Abnormal development and dysconnectivity of distinct thalamic nuclei in patients with 22q11.2 deletion syndrome experiencing auditory

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Article

Reference

Abnormal development and dysconnectivity of distinct thalamic nuclei in patients with 22q11.2 deletion syndrome experiencing auditory

hallucinations

MANCINI, Valentina, et al .

Abstract

Several studies in patients with schizophrenia have demonstrated an abnormal thalamic volume and thalamocortical connectivity. Specifically, hyperconnectivity with somatosensory areas has been related to the presence of auditory hallucinations (AHs). The 22q11.2 deletion syndrome is a neurogenetic disorder conferring proneness to develop schizophrenia, and deletion carriers (22qdel carriers) experience hallucinations to a greater extent than the general population.

MANCINI, Valentina, et al . Abnormal development and dysconnectivity of distinct thalamic nuclei in patients with 22q11.2 deletion syndrome experiencing auditory hallucinations.

Biological Psychiatry , 2020

DOI : 10.1016/j.bpsc.2020.04.015 PMID : 32620531

Available at:

http://archive-ouverte.unige.ch/unige:139054

Disclaimer: layout of this document may differ from the published version.

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Abnormal Development and Dysconnectivity of Distinct Thalamic Nuclei in Patients With 22q11.2 Deletion Syndrome Experiencing Auditory Hallucinations

Supplemental Information

Structural images preprocessing Quality control of the segmentation

In order to ensure the quality of the segmentation, it was verified for each subject that the mask as whole was correctly

placed with no shifts of the mask beyond the borders of the thalamus and without portions of the thalamus being cut

off. Further, we checked that there was no major mislabeling of thalamic nuclei visible to the naked eye which eventually

resulted in the exclusion of the whole segmentation. Quality control was performed visually by comparing the thalamus

before the segmentation with the segmentation label in the 3 projections of the space (axial, sagittal and transversal).

Criteria based on intensity differences, symmetry with the contralateral side and anatomical landmarks were used. In

this regard, we excluded 5 scans from further analyses (2 HC and 3 22qdel) for the following reasons:

1. The medial margin of the pulvinar was overlapping with the ventricle 2. The whole thalamic mask was not well placed in 2 cases

3. The medial part of the left VLp was considered as part of the left MDI

4. The anterior margin of the right VA nucleus had an indentation that was not compatible with anatomical features

The data of each thalamic nucleus were then tested for normality which is a prerequisite for the use of the following

statistical analyses (i.e. mixed model). All the remaining volumetric data had a normal distribution.

Statistical analyses for volumetric data Mixed model

A toolbox was employed to estimate developmental curves of thalamic nuclei over age in a sample where subjects were

recorded at different ages and at multiple time‐points ( https://github.com/danizoeller/myMixedModelsTrajectories).

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In the present study, a linear model was the most suitable model order for the development of thalamic nuclei, as

exemplified by the following equation:

𝑌 𝛽 𝛽 ∙ 𝑔 𝛽 ∙ 𝑎 𝛽 ∙ 𝑔 ∙ 𝑎 𝑢 𝑢 ∙ 𝑎 𝜖

𝑌:𝑡ℎ𝑎𝑙𝑎𝑚𝑖𝑐 𝑣𝑜𝑙𝑢𝑚𝑒

𝑖,𝑗: 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠,𝑠𝑐𝑎𝑛 𝑖𝑛𝑑𝑒𝑥

𝛽 :𝑓𝑖𝑥𝑒𝑑 𝑒𝑓𝑓𝑒𝑐𝑡𝑠

𝑔: 𝑔𝑟𝑜𝑢𝑝𝑖𝑛𝑔 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒

𝑎:𝑎𝑔𝑒

𝑢:𝑛𝑜𝑟𝑚𝑎𝑙𝑙𝑦 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑒𝑑 𝑟𝑎𝑛𝑑𝑜𝑚 𝑒𝑓𝑓𝑒𝑐𝑡

𝜖:𝑛𝑜𝑟𝑚𝑎𝑙𝑙𝑦 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑒𝑑 𝑒𝑟𝑟𝑜𝑟 𝑡𝑒𝑟𝑚

The significance of the between‐group differences in the intercept and in the slope were evaluated by means of a

likelihood ratio test between the full model and any of the following reduced models:

Reduced group effect model

𝑌 𝛽 𝛽 ∙ 𝑎 𝑢 𝑢 ∙ 𝑎 𝜖

Reduced slope model

𝑌 𝛽 𝛽 ∙ 𝑔 𝛽 ∙ 𝑎 𝑢 𝑢 ∙ 𝑎 𝜖

P‐values resulting from the likelihood ratio tests indicate the difference of intercept and slope of developmental

trajectories of the thalamic volumes of each group. Finally, these p‐values were adjusted for multiple testing with the

false discovery rate correction by using the fdr_bh function in Matlab. When a difference in the slope of the two groups

was detected, the age at deflection was evaluated at the point of intersection of the two linear trajectories.

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P‐values and log‐likelihood ratio are provided for group effect and slope. Furthermore, the difference in percentage

between the intercept of the 2 groups tested for thalamic nuclei of which test‐retest reliability has been evaluated (i.e.

AV, LP, CM, MD, VL and PU) are listed in Supplementary Table S2.

If there was no significant slope difference between the 2 groups but a significant group difference, the difference in

percentage was evaluated as follows:

𝑥

A B 𝑥 100 /A

On the other hand, if there were both significant slope difference between the 2 groups and a significant group

difference or a significant slope difference alone, we computed the maximum estimated group difference, i.e. the

difference between the intercepts in the point of the curve with the maximum difference between the 2 groups:

𝑥

A_𝑚𝑎𝑥 B_𝑚𝑖𝑛 𝑥 100 /A_𝑚𝑎𝑥

Group comparison and correlations of cross‐sectional data

Demographic measures between groups were compared using two‐sample t‐tests and p‐values were corrected for

multiple comparisons with the FDR. We additionally employed a two‐sample t‐test to compare the volume of MGN in

the cross‐sectional group comparison. Pearson’s correlation coefficient was employed to assess the correlation

between FC values and the volume of MGN.

fMRI images preprocessing

The functional images were preprocessed using SPM12 (Statistical Parametric Mapping, Wellcome Department of

Imaging Neuroscience) (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/), Data Processing Assistant for Resting‐

State fMRI (DPARSF)(1) and Individual Brain Atlases using Statistical Parametric Mapping (IBASPM) toolboxes using in‐

house Matlab code and adapting the pipeline of previous studies(2, 3).

All the functional images were realigned to the first volume with a six‐parameter rigid body transformation and the

structural scans were then co‐registered to the functional mean. The anatomical images were segmented into grey

matter, white matter and cerebrospinal fluid (CSF) with the SPM12 Segmentation algorithm(4). In order to improve

anatomical precision, we created a study‐specific template by means of Diffeomorphic Anatomical Registration using

Exponentiated Lie algebra (DARTEL)(5) and the realigned fMRI images were non‐linearly normalized to the study‐specific

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template. The resulting images were affine‐aligned into stereotactic space of the Montreal Neurologic Institute (MNI)

and finally spatially smoothed using an isotropic Gaussian kernel of 3 mm full width maximum (FWHM). The choice of

the smoothing parameter was based on the evidence that using smoothing kernels with a FWMH higher than 4 mm

might mix the signal arising from subcortical nuclei(6). Similar to previous studies, we used a priori anatomically

delineated thalamic nuclei in native space as seeds(7). Bilateral labels of each thalamic nucleus with aberrant

development in subjects having AH were exported from the structural scans processed in FreeSurfer, converted into

nifti format and spatially normalized to MNI.

Further steps of preprocessing and FC analyses were carried out using the CONN‐fMRI Functional Connectivity toolbox

v18(https://web.conn‐toolbox.org)(8). The labels of left and right nuclei of interest based on individual anatomy were

imported in Conn as subject‐specific ROIs. The alignment of the functional mean with the anatomical images and the

labels of the thalamic nuclei of interest was carefully inspected for each subject. The mislabeling of the ROI voxels of

any thalamic nucleus resulted in the exclusion of the entire scan. Outlier scans due to head motion were identified using

the software ART(www.nitrc.org/projects/artifact_detect)(9) and excluded if the movement of either translational or

rotational parameters exceeded 2 mm or 2°. After all these quality control procedures, 10 subjects (6 with and 4 without

AH) were excluded from the following analyses.

