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To develop a physiologic grading system for the severity of acute encephalopathy manifesting as delirium or coma, based on EEG, and to investigate its association with clinical outcomes., Design: This prospective, single-center, observational cohort study was conducted from August 2015 to December 2016 and October 2018 to December 2019., Setting: Academic medical center, all inpatient wards., Patients/subjects: Adult inpatients undergoing a clinical EEG recording; excluded if deaf, severely aphasic, developmentally delayed, non-English speaking (if noncomatose), or if goals of care focused primarily on comfort measures. Four-hundred six subjects were assessed; two were excluded due to technical EEG difficulties., Interventions: None., Measurements and Main Results: A machine learning model, with visually coded EEG features as inputs, was developed to produce scores that correlate with behavioral assessments of delirium severity (Confusion Assessment Method-Severity [CAM-S] Long Form [LF] scores) or coma; evaluated using Spearman R correlation; area under the receiver operating characteristic curve (AUC); and calibration curves. Associations of Visual EEG Confusion Assessment Method Severity (VE-CAM-S) were measured for three outcomes: functional status at discharge (via Glasgow Outcome Score [GOS]), inhospital mortality, and 3-month mortality. Four-hundred four subjects were analyzed (mean [sd] age, 59.8 yr [17.6 yr]; 232 [57%] male; 320 [79%] White; 339 [84%] non-Hispanic); 132 (33%) without delirium or coma, 143 (35%) with delirium, and 129 (32%) with coma. VE-CAM-S scores correlated strongly with CAM-S scores (Spearman correlation 0.67 [0.62-0.73]; p < 0.001) and showed excellent discrimination between levels of delirium (CAM-S LF = 0 vs ≥ 4, AUC 0.85 [0.78-0.92], calibration slope of 1.04 [0.87-1.19] for CAM-S LF ≤ 4 vs ≥ 5). VE-CAM-S scores were strongly associated with important clinical outcomes including inhospital mortality (AUC 0.79 [0.72-0.84]), 3-month mortality (AUC 0.78 [0.71-0.83]), and GOS at discharge (0.76 [0.69-0.82])., Conclusions: VE-CAM-S is a physiologic grading scale for the severity of symptoms in the setting of delirium and coma, based on visually assessed electroencephalography features. VE-CAM-S scores are strongly associated with clinical outcomes., Competing Interests: Dr. Kimchi was supported by the National Institutes of Health (NIH) (K08MH116135). Dr. Westover is a co-founder of Beacon Biosignals. Dr. Westover was supported by the Glenn Foundation for Medical Research and American Federation for Aging Research (Breakthroughs in Gerontology Grant); American Academy of Sleep Medicine (Foundation Strategic Research Award); Football Players Health Study at Harvard University; Department of Defense through a subcontract from Moberg ICU Solutions; and NIH (R01NS102190, R01NS102574, R01NS107291, RF1AG064312, R01AG062989). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Frailty has been associated with increased incidence of postoperative delirium and mortality. We hypothesised that postoperative delirium mediates a clinically significant (≥1%) percentage of the effect of frailty on mortality in older orthopaedic trauma patients., Methods: This was a single-centre, retrospective observational study including 558 adults 65 yr and older, who presented with an extremity fracture requiring hospitalisation without initial ICU admission. We used causal statistical inference methods to estimate the relationships between frailty, postoperative delirium, and mortality., Results: In the cohort, 180-day mortality rate was 6.5% (36/558). Frail and prefrail patients comprised 23% and 39%, respectively, of the study cohort. Frailty was associated with increased 180 day mortality from 1.4% to 12.2% (11% difference; 95% confidence interval [CI], 8.4-13.6), which translated statistically into an 88.7% (79.9-94.3%) direct effect and an 11.3% (5.7-20.1%) postoperative delirium mediated effect. Prefrailty was also associated with increased 180 day mortality from 1.4% to 4.4% (2.9% difference; 2.4-3.4), which was translated into a 92.5% (83.8-99.9%) direct effect and a 7.5% (0.1-16.2%) postoperative delirium mediated effect., Conclusions: Frailty is associated with increased postoperative mortality, and delirium might mediate a clinically significant, but small percentage of this effect. Studies should assess whether, in patients with frailty, attempts to mitigate delirium might decrease postoperative mortality., Competing Interests: Declarations of interest OA has received speaker's honoraria from Masimo Corporation and is listed as an inventor on pending patents on EEG monitoring that are assigned to Massachusetts General Hospital, some of which are assigned to Masimo Corporation. OA has received institutionally distributed royalties for these licensed patents. All other authors declare that no competing interests exist., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: In recent years, it has become increasingly apparent that characterizing individual brain structure, connectivity and dynamics is essential for understanding brain function in health and disease. However, the