Supplemental Information: Cortical thickness and subcortical gray matter volume in pediatric

anxiety disorders

Supplemental Methods

Participants

Patients were recruited when they sought treatment for an anxiety disorder; healthy

volunteers (HVs) were recruited using standard protocols employed throughout the National

Institute of Mental Health (NIMH). All patients in the anxiety group had to suffer from

generalized anxiety, social anxiety, and/or separation anxiety disorders as their major source of

psychiatric impairment and need for treatment. Prior to scheduling magnetic resonance imaging

(MRI) scans, patients’ psychiatric symptoms and commitment to seeking treatment were

assessed on three separate occasions via (1) an initial telephone screen with a psychiatric nurse,

(2) an in-person, standardized diagnostic assessment (KSADS-PL) with a clinician, and (3) an

independent assessment and confirmation of diagnosis by a senior psychiatrist. As part of these

three psychiatric screening and assessment sessions, clinicians assessed patients’ willingness and

motivation to engage in psychotherapy and/or pharmacotherapy. Given that all patients agreed to

enter treatment for their anxiety, the morphometry data reported herein are relevant to treatment-

seeking populations of children and adolescents with anxiety.

Patients with anxiety were permitted to have additional anxiety disorders and attention-

deficit/hyperactivity disorder if presenting as a secondary, minor problem, relative to anxiety

(Table 1). All patients were required to be free of major depressive disorder, bipolar disorder,

obsessive compulsive disorder, disruptive mood dysregulation disorder, and posttraumatic stress

disorder. Importantly, all patients were free of medication at the time of the MRI scan.

Handedness was not exclusionary, but was assessed upon enrollment to the study. Using

the Edinburgh Inventory (Oldfield, 1971), handedness was determined to be left-handed (scores

< -40), ambidextrous (scores between or equal to -40 and +40), or right-handed (scores >40). All

participants with available data (N=128) were either right-handed (45 HV, 51 anxious) or

ambidextrous (12 HV, 20 anxious); groups did not differ in number of right-handed versus

ambidextrous participants, χ2(1, N=128)=.85, p=.36.

2

Treatment

Patients with anxiety disorders received individual cognitive behavioral therapy (CBT)

based one of two treatment manuals from the Child and Adolescent Multimodal Study (CAMS):

children ages 13 or younger followed the “The Coping Cat Workbook” and adolescents ages 14

or older followed the “The C.A.T. Project” workbook (Compton et al, 2010; Kendall and

Hedtke, 2006; Walkup et al, 2008). Parents were involved at the end of each session with a brief

check-in. Patients received up to 12 weeks of treatment based on attendance, and timing was not

extended for missed sessions. The three initial weeks consisted of diagnostic assessments,

consent procedures for the neuroimaging and treatment studies, psychoeducation, and orientation

to CBT treatment. In the fourth session, clinicians continued orientation to CBT and collected

baseline ratings. The active, behavioral and cognitive component of CBT, including exposure-

based techniques, began in the fifth session and spanned eight weeks. In the final treatment

sample (n=53), scans ranged from 38 days before to 16 days after the baseline clinician ratings

session.

3

A subset of 40 of the 53 patients included in the treatment analyses concurrently received

either placebo or active forms of attention bias modification therapy (ABMT), immediately

preceding and following each CBT visit and beginning in the fifth week [see (White et al, In

Press) for further details]. The individual treatment covered psychoeducation, self-monitoring,

cognitive restructuring, relaxation training, and exposure and relapse prevention. Treatment

included imaginal, in-office exposure tasks, as well as actual, in vivo exposures, in which

patients approached, rather than avoided, anxiety-provoking situations. Training strategies, such

as coping modeling by clinicians, role-play, and homework assignments were used. Treatment

was provided by one of two licensed clinical psychologists with at least five years CBT

experience with pediatric anxiety disorders. One of the treatment providers (EMB) was a

supervising CBT clinician in the CAMS study and provided consultation as needed regarding

implementation of the treatment manuals.

