Working memory (WM) and episodic long term memory (LTM) dysfunction is a core feature of schizophrenia (SZ) that limits psychosocial function, is unresponsive to current medications, and shows only modest improvements with cognitive training, demonstrating the need to understand basic neural mechanisms to guide development of new treatments. Our previous research, and that of others, has identified a specific pattern of memory strengths and weaknesses in SZ, suggesting a dual-network model in which dorsolateral prefrontal cortex (DLPFC) and hippocampal (HI) memory circuits important for relating items to a specific spatial or temporal context to support recollection is disproportionately impaired, whereas ventrolateral prefrontal cortex (VLPFC) and perirhinal cortex (PRC) memory circuits important for encoding item information in support of familiarity based retrieval are relatively intact. The goal of the current project is to link this dual- networ model to fundamental molecular and neural candidate mechanisms. We will use an innovative multimodal neuroimaging approach integrating magnetic resonance spectroscopy (MRS), electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to test the central idea that there is a disruption in GABAergic inhibition in the DLPFC in SZ, which contributes to the reduced theta oscillations, DLPFC and HI fMRI impairments, and disproportionate relational memory deficits observed in prior research and preliminary data. This multimodal imaging approach will employ temporal context versus item memory paradigms recently validated in high profile studies of healthy individuals, will assess medication effects (y having equal numbers of medicated and unmedicated participants), and will investigate previously observed relationships with clinical symptoms (disorganization and negative symptoms) and psychosocial function (UPSA-B). The following Specific Aims will be addressed:
Aim 1 - Assess WM and LTM for item and temporal context information in healthy controls (HC) and people with SZ;
Aim 2 - Use EEG to identify neural oscillations associated with WM maintenance and LTM encoding of item and temporal context information in HC and SZ;
Aim 3 - Use MRI to assess GABA concentrations and patterns of fMRI activity during LTM retrieval of item and temporal context information in HC and SZ. By linking hypothesized neurophysiological mechanisms to specific memory strengths and weaknesses the proposed research avoids a generalized deficit explanation of memory dysfunction in SZ, identifies relative strengths that can be enhanced through cognitive remediation, and identifies biomarkers of memory impairment at the molecular, physiological and behavioral level that can guide new treatment development.
As a severe and chronic debilitating disorder, schizophrenia is the 5th leading cause of disability in the world. U.S. healthcare costs, alone, are estimated at $62.7 billion annually (2002 estimates). A substantial portion of this disability can be explained by cognitive dysfunction, which is unresponsive to current treatments, and highly predictive of psychosocial functioning, emphasizing the need to identify potential neural mechanisms to guide new treatment development. The proposed research will use EEG, fMRI and MRS to establish disrupted (GABAergic) neural inhibition in the dorsolateral prefrontal cortex (DLPFC) as a candidate mechanism for the reduced theta oscillations, reduced fMRI activation in DLPFC and hippocampal circuits, and disproportionate relational memory impairments in people with schizophrenia observed in our previous research.
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| Guo, J Y; Ragland, J D; Carter, C S (2018) Memory and cognition in schizophrenia. Mol Psychiatry : |
| Greenland-White, Sarah E; Ragland, J Daniel; Niendam, Tara A et al. (2017) Episodic memory functions in first episode psychosis and clinical high risk individuals. Schizophr Res 188:151-157 |
| Ragland, J D; Layher, E; Hannula, D E et al. (2017) Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes. Neuroimage Clin 13:82-88 |
| Ragland, J Daniel; Solomon, Marjorie (2016) Categorical Dimensions of Social Impairment and Disrupted Functional Connectivity in Autism Spectrum Disorders: When Does Continuous Become Discrete? Biol Psychiatry 80:90-91 |
