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Altered emotion perception linked to structural brain differences in youth with congenital adrenal hyperplasia

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Altered emotion perception linked to structural brain differences in youth with congenital adrenal hyperplasia

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ALTERED EMOTION PERCEPTION LINKED TO STRUCTURAL BRAIN DIFFERENCES
IN YOUTH WITH CONGENITAL ADRENAL HYPERPLASIA
by
Adam Omary

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)

May 2022

Copyright 2022 Adam Omary

ii

TABLE OF CONTENTS

List of Tables iii
List of Figures iv
Abstract v
Introduction 1
Cognitive & Behavioral Differences in CAH 1
Brain Differences in CAH 2
Emotion Perception in the Brain 3
Method 4
Study Participants 4
Structural MRI 4
Emotion Perception 6
Data Analysis 7
Results 9
Group Differences in Emotion Perception 9
Exploratory Brain Analyses 19
Discussion 28
Limitations 30
Conclusion & Future Directions 31
References 33

iii

LIST OF TABLES

Table 1: Participant Demographics, Stratified by Group 5
Table 2: Valence Ratings Mixed-Effects Model 12
Table 3: Arousal Ratings Mixed-Effects Model 12
Table 4: Valence Reaction Time Mixed-Effects Model 13
Table 5: Arousal Reaction Time Mixed-Effects Model 14
Table 6: Valence Mixed-Effects Model, Stratified by Group 18
Table 7: Valence Ratings Mixed-Effects Model with Brain Volumes 21
Table 8: Valence Ratings Mixed-Effects Model with Brain Volumes, Stratified by Group 22

iv

LIST OF FIGURES
Figure 1: Self-Assessment Manikin of Valence and Arousal 7
Figure 2: Mean Valence vs. Arousal ratings for Each Image, Stratified by Group 10
Figure 3: Unadjusted Valence Ratings and Reaction Time by Image Condition by Group 10
Figure 4: Unadjusted Arousal Ratings and Reaction Time by Image Condition by Group 11
Figure 5: Predicted Mean Valence Ratings 15
Figure 6: Predicted Mean Arousal Ratings 16
Figure 7: Predicted Mean Valence Reaction Time 17
Figure 8: Predicted Mean Arousal Reaction Time 18
Figure 9: Group by Right Caudal Middle Frontal Volume Interaction Effect
on Mean Predicted Valence 24
Figure 10: Group by Right Rostral Middle Frontal Volume Interaction Effect
on Mean Predicted Valence 25
Figure 11: Group by Left Rostral Middle Frontal Volume Interaction Effect
on Mean Predicted Valence 26
Figure 12: Group by Right Medial Orbitofrontal Volume Interaction Effect
on Mean Predicted Valence 27
Figure 13: Group by Left Medial Orbitofrontal Volume Interaction Effect
on Mean Predicted Valence 28

v

Abstract
Classical Congenital Adrenal Hyperplasia (CAH) is a genetic disorder which results in hormonal
imbalances due to 21-hydroxylase deficiency. Previous work by Herting and colleagues (2020)
found that youth with classical CAH have altered brain volumes in regions important for
emotional processing (i.e., prefrontal cortex, amygdala, and hippocampus) as compared to
normally developing youth. The present study aims to expand on these findings by examining
group differences in emotion perception, and whether these differences relate to the
aforementioned structural brain differences, using the same sample of 27 youth with classical
CAH (MAge= 12.63 years, 16 female) and 35 age- and sex-matched controls (M Age= 13.03 years,
20 female). Each participant rated 61 images from the International Affective Picture System
(IAPS) for valence and arousal. Reaction time was measured for each rating. CAH youth had
significantly lower valence ratings for positive (p = .002) and neutral (p = .042), but not
negative, valenced images after controlling for age, sex, and image arousal condition. No
significant group differences were observed in arousal ratings or reaction time. Exploratory brain
analyses found that volumes of the right amygdala (p = .025), left hippocampus (p = .002), and
the medial orbitofrontal cortex (p = .034) significantly predicted valence scores, after controlling
for age, sex, image condition, and total intracranial volume. Additionally, group-by-brain
interaction effects were observed in the right caudal middle frontal (p = .033), left rostral middle
frontal (p < .001), and bilateral medial orbitofrontal cortices (p’s < .001). Posthoc tests of
interaction terms found that prefrontal cortex subregion volumes significantly predicted valence
scores only in youth with CAH.

1

Introduction
Congenital Adrenal Hyperplasia (CAH) is a recessive genetic disorder which results in
hormonal imbalances, due to deficient adrenal steroidogenesis (El-Maouche et al., 2017). The
most common form of CAH is due to 21-hydroxylase deficiency, which leads to a malfunction of
cortisol synthesis and excess androgen production (Speiser & White, 2003). This classical,
severe form of CAH is present in approximately 1 out of every 15,000 births (Pang et al., 1993).
While CAH may be detected at birth and treated with glucocorticoid therapy shortly thereafter,
prenatal hormonal imbalances may still result in prenatal virilization, along with postnatal
virilization due to varying hormonal control, particularly in females (Speiser et al., 1995). Across
childhood and adolescence, youth with CAH have been shown to have external genitalia
virilization (Speiser & White, 2003), sex-atypical behavior (Hines & Kaufman, 1994), and more
recently, structural and functional brain differences, as compared to normally developing
controls (Ernst et al., 2007; Herting et al., 2020).
Cognitive & Behavioral Differences in CAH
Hormonal imbalances early in development have been linked to a number of cognitive
and behavioral measures, both in humans and other animals (Collaer & Hines, 1995). For
example, in the cognitive domain, several studies have found reduced working memory capacity
in CAH (Browne et al., 2015; Karlsson et al., 2017). Additionally, early elevation of androgen
hormones such as testosterone have been shown to have a masculinizing effect on spatial ability
in both humans and rats (Puts et al., 2007; Sandstrom et al., 2006). Consistent with these
findings, a 2008 meta-analysis on spatial reasoning in CAH by Puts and colleagues found that
CAH females performed better on spatial reasoning than CAH males, whereas control males

