Characterizing the Role of Different Childhood Trauma Subtypes in the Neuroendocrine Functioning of Youth: Implications for Adolescent Depression.

Many depressed youth have been exposed to trauma, and these youth are less responsive to standard depression treatments. This suggests that the mechanisms for the development and maintenance of depression in individuals with a history of childhood trauma may differ from those without, however these mechanisms are poorly understood. One neurobiological mechanism associated with the onset, course, and recurrence of depression is functioning of the HPA-axis. The purpose of this study was to characterize the interplay between exposure to childhood trauma and HPA-axis functioning and integrate this interplay into our understanding of adolescent depression. METHODS: Participants in this study were a community sample of 138 youth (aged 9-16). All youth completed a semi-structured diagnostic interview, a standardized laboratory stress protocol, and the SE-CPT. Each participant contributed 2 pre-stress and 5 post-stress salivary cortisol samples, as well as 4 diurnal salivary cortisol samples at home across 2 consecutive weekdays. All parents completed a semi-structured diagnostic interview, the ETI, and the CDI. RESULTS: We found that more reported exposure to general trauma was associated with greater cortisol awakening response and elevated cortisol at bedtime, physical abuse exposure was associated with faster reactivity to acute stress, and emotional abuse was associated with delayed down-regulation of cortisol following acute stress. Additionally, we found that high reported emotional abuse beginning during the school-aged years was associated with elevated diurnal cortisol throughout the day, while the HPA-axis may be more sensitive to physical abuse exposure during early childhood. Youth with a history of exposure to general trauma who also have depression demonstrate elevated cortisol at bedtime, as well as hypersensitivity to novel settings. DISCUSSION: Our findings convey the importance of research incorporating multiple indices of HPA-axis functioning to inform our understanding of stress reactivity. Furthermore, these findings demonstrate that different forms of childhood stress may influence the neurobiological system in different ways across development. Ultimately, depressed youth with a history of reported trauma exposure demonstrated distinct patterns of neuroendocrine dysregulation compared with other youth. Overall, this dissertation presents a comprehensive examination of neuroendocrine functioning in youth in the context of childhood trauma exposure and psychopathology.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107089/1/katerk_1.pd

Screening for childhood adversity: the what and when of identifying individuals at risk for lifespan health disparities.

Existing research on childhood adversity and health risk across the lifespan lacks specificity regarding which types of exposures to assess and when. The purpose of this study was to contribute to an empirically-supported framework to guide practitioners interested in identifying youth who may be at greatest risk for a lifelong trajectory of health disparities. We also sought to identify the point in childhood at which screening for adversity exposure would capture the largest group of at risk individuals for triage to prevention and intervention services. Participants (n = 4036) collected as part of the Midlife in the United States study reported their medical status and history including physical (cardiovascular disease, hypertension, obesity, diabetes, cancer) and mental health (depression, substance use problems, sleep problems). Participants indicated whether they were exposed to 7 adversities at any point in childhood and their age of exposure to 19 additional lifetime adversities before the age of 18. Parent drug abuse, dropping out or failing out of school, being fired from a job, and sexual assault during childhood exhibited the largest effect sizes on health in adulthood, which were comparable to the effects of childhood maltreatment. Childhood adversity screening in early adolescence may identify the largest proportion of youth at risk for negative health trajectories. The results of this descriptive analysis provide an empirical framework to guide screening for childhood adversity in pediatric populations. We discuss the implications of these observations in the context of prevention science and practice

Stability of diurnal cortisol measures across days, weeks, and years across middle childhood and early adolescence: Exploring the role of age, pubertal development, and sex.

Effective regulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been linked to numerous health outcomes. Within-person variation in diurnal measures of HPA-axis regulation assessed over days, months, and years can range between 50-73% of total variation. In this study of 59 youth (ages 8-13), we quantified the stability of the cortisol awakening response (CAR), the diurnal slope, and tonic cortisol concentrations at waking and bedtime across 8 days (2 sets of 4 consecutive days separated by 3 weeks), 3 weeks, and 3 years. We then compared the stability of these indices across three key developmental factors: age, pubertal status, and sex. Youth provided 4 saliva samples per day (waking, 30 min post-waking, before dinner, and before bedtime) for 4 consecutive days during the 3rd week of an ongoing 8-week daily diary study. Youth repeated this same sampling procedure 3 weeks and 3 years later. Using multi-level modeling, we computed the amount of variance in diurnal HPA-axis regulation that was accounted for by nesting an individual's diurnal cortisol indices within days, weeks, or years. Across days, diurnal slope was the most stable index, whereas waking cortisol and CAR were the least stable. All indices except bedtime cortisol were similarly stable when measured across weeks, and all indices were uniformly stable when measured across 3 years. Boys, younger participants, and youth earlier in their pubertal development at study enrollment exhibited greater HPA-axis stability overall compared with females and older, more physically mature participants. We conclude that important within- and between-subjects questions can be answered about health and human development by studying HPA-axis regulation, and selection of the index of interest should be determined in part by its psychometric characteristics. To this end, we propose a decision tree to guide study design for research in pediatric samples by longitudinal timeframe and sample characteristics

Childhood maltreatment, psychological resources, and depressive symptoms in women with breast cancer.

Childhood maltreatment is associated with elevated risk for depression across the human lifespan. Identifying the pathways through which childhood maltreatment relates to depressive symptoms may elucidate intervention targets that have the potential to reduce the lifelong negative health sequelae of maltreatment exposure. In this cross-sectional study, 271 women with early-stage breast cancer were assessed after their diagnosis but before the start of adjuvant treatment (chemotherapy, radiation, endocrine therapy). Participants completed measures of childhood maltreatment exposure, psychological resources (optimism, mastery, self-esteem, mindfulness), and depressive symptoms. Using multiple mediation analyses, we examined which psychological resources uniquely mediated the relationship between childhood maltreatment and depressive symptoms. Exposure to maltreatment during childhood was robustly associated with lower psychological resources and elevated depressive symptoms. Further, lower optimism and mindfulness mediated the association between childhood maltreatment and elevated depressive symptoms. These results support existing theory that childhood maltreatment is associated with lower psychological resources, which partially explains elevated depressive symptoms in a sample of women facing breast cancer diagnosis and treatment. These findings warrant replication in populations facing other major life events and highlight the need for additional studies examining childhood maltreatment as a moderator of treatment outcomes

Tumor Biology and Immune Infiltration Define Primary Liver Cancer Subsets Linked to Overall Survival After Immunotherapy

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors