Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain

Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

2 Figure S1. Voxel-to-voxel correlations of qCMR glc in gray matter of human brain.
The horizontal axis represents the qCMR glc for the control group (i.e., normal awake sighted people with eyes closed; Figure  showed ~8% lower qCMR glc with 0.25% sevoflurane, ~15% lower qCMR glc with 0.5% sevoflurane, and ~14% lower qCMR glc with 1% desflurane. (D) The disorders of consciousness groups (vs. the control group) showed ~36% lower qCMR glc with EMCS, ~40% lower qCMR glc with MCS, and ~54% lower qCMR glc with UWS. See Table 3 for comparison of slopes and intercepts when the linear regression was conducted without forcing the intercept through the origin.
Normalization effects of regional metabolism in human brain Mortensen et al.
3 Figure S2. Voxel-to-voxel correlations of qCMR glc in white matter of human brain.
The horizontal axis represents the qCMR glc for the control group (i.e., normal awake sighted people with eyes closed; Figure  showed ~8% lower qCMR glc with 0.25% sevoflurane, ~12% lower qCMR glc with 0.5% sevoflurane, and ~9% lower qCMR glc with 1% desflurane. (D) The disorders of consciousness groups (vs. the control group) showed ~29% lower qCMR glc with EMCS, ~31% lower qCMR glc with MCS, and ~43% lower qCMR glc with UWS. See Table 3 for comparison of slopes and intercepts when the linear regression was conducted without forcing the intercept through the origin.
Normalization effects of regional metabolism in human brain Mortensen et al. GMN images. In qCMR glc images there are only large sized negative clusters (>98% of voxels), whereas in GMN images there are many smaller sized negative (6-7% of voxels) and positive (0.1-14% of voxels) clusters. The unthresholded student's t-maps are shown in Figure 3 in the main text.
Normalization effects of regional metabolism in human brain Mortensen et al. Spatial distributions of metabolic variations in patients with sedation (i.e., Des1%, Sev0.25%, Sev0.5% in Figure 2B in the main text) vs. the control group (i.e., HAEC in Figure 2A  Normalization effects of regional metabolism in human brain Mortensen et al. Normalization effects of regional metabolism in human brain Mortensen et al. Normalization effects of regional metabolism in human brain Mortensen et al.  (Table S1), whereas the vertical axis displays ΔCMR glc for 8 groups (vs. the control group), which included healthy awake sighted people with eyes open (i.e., Figure 1A, top), awake people with congenital blindness (i.e., CB in Figure 1A, bottom), normal people under sedation (i.e., Des1%, Sev0.25%, Sev0.5% in Figure 1B), and patients with disorders of consciousness (i.e., UWS, MCS, EMCS in Figure 1C). (A) With qCMR glc images for all groups, except CB, globally unidirectional ΔCMR glc were detected, where the dynamic range of ΔCMR glc from UWS to HAEO was ~0.3 µmol/g/min. (B) With GMN images for all groups regionally bidirectional ΔCMR glc were detected, where the dynamic range of ΔCMR glc from UWS to HAEO was ~0.1 µmol/g/min. See Figures 3-6 and Figures S3-S6 for unthresholded and thresholded t-maps, respectively.

HAEO in
Normalization effects of regional metabolism in human brain Mortensen et al. 9  Regions are some well-defined gray matter regions based on neuroanatomy. Shown above are 41 regions, their description in terms of the underlying neuroanatomy, and size in relation to the entire gray matter space.