lthough the pathophysiology of schizophreniaremains unknown, clues about its mechanisms are emerg-ing.1 It is one of the most studied human illnesses in thefield of neuroscience. Moreover, the most sophisticatedmodern techniques have been brought to bear onanswering its question: cellular and molecular tech-niques,2,3 genetics,4 and in vivo imaging.5 We know that itis a complex genetic illness with little gross pathology orreplicated markers of dysfunction.Investigators in our laboratory, among others, have beenstudying the localization of functional pathology in thisillness. In the future, this information will allow a moredetailed histological, cellular, and molecular examinationof changes in those target regions. Moreover, it will pro-vide an experimental framework for future studies ofdrug action and family studies.Limbic cortex: the ACC and the HCOur first suggestion that the limbic cortex could be aplayer in the functional pathology of schizophrenia camefrom the correlation that we identified between neuronalactivity in the anterior cingulate cortex (ACC) and hip-pocampus (HC) (measured by [18F]deoxyglucose positronemission tomography) and the magnitude of psychosisscore (measured on the Brief Psychiatric Rating Scale[BPRS]) (r=0.590; P=0.03).This correlation between psy-chosis and neuronal activity was only obtained when thestudy volunteers were drug-free, but was entirely obscuredKeywords: schizophrenia; limbic cortex; anterior cingulate cortex; hippocampus;antipsychotic medicationAuthor affiliations: Maryland Psychiatric Research Center, Department ofPsychiatry, University of Maryland School of Medicine, Baltimore, Md, USAAddress for correspondence: Carol A. Tamminga, Maryland PsychiatricResearch Center, Department of Psychiatry, University of Maryland School ofMedicine, Box 21247, Baltimore, MD 21228, USA(e-mail: ctamming@mprc.umaryland.edu)P h a r m a c o l o g i c a l a s p e c t s4 3 2Studies in schizophrenia:pathophysiology and treatmentCarol A. Tamminga, MD; Deborah R. Medoff, PhDAStudies on the pathophysiology of schizophrenia haveimplicated the limbic cortex, using postmortem, structural,and functional data, especially in the hippocampus (HC)and the anterior cingulate cortex (ACC). We have madecontributions to the literature consistent with this idea:first, we describe a positive significant correlationbetween psychotic symptoms in schizophrenia and neu-ronal activity in the ACC and HC, suggesting the involve-ment of limbic cortex in the mediation of symptoms inschizophrenia. Second, in the ACC and the anterior HC(but not in the posterior HC), regional cerebral blood flow(rCBF) is abnormal (ie, reduced in the ACC and elevated inthe HC) in schizophrenia. Third, the relationship of rCBFto task difficulty in the ACC is altered in schizophrenia,suggesting a failure of participation of the ACC in effort-ful tasks. Lastly, connectivity between the ACC and HCduring the performance of an auditory discrimination taskis also lacking, suggesting that cognitive performance inschizophrenia lacks a functional limbic contribution. Onthe basis of these changes, we studied the effects ofantipsychotic drugs in these abnormal areas in personswith schizophrenia. Both first- and second-generationantipsychotics produce functional alterations in these lim-bic cortical areas, in the direction of normals, putativelyacting through the brain’s own cortical-subcortical circuits.Dialogues Clin Neurosci. 2002;4:432-437.
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