2

performed better than control females. A more recent study has replicated these findings
(Berenbaum et al., 2012), though another suggests superior spatial ability is only found in CAH
females with the most severe salt-wasting form of the disorder (Hampson & Rovet, 2015).
Reversal of typical sex-role behavior is likewise seen in behavioral studies of children
with CAH. For example, girls with CAH prefer to play with more masculine toys than control
girls, even after controlling for parental socialization (Wong et al., 2013). Additionally, girls with
CAH show increased rough-and-tumble play and increased preference for playing with boys, as
compared to unaffected control girls, while boys with CAH show decreased rough-and-tumble
play and increased preference for playing with girls, as compared to unaffected control boys
(Hines & Kaufman, 1994). This increased aggression in girls with CAH may be related to
neuropsychological changes due to increased androgen levels (Berenbaum & Resnick, 1997).
Brain Differences in CAH
Together, these cognitive & behavioral findings illustrate various cognitive and
behavioral differences in CAH that may be related to early hormonal imbalances, but little is
known about how these effects are manifested in the brain. However, studies have begun
examining structural and functional brain differences in CAH. Several studies have found
reduced brain volumes in patients with CAH, particularly in the amygdala, hippocampus, and
prefrontal cortex regions (Merke et al., 2003; Webb et al., 2018; Herting et al, 2020).
Additionally, white matter microstructural differences have been observed in these same regions
(Webb et al., 2018; Cotter et al., 2021).

3

Emotion Perception in the Brain
Despite consistent evidence of structural brain differences in regions important for
emotion processing, and differences in behaviors linked to emotion (i.e., aggression), only two
studies have examined the relationship between emotion processing and brain function in CAH.
The first of two functional magnetic resonance imaging (fMRI) studies on the same sample of
children with CAH found that children with CAH showed significantly higher brain activation in
the amygdala, fusiform gyrus, and occipital cortex as compared to control children, when
looking at angry and fearful, but not happy, faces, as compared to neutral faces; and rated these
faces as significantly more negative than controls did (Ernst et al., 2007). A follow-up study
found that CAH youth had significantly poorer memory encoding of fearful faces as opposed to
neutral, and different activation patterns in the amygdala and hippocampus as compared to
control youth (Mazzone et al., 2011).
These studies provide evidence that youth with CAH may perceive emotions differently,
particularly in response to negative stimuli. However, it remains unclear whether these findings
are limited to facial expressions or if they may generalize to all affective stimuli, and whether
these differences in emotion perception can be predicted by structural brain differences, or only
by functional differences in brain activation. Therefore, the present study aims to test for group
differences in the valence and arousal ratings, as well as reaction time, of various emotive
images. Additionally, we aim to relate these findings to structural brain differences in a sample
of children with and without CAH. We hypothesize that brain volumes of regions implicated in
emotion processing (i.e., the amygdala, prefrontal cortex, and hippocampus) will be predictive of
emotion ratings and reaction time, with significant group-by-brain interaction effects moderating
these relationships.

4

Method
Study Participants
Our participants included 62 children and adolescents ages 8 to 18 years old recruited
through convenience sampling. Written consent was obtained from all parents and assent was
obtained from all minors under 14 years of age. 27 of these participants were youth with CAH
(16 female; 12.6 ± 3.4 years) recruited from the Children’s Hospital Los Angeles (CHLA) CAH
Comprehensive Care Center, while 35 control youth (20 female; 13.0 ± 2.8 years) were recruited
from flyers posted at CHLA and the University of Southern California and frequency-matched
with regards to age and sex. Participants did not differ significantly in regards to age, sex,
Wechsler IQ, socioeconomic status, race and ethnicity, maternal education, handedness, or
Tanner puberty stage; full details of the study participants are described in Table 1.
Structural MRI
Structural brain images were acquired at the University of Southern California’s Center
for Image Acquisition using a Siemens Magnetom Prisma 3 Tesla MRI scanner with a 32-
channel head coil. We acquired both T1- and T2-weighted imaging. T1-weighted images used a
sagittal whole brain MPRAGE sequence (TR = 2400 ms, TE = 2.22 ms, flip angle = 8°, BW =
220 Hz/Px, FoV = 256 mm, 208 slices, and 0.8-mm isotropic voxels, with a GRAPPA phase-
encoding acceleration factor of 2). T2-weighted images used a variable flip angle turbo spin-echo
sequence (TR = 3200 ms, TE = 563 ms, BW = 744 Hz/Px, FoV = 256 mm, 208 slices, 0.8-mm
isotropic voxels, and 3.52-ms echo spacing, with a GRAPPA phase-encoding acceleration factor
of 2). We also collected anterior-posterior and posterior-anterior spin-echo field maps (TR =

5

8000 ms, TE = 66.0 ms, flip angle = 90°, BW = 2290 Hz/Px, FoV = 208 mm, 72 slices, and 2.0-
mm isotropic voxels, with a multiband acceleration factor of 1).
Table 1: Participant Demographics, Stratified by Group
Variable CAH (n = 27) Control (n = 35) Group
Differences
p-value
Age (Yrs.) 12.63 ± 3.35 13.03 ± 2.79 t(50.3) = -0.50 .62
Sex:
Male
Female

