Coma Onset Research Articles

Complex auditory regularity processing across levels of consciousness in coma: Stage 1 Registered Report.

A key question for the scientific study of consciousness is whether it is possible to identify specific features in brain activity that are uniquely linked to conscious experience. This question has important implications for the development of markers to detect covert consciousness in unresponsive patients. In this regard, many studies have focused on investigating the neural response to complex auditory regularities. One noteworthy example is the local global paradigm, which allows for the investigation of auditory regularity encoding at the 'global' level, based on the repetition of groups of sounds. The inference of global regularities is thought to depend on conscious access to such complex auditory stimuli as mostly shown in chronic stages of disorders of consciousness patients. However, whether global regularity encoding can identify covert consciousness along the consciousness spectrum including earlier stages of these disorders remains controversial. Here, we aim to fill this gap by investigating whether the inference of global auditory regularities can occur in acute coma, in the absence of consciousness, and how this may be modulated by the severity of the patients' clinical condition and consciousness level measured using the Full Outline of UnResponsiveness (FOUR) score. We will acquire 63-channel continuous electroencephalography to measure the neural response to global auditory regularity in comatose patients (N = 30) during the first day after cardiac arrest, when patients are unconscious, sedated and under normothermia, and during the second day (with reduced or absent sedation and body temperature control). We hypothesize that global regularity encoding will persist in the absence of consciousness independent of patient outcome, observed as above chance decoding of the neural response to global regularities using multivariate decoding analyses. We further hypothesize that decoding performance will positively correlate with the FOUR score, which indexes consciousness level, and typically improves between the first and second day after coma onset following cardiac arrest in patients with favourable outcome. In an exploratory analysis, we will also evaluate whether global regularity encoding may be influenced by the patients' clinical management, specifically sedation, also shown to affect global deviance detection. Our results will shed light on the neurophysiological correlates of complex auditory regularity processing in unconscious patients and on the link to residual levels of consciousness during the underexplored state of coma upon the first days after cardiac arrest.

Alpha-ketoglutarate supplementation in long-lived Drosophila melanogaster: Impact on lifespan and metabolic responses.

Studies on antiaging remedies in insect models sometimes show discrepancies in results. These discrepancies could be explained by different responses of short- and long-lived strains on the antiaging remedies. The purpose of the study was to test whether life-prolonging effects of alpha-ketoglutarate (AKG), observed in nematodes and fruit flies, would be reproduced in long-lived Drosophila melanogaster flies. Lifespan was assayed in flies kept in demographic cages. Fecundity, proportion of flies capable of negative geotaxis, starvation resistance, time of heat coma onset, levels of triacyglycerols, body glucose, glycogen, activities of glutamate dehydrogenase, catalase, glutathione-S-transferase, hexokinase, phosphofructokinase, pyruvate kinase, lactate, and glutamate dehydrogenases were assessed. Dietary AKG did not affect fly lifespan on the diet with 5% yeast and 5% sucrose (5Y:5S) and on the diet with 9% yeast and 1% sucrose (9Y:1S), but increased lifespan on the low-protein diet (1Y:9S). Twenty-five-day-old female flies fed a 5Y:5S diet with 10 mM AKG for 3 weeks, did not differ from the control group (without AKG) in climbing activity, resistance to heat stress, and starvation. The levels of glucose and glycogen were unaffected but the levels of triacylglycerols were lower in AKG-fed female flies. No differences in activities of glycolytic enzymes, NADPH-producing enzymes, glutamate dehydrogenase, oxygen consumption, and levels of oxidative stress markers were observed between the control and AKG-fed flies. However, AKG-fed flies had lower activities of catalase and glutathione-S-transferase. These results suggest that potential antiaging remedies, such as AKG, may not extend lifespan in long-living organisms despite influencing several metabolic parameters.

The effect of sedation and time after cardiac arrest on coma outcome prognostication based on EEG power spectra.