majority of neuroimaging and brain stimulation research has characterized human brain function by averaging measurements from groups of subjects and providing population-level inferences. External perturbations applied directly to well-defined brain regions can reveal distinctive information about the state, connectivity and dynamics of the human brain at the individual level., Objectives: In a series of studies, we aimed to characterize individual brain responses to MRI-guided transcranial magnetic stimulation (TMS), and explore the reproducibility of the evoked effects, differences between brain regions, and their individual specificity., Methods: In the first study, we administered single pulses of TMS to both anatomically (left dorsolateral prefrontal cortex- 'L-DLPFC', left Intra-parietal lobule- 'L-IPL) and functionally (left motor cortex- 'L-M1', right default mode network- 'R-DMN, right dorsal attention network- 'R-DAN') defined cortical nodes in the frontal, motor, and parietal regions across two identical sessions spaced one month apart in 24 healthy volunteers. In the second study, we extended our analyses to two independent data sets (n = 10 in both data sets) having different sham-TMS protocols., Results: In the first study, we found that perturbation-induced cortical propagation patterns are heterogeneous across individuals but highly reproducible within individuals, specific to the stimulated region, and distinct from spontaneous activity. Most importantly, we demonstrate that by assessing the spatiotemporal characteristics of TMS-induced brain responses originating from different cortical regions, individual subjects can be identified with perfect accuracy. In the second study, we demonstrated that subject specificity of TEPs is generalizable across independent data sets and distinct from non-transcranial neural responses evoked by sham-TMS protocols., Conclusions: Perturbation-induced brain responses reveal unique "brain fingerprints" that reflect causal connectivity dynamics of the stimulated brain regions, and may serve as reliable biomarkers of individual brain function., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Medical notes are a rich source of patient data; however, the nature of unstructured text has largely precluded the use of these data for large retrospective analyses. Transforming clinical text into structured data can enable large-scale research studies with electronic health records (EHR) data. Natural language processing (NLP) can be used for text information retrieval, reducing the need for labor-intensive chart review. Here we present an application of NLP to large-scale analysis of medical records at 2 large hospitals for patients hospitalized with COVID-19., Objective: Our study goal was to develop an NLP pipeline to classify the discharge disposition (home, inpatient rehabilitation, skilled nursing inpatient facility [SNIF], and death) of patients hospitalized with COVID-19 based on hospital discharge summary notes., Methods: Text mining and feature engineering were applied to unstructured text from hospital discharge summaries. The study included patients with COVID-19 discharged from 2 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital and Brigham and Women's Hospital) between March 10, 2020, and June 30, 2020. The data were divided into a training set (70%) and hold-out test set (30%). Discharge summaries were represented as bags-of-words consisting of single words (unigrams), bigrams, and trigrams. The number of features was reduced during training by excluding n-grams that occurred in fewer than 10% of discharge summaries, and further reduced using least absolute shrinkage and selection operator (LASSO) regularization while training a multiclass logistic regression model. Model performance was evaluated using the hold-out test set., Results: The study cohort included 1737 adult patients (median age 61 [SD 18] years; 55% men; 45% White and 16% Black; 14% nonsurvivors and 61% discharged home). The model selected 179 from a vocabulary of 1056 engineered features, consisting of combinations of unigrams, bigrams, and trigrams. The top features contributing most to the classification by the model (for each outcome) were the following: "appointments specialty," "home health," and "home care" (home); "intubate" and "ARDS" (inpatient rehabilitation); "service" (SNIF); "brief assessment" and "covid" (death). The model achieved a micro-average area under the receiver operating characteristic curve value of 0.98 (95% CI 0.97-0.98) and average precision of 0.81 (95% CI 0.75-0.84) in the testing set for prediction of discharge disposition., Conclusions: A supervised learning-based NLP approach is able to classify the discharge disposition of patients hospitalized with COVID-19. This approach has the potential to accelerate and increase the scale of research on patients' discharge disposition that is possible with EHR data., (©Marta Fernandes, Haoqi Sun, Aayushee Jain, Haitham S Alabsi, Laura N Brenner, Elissa Ye, Wendong Ge, Sarah I Collens, Michael J Leone, Sudeshna Das, Gregory K Robbins, Shibani S Mukerji, M Brandon Westover. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 10.02.2021.)

