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Evaluation of Brain Structure and Function in Currently Depressed Adults with a History of Early Life Stress
by Joshua Jones

February 23, 2021
Joshua Jones, Half Hollow Hills High School

I. Introduction

Even though Major Depressive Disorder (MDD) is the leading cause of disability worldwide impacting over 300 million individuals, early detection and intervention is hindered by the limited knowledge of its underlying mechanisms [1]. One association found to be significant within MDD is the presence of early life stress (ELS), such as sexual abuse [2], emotional abuse [3] and family conflict [4].  However, the biological mechanism linking ELS and MDD are unknown.

Though the volumetric findings appear consistent, an important open question is the functional consequences of these structural differences. In addition to structure, ELS may affect function by influencing glucocorticoid levels. Glucocorticoids are steroid hormones which play a significant role in the onset of stress response mechanisms and regulate brain development, such as neurogenesis, differentiation, and migration [10, 16, 30]. In a healthy person, the HPA stress response results in the secretion of glucocorticoids to promote energy redistribution for recovery of the system and stress adaptation [31, 32]. In this sense, glucocorticoid signaling controls stress reactivity through the inhibition of the HPA axis [33] and alterations in this signaling due to ELS may lead to dysregulation of HPA axis function [34]. Rodent studies measuring mRNA levels of glucocorticoid receptors in the brain have reported a persistent decrease in mRNA expression in areas such as the HIP and AMY[34, 35]. In humans with a history of ELS decreased glucocorticoid DNA extracted from was reported [33]. These reduced glucocorticoid levels due to ELS may impair brain functioning in adults, affecting metabolic activity.

FDG-PET studies can assess cerebral metabolic rate of glucose uptake [36, 37]. An FDG-PET study involving rhesus monkeys with ELS (maternal separation after birth) reported lower HIP brain activity in the monkeys exposed to ELS compared to controls [6]. In humans, a functional magnetic resonance imaging (fMRI) study also indicated that HPA axis hypo-reactivity after the ELS occurs in adults in a similar manner as seen in animal models [38]. Other human fMRI studies demonstrate that neuronal activity is decreased in the prefrontal‐limbic‐thalamic‐cerebellar circuitry including the AMY in response to stress in adults [5, 39] and in kids [22]. It is thought that activity may be blunted due to ELS because patients adapt to the stressors. However, not all studies have been consistent. For example, hyperreactivity in the AMY following ELS has been shown in other human fMRI studies in adults [15, 16, 40, 41]. Prior studies have found a relationship between ELS and MDD. Figure 4 demonstrates ways in which structural changes and depression are possibly caused due the presence of ELS.

To properly assess the function consequences of ELS within MDD and address these open questions, we propose an analysis of the metabolism of AMY, ACC, HIP, and DLPFC through FDG PET in addition to a structural MRI in MDD patients with and without ELS. We hypothesize that in MDD patients with prior history of ELS, compared to those without ELS, will have a smaller volume/cortical thickness as measured by MRI and decreased metabolism as measured by PET scans in the bilateral DLPFC, ACC, HIP, and AMY. This study would for the first time, assess both structure and function of critical regions of the HPA axis in MDD, while accounting for the common confounder of ELS.

II. Methods and Materials

Clinical Measures

Eligibility: Participants were first screened over the phone by a study team member to determine interest in the study and eligibility. Participants were then asked to visit the laboratory and assessed by a clinician (psychiatric nurse or psychiatrist) and a rater (psychologist or trained staff). The rater completed the clinical interview for current and lifetime psychiatric diagnosis (SCID-IV)  substance use disorders, eating disorders, psychotic disorders, anxiety disorders, covering mood disorders, and somatoform disorders [58] and MADRS.

Eligible participants were scheduled for a simultaneous positron emission tomography and magnetic resonance (PET/MR) scan with the fluorodeoxyglucose (FDG) tracer (see below for methods) on a Siemens Biograph mMR. As FDG is an analogue of sugar, it gets taken up to a greater extent in regions of the brain with higher metabolic activity.  This study examined T1 weighted MRO (for thickness/volume) and FDG-PET (for metabolism) imaging only.

Within 7 days of imaging, participants completed the Childhood Trauma Questionnaire (CTQ) [59]. The presence of ELS was established by have a subscale score of ‘none’ (0), ‘low’ (1), ‘moderate’ (2) or ‘severe’ (3) in one or more groups of emotional abuse, emotional neglect, physical abuse, physical neglect, and sexual abuse as seen in Table 1. Total CTQ was divided into 2 groups: ‘none to low’ and ‘moderate to severe’.

Statistical Analysis

Covariates: A chi-squared test with exact p-values based on Monte Carlo simulation was used to examine the marginal association between the categorical variable (sex) and ELS (4 levels). Kruskal-Wallis tests were used to compare unadjusted marginal differences for any continuous covariates (age, age2 [to account for a potential non-linear relationship between variables and age], total childhood trauma severity) as well as continuous outcome variables (thickness in ACC/DLPFC, volume in HIP/AMY/ACC/DLPFC, metabolism in HIP/AMY/ACC/DLPFC) among three or more groups (4 levels of ELS (0 vs. 1 vs. 2 vs. 3)). A Wilcoxon rank sum test was used to compare unadjusted marginal differences for the continuous variable (total childhood trauma severity) across the categorical variable (sex). Spearman rank correlation coefficient was used to measure the linear relationship between the continuous outcome variables and total childhood trauma severity.