Early prognostication of long-term outcome of comatose patients after cardiac arrest remains challenging. Electroencephalography-based power spectra after cardiac arrest have been shown to help with the identification of patients with favourable outcome during the first day of coma. Here, we aim at comparing the power spectra prognostic value during the first and second day after coma onset following cardiac arrest and to investigate the impact of sedation on prognostication. In this cohort observational study, we included comatose patients (N = 91) after cardiac arrest for whom resting-state electroencephalography was collected on the first and second day after cardiac arrest in four Swiss hospitals. We evaluated whether the average power spectra values at 4.6-15.2 Hz were predictive of patients' outcome based on the best cerebral performance category score at 3 months, with scores ranging from 1 to 5 and dichotomized as favourable (1-2) and unfavourable (3-5). We assessed the effect of sedation and its interaction with the electroencephalography-based power spectra on patient outcome prediction through a generalized linear mixed model. Power spectra values provided 100% positive predictive value (95% confidence intervals: 0.81-1.00) on the first day of coma, with correctly predicted 18 out of 45 favourable outcome patients. On the second day, power spectra values were not predictive of patients' outcome (positive predictive value: 0.46, 95% confidence intervals: 0.19-0.75). On the first day, we did not find evidence of any significant contribution of sedative infusion rates to the patient outcome prediction (P > 0.05). Comatose patients' outcome prediction based on electroencephalographic power spectra is higher on the first compared with the second day after cardiac arrest. Sedation does not appear to impact patient outcome prediction.

A predictive model for consciousness recovery of comatose patients after acute brain injury.

Predicting the consciousness recovery for comatose patients with acute brain injury is an important issue. Although some efforts have been made in the study of prognostic assessment methods, it is still unclear which factors can be used to establish model to directly predict the probability of consciousness recovery. We aimed to establish a model using clinical and neuroelectrophysiological indicators to predict consciousness recovery of comatose patients after acute brain injury. The clinical data of patients with acute brain injury admitted to the neurosurgical intensive care unit of Xiangya Hospital of Central South University from May 2019 to May 2022, who underwent electroencephalogram (EEG) and auditory mismatch negativity (MMN) examinations within 28 days after coma onset, were collected. The prognosis was assessed by Glasgow Outcome Scale (GOS) at 3 months after coma onset. The least absolute shrinkage and selection operator (LASSO) regression analysis was applied to select the most relevant predictors. We combined Glasgow coma scale (GCS), EEG, and absolute amplitude of MMN at Fz to develop a predictive model using binary logistic regression and then presented by a nomogram. The predictive efficiency of the model was evaluated with AUC and verified by calibration curve. The decision curve analysis (DCA) was used to evaluate the clinical utility of the prediction model. A total of 116 patients were enrolled for analysis, of which 60 had favorable prognosis (GOS ≥ 3). Five predictors, including GCS (OR = 13.400, P < 0.001), absolute amplitude of MMN at Fz site (FzMMNA, OR = 1.855, P = 0.038), EEG background activity (OR = 4.309, P = 0.023), EEG reactivity (OR = 4.154, P = 0.030), and sleep spindles (OR = 4.316, P = 0.031), were selected in the model by LASSO and binary logistic regression analysis. This model showed favorable predictive power, with an AUC of 0.939 (95% CI: 0.899-0.979), and calibration. The threshold probability of net benefit was between 5% and 92% in the DCA. This predictive model for consciousness recovery in patients with acute brain injury is based on a nomogram incorporating GCS, EEG background activity, EEG reactivity, sleep spindles, and FzMMNA, which can be conveniently obtained during hospitalization. It provides a basis for care givers to make subsequent medical decisions.

Prognostic values of optic nerve sheath diameter for comatose patients with acute stroke: An observational study.