Objective: Brain Age Index (BAI), calculated from sleep electroencephalography (EEG), has been proposed as a biomarker of brain health. This study quantifies night-to-night variability of BAI and establishes probability thresholds for inferring underlying brain pathology based on a patient's BAI., Methods: 86 patients with multiple nights of consecutive EEG recordings were selected from Epilepsy Monitoring Unit patients whose EEGs reported as within normal limits. While EEGs with epileptiform activity were excluded, the majority of patients included in the study had a diagnosis of chronic epilepsy. BAI was calculated for each 12-hour segment of patient data using a previously established algorithm, and the night-to-night variability in BAI was measured., Results: The within-patient night-to-night standard deviation in BAI was 7.5 years. Estimates of BAI derived by averaging over 2, 3, and 4 nights had standard deviations of 4.7, 3.7, and 3.0 years, respectively., Conclusions: Averaging BAI over n nights reduces night-to-night variability of BAI by a factor of n, rendering BAI a more suitable biomarker of brain health at the individual level. A brain age risk lookup table of results provides thresholds above which a patient has a high probability of excess BAI., Significance: With increasing ease of EEG acquisition, including wearable technology, BAI has the potential to track brain health and detect deviations from normal physiologic function. The measure of night-to-night variability and how this is reduced by averaging across multiple nights provides a basis for using BAI in patients' homes to identify patients who should undergo further investigation or monitoring., Competing Interests: Declaration of Competing Interest Dr. Thomas declares the following conflicts: 1) Patent and license for a technology using ECG to assess sleep quality and sleep apnea, licensed to MyCardio, LLC; 2) Patent and license for an auto-CPAP algorithm, licensed to DeVilbiss-Drive. 3) Unlicensed [patent to treat central sleep apnea with low concentration CO2 with positive airway pressure. 4) Consultant to Jazz Pharmaceuticals; 5) General sleep medicine consulting for GLG Councils and Guidepoint Global., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Burst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified., Methods: The dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding., Results: The expected outcomes in a "counterfactual" randomized controlled trial (cRCT) that assigned patients to mild versus severe illness are expected to show a difference in burst suppression burden of 39%, 95% CI [8-66]%, and in mortality of 35% [29-41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7-17]% compared to 0% burden. Burst suppression mediates 10% [2-21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8-12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression., Conclusions: Our analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.

The brain age index (BAI) measures the difference between an individual's apparent "brain age" (BA; estimated by comparing EEG features during sleep from an individual with age norms), and their chronological age (CA); that is BAI = BA-CA. Here, we evaluate whether BAI predicts life expectancy. Brain age was quantified using a previously published machine learning algorithm for a cohort of participants ≥40 years old who underwent an overnight sleep electroencephalogram (EEG) as part of the Sleep Heart Health Study (n = 4877). Excess brain age (BAI >0) was associated with reduced life expectancy (adjusted hazard ratio: 1.12, [1.03, 1.21], p = 0.002). Life expectancy decreased by -0.81 [-1.44, -0.24] years per standard-deviation increase in BAI. Our findings show that BAI, a sleep EEG-based biomarker of the deviation of sleep microstructure from patterns normal for age, is an independent predictor of life expectancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Develop a high-performing algorithm to detect mesial temporal lobe (mTL) epileptiform discharges on intracranial electrode recordings., Methods: An epileptologist annotated 13,959 epileptiform discharges from a dataset of intracranial EEG recordings from 46 epilepsy patients. Using this dataset, we trained a convolutional neural network (CNN) to recognize mTL epileptiform discharges from a single intracranial bipolar channel. The CNN outputs from multiple bipolar channel inputs were averaged to generate the final detector output. Algorithm performance was estimated using a nested 5-fold cross-validation., Results: On the receiver-operating characteristic curve, our algorithm achieved an area under the curve (AUC) of 0.996 and a partial AUC (for specificity > 0.9) of 0.981. AUC on a precision-recall curve was 0.807. A sensitivity of 84% was attained at a false positive rate of 1 per minute. 35.9% of the false positive detections corresponded to epileptiform discharges that were missed during expert annotation., Conclusions: Using deep learning, we developed a high-performing, patient non-specific algorithm for detection of mTL epileptiform discharges on intracranial electrodes., Significance: Our algorithm has many potential applications for understanding the impact of mTL epileptiform discharges in epilepsy and on cognition, and for developing therapies to specifically reduce mTL epileptiform activity., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Electroencephalogram (EEG)-based prediction systems are used to target anesthetic-states in patients undergoing procedures with general anesthesia (GA). These systems are not widely employed in resource-limited settings because they are cost-prohibitive. Although anesthetic-drugs induce highly-structured, oscillatory neural dynamics that make EEG-based systems a principled approach for anesthetic-state monitoring, anesthetic-drugs also significantly modulate the autonomic nervous system (ANS). Because ANS dynamics can be inferred from electrocardiogram (ECG) features such as heart rate variability, it may be possible to develop an ECG-based system to infer anesthetic-states as a low-cost and practical alternative to EEG-based anesthetic-state prediction systems. In this work, we demonstrate that an ECG-based system using ANS features can be used to discriminate between non-GA and GA states in sevoflurane, with a GA F 1 score of 0.834, [95% CI, 0.776, 0.892], and in sevoflurane-plus-ketamine, with a GA F 1 score of 0.880 [0.815, 0.954]. With further refinement, ECG-based anesthetic-state systems could be developed as a fully automated system for anesthetic-state monitoring in resource-limited settings.

