The Minimal Energetic Requirement of Sustained Awareness after Brain Injury

Classified as probably not a substantial claim.

The global cerebral metabolic rate of glucose has been proposed as an indicator of consciousness based on PET studies during sleep and anesthesia.

“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].”

• cites [2] Shulman, 2009, Baseline brain energy supports the state of consciousness, Proc. Natl. Acad. Sci. USA sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [3] Alkire, 1998, Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers, Anesthesiology sourceNot checked — no full text of the source

May combine two claims.

No absolute cerebral metabolic criteria exist that allow distinguishing minimally conscious state from unresponsive wakefulness syndrome, mainly because severe brain pathology interferes with conventional non-invasive quantification methods.

“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.”

• cites [1] Laureys, 2012, Coma and consciousness: paradigms (re)framed by neuroimaging, Neuroimage sourceNot checked — no full text of the source
• cites [6] Stender, 2015, Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients, J. Cereb. Blood Flow Metab. sourcePartly supported

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

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Severe brain pathology interferes with conventional non-invasive quantification methods.

Probably not a substantial claim: may not pass S3 (load-bearing).

The FDG-PET literature on anesthesia suggests causation between high brain glucose metabolism and conscious awareness.

“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.”

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

May combine two claims.

Large lateralized cerebral lesions are prevalent in this population and may selectively impair functioning of the affected hemisphere.

“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.”

• cites [11] Bruno, 2011, Multimodal neuroimaging in patients with disorders of consciousness showing “functional hemispherectomy”, Prog. Brain Res. sourcePartly 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)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

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.

“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].”

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

May combine two claims.

Metabolic rates were not influenced by age, etiology, time since onset, or use of sedation during imaging.

“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).”

May combine two claims.

In the validation cohort, the diagnostic threshold gave 87% correct classification between unresponsive wakefulness syndrome and minimally conscious state, with 95% sensitivity and 77% specificity to minimally conscious state.

“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.”

May combine two claims.

All conscious groups showed interregional variations with a coefficient of variance of 13%-15%, while glucose metabolic activity was nearly uniform across all cortical regions in unresponsive wakefulness syndrome patients.

“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.”

May combine two claims.

Every patient in emergence from minimally conscious state and every healthy control was correctly identified as conscious.

“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.”

May combine two claims. The quote only partly states this claim.

Age, weight, blood glucose, tracer dose, and circulation time did not correlate significantly with metabolism in the tested models.

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

May combine two claims.

Brodmann area 18 classification rate (86%), sensitivity to minimally conscious state (94%), and outcome prediction (80%) were slightly inferior to classification by the entire hemisphere.

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

May combine two claims.

Regional metabolic patterns in minimally conscious state and emergence from minimally conscious state groups were qualitatively similar to normal subjects, relatively higher in primary sensorimotor areas, although peaks had lower absolute values and less variability.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Changing the histogram bin size produced negligible differences in the final extracerebral normalization result, with an average coefficient of variation of 2.2%.

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

May combine two claims.

No specific regional drivers of the patients' condition could be identified, because metabolic group differences were present in all volumes of interest.

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

May combine two claims. The quote only partly states this claim.

Capacity for command following correlated with both global-mean-normalized and extracerebral-normalized metabolic index in auditory and language-related areas (r = 0.49, p < 0.0001 and r = 0.39, p = 0.002, respectively).

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

May combine two claims.

Of three minimally conscious state patients with sub-threshold metabolism, one died, one had no change, and one was lost to follow-up.

“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).”

May combine two claims.

In the derivation cohort, the best classification rate occurred at a metabolic index of 3.17 (41% of normal activity), yielding 89% correct classification between unresponsive wakefulness syndrome and minimally conscious state, with 95% sensitivity and 79% specificity to minimally conscious state.

“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”

May combine two claims.

Head shape and the anatomical volume included in the image window did not significantly change curve shapes.