Optic nerve sheath diameter (ONSD) measurement is one of the non-invasive methods recommended for increased intracranial pressure (ICP) monitoring. This study aimed to evaluate the roles of optic nerve sheath diameter (ONSD) and ONSD/eyeball transverse diameter (ETD) ratio in predicting prognosis of death in comatose patients with acute stroke during their hospitalization. A total of 67 comatose patients with acute stroke were retrospectively recruited. The ONSD and ETD were measured by cranial computed tomography (CT) scan. All patients underwent cranial CT scan within 24 h after coma onset. Patients were divided into death group and survival group according to their survival status at discharge. The differences of the ONSD and ONSD/ETD ratio between the two groups and their prognostic values were compared. The ONSD and ONSD/ETD ratio were 6.07 ± 0.72 mm and 0.27 ± 0.03 in the comatose patients, respectively. The ONSD was significantly greater in the death group than that in the survival group (6.32 ± 0.67 mm vs 5.65 ± 0.62 mm, t = 4.078, P < 0.0001). The ONSD/ETD ratio was significantly higher in the death group than that in the survival group (0.28 ± 0.03 vs 0.25 ± 0.02, t = 4.625, P < 0.0001). The area under the receiver operating characteristic curve was 0.760 (95%CI: 0.637-0.882, P < 0.0001) for the ONSD and 0.808 (95%CI: 0.696-0.920, P < 0.0001) for the ONSD/ETD ratio. The mortality increased in comatose patients with acute stroke when the ONSD was > 5.7 mm or the ONSD/ETD ratio was > 0.25. Both indexes could be used as prognostic tools for comatose patients with acute stroke. The ONSD/ETD ratio was more stable than the ONSD alone, which would be preferred in clinical practice.

Infraclinical detection of voluntary attention in coma and post-coma patients using electrophysiology

ObjectiveEarly functional evaluation and prognosis of patients with disorders of consciousness is a major challenge that clinical assessments alone cannot solve. Objective measures of brain activity could help resolve this uncertainty. We used electroencephalogram at bedside to detect voluntary attention with a paradigm previously validated in healthy subjects. MethodsUsing auditory-oddball sequences, our approach rests on detecting known attentional modulations of Event Related Potentials that reflect compliance with verbal instructions. Sixty-eight unresponsive patients were tested in their first year after coma onset (37 coma and 31 first year post-coma patients). Their evolution 6 months after the test was considered. ResultsFourteen of the 68 patients, showed a positive response. Nine were in a coma and 5 in a minimally conscious state (MCS). Except for one who died early, all responders evolved to exit-MCS within 6 months (93%), while 35 (65%) among non-responders only. ConclusionsAmong those patients for whom the outcome is highly uncertain, 21% responded positively to this simple but cognitively demanding test. Strikingly, some coma patients were among responders. SignificanceThe proposed paradigm revealed cognitive-motor dissociation in some coma patients. This ability to sustain attention on demand predicted awakening within 6 months and represents an immediately useful information for relatives and caregivers.

Assessment of electroencephalography and event-related potentials in unresponsive patients with brain injury

ObjectiveTo investigate the predictors of clinical outcomes in unresponsive patients with acquired brain injuries. MethodsPatients with coma or disorders of consciousness were enrolled from August 2019 to March 2021. A retrospective analysis of demographics, etiology, clinical score, diagnosis, electroencephalography (EEG), and event-related potential (ERP) data from 1 week to 2 months after coma onset was conducted. Findings were assessed for predicting favorable outcomes at 6 months post-coma, and functional outcomes were determined using the Glasgow Outcome Scale–Extended (GOS-E). ResultsOf 68 patients, 22 patients had a good neurological outcome at 6 months, while 11 died. Univariate analysis showed that motor response (Motor-R; p < 0.001), EEG pattern (p = 0.015), sleep spindles (p = 0.018), EEG reactivity (EEG-R; p < 0.001), mismatch negativity (MMN) amplitude at electrode Fz (FzMMNA; p = 0.001), P3a latency (p = 0.044), and P3a amplitude at electrode Cz (CzP3aA; p < 0.001) were significantly correlated with patient prognosis. Multivariable logistic regression analysis showed that FzMMNA, CzP3aA, EEG-R, and Motor-R were significant independent predictors of a favorable outcome. The sensitivity and specificity of FzMMNA (dichotomized at 1.16 μV) were 86.4% and 58.5%, and of CzP3aA (cut-off value 2.76 μV) were 90.9% and 70.7%, respectively. ERP amplitude (ERP-A), a combination of FzMMNA and CzP3aA, improved prediction accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.884. A model incorporating Motor-R, EEG-R, and ERP-A yielded an outstanding predictive performance (AUC=0.921) for a favorable outcome. ConclusionERP-A and the prognostic model resulted in the efficient prediction of a favorable outcome in unresponsive patients.

