Bidirectional Causal Connectivity in the Cortico-Limbic-Cerebellar Circuit Related to Structural Alterations in First-Episode, Drug-Naive Somatization Disorder

Abstract

Background: Anatomical and functional deficits in the cortico-limbic-cerebellar circuit are involved in the neurobiology of somatization disorder (SD). The present study was performed to examine causal connectivity of the cortico-limbic-cerebellar circuit related to structural deficits in first-episode, drug-naive patients with SD at rest. Methods: A total of 25 first-episode, drug-naive patients with SD and 28 healthy controls underwent structural and resting-state functional magnetic resonance imaging. Voxel-based morphometry and Granger causality analysis (GCA) were used to analyze the data. Results: Results showed that patients with SD exhibited decreased gray matter volume (GMV) in the right cerebellum Crus I, and increased GMV in the left anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), and left angular gyrus. Causal connectivity of the cortico-limbic-cerebellar circuit was partly affected by structural alterations in the patients. Patients with SD showed bidirectional cortico-limbic connectivity abnormalities and bidirectional cortico-cerebellar and limbic-cerebellar connectivity abnormalities. The mean GMV of the right MFG was negatively correlated with the scores of the somatization subscale of the symptom checklist-90 and persistent error response of the Wisconsin Card Sorting Test (WCST) in the patients. A negative correlation was observed between increased driving connectivity from the right MFG to the right fusiform gyrus/cerebellum IV, V and the scores of the Eysenck Personality Questionnaire extraversion subscale. The mean GMV of the left ACC was negatively correlated with the WCST number of errors and persistent error response. Negative correlation was found between the causal effect from the left ACC to the right middle temporal gyrus and the scores of WCST number of categories achieved. Conclusions: Our findings show the partial effects of structural alterations on the cortico-limbic-cerebellar circuit in first-episode, drug-naive patients with SD. Correlations are observed between anatomical alterations or causal effects and clinical variables in patients with SD, and bear clinical significance. The present study emphasizes the importance of the cortico-limbic-cerebellar circuit in the neurobiology of SD.

Keywords: cortico-limbic-cerebellar; granger causality analysis; gray matter volume; resting-state functional magnetic resonance imaging; somatization disorder; voxel-based morphometry.

Figure 1

Hypothesized model in first-episode, drug-naive somatization disorder: overall reduced causal connectivities in the cortico-limbic-cerebellar circuit.

Figure 2

Regions with abnormal gray matter volume in the patients.

Figure 3

Integrated model of voxel-wise Granger causality analyses in first-episode, drug-naive somatization disorder (Seed-to-Whole-Brain Analyses): affected causal connectivities in the cortico-limbic-cerebellar circuit (A). Brain regions and circuitry implicated in first-episode, drug naive somatization disorder (Seed-to-Whole-Brain Analyses) (B). MFG, Middle Frontal gyrus; MPFC, Medial Prefrontal Cortex; ACC, Anterior Cingulate Cortex; MCC, Middle Cingulate Cortex; PCC, Posterior Cingulate Cortex; AG, Angular Gyrus; Cere Crus, Cerebellum Crus; Cere Vermis, Cerebellum Vermis; Lingual/Cere, Lingual Gyrus/Cerebellum Vermis; Fusiform/Cere, Fusiform Gyrus/Cerebellum. Lateral cortical regions are shown in red, medial cortical regions in blue, subcortical regions in green, and cerebellum regions in purple. The functional pathways in (A,B) are indicated with red arrows (excitatory effect) and blue arrows (inhibitory effect).

Figure 4

Integrated model of voxel-wise Granger causality analyses in first-episode, drug-naive somatization disorder (Whole-Brain-to-Seed Analyses): affected causal connectivities in the cortico-limbic-cerebellar circuit (A). Brain regions and circuitry implicated in first-episode, drug naive somatization disorder (Whole-Brain-to-Seed Analyses) (B). MFG, Middle Frontal gyrus; MPFC, Medial Prefrontal Cortex; ACC, Anterior Cingulate Cortex; MCC, Middle Cingulate Cortex; PCC, Posterior Cingulate Cortex; AG, Angular Gyrus; Cere Crus, Cerebellum Crus; Cere Vermis, Cerebellum Vermis; Lingual/Cere, Lingual Gyrus/Cerebellum Vermis; Fusiform/Cere, Fusiform Gyrus/Cerebellum. Lateral cortical regions are shown in red, medial cortical regions in blue, subcortical regions in green, and cerebellum regions in purple. The functional pathways in (A,B) are indicated with red dotted arrows (positive feedback) and blue dotted arrows (negative feedback).

Figure 5

Correlations between abnormal GMV or causal effects and clinical variables in patients with somatization disorder. GMV, gray matter volume; ACC, anterior cingulate cortex; WCST, Wisconsin Card Sorting Test; WCST-Pre, persistent error response of WCST; MFG, middle frontal gyrus; MTG, middle temporal gyrus.