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

May combine two claims.

In UWS, MCS, and EMCS groups, hemispheric glucose metabolism was reduced to 37%, 56%, and 63%, respectively.

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

May combine two claims.

Group discrimination by the metabolic criterion correctly predicted 88% of all known patient outcomes, with 95% sensitivity and 76% specificity to manifest consciousness at follow-up.

“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).”

May combine two claims.

There was 88% correct classification between minimally conscious state and unresponsive wakefulness syndrome, with 95% sensitivity and 78% specificity to minimally conscious state.

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

May combine two claims.

The FDG metabolic index in minimally conscious state groups largely overlapped with that in emergence from minimally conscious state and was in a few cases within the range of healthy control values.

“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.”

May combine two claims.

Of the eleven unresponsive wakefulness syndrome patients above threshold, eight recovered consciousness at follow-up and three died.

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

May combine two claims.

Visual responsiveness correlated with global-mean-normalized metabolic rate in visual cortex (r = 0.24, p = 0.028), but not with absolute metabolic rates (r = 0.12, p = 0.29).

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The choice of the first subject for creating the reference distribution had only a minor effect on results, with an average coefficient of variation of 3% across all possible initial subjects.

“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).”

May combine two claims.

All patients were medically stable, and none were intubated or in pharmacological coma during behavioral examinations or at the start of image acquisition.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Lesion masks were needed in 25 subjects and covered on average 2% (range 0.5-15%) of the total volume in the best cortical hemisphere mask.

“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.”

May combine two claims.

Applying lesion masks did not significantly change group mean cortical metabolism results or classifier performance.

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

May combine two claims.

Quantitative FDG-PET measurement of whole-brain glucose metabolic state permits accurate diagnosis and prediction of disorders of consciousness.

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

May combine two claims.

These findings provide a simple and objective metabolic marker of consciousness that can readily be implemented clinically.

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

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The method requires high standards in image quality and registration.

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

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

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

May combine two claims.

The signal from extracerebral tissue can serve as a valid reference for normalization and is comparable in principle to other non-invasive quantification approaches.

“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].”

• cites S12Not matched

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

• cites S13Not matched

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

May combine two claims.

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

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

May combine two claims.

The extracerebral normalization results have face validity and remain robust despite the absence of a suitable cerebral reference region in these patients.

“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.”

Classified as probably not a substantial claim.

The patient population was split into independent cohorts for derivation and validation of the diagnostic model.

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

Classified as probably not a substantial claim.

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

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

May combine two claims.

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

“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.”

May combine two claims.

Current FDG-PET methods for disorders of consciousness are non-quantitative and inherently examiner dependent.

“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.”

May combine two claims.

Current FDG-PET methods for disorders of consciousness are non-quantitative and have drawbacks from visually guided assessment of relative changes in brain metabolism.

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

• cites [4] Stender, 2014, Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study, Lancet sourceNot checked — no full text of the source

May combine two claims.

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

“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.”

May combine two claims.

The direct correlation between brain metabolism and behavior suggests that disorders of consciousness can fundamentally be understood as pathological neuroenergetic conditions and provide a unifying physiological basis for these syndromes.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

“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.”

May combine two claims.

The FDG-PET diagnostic threshold provides reliable differentiation between conscious and unconscious subjects, with a good balance between type I and type II error risks.

“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.”

May combine two claims.

The pattern in minimally conscious state and emergence from minimally conscious state differs substantially from that of unresponsive wakefulness syndrome, which was characterized by overall low FDG uptake, and is associated with capacity for consciousness.

“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.”

May combine two claims.

The procedure minimized divergence between extracerebral intensities even though the extracerebral signal might increase focally with muscle activity or inflammation.

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

May combine two claims.

The results do not depend on the particular normalization method and could in principle be reproduced by any FDG-PET quantification approach, provided the difficulties of imaging severely injured brains are adequately handled.

“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.”