Predictive value of mismatch negativity and P3a combined with electroencephalogram reactivity for the prognosis of comatose patients after severe brain injury

Objective: To explore the clinical value of mismatch negativity and P3a combined with electroencephalogram (EEG) reactivity to predict the prognosis of patients after severe brain injury. Methods: The clinical data of patients with severe brain injury who were admitted to the neurosurgical intensive care unit of Xiangya Hospital of Central South University from October 2019 to July 2020 were retrospectively analyzed. All patients underwent evaluation of auditory mismatch negativity (MMN), P3a, and EEG reactivity (EEG-R) within 28 days after the onset of coma. Patients were divided into two groups using the 3-month Glasgow Outcome Scale (GOS) after coma onset, a GOS score of 3-5 was defined as a favorable outcome, and GOS grades 1-2 were defined as an unfavorable outcome. The correlation between clinical indicators and prognosis was analyzed, and the predictive values of statistically significant indicators and the cut-off values were determined using the receiver operating characteristic (ROC) curve. Results: A total of 48 patients were enrolled in the study, including 35 males and 13 females (age range:18-68 years old). Twenty-nine of the patients had a favorable outcome and 19 had an unfavorable outcome. The Glasgow Coma Scale (GCS), EEG-R, absolute amplitude of MMN at Fz (FzMMNA), and amplitude of P3a at Cz (CzP3aA) were significantly correlated with the prognosis of comatose patients (P<0.001). Multivariate logistic regression analysis revealed that only EEG-R, FzMMNA, and CzP3aA were independent predictors for the prognosis of comatose patients after severe brain injury (all P<0.05), with the area under the curve (AUC) of 0.757 (0.613-0.900), 0.912 (0.830-0.994) and 0.887 (0.793-0.981), respectively. The combination of FzMMNA and CzP3aA and the combinationof EEG-R, FzMMNA and CzP3aA increased the value of AUC to 0.942 (0.879-1.000) and 0.964 (0.920-1.000), respectively. Moreover, a cut-off value of 1.27 μV and 2.64 μV for FzMMNA and CzP3aA, respectively, yielded the best sensitivity and specificity for the prognosis prediction of patients with severe brain injury [FzMMNA: 89.66%(26/29) and 84.21%(16/19); CzP3aA:82.76%(24/29) and 84.21%(16/19)]. Conclusion: This study indicates that the combination of EEG-R, FzMMNA, and CzP3aA may serve as a favorable prognostic indicator for comatose patients after severe brain injury.

Functional and Prognostic Assessment in Comatose Patients: A Study Using Somatosensory Evoked Potentials.

AimThe functional prognosis of patients after coma following either cardiac arrest (CA) or acute structural brain injury (ABI) is often uncertain. These patients are associated with high mortality and disability. N20 and N70 somatosensory evoked potentials (SSEP) are used to predict prognosis. We evaluated the utility of SSEP (N20–N70) as an early indicator of long-term prognosis in these patients.MethodsThis was a retrospective cohort study of patients (n = 120) admitted to the intensive care unit (ICU) with a diagnosis of coma after CA (n = 60) or ABI (n = 60). An SSEP study was performed, including N20 and N70 at 24–72 h, after coma onset. Functional recovery was assessed 6–12 months later using the modified Glasgow scale (mGS). The study was approved by our local research ethics committee.ResultsIn the CA and ABI groups, the absence of N20 (36% of CA patients and 41% of ABI patients; specificity = 100%) or N70 (68% of CA patients and 78% of ABI patients) was a strong indicator of poor outcome. Conversely, the presence of N70 was an indicator of a good outcome (AC: specificity = 84.2%, sensitivity = 92.7%; ABI: specificity = 64.2% sensitivity = 91.3%).ConclusionSomatosensory evoked potentials are useful early prognostic markers with high specificity (N20) and sensitivity (N70). Moreover, N70 has additional potential value for improving the prediction of good long-term functional outcomes.Clinical Trial Registration:[https://clinicaltrials.gov/], identifier [2018/01/001].

