Right amygdala–right precuneus connectivity is associated with childhood trauma in major depression patients and healthy controls

Right amygdala–right precuneus connectivity is associated with childhood trauma in major depression patients and healthy controls Jie Fan,1,2,3 Feng Gao,1 Xiang Wang,1 Qian Liu,1 Jie Xia,1 Yan Han,1 Jinyao Yi,1 Changlian Tan,4 and Xiongzhao Zhu 1,2,3 Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China Medical Psychological Institute of Central South University, Changsha, Hunan 410011, China 3 National Clinical Research Center for Mental Disorders, Changsha, Hunan 410011, China 4 Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China Correspondence should be addressed to Xiongzhao Zhu, Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. E-mail: . 2 Abstract The present study investigated the effect of childhood trauma (CT) on amygdala and hippocampus functional connectivity (FC) and the association with clinical presentations of major depressive disorder (MDD). Participants included 73 MDD patients (42 with moderateto-severe CT and 31 with no or low CT) and 64 healthy controls (HC; 30 with moderate-to-severe CT and 34 with no or low CT). Seed-based whole-brain resting-state FC analyses were performed with seeds located in amygdala and hippocampus. Individuals with moderateto-severe CT, irrespective of MDD diagnosis, had decreased right amygdala–right precuneus connectivity compared to those with no or low CT. Right amygdala–right precuneus connectivity was significantly correlated with physical and social trait anhedonia in MDD. Mediation effects of this FC on relationship between CT (specifically neglect but not abuse) and trait anhedonia in MDD were significant. MDD patients demonstrated increased right amygdala–left middle frontal gyrus FC, decreased right amygdala–right medial superior frontal gyrus (mSFG) FC and decreased right hippocampus–bilateral mSFG FC relative to HC. Findings highlight the effect of CT on right amygdala–right precuneus FC irrespective of MDD diagnosis. FC of right amygdala–right precuneus may be involved in the mechanism linking CT and depression through its association with trait anhedonia. Key words: childhood trauma; trait anhedonia; depression; amygdala; hippocampus Introduction Major depressive disorder (MDD) is one of the most common psychiatric conditions, of which the core symptoms were low mood and anhedonia. Previous studies have well established that childhood trauma (CT) is one of the strongest risk factors in the development of later-life MDD (Tunnard et al., 2014); however, the precise mechanism by which CT leads to MDD remains unclear. CT putting individuals at risk for mental health problems is probably due to its effect on the developing brain, as during childhood, the brain is immature, and the brain structure and function might be modified by the traumatic events to a relatively great extent (Glaser, 2014). Hence, the exploration of the effect of CT on brain associated with depression might be a potential strategy to reveal the mechanisms linking CT and MDD. Both amygdala and hippocampus are important areas that have been centrally implicated in MDD (Cullen et al., 2014; Mahar et al., 2014). Amygdala has wide functional connectivity (FC) with both cortical and subcortical brain regions (Ochsner et al., 2012). The amygdala connectivity has been proposed to be involved in critical functions related to depression including modulation of sensory information, generation of emotion experience and emotion regulation (Banks et al., 2007; Morawetz et al., 2020). It was not only a central region in the limbic circuit responsible for negative emotion processing (Morawetz et al., 2020) but also an important area in the reward system involved in the positive emotion processing (Murray, 2007). Hippocampus plays an important role in the processing and regulation of threat and fear and represents a vital position in the stress-related pathology (Mahar et al., 2014). Previous studies have revealed that CT might have effects on structure and function of both amygdala and hippocampus (Dannlowski et al., 2012; Herringa et al., 2013; Hanson et al., 2015; Bounoua et al., 2020; Nogovitsyn et al., 2020). These findings indicate that the connectivity of amygdala and hippocampus might play a quite important role in the neural mechanisms via which CT leads to depression. © The Author(s) 2023. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact 1 2 Social Cognitive and Affective Neuroscience, 2023, Vol. 00, No. 00 Methods Participants A total of 73 MDD patients (42 with moderate-to-severe and 31 with no or low CT) and 64 HC (30 with moderate-to-severe and 34 with no or low CT) participated in the present study. MDD patients were recruited from the psychology clinic at the Second Xiangya Hospital, Changsha, China. They were all experiencing a first episode of depression and had never received psychotropic medication. Exclusion criteria included a history of major medical or neurological problems and any axis I psychiatric disorder comorbidity. Two experienced psychiatrists confirmed the diagnosis of MDD and comorbidity for each patient according to the Structural Clinical Interview for the DSM-IV Axis I (SCID-I). Subjects in HC group were students or staff recruited from colleges and communities in Changsha. They were also screened for psychiatric disorders by two experienced psychiatrists using the SCID-I. Exclusion criteria were history or family history of any psychiatric illnesses, any psychotropic medication and any major medical or neurological problems. The Childhood Trauma Questionnaire (CTQ) (Bernstein et al., 1994) was used to perform the with moderate-to-severe CT vs. with no or low CT group classification (see details in the ‘Clinical assessments’ section). All participants were adults (≥18 years old) and right-handed. A subset of this data set has been previously published (Fan et al., 2020), in which we investigated the effects of CT on anhedonia in depression via reward system. This data set mainly enlarged the sample size of MDD with no or low CT and HC with moderate-to-severe CT to increase the statistical power. The main results of the previous study were replicated with this data set, which we have detailed in the Supplement (Analysis of striatum-based FC, Tables S1–S3, Figure S1). The study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University, and all the participants provided written informed consent. C (...truncated)