Sex Differences and the Neural Substrates of Repetitive Behavior and Restricted Interests

Background: Repetitive behaviors and restricted interests (RBRI) are a broad and heterogeneous set of behaviors and thoughts that include stereotypic motor movements, compulsions, tics, self-injury, as well as obsessions, circumscribed interest patterns, perseverative thought and speech. RBRI are defining features of a range of neurodevelopmental and neuropsychiatric disorders (NDD/NPD), including autism, obsessive-compulsive disorders (OCD), tic disorders, intellectual and developmental conditions. In addition to their clinical significance, RBRI are also common in typically-developing children. Across NDD/NPD RBRI have established links to cortical-striatal-thalamo-cortical pathways, however the degree to which typical and atypical RBRI are subserved by common neural mechanisms is unclear. Structural sex differences in these pathways have also been observed which may indicate a mechanism for the male preponderance of many neurodevelopmental conditions involving repetitive behaviour, such as autism.

Objectives: To examine sex differences in RBRI and gray matter (GM) volume of cortical and subcortical brain regions that have been implicated in the pathogenesis of disorders characterized by RBRI.

Methods: Thirty-three children aged 6 to 15 years (17 females) underwent a 3T structural T1 magnetic resonance imaging scan. GM classification was performed using the Voxel Based Morphometry in SPM8 (Ashburner & Friston, 2000). SPM combines spatial information from the tissue probability map (TPM) of a standard template and the intensity information of the subject image to construct the segmented GM TPM of the individual. The value at a GM TPM voxel represents the percentage of GM content in that voxel (corrected for overall GM volume). GM TPMs were further segmented into 116 AAL atlas regions (Tzourio-Mazoyer, et al, 2002). We then calculated the average GM content in the following bilateral brain regions: supplementary motor area, cingulate cortex, caudate nucleus, putamen, globus pallidus, and amygdala. Parents completed the Childhood Routines Inventory-Revised (Evans et al., 2017). This is a 62-item measure of RBRI that was normed nationally, and reflects a two-factor structure: Repetitive Motor Behaviors/Compulsions (RMBC) and Rigidity/Insistence on Sameness (RIS).

Results: For males, the RMBC factor was significantly and positively linked to GM volumes of the left supplementary motor area, the left inferior frontal gyrus (pars triangularis) and the left cingulum. The anterior cingulum is further divided into anterior, middle, and posterior regions. For males, RMBC correlated with the left (r(16)=.82, p=0.00009) and right (r(16)=.84, p=0.00008) middle , and with the left (r=.52, p=.04) and right (r=.54, p=.04) anterior cingulum, but not the posterior cingulum.

For female participants, a distinctly different pattern emerged. The RMBC factor was significantly, and negatively associated with both the left and right caudate nucleus, and the left putamen, and left amygdala (see Table 1).

Conclusions: This preliminary study suggests that there are sex differences in key brain regions implicated in RBRI. These findings have potentially important implications for understanding the brain-behavior links that underlie neurodevelopmental conditions. Our future research will conduct similar analyses on a larger sample comprising both typically-developing individuals and a well-characterized cohort of probands with autism.