BOLD signal noise from white matter and CSF was defined and addressed with the Component‐based correction

(CompCor) method which models the influence of noise as a voxel‐specific combination of multiple noise sources(8,

10). The first 5 principal components of the subject‐specific WM‐ and CSF‐mask signals were calculated. Then, the linear

effects of the 6 motion parameters estimated during realignment, their temporal derivatives, and the 10 noise

components (including physiological artifacts such as cardiac or respiratory rates) were regressed out at each voxel.

Furthermore, outliers time‐points identified with the software ART by using a global‐signal z‐value threshold of 3 and a

subject motion threshold of 0.5 mm were as well censored from the BOLD time‐series at each voxel. Finally, the BOLD

time‐series within each of the bilateral seeds was estimated and temporally band‐pass filtered with a frequency window

of 0.01 to 0.1 Hz.

Seed‐based functional connectivity analyses

First‐level analyses were performed using general linear models, as implemented in SPM12. Seed‐to‐voxel and ROI‐to‐

ROI FC analyses were carried on between thalamic nuclei of interest as defined by apriori anatomical segmentation and

the whole brain using Harvard‐Oxford atlas in the second case.

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Seed‐to‐voxel and ROI‐to‐ROI FC maps were created for each participant, modeling individual‐specific covariation between the BOLD activity of each seed and the rest of the brain by using Fisher‐transformed bivariate correlation

coefficients(8). To account for the use of 2 scanner models and differences in sex and age and the use of antipsychotic

medications, these parameters were entered as covariates together with head motion information.

Second level analyses allowed to test our hypotheses and compare with independent t‐tests the FC between each

thalamic seed and the rest of the brain in the groups of 22qdel with and without AH. False positive control in ROI‐to‐

ROI analyses was performed using FDR correction and in voxel‐level analyses using a combination of FDR correction at

voxel level and family wise error (FWE) correction at cluster level.

Analyses to test the hypothesis of a VTA‐hippocampal‐thalamic loop dysfunction Here we tested whether:

1. There is a correlation between the volume of Re nucleus and CA1 subfield of the hippocampus by using the fitlme function in MATLAB R2017 (Math Works). As in our previous work(11), a segmentation algorithm

published with FreeSurfer v 6.0 was employed to get the volumetric data(12). Results can be found in

supplementary table S11.

2. There is an increased functional connectivity between ventral tegmental area (VTA) and hippocampus in 22qdel with hallucinations. VTA region was defined as in the paper by Giordano and colleagues: a 3 mm spherical ROI

containing 27 voxels centered in the midline of the brain(13) by employing MarsBar region of interest toolbox

for SPM(14). Similarly, we kept peak Tailarach coordinates fixed across subjects [x =0, y=20, z=12]. Fc analyses

were carried out with Conn as described in the main text. Results can be found in supplementary table S10.

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Supplemental References

1. Chao‐gan Y, Yu‐feng Z (2010): DPARSF : a MATLAB toolbox for “ pipeline ” data analysis of resting‐state fMRI. 4: 1–7.

2. Zöller D, Schaer M, Scariati E, Padula MC, Eliez S, Van De Ville D (2017): Disentangling resting‐state BOLD variability and PCC functional connectivity in 22q11.2 deletion syndrome. Neuroimage. 149. doi:

10.1016/j.neuroimage.2017.01.064.

3. Zöller D, Padula MC, Sandini C, Schneider M, Scariati E, Van De Ville D, et al. (2018): Psychotic symptoms influence the development of anterior cingulate BOLD variability in 22q11.2 deletion syndrome. Schizophr Res. 193: 319–

328. 4. T JA, Friston KJ (2005): Unified segmentation. 26: 839–851.

5. Ashburner J (2007): A fast diffeomorphic image registration algorithm. Neuroimage. 38: 95–113.

6. De Hollander G, Keuken MC, Forstmann BU (2015): The subcortical cocktail problem; Mixed signals from the subthalamic nucleus and substantia nigra. PLoS One. 10. doi: 10.1371/journal.pone.0120572.

7. Hrybouski S, Aghamohammadi‐sereshki A, Madan CR, Shafer AT, Baron CA, Seres P, et al. (2016): NeuroImage Amygdala subnuclei response and connectivity during emotional processing. Neuroimage. 133: 98–110.

8. Whitfield‐gabrieli S, Nieto‐castanon A (2012): Conn : A Functional Connectivity Toolbox for Correlated and Anticorrelated Brain Networks. 2. doi: 10.1089/brain.2012.0073.

9. Tousignant B, Eugène F, Sirois K, Jackson PL (2018): Difference in neural response to social exclusion observation and subsequent altruism between adolescents and adults. Neuropsychologia. 116: 15–25.

10. Behzadi Y, Restom K, Liau J, Liu TT (2007): A component based noise correction method ( CompCor ) for BOLD and perfusion based fMRI. Hum Brain Mapp J. 37: 90–101.

11. Mancini V, Sandini C, Padula MC, Zöller D, Schneider M, Schaer M, Eliez S (2019): Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS. Mol Psychiatry. . doi: 10.1038/s41380‐019‐0443‐z.

12. Iglesias JE, Augustinack JC, Nguyen K, Player CM, Player A, Wright M, et al. (2015): A computational atlas of the hippocampal formation using ex vivo, ultra‐high resolution MRI: Application to adaptive segmentation of in vivo MRI. Neuroimage. 115. doi: 10.1016/j.neuroimage.2015.04.042.

13. Maria Giulia G, Stanziano M, Papa M, Mucci A, Prinster A, Soricelli A, Galderisi S (2018): Functional connectivity of the ventral tegmental area and avolition in subjects with schizophrenia : a resting state functional MRI study. Eur Neuropsychopharmacol. 28: 589–602.

14. Brett M, Anton J, Valabregue R, Poline J, Irmf C, Timone CHU La (2002): Region of interest analysis using an SPM toolbox.

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Supplementary Table S1. Demographic information and medical history comprising psychiatric disorders and medications use in the group of 22qdel with and without hallucinations for the cross‐sectional sub‐analysis with rsfMRI data.

22q11del AH‐ 22q11del AH+ p‐value

Number of subjects (%f) 40 (45%) 36 (50%) 0.3456

Mean age 18.27 ± 4.44 17.98 ± 4.11 0.3192

Age range

12‐25 y.o. 12‐25 y.o. N/A

Number of scans (total) 40 36 N/A

Number of 3 T (Trio) scans 25 24 0.3735

Number of 3 T (Prisma) scans 15 12 0.3735

Left‐handedness (%) 10% 13.9% 0.2370

Mild to moderate auditory deficit 30% 33.3% 0.8036

Subjects medicated 25 (62.5%) 24 (66.7%%) 0.3736

Methylphenidate 15 (37.5%) 12 (30%) 0.3736

Antidepressants 10 (25%) 12 (33.3%) 0.1757

Antipsychotics 0 6 (6%) < 0.001

Anxiolytics 4 (10%) 5 (13.9%) 0.4661

Antiepileptic drugs 1 (2.5%) 1 (2.8%) 0.4989

More than one class of medication

16 (40%) 19 (47.5%) 0.0669

Subjects meeting criteria for psychiatric

diagnosis 27 (67.5%) 25 (69.44%) 0.4692

ADHD 17 (42.5%) 18 (50 %) 0.2294

Generalized anxiety disorder 8 (20 %) 10 (27.78%) 0.1815

Phobia 15 (37.5%) 17 (45.22%) 0.1443

Mood disorders 9 (22.5%) 10 (27.78%) 0.3028

Psychotic disorders 0 8 (22.22%) < 0.001

OCD 2 (5%) 3 (8.33%) 0.2962

More than one diagnosis 16 (40%) 19 (52.78%) 0.06690

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HC vs 22qdel 22qdel hal‐ vs 22qdel hal+

Left side Right side Left side Right side

ICC % reduction ICC % reduction ICC % reduction ICC % reduction

MGN 0.86 15.1% 0.93 12.9% 0.86 19.8% 0.93 18.6%

LGN 0.94 9.8% 0.92 7.5% 0.94 N/A 0.92 N/A

AV 0.86 N/A 0.93 N/A 0.86 18.7% 0.93 N/A

LP 0.85 14.7% 0.90 14.25% 0.85 10.6% 0.90 N/A

CM 0.94 N/A 0.92 N/A 0.94 N/A 0.92 N/A

MD 0.89 N/A 0.95 N/A 0.89 N/A 0.95 N/A

VL 0.96 N/A 0.99 N/A 0.96 N/A 0.99 N/A

PU 0.96 7.6% 0.87 5.7% 0.96 N/A 0.87 N/A

Whole

thalamus 0.97 N/A 0.98 N/A 0.97 N/A 0.98 N/A

Supplementary Table S2. Percentage of thalamic nuclei volume reduction for significant differences in group comparisons and ICC values for test‐retest reliability as provided by Iglesias et al., Neuroimage, 2018. As the MGN and LGN nuclei have a central role in our study, we compared their percentage of volume reduction to the ICC of nuclei with a comparable volume: AV for MGN and CM for LGN.

