In this revised application for a Pathway to Independence Award (K99/R00), Dr. Kymberly Young requests support to acquire the training necessary to establish herself as an independent investigator studying novel neurobehavioral interventions for major depressive disorder (MDD), with a specific focus on emotional processing biases that serve as a biological marker and treatment target both for the onset and remission of MDD symptoms. Accomplishing this long-term goal requires that Dr. Young develop skills that cut across disciplines, including the clinical neuroscience of MDD, translational neuroscience, and functional neuroimaging. Her prior training and publication record clearly indicate that Dr. Young has expertise in cognitive neuroscience and the biological basis of depression. In order to fully attain her goals, however, she needs additional training and experience that comes from working with experts in the field of neurobehavioral treatments of psychiatric disorders and cutting-edge functional neuroimaging techniques. To that end, Dr. Young will receive mentoring in neurobehavioral treatments for MDD from Dr. Greg Siegle, director of the Program in Cognitive and Affective Neuroscience at University of Pittsburgh School of Medicine, who is also on the executive team of the Mood Disorders Treatment and Research Program, which serves as the clinical trials unit for the Western Psychiatric Institute and Clinic. To receive training in cutting-edge functional neuroimaging methods, Dr. Young will work closely with Dr. Jerzy Bodurka, an internationally-renowned MRI physicist with expertise in advanced blood-oxygen level dependent (BOLD) fMRI techniques and methodology, and the Chief Technology Officer and director of the Laureate Institute for Brain Research (LIBR) MRI and EEG facility. The training, and associated research, will take place at LIBR, a state-of-the-art independent biomedical research institute dedicated to conducting neuroimaging research with the mission of developing effective treatments for neuropsychiatric disorders. LIBR is affiliated with the Laureate Psychiatric Clinic and Hospital, which provides exceptional access to clinical populations available for research, particularly patients with MDD. With the training offered by her mentors and collaborators, and institutional resources at LIBR, Dr. Young will be able to achieve the research objectives of this proposal, namely to determine the degree to which real-time fMRI neurofeedback (rtfMRI-nf) enhances voluntary control over amygdala neural activity, co-modulates other brain regions within the emotion regulation circuitry, and alters depressive symptom severity ratings (Specific Aim 1). She also will determine the degree amygdala rtfMRI-nf restores a normative emotional processing bias during exposure to emotionally valenced stimuli (Specific Aim 2). Finally, this training will prepare Dr. Young for th R00 phase of the award in which she will transition to an independent faculty-level research position and investigate whether the time course of symptom improvement and the overall efficacy of cognitive behavioral therapy can be improved by augmenting it with rtfMRI-nf involving amygdala activity (Specific Aim 3).
Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide. Traditional pharmacological and/or psychological interventions are ineffective in up to one-half of patients, and treatments (such as electroconvulsive therapy, vagus nerve stimulation, and deep brain stimulation) available for severely ill patients who do not respond to standard interventions are invasive, and potentially associated with significant side effects. Therefore, there is a need to explore and develop novel non-invasive treatments, which is the goal of this application.