Publication

2021
Rajesh Amerineni, Haoqi Sun, Hang Lee, John Hsu, Elisabetta Patorno, M. Brandon Westover, and Sahar Zafar. 11/21/2021. “Using electronic health data to explore effectiveness of ICU EEG and anti-seizure treatment.” Annals of Clinical and Translational Neurology. Publisher's VersionAbstract

Objectives
The purpose of this study was to examine critical care continuous electroencephalography (cEEG) utilization and downstream anti-seizure treatment patterns, their association with outcomes, and generate hypotheses for larger comparative effectiveness studies of cEEG-guided interventions.

Methods
Single-center retrospective study of critically ill patients (n = 14,523, age ≥18 years). Exposure defined as ≥24 h of cEEG and subsequent anti-seizure medication (ASM) escalation, with or without concomitant anesthetic. Exposure window was the first 7 days of admission. Primary outcome was in-hospital mortality. Multivariable analysis was performed using penalized logistic regression.

Results
One thousand and seventy-three patients underwent ≥24 h of cEEG within 7 days of admission. After adjusting for disease severity, ≥24 h of cEEG followed by ASM escalation in patients not on anesthetics (n = 239) was associated with lower in-hospital mortality (OR 0.76 [0.53–1.07]), though the finding did not reach significance. ASM escalation with concomitant anesthetic use (n = 484) showed higher odds for mortality (OR 1.41 [1.03–1.94]). In the seizures/status epilepticus subgroup, post cEEG ASM escalation without anesthetics showed lower odds for mortality (OR 0.43 [0.23–0.74]). Within the same subgroup, ASM escalation with concomitant anesthetic use showed higher odds for mortality (OR 1.34 [0.92–1.91]) though not significant.

Interpretation
Based on our findings we propose the following hypotheses for larger comparative effectiveness studies investigating the direct causal effect of cEEG-guided treatment on outcomes: (1) cEEG-guided ASM escalation may improve outcomes in critically ill patients with seizures; (2) cEEG-guided treatment with combination of ASMs and anesthetics may not improve outcomes in all critically ill patients.

Physiological Assessment of Delirium Severity: The Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S)
Meike van Sleuwen, Haoqi Sun, Christine Eckhardt, Anudeepthi Neelagiri, Ryan A. Tesh, Mike Westmeijer, Luis Paixao, Subapriya Rajan, Parimala Velpula Krishnamurthy, Pooja Sikka, Michael J. Leone, Ezhil Panneerselvam, Syed A. Quadri, Oluwaseun Akeju, Eyal Y. Kimchi, and M. Brandon Westover. 9/24/2021. “Physiological Assessment of Delirium Severity: The Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S).” Critical Care Medicine. Publisher's VersionAbstract

Objectives: 
Delirium is a common and frequently underdiagnosed complication in acutely hospitalized patients, and its severity is associated with worse clinical outcomes. We propose a physiologically based method to quantify delirium severity as a tool that can help close this diagnostic gap: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S).

Design: 
Retrospective cohort study.

Setting: 
Single-center tertiary academic medical center.

Patients: 
Three-hundred seventy-three adult patients undergoing electroencephalography to evaluate altered mental status between August 2015 and December 2019.

Interventions: 
None.

Measurements and Main Results: 
We developed the E-CAM-S based on a learning-to-rank machine learning model of forehead electroencephalography signals. Clinical delirium severity was assessed using the Confusion Assessment Method Severity (CAM-S). We compared associations of E-CAM-S and CAM-S with hospital length of stay and inhospital mortality. E-CAM-S correlated with clinical CAM-S (R = 0.67; p < 0.0001). For the overall cohort, E-CAM-S and CAM-S were similar in their strength of association with hospital length of stay (correlation = 0.31 vs 0.41, respectively; p = 0.082) and inhospital mortality (area under the curve = 0.77 vs 0.81; p = 0.310). Even when restricted to noncomatose patients, E-CAM-S remained statistically similar to CAM-S in its association with length of stay (correlation = 0.37 vs 0.42, respectively; p = 0.188) and inhospital mortality (area under the curve = 0.83 vs 0.74; p = 0.112). In addition to previously appreciated spectral features, the machine learning framework identified variability in multiple measures over time as important features in electroencephalography-based prediction of delirium severity.

