We note several limitations of this study. First, the non- differences were likely minimized due to the very brief
ASD participants in this study did not undergo full diagnostic stimulus presentation (250 milliseconds), which limited op-
screening, and it is therefore possible that some subjects met portunities for multiple saccades, and having participants
diagnostic criteria for psychopathology. However, the pri- identify the gender of the face, which required them to look at
mary focus of this study was to capture dimensionally the entire face.
measured irritability levels, rather than diagnostic categori- Our findings suggest that alterations in neural processing of
zation. In addition, to control for potential effects of affective face emotion may contribute to irritability symptoms. Under-
symptomatology, our results were adjusted for depression and standing the neural mechanisms of pediatric irritability may be
anxiety, also measured dimensionally, across all subjects. leveraged for future intervention development. Our findings
Second, a more rigorous approach to controlling for con- and the research program for which they pave the way are
founding variables would have been to add them to the important, because interventions targeting irritability during
second-level fMRI analyses; however, to retain power and to adolescence may not only help us to improve the well-being of
avoid collinearity, we chose a post hoc method to control for children and adolescents, but may also help us to prevent long-
confounding variables. Third, although our measure of irri- term sequelae in adulthood. Prevention-focused interventions
tability, like all Likert-style measures, is an ordinal scale, we for irritable adolescents that target implicit emotion processing
modeled it continuously to be consistent with prior studies. A may be effective. Computer-based behavioral interventions,23
true “continuous” measure (ie, in which each step increase mindfulness approaches,45 and emerging treatments such as
reflects exactly the same increase in irritability rather than neurofeedback49 may be promising approaches.
“0 ¼ Not True,” “1 ¼ Somewhat or Sometimes True,” “2 ¼ The present study is one of the first to evaluate the neural
Very True or Often True” for each item) would better capture mechanisms of irritability from an RDoC-based dimensional
the dimension, yet such a scale does not yet exist for irrita- perspective; nevertheless, to document the full dimension of
bility. Future psychometric work improving measures must irritability and to assess generalizability across other diagnoses
go hand in hand with neuroscientific advances to best move on the irritability spectrum, future work with other diagnoses
the field forward. Fourth, despite controlling for differences will be necessary. As youth with ASD are included in the future
between youths with and without ASD diagnoses and transdiagnostic studies of irritability symptoms, it will be
adjusting for social communication impairment symptom important to examine the overlap of symptoms such as rigidity
severity, residual confounding factors may have remained. with irritability. Furthermore, the present study explored
There may be pathophysiological mechanisms of irritability emotional face processing related to varying levels of irritabil-
that are unique to youths with ASD. The focus of the current ity; yet, because there are documented changes in irritability
study was to evaluate neural mechanisms of irritability above levels across development50 as well as maturation of the
and beyond ASD symptoms, and we did not additionally emotional networks of the brain,51 future longitudinal study
focus on comparing HF-ASD and non-ASD youths on neural investigators may wish to follow youths with varying levels of
mechanisms of the irritability dimension because of the irritability to assess for changes in neural patterns as the youths
inherent differences in variance of irritability in the two develop.
diagnostic groups. However, we included these analyses,
which have limited interpretability, in Supplement 1 and
Accepted September 5, 2019.