The Added Value of Somatosensory Potential N70 in Neurological Prognosis After Coma by Acute Brain Structural Injury: A Retrospective Study.

Coma after acute brain structural injury (ABI) are associated with high mortality and disability. Somatosensory evoked potentials (SSEP) N20 and N70 are used to predict prognosis. We assessed the utility of SSEP (N20-N70) as an early indicator of long-term functional prognosis in these patients. We conducted a retrospective cohort study of patients admitted to the intensive care unit (ICU) with a diagnosis of coma after ABI (n=60). An SSEP study including N20 and N70 was performed 24-72 hours after coma onset. Functional recovery was evaluated 6 to 12 months later using the Modified Glasgow Scale (mGS). The study was approved by our local research ethics committee. The absence of N20 (41% specificity=100%) or N70 (78%) was a strong indicator of a poor outcome. In contrast, the presence of N70 was an indicator of a good outcome (specificity=64.2% sensitivity=91.3%). SSEP N20 and N70 are useful early prognostic markers with high specificity (N20) and sensitivity (N70). N70 has potential additional value for improving the prediction of good functional outcomes in the long term.

The Combination of N60 with Mismatch Negativity Improves the Prediction of Awakening from Coma.

Our objective was to evaluate the use of event-related potentials and the middle-latency somatosensory evoked potential (MLSEP) for the prediction of awakening in coma, determine the evaluation day that evoked potentials (EPs) best predict an awakening outcome, and determine whether the mismatch negativity (MMN) combined with the MLSEP, when recorded at 7days after coma, improved the prediction of awakening from coma. Design prospective blinded cohort study. Setting neurointensive care unit of a university hospital. Patients 113 consecutive patients who were severely comatose, whose etiologies of coma included stroke (65 patients), hypoxic-ischemic encephalopathy (28 patients), intracranial infection (6 patients), and other (14 patients). Interventions none. Measurements we gathered Glasgow Coma Scale scores and recorded EPs for all patients who were comatose at 7, 14, and 30days after coma onset, unless the patients returned to consciousness. The EPs examined included the MLSEP, the middle-latency auditory evoked potential, the N100, and the MMN. With telephone follow-up after 3months, the patients were classified as awakening or nonawakening according to Glasgow Outcome Scale. When predicting an awakening outcome, at least the unilateral presence of the N60 had the highest sensitivity (82.7%), whereas the presence of the MMN showed the highest specificity (82.0%). The area under the receiver operating characteristic curve for the EPs were high at 7days after coma onset. At 7days after coma onset, the combination of the N60 and MMN offered good predictive performance for awakening (area under the receiver operating characteristic curve = 0.852, 95% confidence interval 0.765-0.940), with increased sensitivity (70.0%) and improved specificity (91.7%). The N60 and MMN were the strongest prognostic factors for an awakening outcome. Furthermore, at 7days after coma onset, the combination of the N60 and MMN improved the prediction of an awakening outcome in patients who were comatose.

Motor patterning, ion regulation and spreading depolarization during CNS shutdown induced by experimental anoxia in Locusta migratoria