MRI Acquisition Parameters

Participants underwent MRI scanning at the National Institute of Mental Health (NIMH)

Functional Magnetic Resonance Imaging Core Facility between September 2011 and January

2016. Participants completed a high-resolution, T1-weighted magnetization-prepared rapid-

acquisition gradient-echo scan (MPRAGE) with the following parameters: sagittal acquisition;

176 slices; 256x256 matrix; 1mm3 isotropic voxels; flip angle = 7°; repetition time [TR] = 7.7ms,

echo time [TE] = 3.42ms).

4

Image Processing

Images were processed using standard, automated procedures in the FreeSurfer image

analysis software suite (Version 5.3, http://surfer.nmr.mgh.harvard.edu). For details, see prior

reports (Dale et al, 1999; Fischl and Dale, 2000). Cortical thickness measurements in FreeSurfer

show good test-retest reliability across scanner manufacturers and field strengths (Han et al,

2006; Reuter et al, 2012) and have been validated in previous studies using histological analysis

(Rosas et al, 2002) and manual measurements (Kuperberg et al, 2003). FreeSurfer methods for

obtaining cortical thickness and subcortical gray matter volume measurements have been used in

prior psychiatric research on pediatric populations (McLaughlin et al, 2014; Ostby et al, 2009;

Sheridan et al, 2012; Strawn et al, 2014; Sylvester et al, 2016). Standard processing procedures

included removal of non-brain tissue (Ségonne et al, 2004), image intensity normalization (Sled

et al, 1998), and construction of boundaries between white and gray matter and between gray

matter and cerebrospinal fluid (CSF), which utilized intensity gradients to optimally place the

boundary at the location where the greatest shift in intensity defines the transition to the other

tissue class (Dale et al, 1999; Fischl and Dale, 2000). Subcortical white matter and deep grey

matter structures were then identified by an automated segmentation process (Fischl et al, 2002,

2004b). Following cortical reconstruction, automated procedures parcellate the cerebral cortex

into regions based on gyral and sulcal structure (Desikan et al, 2006; Fischl et al, 2004a). As

needed, manual edits were made to optimize accurate placement of boundaries between white

and gray matter and between gray matter and cerebrospinal fluid (CSF)(Dale et al, 1999; Fischl

and Dale, 2000). Finally, using both intensity and continuity information, cortical thickness

measurements were defined as the closest distance from the gray/white matter boundary to the

gray matter/CSF boundary at each vertex on the tessellated surface (Fischl and Dale, 2000).

5

Exploratory anxiety subscale analyses

Secondary, exploratory analyses tested associations of structural brain measures with the

generalized and social anxiety subscales from the Screen for Child Anxiety Related Emotional

Disorders (SCARED)(Birmaher et al, 1997) in the N=108 participants (37 healthy, 71 anxious)

with available SCARED data. The generalized and social anxiety subscales were highly

correlated with each other (r=.62, p<.001) and with the total anxiety scale (generalized: r=.90,

p<.001; social: r=.73, p<.001). Given these high inter-correlations (all rs>.6, p<.001) and

concerns regarding multi-collinearity, each scale was analyzed separately. The generalized and

social anxiety analyses were considered to be secondary to the primary analyses that relied on

the total score. Severity measures were based on the average of parent and child reports, which

were correlated for each of the subscales (generalized anxiety subscale: r=.52, p<.001; and social

anxiety subscale: r=.60, p<.001).

Post-hoc analyses of anxiety disorder specificity

Post-hoc analyses tested for specificity of anxiety disorder type using 2-by-2 analyses of

variance (ANOVAs) for generalized anxiety disorder (GAD: 55 yes, 91 no) and social anxiety

disorder (SoPH: 41 yes, 105 no) diagnoses. The n=5 patients with only separation anxiety were

excluded from this analysis due to small cell size, resulting in the following four cells: 29

GAD+/SoPH-, 15 GAD-/SoPh+, 26 GAD+/SoPh+, 76 GAD-/SoPH-. Analyses of covariance

(ANCOVAs) were conducted for subcortical GMV, to additionally control for estimated total

intracranial volume (ICV). These post-hoc specificity analyses utilized KSADS diagnoses, rather

than SCARED scores, given that the diagnoses were available in all N=151 participants and were

6

based on clinician interviews, rather than self-report, reflecting more careful clinical

phenotyping.