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22qdel vs HC 22qdel hal+ vs 22qdel hal‐

Scan 1 Scan 2 Scan 1 Scan 2

Thalamic nuclei

p

group

p interaction

p group

p interaction

p group

p interaction

p group

p interaction

MGN Left <0.0001 0.1860 0.0023 0.3827 0.0025 0.01237 0.0002 0.0392 Right <0.0001 0.7903 0.0060 0.9720 0.0067 0.0016 0.0018 0.0246 LGN Left <0.0001 0.3682 0.0068 0.6464 0.6675 0.4085 0.0252 0.7188 Right <0.0001 0.2421 0.0029 0.8693 0.6021 0.4455 0.0489 0.1365

PuI Left 0.0048 0.0874 0.0451 0.7677 0.1902 0.0686 0.0545 0.3502

Right 0.0013 0.0032 0.0452 0.7958 0.7913 0.8893 0.1224 0.5322

PuM Left <0.0001 0.4219 0.0012 0.1330 0.3776 0.3987 0.0049 0.6083

Right 0.0002 0.2433 0.0434 0.9859 0.3717 0.2854 0.0390 0.9589

PuA Left ^0.0857 ^0.2161 ^0.0335 ^0.5167 ^0.4303 ^0.4578 ^0.0464 ^0.8853

Right ^0.5855 ^0.5454 ^0.1205 ^0.3643 ^0.5239 ^0.3684 ^0.7054 ^0.5621

PuL Left 0.0840 0.0586 0.1287 0.1669 0.2340 0.4129 0.1630 0.3080

Right 0.1972 0.0860 0.6458 0.9126 0.7975 0.5534 0.1490 0.2553

L‐Sg Left 0.7214 0.7358 0.3085 0.3738 0.7043 0.4116 0.2532 0.6962

Right 0.8364 0.6517 0.4699 0.2325 0.5817 0.4171 0.5171 0.7043

MD Left 0.3236 0.2306 0.5566 0.8688 0.9985 0.9735 0.2657 0.1668

Right 0.5658 0.4586 0.2672 0.4169 0.7316 0.4786 0.2913 0.7497

Pf Left ^0.8765 ^0.7183 ^0.2290 ^0.1417 ^0.6916 ^0.6730 ^0.0517 ^0.5978

Right 0.1842 0.4381 0.2519 0.2990 0.1724 0.4168 0.0724 0.9453

Pt Left 0.5119 0.4510 0.8792 0.6118 0.8918 0.6600 0.0151 0.4465

Right 0.7627 0.4618 0.4509 0.6144 0.5125 0.7441 0.2777 0.6770

Pc Left 0.0336 0.6778 0.0080 0.4457 0.4932 0.9241 0.0119 0.1885

Right 0.0077 0.7151 0.0356 0.6040 0.7927 0.9995 0.1180 0.3718

CM Left 0.7572 0.4949 0.7350 0.4736 0.5258 0.3764 0.0218 0.3272

Right 0.3925 0.3633 0.5737 0.3453 0.7639 0.6961 0.1965 0.7085

CeM Left 0.8097 0.6045 0.4792 0.2303 0.8031 0.7985 0.0331 0.0265

Right 0.5675 0.4746 0.1471 0.0842 0.3703 0.5812 0.0278 0.3180

MV(Re) Bilateral 0.2655 0.4672 0.2381 0.4293 0.0381 0.0401 0.0367 0.0125

CL Left 0.9819 0.8587 0.5538 0.6497 0.2987 0.3941 0.0199 0.1236

Right 0.4667 0.4566 0.2627 0.9432 0.1565 0.4172 0.3822 0.1673

VA Left 0.0355 0.2940 0.0401 0.6093 0.0758 0.1524 0.0451 0.7066

Right ^0.0005 ^0.2273 ^0.0006 ^0.3281 ^0.6008 ^0.3474 ^0.0223 ^0.9546

VPL Left 0.5547 0.6135 0.6897 0.6346 0.8574 0.9745 0.0133 0.8229

Right 0.8287 0.5634 0.8482 0.7657 0.6986 0.4080 0.0076 0.0454

VLa Left 0.0032 0.3942 0.0437 0.5876 0.1120 0.4226 0.0242 0.1506

Right 0.0006 0.4106 0.0115 0.4720 0.7449 0.4431 0.0307 0.4906

VLp Left 0.0336 0.6778 0.3411 0.8184 0.4932 0.9241 0.0119 0.1885

Right 0.0668 0.4882 0.3737 0.7015 0.6881 0.4038 0.0333 0.3974

VM Left ^0.1592 ^0.4911 ^0.8792 ^0.6931 ^0.8073 ^0.6211 ^0.0496 ^0.6368

Right 0.0788 0.8545 0.7952 0.9926 0.6933 0.5036 0.0129 0.0360

AV Left 0.8635 0.7461 0.5060 0.5102 0.0434 0.9774 0.0114 0.1190

Right 0.1559 0.1889 0.6425 0.9064 0.1786 0.7057 0.0457 0.4195

LP Left 0.0001 0.2681 0.0473 0.3340 0.7292 0.4694 0.0224 0.0588

Right <0.0001 0.4557 0.0039 0.4466 0.5086 0.2537 0.2260 0.2226

LD Left 0.0774 0.0937 0.8810 0.6147 0.7886 0.9815 0.1871 0.4714

Right 0.5102 0.3520 0.5232 0.3457 0.4162 0.9534 0.9295 0.7454

Thalamus Left 0.4459 0.2508 0.8416 0.6934 0.5426 0.3503 0.2750 0.6681

Right 0.3679 0.1625 0.8558 0.5889 0.3271 0.1375 0.3943 0.6868

Supplementary Table S3. P‐values for group effect and age x group interaction of the comparison between 22q11Del and HC and between 22qdel with and without hallucination for each type of scanner used in the longitudinal study.

There seems to be a good agreement between the results with the 2 scans.

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Supplementary Table S4. P‐values for group effect (models were fixed to a constant model order) between left and right volumes in the groups tested (22qdel, HC, 22qdel with and without hallucination). Patterns of laterality (i.e. higher right or left volume) do not differ across groups.

Thalamic nuclei

HC 22qdel 22qdel hal+ 22qdel hal‐

p‐value group Laterality p‐value group

Laterality p‐value group

Laterality

MGN < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R LGN < 0.001 R>L < 0.001 R>L < 0.001 R>L < 0.001 R>L PuI < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R PuM < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R PuA < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R PuL < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R

MD 0.0027 L>R 0.0018 L>R 0.0573 L>R 0.0019 L>R

VA 0.4893 N/A < 0.001 L>R 0.0003 L>R 0.0004 L>R

Sg < 0.001 R>L < 0.001 R>L < 0.001 L>R < 0.001 L>R

VPL 0.6869 N/A 0.9623 N/A 0.0973 N/A 0.7896 N/A

CM 0.1136 N/A 0.3656 N/A 0.8091 N/A 0.0373 R>L

Vla < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R

Pf 0.9128 N/A 0.5779 N/A 0.6756 N/A 0.1563 N/A

MV(Re) < 0.001 L>R 0.0046 L>R 0.1975 N/A 0.2613 N/A

CeM 0.8934 N/A < 0.001 L>R < 0.001 L>R < 0.001 L>R

VM 0.0688 N/A 0.2613 N/A < 0.001 L>R 0.0007 L>R

CL 0.1707 N/A 0.3156 N/A 0.4208 N/A 0.5471 N/A

VLp 0.8696 N/A 0.0996 N/A < 0.001 L>R 0.0015 L>R

Pc < 0.001 L>R < 0.001 L>R 0.0298 L>R 0.0226 L>R

Pt 0.0295 N/A 0.0904 N/A < 0.001 R>L < 0.001 R>L

AV 0.0012 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R LP < 0.001 R>L < 0.001 R>L < 0.001 L>R < 0.001 L>R

