functional dysconnectivity of the inferior frontal gyrus in young … · 2017. 3. 17. · head...

Roberts et al. Supplement

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Functional Dysconnectivity of the Inferior Frontal Gyrus in Young People with Bipolar Disorder or at Genetic Risk

Supplemental Information

Supplemental Methods & Materials

Participants

Subjects comprised three groups, all aged between 16 and 30 years: 1) 71 participants ‘at-

risk’ (AR) for bipolar disorder who were children or siblings of a proband with a confirmed

DSM-IV diagnosis of bipolar I or II disorder, but who did not themselves have this condition;

2) 80 matched controls (CON) defined as subjects with no parent or sibling with bipolar I or

II disorder, recurrent major depression, schizoaffective disorder, schizophrenia, recurrent

substance abuse or any past psychiatric hospitalisation; and no parent with a first degree

relative who had a past mood disorder hospitalisation or history of psychosis; and 3) 49

bipolar disorder participants (BD) who met DSM-IV criteria for either bipolar (I or II)

disorder (28 Bipolar I, 21 Bipolar II). More detailed clinical findings on these groups have

been recently reported (1), as have differences in polygenic risk scores (2).

A lifetime history of a psychiatric disorder in a parent or sibling was an exclusion

criterion for our CON group. However, the history of a major depressive or anxiety episode

in the subjects themselves was not an exclusion criterion: Our CON group thus contained

individuals with lifetime non-bipolar psychiatric diagnoses. This ecological design avoids

contrasts of high-risk groups against “super-healthy” controls which preclude disambiguation

of any group differences due to the underlying genetic risk from differences due to these co-

morbid diagnoses. We undertook extensive post-hoc analyses to quantify the possible

influence of these factors on any group differences.


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Of the 71 AR participants, 76.6% had a parent with BD and 23.4% a sibling with BD.

Control subjects were recruited via print and electronic media, and noticeboards in

universities and local communities. Notably, the lifetime or current presence of psychiatric

symptoms (including depression) – apart from the occurrence of bipolar disorder - in either

AR or control subjects was not an exclusion factor. This ecological approach has been used

by similar studies of individuals at high genetic risk for bipolar disorder (3).

Participants were drawn from an ongoing longitudinal study of at-risk individuals

aged 12-30 years. The Australian subjects aged 12-21 years are involved in a collaborative

clinical and genetic high-risk study with four US campuses: Indiana University, Johns

Hopkins University, Washington University in St. Louis, and Michigan University (3). As

this US-Australian collaboration involves common assessments for participants aged 12-21

years, we report separately on instruments used for the younger (16-21 years) and older (22-

30 years) age groups in this sample. Both groups shared consensus Best-Estimate DSM-IV

current and lifetime diagnoses derived from semi-structured diagnostic interviews.

Neuroimaging was only undertaken on the Australian sample.

The study was conducted with approval from the University of New South Wales

Human Research Ethics Committee (HREC Protocol 09/097) and the South Eastern Sydney

Illawarra Health Service HREC (Protocol 09/104). Written informed consent was obtained

from all participants.

Clinical and Neuropsychiatric Assessment

The BD proband consensus DSM-IV diagnosis was determined by two independent raters

(Drs Mitchell and Chan) following Best Estimate methodology,(4) using information from

the Diagnostic Interview for Genetic Studies (DIGS) Version 4 (5), the Family Interview for

Genetic Studies (FIGS) (6), and medical records (where available). Structured diagnostic


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interviews were also performed on all AR, control and BD participants. For those aged

between 16 and 21 (AR, n = 23; CON, n = 19; BD, n = 9), an adapted version of the Schedule

for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime

Version (K-SADS-BP) was developed specifically for use in the US-Australia collaborative

study of young people at genetic risk for bipolar disorder (3). The K-SADS-BP combines

items from the K-SADS Present and Lifetime Version (7) and uses extended sections on

depression, mania and attention-deficit/hyperactivity disorder (ADHD) derived from the

Washington University in St Louis K-SADS (WASH-U K-SADS) (8) to elicit detailed

information on pre-pubertal mania, rapid-cycling, attentional and sub-threshold bipolar

symptoms. The KSADS-BP was administered to both the child and one parent (9). For

participants aged between 22 and 30 years (AR, n = 48; CON, n = 61; BD, n = 40), the DIGS

(Version 4) was used to measure the current and lifetime presence of axis I DSM-IV

disorders. Participants aged between 22 and 30 years also completed the Global Assessment

Scale (GAS) as a measure of overall functioning (10). As for the probands, consensus DSM-

IV diagnoses of the AR, BD and control subjects were determined by two independent raters

(two of Drs Mitchell, Levy, Lenroot and Chan) with Best Estimate methodology,(4) using the

K-SADS-BP or DIGS, the FIGS and medical records (where available).

To determine current depressive mood state for those aged between 16 and 21, the

Children’s Depression Inventory (CDI) (11) was administered. For participants aged 22-30

years, the Montgomery-Asberg Depression Rating Scale (MADRS) (12) was used. IQ was

assessed with the Wechsler Abbreviated Scale of Intelligence (WASI) (13).


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Imaging Acquisition and Preprocessing

Imaging Acquisition

Imaging data were acquired on a 3-T Philips Achieva scanner equipped with an 8-channel

head coil. During acquisition of the resting-state fMRI data, participants were asked to lie

quietly in the scanner with their eyes closed. Functional images were collected using a T2*

weighted echo-planar imaging sequence (TE = 30 ms, TR = 2000 ms, flip angle = 90º, FOV

250 mm, 136 x 136 mm matrix size in Fourier space) and consisted of twenty-nine

contiguous 4.5 mm axial slices (no gap) covering the entire brain. Structural imaging

consisted of 188 T1-weighted anatomic 3D turbo field-echo sagittal images (voxel size 1 x 1

x 1), acquired to allow subsequent spatial normalization.

Image Preprocessing

fMRI data were preprocessed in MATLAB R2012b using SPM8 (14). Functional blood

oxygen level-dependent (BOLD) scans were realigned to the first scan of each, unwarped and

co-registered to the anatomical T1 image. The structural image and co-registered BOLD

images were then spatially normalized into standard Montreal Neurological Institute (MNI)

space (MNI/CBM avg 152 T2* template). The BOLD images were re-sampled into 3×3×3

mm isotropic voxels, and smoothed with a 4mm Gaussian kernel. The functional data were

corrected for white matter and cerebrospinal fluid signal. Global signal regression was not

performed unless otherwise stated. All participants had head movement of < 5mm translation

and 5 degrees rotation. Separate two sided t-tests were performed to check for differences in

head motion between the three groups (AR:CON, BD:AR, BD:CON). There were no

significant differences for total head translation - i.e. the maximum minus the minimum

position (p = 0.77, 0.40, 0.51), or total head rotation (p = 0.62, 0.83, 0.52).We repeated

analysis of our main effect - the contrast between BD and CON participants (Figure 1A) -


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including total head translation and rotation as covariates: Our between-group difference

remained significant (Wald χ2 = 37.61, df = 2, CON > BD group p =< 0.001, total translation

p => 0.89, total rotation p =< 0.50; see methods).

Inferior Frontal Gyrus Region and Whole Brain Parcellation

Inferior Frontal Gyrus

In this report, we focus on the functional connectivity of the left IFG. To construct a local

IFG gray matter parcel, we used a contrast reported in our previous analysis of AR and CON

participants performing an emotional Go-NoGo task (15). The BD group reported in the

current study are a new cohort whereas, the AR and CON participants that were included in

our previous analysis are also included in the current analysis. Briefly, participants viewed a

series of faces displaying fearful, happy, and calm (neutral) faces in blocks and were asked to

execute a button press response to faces that showed the target emotion for that block. Target

emotions cycled between fearful, happy and calm. For successful trials a between-group

contrast of Fear Distractors (fearful faces present in a calm block) minus Fear Targets (fearful

faces present in a fear block) comparing BD at-risk participants to matched controls revealed

a robust between-group effect in the left IFG. This effect – associated with inhibiting a motor

response to the perception of a fearful face - was expressed in a single contiguous cluster that

extended from the left IFG into the adjacent cortex, principally portions of the anterior insula,

orbitofrontal cortex and putamen (Figure S1 and Table S1).