ABMT-specific treatment response analyses

Post-hoc analyses tested whether ABMT moderated treatment response in the 40 patients

(17 active ABMT, 23 placebo ABMT) who participated in the ABMT trial reported by White

and colleagues (In Press). Of the N=53 patients included in the overall treatment response

analyses, 13 patients were excluded from this analysis: n=12 patients were not randomized to

ABMT, one patient was randomized to ABMT but did not receive any ABMT sessions. Cortical

thickness and subcortical GMV analyses testing associations of post-treatment PARS,

controlling for pre-treatment PARS, were repeated with the addition of the ABMT-by-post-

treatment PARS interaction term.

Supplemental Results

Exploratory anxiety subscale analyses

Cortical thickness. Social anxiety severity was inversely related to thickness in the

ventrolateral PFC, with the peak coordinate in the right rostral middle frontal gyrus (MFG; Peak

Talairach Coordinates [XYZ]: 19.0, 58.4, 3.9; 1372.78mm2; 1819 vertices; Figure S2), based on

the whole-brain correction. The PFC-corrected threshold also resulted in the same right

hemisphere cluster, as well as a left hemisphere cluster in rostral middle frontal gyrus (Peak

Talairach Coordinates [XYZ]: -23.6, 48.1, -0.6; 874.23mm2; 1206 vertices). When tested in the

anxious group only (n=71), there were similar ventrolateral PFC clusters in both hemispheres,

with a left hemisphere cluster that included rostral MFG and extended to a peak in the rostral

anterior cingulate cortex, and a right hemisphere cluster that again included the rostral MFG and

7

extended to both the insula and anterior cingulate cortex (whole-brain corrected p<.05). No

significant clusters emerged using either threshold for generalized anxiety severity.

Subcortical GMV. Greater generalized anxiety severity was related to smaller right

hippocampal GMV, but not left hippocampal or left or right amygdala GMV (Table S2). The

association of generalized anxiety severity with right hippocampal GMV was non-significant

when tested in the anxious group only. Social anxiety severity was not associated with either

hippocampal or amygdala GMV.

Post-hoc analyses of anxiety disorder specificity

Cortical thickness. No significant clusters emerged using either the whole-brain-

corrected or PFC-corrected thresholds for the main effects or interaction analyses.

Subcortical GMV. The right hippocampus showed a main effect of GAD

[F(1,141)=8.93, p=.003], but no main effect of SoPH [F(1,141)=1.18, p=.28] or interaction effect

[F(1,141)=.09, p=.76]. Smaller GMV in the right hippocampus was observed in the GAD

patients (n=55, estimated marginal mean = 3991.0 mm3, s.e. = 50.62 mm3) relative to participants

without GAD (n=91, estimated marginal mean = 4209.47 mm3, s.e. = 52.73 mm3). The effect

size was medium (Cohen’s d = .49, controlling for ICV). The main effect of GAD did not

survive Bonferroni correction for two hemispheres for the left hippocampus [F(1,141)=4.97,

p=.027], left amygdala [F(1,141)=4.62, p=.03], or right amygdala [F(1,141)=.89, p=.35]. The

main effect of SoPH and interaction effect were non-significant for both regions (all ps>.36).

8

ABMT-specific treatment response analyses

Cortical thickness. ABMT group moderated the association between anxiety treatment

response and cortical thickness in the left superior frontal cortex, extending to the rostral anterior

cingulate cortex (Peak Talairach Coordinates [XYZ]: -11.7, 53.3, 4.4; 737.45mm2; 1185 vertices;

Figure S3), based on the PFC-corrected threshold (p<.05, corrected). In the placebo group,

thinner cortex was associated with worse treatment response, i.e., higher continuous anxiety

symptom ratings post-treatment controlling for baseline (β=-.63, p=.002). However, the active

group showed no such association (β=.25, p=.35). No clusters emerged for the right hemisphere

using the PFC-corrected threshold or for either hemisphere using the whole-brain corrected

threshold.

