Real time neurofeedback, its neurotransmitter underpinnings, and therapeutic effects, in clinical high risk individuals

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Clinical high risk (CHR) for psychosis states are symptomatic, dynamic periods that occur before psychosis onset and are subjects of intensive research. The focus on CHR is driven by evidence of behavioral and brain level impairments in many individuals experiencing their attenuated psychotic symptoms which are similar to those found in first episode and chronic schizophrenia (SZ): our work, and that of others, demonstrated that CHR individuals show deficits in both brain function and cognition reminiscent of those found in SZ. For example, increased default mode network (DMN) connectivity found in SZ was also identified in CHR. The CHR period offers the most hope for mitigating or preventing disease development yet effective treatment options are still lacking. The overarching goal of this R61/33 study is early efficacy testing of the real-time functional MRI-based neurofeedback (rt-NFB), aided by mindfulness (rt-NFB+M), to impact both brain connectivity and clinical and neurocognitive (NP) outcomes. In the R61 phase, we will examine the efficacy of rt-NFB+M targeting the DMN to reduce medial prefrontal and posterior cingulate cortex (MPFC-PCC) hyperconnectivity and to increase MPFC-dorsolateral prefrontal cortex (DLPFC) anti-correlations in CHR subjects who will be randomly assigned to either real-rt-NFB+M (N=24) or sham/control -rt-NFB+M (N=24) condition. Thirty healthy controls scanned once will serve as an additional control group. Neurotransmitters in MPFC and DLPFC will also be assessed using magnetic resonance spectroscopy to relate cellular level measures to brain network measures. MPFC- PCC connectivity reductions and MPFC-DLPFC increased anticorrelation, post-NFB, in the real rt-NFB+M group, will be the R61 GO criteria. In the R33 phase, we will replicate R61 results in an independent sample of 51 CHR in the real-fMRI NFB+M condition, compare the effects of rt-NFB+M (N=51 CHR) versus meditation only (N=30 CHR), examine dose-response over 4 sessions, and the relationship between network connectivity and glutamate (Glu) and GABA changes, as well as clinical and neuropsychological changes, especially in working memory (WM) and attention, post-intervention, in both rt-NFB+M and in the meditation only group. This proposal builds on our successful use of rt-NFB in SZ to modulate the DMN connectivity and mitigate symptoms. As one of the first in the field, we demonstrated that rt-NFB targeting the DMN reduced its hyper-connectivity in SZ which; in turn, was associated with auditory hallucinations reduction after rt-NFB. Increased MPFC-DLPFC anticorrelations were also observed and associated with increases in MPFC GABA in a separate study. Furthermore, we have observed that increases in DMN-DLPFC anticorrelations due to pharmacological or behavioral interventions are associated with improved WM and attention. Since our preliminary data suggest that SZ with the least abnormal brain patterns benefited most from our rt-NFB intervention, we believe that adopting the rt-NFB in CHR will be highly effective in altering the disease trajectory.