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.
Lack of perceived control, particularly during stress, has been critically implicated in major depressive disorder (MDD) and anhedonic symptoms, especially among female adolescents; yet the neural underpinnings of perceived control disruptions in MDD remain poorly understood. Using functional magnetic resonance imaging with a novel ?value of control task? in conjunction with a prospective design, this study will provide a comprehensive understanding of stress and perceived control related mechanisms in female adolescents with MDD and will examine stress-induced disruptions in perceived control as a predictor of ?real world? expressions of maladaptive coping and anhedonia. This work is aligned with NIMH?s Strategic Objective 1 Strategy 1.1 (Describe the molecules, cells, and neural circuits associated with complex behaviors) and Strategic Objective 2 Strategy 2.2. (Identify useful biomarkers and behavioral indicators that predict change across the trajectory of illness) and may facilitate the identification of MDD biomarkers that could assist with earlier detection of adolescents vulnerable to MDD.
