This renewal application builds upon our current study supported by the R01 NIH Fogarty International Center grant, entitled “Psychobiological Follow-up Study of Transition from Prodrome to Early Psychosis” (R01MH111448). This proposal focuses on two persistent needs in clinical high risk (CHR) research: 1) the identification of novel biomarkers associated with transition to psychosis and other functional and clinical outcomes; and 2) the identification of symptom-specific brain circuit targets that can be engaged in future clinical trials. We hypothesize that clinically relevant biomarkers for individual-specific prognosis in CHR will be enhanced by the inclusion of measures that capitalize on the quantitative assessment of neural plasticity and are likely amenable to change. In this view, CHR outcomes are likely determined by both pathophysiology and by the brain’s capacity to adapt and respond to pathophysiology via neural plasticity mechanisms (i.e., allostasis). We thus propose to examine brain circuit plasticity biomarkers relevant to CHR by administering non-invasive neuromodulation via two novel paradigms that, as we have demonstrated, engage brain networks involved in negative and positive symptoms in schizophrenia. These two neuromodulation techniques are: 1. repetitive transcranial magnetic stimulation (rTMS)1 and 2. real time fMRI neurofeedback enhanced mindful meditation (mb-rt-fMRI-NFB)2. We will collect both traditional biomarkers (clinical, neuropsychological, ERP, MRI, DTI and resting state MRI) as well as novel allostatic biomarkers (i.e., biomarkers that quantify neural changes pre- relative to post-intervention). These two interventions, which have not been used with CHR subjects before, will be tested in 200 CHR (50 CHR per experimental condition) and 100 HC over 5 years. Furthermore, we will continue to enhance knowledge capacity at the Shanghai Mental Health Center (SMHC), where our Chinese collaborators are based. We will also examine the effectiveness of these interventions in CHR as a bridge to future therapeutic treatments (Aims 1 and 2), and we will test traditional and allostatic biomarkers as predictors of clinical and neurocognitive outcomes (Aim 3). Additionally, we will significantly enhance research capacity by building on already established achievements and collaborations, and by extending our reach to new institutions (Aim 4). This competitive renewal capitalizes on a unique set of strengths at a single site (SMHC) and on a collaboration with the Shanghai research team, which has proven to be most productive in the current grant cycle. We believe that this highly novel study will contribute to the development of future therapeutic interventions in CHR, which will prevent this vulnerable population from developing adverse outcomes and, at the same time, will enrich the CHR field with new insights into the pathophysiology of this condition.

This is a renewal application of an R01 NIH Fogarty International Center grant entitled, “Psychobiological Follow- up Study of Transition from Prodrome to Early Psychosis” (R01MH111448), which is conducted in collaboration with the Shanghai Mental Health Center (SMHC). The current application builds on findings from the previous grant period that identified several biomarkers of clinical high risk outcomes (CHR) and responds to the critical need for better links between biomarkers and outcomes, especially with respect to relating biomarker responses to interventions. We posit that the two interventions: 1. repetitive transcranial magnetic stimulation (rTMS)1 and 2. real time fMRI neurofeedback enhanced mindful meditation (mb-rt-fMRI-NFB)2 will yield measures of brain capacity for change (allostatic biomarkers) in CHR, thus paving the way forward for future therapeutic interventions, and offering the opportunity for comparing more traditional and novel biomarkers as predictors of clinical and neurocognitive outcomes, thus enhancing our current understanding of CHR amenability to treatment.