Conclusions: 
The E-CAM-S is an automated, physiologic measure of delirium severity that predicts clinical outcomes with a level of performance comparable to conventional interview-based clinical assessment.

Prediction of operative mortality for patients undergoing cardiac surgical procedures without established risk scores
Chin Siang Ong, Erik Reinertsen, Haoqi Sun, Philicia Moonsamy, Navyatha Mohan, Masaki Funamoto, Tsuyoshi Kaneko, Prem S. Shekar, Stefano Schena, Jennifer S. Lawton, David A. D'Alessandro, M. Brandon Westover, Aaron D. Aguirre, and Thoralf M. Sundt. 9/14/2021. “Prediction of operative mortality for patients undergoing cardiac surgical procedures without established risk scores.” The Journal of Thoracic and Cardiovascular Surgery. Publisher's VersionAbstract

Objective
Current cardiac surgery risk models do not address a substantial fraction of procedures. We sought to create models to predict the risk of operative mortality for an expanded set of cases.

Methods
Four supervised machine learning models were trained using preoperative variables present in the Society of Thoracic Surgeons (STS) data set of the Massachusetts General Hospital to predict and classify operative mortality in procedures without STS risk scores. A total of 424 (5.5%) mortality events occurred out of 7745 cases. Models included logistic regression with elastic net regularization (LogReg), support vector machine, random forest (RF), and extreme gradient boosted trees (XGBoost). Model discrimination was assessed via area under the receiver operating characteristic curve (AUC), and calibration was assessed via calibration slope and expected-to-observed event ratio. External validation was performed using STS data sets from Brigham and Women's Hospital (BWH) and the Johns Hopkins Hospital (JHH).

Results
Models performed comparably with the highest mean AUC of 0.83 (RF) and expected-to-observed event ratio of 1.00. On external validation, the AUC was 0.81 in BWH (RF) and 0.79 in JHH (LogReg/RF). Models trained and applied on the same institution's data achieved AUCs of 0.81 (BWH: LogReg/RF/XGBoost) and 0.82 (JHH: LogReg/RF/XGBoost).

Conclusions
Machine learning models trained on preoperative patient data can predict operative mortality at a high level of accuracy for cardiac surgical procedures without established risk scores. Such procedures comprise 23% of all cardiac surgical procedures nationwide. This work also highlights the value of using local institutional data to train new prediction models that account for institution-specific practices.

Sahar F. Zafar, Eric S. Rosenthal, Jin Jing, Wendong Ge, Mohammad Tabaeizadeh, Hassan Aboul Nour, Maryum Shoukat, Haoqi Sun, Farrukh Javed, Solomon Kassa, Muhammad Edhi, Elahe Bordbar, Justin Gallagher, Valdery Moura, Manohar Ghanta, Yu-Ping Shao, Sungtae An, Jimeng Sun, Andrew J. Cole, and M. Brandon Westover. 7/7/2021. “Automated annotation of epileptiform burden and its association with outcomes.” Annals of Neurology. Publisher's VersionAbstract

Objective
To determine the dose-response relation between epileptiform activity burden and outcomes in acutely ill patients.

Methods
Single center retrospective analysis of 1967 neurologic, medical and surgical patients who underwent > 16 hours of continuous EEG between 2011-2017. We developed an AI algorithm to annotate 11.02 terabytes of EEG and quantify epileptiform activity burden within 72 hours of recording. We evaluated burden in 1) the first 24 hours of recording, 2) the 12-hr epoch with highest burden (peak burden), and 3) cumulative through the first 72 hours of monitoring. Machine learning was applied to estimate the effect of epileptiform burden on outcome. Outcome measure was discharge modified Rankin Scale, dichotomized as good (0-4) vs. poor (5-6).

Results
Peak epileptiform burden was independently associated with poor outcomes (p<0.0001). Other independent associations included age, APACHE II, seizure on presentation, and diagnosis of hypoxic ischemic encephalopathy. Model calibration error was calculated across three strata based on the time interval between last EEG measurement (up to 72 hours of monitoring) and discharge: 1) < 5 days between last measurement and discharge: 0.0941 [CI 0.0706, 0.1191); 5-10 days between last measurement and discharge: 0.0946 [CI 0.0631, 0.1290]; > 10 days between last measurement and discharge: 0.0998 [CI 0.0698, 0.1335]. After adjusting for covariates, increase in peak epileptiform activity burden from 0% to 100% increased the probability of poor outcome by 35%.