11 (40.7%)
16 (59.3%)

15 (42.9%)
20 (57.1%)

𝜒 2
(1) = 0.00

1
Wechsler IQ 100.22 ± 16.67 103.03 ± 15.30 t(53.5) = -0.68 .50
Family Income:
< $49k
> $49k
Not Reported

11 (40.7%)
14 (51.9%)
2 (7.4%)

15 (42.9%)
19 (54.3%)
1 (2.8%)

𝜒 2
(1) = 0.00

1
Ethnicity:
Hispanic
Non-Hispanic

11 (40.7%)
16 (59.3%)

20 (57.1%)
15 (42.9%)

𝜒 2
(2) = 2.53

.28
Race:
White
Black
Asian
Mixed
Not Reported

12 (44.4%)
2 (7.4%)
1 (3.7%)
4 (14.8%)
8 (29.6%)

17 (48.6%)
4 (11.4%)
2 (5.7%)
2 (5.7%)
10 (28.6%)

𝜒 2
(4) = 2.09

.72
Maternal Education
(Yrs.)
13.85 ± 3.32 4.85 ± 3.47 t (55.1) = 1.14 .26
Handedness:
Right
Left

25 (92.6%)
2 (7.4%)

30 (85.7%)
5 (14.3%)

𝜒 2
(1) = 1.97

.66

Tanner Puberty Stage 2.81 ± 1.64 3.31 ± 1.62 t(55.7) = -1.19 .24
CAH Form:
Salt Wasting
Simple
Virilizing

25 (92.6%)
2 (7.4%)

-

-

-
Screened for CAH at
Birth:

6

Yes
No
12 (44.4%)
15 (55.6%)
- - -
Fludrocortisone Total
Daily Dose (mg)
0.11 ± 0.04 - - -
Glucocorticoid Total
Daily Dose (mg/m
2
)
16.5 ± 4.7 - - -
17-OHP (ng/dL)
[nmol/L]
3,656 ± 4,694.8 - - -
Plasma Renin Activity
(ng/mL/hr and μg/L/hr)
3.5 ± 2.9 - - -
Androstenedione
(ng/dL) [nmol/L]
150.5 ± 227.8 - - -
Testosterone (ng/dL)
[nmol/L]
76.5 ± 155.3 - - -
Continuous Variables: Mean ± SD
Categorical Variables: Frequency (%)

All scans were sent to a radiologist to review for incidental findings of brain
abnormalities. Total intracranial volume, bilateral hippocampus and amygdala volumes, and
bilateral volumes of the superior, rostral middle, caudal middle, lateral orbitofrontal, and medial
orbitofrontal prefrontal cortex were obtained and segmented using the Desikan-Killiany Atlas.
Full details of these findings are reported in Herting et al. (2020).
Emotion Perception
Each participant was shown 61 images from the International Affective Picture System
(IAPS; Lang et al., 1997). Each image was classified as either negative, neutral, or positive
valence (e.g., sick people, books, or puppies) and low, moderate, or high arousal (e.g., people
reading, eating, or screaming) based on IAPS reference data (Lang et al., 2008). Participants
rated each image on a 1-9 scale for valence (negative to positive) and arousal (low to high) using
the Self-Assessment Manikin depicted in Figure 1 (Bradley & Lang, 1994; Blekić et al., 2021).

7

Each image rating trial began with a 5 second preparation slide “Get ready to rate the next slide.”
Each image was then shown for 6 seconds. Immediately after the image left the screen,
participants rated each image for valence and arousal. Reaction times were also measured for
each rating. Participants went through 3 practice trials prior to data collection, and a total of 61
experimental trials for which data was collected.
Figure 1: Self-Assessment Manikin of Valence and Arousal

Data Analysis
Prior to analysis, all variables were examined for outliers, normality, and implausible
values. No significant outliers or implausible values were observed. All variables except valence
reaction time, arousal reaction time, and right hippocampus volumes were approximately
normally distributed. These skewed variables were accordingly log transformed to achieve
normality.
Data was analyzed using RStudio v1.4 (R Core Team, 2021) using packages “lme4”
(Bates et al., 2015) and “lmerTest” (Kuznetsova et al., 2017) for linear mixed-effects modeling.
Initial mixed-effects models were conducted for each valence and arousal, and their

8

corresponding reaction times, as dependent variables with subject ID as the random effect, to
account for the repeated-measures design. Group by valence or arousal condition interaction
effects were tested for based on the outcome variable (i.e., group by valence condition
interaction for valence outcomes, group by arousal condition interaction for arousal outcomes)
while controlling for age and sex. Age and sex were controlled for given a priori assumptions of
their potential for confounding the relation between emotion perception, CAH, and brain
structure.
Age was centered on its mean in order to make the output intercepts more meaningfully
interpretable. Controls were selected as the reference group, with CAH representing the main
effect group. Male was coded as the reference sex, with main effects for sex representing
females. Neutral valence and moderate arousal were coded as the reference image conditions for
valence and arousal, respectively, with main effects for low or high arousal and negative or
positive valence. The model was formatted as follows:
Outcome ~ Valence Condition + Arousal Condition + Group + Sex + Age MC +
Group*Image Condition | SubjectID
A total of four models were constructed, where “Outcome” refers to each of the following four
outcome variables: valence rating, arousal rating, valence reaction time, and arousal reaction
time. “Image Condition” refers to the affective marker corresponding to the model outcome (i.e.,
valence condition for valence ratings and reaction times, arousal condition for arousal ratings and
reaction times).
Following detecting group differences in valence ratings, backward stepwise selection
was used to select a model examining the explanatory power of structural brain differences in
these differences. The initial model considered all brain regions of interest, which were all mean-
centered for ease of interpretability. Valence and arousal image conditions and mean-centered