Subcortical GMV. ABMT did not moderate the association of treatment response with

hippocampal (left: p=.97; right: p=.98) or amygdala GMV (left: p=.80; right: p=.96).

9

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Supplemental Figure Legends.

Figure S1. Prefrontal cortex (PFC) region-of-interest (ROI) mask.

A PFC mask was created for the left and right hemispheres, separately, for use in the a priori

PFC cortical thickness analyses. The following twelve regions in the Desikan-Killiany Atlas

(Desikan et al, 2006; Fischl et al, 2004a) were combined to create the mask: medial and lateral

orbitofrontal cortices, pars orbitalis, pars triangularis, pars opercularis, rostral and caudal anterior

cingulate cortices, rostral and caudal middle frontal cortices, superior frontal cortex, frontal pole,

and insular cortex. The PFC mask is shown here on the inflated surface from the lateral (A) and

medial (B) views for the left hemisphere, and from the inferior view for the right (C) and left (D)

hemispheres.

Figure S2. Association of cortical thickness and social anxiety severity.

Based on the whole-brain vertex-wise correction (p<.05, corrected), cortical thickness in the

right ventrolateral prefrontal cortex, with a peak in the rostral middle frontal gyrus, was inversely

related to social anxiety symptoms (β=-.30), i.e., higher severity was related to thinner cortex.

Results are shown on both the inflated and pial surfaces. The scatterplot shows the average

cortical thickness of this cluster on the x-axis and continuous social anxiety symptom scores on

the y-axis.

Figure S3. ABMT-specific treatment response.

Based on the PFC-corrected threshold (p<.05, corrected), attention bias modification therapy

(ABMT) group moderated the association between anxiety treatment response and cortical

13

thickness in the medial PFC, with a peak in the left superior frontal cortex, extending to the

rostral anterior cingulate cortex. This interaction effect was driven by an association of thinner

cortex with worse treatment response, i.e., higher continuous anxiety symptom ratings post-

treatment controlling for baseline, in the placebo group (β=-.63, p=.002) compared to no

association in the active group (β=.25, p=.35). This cluster is shown on both the inflated (top

row) and pial surfaces (bottom row) of the left hemisphere. The scatterplot shows average

cortical thickness of this cluster on the x-axis and continuous treatment response (i.e., post-

treatment Pediatric Anxiety Rating Scale [PARS] scores, residualized for pre-treatment PARS

scores) on the y-axis for the placebo (green; n=23) and active groups (blue; n=17).

14

Table S1. Structural MRI studies of pediatric anxiety

First Author(Year)

Age range; Mean age

(yrs)

Between subjects compar-

ison

ANXtype

Comorbid dx in ANX group

Method

ROI and/or

WB approach

Associations with anxiety?

PFC Hipp Amyg Insula Other regions

DICHOTOMOUS ANXIETY MEASURE: ANXIOUS VS. NON-ANXIOUS YOUTHS

De Bellis(2000)a

8-16;ANX: 12.7, HV: 12.5

12 ANX vs.

24 HVGAD

MDD, DEP-NOS,

Panic, SoPh

Manual Tracing;

1.5T MRI

ROI only (hipp, amyg, basal ganglia,

temporal lobe, global measures)

n/a n.s↑ R & total amyg

n/a n.s.

