The long-term goal of this project is to understand the mechanisms by which the build-up of coherent thought and meaning breaks down in schizophrenia. Our experiments will test a cognitive neuroscience model which proposes that schizophrenia is characterized by an imbalance in activity between two distinct but interactive neural mechanisms of processing: (1) Associative-based mechanisms subserved within temporal and inferior frontal cortices, and operating maximally between 300-500ms, and (2) Integrative mechanisms, mediated by inferior parietal and dorsal prefrontal cortices, and operating between 500-800ms when there are requirements to override semantic associations to build whole meaning. We hypothesize that patients fail to effectively engage integrative processes, leading to an over-reliance on semantic associative-based processes. We further hypothesize that the symptom of thought disorder arises from superimposed bottom-up, purely automatic semantic associative hyperactivity between 300-400ms, within the temporal cortex. This tips the two mechanisms of processing into further imbalance leading to 'loosening of associations'. To test this model, complementary multimodal techniques will be used. Event-related potentials (ERPs) and Magneto-encephalography (MEG) will determine the time course of neurocognitive abnormalities in schizophrenia. Event-related functional magnetic resonance imaging (fMRI) studies will characterize the functional neuroanatomy of these mechanisms. Thirteen experiments are proposed (1 MEG, 7 ERP and 5 fMRI). All use carefully controlled psycholinguistic designs, based on theoretical models of normal semantic and language processing. Experiments under Aim 1 focus on semantic associations between individual words. They will isolate fully automatic semantic associative activity within the temporal cortex using a subliminal priming paradigm. In addition, they will, for the first time, elucidate the neural mechanisms by which automatic associative activity directly impacts language production in schizophrenia. Experiments under Aim 2 will determine whether semantic associations can fully override the build-up of whole sentence context in schizophrenia. Experiments under Aim 3 will, for the first time, determine whether an over-reliance on semantic associative neural activity can lead to failures of establishing causal and referential coherence across sentences in schizophrenia. Overall, this translational cognitive neuroscience approach taps into the neural mechanisms underlying psychotic thought in schizophrenia, and can explain how its symptoms and functional impairment arise from specific abnormalities in the modulation of underlying brain circuitry. Establishing such direct links between cognitive, clinical, neurophysiological and neuroanatomical dysfunction is essential for the targeted development of effective pharmacological and neurocognitive remediation strategies to treat this devastating disorder.

Public Health Relevance

Schizophrenia is a devastating neuropsychiatric disorder, affecting 1% of the adult population, that can lead to a breakdown in the build-up of coherent thought and communication. This project uses multimodal neuroimaging techniques to determine where, when and how such disorganized and illogical thinking arises in the brain. This is essential for targeting key neurocognitive systems for the development of new pharmacological and cognitive approaches for remediation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071635-09
Application #
8461990
Study Section
Special Emphasis Panel (ZRG1-BBBP-D (05))
Program Officer
Rumsey, Judith M
Project Start
2004-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$585,016
Indirect Cost
$222,708
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Cohn, Neil; Jackendoff, Ray; Holcomb, Phillip J et al. (2014) The grammar of visual narrative: Neural evidence for constituent structure in sequential image comprehension. Neuropsychologia 64C:63-70
Paczynski, Martin; Jackendoff, Ray; Kuperberg, Gina (2014) When events change their nature: the neurocognitive mechanisms underlying aspectual coercion. J Cogn Neurosci 26:1905-17
Wittenberg, Eva; Paczynski, Martin; Wiese, Heike et al. (2014) The difference between "giving a rose" and "giving a kiss": Sustained neural activity to the light verb construction. J Mem Lang 73:31-42
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Lau, Ellen F; Holcomb, Phillip J; Kuperberg, Gina R (2013) Dissociating N400 effects of prediction from association in single-word contexts. J Cogn Neurosci 25:484-502
Delaney-Busch, Nathaniel; Kuperberg, Gina (2013) Friendly drug-dealers and terrifying puppies: affective primacy can attenuate the N400 effect in emotional discourse contexts. Cogn Affect Behav Neurosci 13:473-90
Lau, Ellen F; Gramfort, Alexandre; Hamalainen, Matti S et al. (2013) Automatic semantic facilitation in anterior temporal cortex revealed through multimodal neuroimaging. J Neurosci 33:17174-81
Cohn, Neil; Paczynski, Martin (2013) Prediction, events, and the advantage of agents: the processing of semantic roles in visual narrative. Cogn Psychol 67:73-97
Cohn, Neil; Paczynski, Martin; Jackendoff, Ray et al. (2012) (Pea)nuts and bolts of visual narrative: structure and meaning in sequential image comprehension. Cogn Psychol 65:1-38
Blackford, Trevor; Holcomb, Phillip J; Grainger, Jonathan et al. (2012) A funny thing happened on the way to articulation: N400 attenuation despite behavioral interference in picture naming. Cognition 123:84-99

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