Sequential Regional Cerebral Blood Flow Brain Scans Using PET with H215O Demonstrate Ketamine Actions in CNS Dynamically

Abstract

The aim of this study was to examine the potential of serial rCBF studies to directly characterize the regional effects and dynamic time course of the centrally active drug ketamine. The value of a broader application of this technique to other neurally active drugs to characterize the pharmacodynamics of CNS compounds is suggested by these data. Thirteen normal subjects received a 0.3 mg/kg intravenous dose of ketamine over 60 seconds; ten other individuals received placebo in the same manner. For each subject, three baseline PET rCBF scans and seven sequential post-ketamine scans at 10-minute intervals were obtained using H(2)(15)O water. SPM techniques were employed to identify the maxima of any cluster significant by spatial extent analysis at any post-ketamine time point between 0 and 36 min. These extremes from the ketamine group, were identified in placebo scans similarly and grown to a 6x6x12 mm voxel set. The average rCBF values of the ketamine-defined clusters were determined in the drug and placebo conditions at all time points. rCBF across time was plotted for each cluster and compared between drug and placebo. Area under the curve (AUC) was calculated between baseline and 36 minutes. The kinetic characteristics of the ketamine-induced rCBF curves were compared to induced behaviors in each maxima. Ketamine produced distinct patterns of rCBF change over time in different brain regions; maxima within an anatomically defined region responded similarly. Ketamine induced rCBF activations in anterior cingulate, medial frontal and inferior frontal cortices. All maxima with a relative flow reduction with ketamine were in the cerebellum. The pattern of all activations and suppressions was monophasic with the peak changes at 6-16 minutes. In preliminary analysis, individual C(max) and AUC of maxima in the anterior cingulate/medial frontal region tended to correlate with the mild psychotomimetic action of ketamine; whereas, there was no tendency toward correlation with this psychological change in cerebellar maxima. The direct action of a centrally active drug can be assessed regionally and dynamically in brain using rCBF and a scan sequence optimally timed to complement the drug's time course. Ketamine pharmacodynamic response can be related to concurrent behavioral changes, tending to link the behavior with a brain region. This experimental design provides direct characterization of drug action in the CNS in ways heretofore unavailable.

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

“…Figure 1 depicts areas of increased CBF, by region, across time at the four post-ketamine time points in the normal and the schizophrenia volunteers. Relative to the whole brain, CBF diminished as previously described (Holcomb et al, 2001), in SV and NV groups. No significant difference in group cerebellar rCBF was observed.…”

“…The NV described in this report are the same volunteer subjects described in a previous publication (Holcomb et al, 2001).…”

“…The methods used to analyze the scan data were described in detail in a previous publication (Holcomb et al, 2001). Blood flow data were normalized with respect to anatomical and mean flow rates for the whole brain (50 ml/100 gm/ min), according to the algorithms applied by SPM99 software (Friston et al, 1994(Friston et al, , 1996.…”

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

“…rCBF in ACC significantly correlates with psychosis levels in unmedicated SV Lee et al, 2003). Psychosis exacerbation with the NMDA antagonist, ketamine, is accompanied by increases in ACC rCBF and the induced behavioral changes correlate with the ACC rCBF (Lahti et al, 1995;Holcomb et al, 2001). Thus, the suggestion that the normalization of rCBF in the schizophrenic ACC by clozapine mediates that drug's clinical advantage in psychosis is not without basis.…”

Effects of neonatal amygdala or hippocampus lesions on resting brain metabolism in the macaque monkey: A microPET imaging study

“…After being transported to an animal preparation room, animals were intubated with an endotracheal canula for isoflurane sedation (1 -2%) during the imaging session. Although several previous studies have demonstrated that ketamine (Holcomb et al, 2001, Langsjo et al, 2003, Freo and Ori, 2004, Honey et al, 2004, Langsjo et al, 2004, Itoh et al, 2005 and isoflurane (Maekawa et al, 1986, Ori et al, 1986, Alkire et al, 1997, Shimoji et al, 2004, Toyama et al, 2004 anesthesia can affect cerebral metabolism and regional cerebral blood flow in rodents, monkeys and humans, the affects appear to be constant across subjects within a given study. Since all animals underwent the same protocol, anesthesia per se should not induce group differences in glucose metabolism.…”