LD < 0.001 R>L < 0.001 R>L 0.0002 R>L 0.0002 R>L

Whole_thalamus < 0.001 L>R < 0.001 L>R < 0.001 L>R < 0.001 L>R

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Delusions (P1) Suspiciousness (P2) Disorganization (P5) Thalamic nuclei

p group p interaction p group p interaction p group p interaction

MGN Left 0.6491 0.7200 0.4536 0.4027 0.0972 0.1033

Right ^0.4944 ^0.7202 ^0.9440 ^0.8346 ^0.0620 ^0.1296

LGN Left 0.9856 0.9024 0.7360 0.4386 0.4082 0.1430

Right 0.9154 0.8737 0.9626 0.9550 0.6807 0.5064

PuI Left 0.4493 0.2086 0.1452 0.2166 0.8842 0.9645

Right ^0.3736 ^0.1869 ^0.8239 ^0.7404 ^0.1769 ^0.0670

PuM Left 0.6764 0.5885 0.4323 0.3784 0.4542 0.6905

Right 0.0783 0.0568 0.9800 0.8795 0.3260 0.5025

PuA Left 0.7940 0.9394 0.9508 0.7515 0.4450 0.9320

Right ^0.2805 ^0.1175 ^0.4025 ^0.1818 ^0.2797 ^0.4778

PuL Left 0.4312 0.6060 0.8657 0.8662 0.6706 0.8311

Right 0.4299 0.3749 0.9996 0.9999 0.8716 0.8772

L‐Sg Left 0.5385 0.2665 0.5429 0.5996 0.6521 0.3664

Right ^0.1497 ^0.0615 ^0.5436 ^0.3070 ^0.8380 ^0.7626

MD Left 0.9861 0.9067 0.6391 0.3621 0.9179 0.7693

Right 0.6355 0.4350 0.8338 0.8442 0,1541 0.7300

Pf Left ^0.3878 ^0.3063 ^0.4815 ^0.2460 ^0.2845 ^0.3902

Right ^0.3329 ^0.2517 ^0.8282 ^0.6018 ^0.4109 ^0.5409

Pt Left 0.2798 0.1120 0.4113 0.1930 0.0809 0.0590

Right 0.0721 0.1860 0.7680 0.4842 0.8036 0.8133

Pc Left ^0.5809 ^0.3770 ^0.9183 ^0.7733 ^0.9108 ^0.8695

Right 0.5260 0.9496 0.7077 0.4789 0.5526 0.9425

CM Left 0.8702 0.6313 0.5755 0.3096 0.7241 0.6196

Right 0.2208 0.0947 0.6948 0.3958 0.5960 0.4482

CeM Left ^0.4268 ^0.5913 ^0.0160 ^0.0742 ^0.1775 ^0.1596

Right 0.7980 0.5052 0.9561 0.0879 0.1074 0.3639

MV(Re) Bilateral 0.8348 0.8642 0.0772 0.3163 0.0780 0.1437

CL Left 0.1379 0.6091 0.8200 0.9372 0.8871 0.7916

Right ^0.2289 ^0.0897 ^0.7187 ^0.5256 ^0.9081 ^0.1290

VA Left 0.1926 0.1093 0.0562 0.1394 0.6561 0.3709

Right 0.3104 0.1290 0.9127 0.8579 0.9672 0.8457

VPL Left ^0.1940 ^0.0706 ^0.0976 ^0.0522 ^0.1830 ^0.0661

Right ^0.2518 ^0.1165 ^0.8228 ^0.9837 ^0.7198 ^0.6140

VLa Left 0.7403 0.4382 0.5217 0.5158 0.7994 0.6495

Right 0.4998 0.8494 0.6525 0.5916 0.9469 0.7674

VLp Left ^0.7421 ^0.4615 ^0.8453 ^0.7175 ^0.7154 ^0.6653

Right 0.3843 0.5042 0.4599 0.4900 0.8879 0.6263

VM Left 0.4050 0.1908 0.1614 0.0586 0.0747 0.2346

Right 0.0929 0.0596 0.5133 0.3448 0.8383 0.9185

AV Left ^0.1286 ^0.2427 ^0.0958 ^0.8604 ^0.2637 ^0.2878

Right 0.3250 0.3320 0.0959 0.0703 0.0794 0.0689

LP Left 0.2078 0.1591 0.8961 0.6468 0.9900 0.8901

Right 0.3838 0.7035 0.7944 0.7461 0.2851 0.9806

LD Left ^0.4556 ^0.8803 ^0.3897 ^0.4139 ^0.3572 ^0.7784

Right 0.2490 0.1189 0.5611 0.7200 0.0480 0.0531

Thalamus Left 0.8873 0.7138 0.9265 0.8685 0.8626 0.5876

Right ^0.8417 ^0.8191 ^0.0746 ^0.5402 ^0.8051 ^0.7739

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Supplementary Table S5. P‐values for group effect and age x group interaction of the developmental trajectories of 22qdel divided according to the scores of the SIPS for delusions (left), suspiciousness (center) and disorganization (right).

MGN= medial geniculate nucleus; LGN= lateral geniculate nucleus; PuI= inferior putamen; PuL= lateral pulvinar; PuA=

anterior pulvinar; PuM= medial pulvinar; L‐Sg= Limitans suprageniculate; MD = mediodorsal nucleus; Pf= parafascicular;

Pt= paratenial; Pc= paracentral; VA= ventral anterior; Vamc= ventral anterior magnocellular; VPL= ventral posterolateral; Vla= ventral latral anterior; VLp= ventral lateral posterior; VM= ventromedial; CM= centromedian; CeM=

central medial; MV(Re)= reuniens (medial ventral); CL= central lateral; AV= anteroventral; LP= lateral posterior; LD=

laterodorsal.

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22q11del AH+ 22q11del AH‐ p‐value Mean translation

(mm)

x 0.0203 ± 0.0140 0.0211 ± 0.0118 0.405 y 0.0359 ± 0.0183 0.0328 ± 0.0201 0.264 z 0.0361 ± 0. 0125 0.0389 ± 0.0230 0.279 Mean rotation

(rad)

pitch 0.0012 ± 0.0006 0.0013 ± 0.0012 0.330 roll 0.0046 ± 0.0030 0.0047 ± 0.0043 0.479 yaw 0.0043 ± 0.0034 0.0054 ± 0.0046 0.422 Framewise displacement (mm) 0.0329 ± 0.017 0.0397 ± 0.058 0.268 Global signal z‐value 0.864 ± 0.072 0.847 ± 0.077 0.183

Valid scans (%)

193.94 ± 5.53 (96.97%)

192.17 ± 6.22 (96.08%)

0.107

Supplementary Table S6. fMRI motion parameters and standard deviation of the signal. The percentage of valid scans

refers to the number of scans that survived after censoring bad data points (defined as data points with a global‐signal

z‐value higher than 3 or mean motion measured with framewise displacement higher than 0.5 mm) from the data.

