7. 10. 2010 - 10. 10. 2010
Rationale:
The glutamatergic hypothesis postulates that the N-methyl-D-aspartate (NMDA) receptor hypofunction results in the schizophrenia symptoms. With respect to this hypothesis ketamine, the non-completive antagonist of NMDA is used to model schizophrenia in animals and in humans as well. The aim of our placebo-controlled study was to detect the changes in brain electrical activity following ketamine administration to healthy volunteers by means of standardized low-resolution brain electromagnetic tomography (sLORETA) and functional magnetic resonance (fMRI).
Methods:
EEG recordings were obtained from 20 healthy subjects during resting condition in the placebo/ketamine randomized design. Ketamine was applied i.v. in the dose of 0.27 mg/kg within first 10 min, followed by a maintenance infusion of 0.27 mg/kg/h for 20 min. The intracerebral current density distribution was computed from spectrally analyzed data (at baseline and 10 and 20min after administration) by means of sLORETA. The localization of the differences in source distribution was assessed by voxel-by-voxel paired t-tests of sLORETA images of the log-transformed current density power in eight frequency bands.
In the second experiment, the effect of intravenous ketamine on blood oxygenation level–dependent (BOLD) signal was measured in the group of 11 healthy volunteers The imaging began 5 minutes before infusion and continued for a further 30 minutes (scanner: 3T Siemens Trio, ISI: 3s, isovoxel: 2 mm, smoothing: 10 mm). For the SPM5 analyses we used the „pseudoblock“ design: 5 minutes intervals before infusion were compared with 5 min. intervals throughout the infusion of ketamine or placebo. In the 2nd level analysis, the contrasts form previous steps were compared with placebo (paired t-test, p≤.01 with FDR correction).
Results:
Significant decrease of magnitude of alpha-1 and alpha-2 sources over posterior cortical regions were observed for both time intervals after ketamine administration compared to the baseline values. Further, the decrease of magnitude of beta-1 and beta-2 sources was observed in the posterior cingulate and precuneus. Cortical beta-3 and gamma sources significantly increased mainly in the cingulate and parahippocampal structures and over the right frontotemporal cortical regions. No significant differences were found in placebo condition. In fMRI, ketamine induced increase of BOLD in a large cluster consisting of 2524 voxels in the right temporal lobe (superior temporal gyrus and insula) and in lesser extend also in the left temporal cortex.
Conclusions:
In congruence with previous studies we observed the involvement of heteromodal association cortex and limbic structures in the neurophysiological effects elicited by ketamin. We confirmed that the NMDA antagonism increases activity in temporal and cingulate regions. The alteration in temporo-cingulate network would be responsible for the deficit of information processing in schizophrenia and ketamine model of this psychosis as well.
This work was supported by the grants IGA MZ CR No. NS9751-3/2008 and NS10379-3/2009, and project 1M0517 MSMT CR.