Models: Multiple linear regression models were utilized to examine (1) the differences between discrete levels of childhood trauma for each outcome variable (thickness in bilateral ACC/DLPFC, volume in bilateral HIP/AMY/ACC/DLPFC, metabolism in bilateral HIP/AMY/ACC/DLPFC) (2) the relationships between each outcome variable and continuous total childhood trauma severity, after controlling for age, age2 and sex. A two-way interaction between ELS level (discrete) and brain region or total childhood trauma severity (continuous) and brain region were examined first. If no significant results were found, then individual variables were considered in the linear mixed models. Age, age2 and sex were adjusted for in the model, and a Compound Symmetric variance-covariance structure for the longitudinal measurements was selected based on Akaike Information Criteria (AIC). Other variance-covariance structures considered included Unstructured and Autoregressive. Pairwise comparisons between levels of early life stress were reported. Statistical analysis was performed using SAS 9.4 and significance level was set at 0.05 (SAS Institute Inc., Cary, NC). To examine the relationship between structure and function, the Spearman Correlation coefficient was calculated between metabolic rate of glucose uptake and either thickness or metabolism of each region.

III. Results

Categorical Analysis

Of the variables shown in Figure 5, three showed significant differences across ELS levels (Table 3).  DLPFC thickness differences were driven by significant differences between low and moderate childhood trauma levels as well as between low and severe levels.  Metabolism in the ACC was only significantly different between none and low levels, while metabolism in the DLPFC was significantly different between none and low as well as between none and moderate.

Structure vs Function

We additionally wanted to determine whether there was a correlation between the structural and functional components of each of the four areas. Figure 7 presents a direct significant correlation between metabolism and thickness in the DLPFC (p=.006). Volume in this area was not significant with metabolism, nor was thickness or volume in any of the other regions.

IV. Discussion

Cortical Thickness vs Cortical Volume

In this work, both cortical thickness and volume of the ACC and DLPFC were examined.  Both point to different properties. Cortical thickness and surface area measurements are independent globally and regionally. These two measurements are also genetically and phenotypically uncorrelated. Grey matter volume contains aspects of both traits but is more genetically and environmentally correlated to surface area. As a result, volume is likely to be influenced by some combination of these genetic factor, indicating that area or thickness measurements would be advantageous to volume for gene discovery [66].

However, volume measurements are generally more reliable than thickness measurements as they are highly correlated with head size, whereas thickness is not [67]. Volume-based techniques may also be advantageous for multivariate analysis that include voxel-based functional imaging such as PET and fMRI.

Cortical Regions: Anterior Cingulate Cortex and Dorsolateral Prefrontal Cortex

Following AMY activation, stress is regulated by the prefrontal cortex [10] which not only maintains homeostasis, but also assists in the detection of threats [11]. The ACC is a region that connects the prefrontal cortex and the limbic system and holds a crucial role in emotional regulation. In this study, ACC and DLPFC volume were not associated with CT, either in the categorical or the continuous analysis.  However, DLPFC thickness and metabolism were significantly different across some of the categories of childhood trauma.  The lack of linear association with childhood trauma may suggest that DLPFC is more susceptible to any level of trauma, regardless of severity.

Relatedly, DLPFC thickness (but not volume) and metabolism showed a significant correlation. The prefrontal cortex is heavily involved in executive function, attention, and memory. Additionally, the DLPFC is one of the last cortical regions to mature functionally and structurally.

It is important, however, to note that statistical significance does not imply clinical significance.  The significant differences in DLPFC thickness ranged from 0.08 to 0.10 mm. For metabolism, differences ranged from 0.72 to 0.87.  As such, the functional consequences may be more relevant to therapy targets.

The magnitude of significant difference in ACC metabolism is like that of the DLPFC (0.70); however, is only evident between those with no childhood trauma a low levels of childhood trauma.  Interestingly, average ACC metabolism the low childhood trauma group appears significantly lower than that the other groups (Figure 5).  However, examining the plot in comparison to metabolism in the other regions reveals the same general trend in which metabolism of the cohort without childhood trauma is highest on average, and the other cohorts appear to have similar ranges.  In this context, ACC metabolism, like DLPFC metabolism may be sensitive to any level of childhood trauma.

V. Conclusions

It is critically important to examine the effects of CT within MDD, because of the high prevalence of CT within MDD.  Without understanding this relationship, MDD-control comparisons will be confounded by effects of CT.  This may explain equivocal results on structural differences examined in MDD to date.  This study demonstrated functional and structural changes associated with CT and MDD. Among the regions, exhibited both differences in thickness and metabolism with CT, as well as a strong structure/function relationship, suggesting it might be an important treatment target for prevention of MDD following CT.

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