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Left MGN Right MGN

T value p‐value p‐value fdr T value p‐value p‐value fdr

Right TP 3.70 0.0002 0.0217 3.38 0.0006 0.0471

networks.DefaultMode.LP (left) 3.59 0.0003 0.0217 2.86 0.0028 0.0637

Left TOFusC 3.49 0.0004 0.0217 2.93 0.0023 0.0637

Left sLOC 3.42 0.0005 0.0217 2.76 0.0037 0.0637

Left PT 3.35 0.0007 0.0218 3.28 0.0008 0.0471

Left aSTG 3.16 0.0012 0.0286 3.27 0.0008 0.0471

Right TOFusc 3.15 0.0012 0.0286 2.79 0.0034 0.0637

Right amygdala 2.95 0.0038 0.0637 2.57 0.0061 0.1170

Right PT 2.78 0.0035 0.0669 2.44 0.0087 0.1375

Left pSMG 2.65 0.0049 0.0860 2.76 0.0037 0.1170

Left FOrb 2.6 0.0056 0.0893 2.54 0.0067 0.1170

Left AG 2.46 0.0082 0.1194 2.35 0.0109 0.1461

Left OFusG 2.38 0.0099 0.1233 1.99 0.0255 0.1886

networks.Language.pSTG (left) 2.36 0.0106 0.1233 2.64 0.0051 0.1170

Left pTFusC 2.33 0.0113 0.1233 2.05 0.0223 0.1762

networks.DefaultMode.MPFC 2.31 0.0121 0.1233 1.98 0.0260 0.1886

networks.Visual.Lateral (left) 2.3 0.0121 0.1233 2.11 0.0190 0.1657

Left aMTG 2.27 0.0133 0.1233 2.25 0.0139 0.1587

Left IFG 2.25 0.0138 0.1233 1.95 0.0276 0.1891

networks.Visual.Lateral (right) 2.24 0.0142 0.1233 1.85 0.0341 0.1976

Right pSTG 2.2 0.0155 0.1237 2.22 0.0149 0.1587

Right Accumbens 2.2 0.0156 0.1237 2.25 0.0138 0.1587

Left HG 2.16 0.0170 0.1277 2.12 0.0186 0.1657

Left PP 2.15 0.0176 0.1277 2.18 0.0164 0.1587

MedFC 2.13 0.0184 0.1282 1.7 0.0464 0.2170

Left pMTG 2.05 0.0218 0.1412 2.05 0.0218 0.1762

Right iLOC 2.04 0.0224 0.1412 1.83 0.0354 0.1988

networks.DefaultMode.LP (left) 2.02 0.0235 0.1412 1.91 0.0304 0.1891

networks.Language.pSTG (right) 2.02 0.0235 0.1412 1.72 0.0453 0.2170

Left TP 1.98 0.0256 0.1440 1.94 0.0283 0.1891

AC 1.98 0.0257 0.1440 1.49 0.0702 0.2546

Right IC 1.96 0.0272 0.1479 1.92 0.0295 0.1891

Right Hippocampus 1.94 0.0282 0.1488 1.51 0.0683 0.2530

Left IC 1.91 0.0300 0.1524 1.51 0.0672 0.2530

SubCalC 1.9 0.0307 0.1524 1.8 0.0384 0.2089

Left pSTG 1.88 0.0322 0.1558 2.18 0.0163 0.1587

networks.SensoriMotor.Lateral 1.84 0.0350 0.1583 1.86 0.0334 0.1976

Left aPaHC 1.82 0.0362 0.1583 1.65 0.0522 0.2327

Right PP 1.8 0.0383 0.1583 1.36 0.0896 0.3057

Left iLOC 1.79 0.0386 0.1583 1.73 0.0440 0.2170

Right Cuneal 1.78 0.0394 0.1583 1.36 0.0889 0.3057

Left Amygdala 1.75 0.0418 0.1583 1.72 0.0446 0.2170

Right aMTG 1.71 0.0455 0.1644 1.32 0.0950 0.3082

Left pPaHC 1.71 0.0455 0.1644 1.57 0.0610 0.2530

Left SPL 1.7 0.0469 0.1644 1.31 0.0978 0.3082

Right Caudate 1.69 0.0473 0.1644 1.7 0.0472 0.2170

Left PO 1.68 0.0491 0.1644 1.63 0.0535 0.2329

Right SCC 1.68 0.0491 0.1644 1.56 0.0616 0.2530

Right aPaHC 1.65 0.0514 0.1660 1.65 0.0522 0.2327

networks.FrontoParietal.PPC (left) 1.65 0.0521 0.1660 1.52 0.0663 0.2530

Left Accumbens 1.64 0.0525 0.1660 1.55 0.0628 0.2530

Right pMTG 1.63 0.0543 0.1686 1.31 0.0974 0.3082

networks.DorsalAttention.FEF (left) 1.6 0.0571 0.1713 1.33 0.0943 0.3082

Left LG 1.59 0.0577 0.1713 1.07 0.1434 0.3648

Right sLOC 1.59 0.0587 0.1713 0.92 0.1807 0.4031

Right aSTG 1.57 0.0599 0.1713 1.28 0.1017 0.3104

networks.Language.IFG (left) 1.57 0.0604 0.1713 1.69 0.0474 0.2170

Left CO 1.57 0.0610 0.1713 1.51 0.0682 0.2530

Left Hippocampus 1.55 0.0628 0.1733 1.38 0.0862 0.3057

Right OFusG 1.54 0.0643 0.1748 1.18 0.1211 0.3398

Right LG 1.47 0.0731 0.1957 1.06 0.1468 0.3648

Left IFG 1.46 0.0747 0.1959 1.3 0.0992 0.3082

Right IFG 1.45 0.0754 0.1959 1.01 0.1583 0.3648

Right CO 1.42 0.0802 0.2052 1.03 0.1530 0.3648

PC 1.33 0.0939 0.2344 1.23 0.1115 0.3262

Right OP 1.33 0.0944 0.2344 1.17 0.1236 0.3413

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Left Cuneal 1.32 0.0957 0.2344 1.04 0.1505 0.3648

