Physician-Scientist Projects - Psychiatry Residency
Mark Kvarta, MD, PhD
PGY-4 PSTP Resident
Project: Dynamic integration of stress and genetics to reward circuit dysconnectivity in depression
Primary mentor: Elliot Hong, MD
Depression is a devastating, deadly, and costly disease. It is most commonly treated, often unsatisfactorily, by manipulating synaptic serotonergic tone, yet the key substrates that mediate antidepressant efficacy are largely unknown and a better understanding of the etiology and neurobiological pathophysiology is needed. My doctoral work focused on the role of chronic stress in causing excitatory synaptic dysfunction within the hippocampus and ultimately downstream at the corticolimbic interface with the reward system in the nucleus accumbens, resulting in reward deficits including anhedonia in rodents. I described how chronic stress and successful antidepressant treatment bidirectionally altered excitatory synaptic strength using electrophysiology and molecular and behavioral techniques.
With my current project I aim to extend these findings into human populations and study circuit dynamics between these key brain areas using functional imaging (fMRI) and electrophysiology (EEG) in depressed and non-depressed individuals.
Furthermore, I am investigating the role of major stressors experienced at different time points throughout life, and the interaction of this stress with genetic vulnerability towards altering circuit function and ultimately depressive symptomatology. Understanding how these brain regions communicate with each other and are perturbed by genetics and environment in depression are critical in order to develop meaningful biomarkers and the next generation of therapeutics.
Gustavo C. Medeiros, MD
- Impact of psychiatric comorbidities in antidepressant efficacy treatment with ketamine and esketamine: A meta-analysis; and
- Too much stress; a critical assessment of the use of animal models of stress to study depression.
Primary mentor: Todd D. Gould, MD
My first project is a meta-analysis assessing the impact of psychiatric comorbidities in antidepressant response with ketamine and esketamine. It is widely known that MDD is often accompanied by other psychiatric comorbidities, which tend to further complicate its treatment. There are some intriguing findings in the ketamine/esketamine literature suggesting a more substantial response in individuals with personal or family history of alcohol use disorder and anxiety comorbidities when compared to individuals without these comorbidities. However, it is still unclear if a broader and systematic review of the literature will support whether some patients may respond more favorably to one over the other. Therefore, our project will answer the following question: Does personal and/or a family history of psychiatric comorbidities (such as alcohol use disorder, substance use disorder, anxiety disorders, post-traumatic stress disorder, personality disorders, etc.) moderate the antidepressant efficacy of ketamine or esketamine?
Our second project is a review of current animal models of depression and the potential excessive reliance on stress-based models. Pre-clinical research is vital to improve the understanding of the physiopathology of MDD but it is surrounded by misconceptions regarding its strengths and limitations. A common misconception in the existence of animal models of MDD since MDD in humans is very unique and heterogeneous disorder that cannot to be fully replicated in other species. Animal paradigms model a specific aspect of MDD, and most of them are stress models where depression-like arise secondary to despair and hopelessness. Our review critically examines current animals used to study depression.
Eric Luria Goldwaser, DO, PhD
PGY-3 PSTP Resident
Project: Development stress and blood-brain barrier integrity in schizophrenia.
Primary mentor: Elliot Hong, MD and Peter Kochunov, PhD
Secondary mentor: Scott Aaronson, M.D.
Endothelial cell monolayers are shared within the body's many vascular systems. A peripheral assessment may provide surrogate information on the blood-brain barrier (BBB) endothelial function in schizophrenia. My doctoral research project was focused on the assessment of endothelial dysfunction in Alzheimer's disease at the molecular and cellular level of the BBB. This current project will extend my prior research experiences in BBB endothelial integrity to schizophrenia at the clinical biomarker level during my PSTP training.
The primary goals of this project are to:
- Test the central and peripheral endothelial integrity in schizophrenia which can be assessed with state-of-the-art neuroimaging for BBB integrity, ophthalmologic tools for blood-retina barrier function, and peripheral endothelial assays.
- Ascertain developmental insults as a significant contributor to the endothelial dysfunction in schizophrenia.
Neurocircuitry involved in aberrant processing and connectivity may further be explored at the junction between perfusion and metabolism utilizing various diffusion MRI sequences, and to carve out putative targets for non-invasive neuromodulation.