PECASE: Using Control Systems to Quantify Limbic Dysregulation for Neurobiologically-Based Diagnoses of Psychiatric Disabilities

PI: Mujica-Parodi, Lilianne Proposal Number: 0954643 PROJECT SUMMARY Intellectual Merit: For this proposal, we will develop and test computational methods for quantifying dysregulation between the excitatory and inhibitory components of the negative feedback loops in the brain that control homeostatic regulation of emotional arousal. This work conceptually integrates systems neuroscience with techniques originally developed for physics and engineering (power spectrum scale invariance, Shannon entropy) that have been successfully applied towards characterizing autonomic regulation via heart-rate variability analysis. Historically, neuroimaging has focused on measuring the amplitude of activation-levels in different regions of interest for some specific task. While in the past few years newer connectivity methods such as structural equation modeling, Granger causality, and dynamic causal modeling are important advances in investigating the temporal components of the time-series, these techniques are designed to investigate the strength of connections between node pairs. In contrast, our approach builds upon this work to answer a completely different type of question: to what degree does the system as a whole respond efficiently to perturbation in its maintenance of homeostasis? Our approach is explicitly motivated by the fact that many diseases-from diabetes to cancer to Cushing's disease-are dysregulatory in nature. As such, one technique that has enjoyed much diagnostic success is to "perturb" the system and then measure dynamic features of its return to baseline. In this proposal, we measure dysregulation of the limbic circuit, with neural timeseries obtained first from functional MRI and then near-infrared spectroscopy, in developing a neurobiologically-based instrument for objective and quantitative diagnosis of mental illness. The three patient groups with whom we will optimize our methods will include generalized anxiety disorder, major depression, and their comorbidity. These diagnostic choices provide a rational extension of our previous research on limbic dysregulation as a marker for individual variability in trait anxiety within the healthy population. Moreover, the symptoms associated with anxiety and depression have clearly-defined excitatory and inhibitory components with respect to physiological and behavioral arousal, and therefore will allow us to test dissociation between groups. The development of engineering techniques to assist individuals with psychiatric illness qualifies this proposal for consideration in the RAPD category as it advances innovation beyond the frontiers of current knowledge in disability-related research of mental illness. Given that psychiatric illnesses are currently diagnosed solely by clinicians' assessment of patients' self-reported moods, and therefore are highly subjective and wholly dependent upon patient compliance, the broad societal impact of this research lies in the potential ability to harness the functional neuroimaging technologies for applications that could be revolutionary in the diagnosis of mental health disorders, providing objective and quantifiable criteria for assessing prodromal risk, treatment efficacy, and identifying clean phenotypes for genetic research. This CAREER award would permit me, over the next five years, to collect the necessary data and to iteratively develop and adapt the computational engineering tools necessary to lead development in this critical evolving area of research. Broader Impact: In 2007, the National Academy of Science, National Academy of Engineering, and Institute of Medicine were charged by Congress to form a committee to address the challenges associated with maintaining scientific innovation and economic competitiveness within an increasingly global economy. For this CAREER award, I will focus on addressing two specific recommendations made by this committee. One action item was to strengthen children's K-12 preparation in science and technology by enhancing the science and engineering education of the science teachers themselves. A second action item was to increase the total number of individuals qualified and motivated to pursue postgraduate study in science and engineering. This CAREER award will directly address both of these action items. The first action item will be addressed in three parts: (1) through the development of a fun and intellectually engaging hands-on 7th grade curriculum in "systems-based thinking" using STELLA software; (2) through training science teachers to use the curriculum during summer workshops; and, (3) through dissemination of the curriculum and workshop materials by posting them on our website and follow-up assessment to measure the curriculum's efficacy. The second action item will be addressed by setting up a collaborative program with the Georgia Institute of Technology Department of Biomedical Engineering to recruit minority biomedical engineers into our Biomedical Engineering Ph.D. program: first as summer-research undergraduates, and then as full-time students. By training students in the lab to exploit the benefits of thinking in terms of systems in their own research, and then training them to teach teachers and by extension junior high school students the same conceptual tools at a more basic level, we are able to integrate our research and educational goals to the fullest extent possible.