Neurovascular Uncoupling in Schizophrenia: A Bimodal Meta-Analysis of Brain Perfusion and Glucose Metabolism

Abstract

The use of modern neuroimaging approaches has demonstrated resting-state regional cerebral blood flow (rCBF) to be tightly coupled to resting cerebral glucose metabolism (rCMRglu) in healthy brains. In schizophrenia, several lines of evidence point toward aberrant neurovascular coupling, especially in the prefrontal regions. To investigate this, we used Signed Differential Mapping to undertake a voxel-based bimodal meta-analysis examining the relationship between rCBF and rCMRglu in schizophrenia, as measured by arterial spin labeling (ASL) and ¹⁸Flurodeoxyglucose positron emission tomography (FDG-PET) respectively. We used 19 studies comprised of data from 557 patients and 584 controls. Our results suggest that several key regions implicated in the pathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC, putamen, and temporal pole show conjoint metabolic and perfusion abnormalities in patients. In contrast, discordance between metabolism and perfusion were seen in superior frontal gyrus and cerebellum, indicating that factors contributing to neurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction, oxidative stress) are likely operates at these loci. Studies enrolling patients on high doses of antipsychotics had showed larger rCBF/rCMRglu effects in patients in the left dorsal striatum. Hybrid ASL-PET studies focusing on these regions could confirm our proposition regarding neurovascular uncoupling at superior frontal gyrus in schizophrenia.

Keywords: arterial spin labeling; cerebral blood flow; cerebral glucose metabolism; dorsal anterior cingulate cortex; positron emission tomography; schizophrenia.

Figure 1

Flowchart of literature search.

Figure 2

The Quality Index Score is the proportion of studies that are scored as adequate, inadequate, or unclear.

Figure 3

Regions of conjoint findings are shown on the left (A), and regions with disjoint findings are shown on the right (B). Bilateral striatum and temporal pole were found to have conjoint increases in regional cerebral blood flow (rCBF) and resting cerebral glucose metabolism (rCMRglu) (shown in blue). Left frontoinsular cortex and bilateral dorsal anterior cingulate cortex were found to have conjoint reductions in rCBF and rCMRglu. Regional neurovascular uncoupling was notable in the left superior frontal gyrus (−6,30,44; Left BA 8; SDM-z = −2.001, p=0.00033, reduced rCMRglu, normal rCBF – shown in yellow) and left cerebellum (−38,−66,−34; crus I and II; SDM-Z=2.27, p=0.00026, no. of voxels = 129; increased rCMRglu, normal rCBF – shown in green).

Figure 4

The conjunction and disjunction findings in the anterior cingulate region are shown. The more ventral cluster (red; 6, 22, 34) has reduced resting cerebral glucose metabolism (rCMRglu) as well as reduced regional cerebral blood flow (rCBF), while the more dorsal (yellow; −6, 30, 44) has normal rCBF despite reduced metabolism.