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Research Projects
Link to MIRECC publication list
Projects
Mouse model of a schizophrenia-like deficit in sensorimotor gating
We have developed a promising animal model of disturbances in cognitive function in schizophrenia that may facilitate the development of new drugs. The model is based on the theory that there is an alteration in the function of glutamate receptors in schizophrenia. In animals, drugs that antagonize glutamate disrupt prepulse inhibition, a measure of sensorimotor gating that models the impaired ability of many schizophrenia patients to filter out irrelevant information in their environment. We have discovered that a particular form of this receptor, the mGluR5 metabotropic glutamate receptor, modulates prepulse inhibition and that - like the deficits in prepulse inhibition in schizophrenia patients - these deficits are insensitive to treatments with typical antipsychotic drugs. Based on these and related findings, several groups are now developing new drugs to enhance transmission at mGluR5 glutamate receptors to test the hypothesis that such compounds might ameliorate some of the cognitive deficits in schizophrenia patients that are refractory to treatment with existing antipsychotic medications.
Reference
Brody, S.A., Dulawa, S.C., Geyer, M.A., and Conquet, F.: Assessment of a prepulse inhibition deficit in a mutant mouse lacking mglu5 receptors. Molecular Psychiatry, 9:35-41, 2004.
Brody, S.A., Conquet, F., and Geyer, M.A.: Effect of antipsychotic treatment on the prepulse inhibition deficit of mgluR5 knockout mice. Psychopharmacology, 172:187-195, 2004.
Brody, S.A. and Geyer, M.A.: Interactions of the mGluR5 gene with breeding and maternal factors on startle and prepulse inhibition in mice. Neurotoxicity Research, 6:79-90. 2004
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Mismatch negativity (MMN) as a biomarker in clinical trials of innovative drugs
We recently found that mismatch negativity (MMN), which is a very early electrophysiological response to an auditory stimulus, may be useful for drug development. Since MMN can be elicited in the absence of conscious and effortful attention, it probes a preattentive form of sensory memory and is not influenced by the subject's motivation. We found that these neurophysiological impairments in MMN are highly correlated with patients' everyday functioning. MMN is also interesting because it is genetically transmitted and can be used to improve our understanding of the complex genetics of schizophrenia.
Reference
Light GA, Braff DL (2005): Mismatch negativity deficits are associated with poor functioning in schizophrenia patients. Archives of General Psychiatry 62:127-136.
Light GA, Braff DL (2005): Stability of mismatch negativity deficits and their relationship to functional impairments in chronic schizophrenia. American Journal of Psychiatry 162:1741-3.
Braff DL, Light GA (2005): The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues in Clinical Neuroscience 7:125-135.
Braff DL, Light GA (2004): Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology 174:75-85.
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fMRI shows abnormal brain activity during a vigilance task in patients performing normally.
To explore the brain systems underlying attentional abnormalities in schizophrenia, we compared the response of nine patients with chronic schizophrenia or schizoaffective disorder to that of 10 matched healthy individuals performing a simple visual vigilance task during functional magnetic resonance imaging. The two groups performed equivalently on the task, but the schizophrenia patients demonstrated decreased activity in one brain region (inferior frontal cortex) and abnormally increased activity in others (in right postcentral gyrus, right medial temporal lobe and left cerebellum). The results suggest that abnormalities of functional brain response to attentional tasks can be observed among patients with schizophrenia even when behavioral performance is unimpaired, and provide further evidence that brain systems related to attention are likely to be involved in the pathophysiology of the disorder.
Reference
Eyler LT, Olsen RK, Jeste DV, Brown GG: Abnormal brain response of chronic schizophrenia patients despite normal performance during a visual vigilance task. Psychiatry Res 2004; 130(3):245-57
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Disordered brain circuitry underlying verbal fluency abnormalities in schizophrenia
Ten schizophrenia patients and 10 healthy volunteers were compared on a task requiring them to generate words during functional magnetic imaging. Results indicate that the schizophrenia patients demonstrated altered activity in the pre-supplementary motor area. We developed a Communication and Social Skills Training (CSST) module to improve brain response in this brain area.
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Review of longitudinal functional neuroimaging studies of drug treatments in patients with schizophrenia.
We reviewed twenty-one functional neuroimaging studies that used longitudinal designs to investigate the effects of medication treatments on brain functioning among patients with schizophrenia. The studies reviewed were comprised of functional magnetic resonance imaging and positron emission tomography research using a baseline and at least one follow-up. The present review summarizes the different effects of medication and disease status on brain function, with attention to functional normalization, specific drug effects, and comparisons of typical versus atypical antipsychotics. Methodological limitations were found in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistics.
Reference
Davis CE, Jeste DV, Eyler LT. Review of longitudinal functional neuroimaging studies of drug treatments in patients with schizophrenia. Schizophr Res. 2005 Oct 1;78(1):45-60.
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