The overall objective of this proposal is to define the functional neuroanatomy of ketamine (an NMDA receptor antagonist) induced psychosis. Within this general objective are 3 specific aims. 1) We will compare and contrast regional cerebral blood flow (rCBF) time activity curves in normal volunteers and unmedicated schizophrenic (SZ) patients given an acute intravenous dose of ketamine. We expect ketamine to effect larger limbic regions for longer time periods in schizophrenics than normals. 2) We will compare and contrast time activity rCBF changes in neuroleptic medicated and unmedicated SZ patients given acute ketamine to assess the role of dopaminergic blockade in ketamine induced limbic rCBF changes. Haloperidol is expected to reduce regional activity changes and the duration of activation in limbic areas (cingulate, hippocampus, anterior thalamus, striatum). 3) In these three groups, neuroleptic treated and neuroleptic withdrawn SZ and normal volunteers we will assess the correlation between psychosis ratings, using the Brief Psychiatric Rating Scale, and rCBF at peak drug effect measurements. These goals will be accomplished using serial 15-oxygen labeled water rCBF positron emission tomography (PET) studies. By acquiring three studies prior to drug administration and seven studies, at ten minute intervals, after the drug is given we will be able to determine the correlation between a subject's mental status change and his rCBF pattern. Hallucinations, perceptual distortions, delusions, social withdrawal, and anxiety will be assessed. Subjects will be studied at rest, with their eyes open. Within and between group statistical analyses of time activity curves at each brain image pixel will be facilitated by two preprocessing steps. First, within each subject all PET scans will be aligned with one another and these will in turn be aligned with each subject's MRI. Second, using each subject's MRI all data sets will be elastically warped to fit a common template in """"""""Talairach space."""""""" Within and between group time activity curve patterns will be assessed using the Statistical Parametric Mapping program (Friston, et al, 1991). Preliminary data have established ketamine elicits, in dose dependent fashion, psychotic exacerbations congruent with their endogenous symptoms. Normal volunteers receiving ketamine also exhibit a wide range of behavioral changes similar to those observed with PCP toxicity. In these studies we will use time activity measures of rCBF in the cingulate cortex and other limbic regions to assess the anatomical substrate of ketamine induced behavioral changes.
| Holcomb, Henry H; Lahti, Adrienne C; Medoff, Deborah R et al. (2005) Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia. Neuropsychopharmacology 30:2275-82 |
| Avila, Matthew T; Weiler, Martin A; Lahti, Adrienne C et al. (2002) Effects of ketamine on leading saccades during smooth-pursuit eye movements may implicate cerebellar dysfunction in schizophrenia. Am J Psychiatry 159:1490-6 |
| Lahti, A C; Warfel, D; Michaelidis, T et al. (2001) Long-term outcome of patients who receive ketamine during research. Biol Psychiatry 49:869-75 |
| Lahti, A C; Weiler, M A; Tamara Michaelidis, B A et al. (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455-67 |
