Schizophrenia is a disabling illness associated with impairments in independent living and functioning. Episodic memory (EM) is an important cognitive domain commonly impaired in schizophrenia. The precuneus is a key node in EM circuitry that has reciprocal connections with other EM relevant structures, including the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). Alterations in precuneus connectivity are associated with EM deficits in schizophrenia. However, the exact mechanisms by which precuneus dysfunction is related to EM impairment is unclear. There is a critical need to better define the neural underpinnings subserving this clinical phenomenon. Repetitive transcranial magnetic stimulation (rTMS) enables direct manipulation of local brain activation and indirect manipulation of activation in the target's associated neural networks. This creates an opportunity to effect disparate physiologic changes in brain circuits, clarifying the role of disrupted neural structures and networks in psychiatric illness. Our objectives are to demonstrate that rTMS engages the precuneus and to clarify the mechanisms underlying EM dysfunction in schizophrenia. Our central hypotheses are that rTMS will modulate functional activation of the precuneus and connectivity with associated EM circuitry. We will also examine the effect of rTMS on EM performance. Our long-term goal is to provide a path for investigators considering the precuneus as a potential target for the treatment of EM dysfunction in schizophrenia.
In Aim 1, we will demonstrate the impact of rTMS targeting the precuneus on functional activation during performance of an in-scanner EM task. We hypothesize that rTMS will modulate precuneus activity, serving as evidence of rTMS target engagement. We expect that, compared to sham stimulation, 1 Hz rTMS will decrease activation and 20 Hz rTMS will increase activation of the precuneus.
In Aim 2, we will demonstrate the effects of rTMS on precuneus functional connectivity in individuals with schizophrenia. We hypothesize that rTMS will alter resting state functional connectivity between the precuneus and associated EM circuitry, specifically the DLPFC and the ACC. We expect that, compared to sham stimulation, functional connectivity at rest between the precuneus, the DLPFC, and the ACC will decrease in response to 1 Hz rTMS and increase in response to 20 Hz rTMS.
In Aim 3, we will demonstrate the effect of rTMS on EM performance in schizophrenia. We hypothesize that precuneus rTMS will be associated with changes in EM performance. We expect that compared to sham stimulation, 1 Hz rTMS will impair performance and that 20 Hz rTMS will improve performance during an in-scanner EM task. This study will provide evidence that rTMS modulates activity within the precuneus and associated EM circuitry in individuals with schizophrenia. This will inform subsequent clinical trials targeting the precuneus for the treatment of EM dysfunction in schizophrenia.
Episodic memory (EM) deficits in schizophrenia are related to disrupted function of the precuneus, though the precise mechanisms by which the precuneus is involved are unclear. Repetitive transcranial magnetic stimulation (rTMS) allows direct manipulation of local brain activation and indirect manipulation of activation in the target's associated neural networks. Our goal is to demonstrate the effect of rTMS on precuneus activity, as well as functional connectivity between the precuneus and other EM relevant structures, which will better define the neural underpinnings of EM impairment and guide the development of innovative therapeutics for this important cognitive impairment.
