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. 2015 Apr 30;10(4):e0125286.
doi: 10.1371/journal.pone.0125286. eCollection 2015.

Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder

Joshua Manning  1 , Gretchen Reynolds  2 , Zeynep M Saygin  1 , Stefan G Hofmann  3 , Mark Pollack  4 , John D E Gabrieli  5 , Susan Whitfield-Gabrieli  5
Affiliations

Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder

Joshua Manning et al. PLoS One. .

Abstract

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

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Conflict of interest statement

Competing Interests: Dr. Pollack is a member of the advisory boards as a consultant for Corcept Therapeutics, Eli Lilly, Ironwood Pharmaceuticals, Medavante, Merck, and Targia Pharmaceuticals. Dr. Pollack holds equity in Doyen Medical, Medavante, Mensante Corporation, Mindsite, and Targia Pharmaceuticals. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Nucleus Accumbens Seed.
Bilateral nucleus accumbens seed used in resting-state functional connectivity analysis. MNI coordinates: (-8,12,1), (11,11,1).
Fig 2
Fig 2. Nucleus Accumbens Seed Functional Connectivity Network of Control > SAD.
Resting-state connectivity for (A) Control group, (B) SAD group, and (C) Control group > SAD group with bilateral nucleus accumbens seed from Fig 1 (Cluster-wise FDR corrected, p < .05; Peak voxel: (MNI Coordinates) (30, 12, -6; p = .001). (vmPFC = ventromedial prefrontal cortex).
Fig 3
Fig 3. Peak Voxel Axial View for Nucleus Accumbens Seed Functional Connectivity Network of Control > SAD.
Resting-state connectivity for Control group > SAD group with bilateral nucleus accumbens seed from Fig 1 (Cluster-wise FDR corrected, p < .05; Peak voxel: (MNI Coordinates) (30, 12, -6; p = .001). (vmPFC = ventromedial prefrontal cortex).
Fig 4
Fig 4. Nucleus Accumbens Seed Functional Connectivity Network Z-Scores of Control > SAD.
Mean Fisher transformed correlation values for resting-state connectivity for ventromedial prefrontal cortex cluster from Fig 2C showing significant difference for Control group > SAD group with bilateral nucleus accumbens seed from Fig 1. Peak voxel (MNI coordinates): (30, 12, -6). Bars represent mean connectivity for each group for the ventromedial prefrontal cluster from Fig 2C. One-sample t-test relative to 0: Control: p < .0001; SAD: p = .22. Error bars represent standard errors.
Fig 5
Fig 5. Nucleus Accumbens Seed Functional Connectivity Network of SAD > Control and Z-Scores.
(A) Resting-state connectivity for SAD group > Control group with bilateral nucleus accumbens seed from Fig 1 (Cluster-wise FDR corrected, p < .05; Peak voxel: (MNI Coordinates) (0, -34, 64; p = .006). (B) Mean Fisher transformed correlation values for resting-state connectivity for cluster from Fig 5A showing significant difference for SAD group > Control group with bilateral nucleus accumbens seed from Fig 1. Peak voxel (MNI coordinates): (0, -34, 64). Bars represent the mean connectivity among for each group for the ventromedial prefrontal cluster from Fig 5A. One-sample t-test relative to 0: Control: p < .0001; SAD: p = .07. Error bars represent standard errors.
Fig 6
Fig 6. Ventromedial Prefrontal Cortex Seed Functional Connectivity Network.
(A) Ventromedial prefrontal cortex seed used in resting-state functional connectivity analysis. MNI coordinates: (-6, 24, -21), (6, 30, -9), (9, 27, -12). (B) Resting-state connectivity for Control group > SAD group with ventromedial prefrontal cortex seed from Fig 6A (Cluster-wise FDR corrected, p < .05). Peak voxel (MNI coordinates): (-12, 20, -20; p < .001). (C) Resting-state connectivity for SAD group > Control group with ventromedial prefrontal cortex seed from Fig 6A (Cluster-wise FDR corrected, p < .05). Peak voxel cluster 1 (MNI coordinates): (6, -42, 60; p = .001). Peak voxel cluster 2 (MNI coordinates: (20, -50, 6; p = .002). Peak voxel cluster 3 (MNI coordinates): (-50, -56, -4; p = .006).
Fig 7
Fig 7. Peak Voxel Axial View for Ventromedial Prefrontal Cortex Seed Functional Connectivity Network of Control > SAD.
Resting-state connectivity for Control group > SAD group with ventromedial prefrontal cortex seed from Fig 6A (Cluster-wise FDR corrected, p < .05). Peak voxel (MNI coordinates): (-12, 20, -20); p < .001).
Fig 8
Fig 8. Ventromedial Prefrontal Cortex Seed Functional Connectivity Network Z-Scores of Control > SAD.
Mean Fisher transformed correlation values for resting-state connectivity for clusters from Fig 5B showing significant difference for Control group > SAD group with ventromedial prefrontal cortex seed from Fig 6A. Bars represent the mean connectivity for each group for the medial prefrontal cluster from Fig 6B. Peak voxel Cluster 1 (MNI coordinates): (-12, 20, -20). One-sample t-test relative to 0: Control: p < .0001. SAD p < .0001. Error bars represent standard errors.
Fig 9
Fig 9. Ventromedial Prefrontal Cortex Seed Functional Connectivity Network Z-Scores of SAD > Control.
Mean Fisher transformed correlation values for resting-state connectivity for clusters from Fig 6C showing significant difference for SAD group > Control group with ventromedial prefrontal cortex seed from Fig 6A. Bars represent the mean connectivity for each group for the clusters from Fig 6C. (A) Peak voxel Cluster 1 (MNI coordinates): (6, -42, 60). One-sample t-test relative to 0: Control: p = .003; SAD: p = .001. (B) Peak voxel Cluster 2 (MNI coordinates): (20, -50, 6). One-sample t-test relative to 0: Control: p < .0001; SAD: p .031. (C) Peak voxel Cluster 3 (MNI coordinates): (-50, -56, -4). One-sample t-test relative to 0: Control: p < .0001; SAD: p = .58. Error bars represent standard errors.
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