# Uncovering pathophysiological mechanisms of psychosis using the oculomotor system.

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $387,864

## Abstract

PROJECT SUMMARY
 Disturbances in a sense of self are a hallmark of schizophrenia. These disturbances can be
characterized by a distorted sense of agency—the subjective sense that I cause the actions I produce. Agency
distortions are manifest in many psychotic symptoms of schizophrenia, for example, the delusion that one is
being controlled by aliens. The physiological mechanisms of these agency disturbances have been difficult to
identify. The most convincing biological explanation for agency distortions is a disturbance in corollary
discharge (CD). CD refers to “copies” of motor signals. Rather than being sent to the muscles, CD signals are
sent to sensory areas and allow the organism to anticipate the sensory consequences of the impending action.
A match between the anticipated and actual sensory events following an action engenders a sense of agency,
whereas a mismatch results in the subjective experience that sensations are caused by an external agent.
 The oculomotor system provides an ideal framework in which to investigate CD. The most robust
behavioral paradigms for studying CD as well as the only neurophysiological evidence for CD signals in
primates has come from eye movement research. This body of work provides an unprecedented translational
framework for understanding the agency disturbances that characterize psychosis and allows us to translate
single-cell findings in animals to studies of the mechanisms of self-related symptoms characterizing psychosis.
 Recently, we have shown evidence for disturbed CD in the saccadic eye movement system in patients
with chronic schizophrenia. Informed by neurophysiology studies, these behavioral findings generate testable
hypotheses about dysfunctional networks that might be giving rise to CD abnormalities in schizophrenia. This
4-year proposal has three major aims. The first is to identify the neural correlates of disrupted CD in chronic
schizophrenia patients using structural and functional neuroimaging and state-of-the-art connectivity analyses.
The second is to examine whether CD impairments are also present in recent-onset schizophrenia patients, as
the conditions for detecting relevant pathophysiological mechanisms are better in this sample. The third is to
investigate whether CD impairments are specific to schizophrenia or represent a trans-diagnostic mechanism
of psychosis by including patients with bipolar disorder with a history of psychosis. A fourth exploratory aim
explores the implications of this CD abnormality for impaired cognition in psychosis.
 These findings have the potential to link core phenomenological experiences in schizophrenia to activity
of single neurons and to understand shared and distinct biological substrates of psychosis across a range of
syndromes. In addition, finding abnormalities in specific neural pathways that are known to convey CD signals
holds the promise to inform pharmacological treatments. Finally, our behavioral paradigms can provide a
useful translat...

## Key facts

- **NIH application ID:** 9976587
- **Project number:** 5R01MH112644-04
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Katharine Natasha Thakkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,864
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976587

## Citation

> US National Institutes of Health, RePORTER application 9976587, Uncovering pathophysiological mechanisms of psychosis using the oculomotor system. (5R01MH112644-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976587. Licensed CC0.

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