9

age and total intracranial volume were fixed in the model, alongside subject ID as the random
effect, to remain controlled for. Interaction effects between group and all variables of interest
were also considered. The analysis plan for significant group interaction effects was to rerun the
model stratified by group. The p-value for exclusion in backward stepwise selection was set at
.05.
Lastly, for both initial models on emotion perception and later models including brain
volumes, posthoc tests comparing model-predicted outcomes between groups were conducted
using the R package “emmeans” (Lenth, 2021). This serves as a test for equality of means of
each outcome variable across groups, after controlling for all covariates and model assumptions.
Results
Group Differences in Emotion Perception
As preliminary exploration for group differences in emotion perception, valence vs.
arousal ratings were plotted for CAH participants, control participants, and the IAPS reference
data (Lang et al., 2008). These comparisons are visualized in Figure 2. Descriptive statistics
(means and standard deviations) of valence and arousal ratings and reaction times, stratified by
group and valence or arousal condition, are plotted in Figures 3-4.

10

Figure 2: Mean Valence vs. Arousal ratings for Each Image, Stratified by Group

Figure 3: Unadjusted Valence Ratings and Reaction Time by Image Condition by Group

11

Figure 4: Unadjusted Arousal Ratings and Reaction Time by Image Condition by Group

After controlling for age, sex, subject ID, and valence and arousal image condition,
significant group differences were observed in valence ratings, but not arousal ratings nor
valence or arousal reaction times. Additionally, group by image condition interaction effects
were observed for valence ratings and arousal reaction times, however, posthoc tests of these
interaction terms using the “simple_slopes” function in R package “reghelper” (Hughes, 2021)
revealed that these interaction terms were significant after taking into account model
assumptions for valence ratings (p’s < .001) but not arousal reaction times (p’s > .065). These
results are shown in Tables 2-5 and Figures 5-9.
To serve as posthoc decomposition of significant interaction effects on valence ratings,
this model was reran, stratified by group (Table 6). Specifically, we found CAH youth to rate
negative and neutral valenced images, but not positive images, as more negative compared to
control youths’ ratings. Posthoc tests of model-predicted means using “emmeans” confirmed that
these lower valence ratings for youth with CAH were statistically significant in the negative (p =
.002) and neutral (p = .042) valence conditions, with no statistically significant difference in
positive valenced image ratings (p = .995).

12

Table 2: Valence Ratings Mixed-Effects Model
Variable β Standard
Error
t-statistic (df) p-value
Intercept 5.785 0.222 26.021 (3983) < .001***
Negative (vs. Neutral)
Valence
-2.176 0.162 -2.176 (3983) < .001***
Positive (vs. Neutral)
Valence
1.178 0.155 1.178 (3983) < .001***
CAH (vs. Controls) -0.686 0.217 -0.686 (63) .002**
Low (vs. Moderate)
Arousal
-0.743 0.135 -0.743 (3983) < .001***
High (vs. Moderate)
Arousal
-0.052 0.081 -0.052 (3983) .525
Female (vs. Male) -0.279 0.205 -0.279 (63) .179
Age
(Mean Centered)
-0.019 0.035 -0.019 (63) .594
CAH*Neg. Val.
-0.084 0.158 -0.084 (3983) .596
CAH*Pos. Val. 0.601 0.156 0.601 (3983) < .001***
Intercept reflects mean predicted valence rating for a male control participant of mean age,
shown a neutral valence and moderate arousal image. Unstandardized β values reflect predicted
change in mean valence rating per unit change in each predictor variable.
*p < .05, **p < .01, ***p < .001
Table 3: Arousal Ratings Mixed-Effects Model
Variable β Standard
Error
t-statistic (df) p-value
Intercept
4.310 0.307 14.053 (3987) < .001***
Negative (vs.
Neutral) Valence
-1.520 0.180 -8.458 (3987) < .001***
Positive (vs. Neutral)
Valence
0.739 0.129 5.743 (3987) < .001***

13

CAH (vs. Controls) -0.029 0.311 -0.094 (63) .925
Low (vs. Moderate)
Arousal
-0.425 0.169 -2.509 (3987) .012*
High (vs. Moderate)
Arousal
0.484 0.161 3.003 (3987) .003**
Female (vs. Male) -0.339 0.303 -1.119 (63) .267
Age
(Mean Centered)
-0.131 0.051 -2.567 (63) .013*
CAH*Low Aro.
0.158 0.183 0.860 (3987) .390
CAH*High Aro. -0.363 0.186 -1.952 (3987) .051
Intercept reflects mean predicted arousal rating for a male control participant of mean age,
shown a neutral valence and moderate arousal image. Unstandardized β values reflect predicted
change in mean arousal rating per unit change in each predictor variable.
*p < .05, **p < .01, ***p < .001