Anoxia induces a reversible coma in insects. Coma onset is triggered by the arrest of mechanisms responsible for maintaining membrane ion homeostasis in the CNS, resulting in a wave of neuronal and glial depolarization known as spreading depolarization (SD). Different methods of anoxia influence the behavioural response but their effects on SD are unknown. We investigated the effects of CO2, N2, and H2O on the characteristics of coma induction and recovery in Locusta migratoria. Water immersion delayed coma onset and recovery, likely due to involvement of the tracheal system and the nature of asphyxiation but otherwise resembled N2 delivery. The main difference between N2 and CO2 was that CO2 hastened onset of neural failure and SD and delayed recovery. In the CNS, this was associated with CO2 inducing an abrupt and immediate decrease of interstitial pH and increase of extracellular [K+]. Recording of the transperineurial potential showed that SD propagation and a postanoxic negativity (PAN) were similar with both gases. The PAN increased with ouabain treatment, likely due to removal of the counteracting electrogenic effect of Na+/K+-ATPase, and was inhibited by bafilomycin, a proton pump inhibitor, suggesting that it was generated by the electrogenic effect of a Vacuolar-type ATPase (VA). Muscle fibres depolarized by ~20 mV, which happened more rapidly with CO2 compared with N2. Wing muscle motoneurons depolarized nearly completely in two stages, with CO2 causing more rapid onset and slower recovery than N2. Other parameters of SD onset and recovery were similar with the two gases. Electrical resistance across the ganglion sheath increased during anoxia and at SD onset. We provisionally attribute this to cell swelling reducing the dimensions of the interstitial pathway from neuropil to the bathing saline. Neuronal membrane resistance decreased abruptly at SD onset indicating opening of an unidentified membrane conductance. Consideration of the intracellular recording relative to the saline suggests that the apical membrane of perineurial glia depolarizes prior to neuron depolarization. We propose that SD is triggered by events at the perineurial sheath and then propagates laterally and more deeply into the neuropil. We conclude that the fundamental nature of SD is not dependent on the method of anoxia however the timing of onset and recovery are influenced; water immersion is complicated by the tracheal system and CO2 delivery has more rapid and longer lasting effects, associated with severe interstitial acidosis.

Chill coma onset and recovery fail to reveal true variation in thermal performance among populations of Drosophila melanogaster

Species from colder climates tend to be more chill tolerant regardless of the chill tolerance trait measured, but for Drosophila melanogaster, population-level differences in chill tolerance among populations are not always found when a single trait is measured in the laboratory. We measured chill coma onset temperature, chill coma recovery time, and survival after chronic cold exposure in replicate lines derived from multiple paired African and European D. melanogaster populations. The populations in our study were previously found to differ in chronic cold survival ability, which is believed to have evolved independently in each population pair; however, they did not differ in chill coma onset temperature and chill coma recovery time in a manner that reflected their geographic origins, even though these traits are known to vary with origin latitude among Drosophila species and are among the most common metrics of thermal tolerance in insects. While it is common practice to measure only one chill tolerance trait when comparing chill tolerance among insect populations, our results emphasise the importance of measuring more than one thermal tolerance trait to minimize the risk of missing real adaptive variation in insect thermal tolerance.

Cold hardening improves larval tick questing under low temperatures at the expense of longevity

Questing in ticks is essential for locating a host, and this behavioral response can occur at regionally specific low temperatures for most tick species. Little is known about the dynamics between tick questing behavior and temperature in ticks, specifically how this may impact other aspects of tick biology. Here, we examine whether cold hardening increases questing in three larval tick species (Ixodes uriae, Dermacentor variabilis, and Amblyomma americanum) at low temperatures and whether cold hardening impacts longevity. Rapid cold hardening and prolonged cold acclimation benefitted ticks by decreasing the temperature of chill coma onset, and increased survival, activity, and questing in ticks at low temperatures. Oxygen consumption increased at low temperatures following acclimation in larvae, suggesting this process has a distinct metabolic expense. This increased metabolism associated with hardening led to a substantial reduction in larval longevity as nutrient reserves are limited and cannot be replenished until a host is located. These studies suggest that tick larvae, and likely other developmental stages, require a delicate balance between the need for questing at low temperatures and survival until the first blood meal.

Thermal acclimation alters Na+/K+-ATPase activity in a tissue-specific manner in Drosophila melanogaster