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Figure S1. Left IFG Cluster. Between-group (CON > AR) contrast of fear distractors minus fear targets in emotion go-nogo task (BA 47; Height p < 0.005, FWE corrected and cluster-level p < 0.024 FWE corrected; cluster size =107 voxels; Montreal Neurological Institute peak voxel coordinates: x = -21, y = 11; z = -17). This cluster was used as the IFG ROI in the present study. Whole Brain Parcellation

This left IFG cluster contained 107 voxels. We then parcellated the remaining gray matter

voxels into contiguous regions of approximately the same volume as this ROI. This was

achieved by successively subdividing the AAL parcellation (which contains 90 ROIs of

highly varying volumes) into some 512 regions of approximately uniform volume using the

algorithm of Zalesky et al (16). The center of mass co-ordinates and parcellation labels for

these regions are provided in Table S2.


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Network Analyses Using NBS, Network Metrics, and Machine Learning on Functional

Connectivity rs-fMRI

Network-Based Statistic

NBS is a permutation-based method to control family-wise error (FWE) when mass-

univariate testing is performed across multiple edges in a network, and exploits the extent to

which the edges comprising the contrast are topologically connected. Here we tested for

group differences in the strength of functional connectivity between the left IFG and each of

the other 512 gray matter parcels (hence a single column of the functional connectivity

matrix). NBS is traditionally employed to detect subnetwork differences from within a larger,

connected (NxN) network. Here we focus on subnetworks that all derive from the left IFG

seed - hence our focus is on subnetworks that differ from within a 1xN network. Practically,

this is achieved simply by setting all rows and columns to zero except for the single row and

column corresponding to the seed node. NBS is able to infer statistical differences using the

same principles in this setting.

NBS is based on the principles underpinning traditional cluster-based thresholding of

statistical parametric maps and hence proceeds with a preliminary height threshold (pair-wise

connections) followed by a FWE-corrected cluster threshold (topological subnetworks of

connections). We first used an omnibus F-test with a height threshold of 7.5 followed by a

FWE corrected p < 0.05. We then used a t-statistic (absolute value) of 3.75 as our height

threshold, followed by a conservative FWE corrected p < 0.05 for our one-sided pair-wise

contrasts. These are presented in Figure 1A,B. The omnibus tests are essentially the

conjunctions of the individual t-tests: For the purposes of redundancy, these are not shown.

Whilst the focus of the present study was on functional connectivity of the left IFG,

we also undertook a whole-brain network-based analysis. A whole brain omnibus F-test was

first performed with a height threshold of 9.5 followed by a FWE corrected p < 0.05. We then


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performed one-sided paired t-tests with a height threshold of 4.25 followed by a FWE

corrected p < 0.05. These are presented in Figure 1 C,D.

To test for the possible effect of mood, Pearson’s correlations were then calculated

between the average of the functional connections presented in Figure 1A-D and current

mood state (as detailed in Clinical and Neuropsychiatric Assessment, above) for each group

separately. To investigate if the association between our functional subnetworks presented in

Figure 1A-D and diagnostic category were influenced by depressive mood state, generalized

estimating equations (GEE) (17) - which accommodate within-family correlations - were

performed with current mood state included as a mean-centred covariate. Because current

mood state was assessed by different instruments in younger and older age ranges, each

model was run separately for the younger and older age groups. In the whole-sample a second

set of GEE models that included an age x group interaction were run using the average of the

functional connections presented in Figure 1A-D as the dependant variable. An additional

GEE analysis was also carried out in the whole-sample with global signal included as a

mean-centred covariate to investigate if the average of the 17 functional connections

presented in Figure 1A was influenced by global signal. All GEE analyses (for total sample,

younger only, and older only) included age and gender as covariates. All reported p-values

are Wald chi-square statistics and all post hoc tests are Šidák tests from the GEE analysis.

Graph Theoretical Analysis: Network Metrics

We characterized the local topology of the left IFG using three metrics: 1) The path length

(PL), a global measure which captures the average distance (the number of edges weighted

by the strength of those edges) between our left IFG ROI and all other regions; 2) The

participation index (PI) first requires functional connectivity to be decomposed into an

optimal set of modules (tightly connected subnetworks). The PI is then defined as the ratio of


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connections inside the module to which the IFG belongs to connections outside the module;

3) The clustering coefficient (CC) captures the tendency of nodes to form local cliques.

Estimation of the PL and CC require a sparse matrix (18-20). We thresholded the functional

connectivity matrices at 12% sparsity, a choice which has been widely used in previous

studies, yielding robust estimates of network topology whilst eliminating the influence of

weak, noise dominated connections (21, 22). All metrics were calculated using the brain

connectivity toolbox (BCT: http://www.brain-connectivity-toolbox.net/). Mathematical

definitions of these selected graph metrics are provided in Table S3.

Graph Theoretical Analysis: Statistical Evaluation

GEEs (17) were also used to accommodate within-family correlations when assessing the

association between diagnostic category and the network metrics. All reported p-values are

Wald chi-square statistics and all post hoc tests are Šidák tests from the GEE analysis.

To investigate if the association between our network metrics and diagnostic category

was influenced by depressive mood state, all GEE analyses were also carried out with current

mood state included as a mean-centred covariate (as detailed for ‘Network-based statistic’

above). Each model was run separately for the younger and older age groups as current

mood state was assessed by different instruments in younger and older age ranges. Age x

group interactions were also assessed in the total sample (as detailed for ‘Network-based

statistic’ above).

Classification Using Machine Learning

Multi-class support vector classification was carried out using a ‘one-against-one’ approach,

where the appropriate class for each subject was assigned by identifying the class yielding the

http://www.brain-connectivity-toolbox.net/)


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highest confidence in any of the tests. Classification was carried out in R using the ‘caret’

package (23-25).

We assessed the accuracy of these techniques by splitting our data into training and

testing sets, with half the data in each. Feature reduction was achieved by identifying the

most salient features through recursive feature elimination on the training set. The resulting

features were then used to train one support vector classifier. We recorded the accuracy of the

trained classifiers on the testing set. As small data sets have an increased chance of

producing highly variable results based on the data used to train and test (26), a technique

known as bagging was used. Bagging requires analyses to be run multiple times; in this study

1000 repetitions were performed, which has been shown to be highly resilient to effects of

sample size (27). Statistics are derived from the mean and standard deviation of all 1000

classifiers. The positive predictive value (PPV) is the ratio of the true positives to all positive

classifications (true and false positives). The negative predictive value (NPV) is the ratio of

the true negatives to all negatives classifications (true and false negatives). Note that due to

different numbers of participants in each of the three groups, the background (chance)

accuracy is 40.8% (not 33%).

Post-Hoc Analyses on Functional Subnetworks Identified in Figure 1 A-D, and Clustering

Coefficient

As rates of non-bipolar psychopathology were significantly higher in the AR compared to the

CON group (Table 1), a secondary analysis was performed in order to determine whether

non-bipolar psychopathology influenced our results. Within the AR group, using multiple

linear regressions, diagnosis of at least one depressive episode (n = 23) and anxiety (n = 19)

were included as predictors, along with age and gender.


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Within the BD group, current use of lithium, mood stabilizers, antipsychotics, and

antidepressants were included as predictors, along with age and gender, using multiple linear

regressions. Similarly, within the AR group in a linear regression current use of anti-

depressants was included as a predictor, along with age and gender.

As an additional check, we also divided each of our 3 groups into subgroups with and

without lifetime diagnoses of a depressive episode or anxiety disorder. For the functional

networks that differed between the main groups (AR, BP, CON), we then used GEE to

perform subgroup contrasts within each group. We additionally repeated our analyses after

including lifetime diagnoses of any major depressive and/or anxiety disorders as regressors of

no interest in our GEE models.

Given the inclusion of siblings from within the same family, generalized estimating

equations were used for all post hoc analyses. Separate models predicted each functional

network identified in Figure 1 A-D, and clustering coefficient.

Supplemental Results

Demographic and Clinical Data

The three groups did not significantly differ on age, IQ, or gender distribution (see Table 1).

