Moria Smoski, Ph.D. - US grants

DESCRIPTION (provided by applicant): In this application for a Mentored Patient-Oriented Research Career Development Award (K-23), the candidate proposes to develop expertise in the study of emotion regulation among elders with Major Depressive Disorder (MDD). The research component of this application focuses on the effectiveness of two conscious emotion regulation strategies - reappraisal and distraction - in modulating positive and negative affect in individuals age 65+with or without MDD. Effectiveness will be assessed using both behavioral and neuroimaging experimental techniques. The candidate training plan involves focused, mentored training aimed at integrating: 1) The study of emotion regulation;2) Etiology, symptoms, and course of late-life MDD;3) Neurocognitive contributions to emotion regulation;and 4) The use of basic experimental data to inform treatment development. To establish a career as a productive and independent investigator with a specialty in the mechanisms of emotion regulation in late-life MDD, the applicant is seeking support to obtain training in the disciplines listed above. This proposal is based on the hypothesis that despite neurologically-based changes in emotion regulation abilities associated with both normal aging and MDD, structured training in emotion regulation techniques can help to ameliorate negative affect associated with external and internal stressors in this population. Building upon the training outlined in this award proposal, the candidate will undertake a set of behavioral and fMRI-based studies to investigate both the neural mechanisms underlying emotion regulation as well as the effectiveness of specific emotion regulation strategies in older adults with MDD. A follow-up study will examine the relationship between emotion regulation abilities and both cognitive and symptom status one year after testing. This translational research program will extend existing knowledge by innovatively integrating work in basic emotions, geriatrics, and psychopathology. In addition to helping establish the candidate's career in the study of emotion regulation in affective disorders, this line of research has the potential to inform improved and novel interventions for late-life MDD. RELEVANCE (See instructions): MDD is a costly and burdensome condition that affects a significant proportion of elders. The series of proposed studies will shed light on ways that depressed older adults can manage their negative emotions. The findings of these studies may lead to the future development of psychotherapeutic interventions targeting mood symptoms in late-life MDD.

DESCRIPTION (provided by applicant): Though there are many effective interventions for Major Depressive Disorder (MDD) available, there is significant heterogeneity in treatment response. One obstacle to improved treatment response rates is the lack of biomarkers to predict who will respond to a given treatment. Further, there is a lack of understanding of genetic mediators of both depressive symptoms and treatment response. In the attempt to form links from genes to depressive phenotype, brain activity is a key intermediate between genes and behavior. In MDD, dopamine (DA) systems are of particular interest, as they underlie reward responsivity (or its lack, anhedonia). This proposal will examine relations between neural response to rewards in MDD, allelic variations of candidate genes regulating functional output of DA systems, and response to psychotherapy. Imaging-genetics has been a fruitful approach in basic and clinical cognitive neuroscience but has not yet been applied to understand heterogeneity of psychotherapy response in MDD. Participants will undergo functional neuroimaging during a reward anticipation and feedback task (Monetary Incentive Delay) and will be genotyped for candidate dopamine genes (COMT, DAT1, and others) before initiating a course of Brief Behavioral Activation Treatment for Depression (BATD) psychotherapy. Candidate DA polymorphisms will be examined as predictors of both fronto-striatal reward network activation as well as psychotherapy treatment response. Fronto-striatal reward network activation will be examined further as a mediator of DA polymorphism effects on treatment response. This approach is an important step in a program of research with the ultimate goal of generating and validating imaging genetic models that may ultimately predict response to both pharmacological and psychotherapeutic antidepressant treatments in MDD.

ABSTRACT The ability to regulate one?s emotional responses is critical for maintaining emotional health in the face of adverse events that cumulate over the lifespan. Although some emotion regulation abilities are thought to be maintained or even improve in healthy older adults, such beneficial maturation effects are moderated by individual differences in depression and neurocognition that contribute to disability, morbidity, and loss of quality of life into old age. Frontolimbic circuit dysfunction is a hallmark of both younger and older adults with major depressive disorder (MDD), while both activation in and connectivity among components of these circuits predicts treatment response. Such disruptions impact core cognitive processes, including cognitive control and attentional biasing, that influence emotion regulation ability, although it is unknown how their susceptibility to depressive influences varies across the adult lifespan. Moreover, MDD patients are less able to utilize compensatory resources that help older adults cope with adversity, such as social support, in the face of age- associated neurocognitive decline. Given the projected growth of the elderly population in the U.S. and the associated burden on the public health system, it is imperative to develop effective interventions to target regulatory deficits associated with depression in late life and to begin to identify neurocognitive predictors of increasing depressive symptoms. Preliminary evidence from the study team demonstrates that the effectiveness of regulatory strategies such as reappraisal and distraction vary with age and depressive status. However, there is a pressing need for a comprehensive, integrative approach to study emotion regulation strategy use that links brain circuitry integrity, cognitive function, social support, and clinical symptoms, and investigates how these relationships change with age. The central hypothesis of the proposed study is that age, diagnostic status, neurocognitive functioning, and social support will differentially impact reappraisal and distraction efficacy, and that their combined effect on strategy use will predict depressive symptoms at 1 year post-scan. The proposed study is expected to yield new insights in how maturational changes contribute to the conscious ability to reduce negative affect in depressed adults. A total of 200 adults in stratified age groups from 35 to 75 years with and without MDD will undergo structural and task-based functional neuroimaging. We will test age- and diagnosis-specific differences in the success of two different emotion regulation strategies in reducing experimentally induced negative affect, identify brain regions associated with successful use of reappraisal and distraction using structural and functional magnetic resonance imaging, and test emotion regulation as a predictor of future depression symptom severity. Results will be used to better target emotion regulation interventions based on a patient?s age and diagnostic status.