Table S2, available online. Furthermore, despite enriching
Ms. Kryza-Lacombe and Dr. Wiggins are with the Joint Doctoral Program in
our sample by including youth with HF-ASD to increase the Clinical Psychology, San Diego State University/University of California, San
variability in irritability, lower levels of irritability were still Diego. Ms. Iturri is with San Diego State University, California. Dr. Monk is with
the University of Michigan, Ann Arbor.
more prominently represented compared to higher levels,
This work was supported by an Autism Speaks Predoctoral Fellowship (4773 to
which may have introduced effects of heteroscedasticity in J.L.W.) and grant (2573 to C.S.M.).
our analyses. Fifth, because our paradigm did not include Dr. Wiggins served as the statistical expert for this research.
angry faces, our study is less directly comparable to the many The authors thank the families for participating. They also gratefully acknowl-
studies that investigated irritability in response to angry faces. edge Richard Reynolds, MS, of the Scientific and Statistical Computing Core,
National Institute of Mental Health, National Institutes of Health, and Jill
However, our inclusion of other emotional faces (ie, fearful, Weisberg, PhD, of San Diego State University, for their assistance in setting up
happy, and sad), which all showed involvement in irritability the data processing pipeline. They thank Catherine Lord, PhD, of the University
of California, Los Angeles, for her support in the recruitment of youths with HF-
symptom mechanisms, contributes to the literature, as many
ASD, and Nader Amir, PhD and Lisa Eyler, PhD, of the San Diego State Uni- biomedical stocks which are unrelated to her research or the research presented
versity/University of California, San Diego Joint Doctoral Program in Clinical in the present manuscript. Mss. Kryza-Lacombe and Iturri have reported no
Psychology, for helpful comments on an earlier version of this manuscript. They biomedical financial interests or potential conflicts of interest.
also thank Yonca Cam, BA, of San Diego State University, for her assistance
with preprocessing. Correspondence to Maria Kryza-Lacombe, MS, 6363 Alvarado Court, Suite 103,
San Diego, CA 92120; e-mail: mkryza-lacombe@sdsu.edu
Disclosure: Dr. Monk has reported mutual funds that include biomedical stocks
0890-8567/$36.00/ª2019 American Academy of Child and Adolescent
as well as stock ownership (Johnson and Johnson), both of which are unrelated
to his research or the research presented in the present manuscript. Dr. Wiggins Psychiatry
has received financial support by a Pilot Grant (NIH UL1TR001442) and a NAR- https://doi.org/10.1016/j.jaac.2019.09.002
SAD Young Investigator Grant (#26802) and reported mutual funds that include
REFERENCES
1. Brotman MA, Kircanski K, Stringaris A, Pine DS, Leibenluft E. Irritability in youths: a 23. Stoddard J, Sharif-Askary B, Harkins EA, et al. An open pilot study of training hostile
translational model. Am J Psychiatry. 2017;174:520-532. interpretation bias to treat disruptive mood dysregulation disorder. J Child Adolesc
2. Collishaw S, Maughan B, Natarajan L, Pickles A. Trends in adolescent emotional Psychopharmacol. 2016;26:49-57.
problems in England: a comparison of two national cohorts twenty years apart. J Child 24. Kircanski K, White LK, Tseng WL, et al. A latent variable approach to differentiating
Psychol Psychiatry. 2010;51:885-894. neural mechanisms of irritability and anxiety in youth. JAMA Psychiatry. 2018;75:
3. Stringaris A. Irritability in children and adolescents: a challenge for DSM-5. Eur Child 631-639.
Adolesc Psychiatry. 2011;20:61-66. 25. Thomas LA, Kim P, Bones BL, et al. Elevated amygdala responses to emotional faces
4. McGuire K, Fung LK, Hagopian L, et al. Irritability and problem behavior in autism in youths with chronic irritability or bipolar disorder. Neuroimage Clin. 2013;2:
spectrum disorder: a practice pathway for pediatric primary care. Pediatrics. 2016; 637-645.
137(Suppl 2):S136-S148. 26. Wiggins JL, Swartz JR, Martin DM, Lord C, Monk CS. Serotonin transporter genotype