Table 4: Valence Reaction Time Mixed-Effects Model
Variable β Standard
Error
t-statistic (df) p-value
Intercept 216.812 120.752 1.796 (3983) .073
Negative (vs.
Neutral) Valence
30.949 66.810 0.463 (3983) .643
Positive (vs. Neutral)
Valence
-114.011 64.078 -1.779 (3983) .075
CAH (vs. Controls) -130.123 124.758 -1.043 (63) .301
Low (vs. Moderate)
Arousal
15.725 55.520 0.283 (3983) .777
High (vs. Moderate)
Arousal
7.592 33.500 0.227 (3983) .821
Female (vs. Male) 169.293 123.296 1.373 (63) .175
Age
(Mean Centered)
-38.743 20.829 -1.860 (63) .068

14

CAH*Neg. Val.
-96.021 65.252 -1.472 (3983) .141
CAH*Pos. Val. 108.559 64.450 1.684 (3983) .092
Intercept reflects mean predicted valence reaction time (milliseconds) for a male control
participant of mean age, shown a neutral valence and moderate arousal image. Unstandardized
β values reflect predicted change in mean valence reaction time per unit change in each
predictor variable.
*p < .05, **p < .01, ***p < .001

Table 5: Arousal Reaction Time Mixed-Effects Model
Variable β Standard
Error
t-statistic (df) p-value
Intercept -162.262 159.253 -1.019 (3987) .308
Negative (vs.
Neutral) Valence
-108.909 75.445 -1.444 (3987) .149
Positive (vs. Neutral)
Valence
-99.556 54.007 -1.843 (3987) .065
CAH (vs. Controls) -181.546 166.675 -1.089 (63) .280
Low (vs. Moderate)
Arousal
295.548 71.085 4.158 (3987) < .001***
High (vs. Moderate)
Arousal
167.114 67.597 2.472 (3987) .014*
Female (vs. Male) 151.990 166.191 0.915 (63) .364
Age
(Mean Centered)
47.198 28.077 1.681 (63) .098
CAH*Low Aro.
192.028 76.934 2.496 (3987) .013*
CAH*High Aro. 32.648 77.964 0.419 (3987) .675
Intercept reflects mean predicted arousal reaction time (milliseconds) for a male control
participant of mean age, shown a neutral valence and moderate arousal image. Unstandardized
β values reflect predicted change in mean arousal reaction time per unit change in each
predictor variable.
*p < .05, **p < .01, ***p < .001

15

Figure 5: Predicted Mean Valence Ratings

Group differences are significant in the negative (p = .002) and neutral (p = .042) image
conditions.

16

Figure 6: Predicted Mean Arousal Ratings

No group differences in arousal ratings were statistically significant at the .05 level. Bars
represent 95% confidence intervals.

17

Figure 7: Predicted Mean Valence Reaction Time

No group differences in valence reaction times were statistically significant at the .05 level. Bars
represent 95% confidence intervals.

18

Figure 8: Predicted Mean Arousal Reaction Time

No group differences in arousal reaction times were statistically significant at the .05 level. Bars
represent 95% confidence intervals.

Table 6: Valence Mixed-Effects Model, Stratified by Group
Variable β Standard Error t-statistic (df) p-value
CAH Control CAH Control CAH Control CAH Control
Intercept 5.481 5.445 0.335 0.237 16.376
(1854)
23.017
(2127)
< .001*** < .001***
Negative
(vs.
Neutral)
Valence
-2.548 -1.922 0.218 0.191 -11.692
(1854)
-10.046
(2127)
< .001*** < .001***
Positive
(vs.
Neutral)
Valence
1.505 1.420 0.207 0.182 7.267
(1854)
7.800
(2127)
< .001*** < .001***

19

Low (vs.
Moderate)
Arousal
-1.113 -0.418 0.203 0.179 -5.477
(1854)
-2.341
(2127)
< .001*** .019*
High (vs.
Moderate)
Arousal
-0.111 0.000 0.123 0.108 -0.902
(1854)
-0.001
(2127)
.367 .999
Age
(Mean
Centered)
-0.385 -0.177 0.363 0.228 -1.060
(28)
-0.777
(34)
.298 .443
Female
(vs. Male)
-0.013 -0.027 0.058 0.041 -0.229
(28)
-0.658
(34)
.820 .515
Intercept reflects mean predicted valence ratings for a male control participant of mean age,
shown a neutral valence and moderate arousal image. Unstandardized β values reflect predicted
change in mean predicted valence ratings per unit change in each predictor variable.
*p < .05, **p < .01, ***p < .001
Exploratory Brain Analyses
Stepwise selection resulted in a final model including the right amygdala, left
hippocampus, right caudal middle frontal, and left and right rostral middle frontal and medial
orbitofrontal cortices, in addition to all aforementioned controlled variables (i.e., age, sex,
subject ID, and valence and arousal image condition). Group-by-brain interaction effects were
retained by stepwise selection for the latter five brain regions. Upon selecting the final model,
subsequent analyses stratified by group were performed. Stratified results are shown in Table 7.
For ease of interpretability, brain volumes in cubic millimeters were scaled by 100 for each
subregion, and by 10,000 for total intracranial volume.
Notably, we found volumes of the right amygdala, left hippocampus, and left medial
orbitofrontal cortex to be significant predictors of valence ratings, with larger left hippocampus
and medial orbitofrontal cortices associated with more positive valence ratings, and large right
amygdalae associated with more negative valence ratings. Moreover, we observed significant
group by brain volume interaction effects for the right caudal middle frontal cortex, and