De Bellis(2002)a

8-16;ANX: 12.5, HV: 12.0

13 ANX vs.

98 HVGAD

MDD, DEP-NOS,

Panic, SoPh

Manual Tracing;

1.5T MRI

ROI only (STG,

thalamus, PFC, global measures)

n.s. n/a n/a n/a ↑ STG

Jones(2015)

8-18; Epilepsy w/ ANX: 12.1,

Epilepsy w/o ANX:

12.9,HV: 13.2

25 Epilepsy w/ANX;

63 Epilepsy

w/o ANX;49 HV

SP, SAD, SoPh, GAD, ANX-NOS

MDD, ADHD

FS (GMV & CT);

1.5T MRI

ROI only (GMV: amyg,

hipp; CT: medial OFC, lateral OFC, frontal pole)

↓ L vmPFC/medial

OFC,R lateral OFC &

R frontal pole

n.s. ↑ L amyg n/a n/a

Liao(2014)

16-18;ANX: 16.8,

16.9,HV: 16.9,

16.5 b

26 ANX vs.

25 HVGAD None VBM;

3T MRI WB n.s. n.s. n.s. n.s. ↑ R putamen

Milham(2005)

ANX: 12.9, HV: 12.4

17 ANX vs.

34 HV

SoPh, GAD, SAD

MDD VBM;3T MRI

ROI (amyg, ACC, hipp,

OFC) & exploratory

WB

n.s. n.s. ↓ L amyg n.s. n.s.

15

Mueller(2013)

ANX:11.3, 13.7,

HV: 13.5, 13.9c

39 ANX vs.

63 HV

SoPh, GAD, SAD

SP, MDD, ADHD, ODD,Tic dx,

Enuresis

VBM; 3T MRI

ROI only (amyg, hipp, ACC, insula)

n.s. ↓ R ant. hipp.

↓ R amyg

↑ R & L insula n/a

Strawn(2014)d

ANX: 14.0, HV: 14.0

13 ANX vs.

19 HVGAD SoPh, SP

FS (CT);

4T MRIWB

↑ R rostral middle frontal, spanning vmPFC & IFG

n/a n/a n.s. ↑ R occipital, L MTG & L ITG

Strawn(2013)d

10-18; ANX: 13.0, HV: 13.0

15 ANX vs.

28 HVGAD SoPh, SP,

ADHDVBM;

4T MRI WB ↓ L OFC n.s. n.s. n.s.↓ R PCC;

↑ R precuneus, R precentral gyrus

Strawn(2015)

7-19; ANX: 14.4, HV: 14.8

38 ANX vs.

27 HV

GAD, SoPh, SAD

SP, ADHD VBM;3T MRI

WB & ROI (amyg only)

↑ L dACC;↓ L IFG/vlPFC n/a ↓ L & R

amyg. n/a↓ L postcentral

gyrus & L cuneus/precuneus

CONTINUOUS ANXIETY MEASURE IN HV YOUTHS

Ducharme (2014)e

4.9-18.0; 11.9

300 HV w/

anx/dep CBCL sx

n/a n/a

CIVET (CT);1.5T MRI

ROI only (ACC,

sgACC, OFC)

n.s. collapsing across age;

age-by-anx/dep interaction in

R vmPFC(↓ in ages 5-8,

↑ ages 15+)

n/a n/a n/a n/a

Koolschijn(2013) 8-17

179 HV w/CBCL internal-izing sx

n/a n/aFS

(GMV);3T MRI

ROI only (hipp, amyg) n/a ↓ L & Total

hipp. n.s. n/a n/a

aThese studies contain overlapping samples; 12 of the 13 GAD patients in de Bellis et al. (2000) were included in de Bellis et al. (2002).

bMean ages reported separately for male and female subgroups, respectively.

cMean ages reported separately for Met and Val genotype subgroups, respectively.

dThese studies contain overlapping samples; 10 of the 13 GAD patients in Strawn et al. (2014) were included in Strawn et al. (2013).

eResults summarized for Visit 1 data only.