Insects, like the model species Drosophila melanogaster, lose neuromuscular function and enter a state of paralysis (chill coma) at a population- and species-specific low temperature threshold that is decreased by cold acclimation. Entry into this coma is related to a spreading depolarization in the central nervous system, while recovery involves restoration of electrochemical gradients across muscle cell membranes. The Na+/K+-ATPase helps maintain ion balance and membrane potential in both the brain and hemolymph (surrounding muscles), and changes in thermal tolerance traits have therefore been hypothesized to be closely linked to variation in the expression and/or activity of this pump in multiple tissues. Here, we tested this hypothesis by measuring activity and thermal sensitivity of the Na+/K+-ATPase at the tagma-specific level (head, thorax and abdomen) in warm- (25 °C) and cold-acclimated (15 °C) flies by measuring Na+/K+-ATPase activity at 15, 20, and 25 °C. We relate differences in pump activity to differences in chill coma temperature, spreading depolarization temperature, and thermal dependence of muscle cell polarization. Differences in pump activity and thermal sensitivity induced by cold acclimation varied in a tissue-specific manner: While thermal sensitivity remained unchanged, cold-acclimated flies had decreased Na+/K+-ATPase activity in the thorax (mainly muscle) and head (mainly composed of brain). We argue that these changes may assist in maintenance of K+ homeostasis and membrane potential across muscle membranes, and discuss how reduced Na+/K+-ATPase activity in the brain may counterintuitively help insects delay coma onset in the cold.

Sestrin regulates acute chill coma recovery in Drosophila melanogaster

When chill-susceptible insects are exposed to low temperatures they enter a temporary state of paralysis referred to as a chill coma. The most well-studied physiological mechanism of chill coma onset and recovery involves regulation of ion homeostasis. Previous studies show that changes in metabolism may also underlie the ability to recovery quickly, but the roles of genes that regulate metabolic homeostasis in chill coma recovery time (CCRT) are not well understood. Here, we investigate the roles of Sestrin and Spargel (Drosophila homolog of PGC-1α), which are involved in metabolic homeostasis and substrate oxidation, on CCRT in Drosophila melanogaster. We find that sestrin and spargel mutants have impaired CCRT. sestrin is required in the muscle and nervous system tissue for normal CCRT and spargel is required in muscle and adipose. On the basis that exercise induces sestrin and spargel, we also test the interaction of cold and exercise. We find that pre-treatment with one of these stressors does not consistently confer acute protection against the other. We conclude that Sestrin and Spargel are important in the chill coma response, independent of their role in exercise.

Reversing sodium differentials between the hemolymph and hindgut speeds chill coma recovery but reduces survival in the fall field cricket, Gryllus pennsylvanicus

Chill-susceptible insects enter the reversible state of chill coma at their critical thermal minimum (CTmin). During chill coma, movement of Na+ and water from the hemolymph to the gut lumen disrupt ion and water balance. Recovery from cold exposure requires re-establishment of this balance, and failure to do so results in chilling injury or death. We hypothesized that the passive leak of Na+ and consequently water during cold exposure is driven by the [Na+] differential between the gut and hemolymph. To determine the extent to which this [Na+] differential affects cold tolerance, we used artificial diets to load the guts of fall field crickets (Gryllus pennsylvanicus) with various concentrations of Na+. Manipulating [Na+] differentials had no effect on the CTmin, agreeing with recent studies demonstrating that chill coma onset precedes loss of ion balance in the cold. A high [Na+] diet reversed the direction of the [Na+] differential between the gut and hemolymph. Crickets fed a high [Na+] diet recovered from 12 h of chill coma nearly twice as fast as those fed low [Na+] diets. However, the high [Na+] diet was detrimental to survival after prolonged cold exposure (three days at 0 °C). Therefore, while a reduced [Na+] differential helps crickets recover from short-term cold exposure, an increased gut Na+ load itself appears to carry longer-term costs and promotes irreversible chilling injury.

Brain functional connectivity during the first day of coma reflects long-term outcome