Maintaining anesthetic states using automated brain-state prediction systems is expected to reduce drug overdosage and associated side-effects. However, commercially available brain-state monitoring systems perform poorly on drug-class combinations. We assume that current automated brain-state prediction systems perform poorly because they do not account for brain-state dynamics that are unique to drug-class combinations. In this work, we develop a k-nearest neighbors model to test whether improvements to automated brain-state prediction of drug-class combinations are feasible. We utilize electroencephalogram data collected from human subjects who received general anesthesia with sevoflurane and general anesthesia with the drug-class combination of sevoflurane-plus-ketamine. We demonstrate improved performance predicting anesthesia-induced brain-states using drug-specific models.

The human electroencephalogram (EEG) of sleep undergoes profound changes with age. These changes can be conceptualized as "brain age (BA)," which can be compared to chronological age to reflect the degree of deviation from normal aging. Here, we develop an interpretable machine learning model to predict BA based on 2 large sleep EEG data sets: the Massachusetts General Hospital (MGH) sleep lab data set (N = 2532; ages 18-80); and the Sleep Heart Health Study (SHHS, N = 1974; ages 40-80). The model obtains a mean absolute deviation of 7.6 years between BA and chronological age (CA) in healthy participants in the MGH data set. As validation, a subset of SHHS containing longitudinal EEGs 5.2 years apart shows an average of 5.4 years increase in BA. Participants with significant neurological or psychiatric disease exhibit a mean excess BA, or "brain age index" (BAI = BA-CA) of 4 years relative to healthy controls. Participants with hypertension and diabetes have a mean excess BA of 3.5 years. The findings raise the prospect of using the sleep EEG as a potential biomarker for healthy brain aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acute hepatic encephalopathy (AHE) is a common form of delirium, a state of confusion, impaired attention, and decreased arousal due to acute liver failure. However, the neurophysiological mechanisms underlying AHE are poorly understood. In order to develop hypotheses for mechanisms of AHE, our work builds on an existing neural mean field model for similar EEG patterns in cerebral anoxia, the bursting Liley model. The model proposes that generalized periodic discharges, similar to the triphasic waves (TPWs) seen in severe AHE, arise through three types of processes a) increased neuronal excitability; b) defective brain energy metabolism leading to impaired synaptic transmission; c) and enhanced postsynaptic inhibition mediated by increased GABA-ergic and glycinergic transmission. We relate the model parameters to human EEG data using a particle-filter based optimization method that matches the TPW inter-event-interval distribution of the model with that observed in patients EEGs. In this way our model relates microscopic mechanisms to EEG patterns. Our model represents a starting point for exploring the underlying mechanisms of brain dynamics in delirium.

Over and under-sedation are common in critically ill patients admitted to the Intensive Care Unit. Clinical assessments provide limited time resolution and are based on behavior rather than the brain itself. Existing brain monitors have been developed primarily for non-ICU settings. Here, we use a clinical dataset from 154 ICU patients in whom the Richmond Agitation-Sedation Score is assessed about every 2 hours. We develop a recurrent neural network (RNN) model to discriminate between deep vs. no sedation, trained end-to-end from raw EEG spectrograms without any feature extraction. We obtain an average area under the ROC of 0.8 on 10-fold cross validation across patients. Our RNN is able to provide reliable estimates of sedation levels consistently better compared to a feed-forward model with simple smoothing. Decomposing the prediction error in terms of sedatives reveals that patient-specific calibration for sedatives is expected to further improve sedation monitoring.