Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress

Stress early in life is associated with increased rates of mood and anxiety disorders in adulthood [1] with a recent meta-analysis showing a 62% increase in the risk for anxiety disorders in individuals who have suffered early trauma [2]. With over one in eight children in the US experiencing early adversity such as child maltreatment [3], this represents a major public health problem. Though well-studied and well-replicated in psychological and epidemiological research, little is known regarding the mechanisms mediating the association between adverse childhood experiences and later affective psychopathology, particularly anxiety disorders.

Preclinical research has begun to uncover potential neurobiological mechanisms underlying these relationships, as a multitude of animal models of early life stress (e.g., maternal deprivation, maternal abuse), result in an increase in anxiety-like behavioral phenotypes and also structural alterations in corticolimbic regions such as the hippocampus, amygdala, and prefrontal cortex [4, 5]. Similar alterations have been noted in human samples exposed to childhood maltreatment, with reduced gray matter volume within the hippocampus and alterations in an interconnected network of corticolimbic structures, including the amygdala, orbitofrontal cortex, and anterior cingulate cortex as a function of stressors experienced during childhood [6‐10]. Such results have important implications for the vulnerability to affective psychopathology. Reduced gray matter within these brain structures has also been associated with higher trait anxiety as well as mood and anxiety disorders in adults [11‐17].

Missing from this body of research, however, are strong links to behavior, as many of the past studies have simply noted brain differences between groups. Rao and colleagues [18] took an important initial step to close this gap, finding decreased hippocampal gray matter mediated the relationship between adversity during childhood and increased risk for major depression. While these investigators importantly connected alterations in neurobiology and behavior, it is still unclear how differences in the brain are associated with higher rates of affective dysregulation after early stress. Further studies are needed to drill down to understand how neurobiological vulnerabilities may mechanistically contribute to the reported link between adverse childhood experiences and later affective psychopathology.

Related to this idea, a growing body of psychological research has found that environmental stressors often play a precipitating role in the onset of mood and anxiety disorders and that the experience of stress early in life confers risk for psychopathology by sensitizing organisms to stress in adulthood [19, 20]. Tellingly, childhood maltreatment is further associated with increased trait anxiety, alterations in hypothalamic-pituitary-adrenal (HPA) axis stress reactivity, and greater potentiated startle to threat [1, 21, 22]. These collective findings suggest that early adversity may create a dispositional sensitivity to perceived threat and may be associated with elevated risk for mood and anxiety disorders following stressful life events in adulthood [23‐25]. No study to date, however, has formally linked individual differences in the intermediate risk phenotype of trait anxiety with the experience of childhood maltreatment, particularly in relation to later stress, and associated changes in corticolimbic morphology. It is likely that alterations in corticolimbic gray matter associated with childhood maltreatment interact with experiences of stress in the future and these neural phenotypes associated with early adversity may aid researchers in prospectively predicting relative risk and resilience in the context of environmental challenge.

In the current study, we examined if the association between self-reported childhood maltreatment and the expression of trait anxiety in adulthood is mediated by differences in corticolimbic morphology. Specifically, we tested whether childhood maltreatment was associated with trait anxiety via reductions in gray matter within neural circuits regulating stress responsiveness. To this end, structural MRI and self-reported measures of childhood maltreatment, recent life stress, and negative affect were examined in 818 participants of the ongoing Duke Neurogenetics Study (DNS). A subset of 196 participants completed additional behavioral assessments at least 1 year after the DNS. This unique longitudinal component allowed us to further determine if the structural correlates of childhood maltreatment predict subsequent vulnerability to future stressful life events. Based on prior preclinical and clinical research, we hypothesized that childhood maltreatment would be negatively correlated with corticolimbic gray matter volume with a specific focus on the hippocampus, amygdala, and medial prefrontal cortex (mPFC) including the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). Further, we hypothesized that gray matter reductions within these structures would mediate the relationship between childhood maltreatment and adult trait anxiety. Given the importance of these corticolimbic structures in orchestrating adaptive responses to stress, we lastly hypothesized that these gray matter reductions would predict increased anxiety, following stressful life events in the future.

Here, fitting with past research, we find that self-reported childhood maltreatment was associated with reduced gray matter volumes within the medial prefrontal cortex and left hippocampus. We also for the first time to date, formally demonstrate that gray matter volume reductions within the hippocampus and mPFC mediate the association between the self-reported childhood maltreatment and the increased expression of trait anxiety in adulthood. Our results expand on prior preclinical and clinical research and begin to fill in important gaps in the understanding of the sequelae of early life stress including associated variance in neurobiology. Unique to our work, we then attempted to link these neurobiological phenotypes to susceptibility to environmental challenge in the future by focusing on the relationship between stress later in life and state anxiety as a function of individual differences in corticolimbic morphology. Consistent with our hypotheses, our secondary analyses demonstrate this intermediate behavioral phenotype is related to reduced hippocampal and mPFC gray matter volume. As such, gray matter within these structures may represent a neural embedding of early life stress through which later psychopathology emerges.