5. Hameed U, Dellasega CA. Irritability in pediatric patients: normal or not? Prim Care impacts amygdala habituation in youth with autism spectrum disorders. Soc Cogn Affect
Companion CNS Disord. 2016;18. Neurosci. 2014;9:832-838.
6. Leibenluft E, Stoddard J. The developmental psychopathology of irritability. Dev Psy- 27. Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for
chopathol. 2013;25:1473-1487. psychiatry. Am J Psychiatry. 2014;171:395-397.
7. Fichter MM, Kohlboeck G, Quadflieg N, Wyschkon A, Esser G. From childhood 28. Peterson BS, Zhang H, Santa Lucia R, King RA, Lewis M. Risk factors for presenting
to adult age: 18-year longitudinal results and prediction of the course of mental problems in child psychiatric emergencies. J Am Acad Child Adolesc Psychiatry. 1996;35:
disorders in the community. Soc Psychiatry Psychiatr Epidemiol. 2009;44:792-803. 1162-1173.
8. Stringaris A, Cohen P, Pine DS, Leibenluft E. Adult outcomes of youth irritability: a 20- 29. Lord C, Risi S, Lambrecht L, et al. The Autism Diagnostic Observation Sched-
year prospective community-based study. Am J Psychiatry. 2009;166:1048-1054. uleGeneric: a standard measure of social and communication deficits associated with
9. Pickles A, Aglan A, Collishaw S, Messer J, Rutter M, Maughan B. Predictors of the spectrum of autism. J Autism Dev Disord. 2000;30:205-223.
suicidality across the life span: the Isle of Wight study. Psychol Med. 2010;40: 30. Lord C, Rutter M, Le Couteur A. Autism Diagnostic InterviewRevised: a
1453-1466. revised version of a diagnostic interview for caregivers of individuals with
10. Copeland WE, Shanahan L, Egger H, Angold A, Costello EJ. Adult diagnostic and possible pervasive developmental disorders. J Autism Dev Disord. 1994;24:
functional outcomes of DSM-5 disruptive mood dysregulation disorder. Am J Psychiatry. 659-685.
2014;171:668-674. 31. Wiggins JL, Bedoyan JK, Carrasco M, Swartz JR, Martin DM, Monk CS. Age-related
11. Leibenluft E. Irritability in children: what we know and what we need to learn. World effect of serotonin transporter genotype on amygdala and prefrontal cortex function in
Psychiatry. 2017;16:100-101. adolescence. Hum Brain Mapp. 2014;35:646-658.
12. Brotman MA, Kircanski K, Leibenluft E. Irritability in children and adolescents. Annu 32. Stringaris A, Zavos H, Leibenluft E, Maughan B, Eley TC. Adolescent irritability:
Rev Clin Psychol. 2017;13:317-341. phenotypic associations and genetic links with depressed mood. Am J Psychiatry. 2012;
13. Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural circuits, 169:47-54.
and dimensions of behavior. Dialogues Clin Neurosci. 2012;14:29-37. 33. Wiggins JL, Mitchell C, Stringaris A, Leibenluft E. Developmental trajectories of irri-
14. Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of tability and bidirectional associations with maternal depression. J Am Acad Child Adolesc
RDoC. BMC Med. 2013;11:126. Psychiatry. 2014;53:1191-1205.
15. Mayes SD, Calhoun SL, Murray MJ, Ahuja M, Smith LA. Anxiety, depression, and 34. Achenbach TM, Rescorla LA. Manual for the ASEBA Preschool Forms and Profiles, Vol 30.
irritability in children with autism relative to other neuropsychiatric disorders and typical Burlington, VT: University of Vermont, Research Center for Children, Youth, & Fam-
development. Res Autism Spect Dis. 2011;5:474-485. ilies; 2000.
16. Griffiths S, Jarrold C, Penton-Voak IS, Woods AT, Skinner AL, Munafo MR. Impaired 35. Tottenham N, Tanaka JW, Leon AC, et al. The NimStim set of facial expressions:
recognition of basic emotions from facial expressions in young people with autism judgments from untrained research participants. Psychiatry Res. 2009;168:
spectrum disorder: assessing the importance of expression intensity. J Autism Dev Dis- 242-249.
ord. 2019;49:2768-2778. 36. Dannlowski U, Ohrmann P, Bauer J, et al. Amygdala reactivity predicts automatic
17. Stoddard J, Tseng WL, Kim P, et al. Association of irritability and anxiety with the neural negative evaluations for facial emotions. Psychiatry Res. 2007;154:13-20.
