Shawn M McClintock, PhD, MSCS - US grants

DESCRIPTION (provided by applicant): This proposal is for a K23 Mentored Patient Oriented Research Career Development Award that will prepare the candidate for a successful independent career in translational neurocognitive research. The candidate and his mentors at UT Southwestern Medical Center (UTSW) and Columbia University/New York State Psychiatric Institute (CU/NYSPI) designed a Staged Mentored and Arranged Transition (SMART) career development pathway to enable him to become a proficient, independent investigator working at the intersection of neurocognitive function, mood disorders, and neurostimulation interventions. This unique research niche will allow the candidate to leverage the expertise of his preceptors while establishing his individual identity as an independent investigator. The SMART pathway forms a collaborative network of expert mentors and advisors (Drs. Mustafa M. Husain, Sarah H. Lisanby, C. Munro Cullum, Herb Terrace, Ira Bernstein, George Alexopoulos, and Harold A. Pincus). The career development plan is comprised of scholarly didactics and seminars, expert preceptorship, hands-on experience at UTSW and CU/NYSPI, as well as tangible productivity including peer-reviewed manuscripts and grant applications. Unique to the candidate's career path is the pre- planned shift in primary appointment from UTSW to CU/NYSPI during this award period. This will facilitate his transitional goals as well as smooth his transition to independent status. The goal of his research project is to develop and conduct Translational Research Evaluating Neurocognitive Memory Processes (TREC-MP). The use of model animals to study neurocognitive functions has been employed extensively in basic science methodologies. However, the resulting applications for clinical human use have been limited. TREC-MP is a translational project that examines the psychometric properties in humans of experimental computerized neurocognitive measures developed for nonhuman primates undergoing electroconvulsive shock and magnetic seizure therapy. This incremental research study is designed to optimize the experimental neurocognitive battery in a healthy human cohort, then to determine the effects of depression on test performance, and finally to determine the neurocognitive performance of depressed subjects undergoing electroconvulsive therapy (ECT). The cognitive impact of ECT is well recognized and of considerable clinical significance, but what is less well understood is the complex interaction between depression and ECT on cognitive component processes. As such, newer methods of cognitive assessment are needed to elucidate similar and divergent cognitive processes across species, and identify underlying cognitive component processes of memory impairment in patients receiving ECT. As exemplified in recent NIMH translational neurocognitive research and clinical initiatives, one useful strategy would be the development of comparative nonhuman primate and human neurocognitive measures for specific neurocognitive domains and component processes. The application of a specific neurocognitive battery, predicated on basic science neurocognitive research with nonhuman primates provides a powerful method for understanding the cognitive component processes of memory deficits, thereby permitting the future development of targeted treatment interventions and useful clinical neurocognitive measures. [The aims of this project are: 1) Develop and validate experimental neurocognitive measures for use with healthy human participants, 2) Determine effects of depression on performance on experimental neurocognitive measures, and 3) Determine effects of ECT on performance on experimental neurocognitive measures.] Analyses will be conducted with both classical test and item response theory statistics. This project is scientifically innovative and important because it will provide a platform for the candidate to conduct translational neurocognitive research to help him understand the etiology of memory impairment and ultimately design appropriate clinical neurocognitive measures and interventions. The candidate's SMART pathway and TREC-MP project set the stage for his individualized and systematic development as an independent translational neurocognitive scientist. PUBLIC HEALTH RELEVANCE: Impaired cognitive functions associated with psychiatric treatments of severe depression contribute to poor functional outcomes. The objective of this career development award is for the candidate to become a proficient translational neurocognitive scientist. The long-term goal is for this translational neurocognitive research to provide a clearer understanding of the cognitive component processes that underscore cognitive functional impairments in order to develop psychometrically sound neurocognitive outcome measures and targeted treatment interventions.

PROJECT ABSTRACT Major depressive disorder (MDD) is ranked second among all diseases in global impact. Unfortunately, many patients have treatment-resistant MDD (TRD), for which the most effective antidepressant treatment option is electroconvulsive therapy (ECT). However, the neurocognitive adverse effects (e.g., anterograde and retrograde amnesia) induced by ECT mitigate the attainment of desired clinical outcomes. As such, the development of new and safe neuromodulatory antidepressant interventions is strongly warranted. One new type of neuromodulation treatment that has antidepressant properties and is under active development is magnetic seizure therapy (MST). MST is neurocognitively safer than ECT because it uses magnetic rather than electrical fields to induce seizures, which have shallower penetration and therefore avoid the undesired side- effect of delivering intense electrical stimulation to the medial temporal lobe. As yet there has been no research into the neuromechanisms underlying MST?s antidepressant and neurocognitive effects. To systematically uncover these mechanisms, we are building upon an international, NIMH funded (R01 MH112815), US Food and Drug Administration Investigational Device Exemption (IDE; #G170127) approved clinical study that will compare and contrast clinical and neurocognitive outcomes of ECT and MST. The goal of this R01 is to conduct research Ascertaining Neurocircuitry to Enhance Neuromodulation Development (ASCEND). In the proposed study, we will capitalize on that project by adding advanced magnetic resonance imaging (MRI), individualized 3-D computational head modeling of ECT and MST (E-fields in stimulated brain regions), and neurophysiological modeling of activity propagation and plasticity resulting from each treatment type. This innovative 5-year project has two aims: 1) Determine the common and distinct neural circuit correlates of antidepressant treatment response between RUL-UB-ECT and MST, and 2) Determine the common and distinct neural circuit correlates of memory side effects between RUL-UB-ECT and MST. The proposed study will draw upon an interdisciplinary team from diverse backgrounds including translational neurocognitive science, neuropsychology, computational neuroscience, psychiatry, neuroimaging, bioengineering, and biostatistics. The synthesis of physical (E-field) and physiological (neural activity and dynamics) computational modeling and MRI with the clinical and neurocognitive metrics from the current NIMH-funded clinical trial will allow us to determine neuromodulation-induced changes in neurocircuitry, and their corresponding relationships to behavior. Such knowledge will elucidate the neural mechanisms of antidepressant seizure therapy (ECT, MST) to inform new treatment methods that optimally target neurocircuitry related to symptom improvement, while ensuring neurocognitive safety. These developments will make a major contribution to improving the lives of the many patients with TRD and yield a substantial positive public health impact.