ObjectiveIn patients with disorders of consciousness (DOC), properties of functional brain networks at rest are informative of the degree of consciousness impairment and of long-term outcome. Here we investigate whether connectivity differences between patients with favorable and unfavorable outcome are already present within 24 h of coma onset. MethodsWe prospectively recorded 63-channel electroencephalography (EEG) at rest during the first day of coma after cardiac arrest. We analyzed 98 adults, of whom 57 survived beyond unresponsive wakefulness. Functional connectivity was estimated by computing the ‘debiased weighted phase lag index’ over epochs of five seconds duration. We evaluated the network’s topological features, including clustering coefficient, path length, modularity and participation coefficient and computed their variance over time. Finally, we estimated the predictive value of these topological features for patients’ outcomes by splitting the patient sample in training and test datasets. ResultsGroup-level analysis revealed lower clustering coefficient, higher modularity and path length variance in patients with favorable compared to those with unfavorable outcomes (p < 0.01). Within all features, the path length variance in the network provided the best positive predictive value (PPV) for favorable outcome and specificity for unfavorable outcome in the test dataset (PPV: 0.83, p < 0.01; specificity: 0.86, p < 0.01) with above-chance negative predictive value and accuracy. Of note, the exclusion of patients with epileptiform activity (20 in total) eliminates all false positive predictions (n = 6) for path length variance. InterpretationTopological features of functional connectivity differ as a function of long-term outcome in patients on the first day of coma. These differences are not interpretable in terms of consciousness levels as all patients were in a deep unconscious state. The time variance of path length is informative of comatose patients’ outcome, as patients with favorable outcome exhibit a richer repertoire of path length than those with unfavorable outcomes.

Electroencephalography-based power spectra allow coma outcome prediction within 24 h of cardiac arrest

BackgroundOutcome prediction in comatose patients following cardiac arrest remains challenging. Here, we assess the predictive performance of electroencephalography-based power spectra within 24 h from coma onset. MethodsWe acquired electroencephalography (EEG) from comatose patients (n = 138) on the first day of coma in four hospital sites in Switzerland. Outcome was categorised as favourable or unfavourable based on the best state within three months. Data were split in training and test sets. We evaluated the predictive performance of EEG power spectra for long term outcome and its added value to standard clinical tests. ResultsOut of 138 patients, 80 had a favourable outcome. Power spectra comparison between favourable and unfavourable outcome in the training set yielded significant differences at 5.2–13.2 Hz and above 21 Hz. Outcome prediction based on power at 5.2–13.2 Hz was accurate in training and test sets. Overall, power spectra predicted patients’ outcome with maximum specificity and positive predictive value: 1.00 (95% with CI: 0.94–1.00 and 0.89–1.00, respectively). The combination of power spectra and reactivity yielded better accuracy and sensitivity (0.81, 95% CI: 0.71–0.89) than prediction based on power spectra alone. ConclusionsOn the first day of coma following cardiac arrest, low power spectra values around 10 Hz, typically linked to impaired cortico-thalamic structural connections, are highly specific of unfavourable outcome. Peaks in this frequency range can predict long-term outcome.

Coma in Thyroid Storm: Review of Aggregated English-Language Case Reports.

ContextComa is a serious manifestation of thyroid storm (TS) about which little is known.ObjectiveTo describe the features, duration, treatment response, and prognosis of coma in the setting of TS.DesignAggregate analysis of individual English-language case reports of coma in the setting of TS from 1935 to January 2019.SettingHospitals.PatientsSixty-five cases were identified, 29 from case reports and 36 from case series.InterventionsAntithyroid drugs, corticosteroids, beta-blockers, iodine, intubation, plasmapheresis, antibiotics, thyroidectomy, radioiodine, dialysis, and l-carnitine.Main Outcome MeasuresAwakening and death rates overall and in relation to administered treatments, day of coma presentation, and time from coma onset; symptoms associated with coma; TS and coma scales; thyroid and cerebrospinal laboratory tests; electroencephalogram; brain imaging; and autopsy results.ResultsMortality was 38% in the setting of TS-related coma, 11% during the years 1978 to 2019 compared with 70% for 1935 to 1977. Both awakening and death commonly occurred within the first 2 days of coma onset. Reduction in total and free T4 values, and possibly also total T3 value, correlated with awakening from coma. Lower death rates were associated with use of antithyroid drugs, corticosteroids, beta-blockers, and intubation. Plasmapheresis was associated with awakening in 67% of cases but not with lower death rates.ConclusionsPrognosis of coma associated with TS remains poor. Current guidelines for the early use of plasmapheresis in unresolving TS are advocated and should be considered urgently at the point of confusion or delirium in an effort to abort coma.