Aberrant Hippocampal Development in Early-onset Mental Disorders and Promising Interventions: Evidence from a Translational Study
Jingyu Yang1 · Huiling Guo1,2 · Aoling Cai1,2,3 · Junjie Zheng1 · Juan Liu1 · Yao Xiao1 · Sihua Ren4 · Dandan Sun5 · Jia Duan1 · Tongtong Zhao1 · Jingwei Tang1 · Xizhe Zhang2 · Rongxin Zhu1 · Jie Wang6,7 · Fei Wang1,81 Early Intervention Unit, Department of Psychiatry, Afliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing 210029, China
2 School of Biomedical Engineering and Informatics, Nanjing, Medical University, Nanjing 211166, China
3 The Afliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213004, China
4 Department of Radiology, First Hospital of China Medical University, Shenyang 110002, China
5 Department of Cardiac Function, The People’s Hospital of China Medical University and the People’s Hospital of Liaoning Province, Shenyang 110067, China
6 Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan 430064, China
7 Institute of Neuroscience and Brain Diseases; Xiangyang Central Hospital, Afliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China
8 Functional Brain Imaging Institute of Nanjing Medical University, Nanjing 210029, China
Abstract
Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence. The methylazoxymethanol acetate (MAM) animal model, in which disruption in neurodevelopmental processes is induced, mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective. We conducted longitudinal structural magnetic resonance imaging (MRI) scans during childhood, adolescence, and adulthood in MAM rats to identify specific brain regions and critical windows for intervention. Then, the effect of repetitive transcranial magnetic stimulation (rTMS) intervention on the target brain region during the critical window was investigated. In addition, the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders (diagnosed with major depressive disorder or bipolar disorder) to evaluate its clinical translational potential. The results demonstrated that, compared to the control group, the MAM rats exhibited significantly lower striatal volume from childhood to adulthood (all P <0.001). In contrast, the volume of the hippocampus did not show significant differences during childhood (P >0.05) but was significantly lower than the control group from adolescence to adulthood (both P <0.001). Subsequently, rTMS was applied to the occipital cortex, which is anatomically connected to the hippocampus, in the MAM models during adolescence. The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group (P <0.01), while the volume of the striatum remained unchanged (P >0.05). In the clinical trial, adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline (P <0.01), and these volumetric changes were associated with improvement in depressive symptoms (r = − 0.524, P = 0.018). These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for early-onset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.
Keywords
Early-onset; Mental disorder; Neurodevelopment; Animal model; Hippocampus; Repetitive transcranial magnetic stimulation