Interpretation
Automated measurement of peak epileptiform activity burden affords a convenient, consistent, and quantifiable target for future multi-center randomized trials investigating whether suppressing epileptiform activity improves outcomes.

Sophie Ligtenstein, Jiangling Song, Jin Jing, Haoqi Sun, Luis Paixao, Sahar Zafar, and Brandon Westover. 6/18/2021. “Do Triphasic Waves and Nonconvulsive Status Epilepticus Arise From Similar Mechanisms? A Computational Model.” Journal of Clinical Neurophysiology. Publisher's VersionAbstract

Purpose: 
Triphasic waves arising in patients with toxic metabolic encephalopathy (TME) are often considered different from generalized periodic discharges (GPDs) in patients with generalized nonconvulsive status epilepticus (GNCSE). The primary objective of this study was to investigate whether a common mechanism can explain key aspects of both triphasic waves in TME and GPDs in GNCSE.

Method: 
A neural mass model was used for the simulation of EEG patterns in patients with acute hepatic encephalopathy, a common etiology of TME. Increased neuronal excitability and impaired synaptic transmission because of elevated ammonia levels in acute hepatic encephalopathy patients were used to explain how triphasic waves and GNCSE arise. The effect of gamma-aminobutyric acid-ergic drugs on epileptiform activity, simulated with a prolonged duration of the inhibitory postsynaptic potential, was also studied.

Results: 
The simulations show that a model that includes increased neuronal excitability and impaired synaptic transmission can account for both the emergence of GPDs and GNCSE and their suppression by gamma-aminobutyric acid-ergic drugs.

Conclusions: 
The results of this study add to evidence from other studies calling into question the dichotomy between triphasic waves in TME and GPDs in GNCSE and support the hypothesis that all GPDs, including those arising in TME patients, occur via a common mechanism.

Postoperative delirium mediates 180-day mortality in orthopaedic trauma patients
Juan C. Pedemonte, Haoqi Sun, Esteban Franco-Garcia, Carmen Zhou, Marilyn Heng, Sadeq Quraishi, M. Brandon Westover, and Oluwaseun Akeju. 5/29/2021. “Postoperative delirium mediates 180-day mortality in orthopaedic trauma patients.” British Journal of Anaesthesia. Publisher's VersionAbstract

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.

Prolonged Intubation in Patients With Prior Cerebrovascular Disease and COVID-19
Shibani S. Mukerji, Sudeshna Das, Haitham Alabsi, Laura N. Brenner, Aayushee Jain, Colin Magdamo, Sarah I. Collens, Elissa Ye, Kiana Keller, Christine L. Boutros, Michael J. Leone, Amy Newhouse, Brody Foy, Matthew D. Li, Min Lang, Melis N. Anahtar, Yu-Ping Shao, Wendong Ge, Haoqi Sun, Virginia A. Triant, Jayashree Kalpathy-Cramer, John Higgins, Jonathan Rosand, Gregory K. Robbins, and M. Brandon Westover. 4/9/2021. “Prolonged Intubation in Patients With Prior Cerebrovascular Disease and COVID-19.” Frontiers in Neurology, 12, Pp. 416. Publisher's VersionAbstract

Objectives: Patients with comorbidities are at increased risk for poor outcomes in COVID-19, yet data on patients with prior neurological disease remains limited. Our objective was to determine the odds of critical illness and duration of mechanical ventilation in patients with prior cerebrovascular disease and COVID-19.

Methods: A observational study of 1,128 consecutive adult patients admitted to an academic center in Boston, Massachusetts, and diagnosed with laboratory-confirmed COVID-19. We tested the association between prior cerebrovascular disease and critical illness, defined as mechanical ventilation (MV) or death by day 28, using logistic regression with inverse probability weighting of the propensity score. Among intubated patients, we estimated the cumulative incidence of successful extubation without death over 45 days using competing risk analysis.

