ABSTRACT: High rates of depression in older family dementia caregivers (dCGs) present both a public health priority, and an opportunity, to study the common depression mechanisms expressed in this group. Preliminary target-identification research in dCGs (K01MH112683) evaluated sleep-wake behaviors, which are potentially modifiable targets, in relation to depression symptoms. Morning activation deficits (MADs) were the only factor related to depression symptom persistence over six-months. Preliminary 7T MRI data indicate that MADs related to depression symptoms via heightened resting-state connectivity of amygdala and posterior cingulate cortex (PCC) regions. In the context of prior literature, this implicates limbic and default mode network systems, and suggests that ruminative processes may be involved (i.e., negative emotional self-focus). But gaps remain in understanding of this mechanism, with respect to psychological and neurobiological factors, and modifiability. Critically, will targeting MADs “derail” related depression mechanisms and symptoms? This proposal is for a combined observational-experimental probe study of MADs in dCGs age 60+. Participants will include 120 dCGs with depression-relevant levels of MADs (C.1.4). Aim 1 will compare this group with MADs against 60 dCGs on the other end of the spectrum, relatively protected from depression, by virtue of being “morning types.” Planned neuroimaging analyses will validate the resting-state biomarker previously identified on this pathway, and support additional inference, by evaluating group differences in brain responses to rumination cues. Ecological Momentary Assessment (EMA) and actigraphy will be used to characterize patterns of activity, mood, and rumination. We will also measure other plausibly relevant factors, e.g., nocturnal mentation and reward anticipation. In Aims 2/3, the 120 dCGs with MADs will be randomized to an active probe or control condition. The active probe repurposes a simple component of existing behaviorally activating therapies to target MADs: Scheduling Activity and Monitoring Mornings (SAMM). Uncontrolled pilot data (n=10) support the feasibility that six weekly sessions of SAMM engages the target (MADs) and influences mood. The proposed randomized controlled probe study will confirm effects on subjective and objective morning activation (Aim 2) and characterize changes in the putative mechanism (ruminative processes; Aim 3). Accomplishing these aims together will add to knowledge regarding the potential active effects that MADs have on depression mechanisms. The proposed study employs NIMH strategies of investigating mechanisms with multi-modal methods (Strategy 2.2); and re-purposing existing treatments to probe target engagement and personalize therapeutics for key groups (Strategy 3.2). Analyses of multi-modal data will support the development of new methods to detect the process underlying MADs. Experimental results will support or refute targeting MAD...