A multi-modal MRI analysis of brain structure and function in relation to OXT methylation in maltreated children and adolescents

Shota Nishitani,Akiko Yao,Daiki Hiraoka,Koji Shimada,Shinichiro Takiguchi,Akemi Tomoda,Kai Makita,Takashi X Fujisawa,Shoko Hamamura,Alicia K Smith

doi:10.1038/s41398-021-01714-y

Abstract

Child maltreatment dysregulates the brain’s oxytocinergic system, resulting in dysfunctional attachment patterns. However, how the oxytocinergic system in children who are maltreated (CM) is epigenetically affected remains unknown. We assessed differences in salivary DNA methylation of the gene encoding oxytocin (OXT) between CM (n = 24) and non-CM (n = 31), alongside its impact on brain structures and functions using multi-modal brain imaging (voxel-based morphometry, diffusion tensor imaging, and task and resting-state functional magnetic resonance imaging). We found that CM showed higher promoter methylation than non-CM, and nine CpG sites were observed to be correlated with each other and grouped into one index (OXTmi). OXTmi was significantly negatively correlated with gray matter volume (GMV) in the left superior parietal lobule (SPL), and with right putamen activation during a rewarding task, but not with white matter structures. Using a random forest regression model, we investigated the sensitive period and type of maltreatment that contributed the most to OXTmi in CM, revealing that they were 5–8 years of age and physical abuse (PA), respectively. However, the presence of PA (PA+) was meant to reflect more severe cases, such as prolonged exposure to multiple types of abuse, than the absence of PA. PA+ was associated with significantly greater functional connectivity between the right putamen set as the seed and the left SPL and the left cerebellum exterior. The results suggest that OXT promoter hypermethylation may lead to the atypical development of reward and visual association structures and functions, thereby potentially worsening clinical aspects raised by traumatic experiences.

Highlights

Child abuse and neglect have severe consequences on the developing brain, even extending into adulthood [1]
OXT methylation index (OXTmi) and brain structures and functions OXTmi was negatively correlated with the regional gray matter volume (GMV) in the left superior parietal lobule (SPL; Fig. 2A) (Broadman area (BA) 7; MNI x = −17, y = −56, z = 65, T = 4.50; cluster size = 157 voxels, P = 0.047, FDR-corrected for cluster level)
We assessed the relationship between OXTmi and brain structures and functions using multi-modal MRI and found that the greater the OXTmi, the smaller the left SPL GMV

Summary

Introduction

Child abuse and neglect (child maltreatment) have severe consequences on the developing brain, even extending into adulthood [1]. It has been widely reported that adults who were abused growing up develop atypical and vulnerable brain substrates [2,3,4,5], resulting in a broad range of psychiatric disorders and higher rates of suicide. The development of neocortical regions, which are essential for regulating social interactions such as interpersonal relationships, undergoes major structural and functional reorganization during adolescence and young adulthood [6]. It is crucial to identify a target neurobiological mechanism which can be used to intervene in children who were maltreated (CM) prior to this completion of brain reorganization to improve their subsequent quality of life and break the intergenerational transmission of child maltreatment. We assessed the neurobiological impact of child maltreatment using cognitive and clinical assessments [10,11,12] and brain imaging [13,14,15,16] under the care of appropriate institutions

Methods

Results

Conclusion