Our findings of structural alterations within the hippocampus and mPFC associated with self-reported childhood maltreatment are broadly consistent with findings from animal models showing decreased dendritic arborization, spine density, and neuronal number within these areas [43‐45]. Though, care should be taken in direct translation, as the resolution of MRI precludes focusing on neural architecture at that level and our data is correlative in nature. Thinking about what these neural alterations may mean for behavior, the hippocampus is critical in shaping emotional responses to environmental challenge through its regulation of the HPA axis and encoding of contextual memory for emotional experiences as exemplified by fear learning [40, 41]. The mPFC is essential for the process of fear extinction and functions to regulate behavioral and neuroendocrine responses to controllable stressors [46, 47]. The hippocampus and mPFC both support multiple processes that likely contribute to trait anxiety; however, it is currently unclear which exact processes are being affected by gray matter reductions in these regions.

Of note, our study contained both (primary) cross-sectional and (secondary) longitudinal assessments. The deployment of longitudinal designs is especially important when considering how stress affects brain structure across development and how early adversity shapes future responses to stress. Although much research has addressed the relationship between childhood maltreatment and gray matter volume in adulthood, certain studies provide unique insight into the complexity of these relationships. Meta-analyses demonstrate that childhood maltreatment is associated with reduced hippocampal gray matter in adulthood, but not during childhood [34] suggesting that the impact of adversity on neural morphology is not immediate but develops over time. A better understanding of how childhood maltreatment is associated with gray matter in neural structures that generate and regulate responses to stress may facilitate our understanding of how early adversity impacts risk in the context of stress over the lifespan and may implicate specific developmental windows during which treatment and prevention strategies are most effective. It is possible that intervention strategies immediately following childhood maltreatment may prevent the emergence of hippocampal deficits, which are associated with risk for mood and anxiety disorders. Preventing these morphological changes via intervention during childhood may be more effective than treating the negative sequelae that emerge in adulthood.

Our work is not without limitations. First, our measures of self-reported childhood maltreatment, trait anxiety, and gray matter morphology were assessed concurrently, and as such are correlative in nature and cannot establish temporal order. For example, it is possible that persons who are high in trait anxiety, in addition to having reduced gray matter volume, are also more likely to retrospectively remember or report maltreatment during childhood. It is thus possible that hippocampal and mPFC gray matter volume mediates the impact of trait anxiety on self-reported childhood maltreatment, rather than vice versa. However, our finding that individual differences in gray matter volume within these structures prospectively predicts anxious arousal and subsequent to the experience of stressful life events supports the importance of gray matter deficits within the hippocampus and mPFC associated with childhood maltreatment as a mechanism through which sensitivity to stressful life events emerges. Developmental longitudinal studies in high-risk populations (e.g., individuals with positive family history for disorder) could advance the relevance of this potential mechanism for understanding etiology and pathophysiology of anxiety disorders.

Additionally, we observed decreased gray matter within the left hippocampus as a function of self-reported childhood maltreatment, but no effect of early life stress was significant within the right hemisphere. We did not hypothesize a lateralized effect, and it is possible that results in the right hemisphere are simply less robust. A recent meta-analysis found evidence for bilateral reductions in hippocampal gray matter in participants with PTSD related to childhood trauma [34]. We observe only a weak effect of childhood maltreatment on gray matter volume within the right hippocampus and only at more liberal statistical threshold (p <0.005 uncorrected, 21 voxels). Future research will be needed to determine whether gray matter reductions in the right hippocampus are linked to vulnerability to stress similarly to the results reported here.

Lastly, the effect sizes observed in our analyses are relatively small. Further, our sample consists of undergraduate students who report experiencing childhood maltreatment yet are free of past or current mood and anxiety disorders. As such, this sample may represent a relatively resilient population, and it is not immediately clear if our results have direct parallels to clinical outcomes. Nonetheless, previous research has demonstrated that reduced gray matter within the hippocampus mediates the association between early life adversity and vulnerability to major depression [42], which parallels the results reported here. Additionally, the age of our participants (18–22 years of age) is relatively young compared to the average onset of mood and anxiety disorders [48, 49], and it is possible that some of our participants will go on to develop psychopathology within their lifetime. Future research will be needed to determine whether gray matter reductions within healthy participants exist on a continuum with clinical samples, and whether gray matter morphology is associated with responses to stress later in life in a manner that is clinically meaningful.

These limitations notwithstanding, our results suggest that structural variance in hippocampal and mPFC gray matter volume represent mechanisms through which childhood maltreatment may shape not only the expression of trait anxiety but also the responsiveness to stress. By specifically modeling the effects of childhood maltreatment onto behavioral processes indirectly through variability in neural phenotypes, our work can serve as a springboard for future research. A wealth of preclinical and clinical evidence suggests that the experience of stress early in life and higher levels of trait anxiety are risk factors for the development of mood and anxiety disorders. Our results suggest that structural changes within the hippocampus and mPFC may represent the neural embedding of early life stress, which shapes risk for subsequent psychopathology by affecting how we respond to challenges in the environment.

Our findings suggest that reduced corticolimbic gray matter, particularly within the hippocampus and medial prefrontal cortex, mediates the relationship between reported childhood maltreatment and individual differences in adult trait anxiety. Further, our results suggest that these structural alterations contribute to increased affective sensitivity to stress later in life. These findings contribute to the literature addressing how early stress may affect the development of corticolimbic structures supporting adaptive functioning later in life.