The Minimal Energetic Requirement of Sustained Awareness after Brain Injury

In the paper

“Based on positron emission tomography (PET) studies with [ 18 F]-fluorodeoxyglucose (FDG) during sleep and anesthesia, the global cerebral metabolic rate of glucose has been proposed as an indicator of consciousness [2, 3].”

What the sources say

• Partly supported

  The Results section says PET measurements of cerebral glucose and oxygen metabolism during anesthesia show widespread reductions in energy demand, and proposes that global energy reduction is associated with loss of consciousness. The passages do not establish the sleep-study or FDG-specific parts of the citing sentence; searches for sleep and FDG did not find supporting passages in our copy. (LLM, conf=0.87)

  cites [2] Shulman, 2009, Baseline brain energy supports the state of consciousness, Proc. Natl. Acad. Sci. USA sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [3] Alkire, 1998, Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers, Anesthesiology source

In the paper

“However, no absolute cerebral metabolic criteria exist that allow to distinguish between MCS and the more severe UWS[1, 6], mainly because the presence of severe brain pathology interferes with conventional non-invasive quantification methods.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Laureys, 2012, Coma and consciousness: paradigms (re)framed by neuroimaging, Neuroimage source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [6] Stender, 2015, Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients, J. Cereb. Blood Flow Metab. sourceExperimental — accuracy not yet measured

In the paper

“While we cannot attribute causation in the link between high brain glucose metabolism and conscious awareness, the FDG-PET literature on anesthesia [2, 3] suggests causation.”

What the sources say

• Supported

  The Results describe PET measurements of glucose and oxygen metabolism during anesthesia and propose that reduced brain energy is responsible for loss of consciousness. This supports the citing sentence’s qualified claim that the anesthesia PET literature suggests a causal link; the paper presents it as a hypothesis, not a demonstrated causal effect. (LLM, conf=0.88)

  cites [2] Shulman, 2009, Baseline brain energy supports the state of consciousness, Proc. Natl. Acad. Sci. USA sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [3] Alkire, 1998, Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers, Anesthesiology source

In the paper

“As large lateralized cerebral lesions are prevalent in this population and may selectively impair functioning of the affected hemisphere [11], global mean metabolic activity is a poor representation of preserved cerebral function.”

What the sources say

• Partly supported

  Multimodal imaging (p. 6) reports impaired left-hemisphere function with relatively preserved right-hemisphere function in two patients. The Discussion (p. 9) calls these cases exceptional, not prevalent, and says only one patient’s functional impairment appeared related to left-sided structural white-matter impairment. The paper therefore supports selective hemispheric dysfunction, but not the claim that large lateralized cerebral lesions are prevalent in this population. (LLM, conf=0.88)

  cites [11] Bruno, 2011, Multimodal neuroimaging in patients with disorders of consciousness showing “functional hemispherectomy”, Prog. Brain Res. sourceExperimental — accuracy not yet measured

In the paper

“Brain activation in response to specific sensory or cognitive tasks can cause 10%-30% local increases in the magnitude of cortical glucose metabolism relative to resting baseline [9].”

What the sources say

• Supported

  The Abstract (page not available) reports focal increases in glucose metabolism of 10–40% during sensory activation in awake humans and says increases of about 10% are usual with physiological visual stimuli or cognitive tasks. The claimed 10–30% describes a possible range within those reported increases, rather than a universal range across conditions. (LLM, conf=0.87)

  cites [9] Shulman, 1999, Stimulated changes in localized cerebral energy consumption under anesthesia, Proc. Natl. Acad. Sci. USA source

In the paper

“Metabolic rates were not influenced by any of a range of possible confounders, including age, etiology, time since onset, and use of sedation during imaging (Supplemental Experimental Procedures).”

In the paper

“In the validation cohort, this diagnostic threshold provided an 87% correct classification rate between UWS and MCS, with 95% sensitivity and 77% specificity to MCS.”

In the paper

“Thus, while all conscious groups showed interregional variations with a coefficient of variance of 13%-15%, i.e., within the range of the proposed modular activation effect, glucose metabolic activity was nearly uniform across all cortical regions in UWS patients.”

In the paper

“Every EMCS patient and healthy control was correctly identified as conscious.”

• Also stated in: § DISCUSSION · p. 4 · plain

  “Moreover, all EMCS patients and healthy controls were correctly identified as being conscious.”

In the paper

“None of the tested physiological confounders correlated significantly with metabolism (Table S1).”

In the paper

“BA 18 classification rate (86%), sensitivity to MCS (94%), and outcome prediction (80%) were slightly inferior to classification by the entire hemisphere.”

In the paper

“Regional metabolic patterns in the MCS and EMCS groups were qualitatively similar to that observed in normal subjects, i.e., relatively higher in primary sensorimotor areas, although the peaks had lower absolute values and less variability.”

In the paper

“Differences in bin size provided negligible differences in final result of ED normalization (average CV: 2.2%).”

