The proposed research and training plan is designed to promote my development as an independent investigator in the field of brain-immune interactions as they relate to negative symptoms in schizophrenia. Negative symptoms, including motivational deficits, are some of the most debilitating aspects of the disorder, being both difficult to treat and representing one of the most significant barriers to functional recovery. Regarding potential mechanisms of these deficits, individuals with schizophrenia reliably show decreased activation of the ventral striatum in reward-based neuroimaging tasks. One pathophysiologic pathway that may contribute to alterations in reward circuitry in schizophrenia is inflammation. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward- relevant neural circuitry. In addition, my published work and that of others has found that patients with schizophrenia reliably exhibit elevated concentrations of inflammatory markers, and my preliminary data indicate that inflammatory cytokines of monocytic origin, including tumor necrosis factor (TNF), are related to negative symptoms including decreased motivation and decreased functional connectivity in reward circuitry in these patients. Based on these findings, I hypothesize that increased inflammation in schizophrenia contributes to negative symptoms by disrupting neural activity in reward circuits leading to motivational deficits. To test this hypothesis, I propose the following Specific Aims: (1) To determine the association of inflammation with objective and clinical measures of motivation and negative symptoms, such as the Effort Expenditure for Reward Task, the Intrinsic Motivation Inventory, the Snaith Hamilton Pleasure Scale, and the Brief Negative Symptom Scale. (2) To determine the association of inflammation with reward circuitry in patients with schizophrenia using both task-based and resting state functional magnetic resonance imaging. (3) To explore whether the TNF antagonist, infliximab, will increase connectivity in reward circuitry leading to improvements in motivational deficits and negative symptoms. This work will inform future studies of novel therapeutic strategies to treat negative symptoms in patients with schizophrenia. As part of this proposal, I will also train in clinical research methods, neuroimaging techniques and analysis, immunology, assessments of motivation and negative symptoms in schizophrenia, and the ethical conduct of research. My development plan combines formal didactics, workshops, and hands-on training in neuroimaging, immunology, and schizophrenia, in addition to the proposed research. I have also assembled a team of recognized leaders in brain-immune interactions, schizophrenia and neuroimaging to provide mentorship during the award period. A K23 award is critical to my career development because it provides the needed protected time and resources to achieve my goals. The K23 award will also allow for data collection that will serve as the basis for R01 applications focused on translational research on the immune system and negative symptoms in schizophrenia.
Schizophrenia is a major public health concern, accounting for a high degree of morbidity and mortality, high costs to the healthcare system, and a major socioeconomic burden. Negative symptoms, such as motivational deficits, are often resistant to treatment and represent some of the most debilitating aspects of this disorder, disproportionally contributing to impaired functional outcomes. The proposed research will test the novel hypothesis that the immune system may target brain reward circuitry, playing a role in the pathophysiology of negative symptoms in schizophrenia, and thus may represent a target for future immune-based therapies.