This is a revised application to study the neural bases of executive function deficits in schizophrenia using complementary neuroimaging techniques. Executive function deficits are reflected in behavior that is stimulus-bound rather than guided by context, perseverative, and stereotyped. They reliably predict poor functional outcome (Green et al 2000). We recently reported intact task-switching in the context of deficient saccadic inhibition during a single paradigm in schizophrenia (Manoach et al 2002b). This behavioral dissociation demonstrates that executive function deficits in schizophrenia are selective and suggests that these functions are mediated by distinct neural circuitry. The primary aim of the proposed work is to identify this spared and impaired neural circuitry using the same saccadic paradigm adapted for neuroimaging. However, a purely anatomical approach may be too limited. Accumulating evidence, including our preliminary data, suggests that the timing of neuronal processes across regions may be key to understanding these deficits. To explore this possibility, we will integrate the findings of event-related functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). MEG alone has poor spatial resolution, but by using the detailed spatial information provided by anatomical and functional MRI as constraints, the exact timing of the contribution of each region can be discerned. We will recruit 20 first episode (FE) patients (neuroleptic naive when possible), 20 chronic medicated patients and 20 healthy subjects to participate in the paired fMRUMEG saccadic studies. Saccadic eye movements utilize a control system with a well-delineated neuroanatomy and physiology. They will be measured during scanning so that correct and error trials can be separated and compared. We will isolate processes involved in inhibition and task-switching. By integrating the findings of fMRI and MEG, we will create spatiotemporal maps of task-related brain activity changes. The schizophrenic and healthy groups will be compared with regard to the timing, location, and magnitude of task-related fMRI and MEG signal changes. This will allow us to precisely delineate differences in the spatiotemporal patterns of activation associated with inhibition and task-switching in schizophrenia. Identifying the neural processes underlying intact and deficient executive function will aid investigations of neuropathology and contribute to the development of more focused interventions and rehabilitative strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH067720-01A1
Application #
6724358
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Project Start
2003-12-01
Project End
2006-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$369,363
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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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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