In the paper

“No specific regional drivers of the patients' condition could be identified, as the metabolic group differences were present in all VOIs (Figure 3).”

In the paper

“Conversely, these patients' ability of command responding correlated with FDG uptake in auditory and language areas.”

In the paper

“Of the three MCS patients with sub-threshold metabolism, one died, while another one had no change of clinical condition. The third patient was lost to follow-up (Figure 2).”

In the paper

“The best classification rate in the derivation cohort was achieved at a metabolic index of 3.17 (41% of normal activity; Figure 2), resulting in 89% correct classification between UWS and MCS, with 95% sensitivity and 79% specificity to MCS”

In the paper

“Differences in head-shape, or anatomical volume included in the image window did not affect curve shapes significantly (Figure S3).”

In the paper

“we found that hemispheric glucose metabolism was reduced to 37% in UWS, 56% in MCS, and 63% in EMCS groups”

In the paper

“Group discrimination by the metabolic criterion correctly predicted 88% of all known patient outcomes, with 95% sensitivity and 76% specificity to manifest consciousness at followup (Figure 2; Table S3).”

In the paper

“There was 88% correct classification between MCS and UWS, with 95% sensitivity and 78% specificity to MCS.”

In the paper

“The FDG metabolic index in the MCS groups largely overlapped with that in EMCS and was in a few cases within the range of healthy control values.”

In the paper

“Of these, eight had recovered consciousness at follow-up, and the remaining three had died.”

In the paper

“The presence of visual responsiveness correlated with GM-normalized metabolic rate in the visual cortex (r = 0.24, p = 0.028), but not with absolute metabolic rates (r = 0.12, p = 0.29).”

In the paper

“Similarly, the choice of the first subject in the creation of the RD had minor influence on the results (average CV: 3% across all possible initial subjects).”

In the paper

“All patients were in a medically stable condition; none were intubated or in pharmacological coma during the behavioral examinations or at the start of the image acquisition.”

In the paper

“Lesion masks were required in 25 subjects, comprising on average 2% (range 0.5-15%) of the total volume in the best cortical hemisphere mask.”

In the paper

“Inclusion of the lesion masks did not significantly alter group mean cortical metabolism results or classifier performance (Table S2).”

In the paper

“Stender et al. show that positron emission tomography measurement of whole-brain glucose metabolic state allows accurate diagnosis and prediction of disorders of consciousness.”

In the paper

“These findings provide a simple and objective metabolic marker of consciousness, which can readily be implemented clinically.”

In the paper

“The method requires high standards in image quality and registration.”

In the paper

“The present study was cross-sectional and did not allow evaluation of rapid evolution of metabolic status or their potential effects on clinical outcome.”

In the paper

“As such, we contend that the extracerebral tissue signal is a valid normalization reference, and is in principle analogous to other methods for non-invasive quantitation [S12, S13].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites S12
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites S13

In the paper

“The diagnostic performance of this method was equally good in the derivation and validation samples, indicating that the method is valid across independent cohorts.”

In the paper

“Taken together, our extracerebral normalization results thus have face validity and are robust to the lack of a suitable cerebral reference region in these patients.”

In the paper

“The patient population was split into independent cohorts for derivation and validation of the diagnostic model (Table S1).”

In the paper

“Outcome data at 1-year follow-up were obtained for 91% of the patients.”

In the paper

“Notably, these correlations emerged or became stronger after global mean scaling and therefore indicate relative preservation of energy metabolism in regions subserving preserved cognitive domains.”

In the paper

“Although assessment of relative cerebral metabolic patterns with FDG-PET is a sensitive diagnostic tool in DOCs, current methods are non-quantitative and inherently examiner dependent.”

In the paper

“However, current methods are non-quantitative and have important drawbacks deriving from visually guided assessment of relative changes in brain metabolism [4].”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Stender, 2014, Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study, Lancet source

In the paper

“This direct correlation between brain metabolism and behavior indicates that global reduction of cortical neuronal work is a defining characteristic of DOCs and may provide a unifying physiological basis for these syndromes.”

In the paper

“The direct correlation between brain metabolism and behavior further suggests that DOCs can fundamentally be understood as pathological neuroenergetic conditions and provide a unifying physiological basis for these syndromes.”

In the paper

“The study was approved by the Ethics Committee of the University Hospital of Lie ` ge, and all healthy controls and legal guardians of all participating patients gave written informed consent.”

In the paper

“We conclude that this FDG-PET diagnostic threshold provides reliable differentiation between conscious and unconscious subjects, with a good balance between type I and type II error risks.”

In the paper

“This pattern differs substantially from that of UWS patients, which was characterized by overall low FDG uptake, and is accordingly associated with capacity for consciousness.”

In the paper

“While this extracerebral signal might increase focally with muscle activity or inflammation, our procedure minimized the divergence between extracerebral intensities.”

In the paper

“Overall, the above indicates that our findings are not specific to the normalization method, but could in principle be derived with any FDG-PET quantitation method, as long as the challenges of imaging in the severely injured brain are properly addressed.”