Neuromodulation of Social Cognitive Circuitry in People with Schizophrenia Spectrum Disorders

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PROJECT SUMMARY People with schizophrenia spectrum disorders (SSDs) (i.e., schizophrenia, schizoaffective disorder, schizophreniform disorder) exhibit considerable impairment in social functioning. Current treatments are minimally effective, and impairments tend to persist. Our recent collaborative multi-center study increased knowledge regarding the neurobiology of social cognitive (SCog) impairment in people with SSDs, identifying the neural circuitry of SCog impairments and their behavioral and functional correlates. The present study aims to use repetitive transcranial magnetic stimulation (rTMS), a form of neuromodulation, to target the neural circuitry of SCog impairments in people with SSDs. In the 2-year R61 phase of this application, we will randomize 60 people with SSDs to three groups: 20 to a conventional form of rTMS (i.e., 10Hz rTMS); 20 to a newer, more rapid form known as intermittent theta burst stimulation (iTBS); and 20 to either sham 10 Hz rTMS stimulation or sham iTBS. We will determine whether these treatments can change the functional connectivity of key SCog brain circuits by targeting a brain region known as the dorsomedial prefrontal cortex (DMPFC). Since each person’s anatomical and functional brain profile is slightly different, we will optimize the orientation and location of the placement of the brain stimulation coils in each individual, using novel approaches pioneered by members of our team and others, to maximize the impact on brain function. If we find that either form of active brain stimulation (compared to sham) we can changes functional connectivity in the hypothesized SCog brain circuit at a predetermined effect size, we will have achieved our ‘Go/No-Go criterion’ and will then request permission to proceed to the 3-year R33 phase. In the R33 phase, we will apply brain stimulation for 4 -weeks (5 days/week), carrying forward the brain stimulation modality which best engaged the target, and compare to sham. Wewill randomize 120 people with an SSD across our three sites. Our primary outcome measure will be SCog performance at the end of the four week period, and our secondary outcome measure will be FC change in SCog circuitry. We will determine if this treatment can lead to improvements in SCog performance in people with SSDs, and accompanying changes in FC of SCog circuitry. We will also evaluate SCog performance at 8 weeks to determine the sustained effect of brain stimulation. Overall, our proposal is modeled directly on the NIMH clinical trials target engagement framework, including specifics regarding testing brain stimulation parameters (i.e., rTMS vs. iTBS) and individualizing coil placement for optimal targeting. We anticipate that brain stimulation will demonstrate target engagement, and potentially ameliorate SCog deficits in people with SSDs. The main goal of the current study is to demonstrate and optimize a novel therapeutic approach for SCog impairment, which we hope will ultimately lead to confirmatory efficacy work, and ideally broader uptake by mental health practitioners helping people with SSDs.