Neurophysiology, Estrogen, and Stress Exposure in the Emergence of Depression in Adolescent Girls

Overview

The prevalence of adolescent depression is steadily rising in the U.S., especially among adolescent girls. Currently 20% of adolescent girls experience major depression compared with 6% of boys (National Institute of Mental Health, 2016). The profound gender disparity in depression that emerges at puberty, but not before, implicates a role of ovarian steroid hormones in promoting affective (mood) symptoms in adolescent girls. In addition to dramatic physical maturation and a rapidly changing reproductive hormone environment at puberty, adolescence is also a time of exposure to substantial psychosocial stress, particularly in girls. It is well documented that stress interferes with the maturation of neurodevelopmental trajectories and is a critical precipitating factor in the pathway to psychopathology. However, the neuropathophysiological mechanisms linking stress exposure and sensitivity to ovarian hormone fluctuations at puberty to the onset and maintenance of depression symptoms in adolescence have yet to be elucidated, and is the purpose of this research.

Framed within a diathesis-stress model of disease, the primary objective of this research is to determine a pathophysiological role of estradiol (E2) variability in the context of severe psychosocial stress exposure in regulating neurophysiological correlates of affective state change in girls (ages 11-14) during the pubertal transition (i.e., Tanner developmental stages 3 or 4). The rationale for examining E2 variability as a diathesis for mood impairment is twofold. First, sensitivity to hormonal flux during specific reproductive events has been shown to trigger affective symptoms in susceptible women, and second, E2 is a powerful neuroregulator of neural networks implicated in depression. 55 peripubertal girls undergoing a healthy pubertal transition will be recruited for the study. Over an 8-week period, depression symptoms (Center for Epidemiological Studies Depression Scale for Children (CES-DC)), anxiety (State Trait Anxiety Inventory (STAI-C)), and perceived stress (perceived stress scale (PSS)), and salivary E2 measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) will be assessed on a weekly basis. An electroencephalogram (EEG) during an emotional go/no-go task will be performed after the 8-week collection period to probe neurophysiological correlates of maturing fronto-limbic circuitry and assess key domains of cognitive and emotional processing impacted by the hormonal milieu. At the follow-up visit, an acute psychosocial stressor (Trier Social Stress Test) will be administered to examine cortisol and autonomic stress reactivity. The central hypothesis of the proposed research is that the amplitude and synchrony of frontal neural oscillations evoked during the cognitive-affective processing paradigm, and cortisol reactivity to the psychosocial stressor will partially mediate the relationship between greater E2 variability and elevated depression symptoms in peripubertal girls, and this relationship will be particularly strong in girls who have experienced recent (within six months) psychosocial stress.