BD subjects had higher depression symptom severity scores (MADRS) than both the AR and

control participants, with no significant differences between the latter two groups. At the time

of testing, no participants in any of the three groups met DSM-IV criteria for a current

episode of major depression or mania/hypomania. Consistent with prior reports of at-risk

populations (3, 28), the lifetime occurrence of any lifetime affective disorder (including a

major depressive episode) was significantly greater in the AR group (p < 0.001) compared to

the control group. Rates of any lifetime anxiety disorder (p < 0.001) were also significantly


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higher in the BD disorder group, compared to both the AR and the control participants. There

was also a significant difference between the latter two groups (p < 0.001). Furthermore,

rates of any lifetime behavioral disorder (p < 0.05) and any lifetime substance disorder (p <

0.01) were significantly higher in the BD group, compared to both the AR and the control

participants.

Psychotropic Medication

At the time of testing, 9 (12.9%) AR participants and 2 (2.5%) control participants were

currently taking psychotropic medication (all antidepressants). Thirty-six (73.5%) BD

participants were currently taking psychotropic medication. Among them, 30 (61.2%) were

taking a mood stabilizer (6 were taking lithium, 16 were taking another mood stabilizer, and

8 were taking lithium in addition to another mood stabilizer). Sixteen (33.3%) BD

participants were taking an antipsychotic, twelve of whom were also taking a mood stabilizer.


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Table S1. Inferior Frontal Gyrus Voxels

Region Brodmann area x y z

Left Superior Temporal Pole 34 -21 5 -23


Left Orbi ta l Inferior Fronta l Gyrus -18 8 -23


Left Orbi ta l Inferior Fronta l Gyrus + 28 -24 8 -23



Left Superior Temporal Pole -21 5 -20




Left Orbi ta l Inferior Fronta l Gyrus + -24 8 -20

Left Orbi ta l Inferior Fronta l Gyrus 47 -18 11 -20


Left Insula 47 -24 11 -20




Left Ol factory Cortex 34 -18 5 -17



Left Ol factory Cortex -18 8 -17




Left Gyrus Rectus -18 11 -17


Left Superior Fronto-Orbi ta l Gyrus -24 11 -17

Left Gyrus Rectus 13 -18 14 -17



Left Insula -27 14 -17

Left Inferior Fronto-Orbi ta l Gyrus -21 17 -17

Left Inferior Fronto-Orbi ta l Gyrus -24 17 -17





Left Superior Temporal Pole -42 5 -14












Left Gyrus Rectus 13 -18 14 -14

MNI Coordinates


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⁺ denotes cases where the nearest Automated Anatomical Label (AAL) (29) label was used as coordinates gave no corresponding AAL in WFU PickAtlas (30).


Left Superior Fronto-Orbi ta l Gyrus -24 14 14




Left Insula + -33 -1 -11

Left Insula + -30 2 -11



Left Putamen -24 5 -11

Left Insula+ -27 5 -11









Left Putamen+ -27 8 -11






































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Region x y z Region x y z Region x y z

1 Left Medial Cingulate Gyrus -13.18 -41.34 47.24 172 Left Supramarginal Gyrus -55.48 -41.97 38.55 343 Right Middle Frontal Gyrus⁺ 45.00 2.00 61.00

2 Lentiform Nucleus⁺ -25.81 -12.26 -5.61 173 Left Middle Frontal Gyrus -34.68 38.52 44.52 344 Right Middle Occipital Gyrus 32.03 -80.23 22.19

3 Left Postcentral Gyrus -58.39 -16.61 35.58 174 Left Middle Occipital Gyrus -30.71 -88.32 5.06 345 Right Precuneus 16.12 -60.39 23.79

4 Left Superior Occipital Gyrus -16.39 -90.55 20.03 175 Left Supramarginal Gyrus -36.97 -53.45 40.55 346 Right Orbital Inferior Frontal Gyrus 36.22 20.06 -21.85

5 Left Postcentral Gyrus -66.00 -16.00 19.00 176 Left Precentral Gyrus -21.00 -16.00 79.00 347 Right Postcentral Gyrus 45.32 -35.81 66.87

6 Left Superior Parietal Gyrus -17.74 -56.35 43.71 177 Left Superior Parietal Gyrus -32.29 -50.71 55.26 348 Right Superior Temporal Gyrus (a)ₐ 71.74 -13.06 0.20

7 Left Thalamus -16.13 -34.77 6.84 178 Left Middle Temporal Gyrus -46.58 -55.03 6.39 349 Right Middle Frontal Gyrus 42.39 42.03 29.68

8 Left Angular Gyrus -39.71 -64.68 36.00 179 Left Superior Frontal Gyrus -6.19 10.65 61.52 350 Right Inferior Temporal Gyrus 47.30 -74.76 -7.11

9 Left Middle Occipital Gyrus -33.97 -72.74 0.94 180 Left Superior Frontal Gyrus -15.00 44.00 52.00 351 Right Postcentral Gyrus 26.65 -32.03 80.45

10 Left Superior Temporal Pole -27.00 5.00 -26.00 181 Left Calcarine Fissure -9.84 -90.77 -1.65 352 Right Superior Frontal Gyrus⁺ 21.00 35.00 58.00

11 Left Putamen -23.19 1.06 6.87 182 Left Superior Parietal Gyrus -21.23 -70.61 53.13 353 Right Precental Gyrus 60.74 5.06 20.39

12 Left Putamen -30.00 -19.00 -2.00 183 Left Medial Cingulate Gyrus -10.60 -7.99 49.61 354 Right Middle Temporal Gyrus 69.77 -14.97 -10.16

13 Left Supramarginal Gyrus -42.35 -44.53 49.54 184 Left Cingulate Gyrus⁺ -11.42 24.32 29.87 355 Right Middle Temporal Gyrus 46.65 -73.97 12.39

14 Left Caudate -15.57 8.67 18.65 185 Left Superior Parietal Gyrus -30.84 -47.65 69.87 356 Right Cingulate Gyrus 11.46 -0.71 44.98

15 Left Superior Frontal Gyrus -5.97 -1.29 73.42 186 Left Precentral Gyrus -26.29 -27.19 61.87 357 Right Superior Parietal Gyrus 39.48 -57.46 64.35

16 Left Postcentral Gyrus -42.45 -44.84 59.90 187 Left Inferior Frontal Gyrus⁺ -62.42 13.39 28.61 358 Right Middle Occipital Gyrus 45.29 -72.14 26.98

17 Left Middle Temporal Gyrus -56.71 -58.65 5.29 188 Left Lingual Gyrus ⁺ -22.71 -58.58 0.58 359 Right Middle Orbitofrontal Gyrus 11.81 61.55 -1.68

18 Left Middle Frontal Gyrus⁺ -48.00 50.00 19.00 189 Left Postcentral Gyrus⁺ -45.10 -19.71 23.06 360 Right Rolandic Operculum 64.91 -12.11 11.66

19 Left Fusiform Gyrus -40.12 -55.22 -11.29 190 Left Middle Temporal Gyrus -44.26 -53.94 20.16 361 Right Postcentral Gyrus 24.26 -37.80 75.62

20 Left Putamen -21.00 20.00 1.00 191 Left Middle Orbitofrontal Gyrus -7.60 53.10 -10.81 362 Right Angular Gyrus 53.10 -61.32 45.39

21 Left Middle Temporal Gyrus -69.13 -26.94 -2.10 192 Left Middle Temporal Pole -47.20 9.98 -29.99 363 Right Supramarginal Gyrus 68.61 -25.48 32.03

22 Left Rolandic Operculum -58.87 1.03 6.74 193 Left Middle Temporal Gyrus -52.88 -58.35 20.69 364 Right Superior Parietal Gyrus 25.68 -52.48 59.26

23 Left Middle Temporal Gyrus -49.74 -24.52 -16.19 194 Left Superior Temporal Gyrus⁺ -42.58 3.29 -25.19 365 Right Paracentral Lobule 14.00 -25.68 58.90

24 Left Precentral Gyrus -36.26 -24.52 60.87 195 Left Superior Frontal Gyrus -24.61 64.87 8.37 366 Right Superior Orbitofrontal Gyrus 15.94 35.23 -16.19

25 Left Middle Temporal Gyrus -56.43 -54.43 -4.11 196 Left Superior Temporal Gyrus (b)ₐ -62.87 -26.42 7.48 367 Right Insula 41.68 -1.03 3.39

26 Left Medial Cingulate Gyrus -6.81 -40.61 33.94 197 Left Superior Frontal Gyrus -31.55 -5.23 68.77 368 Right Superior Temporal Pole 36.54 25.84 -28.20