networks.Visual.Medial 1.3 0.0998 0.2411 0.81 0.2090 0.4489

Right toMTG 1.27 0.1033 0.2458 1 0.1605 0.3648

networks.Language.IFG (right) 1.27 0.1045 0.2458 1.02 0.1552 0.3648

Left SCC 1.24 0.1094 0.2500 1.06 0.1454 0.3648

Right AG 1.23 0.1115 0.2500 0.79 0.2153 0.4513

networks.SensoriMotor.Lateral 1.23 0.1121 0.2500 1.01 0.1569 0.3648

Left FO 1.15 0.1261 0.2769 0.81 0.2116 0.4489

Right FOrb 1.15 0.1276 0.2769 1.22 0.1125 0.3262

Left MidFG 1.14 0.1294 0.2769 0.75 0.2288 0.4740

Left toMTG 1.13 0.1305 0.2769 1 0.1610 0.3648

Left OP 1.11 0.1360 0.2849 0.82 0.2071 0.4489

Right FO 1.05 0.1477 0.3023 1.18 0.1203 0.3398

networks.FrontoParietal.LPFC (left) 1 0.160378 0.3209 0.66 0.2546 0.4978

Left PaCiG 1 0.16047 0.3209 0.72 0.2373 0.4801

networks.Visual.Occipital 0.98 0.166038 0.3283 0.89 0.1892 0.4168

Right Putamen 0.93 0.176863 0.3458 0.52 0.3020 0.5418

networks.DorsalAttention.IPS (left) 0.92 0.179277 0.3466 0.56 0.2898 0.5418

Right ICC 0.91 0.182593 0.3478 0.40 0.3436 0.5571

Left SFG 0.91 0.1839 0.3478 0.63 0.2653 0.5072

networks.Salience.SMG (left) 0.89 0.187327 0.3505 1.26 0.1056 0.3169

Right PaCiG 0.87 0.194905 0.3608 0.69 0.2462 0.4912

networks.DorsalAttention.IPS (right) 0.82 0.206164 0.3776 0.4 0.3457 0.5570

Right Cerebellum9 0.8 0.2124 0.3849 1 0.1614 0.3648

networks.Salience.ACC 0.79 0.216756 0.3862 0.45 0.3267 0.5466

networks.Salience.Ainsula (left) 0.79 0.217549 0.3862 0.68 0.2484 0.4912

Precuneous 0.76 0.224848 0.3941 0.48 0.3163 0.5466

Left Cerebellum9 0.75 0.2265 0.3941 0.72 0.2360 0.4801

Left FP 0.74 0.2319 0.3958 0.29 0.3867 0.5903

Right aSMG 0.74 0.23201 0.3958 0.43 0.3330 0.5466

Right SMA 0.7 0.243775 0.4118 0.47 0.3206 0.5466

Right aTFusC 0.65 0.260436 0.4319 ‐0.03 0.5099 0.6932

Left Caudate 0.64 0.263482 0.431925 0.52 0.3019 0.5418

Right PO 0.62 0.2684 0.4319 0.33 0.3708 0.5770

Right MidFG 0.62 0.2691 0.4319 0.23 0.4095 0.6109

Right pTFusC 0.62 0.269094 0.4319 0.45 0.3283 0.5466

Left PreCG 0.61 0.270574 0.4319 0.38 0.3533 0.5641

Right HG 0.59 0.2786 0.4398 0.53 0.2991 0.5418

Left Putamen 0.58 0.280586 0.439838 0.51 0.3070 0.5450

Right Pallidum 0.56 0.289716 0.449294 0.36 0.3610 0.5711

networks.DorsalAttention.FEF (right) 0.55 0.291783 0.449294 0.33 0.3714 0.5770

Right Cerebellum7 0.48 0.3166 0.4737 0.14 0.4459 0.6388

Right FP 0.47 0.3205 0.4737 0.47 0.3192 0.5466

Right pPaHC 0.47 0.320456 0.4737 0.2 0.4204 0.6134

Left SMA 0.47 0.321231 0.47368 0.44 0.3302 0.5466

networks.DefaultMode.PCC 0.45 0.325639 0.476145 0.19 0.4231 0.6134

Left PostCG 0.44 0.329028 0.4771 0.23 0.4118 0.6109

Left aSMG 0.42 0.336148 0.4834 0.32 0.3755 0.5783

Left aITG 0.38 0.351996 0.4997 0.53 0.3002 0.5418

Right SPL 0.38 0.3537 0.4997 0.13 0.4479 0.6388

networks.Salience.SMG (right) 0.37 0.357185 0.4997 0.23 0.4096 0.6109

Right toITG 0.36 0.358955 0.4997 0.04 0.4858 0.6708

Left ICC 0.3 0.382469 0.5262 0.4 0.3436 0.5571

Left toITG 0.26 0.397432 0.5403 ‐0.07 0.5282 0.7070

Left Cerebellum6 0.23 0.4078 0.5500 0.2 0.4195 0.6134

networks.SensoriMotor.Superior 0.13 0.447925 0.5995 ‐0.26 0.6033 0.7564

Right PreCG 0.12 0.453684 0.5996 ‐0.31 0.6207 0.7593

Left Pallidum 0.1 0.458877 0.5996 ‐0.1 0.5385 0.7099

Right SFG 0.1 0.4613 0.5996 0.07 0.4735 0.6591

Right PostCG 0.1 0.461782 0.5996 ‐0.24 0.5937 0.7564

networks.Salience.RPFC (left) 0.08 0.469715 0.603 ‐0.1 0.5381 0.7099

Right pSMG ‐0.04 0.516314 0.6372 ‐0.35 0.6348 0.7608

Right pITG ‐0.04 0.515173 0.6372 ‐0.27 0.6043 0.7564

Left Thalamus ‐0.03 0.512897 0.6371 ‐0.14 0.5550 0.7261

networks.Salience.Ainsula (right) ‐0.01 0.505763 0.6371 ‐0.33 0.6284 0.7593

Left pITG ‐0.1 0.538653 0.6600 ‐0.46 0.6755 0.7784

Left Cerebellum1 ‐0.12 0.547908 0.6621 0.07 0.4735 0.6591

networks.FrontoParietal.LPFC (right) ‐0.12 0.546297 0.6620 ‐0.31 0.6196 0.7593

Right Thalamus ‐0.13 0.55247 0.6629 ‐0.26 0.6034 0.7564

Left aTFusC ‐0.17 0.56912 0.6737 ‐0.23 0.5894 0.7564

Right aITG ‐0.17 0.565844 0.6737 ‐0.38 0.6491 0.7684

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Right Cerebellum10 ‐0.31 0.6195 0.7235 ‐0.58 0.7167 0.8205

Left Cerebellum8 ‐0.3 0.6182 0.7235 ‐0.44 0.6706 0.7784

Vermis8 ‐0.34 0.632984 0.734261 ‐0.31 0.6204 0.7593

Vermis10 ‐0.46 0.676231 0.779233 ‐0.32 0.6258 0.7593

Vermis3 ‐0.55 0.708044 0.799997 ‐0.64 0.7370 0.8328

Left Cerebellum45 ‐0.04 ‐0.6400 0.7375 ‐0.84 0.7971 0.8834

Right IFG ‐0.74 0.7703 0.8592 ‐1 0.8393 0.9015

networks.FrontoParietal.PPC (right) ‐0.83 0.795083 0.859282 ‐0.91 0.8174 0.8889

Left Cerebellum7 ‐0.82 0.7919 0.8593 ‐0.82 0.7923 0.8834

networks.Salience.RPFC ‐0.8 0.785704 0.859282 ‐0.88 0.8090 0.8853

Left Cerebellum3 ‐0.94 0.8239 0.8741 ‐1.30 0.9012 0.9446

Left Cerebellum6 ‐0.93 0.8211 0.8741 ‐1.14 0.8704 0.9263

Vermis9 ‐0.92 0.819925 0.874085 ‐0.61 0.7274 0.8272

Vermis7 ‐1.1 0.862065 0.909087 ‐1.18 0.8784 0.9263

networks.Cerebellar.Anterior ‐1.22 0.886194 0.928902 ‐1.15 0.8740 0.9263

Vermis12 ‐1.31 0.903056 0.9353 ‐1.35 0.9089 0.9470

Vermis45 ‐1.29 0.899115 0.9353 ‐1.49 0.9298 0.9560

Right Cerebellum45 ‐0.08 ‐1.3700 0.9118 ‐1.69 0.9521 0.9688

Left Cerebellum10 ‐1.42 0.9195 0.9411 ‐1.50 0.9310 0.9560

networks.Cerebellar.Posterior ‐1.58 0.940699 0.951638 ‐1.52 0.9341 0.9560

Brainstem ‐1.55 0.936584 0.951638 ‐1.89 0.9683 0.9739

Left Cerebellum2 ‐1.87 0.966999 0.9670 ‐1.83 0.9644 0.9739

Vermis6 ‐1.83 0.9640 0.9670 ‐2.18 0.9836 0.9836

Supplementary Table S7: Group differences (AH+>AH‐) in ROI to ROI functional connectivity between the left and right

MGN and the whole brain using Harvard‐Oxford atlas.