Results: Of the 1,128 adults with COVID-19, 350 (36%) were critically ill by day 28. The median age of patients was 59 years (SD: 18 years) and 640 (57%) were men. As of June 2nd, 2020, 127 (11%) patients had died. A total of 177 patients (16%) had a prior cerebrovascular disease. Prior cerebrovascular disease was significantly associated with critical illness (OR = 1.54, 95% CI = 1.14–2.07), lower rate of successful extubation (cause-specific HR = 0.57, 95% CI = 0.33–0.98), and increased duration of intubation (restricted mean time difference = 4.02 days, 95% CI = 0.34–10.92) compared to patients without cerebrovascular disease.

Interpretation: Prior cerebrovascular disease adversely affects COVID-19 outcomes in hospitalized patients. Further study is required to determine if this subpopulation requires closer monitoring for disease progression during COVID-19.

HIV Increases Sleep-based Brain Age Despite Antiretroviral Therapy
Michael J Leone, Haoqi Sun, Christine L Boutros, Lin Liu, Elissa Ye, Lee Sullivan, Robert J Thomas, Gregory K Robbins, Shibani S Mukerji, and Brandon M Westover. 3/30/2021. “HIV Increases Sleep-based Brain Age Despite Antiretroviral Therapy.” Sleep, zsab058. Publisher's VersionAbstract

Study Objectives
Age-related comorbidities and immune activation raise concern for advanced brain aging in people living with HIV (PLWH). The brain age index (BAI) is a machine learning model that quantifies deviations in brain activity during sleep relative to healthy individuals of the same age. High BAI was previously found to be associated with neurological, psychiatric, cardiometabolic diseases, and reduced life expectancy among people without HIV. Here, we estimated the effect of HIV infection on BAI by comparing PLWH and HIV-controls.

Methods
Clinical data and sleep EEGs from 43 PLWH on antiretroviral therapy (HIV+) and 3,155 controls (HIV-) were collected from Massachusetts General Hospital. The effect of HIV infection on BAI, and on individual EEG features, was estimated using causal inference.

Results
The average effect of HIV on BAI was estimated to be +3.35 years (p < 0.01, 95% CI = [0.67, 5.92]) using doubly robust estimation. Compared to HIV- controls, HIV+ participants exhibited a reduction in delta band power during deep sleep and rapid eye movement sleep.

Conclusion
We provide causal evidence that HIV contributes to advanced brain aging reflected in sleep EEG. A better understanding is greatly needed of potential therapeutic targets to mitigate the effect of HIV on brain health, potentially including sleep disorders and cardiovascular disease

Recep A. Ozdemir, Ehsan Tadayon, Pierre Boucher, Haoqi Sun, Davide Momi, Wolfgang Ganglberger, M. Brandon Westover, Alvaro Pascual-Leone, Emiliano Santarnecchi, and Mouhsin M. Shafi. 2/12/2021. “Cortical Responses to Noninvasive Perturbations Enable Individual Brain Fingerprinting.” Brain Stimulation. Publisher's Version
Classification of the Disposition of Patients Hospitalized with COVID-19: Reading Discharge Summaries using Natural Language Processing
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, and M. Brandon Westover. 1/15/2021. “Classification of the Disposition of Patients Hospitalized with COVID-19: Reading Discharge Summaries using Natural Language Processing.” JMIR medical informatics. Publisher's Version
2020
Night-to-Night Variability of Sleep Electroencephalography-Based Brain Age Measurements
Jacob Hogan, Haoqi Sun, Luis Paixao, Mike Westmeijer, Pooja Sikka, Jing Jin, Ryan Tesh, Madalena Cardoso, Sydney S Cash, Oluwaseun Akeju, Robert J Thomas, and M. Brandon Westover. 10/29/2020. “Night-to-Night Variability of Sleep Electroencephalography-Based Brain Age Measurements.” Clinical Neurophysiology. Publisher's VersionAbstract

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 sqrt(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.

CoVA: An Acuity Score for Outpatient Screening that Predicts COVID-19 Prognosis
Haoqi Sun, Aayushee Jain, Michael J Leone, Haitham S Alabsi, Laura N Brenner, Elissa Ye, Wendong Ge, Yu-Ping Shao, Christine L Boutros, Ruopeng Wang, