Uncovering pathophysiological mechanisms of psychosis using the oculomotor system

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 translational and quantitative measure of treatment targets and aid in early illness detection.

Principal Investigators
Rolfs, Martin Prof. Dr. (Details) (General Psychology - Active Perception and Cognition)

Participating external organizations

Financer
Sonstige internationale öffentliche Mittelgeber

Duration of Project
Start date: 09/2017
End date: 07/2021

Research Areas
Clinical Neurosciences II - Psychiatry, Psychotherapy, Child and Adolescent Psychiatry, General, Biological and Mathematical Psychology

Research Areas
Psychotische Störungen, Sensumotorik, Visuelle Wahrnehmung

Publications
Thakkar, K.N. & Rolfs, M. (2019). Disrupted corollary discharge in schizophrenia: evidence from the oculomotor system. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 4, 773-781. https://doi.org/10.1016/j.bpsc.2019.03.009

Yao, B., Neggers, S. F. W., Rolfs, M., Rösler, L., Thompson, I. A., Hopman, H. J., Ghermezi, L., Kahn, R. S., & Thakkar, K. N. (2019). Structural thalamofrontal hypoconnectivity is related to oculomotor corollary discharge dysfunction in schizophrenia. Journal of Neuroscience, 39(11), 2102–2113. https://doi.org/10.1523/jneurosci.1473-18.2019

Last updated on 2020-01-06 at 18:55