27 Left Putamen -13.21 14.55 -4.84 198 Left Insula -31.29 21.52 4.29 369 Right Inferior Frontal Gyrus⁺ 38.62 30.18 13.10

28 Left Inferior Frontal Gyrus/ Pars Opercularis -61.06 11.84 7.42 199 Left Postcentral Gyrus -53.16 -20.55 20.13 370 Right Middle Orbitofrontal Gyrus 43.13 49.23 -8.68

29 Left Superior Temporal Pole -41.23 21.06 -31.03 200 Left Middle Frontal Gyrus⁺ -57.00 11.00 43.00 371 Right Insula 33.00 5.00 8.00

30 Left Precuneus -10.16 -72.29 52.32 201 Left Lateral Ventricle ⁺ -15.77 24.44 14.63 372 Right Heschls Gyrus 51.35 -18.45 8.13

31 Left Precentral Gyrus -19.71 -20.90 73.26 202 Left Claustrum⁺ -28.47 -0.01 16.00 373 Right Superior Frontal Gyrus 16.81 -12.29 76.35

32 Left Middle Frontal Gyrus -46.32 32.06 34.58 203 Left Middle Frontal Gyrus -42.00 23.00 40.00 374 Right Rolandic Operculum 43.81 -13.81 17.52

33 Left Postcentral Gyrus -41.68 -23.88 49.10 204 Left Middle Frontal Gyrus -51.52 25.74 38.68 375 Right Orbital Inferior Frontal Gyrus 32.29 34.94 -8.45

34 Left Superior Parietal Gyrus -22.61 -48.55 73.55 205 Left Precuneus⁺ -21.00 -49.00 31.00 376 Right Middle Frontal Gyrus⁺ 55.58 41.23 22.81

35 Left Middle Temporal Gyrus -56.06 6.00 -25.97 206 Left Superior Temporal Pole -46.32 19.77 -22.06 377 Right Middle Frontal Gyrus 36.00 50.00 31.00

36 Left Medial Superior Frontal Gyrus -11.74 70.29 -1.00 207 Left Inferior Frontal Gyrus/ Pars Triangularis -40.81 32.52 6.55 378 Right Hippocampus 35.52 -27.90 -8.26

37 Left Middle Frontal Gyrus -26.81 22.00 60.10 208 Left Lingual Gyrus⁺ -15.55 -75.13 -0.90 379 Right Middle Temporal Gyrus 53.10 -65.52 12.90

38 Left Supramarginal Gyrus -32.52 -70.52 42.10 209 Left Middle Frontal Gyrus -30.00 14.00 64.00 380 Right Middle Orbitofrontal Gyrus 32.90 56.67 -5.89

39 Left Postcentral Gyrus -49.19 -16.48 49.00 210 Left Inferior Frontal Gyrus/ Pars Triangularis -49.65 44.23 4.48 381 Right Inferior Frontal Gyrus/Pars Triangularis 56.03 25.68 9.32

40 Left Middle Frontal Gyrus -42.00 38.00 48.00 211 Left Middle Orbitofrontal Gyrus -22.90 35.10 -17.74 382 Right Supramarginal Gyrus 68.74 -27.55 23.00

41 Left Middle Frontal Gyrus -34.97 28.52 39.32 212 Left Precuneus -11.00 -44.10 77.90 383 Right Middle Occipital Gyrus 31.47 -80.88 34.48

42 Left Precentral Gyrus -52.13 -0.90 44.29 213 Left Thalamus -13.39 -19.81 5.29 384 Right Superior Orbitofrontal Gyrus 30.00 62.00 -2.00

43 Left Middle Temporal Pole -32.07 6.98 -35.80 214 Left Middle Frontal Gyrus⁺ -33.00 35.00 52.00 385 Right Postcentral Gyrus 64.32 -5.71 40.81

44 Left Precuneus -11.84 -61.29 53.90 215 Left Precuneus -14.36 -51.27 33.43 386 Right Middle Temporal Gyrus 57.10 -7.48 -16.74

45 Left Middle Temporal Gyrus -64.56 -39.94 -5.38 216 Left Paracentral Lobule -10.42 -30.39 66.16 387 Right Cingulate Gyrus 13.82 -18.17 43.54

46 Left Medial Superior Frontal Gyrus -7.00 44.16 50.35 217 Left Precuneus -15.94 -58.23 68.58 388 Right Inferior Temporal Gyrus 45.13 -6.49 -28.59

47 Left Inferior Frontal Gyrus/ Pars Triangularis -41.90 20.57 3.94 218 Left Medial Superior Frontal Gyrus -9.00 68.00 13.00 389 Right Superior Frontal Gyrus 16.06 26.35 52.23

48 Left Precuneus -7.23 -43.52 63.42 219 Left Superior Occipital Gyrus -17.16 -71.55 28.29 390 Right Calcarine Fissure 11.84 -90.27 6.11

49 Left Hippocampus -26.04 -11.69 -18.53 220 Left Postcentral Gyrus -51.70 -7.89 54.30 391 Right Middle Temporal Gyrus 51.00 -49.00 -2.00

50 Left Medial Cingulate Gyrus -6.57 -32.34 47.21 221 Left Gyrus Rectus -11.10 25.58 -11.71 392 Right Superior Frontal Gyrus⁺ 25.84 60.65 32.84

51 Left Medial Superior Frontal Gyrus -10.84 58.84 19.13 222 Left Superior Frontal Gyrus -15.00 59.00 37.00 393 Right Superior Frontal Gyrus 21.61 -2.87 73.29

52 Left Middle Frontal Gyrus -35.52 45.84 13.06 223 Left Precentral Gyrus -45.58 -3.45 60.26 394 Right Superior Frontal Gyrus 21.71 -1.97 62.65

53 Left Parahippocampal Gyrus -20.04 8.30 -23.66 224 Left Calcarine Fissure -4.91 -75.43 14.95 395 Right Middle Occipital Gyrus⁺ 30.00 -73.00 4.00

54 Left Inferior Frontal Gyrus/ Pars Opercularis -47.68 12.68 12.61 225 Left Middle Temporal Gyrus -55.60 -16.93 -19.97 396 Right Middle Frontal Gyrus⁺ 54.00 20.00 43.00

55 Left Superior Frontal Gyrus -13.71 42.06 42.26 226 Left Medial Superior Frontal Gyrus -7.03 68.19 24.45 397 Right Inferior Frontal Gyrus⁺ 52.87 -1.52 20.29

56 Left Middle Frontal Gyrus -24.71 47.03 47.13 227 Left Anterior Cingulate Cortex⁺ -7.32 34.81 -2.84 398 Right Inferior Temporal Gyrus 45.00 -52.00 -8.00

57 Left Middle Occipital Gyrus -27.39 -88.58 16.42 228 Left Superior Frontal Gyrus -27.00 59.00 28.00 399 Right Cingulate Gyrus⁺ 14.23 24.76 41.63

MNI Coordinates MNI Coordinates MNI Coordinates

Table S2. Center of Mass and Parcellation Labels


16

58 Left Supramarginal Gyrus -60.00 -22.00 46.00 229 Left Middle Frontal Gyrus -36.39 50.81 20.81 400 Right Supramarginal Gyrus 57.87 -51.68 43.32

59 Left Middle Frontal Gyrus -26.10 7.48 59.32 230 Left Inferior Frontal Gyrus/ Pars Triangularis -55.47 26.89 28.45 401 Right Postcentral Gyrus 48.00 -31.00 64.00

60 Left Lingual Gyrus -15.22 -85.26 -5.89 231 Left Medial Superior Frontal Gyrus -7.87 33.97 57.16 402 Right Superior Temporal Gyrus (b)ₐ 51.00 11.00 -5.00

61 Left Rolandic Operculum -45.90 1.29 5.16 232 Left Middle Frontal Gyrus⁺ -36.00 62.00 16.00 403 Right Precuneus 11.26 -56.74 29.13

62 Left Supramarginal Gyrus -46.94 -37.00 23.65 233 Left Cuneus -8.71 -91.16 14.55 404 Right Medial Superior Frontal Gyrus 15.87 46.48 0.42

63 Left Inferior Temporal Gyrus -45.00 -37.00 -14.00 234 Left Calcarine Fissure -13.03 -57.29 9.16 405 Right Precentral Gyrus⁺ 16.90 -25.87 81.81

64 Left Postcentral Gyrus -60.77 -4.35 31.16 235 Left Superior Frontal Gyrus -9.10 18.55 61.06 406 Right Inferior Temporal Gyrus 68.42 -40.74 -16.19