20

bilaterally in the rostral middle and medial orbitofrontal cortices (though the right medial
orbitofrontal by group interaction was only marginally significant, p = .051). These interactions
showed that in CAH youth, volumes of the the right rostral middle, right caudal middle, and left
medial orbitofrontal cortices were more positively associated with valence ratings, while the left
rostral middle and right medial orbitofrontal cortex volumes were more negatively associated
with valence ratings, as compared to controls. Additionally, we observed a significant group by
sex interaction effect on valence ratings: CAH females rated images as more negative than CAH
males, after controlling for image condition, age, and brain volumes. Full details of these results
are shown in Table 7.
To serve as posthoc decomposition of these group interaction effects, models were reran,
stratified by group (Table 8). Notably, sex and age were significant predictors of valence ratings
only in youth with CAH, as were bilateral brain volumes in the rostral middle and medial
orbitofrontal cortices. Group interaction effects of prefrontal cortex region volumes predicting
valence scores are plotted in Figures 9-13.
While no significant interaction effects were observed in the right amygdala and left
hippocampus, after controlling for prefrontal cortex volumes and stratifying by group, right
amygdala and left hippocampus volumes became significant predictors of valence scores in
controls but not in youth with CAH (Table 8).

21

Table 7: Valence Ratings Mixed-Effects Model with Brain Volumes
Variable β SE t-statistic (df) p-value
Intercept 5.338 0.244 21.903 (249.594) < .001***
CAH (vs. Control) 0.644 0.355 1.816 (281.644) .070
Negative (vs. Neutral)
Valence
-1.876 0.200 -9.364 (3689.264) < .001***
Positive (vs. Neutral)
Valence
1.424 0.191 7.474 (3688.943) < .001***
Low (vs. Moderate)
Arousal
-0.439 0.187 -2.349 (3688.953) .019*
High (vs. Moderate)
Arousal
-0.016 0.113 -0.143 (3689.051) .886
Female (vs. Male) -0.071 0.239 -0.299 (62.337) .766
Age
(Mean Centered)
-0.131 0.031 -4.222 (61.653) < .001***
CAH*Neg. Val. -0.856 0.302
-2.833 (3689.076) .005**
CAH*Pos. Val. 0.002 0.287
0.006 (3688.939) .995
CAH*Low Aro. -0.819 0.282
-2.908 (3688.939) .004**
CAH*High Aro. -0.089 0.170
-0.521 (3688.998) .603
CAH*Female -1.202 0.343
-3.499 (61.789) .001***
Brain Volume Predictors in Cubic Millimeters (Mean Centered and Scaled)
ICV 10,000
0.002 0.009 0.184 (62.098) .854
Right Amygdala 100 -0.156 0.068 -2.303 (62.057) .025*
Left Hippocampus 100 0.114 0.035 3.264 (62.505) .002**
Right CMF 100 -0.013 0.008 -1.606 (61.880) .113

22

Right RMF 100 0.000 0.007 0.009 (61.699) .993
Left RMF 100 0.008 0.007 1.06 (61.876) .293
Right MOF 100 0.001 0.014 0.076 (62.344) .939
Left MOF 100 -0.042 0.019 -2.169 (61.715) .034*
CAH*Right CMF 100 0.028 0.013 2.176 (61.990) .033*
CAH*Right RMF 100 0.022 0.011 1.988 (61.783) .051
CAH*Left RMF 100 -0.054 0.012 -4.34 (61.683) < .001***
CAH*Right MOF 100 -0.101 0.027 -3.75 (61.790) < .001***
CAH*Left MOF 100 0.121 0.025 4.772 (61.729) < .001***
Abbreviations: RH = Right Hemisphere; LH = Left Hemisphere; ICV = Total Intracranial
Volume; CMF = Caudal Middle Frontal; RMF = Rostral Middle Frontal; MOF = Medial
Orbitofrontal.

Intercept reflects mean predicted valence rating for a male control participant of mean age with
mean brain volumes, shown a neutral valence and moderate arousal image. Unstandardized β
values reflect predicted change in mean arousal reaction time per unit change in each predictor
variable. Numbers in subtext beside brain volumes represent scaling factors (β represents mean
change in predicted valence ratings per 100mm
3
in brain regions or per 10,000mm
3
change in
ICV). *p < .05, **p < .01, ***p < .001

Table 8: Valence Ratings Mixed-Effects Model with Brain Volumes, Stratified by Group
Variable β Standard Error t-statistic (df) p-value
Variable CAH Control CAH Control CAH Control CAH Control
Intercept
5.861 5.433 0.296 0.249
19.797
(97.867)
21.779
(110.646) < .001*** < .001***
Negative
(vs.
Neutral)
Valence
-2.731 -1.876 0.238 0.191
-11.453
(1618.002)
-9.81
(2071.111) < .001*** < .001***

23

Positive
(vs.
Neutral)
Valence
1.426 1.424 0.227 0.182
6.294
(1618.004)
7.829
(2070.936) < .001*** < .001***
Low (vs.
Moderate)
Arousal
-1.259 -0.439 0.222 0.179
-5.661
(1618.001)
-2.461
(2070.942) < .001*** .014*
High (vs.
Moderate)
Arousal
-0.105 -0.016 0.135 0.107
-0.778
(1618.012)
-0.149
(2070.991) .437 .882
Female (vs.
Male) -1.141 -0.223 0.301 0.263
-3.786
(26.987)
-0.85
(35.147) .001*** .401
Age
(Mean
Centered)
-0.145 -0.082 0.043 0.049
-3.37
(26.985)
-1.658
(34.663) .002** .106
Brain Volume Predictors in Cubic Millimeters (Mean Centered and Scaled)
ICV 10,000
0.000 -0.005 0.015 0.000
0.031
(26.994)
-0.414
(35.115) .975 .682
Right
Amygdala
100
-0.015 -0.222 0.159 0.077
-0.097
(26.989)
-2.896
(35.019) .923 .006**
Left HC 100
0.058 0.136 0.065 0.041
0.898
(26.995)
3.323
(35.435) .377 .002**
Right
CMF 100
0.010 -0.011 0.012 0.007
0.863
(26.992)
-1.535
(34.771) .396 .134
Right
RMF 100
0.023 0.001 0.010 0.007
2.307
(27.021)
0.187
(34.67) .029* .852
Left
RMF 100
-0.048 0.009 0.011 0.007
-4.447
(27.009)
1.224
(34.698) < .001*** .229
Right
MOF 100
-0.098 0.000 0.027 0.013
-3.661
(27.024)
0.024
(35.137) .001*** .981

