UC Berkeley

Background. Social epidemiology has become increasingly interested in the effect of early-life experiences on health outcomes in adulthood. It is now widely recognized that early-life adversity (such as being abused or neglected) is an important risk factor for adulthood depression and other psychological disorders. Research emerging from the developmental programming paradigm posits that suboptimal early-life environments can encode vulnerability to later-life psychological impairment through permanent alterations in biological systems, particularly the neuroendocrine and immune systems. However, a subset of persons exposed to early-life adversity appear to be psychologically resilient, experiencing no or very minimal mental health problems later in life. It is a critical goal in epidemiology to ascertain whether these distinct life-course psychological trajectories are mediated by distinct biological characteristics. In this dissertation, I used data from a unique cohort study to explore the relationship between participants' early adversity exposure, their longitudinal history of psychological distress, and their neuroendocrine and immunological stress reactivity systems.

Methods. The dataset comprised a subsample of the ongoing Whitehall II occupational epidemiologic cohort study. The subsample was a group of healthy older male and female Whitehall II members (n = 543) who participated in the 2008 Heart Scan Study (HSS), which was primarily designed to investigate the association between physiological reactivity to an experimental laboratory stressor and sub-clinical coronary artery calcification. The Heart Scan Study data were subsequently linked to six waves of the participants' previously collected Whitehall II study data (spanning years 1985-2004).

I defined exposure to early-life adversity using a composite variable derived from questions collected during both the Heart Scan Study and in one Whitehall II wave. Participants were categorized as exposed if they reported experiencing physical abuse, parental death, separation from their mother or time spent in an orphanage for 1+ years, serious familial mental illness or substance abuse, parental divorce, frequent parental conflict, and/or a harsh parenting style before the age of 16. Participants' history of psychological distress during adulthood was derived from their Whitehall II data, which included General Health Questionnaire-28 (a measure of psychiatric symptoms) scores at each wave. I used two of the physiological reactivity parameters measured in the HSS - cortisol (a key stress hormone) and interleukin-6 (an important inflammatory protein marker) - as my outcome variables.

First, I used piecewise multilevel growth curve modeling to examine whether study participants' joint early-life adversity and psychological history status - i.e., early-life adversity exposure (yes/no) and recurrent psychological symptoms (yes/no) - predicted mean differences in their cortisol response trajectories. Second, I used the mixture model technique of group-based trajectory modeling to identify whether distinct clusters of stress-reactivity patterning existed within cortisol and interleukin-6, and if so, whether the clustering pattern within on biomarker was associated with clustering in the other. Lastly, I used an extension of group-based trajectory modeling to determine whether early-life adversity and longitudinal history of psychological distress predicted study members' membership in those clusters.

Results. Using the piecewise multilevel growth curve analysis, I found that participants exposed to early-life adversity had dysregulated cortisol reactivity trajectories, but that the pattern of those trajectories differs based on their history of psychological distress during adulthood. Adversity-exposed adults with a history of recurrent psychological distress had blunted cortisol responses compared to non-adversity-exposed adults, as well as decreased overall cortisol output. In contrast, adversity-exposed adults with minimal psychological distress had elevated levels of cortisol at baseline and prolonged responses to stress. There was also some evidence that this association was modified by gender.

Using group-based trajectory modeling, I found that distinct clusters did appear to exist within both the cortisol and IL-6 data, although these results need to be interpreted with extreme caution due to statistical flaws in the modeling approach. The four cortisol clusters were distinguished from each other by both mean baseline cortisol levels as well as slightly different reactivity patterns during the experimental laboratory session; the clusters corresponded to a "low-declining" group, a "middle-flat" group, a "higher-flat" group, and finally a "high-declining" group. Within the IL-6 data, the fitted solution comprised five trajectory groups, all of which shared a similar growth pattern (steadily increasing) but had slightly different mean baseline values. The cortisol and IL-6 trajectory groups appeared to be moderately correlated with each other, such that "opposite" biomarker groups had a slight tendency to associate together; however, the principal finding from this dual trajectory analysis was that membership in a given cortisol or IL-6 group is not a very sensitive predictor of group membership in the other biomarker.

In the last piece of analysis, I found that adversity-exposed individuals who subsequently had recurring psychological distress symptoms were marginally more likely to fall into the lowest cortisol trajectory group. Otherwise, cortisol and IL-6 trajectory group membership was not significantly predicted by any combination of early adversity exposure and psychological distress history. Participants' age, body mass index, and socioeconomic status did predict both cortisol and IL-6 group memberships.

Conclusions. My findings partially support the hypothesis that different patterns of atypical stress reactivity - in this case, blunted vs. heightened cortisol responses - may be encoded in the aftermath of early-life adversity, and that these patterns in turn may promote divergent susceptibilities to lifetime psychological disorder. Inflammatory stress reactivity, as measured by interleukin-6, does not appear to play a role in this association. However, distinct clusters of stress reactivity patterning do appear to exist within cortisol and interleukin-6, and may be predicted by theoretically important sociodemographic variables, an observation that should be explored in future research. Although is unclear how much of the burden of depression/anxiety symptoms the observed cortisol patterns might explain among adversity-exposed populations, my findings do provide support for the notion that social experiences "get under the skin" and contribute to population ill-health. This work may lead to a better understanding of the biological sequelae of early-life adversity, and the effects those sequelae can have on psychological risk and resilience throughout the lifecourse.