Optimizing behavior depends on the ongoing monitoring and flexible adjustment of responses. Schizophrenia is characterized by responses that are rigid, stereotyped, and perseverative rather than guided by context. We propose to study the neural bases of cognitive functions that are essential to adaptive, flexible responding and how they go awry in schizophrenia. First, we will examine the neural bases of spared and impaired aspects of 'error processing'. An intact error processing system is necessary for detecting and providing feedback regarding the occurrence of errors so that behavioral adjustments can be made. While it is critical to learn from feedback regarding past performance, behavior also has to be responsive to current contingencies. We present evidence that the balance between past and present influences is upset in schizophrenia leading to perseveration - the maladaptive persistence of responses.
Our second aim i s to study the mechanisms underlying perseveration by examining how the requirement to inhibit a prepotent behavior leads to abnormally persistent effects on the response system. We propose to use variations of the antisaccade (AS) paradigm in these experiments because of its well-charted neuroanatomy and neurophysiology. We will combine the spatial precision of event-related functional magnetic resonance imaging (fMRI) with the high temporal resolution of magnetoencephalography (MEG) to identify the regions involved and the timing of their contribution at various stages of AS performance. Since AS performance is the product of coordinated activity across a distributed network, we will also assess the integrity of white matter tracts using Diffusion Tensor Imaging (DTI). Together, these methods will allow us to precisely delineate the neural bases of intact and compromised cognitive function in schizophrenia. In order to adapt to the environment, it is necessary to both learn from the past and to respond to present task demands. Brain networks that are critical to evaluating performance, remediating behavior, and responding flexibly to current task demands are impaired in schizophrenia, and this likely contributes to rigid and maladaptive patterns of behavior. This research will identify the neural basis of both spared and impaired cognitive processes, guide investigations of neuropathology, and provide targets for intervention aimed at improving cognition in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067720-07
Application #
7793503
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2003-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$393,750
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Baran, Bengi; Karahano?lu, F I??k; Agam, Yigal et al. (2016) Failure to mobilize cognitive control for challenging tasks correlates with symptom severity in schizophrenia. Neuroimage Clin 12:887-893
Jääskeläinen, Iiro P; Halme, Hanna-Leena; Agam, Yigal et al. (2016) Neural mechanisms supporting evaluation of others' errors in real-life like conditions. Sci Rep 6:18714
Agam, Yigal; Vangel, Mark; Roffman, Joshua L et al. (2014) Dissociable genetic contributions to error processing: a multimodal neuroimaging study. PLoS One 9:e101784
Manoach, Dara S; Lee, Adrian K C; Hämäläinen, Matti S et al. (2013) Anomalous use of context during task preparation in schizophrenia: a magnetoencephalography study. Biol Psychiatry 73:967-75
Agam, Yigal; Carey, Caitlin; Barton, Jason J S et al. (2013) Network dynamics underlying speed-accuracy trade-offs in response to errors. PLoS One 8:e73692
Walton, Esther; Geisler, Daniel; Hass, Johanna et al. (2013) The impact of genome-wide supported schizophrenia risk variants in the neurogranin gene on brain structure and function. PLoS One 8:e76815
Woodward, Todd S; Feredoes, Eva; Metzak, Paul D et al. (2013) Epoch-specific functional networks involved in working memory. Neuroimage 65:529-39
Kenet, Tal; Orekhova, Elena V; Bharadwaj, Hari et al. (2012) Disconnectivity of the cortical ocular motor control network in autism spectrum disorders. Neuroimage 61:1226-34
Agam, Yigal; Hamalainen, Matti S; Lee, Adrian K C et al. (2011) Multimodal neuroimaging dissociates hemodynamic and electrophysiological correlates of error processing. Proc Natl Acad Sci U S A 108:17556-61
Dyckman, Kara A; Lee, Adrian K C; Agam, Yigal et al. (2011) Abnormally persistent fMRI activation during antisaccades in schizophrenia: a neural correlate of perseveration? Schizophr Res 132:62-8

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