Episodic long-term memory (LTM) is among the most severely impaired cognitive domains in schizophrenia, and is also one of the strongest predictors of long-term functional outcome in the illness. Patients with better episodic memory also tend to have better rehabilitative treatment outcome, better work and social role functioning, and higher quality of life. Unfortunately, memory deficits are largely unaffected by our currently available treatments, and new treatments are not yet established. The current proposal aims to identify neurobiological mechanisms of relative strengths and weaknesses in episodic memory function in patients with schizophrenia to provide targets for new treatment development. The proposed research tests the novel theory that, in new learning situations, patients with schizophrenia are specifically impaired in their ability to engage dorsolateral prefrontal (DLPFC) and hippocampal mechanisms necessary for processing items of information in relation to each other while forming and retrieving long-term memories. During memory formation, patients are predicted to have trouble engaging strategies that emphasize relationships amongst items in working memory (i.e., a DLPFC working memory (WM) control deficit), and also to fail at establishing long-term memories of the relationship between items and the context in which they are encountered (i.e., a hippocampal relational binding deficit). In contrast, patients'ability to engage the ventrolateral prefrontal cortex (VLPFC) to maintain individual items in WM and their ability to engage the perirhinal cortex (PRc) to form individual item representations in LTM is predicted to be intact. During memory retrieval, patients are hypothesized to show a similar relational deficit, with retrieval based more upon the memory strength of individual items (i.e., familiarity- based recognition) and less on retrieval of the relational context in which items were encountered (i.e., recollection). Novel behavioral and eye movement memory paradigms along with functional magnetic resonance imaging (fMRI) will address three specific aims:1) To use behavioral and eye movement measures to test the hypothesis that patients have a specific deficit in relational memory, whereas their item memory is intact. 2) To use functional magnetic resonance imaging (fMRI) to test the hypothesis that relational memory deficits in schizophrenia are associated with reduced activity and connectivity of the DLPFC and hippocampus, whereas activity in the VLPFC and PRc is intact. 3) To investigate the relationship between memory performance, DLPFC and hippocampal dysfunction and measures of clinical symptoms and functional disability in patients with schizophrenia. Successful completion of this research will provide new insights into the cognitive and neural mechanisms underlying LTM deficits in schizophrenia;will generate evidence that these mechanisms represent a specific deficit in relational memory and not solely a generalized deficit arising from general inattention, poor motivation or task engagement, etc.;will identify conditions in which there are areas of preserved cognitive function that can be harnessed for remediation efforts;and will identify clinical, cognitive, neural, and functional outcome correlates of memory impairment that can become targets for new drug development and outcome measures to facilitate existing cognitive enhancement clinical trials.

Public Health Relevance

Schizophrenia is characterized by severe memory deficits that compromise daily psycho-social function and limit long-term outcome. This research proposes to use behavioral, fMRI, and eye movement experiments to test a novel theory about a neurocognitive mechanism that can explain memory strengths and weaknesses in the disorder and, thereby, identify target mechanisms for development of new pro-cognitive agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH084895-02
Application #
8046389
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Meinecke, Douglas L
Project Start
2010-03-17
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$341,551
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Tso, Ivy F; Taylor, Stephan F; Grove, Tyler B et al. (2017) Factor analysis of the Scale of Prodromal Symptoms: data from the Early Detection and Intervention for the Prevention of Psychosis Program. Early Interv Psychiatry 11:14-22
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
Solomon, Marjorie; McCauley, James B; Iosif, Ana-Maria et al. (2016) Cognitive control and episodic memory in adolescents with autism spectrum disorders. Neuropsychologia 89:31-41
Ragland, J Daniel; Ranganath, Charan; Harms, Michael P et al. (2015) Functional and Neuroanatomic Specificity of Episodic Memory Dysfunction in Schizophrenia: A Functional Magnetic Resonance Imaging Study of the Relational and Item-Specific Encoding Task. JAMA Psychiatry 72:909-16
Solomon, Marjorie; Ragland, J Daniel; Niendam, Tara A et al. (2015) Atypical Learning in Autism Spectrum Disorders: A Functional Magnetic Resonance Imaging Study of Transitive Inference. J Am Acad Child Adolesc Psychiatry 54:947-55
McFarlane, William R; Levin, Bruce; Travis, Lori et al. (2015) Clinical and functional outcomes after 2 years in the early detection and intervention for the prevention of psychosis multisite effectiveness trial. Schizophr Bull 41:30-43
Wang, Wei-Chun; Montchal, Maria E; Yonelinas, Andrew P et al. (2014) Hippocampal and parahippocampal cortex volume predicts recollection in schizophrenia. Schizophr Res 157:319-20
Solomon, Marjorie; Yoon, Jong H; Ragland, J Daniel et al. (2014) The development of the neural substrates of cognitive control in adolescents with autism spectrum disorders. Biol Psychiatry 76:412-21
Libby, Laura A; Yonelinas, Andrew P; Ranganath, Charan et al. (2013) Recollection and familiarity in schizophrenia: a quantitative review. Biol Psychiatry 73:944-50
Lesh, Tyler A; Westphal, Andrew J; Niendam, Tara A et al. (2013) Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia. Neuroimage Clin 2:590-9

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