mechanisms of implicit face emotion processing in youths with psychopathology. JAMA 37. American Psychological Association. Diagnostic and Statistical Manual of Mental Dis-
Psychiatry. 2017;74:95-103. orders. 5 ed. Washington, DC: American Psychiatric Publishing; 2013.
18. Wiggins JL, Brotman MA, Adleman NE, et al. Neural correlates of irritability in 38. Cox RW, Chen G, Glen DR, Reynolds RC, Taylor PA. FMRI clustering in AFNI: false-
disruptive mood dysregulation and bipolar disorders. Am J Psychiatry. 2016;173: positive rates redux. Brain Connect. 2017;7:152-171.
722-730. 39. Brotman MA, Rich BA, Guyer AE, et al. Amygdala activation during emotion processing
19. Thomas LA, Brotman MA, Muhrer EJ, et al. Parametric modulation of neural activity by of neutral faces in children with severe mood dysregulation versus ADHD or bipolar
emotion in youth with bipolar disorder, youth with severe mood dysregulation, and disorder. Am J Psychiatry. 2010;167:61-69.
healthy volunteers. Arch Gen Psychiatry. 2012;69:1257-1266. 40. Hu Z, Gendron M, Liu Q, Zhao G, Li H. Trait anxiety impacts the perceived gaze
20. Guyer AE, McClure EB, Adler AD, et al. Specificity of facial expression labeling deficits direction of fearful but not angry faces. Front Psychol. 2017;8:1186.
in childhood psychopathology. J Child Psychol Psychiatry. 2007;48:863-871. 41. Sylvester CY, Wager TD, Lacey SC, et al. Switching attention and resolving interference:
21. Swartz JR, Wiggins JL, Carrasco M, Lord C, Monk CS. Amygdala habituation and fMRI measures of executive functions. Neuropsychologia. 2003;41:357-370.
prefrontal functional connectivity in youth with autism spectrum disorders. J Am Acad 42. Vanderhasselt MA, Kuhn S, De Raedt R. ’Put on your poker face’: neural systems
Child Adolesc Psychiatry. 2013;52:84-93. supporting the anticipation for expressive suppression and cognitive reappraisal. Soc
22. Weng SJ, Carrasco M, Swartz JR, et al. Neural activation to emotional faces in Cogn Affect Neurosci. 2013;8:903-910.
adolescents with autism spectrum disorders. J Child Psychol Psychiatry. 2011;52: 43. Granvald V, Marciszko C. Relations between key executive functions and aggression in
296-305. childhood. Child Neuropsychol. 2016;22:537-555.
44. Morawetz C, Bode S, Baudewig J, Heekeren HR. Effective amygdala-prefrontal con- 48. Klin A. Three things to remember if you are a functional magnetic resonance
nectivity predicts individual differences in successful emotion regulation. Soc Cogn Affect imaging researcher of face processing in autism spectrum disorders. Biol Psychiatry. 2008;64:
Neurosci. 2017;12:569-585. 549-551.
45. Doll A, Holzel BK, Mulej Bratec S, et al. Mindful attention to breath regulates 49. Ramot M, Kimmich S, Gonzalez-Castillo J, et al. Direct modulation of aberrant brain
emotions via increased amygdala-prefrontal cortex connectivity. Neuroimage. 2016;134: network connectivity through real-time NeuroFeedback. Elife. 2017;6.
305-313. 50. Copeland WE, Brotman MA, Costello EJ. Normative irritability in youth: develop-
46. Adolfi F, Couto B, Richter F, et al. Convergence of interoception, emotion, and mental findings from the Great Smoky Mountains Study. J Am Acad Child Adolesc
social cognition: a twofold fMRI meta-analysis and lesion approach. Cortex. 2017;88:124-142. Psychiatry. 2015;54:635-642.
47. Deveney CM, Connolly ME, Haring CT, et al. Neural mechanisms of frustration in 51. Casey BJ, Heller AS, Gee DG, Cohen AO. Development of the emotional brain.
chronically irritable children. Am J Psychiatry. 2013;170:1186-1194. Neurosci Lett. 2019;693:29-34.

Jurnal Psikiatri Anak

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jurnal Psikiatri Anak

Uploaded by

Copyright:

Available Formats

N EW R E S E A R C H

Face Emotion Processing in Pediatric Irritability: Neural

TABLE 1 Demographic and Clinical Characteristics of Study Participants

Full sample HF-ASD Non-ASD Independent-samples

Irritability Gender Identiﬁcation Task

FIGURE 1 Irritability Emotion Interaction Is Associated With Prefrontal Cortex Activation

Peak xyz = -44 8 9

TABLE 2 Signiﬁcant Clusters Resulting From Whole-Brain Analyses

Note: BA ¼ Brodmann area.

Peak xyz = -20 14 48

You might also like