Advances in cognitive and affective neuroscience allow us to conceptualize and measure functional neural systems that are related to core dimensions of psychopathology. These distinct neural systems bridge behavior and neurobiology and shed new light on the pathophysiology of mental disorders in a manner that may both clarify and cut across traditional diagnostic boundaries. Much of the preceding research on the pathophysiology of psychotic disorders has followed the categorical distinction between schizophrenia (SZ) and Bipolar Disorder (BD). However, recent genetic, clinical and outcome data suggest significant overlap between the disorders that could reflect shared pathophysiological processes. Hence there is a fundamental need to examine more basic mechanisms driving symptoms that underlie psychopathology in both disorders, as well as to understand points of divergence between SZ and BD. This need is especially salient in the context of first episode (FE) psychosis, where differential diagnosis is highly challenging and the benefits of targeted early treatments are most pronounced. Toward this aim, this proposal focuses on cognitive control and approach motivation in FE psychosis, two core dimensions recommended by RDoC and linked respectively to fronto-parietal (FP) and orbitalfrontal-ventral striatal (OFC-VS) functional brain networks. Using fMRI and two behavioral paradigms that engage 1) the goal maintenance component of cognitive control 2) positive incentive effects on behavior and 3) the effects of repeated incentives on cognitive control, in a prospective longitudinal design we will test the following hypotheses regarding the cognitive and neural mechanisms underlying core behavioral disturbances in SZ and BD. 1) FP dysfunction is related across diagnoses to impaired cognitive control and disorganization, and that in SZ this is a trait feature of the illness while in BD it is largely episode dependant 2) OFC-VS activity in response to positive incentives is reduced in SZ and intact or increased in BD and this is a trait feature o both illnesses and 3) BD patient have a unique pattern of responding to repeated incentives with increased OFC-VS and decreased FP activity and impaired cognitive control, as a trait feature of the illness. Successful completion of this project will provide important links between discrete neural circuits and core symptoms in SZ and BD and highlight areas of overlap as well as divergence in the illness. The results will provide important circuitry level insights into the natral history and pathophysiology of FE psychosis, contribute to the development of imaging biomarkers and help guide the development of interventions that focus on key dimensions of symptoms in FE psychosis.

Public Health Relevance

This project has high relevance for public health by providing new insights into the cognitive and neural mechanisms underlying disabling symptoms in schizophrenia and bipolar disorder. The results of this research will inform more targeted and effective treatment development and lead to the development of imaging biomarkers to enhance earlier identification and more effective early intervention for these common, severe mental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH059883-10A1
Application #
8520739
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2000-03-15
Project End
2018-03-31
Budget Start
2013-05-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$497,861
Indirect Cost
$157,304
Name
University of California Davis
Department
Neurosciences
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Smucny, Jason; Lesh, Tyler A; Newton, Keith et al. (2018) Levels of Cognitive Control: A Functional Magnetic Resonance Imaging-Based Test of an RDoC Domain Across Bipolar Disorder and Schizophrenia. Neuropsychopharmacology 43:598-606
Boudewyn, Megan A; Carter, Cameron S (2018) Electrophysiological correlates of adaptive control and attentional engagement in patients with first episode schizophrenia and healthy young adults. Psychophysiology 55:
Smucny, Jason; Lesh, Tyler A; Iosif, Ana-Maria et al. (2018) Longitudinal stability of cognitive control in early psychosis: Nondegenerative deficits across diagnoses. J Abnorm Psychol 127:781-788
Minzenberg, Michael J; Yoon, Jong H; Soosman, Steffan K et al. (2018) Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition. Transl Psychiatry 8:58
Ray, Kimberly L; Lesh, Tyler A; Howell, Amber M et al. (2017) Functional network changes and cognitive control in schizophrenia. Neuroimage Clin 15:161-170
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
Carter, Cameron S; Bearden, Carrie E; Bullmore, Edward T et al. (2017) Enhancing the Informativeness and Replicability of Imaging Genomics Studies. Biol Psychiatry 82:157-164
CarriĆ³n, Ricardo E; Cornblatt, Barbara A; Burton, Cynthia Z et al. (2016) Personalized Prediction of Psychosis: External Validation of the NAPLS-2 Psychosis Risk Calculator With the EDIPPP Project. Am J Psychiatry 173:989-996
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
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

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