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Left AV Right AV

T value p‐value p‐value fdr T value p‐value p‐value fdr

Left pSMG 3.66 0.0005 0.0307 3.61 0.0006 0.0382

Left FOrb 3.65 0.0005 0.0307 3.43 0.0010 0.0382

Left aSTG 3.59 0.0006 0.0307 3.42 0.0011 0.0382

Left sLOC 3.51 0.0008 0.0307 3.41 0.0012 0.0382

Left PT 3.46 0.0009 0.0307 3.53 0.0007 0.0382

Left AG 3.42 0.0011 0.0307 3.16 0.0023 0.0502

networks.Language.pSTG (left) 3.31 0.0015 0.0336 3.18 0.0022 0.0502

Right TP 3.29 0.0016 0.0336 2.98 0.0040 0.0649

networks.DMN.LP (left) 3.26 0.0017 0.0336 3.03 0.0034 0.0649

Right PT 3.04 0.0034 0.0586 3.18 0.0022 0.0502

networks.DefaultMode.MPFC (left) 2.97 0.0041 0.0603 2.84 0.0059 0.0789

Left aMTG 2.96 0.0042 0.0603 2.73 0.0081 0.0870

Left TOFusC 2.9 0.0050 0.0673 2.97 0.0041 0.0649

Left pMTG 2.79 0.0067 0.0785 2.66 0.0097 0.0889

Left pSTG 2.79 0.0068 0.0785 2.69 0.0090 0.0870

Right Amygdala 2.72 0.0083 0.0903 2.92 0.0047 0.0682

Right pSTG 2.69 0.0089 0.0911 2.72 0.0083 0.0870

Left pTFusC 2.6 0.0112 0.1086 2.7 0.0087 0.0870

Right TOFusC 2.56 0.0125 0.1142 2.7 0.0086 0.0870

Right DMN.LP 2.47 0.0158 0.1379 2.38 0.0202 0.1529

Left IFG 2.41 0.0185 0.1469 2.21 0.0306 0.1836

Left HG 2.38 0.0200 0.1469 2.41 0.0185 0.1462

Right Language.pSTG 2.32 0.0202 0.0734 2.15 0.0348 0.1890

networks.FrontoParietal.PPC (left) 2.32 0.0234 0.1618 2.19 0.0319 0.1849

Left OFusG 2.29 0.0251 0.1618 2.44 0.0171 0.1462

Right Accumbens 2.27 0.0263 0.1635 2.07 0.0418 0.2079

networks.Visual.Lateral (left) 2.25 0.0273 0.1640 2.42 0.0182 0.1462

Left PP 2.2 0.0308 0.1786 2.25 0.0275 0.1710

Right iLOC 2.18 0.0323 0.1811 2.32 0.0235 0.1652

networks.Visual.Lateral (right) 2.16 0.0346 0.1855 2.27 0.0264 0.1704

Left MedFC 2.15 0.0352 0.1855 1.91 0.0601 0.2515

Left AC 2.12 0.0373 0.1862 1.98 0.0519 0.2317

Left IC 2.12 0.0375 0.1862 2.16 0.0343 0.1890

Left aPaHC 2.1 0.0394 0.1902 2.05 0.0441 0.2129

Left Amygdala 2.09 0.0406 0.1908 2.02 0.0477 0.2184

Right Caudate 2.07 0.0419 0.1918 1.95 0.0554 0.2408

Right pMTG 2.02 0.0473 0.1995 1.84 0.0693 0.2681

Left TP 2.01 0.0479 0.1995 1.66 0.1018 0.3261

networks.SensoriMotor.Lateral (left) 2.01 0.0479 0.1995 2.04 0.0453 0.2129

Right aPaHC 2.01 0.0482 0.1995 2.07 0.0418 0.2079

networks.Language.IFG (left) 1.92 0.0594 0.2402 1.77 0.0805 0.2882

Right IC 1.86 0.0672 0.2657 1.85 0.0690 0.2681

Left iLOC 1.82 0.0731 0.2825 2.09 0.0398 0.2079

Left SubCalC 1.81 0.0748 0.2829 1.7 0.0939 0.3204

Left SPL 1.78 0.0797 0.2851 1.9 0.0622 0.2515

Left PC 1.76 0.0823 0.2851 1.65 0.1035 0.3261

Right Cuneal 1.72 0.0893 0.2851 1.65 0.1042 0.3261

Left PO 1.72 0.0893 0.2851 1.9 0.0615 0.2515

Left MidFG 1.72 0.0906 0.2851 1.51 0.1367 0.3550

Left toMTG 1.71 0.0909 0.2851 1.47 0.1450 0.3550

Right sLOC 1.71 0.0912 0.2851 1.73 0.0875 0.3044

Left Accumbens 1.71 0.0918 0.2851 1.62 0.1098 0.3261

Right aMTG 1.67 0.0984 0.2952 1.35 0.1802 0.3882

Right aSTG 1.65 0.1030 0.3015 1.6 0.1151 0.3320

Left IFG 1.64 0.1050 0.3015 1.49 0.1415 0.3550

Right AG 1.63 0.1072 0.3015 1.47 0.1469 0.3550

Right toMTG 1.63 0.1083 0.3015 1.37 0.1764 0.3882

networks.FrontoParietal.LPFC (left) 1.62 0.1093 0.3015 1.48 0.1429 0.3550 networks.DorsalAttention.FEF (left) 1.61 0.1126 0.3015 1.81 0.0739 0.2796

Left SFG 1.6 0.1146 0.3015 1.34 0.1841 0.3882

Left CO 1.59 0.1170 0.3015 1.36 0.1791 0.3882

Left pPaHC 1.58 0.1192 0.3015 1.53 0.1310 0.3522

Right Hippocampus 1.58 0.1195 0.3015 1.52 0.1335 0.3522

Left Hippocampus 1.58 0.1195 0.3015 1.4 0.1670 0.3775

Left PaCiG 1.56 0.1242 0.3086 1.3 0.1979 0.4099

Left FO 1.54 0.1281 0.3138 1.62 0.1106 0.3261

Left LG 1.51 0.1355 0.3274 1.59 0.1165 0.3320

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Right PP 1.49 0.1414 0.3280 1.45 0.1529 0.3595 networks.SensoriMotor.Lateral (right) 1.46 0.1478 0.3385 1.54 0.1280 0.3522

Right FOrb 1.36 0.1779 0.3969 1.22 0.2268 0.4363

Left aITG 1.34 0.1839 0.4051 1.23 0.2238 0.4363

Right CO 1.32 0.1913 0.4109 1.36 0.1791 0.3882

Right OFusG 1.3 0.1966 0.4172 1.52 0.1336 0.3522

Right SCC 1.28 0.2053 0.4305 1.41 0.1621 0.3710

Right FO 1.23 0.2239 0.4546 1.28 0.2040 0.4176

networks.Salience.SMG (left) 1.22 0.2248 0.4546 1.24 0.2179 0.4309

Right LG 1.2 0.2339 0.4546 1.34 0.1830 0.3882

Left FP 1.19 0.2391 0.4546 1.21 0.2307 0.4363

networks.Visual.Occipital (right) 1.18 0.2433 0.4546 1.42 0.1605 0.3710

Left Cuneal 1.18 0.2438 0.4546 1.17 0.2456 0.4498

Right Putamen 1.18 0.2439 0.4546 1.2 0.2348 0.4393

Right IFG 1.17 0.2448 0.4546 ‐1.18 0.2417 0.4474

Left Putamen 1.17 0.2456 0.4546 1.21 0.2295 0.4363

Left SCC 1.12 0.2656 0.4814 1.05 0.2961 0.4771

Right PaCiG 1.12 0.2684 0.4815 1.08 0.2844 0.4625

networks.DorsalAttention.FEF (right) 1.1 0.2747 0.4877 1.09 0.2781 0.4625

Right OP 1.07 0.2882 0.5015 1.25 0.2138 0.4309

networks.Language.IFG (right) 1.03 0.3055 0.5161 0.97 0.3368 0.5232

networks.DorsalAttention.IPS (left) 0.96 0.3387 0.5425 1.1 0.2762 0.4625

networks.Visual.Medial 0.96 0.3398 0.5425 1.1 0.2749 0.4625

Left Caudate 0.94 0.3487 0.5452 0.82 0.4129 0.5889

networks.Salience.Ainsula (left) 0.92 0.3602 0.5538 0.95 0.3460 0.5328

Left Precuneous 0.91 0.3640 0.5538 0.7 0.4873 0.6624

Left PreCG 0.91 0.3660 0.5538 0.89 0.3757 0.5676

Right MidFG 0.88 0.3815 0.5723 0.84 0.4049 0.5823

Right pTFusC 0.83 0.4069 0.6001 0.89 0.3750 0.5676

Left OP 0.82 0.4131 0.6017 1.09 0.2778 0.4625

Right FP 0.82 0.4150 0.6017 0.88 0.3842 0.5676

Right SMA 0.81 0.4204 0.6046 0.98 0.3293 0.5161

Left SMA 0.79 0.4307 0.6143 0.87 0.3849 0.5676

networks.Salience.ACC 0.75 0.4559 0.6447 0.8 0.4271 0.6042

networks.DefaultMode.PCC 0.74 0.4629 0.6447 0.52 0.6041 0.7350

Left Cerebellum9 0.74 0.4632 0.6447 0.63 0.5290 0.6869

Left pITG 0.67 0.5026 0.6893 0.66 0.5140 0.6776

Right toITG 0.66 0.5135 0.6893 0.77 0.4444 0.6236

Right HG 0.66 0.5146 0.6893 0.73 0.4675 0.6457

Right SFG 0.65 0.5150 0.6893 0.61 0.5452 0.7027

Left PostCG 0.64 0.5263 0.6951 0.68 0.4986 0.6726

Left aTFusC 0.63 0.5313 0.6951 0.59 0.5556 0.7097

networks.DorsalAttention.IPS (right) 0.62 0.5398 0.6995 0.88 0.3824 0.5676

Right ICC 0.61 0.5449 0.6995 0.75 0.4554 0.6340

Right PO 0.57 0.5726 0.7220 0.66 0.5093 0.6764

networks.FrontoParietal.LPFC (right) 0.52 0.6048 0.7464 0.56 0.5750 0.7118

Right pPaHC 0.48 0.6359 0.7737 0.41 0.6831 0.7718

Right PreCG 0.46 0.6469 0.7816 0.47 0.6367 0.7587

Right aTFusC 0.42 0.6730 0.7965 0.38 0.7057 0.7764

networks.Salience.RPFC (left) 0.42 0.6751 0.7965 0.44 0.6578 0.7681

Right aSMG 0.42 0.6775 0.7965 0.49 0.6225 0.7522

Left Cerebellum1 0.38 0.7018 0.8087 ‐0.46 0.6471 0.7659

Left aSMG 0.34 0.7342 0.8295 0.53 0.5958 0.7301

Right SPL 0.32 0.7483 0.8346 0.56 0.5765 0.7118

Right Pallidum 0.31 0.7604 0.8405 0.33 0.7458 0.8030

Right PostCG 0.3 0.7688 0.8405 0.28 0.7825 0.8354

Right pITG 0.29 0.7729 0.8405 0.26 0.7961 0.8447

Left Thalamus 0.25 0.8000 0.8539 0.16 0.8762 0.9021

Left ICC 0.23 0.8164 0.8581 0.39 0.6992 0.7764

Left Cerebellum6 0.23 0.8186 0.8581 0.22 0.8258 0.8708

Left toITG 0.2 0.8383 0.8735 0.34 0.7382 0.8028

Right aITG 0.13 0.8982 0.9194 ‐0.11 0.9128 0.9278

Left Pallidum 0.12 0.9063 0.9222 0.16 0.8747 0.9021

networks.SensoriMotor.Superior 0.07 0.9448 0.9520 0.10 0.9172 0.9278

Left Cerebellum8 0 0.9961 0.9961 ‐0.21 0.8376 0.8727

Right Thalamus ‐0.07 0.9465 0.9520 ‐0.08 0.9354 0.9408

networks.Salience.SMG (right) ‐0.17 0.8647 0.8951 0.03 0.9789 0.9789

Right pSMG ‐0.17 0.8694 0.8951 ‐0.13 0.8995 0.9207

networks.Salience.Ainsula (right) ‐0.23 0.8151 0.8581 ‐0.21 0.8316 0.8717

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Right Cerebellum1 ‐0.35 0.7237 0.8230 0.32 0.7476 0.8030