24

Left
MOF 100
0.075 -0.026 0.020 0.023
3.756
(27.038)
-1.133
(34.683) .001*** .265
Abbreviations: RH = Right Hemisphere; LH = Left Hemisphere; ICV = Total Intracranial
Volume; HC = Hippocampus; CMF = Caudal Middle Frontal; RMF = Rostral Middle Frontal;
MOF = Medial Orbitofrontal.

Intercept reflects mean predicted valence rating for a male participant of mean age with mean
brain volumes, shown a neutral valence and moderate arousal image. Unstandardized β values
reflect predicted change in mean arousal reaction time per unit change in each predictor
variable. Numbers in subtext beside brain volumes represent scaling factors (β represents mean
change in predicted valence ratings per 100mm
3
in brain regions or per 10,000mm
3
change in
ICV). *p < .05, **p < .01, ***p < .001

Figure 9: Group by Right Caudal Middle Frontal Volume Interaction Effect on Mean
Predicted Valence

Slopes are not statistically significantly different from 0 for controls (p = .134) nor CAH (p =
.396).

25

Figure 10: Group by Right Rostral Middle Frontal Volume Interaction Effect on Mean
Predicted Valence

Slopes are not statistically significantly different from 0 for controls (p = .852). For CAH, each
100mm
3
increase in RRMF volume is associated with a mean predicted valence score .023 points
higher (p = .029).

26

Figure 11: Group by Left Rostral Middle Frontal Volume Interaction Effect on Mean
Predicted Valence

Slopes are not statistically significantly different from 0 for controls (p = .229). For CAH, each
100mm
3
increase in LRMF volume is associated with a mean predicted valence score .048 points
lower (p < .001).

27

Figure 12: Group by Right Medial Orbitofrontal Volume Interaction Effect on Mean
Predicted Valence

Slopes are not statistically significantly different from 0 for controls (p = .981). For CAH, each
100mm
3
increase in RMOF volume is associated with a mean predicted valence score .098
points lower (p = .001).

28

Figure 13: Group by Left Medial Orbitofrontal Volume Interaction Effect on Mean Predicted
Valence

Slopes are not statistically significantly different from 0 for controls (p = .265). For CAH, each
100mm
3
increase in LMOF volume is associated with a mean predicted valence score .075
points higher (p = .001).

Discussion
Youth with CAH rated emotive IAPS images differently than age- and sex-matched
controls. In particular, after controlling for age, sex, and image arousal condition, CAH youth
rated negative and neutral valenced images, but not positive valenced images, as significantly
more negative than typically developing controls. No significant differences were observed in
arousal ratings or reaction times. Exploratory brain analyses found that brain volumes of regions
implicated in emotion processing, including the amygdala, hippocampus, and several prefrontal
cortex regions, significantly predicted valence ratings.

29

Significant group-by-brain interaction effects were observed in the right caudal middle
frontal (CMF), left rostral middle frontal (RMF), and bilateral medial orbitofrontal (MOF)
cortices. Posthoc decomposition of interaction effects revealed that bilateral volumes of the RMF
and MOF cortices were significant predictors of valence ratings only in CAH, whereas after
controlling for prefrontal cortex volumes and demographic characteristics, volumes of the right
amygdala and left hippocampus were significant predictors of valence ratings only in controls.
Specifically, in youth with CAH, larger right RMF and left MOF volumes were
associated with more positive valence ratings, while larger left RMF and right MOF volumes
were associated with more negative valence ratings. In controls, larger right amygdala volumes
were associated with more negative valence ratings, while larger left hippocampus volumes were
associated with more positive valence ratings. These effects all remained significant after
controlling for age, sex, total intracranial volume, and image valence and arousal conditions.
These findings are consistent with previous findings showing that CAH youth have
altered perception and memory encoding of negative (i.e., angry or fearful) facial stimuli,
corresponding with altered function in aforementioned brain regions, most notably the amygdala
and hippocampus (Ernst et al., 2007; Mazzone et al., 2011). The present research expands on
these findings in two notable ways. Firstly, it shows that individuals with CAH respond
differently to negative affect not only in emotive faces, but to affective stimuli more generally, as
in the case of the IAPS dataset. Secondly, though there are few fMRI studies in patients with
CAH, it shows that altered behavior and emotion perception in CAH may be related to not only
group differences in functional activation (Ernst et al., 2007; Mazzone et al., 2011) or functional
connectivity (Beltz et al., 2021), but to previously noted structural brain differences as well
(Herting et al., 2020).

