Schizophrenia: Neurobiological Substrates of Cognitive and Language Deficits

CCP Co-Director Deanna Barch's research on cognitive and language deficits in schizophrenia posits a central role for both PFC dysfunction and dopamine dysfunction in schizophrenia. Behavioral studies provide indirect evidence consistent with this hypothesis, but do not directly assess PFC nor dopamine function. Thus, we currently are using both functional magnetic resonance imaging (fMRI) and psychopharmacological methods to more directly examine the neurobiological substrates of context processing.

In previous work, we have demonstrated that in healthy individuals, the representation and maintenance of context is supported by PFC function (Barch, Braver et al., 1997) . Further, we have also demonstrated that schizophrenia deficits in context processing are associated with a failure to activate a particular region, dorsolateral PFC, despite intact activation in other PFC regions, such as inferior frontal cortex, and normal activation of motor regions in response to response demands of the task (Barch, Carter et al., submitted) . Currently, we are collecting data on psychotic patients who do not have schizophrenia, to assess the specificity of PFC deficits to schizophrenia. We are also examining the integrity of brain function in chronic patients with schizophrenia in order to examine the relationships among PFC function, cognitive deficits, clinical symptoms, both cross-sectionally and longitudinally. Further, we are now examining whether deficits in PFC function are associated with both WM and LTM deficits in schizophrenia. In schizophrenia, it is not yet clear that deficits in WM and LTM represent two distinct cognitive deficits associated with different neurobiological substrates. An alternative hypothesis is that both WM and LTM deficits in schizophrenia reflect a dysfunction in the same underlying neurobiological mechanism: a disturbance in PFC function. To examine this hypothesis, we are conducting a large scale functional magnetic resonance imaging study in patients with schizophrenia. Specifically, we are using fMRI to examine cortical activation in schizophrenia patients during performance of WM, encoding, and retrieval tasks, to test the hypothesis that deficits in all three tasks may reflect an underlying deficit in PFC function. In addition, our theoretical framework posits that language disturbances in schizophrenia also reflect deficits in WM and PFC function. As such, an eventual goal of our research is to more directly assess PFC function during language processing in schizophrenia. In pursuit of this goal, we have developed methods that allow us to acquire information both about the content and latency of participant's language output during fMRI scanning (Barch, Braver et al., in preparation; Barch, Carter et al., 1999; Barch, Sabb et al., in press) .

Psychopharmaolocial studies provides a means to more directly assess the potential role of dopamine disturbances in schizophrenia. In our prior work, administration of a dopamine agonist to patients with schizophrenia was able improve at least some aspects of cognitive and language function, such as WM and both thought disorder and poverty of speech. In addition, among healthy subjects, the administration of a dopamine agonist was able to improve some aspects of language production, particular when language was produced during conditions designed to reduce WM capacity. To follow up on this work, we have begun new studies designed to more specifically understand what particular cognitive functions dopamine influences. In collaboration with Tammy Hershey, Ph.D, and Kevin Black, M.D. of Washington University Medical School, Todd Braver and Deanna Barch have begun behavioral and fMRI studies looking at the influence of levodopa (a precursor to dopamine) on cognitive function and brain activation. We are assessing a range of cognitive functions that we hypothesize may be positively influenced by increased dopamine production, including WM, context processing, selective attention, and inhibition. We are conducting these studies both in healthy individuals, and individuals with diseases that involves the dopamine system (e.g., Parkinson's Disease, Tourette's syndrome).