Neuromodulation of Social Cognitive Circuitry in People with Schizophrenia Spectrum Disorders - 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.