30

Beyond the paucity of research on CAH, these findings may be understood in relation to
a broader literature linking structural brain differences to differences in emotion processing. For
example, several studies have associated smaller amygdala volumes, or lesioned amygdalae, with
altered processing of negative valenced affective stimuli but intact processing of positive stimuli
(e.g., Berntson et al., 2007; Gerdes et al., 2010). Moreover, past research on psychopathy has
identified structural correlates between emotion perception and volumes in the amygdala and
prefrontal cortex regions, including the medial orbitofrontal cortex, with differential associations
for negatively and positively valenced stimuli (Pera-Guardiola et al., 2016). It is possible that
smaller brain volumes in the amygdala, hippocampus, and prefrontal cortex in our sample of
CAH youth (as reported in Herting et al., 2020) may partially explain our findings of altered
perception for negative and neutral, but not positive, valenced images.
Nevertheless, main effects were observed of the rostral middle and medial orbitofrontal
cortex volumes predicting valence scores in CAH, even after controlling for total intracranial
volume and other subregion volumes. The present findings are notable in finding differential
main effects on emotion perception of opposite directions when examining the same brain
regions (i.e., RMF and MOF) bilaterally, highlighting the importance of bilateral segmentation in
revealing more nuanced structural correlates of brain functioning.
Limitations
There are a number of methodological limitations in both this study and the CAH
literature at large that may be addressed in future research. Firstly, our sample size is small,
consisting of only 27 CAH and 35 control participants. Future research should aim for larger
sample sizes for both increased reliability and increased power to detect small effect results.
Secondly, the present study did not examine the potential moderating factors of hormone levels

31

or glucocorticoid treatments on emotion perception, which may confound true associations.
Finally, while novel in its approach of relating emotional processing differences to structural
brain differences, it is unclear to what degree these findings are reflective of underlying
differences in brain function or connectivity. Therefore, future neuropsychological research in
CAH should seek to also examine brain function, using fMRI or related methods, as they relate
to cognitive and behavioral group differences.
Conclusion & Future Directions
We found significant group differences in emotion perception between youth with CAH
and typically developing controls. Specifically, youth with CAH rated negative and neutral
valenced images as more negative, and these group differences were associated with structural
brain differences in the caudal middle, rostral middle, and medial orbitofrontal cortices.
These findings point to a number of future research directions examining the degree to
which altered emotion perception, particularly in responding to negative stimuli, may relate to
established affective and behavioral differences in children with CAH, such as increased
aggression (Hines & Kaufman, 1994; Berenbaum & Resnick, 1997). Moreover, the present
study, though correlational in design, points towards examining how differences in brain
structure may contribute to other cognitive differences in CAH, such as reduced working
memory capacity (Browne et al., 2015; Karlsson et al., 2017).
Identifying which particular subregions are associated with cognitive and behavioral
differences in CAH may also shed light on the developmental trajectory of how CAH influences
the brain. It remains unclear whether these observed differences are mediated primarily by
hormonal imbalances prenatally or in early development, differences in pubertal development, or
long-term neurophysiological changes brought on by medical interventions such as

32

glucocorticoid treatment (Khalifeh et al., 2022). In this same vein, it is unclear whether the
present findings represent true neuropsychological changes brought on by altered brain structure
in CAH, or whether this relationship is merely a marker for broad-scale impacts of hormonal
imbalances in both the domains of emotion perception and brain structure. To answer these
questions, future longitudinal research should seek to relate behavior, brain structure, and brain
function in patients with CAH to their past or present hormonal imbalances, particularly
considering the effects of androgen levels, glucocorticoid treatment, and CAH phenotypes on
structural and functional brain development.

33

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Abstract (if available)

Abstract Classical Congenital Adrenal Hyperplasia (CAH) is a genetic disorder which results in hormonal imbalances due to 21-hydroxylase deficiency. Previous work by Herting and colleagues (2020) found that youth with classical CAH have altered brain volumes in regions important for emotional processing (i.e., prefrontal cortex, amygdala, and hippocampus) as compared to normally developing youth. The present study aims to expand on these findings by examining group differences in emotion perception, and whether these differences relate to the aforementioned structural brain differences, using the same sample of 27 youth with classical CAH (MAge= 12.63 years, 16 female) and 35 age- and sex-matched controls (MAge= 13.03 years, 20 female). Each participant rated 61 images from the International Affective Picture System (IAPS) for valence and arousal. Reaction time was measured for each rating. CAH youth had significantly lower valence ratings for positive (p = .002) and neutral (p = .042), but not negative, valenced images after controlling for age, sex, and image arousal condition. No significant group differences were observed in arousal ratings or reaction time. Exploratory brain analyses found that volumes of the right amygdala (p = .025), left hippocampus (p = .002), and the medial orbitofrontal cortex (p = .034) significantly predicted valence scores, after controlling for age, sex, image condition, and total intracranial volume. Additionally, group-by-brain interaction effects were observed in the right caudal middle frontal (p = .033), left rostral middle frontal (p < .001), and bilateral medial orbitofrontal cortices (p’s < .001). Posthoc tests of interaction terms found that prefrontal cortex subregion volumes significantly predicted valence scores only in youth with CAH.

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Asset Metadata

Creator Omary, Adam (author)

Core Title Altered emotion perception linked to structural brain differences in youth with congenital adrenal hyperplasia

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 03/28/2022

Defense Date 03/28/2022

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag brain development,congenital adrenal hyperplasia,emotion,Hormones,neuroimaging,OAI-PMH Harvest

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Advisor Herting, Megan (committee chair), Choudhury, Farzana (committee member), Kim, Mimi (committee member)

Creator Email aomaryaas@gmail.com,omary@usc.edu

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Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA

Repository Email cisadmin@lib.usc.edu