65 Left Middle Occipital Gyrus -25.24 -66.68 35.76 236 Left Superior Frontal Gyrus -9.00 10.74 73.97 407 Right Superior Orbitofrontal Gyrus 20.48 62.87 -7.42

66 Left Thalamus -14.06 -19.23 16.48 237 Left Superior Frontal Gyrus -18.00 20.00 64.00 408 Right Inferior Frontal Gyrus/ Pars Opercularis 46.87 15.52 33.55

67 Left Middle Frontal Gyrus -38.13 13.74 53.55 238 Left Inferior Occipital Gyrus -26.06 -87.03 -5.00 409 Right Superior Temporal Gyrus 45.00 -16.00 -11.00

68 Left Precentral Gyrus -62.17 1.07 24.23 239 Left Superior Parietal Gyrus -32.42 -67.71 51.58 410 Right Superior Temporal Gyrus 65.39 -50.81 21.74

69 Left Superior Frontal Gyrus⁺ -45.00 14.00 55.00 240 Left Superior Temporal Gyrus -59.33 0.63 -13.74 411 Right Superior Frontal Gyrus 15.00 62.00 34.00

70 Left Inferior Temporal Gyrus -51.57 -43.22 -16.36 241 Left Precuneus -18.42 -46.45 0.10 412 Right Inferior Frontal Gyrus⁺ 57.00 23.00 -11.00

71 Left Middle Temporal Gyrus -62.29 -44.97 -0.13 242 Left Middle Frontal Gyrus⁺ -36.03 61.48 8.97 413 Right Inferior Frontal Gyrus/Pars Triangularis 60.00 35.00 10.00

72 Left Precentral Gyrus -40.45 -12.13 67.16 243 Left Superior Temporal Gyrus -66.32 -38.10 11.10 414 Right Superior Frontal Gyrus 16.06 41.00 29.65

73 Left Inferior Frontal Gyrus/ Pars Triangularis -54.58 18.06 21.29 244 Left Middle Frontal Gyrus -44.90 55.20 6.49 415 Right Superior Temporal Gyrus (c)ₐ 66.94 -0.77 -2.87

74 Left Precuneus -5.29 -64.52 41.00 245 Left Middle Occipital Gyrus -47.94 -72.00 0.48 416 Right Supramarginal Gyrus 65.87 -43.13 29.48

75 Left Inferior Frontal Gyrus/ Pars Triangularis -53.48 36.74 -0.71 246 Left Calcarine Fissure -9.94 -62.90 16.74 417 Right Putamen 27.00 17.00 -5.00

76 Left Hippocampus -24.03 -40.29 1.29 247 Left Medial Cingulate Gyrus -15.00 -22.00 46.00 418 Right Precental Gyrus 51.61 11.42 41.77

77 Left Superior Frontal Gyrus -21.00 68.00 13.00 248 Left Middle Temporal Gyrus -60.32 -30.45 -12.39 419 Right Superior Temporal Gyrus⁺ 33.00 5.00 -14.00

78 Left Superior Frontal Gyrus -18.39 47.16 33.32 249 Left Medial Cingulate Gyrus -9.06 11.00 43.29 420 Right Fusiform Gyrus 39.94 -17.52 -21.68

79 Left Anterior Cingulate Gyrus -7.58 42.26 14.58 250 Left Supramarginal Gyrus -52.10 -43.61 53.81 421 Right Middle Temporal Gyrus 69.45 -10.87 -19.94

80 Left Superior Frontal Gyrus⁺ -23.58 30.42 58.16 251 Left Postcentral Gyrus -50.32 -27.35 56.52 422 Right Cuneus 15.13 -77.00 41.81

81 Left Insula -36.00 -25.00 22.00 252 Left Cuneus -9.81 -81.13 20.26 423 Right Inferior Occipital Gyrus 36.81 -63.32 -7.29

82 Left Middle Orbitofrontal Gyrus -46.63 50.19 -4.55 253 Left Precuneus -10.71 -50.81 58.06 424 Right Superior Temporal Poleₐ 64.05 11.29 -14.35

83 Left Superior Orbitofrontal Gyrus -25.95 44.61 -13.11 254 Left Lingual Gyrus -9.86 -69.23 1.73 425 Right Superior Occipital Gyrus 20.74 -82.23 36.55

84 Left Angular Gyrus -48.57 -66.59 33.65 255 Left Superior Frontal Gyrus -24.00 -4.00 76.00 426 Right Orbital Inferior Frontal Gyrus 53.06 23.81 -7.94

85 Left Supramarginal Gyrus -54.45 -32.85 46.29 256 Left Precentral Gyrus -35.62 -0.55 50.85 427 Right Superior Temporal Gyrus 60.42 -32.19 10.71

86 Left Medial Superior Frontal Gyrus -5.71 50.26 25.06 257 Right Precuneus 18.00 -40.00 46.00 428 Right Supramarginal Gyrus 61.48 -41.97 38.55

87 Left Middle Frontal Gyrus -42.00 5.00 58.00 258 Right Putamenₐ 31.81 -12.26 -5.61 429 Right Middle Frontal Gyrus 40.68 38.52 44.52

88 Left Middle Occipital Gyrus -26.03 -80.23 22.19 259 Right Postcentral Gyrus 64.39 -16.61 35.58 430 Right Middle Occipital Gyrus 36.71 -88.32 5.06

89 Left Cuneus -10.12 -60.39 23.79 260 Right Superior Occipital Gyrus 22.39 -90.55 20.03 431 Right Supramarginal Gyrus 42.97 -53.45 40.55

90 Left Orbital Inferior Frontal Gyrus -30.29 20.16 -22.02 261 Right Supramarginal Gyrus 69.00 -19.00 19.00 432 Right Precental Gyrus 24.00 -16.00 79.00

91 Left Postcentral Gyrus -39.32 -35.81 66.87 262 Right Precuneus⁺ 23.74 -56.35 43.71 433 Right Superior Parietal Gyrus 38.29 -50.71 55.26

92 Left Middle Temporal Gyrus -65.74 -13.06 0.20 263 Right Hippocampus 22.13 -34.77 6.84 434 Right Middle Temporal Gyrus 52.58 -55.03 6.39

93 Left Middle Frontal Gyrus -36.39 42.03 29.68 264 Right Angular Gyrus 45.71 -64.68 36.00 435 Right Superior Frontal Gyrus 12.19 10.65 61.52

94 Left Inferior Occipital Gyrus -41.30 -74.76 -7.11 265 Right Middle Occipital Gyrus 39.97 -72.74 0.94 436 Right Superior Frontal Gyrus⁺ 21.00 38.00 55.00

95 Left Postcentral Gyrus -20.65 -32.03 80.45 266 Right Amygdala 32.52 4.42 -25.90 437 Right Calcarine Fissure 15.84 -90.77 -1.65

96 Left Superior Frontal Gyrus -15.00 32.00 61.00 267 Right Amygdala 29.19 1.06 6.87 438 Right Superior Parietal Gyrus 27.23 -70.61 53.13

97 Left Precentral Gyrus -54.74 5.06 20.39 268 Right Insula 38.61 -18.26 -0.23 439 Right Cingulate Gyrus⁺ 16.60 -7.99 49.61

98 Left Middle Temporal Gyrus -63.77 -14.97 -10.16 269 Right Supramarginal Gyrus 48.35 -44.53 49.54 440 Right Cingulate Gyrus⁺ 17.42 24.32 29.87

99 Left Middle Occipital Gyrus -40.65 -73.97 12.39 270 Right Caudate 21.57 8.67 18.65 441 Right Postcentral Gyrus 33.00 -49.00 67.00

100 Left Medial Cingulate Gyrusₐ -5.46 -0.71 44.98 271 Right Superior Frontal Gyrus 11.97 -1.29 73.42 442 Right Postcentral Gyrus 32.29 -27.19 61.87

101 Left Superior Parietal Gyrus -33.48 -57.46 64.35 272 Right Superior Parietal Gyrus 48.45 -44.84 59.90 443 Right Precental Gyrus 63.00 11.00 28.00

102 Left Middle Occipital Gyrus -39.29 -72.14 26.98 273 Right Middle Temporal Gyrus 62.71 -58.65 5.29 444 Right Lingual Gyrus 27.00 -58.00 1.00

