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A Truly Simultaneous Combination of Functional Transcranial Doppler Sonography and H₂¹⁵O PET Adds Fundamental New Information on Differences in Cognitive Activation Between Schizophrenics and Healthy Control Subjects

¹ Department of Nuclear Medicine, Aachen University of Technology, Aachen, Germany
² Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany
³ Department of Psychiatry/Psychotherapy, Aachen University of Technology, Aachen, Germany
⁴ Department of Neuropsychology, Aachen University of Technology, Aachen, Germany
⁵ Department of Neurology, Technical University Munich, Munich, Germany
⁶ Department of Neurology, Klinikum Chemnitz, Chemnitz, Germany

View larger version (9K): [in a new window]   FIGURE 1. Schematic illustration of time course of PET and fTCD measurements. Test conditions followed in order 0-back (reference condition) to 2-back (activation condition): R = rest with fTCD acquisition but without activation; x-back = simultaneous PET-fTCD acquisition under 0-back (reference condition) or 2-back task; P = pause without any acquisition for isotope washout (PET).

View larger version (74K): [in a new window]   FIGURE 2. Illustration of 1 subject’s significant activation clusters. (Top left) Sagittal averaged PET image of 4 scans under activation condition (2-back task) for contour finding (green). (Bottom left) Overlay of averaged PET image onto individual MRI dataset. (Top right) Identification and delineation of significant activation clusters (2-back minus reference condition; P < 0.001; minimum cluster size, 30 voxels; voxel size, 2 x 2 x 2 mm3) by SPM99b analysis. For better visualization, these clusters were projected into contour (green) of PET image here. Note that individual SPM analysis was done by normalization to individual, nonstereotactic brains (i.e., averaged PET images) and not to Talairach space (23) to preserve local size of activation volumes for each subject. Cluster volumes are given by SPM analysis; rCBF differences are calculated by projecting clusters onto averaged PET images of each task and computing mean rCBF differences in clusters (rCBFactivation minus rCBFreference condition). Same procedure was done for significant deactivation clusters (reference condition minus 2-back). (Bottom right) Overlay of PET contour (green) and significant activation clusters onto individual MRI dataset for individual anatomic localization. These activation clusters lie in supply area of ACA.

View larger version (61K): [in a new window]   FIGURE 3. SPM projections onto standard template of significant activation clusters from control subjects and schizophrenic patients for working memory activation (2-back task) minus reference condition. (Top row) Significant activations (2-back task) bilateral frontal, parietal, in cerebellum and brain stem (mesencephalon) in healthy control subjects (SPM99b; P < 0.001; all Z > 4.0) on sagittal (left) and top (right) views. (Bottom row) Significant activations (2-back task) bilateral frontal, parietal, in cerebellum and brain stem (mesencephalon) in schizophrenic patients (SPM99b; P < 0.001; all Z > 4.0) on sagittal (left) and top (right) views. Activations in supply area of ACA (sagittal image, left) appear to be more extended compared with those of healthy control subjects (Table 2).

View larger version (94K): [in a new window]   FIGURE 4. SPM projections onto standard template of clusters, where schizophrenic patients activated significantly more than healthy control subjects. Sagittal (top left), lateral (top right), front (bottom left), and top (bottom right) views. Schizophrenic patients show significantly more activations in supply area of ACA (Brodmann areas 9 + 10) and left temporal areas than healthy control subjects (contrast: patients [2-back minus reference condition] minus control subjects [2-back minus reference condition]; SPM99b; P < 0.001; all Z > 3.5).

View larger version (20K): [in a new window]   FIGURE 5. Averaged cerebral blood flow velocity (CBFV) changes of left and right ACA and mean CBFV for both sides during activation in all control subjects and schizophrenics. (A and B) Averaged CBFV changes of left (top) and right (bottom) ACA during cognitive activation (2-back) from 90 s (On) to 170 s (Off) in all healthy control subjects (A) and bilateral (averaged, ACA left and right) CBFV change (B). x-Axis, time (s); y-axis, CBVF (resting CBFV normalized to 1). During activation initial peak, then continuously increasing CBFV, followed by over- and undershoot right after activation (170 s). Regression slope of fitted regression curve of bilateral fTCD signals from 90 to 170 s (from after initial peak to over- and undershoot) was positive: CBFV = 0.9667 + 0.0005 x time. (C and D) Averaged CBFV changes of left (top) and right (bottom) ACA during cognitive activation (2-back) from 90 s (On) to 170 s (Off) in all schizophrenics (C) and bilateral (averaged, ACA left and right) CBFV changes (D). x-Axis, time (s); y-axis, CBVF (resting CBFV normalized to 1). During activation initial peak, then no continuously increasing CBFV but almost slightly decreasing, followed by over- and undershoot right after activation (170 s). Regression slope of fitted bilateral fTCD signals from 95.5 to 170 s was slightly negative: CBFV = 1.0109 - 0.00001 x time. Therefore, temporal behavior of schizophrenic patients under cognitive activation is different from that of control subjects because they show slightly decreasing CBFV during time course of activation, whereas control subjects show significant CBFV increase after initial peak under activation. rel = relative.

View larger version (13K): [in a new window]   FIGURE 6. Regression analysis of mean fTCD changes (CBFVactivation minus CBFVreference condition) of ACA vs. PET volume differences (volume of activated clusters minus volume of deactivated clusters) in healthy control subjects and schizophrenic patients. (A) There is strong and highly significant correlation between mean fTCD changes and PET volume differences in supply area of ACA in healthy control subjects: y = 0.017 + 0.0077x; r = 0.94; P < 0.0005. (B) There is also strong and highly significant correlation between mean fTCD changes and PET volume differences in supply area of ACA in schizophrenic patients: y = -1.476 + 0.0015x; r = 0.91; P < 0.0005. Note that regression slope in schizophrenic patients is significantly lower than that in control subjects: 0.0015 (95% confidence interval, 0.0009–0.0019) vs. 0.0077 (95% confidence interval, 0.0054–0.0099); P < 0.05. This means that schizophrenic patients show significantly larger PET volumes of activation minus deactivation for same height of fTCD changes.

View larger version (15K): [in a new window]   FIGURE 7. Regression analysis of mean fTCD changes (CBFVactivation minus CBFVreference condition) of ACA vs. PET volume-weighted rCBF changes (volume-weighted perfusion change of significant activation clusters minus volume-weighted perfusion change of significant deactivation clusters) in healthy control subjects and schizophrenic patients. (A) There is strong and highly significant correlation between mean fTCD changes and PET volume-weighted rCBF changes in supply area of ACA in healthy control subjects: y = -1.275 + 0.00032x; r = 0.95; P < 0.0005. (B) There is also strong and highly significant correlation between mean fTCD changes and PET volume-weighted rCBF changes in supply area of ACA in schizophrenic patients: y = -1.079 + 0.00024x; r = 0.94; P < 0.0005. Note that regression slope in schizophrenic patients is not significantly different from that in control subjects: 0.00024 (95% confidence interval, 0.00018–0.00037) vs. 0.00032 (95% confidence interval: 0.00024–0.00040); P > 0.2. This means that for both groups during cognitive stimulation of working memory, there is strong and highly significant correlation between CBFV changes measured with fTCD and volume-weighted rCBF changes measured with PET in supply area of ACA.