Neural Correlates of Stress and Perceived Control in Adolescent Depression

Project Summary/Abstract
Perceived lack of control, especially during stress, has garnered substantial interest as a core mechanism
underlying major depressive disorder (MDD), particularly in the context of elevated anhedonic symptoms. This
mechanism is especially relevant for depressive symptoms that develop during adolescence, and particularly
for female adolescents, who show heightened susceptibility to disruptions in their sense of control compared to
their male peers. Yet, the neural underpinnings of perceived control disruptions in MDD remain poorly
understood. Mounting evidence indicates that perceived control shares a common neural circuitry with stress
and MDD that is rooted in the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC). Neuroimaging
studies have consistently linked reduced VS activation to hedonic capacity deficits in MDD. Moreover, an
inability to recruit the vmPFC under stress has been posited to underlie maladaptive stress responses in MDD.
Directly relevant to the proposed research, perceived lack of control has also been associated with reduced
activation of this same VS-vmPFC circuit in healthy adults. However, studies to date have yet to examine
neural mechanisms of perceived control in MDD, and how stress may modulate perceived control-related
neural circuits. Additionally, neuroimaging of perceived control has not yet been extended to adolescent
populations. The current K23 proposal was designed to fill these critical knowledge gaps. Accordingly, female
adolescents (age: 14-18) with and without MDD will undergo a stress induction in conjunction with functional
magnetic resonance imaging (fMRI). A novel fMRI task designed to manipulate perceptions of control will be
administered before and after the stress induction. In order to assess neural predictors of “real-life” stress
responses and anhedonic symptoms, an ecological momentary assessment (EMA) protocol will be
administered in the two weeks after the scan and at three- and six-month follow-ups. We hypothesize that VS-
vmPFC activation/connectivity in relation to perceived control will be blunted in adolescents with MDD
compared to healthy adolescents. We also expect that relative to healthy adolescents, adolescents with MDD
will show decreases in VS-vmPFC activation/connectivity associated with perceived control from before to after
stress. Using different units of analysis, this study will provide a rich understanding of stress-linked
mechanisms in adolescent MDD and will be the first to utilize perceived control-related neural mechanisms to
predict future MDD symptoms. Drawing on the expertise from a complementary team of mentors (Drs. Diego
Pizzagalli & Erika Forbes) and consultants (Drs. Mauricio Delgado, Blaise Frederick, Kate Harkness and
Garrett Fitzmaurice), the applicant will receive training in adolescent MDD functional neuroanatomy (Goal #1),
task-based fMRI (Goal #2), stress neurobiology and stress assessment (Goal #3), and EMA (Goal #4). The
proposed training plan will launch the applicant into an independent research career focusing on stress-related
mechanisms underlying adolescent MDD.

Grant Number: 5K23MH122668-05
NIH Institute/Center: NIH
Principal Investigator: Emily Belleau