Left Cerebellum7 ‐0.36 0.7210 0.8230 ‐0.40 0.6914 0.7761

Vermis8 ‐0.39 0.7003 0.8087 ‐0.41 0.6830 0.7718

networks.FrontoParietal.PPC (right) ‐0.4 0.6886 0.8042 ‐0.37 0.7092 0.7764

Vermis3 ‐0.49 0.6271 0.7684 ‐0.58 0.5641 0.7113

networks.Salience.RPFC (right) ‐0.53 0.5956 0.7402 ‐0.48 0.6349 0.7587

Left Cerebellum45 ‐0.54 0.5907 0.7395 ‐0.67 0.5059 0.6764

networks.Cerebellar.Posterior ‐0.94 0.3509 0.5452 ‐1.04 0.3003 0.4794

networks.Cerebellar.Anterior ‐0.95 0.3432 0.5428 ‐1.09 0.2807 0.4625

Vermis10 ‐0.97 0.3348 0.5425 ‐0.72 0.4716 0.6461

Left Cerebellum3 ‐0.99 0.3272 0.5370 ‐0.84 0.4049 0.5823

Vermis12 ‐1.06 0.2927 0.5026 ‐1.14 0.2602 0.4625

Vermis9 ‐1.06 0.2946 0.5026 ‐0.98 0.3284 0.5161

Left Cerebellum2 ‐1.14 0.2564 0.4697 ‐1.24 0.2179 0.4309

Right IFG ‐1.18 0.2420 0.4546 1.13 0.2616 0.4625

Vermis45 ‐1.19 0.2366 0.4546 ‐1.47 0.1469 0.3550

Vermis7 ‐1.33 0.1876 0.4080 ‐1.34 0.1852 0.3882

Left Cerebellum10 ‐1.5 0.1389 0.3280 ‐1.45 0.1527 0.3595

Vermis6 ‐1.69 0.0960 0.2930 ‐1.77 0.0812 0.2882

Brainstem ‐1.72 0.0899 0.2851 ‐1.62 0.1102 0.3261

Supplementary Table S8: Group differences (AH+>AH‐) in ROI to ROI functional connectivity between the left and right AV and the whole brain using Harvard‐Oxford atlas.

Legend of abbreviations

AC: Cingulate Gyrus, anterior division AG : Angular Gyrus

aITG : Inferior Temporal Gyrus, anterior division aPhG : Parahippocampal Gyrus, anterior division aSMG : Supramarginal Gyrus, anterior division aTFusC : Fusiform Gyrus, anterior division CC : Cuneal Cortex

COpC : Central Opercular Cortex FMC : Frontal Medial Cortex FOpC : Frontal Operculum Cortex FOrb: Orbitofrontal Cortex FP : Frontal Pole

HG : Heschl's Gyrus ICC : Intracalcarine Cortex

IFGpo : Inferior Frontal Gyrus, pars opercularis IFGpt : Inferior Frontal Gyrus, pars triangularis IC : Insular Cortex

LG : Lingual Gyrus

iLOC : Lateral Occipital Cortex, inferior division sLOC : Lateral Occipital Cortex, superior division aMTG : Middle Temporal Gyrus, anterior division pMTG : Middle Temporal Gyrus, posterior division tpMTG : Middle Temporal Gyrus, temporooccipital part OcP : Occipital Pole

OFusG : Occipital Fusiform Gyrus

PaCiG : Paracingulate Gyrus

pPaG : Parahippocampal Gyrus, posterior division PC : Cingulate Gyrus, posterior division

PcC : Precuneous Cortex PcG : Paracingulate Gyrus

pITG : Inferior Temporal Gyrus, posterior division PoG : Postcentral Gyrus

POpC : Parietal Operculum Cortex PP : Planum Polare

PreCG : Precentral Gyrus

pSMG : Supramarginal Gyrus, posterior division PT : Planum Temporale

pTFusC: Fusiform Gyrus, posteriori division ScC : Subcallosal Cortex

SccC : Supracalcarine Cortex SFG : Superior Frontal Gyrus SMC : Juxtapositional Lobule Cortex SPL : Superior Parietal Lobule SPL : Superior Parietal Lobule

STGa : Superior Temporal Gyrus, anterior division STGp : Superior Temporal Gyrus, posterior division TOFusC : Temporal Occipital Fusiform Cortex TP : Temporal Pole

tpITG : Inferior Temporal Gyrus, temporooccipital part

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Regions involved in FC Correlation with FD Correlation with % of valid scans

Pearson r p‐value Pearson r p‐value

L_MGN‐ R_TP ‐ 0.067 0.576 ‐ 0.017 0.147

L_MGN‐ L_PT ‐ 0.041 0.731 ‐ 0.026 0.047

L_MGN‐ L_aSTG ‐ 0.024 0.299 0.022 0.853

L_MGN‐L_DMN ‐ 0.021 0.859 ‐ 0.040 0.741

L_MGN L_TOFusC 0.118 0.324 ‐ 0.104 0.385

L_MGN R_TOFusC ‐ 0.119 0.320 ‐0.111 0.189

L_MGN L_sLOC ‐ 0.012 0.920 ‐ 0.145 0.048

R_MGN R_TP ‐ 0.105 0.152 ‐ 0.019 0.874

R_MGN L_aSTG ‐ 0.158 0.187 ‐ 0.018 0.218

R_MGN L_PT ‐ 0.142 0.045 ‐ 0.085 0.483

L_AV L_pSMG 0.132 0.271 ‐ 0.126 0.072

L_AV L_Forb ‐ 0.118 0.324 ‐ 0.193 0.112

L_AV L_aSTG ‐ 0.084 0.481 ‐ 0.137 0.095

L_AV L_sLOC ‐ 0.057 0.636 ‐ 0.128 0.074

L_AV L_PT ‐ 0.017 0.890 ‐ 0.130 0.115

L_AV L_AG ‐ 0.030 0.804 ‐0.116 0.171

L_AV language_network ‐ 0.043 0.721 ‐ 0.121 0.313

L_AV R_TP ‐ 0.128 0.285 ‐ 0.141 0.238

L_AV DMN ‐ 0.063 0.601 ‐ 0.042 0.725

R_AV L_pSMG 0.139 0.243 0.058 0.225

R_AV L_Forb ‐ 0.118 0.324 0.124 0.299

R_AV L_aSTG ‐ 0.102 0.394 0.154 0.196

R_AV L_sLOC ‐ 0.042 0.726 0.171 0.150

L_AV L_PT ‐ 0.019 0.874 ‐ 0.042 0.240

R_AV L_AG ‐ 0.035 0.770 0.116 0.333

R_AV language_network ‐ 0.027 0.821 0.136 0.256

Supplementary Table S9: Pearson’s correlations between measures of average FC and framewise displacement (FD) and the percentage of valid scans. The percentage of valid scans refers to the number of scans that survived after censoring bad data points (defined as data points with a global‐signal z‐value higher than 3 or mean motion measured with FD higher than 0.5 mm) from the data.

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VTA

T value p‐value

Left Hippocampus 0.58 0.045 Right Hippocampus ‐0.17 0.556

Supplementary Table S10: Comparison of left and right hippocampal fc with VTA between 22qdel with and without hallucinations.

_Left CA1 _Right CA1

R value p‐value fdr R value p‐value fdr

Left Re 0.190 0.019 0.181 0.029

Right Re 0.139 0.087 0.229 0.006

Supplementary Table S11: correlation between the volume of nucleus reuniens (Re) and the volume of the CA1 subfield

of the hippocampus.

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Figure S1. ROI‐to‐ROI functional connectivity of the (A‐C) left and right (B‐D) MGN with the rest of the brain in 22qdel with (A‐B) and without (C‐D) AH. All the ROIs are displayed with relative values of FC. F‐values of ROI‐to‐ROI FC representing the relative strength of the connections are expressed with a color code in the figure.

A B

C D

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Figure S2. ROI‐to‐ROI functional connectivity of the (A‐C) left and right (B‐D) AV nucleus with the rest of the brain in 22qdel with (A‐B) and without (C‐D) AH. All the ROIs are displayed with relative values of FC. F‐values of ROI‐to‐ROI FC representing the relative strength of the connections are expressed with a color code in the figure.

A B

C D

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Figure S3. ROI‐to‐ROI functional connectivity of the: A) left Medial geniculate nucleus (MGN), B) right MGN, C) left anteroventral nucleus (AV), D) right anteroventral nucleus (AV) with the rest of the brain. All the ROIs with a statistically significant increased FC with MGN before correction for multiple comparisons in 22qdel with AH are showed. T‐values of ROI‐to‐ROI FC are expressed with a color code displayed in the figure.

A B

C D