103 Left Middle Orbitofrontal Gyrus -5.81 61.55 -1.68 274 Right Middle Frontal Gyrus⁺ 51.00 50.00 19.00 445 Right Supramarginal Gyrus 51.10 -19.71 23.06

104 Left Superior Temporal Gyrus -58.91 -12.11 11.66 275 Right Inferior Temporal Gyrus 46.12 -55.22 -11.29 446 Right Middle Temporal Gyrus 50.26 -53.94 20.16

105 Left Postcentral Gyrus -18.26 -37.80 75.62 276 Right Putamen 28.84 20.03 0.97 447 Right Middle Orbitofrontal Gyrus 13.60 53.10 -10.81

106 Left Angular Gyrus -47.10 -61.32 45.39 277 Right Superior Temporal Gyrus 72.00 -28.00 -2.00 448 Right Middle Temporal Pole 53.20 9.98 -29.99

107 Left Supramarginal Gyrus -62.61 -25.48 32.03 278 Right Rolandic Operculum 64.87 1.03 6.74 449 Right Middle Temporal Gyrus 58.88 -58.35 20.69

108 Left Superior Parietal Gyrus -19.68 -52.48 59.26 279 Right Inferior Temporal Gyrus 55.74 -24.52 -16.19 450 Right Middle Temporal Gyrus 48.58 3.29 -25.19

109 Left Paracentral Lobule -8.00 -25.68 58.90 280 Right Precental Gyrus 42.26 -24.52 60.87 451 Right Superior Frontal Gyrus 30.61 64.87 8.37

110 Left Gyrus Rectus -9.94 35.23 -16.19 281 Right Middle Temporal Gyrus 62.43 -54.43 -4.11 452 Right Superior Temporal Gyrus 68.87 -26.42 7.48

111 Left Insula -35.68 -1.03 3.39 282 Right Cingulate Gyrus 12.81 -40.61 33.94 453 Right Superior Frontal Gyrus 37.55 -5.23 68.77

112 Left Superior Temporal Pole -30.54 25.84 -28.20 283 Right Putamen 19.26 14.55 -4.90 454 Right Insula 37.29 21.52 4.29

113 Left Middle Frontal Gyrus -33.00 32.00 13.00 284 Right Rolandic Operculum 66.00 11.00 10.00 455 Right Supramarginal Gyrus 59.16 -20.55 20.13


17

Automated Anatomical Labels (AAL) (29) from WFU PickAtlas(30) were used for all cases where the center of mass fell on an AAL region. Where an AAL label was not evident, ⁺ denotes cases where the Talairach Daemon (TD) label was used. If the center of mass did not fall on an AAL or TD label we used the closest voxel to the center of mass that lay within an AAL region.ₐ denotes Network Based Statistic (NBS) identified constellation of fronto-temporal parcellations that differentiated the controls from BD participants, (a), (b), (c), breakdown differentiates between parcellations with same labels. This breakdown is only done for those 12 NBS parcellations.

114 Left Middle Orbitofrontal Gyrus -37.13 49.23 -8.68 285 Right Superior Temporal Pole 47.23 21.06 -31.03 456 Right Precental Gyrus 60.00 11.00 40.00

115 Left Insula -30.00 11.00 16.00 286 Right Superior Parietal Gyrus 16.16 -72.29 52.32 457 Right Caudate 18.00 20.00 13.00

116 Left Heschls Gyrus -45.35 -18.45 8.13 287 Right Precental Gyrus 25.71 -20.90 73.26 458 Right Insula⁺ 34.47 -0.01 16.00

117 Left Superior Frontal Gyrus -10.81 -12.29 76.35 288 Right Middle Frontal Gyrus 52.32 32.06 34.58 459 Right Precental Gyrus 39.00 -25.00 70.00

118 Left Rolandic Operculum -37.81 -13.81 17.52 289 Right Postcentral Gyrus 47.68 -23.88 49.10 460 Right Middle Frontal Gyrus⁺ 57.52 25.74 38.68

119 Left Orbital Inferior Frontal Gyrus -26.29 34.94 -8.45 290 Right Postcentral Gyrus 28.61 -48.55 73.55 461 Right Angular Gyrus 33.00 -52.00 37.00

120 Left Middle Frontal Gyrus⁺ -49.58 41.23 22.81 291 Right Middle Temporal Gyrus 62.06 6.00 -25.97 462 Right Superior Temporal Pole 52.32 19.77 -22.06

121 Left Middle Frontal Gyrus -33.00 50.00 34.00 292 Right Superior Frontal Gyrus 17.74 70.29 -1.00 463 Right Inferior Frontal Gyrus/Pars Triangularis 46.81 32.52 6.55

122 Left Hippocampus -29.52 -27.90 -8.26 293 Right Middle Frontal Gyrus 32.81 22.00 60.10 464 Right Lingual Gyrus 21.55 -75.13 -0.90

123 Left Middle Temporal Gyrus -47.10 -65.52 12.90 294 Right Angular Gyrus 38.52 -70.52 42.10 465 Right Middle Frontal Gyrus 36.00 14.00 61.00

124 Left Superior Orbitofrontal Gyrus -26.90 56.67 -5.89 295 Right Postcentral Gyrus 55.19 -16.48 49.00 466 Right Inferior Frontal Gyrus/Pars Triangularis 55.65 44.23 4.48

125 Left Inferior Frontal Gyrus/ Pars Triangularis -50.03 25.68 9.32 296 Right Superior Frontal Gyrus⁺ 45.00 38.00 37.00 467 Right Orbital Inferior Frontal Gyrus 28.90 35.10 -17.74

126 Left Supramarginal Gyrus -62.74 -27.55 23.00 297 Right Middle Frontal Gyrus 40.97 28.52 39.32 468 Right Postcentral Gyrus 17.00 -44.10 77.90

127 Left Middle Occipital Gyrus -25.47 -80.88 34.48 298 Right Precental Gyrus 58.13 -0.90 44.29 469 Right Thamalus 19.39 -19.81 5.29

128 Left Superior Frontal Gyrus -27.23 65.68 -3.00 299 Right Middle Temporal Pole 38.07 6.98 -35.80 470 Right Middle Frontal Gyrus⁺ 36.00 32.00 52.00

129 Left Postcentral Gyrus -58.32 -5.71 40.81 300 Right Superior Parietal Gyrus 17.84 -61.29 53.90 471 Right Precuneus⁺ 20.36 -51.27 33.43

130 Left Middle Temporal Gyrus -51.10 -7.48 -16.74 301 Right Middle Temporal Gyrus 70.56 -39.94 -5.38 472 Right Precental Gyrus 16.42 -30.39 66.16

131 Left Medial Cingulate Gyrus -7.82 -18.17 43.54 302 Right Superior Frontal Gyrus 13.00 44.16 50.35 473 Right Superior Parietal Gyrus 21.94 -58.23 68.58

132 Left Inferior Temporal Gyrus -39.13 -6.49 -28.59 303 Right Inferior Frontal Gyrus/Pars Triangularis 47.90 20.57 3.94 474 Right Superior Frontal Gyrus 15.00 71.00 10.00

133 Left Medial Superior Frontal Gyrus -10.06 26.35 52.23 304 Right Superior Parietal Gyrus 13.23 -43.52 63.42 475 Right Superior Occipital Gyrus 23.16 -71.55 28.29

134 Left Calcarine Fissure -5.55 -90.20 6.04 305 Right Hippocampus 32.04 -11.69 -18.53 476 Right Precental Gyrus 57.00 -7.00 49.00

135 Left Middle Frontal Gyrus -39.00 -47.47 -0.18 306 Right Paracentral Lobule 12.57 -32.34 47.21 477 Right Gyrus Rectus 15.00 26.00 -14.00

136 Left Superior Frontal Gyrus -19.84 60.65 32.84 307 Right Superior Frontal Gyrus 16.84 58.84 19.13 478 Right Superior Frontal Gyrus 18.00 59.00 37.00

137 Left Superior Frontal Gyrus -15.61 -2.87 73.29 308 Right Middle Frontal Gyrus 41.52 45.84 13.06 479 Right Middle Frontal Gyrus 51.00 -4.00 55.00

138 Left Superior Frontal Gyrus -15.71 -1.97 62.65 309 Right Superior Temporal Pole 26.97 8.94 -20.58 480 Right Calcarine Fissure 10.91 -75.43 14.95

139 Left Middle Occipital Gyrus⁺ -29.26 -76.81 8.00 310 Right Inferior Frontal Gyrus/ Pars Opercularis 53.68 12.68 12.61 481 Right Middle Temporal Gyrus 61.60 -16.93 -19.97

140 Left Middle Frontal Gyrus⁺ -51.29 20.45 45.16 311 Right Superior Frontal Gyrus 19.71 42.06 42.26 482 Right Superior Frontal Gyrus 13.03 68.19 24.45

141 Left Precentral Gyrus -46.87 -1.52 20.29 312 Right Superior Frontal Gyrus 27.00 50.00 43.00 483 Right Anterior Cingulate Cortex⁺ 13.32 34.81 -2.84

142 Left Parahippocampal Gyrus -34.21 -42.68 -8.13 313 Right Middle Occipital Gyrus 33.39 -88.58 16.42 484 Right Middle Frontal Gyrus⁺ 33.00 59.00 25.00

143 Left Medial Superior Frontal Gyrus -8.23 24.76 41.63 314 Right Supramarginal Gyrus 63.00 -25.00 46.00 485 Right Middle Frontal Gyrus 42.39 50.81 20.81

144 Left Supramarginal Gyrus -51.87 -51.68 43.32 315 Right Middle Frontal Gyrus 32.10 7.48 59.32 486 Right Middle Frontal Gyrus⁺ 61.47 26.89 28.45

145 Left Postcentral Gyrus -48.00 -25.00 64.00 316 Right Lingual Gyrus 21.22 -85.26 -5.89 487 Right Medial Superior Frontal Gyrus 13.87 33.97 57.16

146 Left Insula (a)ₐ -43.06 12.26 -2.81 317 Right Rolandic Operculum 51.90 1.29 5.16 488 Right Middle Frontal Gyrus⁺ 45.00 56.00 16.00

147 Left Precuneus -5.26 -56.74 29.13 318 Right Supramarginal Gyrus 52.94 -37.00 23.65 489 Right Cuneus 14.71 -91.16 14.55

148 Left Anterior Cingulate Gyrus -9.87 46.48 0.42 319 Right Middle Temporal Gyrus 50.35 -35.77 -12.94 490 Right Calcarine Fissure 19.03 -57.29 9.16

149 Left Paracentral Lobule -10.90 -25.87 81.81 320 Right Postcentral Gyrus 66.77 -4.35 31.16 491 Right Superior Frontal Gyrus 15.10 18.55 61.06

150 Left Inferior Temporal Gyrus -62.42 -40.74 -16.19 321 Right Middle Occipital Gyrus 31.24 -66.68 35.76 492 Right Superior Frontal Gyrus 12.00 8.00 73.00

151 Left Superior Orbitofrontal Gyrus -14.48 62.87 -7.42 322 Right Thalamus 20.06 -19.23 16.48 493 Right Superior Frontal Gyrus 21.00 20.00 64.00

152 Left Inferior Frontal Gyrus/ Pars Opercularis -40.87 15.52 33.55 323 Right Middle Frontal Gyrus 44.13 13.74 53.55 494 Right Inferior Occipital Gyrus 32.06 -87.03 -5.00

153 Left Insula⁺ -42.00 -19.00 -8.00 324 Right Precental Gyrus 68.17 1.07 24.23 495 Right Angular Gyrus 38.42 -67.71 51.58

154 Left Superior Temporal Gyrus -59.39 -50.81 21.74 325 Right Middle Frontal Gyrus⁺ 54.00 11.00 52.00 496 Right Middle Temporal Gyrus 65.33 0.63 -13.74

155 Left Medial Superior Frontal Gyrus -9.00 62.00 34.00 326 Right Inferior Temporal Gyrus 57.57 -43.22 -16.36 497 Right Precuneus 24.42 -46.45 0.10

156 Left Inferior Frontal Gyrus⁺ -53.48 23.26 -13.03 327 Right Middle Temporal Gyrus 68.29 -44.97 -0.13 498 Right Middle Frontal Gyrus⁺ 42.03 61.48 8.97

157 Left Inferior Frontal Gyrus⁺ -57.13 34.03 11.97 328 Right Precental Gyrus 42.00 -13.00 67.00 499 Right Superior Temporal Gyrus 72.00 -37.00 10.00

158 Left Medial Superior Frontal Gyrus -10.06 41.00 29.65 329 Right Inferior Frontal Gyrus/Pars Triangularis 60.58 18.06 21.29 500 Right Middle Frontal Gyrus⁺ 50.90 55.20 6.49

159 Left Superior Temporal Gyrus (a)ₐ -60.94 -0.77 -2.87 330 Right Precuneus 11.29 -64.52 41.00 501 Right Middle Temporal Gyrus 53.94 -72.00 0.48

160 Left Supramarginal Gyrus -59.87 -43.13 29.48 331 Right Inferior Frontal Gyrus/Pars Triangularis 59.48 36.74 -0.71 502 Right Calcarine Fissure 15.94 -62.90 16.74

161 Left Putamenₐ -27.00 17.00 -5.00 332 Right Hippocampus 30.03 -40.29 1.29 503 Right Postcentral Gyrus⁺ 24.00 -28.00 52.00

162 Left Middle Frontal Gyrus -45.61 11.42 41.77 333 Right Superior Frontal Gyrus 24.00 68.00 16.00 504 Right Middle Temporal Gyrus 66.32 -30.45 -12.39

163 Left Insula (b)ₐ -30.00 2.00 -8.00 334 Right Middle Frontal Gyrus 24.39 47.16 33.32 505 Right Cingulate Gyrus⁺ 15.06 11.00 43.29

164 Left Fusiform Gyrus -33.94 -17.52 -21.68 335 Right Anterior Cingulate Gyrus 13.58 42.26 14.58 506 Right Supramarginal Gyrus 57.00 -43.00 52.00

165 Left Middle Temporal Gyrus -63.45 -10.87 -19.94 336 Right Superior Frontal Gyrus⁺ 29.58 30.42 58.16 507 Right Supramarginal Gyrus 56.32 -27.35 56.52

166 Left Precuneus -9.13 -77.00 41.81 337 Right Rolandic Operculum 42.00 -25.00 22.00 508 Right Cuneus 15.81 -81.13 20.26

167 Left Fusiform Gyrus -30.81 -63.32 -7.29 338 Right Orbital Inferior Frontal Gyrus 52.63 50.19 -4.55 509 Right Superior Parietal Gyrus 16.71 -50.81 58.06

168 Left Superior Temporal Gyrus⁺ -58.05 11.29 -14.35 339 Right Middle Orbitofrontal Gyrus 31.95 44.61 -13.11 510 Right Lingual Gyrus 15.86 -69.23 1.73

169 Left Cuneus -14.74 -82.23 36.55 340 Right Angular Gyrus 54.57 -66.59 33.65 511 Right Superior Frontal Gyrus 30.00 -4.00 70.00

170 Left Orbital Inferior Frontal Gyrusₐ -47.06 23.81 -7.94 341 Right Supramarginal Gyrus 60.45 -32.85 46.29 512 Right Precental Gyrus 41.62 -0.55 50.85

171 Left Superior Temporal Gyrus -54.42 -32.19 10.71 342 Right Medial Superior Frontal Gyrus 11.71 50.26 25.06 513 Left Insula -25.68 9.29 -13.78


18

Table S3. Graph Theoretical Mathematical Definitions

Measure Weighted and Directed Definition Characteristic path length

Characteristic path length of the network , Weighted characteristic path length:

L𝑊 =1n�

∑ 𝑑𝑖𝑗𝑤j∈N,j≠i

n − 1i∈N

Directed characteristic path length:

L→ =1n�

∑ 𝑑𝑖𝑗→j∈N,j≠i

n − 1i∈N

Clustering coefficient Weighted clustering coefficient of the network:

C𝑤 =1n�

2t𝑖𝑤

𝑘𝑖 (ki𝑖 − 1)i∈N

Directed clustering coefficient of the network:

C→ =1n�

𝑡𝑖→

�𝑘𝑖𝑜𝑢𝑡 + 𝑘𝑖𝑖𝑛��𝑘𝑖𝑜𝑢𝑡 + 𝑘𝑖𝑖𝑛 − 1� − 2 ∑ 𝑎𝑖𝑗𝑎𝑗𝑖j∈N i∈N

Participation coefficient

Weighted participation coefficient:

𝑦𝑖𝑤 = 1 −� i�k𝑖𝑤 (m)

k𝑖𝑤�2

m∈M

Out-degree participation coefficient:

𝑦𝑖𝑜𝑢𝑡 = 1 −� i�𝑘𝑖𝑜𝑢𝑡(m)

k𝑖𝑜𝑢𝑡�2

m∈M

In-degree participation coefficient:

𝑦𝑖𝑖𝑛 = 1 −� i�𝑘𝑖𝑖𝑛(m)

k𝑖𝑖𝑛�2

m∈M

Adapted from (19).


