There is a great need to integrate neuroscientific tools into the study of late-life depression (LLD) etiology. My goal is to develop evidence that will help target prevention strategies to the neurobiological basis of LLD vulnerability. Several existing studies demonstrate that LLD pathophysiology is characterized a high burden of structural magnetic resonance imaging (sMRI) measured small vessel disease, white matter damage, and atrophy in key networks, such as those subserving executive and central visceral controls. To build on and extend current literature, there is a need to clarify the specific structural alterations involved in LLD pathogenesis. There is also a fundamental need for evidence regarding the preventable risk factors for pathological brain structural aging. The conceptual model that underlies my research program proposes that 24-hour sleep-wake activity disturbances are a key and understudied risk factor for the specific brain structural alterations that increase LLD risk. To lead future studies that will programmatically advance the neuroscience of depression prevention, I need to build on my past training in risk factor epidemiology and LLD neurobiology in several areas. First, I need clinical research training in the science of depression prevention for high risk older adults, such as dementia caregivers. Second, I must prepare myself to lead multi-modal, longitudinal neuroimaging studies. Third, I must prepare myself to lead studies assessing and interpreting the health relevance of 24-hour sleep-wake activity measures. Therefore, this K01 will provide me with: (1) A capstone field training experience administering ethical, multidisciplinary clinical research studies with older adults who are at high risk for developing depression, plus mentor-guided training in current LLD prevention approaches and the psychosocial/behavioral basis for LLD in at-risk groups; (2) New technical skills collecting, processing, analyzing, and interpreting multi-modal neuroimaging data, plus formal coursework in neuroanatomy/systems neurobiology, and (3) New technical skills measuring and processing 24-hour sleep-wake activity measures, plus grounding in clinical sleep medicine to interpret these metrics. To accomplish these training goals and advance public health relevant knowledge regarding LLD etiology, I propose to longitudinally study changes in depression among older informal dementia caregivers who are experiencing strain delivering care. This group is increasingly public health relevant and at very high risk for depression. Our preliminary data indicates that LLD in strained dementia caregivers may be due to disrupted brain structural connectivity. Longitudinal neuroimaging studies in this group are needed to extend our preliminary findings by evaluating whether/which specific brain structural characteristics predict future increases in the burden of depression. In addition, dementia caregivers often have inadequate sleep and restricted daytime activity, which are both depression risk factors that may increase the rate of brain structural aging (e.g., by activating pro-inflammatory cascades or contributing to vascular disease). I therefore propose a prospective study (n=90) with state-of-the-art 7- Tesla sMRI and actigraphic sleep-wake activity measures repeated at an initial visit and an 18-month follow- up. This will enable me to test and refine a model wherein specific sleep-wake activity disturbances are associated with brain structural changes affecting the key networks underlying LLD risk. The scientific and career development outcomes will be: (1) identification of the specific brain structural networks and sleep-wake activity patterns that predict increases in depression symptom severity among dementia caregivers, (2) refinement of a model linking specific sleep-wake activity characteristics with both pathological brain structural aging and depression symptoms, and (3) a multidisciplinary research scientist with the knowledge, skills, and data needed to develop a confirmatory study (R01) supporting neurobiologically-informed prevention strategies for LLD.

Public Health Relevance

Late-life depression (LLD) impairs quality of life and has serious health consequences that disproportionally affect certain sub-groups of older adults, including informal providers of dementia care. In this K01 application we will test and refine a model of LLD pathogenesis in dementia caregivers that posits sleep- wake activity disruption contributes to accelerated brain structural aging, which in turn, affects the key structural networks (executive and central visceral control) that underlie LLD risk. This will generate evidence regarding the specific alterations to brain structure connectivity, and behavioral drivers of these changes, which increase LLD vulnerability and thereby represent targets for deficit-based LLD prevention strategies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Chavez, Mark
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University of Pittsburgh
Schools of Medicine
United States
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Smagula, Stephen F; DuPont, Caitlin M; Miller, Megan A et al. (2018) Rest-activity rhythms characteristics and seasonal changes in seasonal affective disorder. Chronobiol Int 35:1553-1559
Wallace, Meredith L; Smagula, Stephen F (2018) Promise and Challenges of Using Combined Moderator Methods to Personalize Mental Health Treatment. Am J Geriatr Psychiatry 26:678-679
Smagula, Stephen F; Krafty, Robert T; Thayer, Julian F et al. (2018) Rest-activity rhythm profiles associated with manic-hypomanic and depressive symptoms. J Psychiatr Res 102:238-244
Wallace, Meredith L; Stone, Katie; Smagula, Stephen F et al. (2018) Which Sleep Health Characteristics Predict All-Cause Mortality in Older Men? An Application of Flexible Multivariable Approaches. Sleep 41:
Gebara, Marie Anne; Kasckow, John; Smagula, Stephen F et al. (2018) The role of late life depressive symptoms on the trajectories of insomnia symptoms during antidepressant treatment. J Psychiatr Res 96:162-166
Hughes, Timothy M; Lockhart, Samuel N; Smagula, Stephen F (2018) Blood Pressure's Role in Alzheimer Disease Pathology. Am J Geriatr Psychiatry 26:23-24
Smagula, Stephen F; Karim, Helmet T; Rangarajan, Anusha et al. (2018) Association of Hippocampal Substructure Resting-State Functional Connectivity with Memory Performance in Older Adults. Am J Geriatr Psychiatry 26:690-699
Smagula, Stephen F; Krafty, Robert T; Taylor, Briana J et al. (2017) Rest-activity rhythm and sleep characteristics associated with depression symptom severity in strained dementia caregivers. J Sleep Res 26:718-725
Simning, Adam; Smagula, Stephen F (2017) Engaging Early-Career Geriatric Mental Health Investigators as Associate Editorial Board Members. Am J Geriatr Psychiatry 25:438-439