Abbreviations: ACC, anterior cingulate cortex; ADHD, attention-deficit/hyperactivity disorder; ant, anterior; amyg, amygdala; ANX, anxious; ANX-NOS, anxiety disorder not otherwise specified; CBCL, Child Behavior Checklist; CT, cortical thickness; dACC, dorsal anterior cingulate cortex; dep, depressed; DEP-NOS, depressive disorder not otherwise specified; dx, disorder; FS, FreeSurfer; GAD, generalized anxiety disorder; GM, grey matter; GMV, grey matter volume; hipp, hippocampus; HV, healthy volunteers; IFG, inferior

16

frontal gyrus; ITG, inferior temporal gyrus; L, left; MDD, major depressive disorder; MTG, middle temporal gyrus; n/a, not applicable; n.s., non-significant; ODD, oppositional defiant disorder; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PFC, prefrontal cortex; R, right; ROI, region-of-interest; SAD, separation anxiety disorder; sgACC, subgenual anterior cingulate cortex; SoPh, social anxiety disorder; sx, symptoms; STG, superior temporal gyrus; SP, specific phobia; VBM, voxel-based morphometry; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex; WB, whole-brain; w/, with; w/o, without; WM, white matter; yrs, years

17

Table S2. Associations of anxiety subscale severity with subcortical gray matter volumes.a

Continuous associations with anxiety severity (N=108)b

Generalized anxiety Social anxiety

Region Β t p Β t p

Hippocampus

Left -0.15 -1.81 0.07 -0.12 -1.47 0.15

Right -0.20 -2.41 0.017 -0.12 -1.50 0.14

Amygdala

Left -0.12 -1.58 0.12 -0.04 -0.47 0.64

Right -0.10 -1.32 0.19 -0.05 -0.68 0.50

aAnalyses control for controlled for estimated total intracranial volume (ICV) to examine regional GMV (independent of total brain size).bAnxiety severity scores measured by the SCARED (Birmaher et al, 1997) and based on the average of child and parent reports within 60 days of scan; data available for 108 participants (37 HV, 71 anxious).

Abbreviations: Gen, generalized; HV, healthy volunteer; SCARED, Screen for Child Anxiety Related Emotional Disorders; SD, standard deviation.

18

Table S3. Associations of treatment response with subcortical gray matter volumes. a

Continuous treatment response:

Post-treatment anxiety, controlling for baseline anxiety (N=53)

Region Β t p

Hippocampus

Left -0.01 -0.10 0.92

Right -0.02 -0.16 0.88

Amygdala

Left -0.02 -0.17 0.87

Right -0.02 -0.14 0.89

aAnalyses controlled for estimated total intracranial volume (ICV) to examine regional GMV (independent of total brain size).

Abbreviations: HV, healthy volunteer; SD, standard deviation.

19

Table S4. Region-of-interest analysis: Associations of anxiety diagnosis with PFC thickness

Anxiety diagnosis group differences (N=151)

Region

Anxious (N=75) Healthy (N=76) Bootstrapped95% CI β Cohen’s

d t pMean (SD) (mm) Mean (SD) (mm)

L caudal ACC 2.71 (0.17) 2.69 (0.20) -0.21, 0.44 0.12 0.12 0.71 0.48

R caudal ACC 2.68 (0.23) 2.58 (0.20) 0.17, 0.79 0.47 0.48 2.97 0.003

L caudal middle frontal 2.81 (0.14) 2.81 (0.17) -0.30, 0.35 0.02 0.02 0.14 0.89

R caudal middle frontal 2.75 (0.15) 2.75 (0.17) -0.32, 0.32 -0.001 0.001 -0.004 .997

L lateral OFC 2.81 (0.15) 2.76 (0.18) 0.02, 0.64 0.32 0.32 2.00 0.05

R lateral OFC 2.84 (0.16) 2.81 (0.17) -0.14, 0.50 0.18 0.18 1.08 0.28

L medial OFC 2.67 (0.16) 2.62 (0.18) -0.03, 0.60 0.28 0.28 1.72 0.09

R medial OFC 2.64 (0.18) 2.58 (0.16) 0.05, 0.66 0.35 0.36 2.19 0.03

L pars opercularis 2.87 (0.12) 2.84 (0.15) -0.10, 0.52 0.21 0.21 1.31 0.19

R pars opercularis 2.80 (0.15) 2.79 (0.16) -0.31, 0.32 0.01 0.02 0.09 0.93

L pars orbitalis 3.00 (0.20) 2.97 (0.22) -0.21, 0.43 0.12 0.12 0.73 0.46

R pars orbitalis 3.01 (0.22) 2.93 (0.23) 0.08, 0.70 0.38 0.38 2.34 0.02

L pars triangularis 2.74 (0.17) 2.70 (0.14) -0.05, 0.58 0.26 0.26 1.60 0.11

R pars triangularis 2.69 (0.16) 2.69 (0.17) -0.29, 0.34 0.03 0.03 0.18 0.86

L rostral ACC 3.03 (0.25) 2.96 (0.24) -0.01, 0.62 0.29 0.29 1.81 0.07

R rostral ACC 3.04 (0.25) 2.99 (0.25) -0.15, 0.50 0.17 0.17 1.07 0.29

L rostral middle frontal 2.67 (0.16) 2.64 (0.15) -0.11, 0.52 0.21 0.21 1.31 0.19

R rostral middle frontal 2.61 (0.16) 2.60 (0.17) -0.24, 0.40 0.09 0.09 0.53 0.60

L superior frontal 3.06 (0.15) 3.01 (0.15) 0.02, 0.66 0.34 0.34 2.10 0.04

R superior frontal 3.00 (0.17) 2.98 (0.15) -0.17, 0.46 0.15 0.15 0.94 0.35

L frontal pole 3.09 (0.30) 3.09 (0.33) -0.35, 0.29 -0.03 0.03 -0.18 0.86

R frontal pole 3.00 (0.29) 3.02 (0.27) -0.38, 0.27 -0.05 0.05 -0.29 0.77

L insula 3.26 (0.14) 3.20 (0.15) 0.05, 0.69 0.37 0.38 2.33 0.02

R insula 3.17 (0.15) 3.13 (0.17) -0.04, 0.60 0.28 0.28 1.74 0.08

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Table S5. Region-of-interest analysis: Associations of anxiety severity with PFC thickness

RegionBootstrapped

95% CI β t p

L caudal ACC -0.19, 0.19 -0.001 -0.01 0.99

R caudal ACC -0.07, 0.27 0.09 0.97 0.33

L caudal middle frontal -0.25, 0.14 -0.06 -0.60 0.55

R caudal middle frontal -0.24, 0.19 -0.03 -0.32 0.75

L lateral OFC -0.20, 0.19 -0.02 -0.20 0.85

R lateral OFC -0.29, 0.09 -0.10 -1.08 0.28

L medial OFC -0.20, 0.19 -0.01 -0.11 0.91

R medial OFC -0.19, 0.17 -0.02 -0.17 0.87

L pars opercularis -0.27, 0.14 -0.06 -0.66 0.51

R pars opercularis -0.30, 0.10 -0.09 -0.98 0.33

L pars orbitalis -0.24, 0.16 -0.05 -0.51 0.61

R pars orbitalis -0.14, 0.20 0.02 0.17 0.87

L pars triangularis -0.28, 0.10 -0.09 -0.97 0.34

R pars triangularis -0.30, 0.08 -0.10 -1.08 0.28

L rostral ACC -0.19, 0.15 -0.01 -0.14 0.89

R rostral ACC -0.13, 0.21 0.04 0.37 0.72

L rostral middle frontal -0.25, 0.13 -0.06 -0.66 0.51

R rostral middle frontal -0.30, 0.08 -0.13 -1.31 0.19

L superior frontal -0.19, 0.20 0.01 0.13 0.90

R superior frontal -0.21, 0.17 -0.01 -0.14 0.89

L frontal pole -0.29, 0.12 -0.08 -0.86 0.39

R frontal pole -0.36, 0.002 -0.18 -1.84 0.07

L insula -0.14, 0.23 0.03 0.36 0.72

R insula -0.10, 0.27 0.07 0.77 0.44

21