19

Comparison Using Alternative Preprocessing Steps for the Global Signal

As the contribution of the global signal to between group differences in functional

connectivity is a controversial topic (31), we did not regress the global signal. We instead

performed further analyses to explore potential confounds of global signal. First, we observed

that the average global signal did not significantly differ between our groups (CON vs BD p

=< 0.129, CON vs AR p =< 0.091, AR vs BD p =< 0.998). Second, following prior

recommendations (32), we repeated analysis of our main effect - the contrast between BD

and CON participants (Figure 1A; see below) - including the global signal as a covariate: Our

between-group difference remained significant (Wald χ2 = 29.51, df = 2, CON > BD p =<

0.001).

Figure S2A. NBS with no global signal regression (i.e. original finding of Figure 1A) and a height threshold of t = 3.75.

Median Angle Regression

We also repeated the NBS analysis following a geometric alternative to global signal

regression, namely median angle regression (33). This analysis derives from the observation

that a portion of the global signal can be viewed as an additive confound that increases with

the mean BOLD amplitude. Multivariate analyses are used as a way of identifying this

additive confound that is then regressed out of the signal. NBS following median angle

regression revealed a slightly weakened, albeit significant effect in a network containing 18


20

edges (Figure S2B) that overlap substantially with the 17 edges represented in Figure 1A and

presented in Table 2.

Figure S2B. NBS following median angle regression and a height threshold of t = 3.75 (p < 0.01, FWE corrected).

Global Signal Regression

For completeness, we also repeated the analysis following global signal regression and a

search t-statistic of 2.25. The same contrast (CON > BD) revealed a smaller, but anatomically

similar network of regions. Despite the absence of a significant between group difference in

the global signal, the resulting network did not survive family-wise correction (p = 0.29,

FWE corrected).

Figure S2C. NBS following global signal regression and a height threshold of t = 2.25 (p = 0.29, FWE corrected).

Comparison Using Alternative Preprocessing Steps for Head Motion

Head motion is a potential source of erroneous between group effects in resting state

functional connectivity research (32). In our primary analysis (Figure 1), we corrected


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(realigned) the images for head motion, checked (and excluded) differences in total head

motion (translation and rotation) between groups, excluded subjects with > 5mm of head

motion from our analyses and entered the subject-specific head motion parameters into our

between group statistical contrasts as nuisance regressors. Additional analyses confirm that:

1. There were no between group differences in total head motion, or average or

maximum frame-wise translation and rotation. The p-values are given in the table

below:

Table S4. Group Comparisons in Total Head Motion as Well as Frame-Wise Head Motion

CON vs AR AR vs BD CON vs BD

Maximum (total) head motion p > 0.82 p > 0.68 p > 0.57

Maximum frame-to-frame head motion p > 0.72 p > 0.26 p > 0.38

Average from-to-frame head motion p > 0.66 p > 0.26 p > 0.43 CON, Controls; AR, At-risk; BD, Bipolar disorder

2. The main effects are virtually unchanged when scrubbing is performed, removing

volumes (and replacing with linear interpolation) when there was more than 0.5mm of

frame-wise displacement (34). The removal of such frames was reasonably sparse and

spread evenly between our three groups. In 5 participants, no volumes were scrubbed

(2 in CON, 3 in AR, 0 in BD).The median number of volumes in the remaining 195

participants was 1. Table S5 provides the mean and maximum number of frames

scrubbed in the three groups.

Table S5. The Number of Dropped Frames as a Result of Scrubbing at 0.5mm of Frame-wise Displacement

Dropped frames CON AR BD Mean (SD) 3.0% (±6.77) 4.0% (±8.2) 3.1% (±4.0) Maximum 46.3% 43.8% 12.8%

CON, Controls; AR, At-risk; BD, Bipolar disorder

Entering these scrubbed subject-wise functional connectivity matrices into Network

Based Statistics with a search t-statistic of 3.4 yielded a highly robust (p < 0.001)


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subnetwork of 18 nodes, 16 of which overlap with the 17 edges represented in Figure

1A and presented in Table 2.

Figure S3A. NBS following volume scrubbing and a height threshold of t = 3.45 (p < 0.001, FWE corrected)

1. The main effects are virtually unchanged when enforcing a more restrictive exclusion

criteria of 3mm total head motion, hence removing an additional 9 participants from

the cohort. Figure S3 presents summary data for these additional head movement

effects.

Figure S3B. Effect of alternative head motion preprocessing on the subnetwork of 17 edges from Figure 1A. Colors depict preprocessing choice (green = 5mm exclusion, no scrubbing; red = 3mm exclusion, no scrubbing; blue = scrubbed data). Y-axis corresponds to the average weight of the 17 functional connectivity weights. From left to right shows CON, AR and BD groups. CON, Controls; AR, At-risk; BD, Bipolar disorder.

Tota

l sub

grap

h fu

nctio

nal c

onne

ctiv

ity

CON AR BD


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A: Left IFG

B: Right IFG

Figure S4. Comparison of functional connectivity of left (top row) versus right (lower row) IFG. NBS performed at a liberal height threshold of t = 2.75. A: Original seed region in left IFG yields large subnetwork of functional dysconnectivity (p<0.0001, FWE corrected). B: Contralateral homologous right IFG at height threshold of t = 2.75 (p<0.032, corrected). No edges or subnetwork survive the more stringent search threshold of t = 3.25 as employed in the main analysis.


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Table S5. Whole-Brain Analysis-Other Networks Identified

CON > BD Network 1- Whole brain 2_Lentiform Nucleus to Left Superior Frontal Gyrus_128 2_Lentiform Nucleus to Right Rolandic Operculum_360 2_Lentiform Nucleus to Right Rolandic Operculum_360 Network 2 (Figure 1C)- Whole brain 53_Parahippocampal_L_119_Frontal_Inf_Orb_L 163_Insula_L_170_nogsr_211_Frontal_Mid_Orb_L 53_Parahippocampal_L_240_Temporal_Sup_L 136_Frontal_Sup_L_402_Superior_Temporal_Gyrus 111_Insula_L_513_ Insula_L 119_Frontal_Inf_Orb_L_513_ Insula_L 159_Temporal_Sup_L_513 _Insula_L 170_Frontal_Inf_Orb_L_513_ Insula_L 211_Frontal_Mid_Orb_L_513_ Insula_L 402_Superior_Temporal_Gyrus_513_ Insula_L CON > AR Network 1 (Figure 1D)- Whole brain 61_Rolandic_Oper_L_159_Temporal_Sup_L 111_Insula_L_159_ Temporal_Sup_L 2_Lentiform_Nucleus_348_ Temporal_Sup_R 111_Insula_L_348_ Temporal_Sup_R 171_Temporal_Sup_L_ Temporal_Sup_R 111_Insula_L_415_Temporal_Sup_R 111_Insula_L_513_Insula Network 2- Whole brain 10_Temporal_Pole_Sup_L_131_Cingulum_Mid-L 131_Cingulum_Mid_L_255_Frontal_Sup_L 213_Thalamus_L_255_ Frontal_Sup_L Network 3- Whole brain 231_Left medial superior frontal gyrus to 386_right middle temporal gyrus 381_Right inferior frontal gyrus to 386_right middle temporal gyrus 381_Right inferior frontal gyrus to 481_right middle temporal gyrus


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Figure S4. Clustering Coefficient (CC) in Younger Group. CON, Controls; AR, At-risk; BD, Bipolar disorder; **, p < 0.01; *, p < 0.05

Table S6. Support Vector Classification Accuracy

Group Sensitivity Specificity Accuracy CON 56.3% 59.2% 58.0% AR 46.5% 74.4% 64.5% BD 30.6% 83.4% 70.5%

CON, Controls; AR, At-risk; BD, Bipolar disorder.


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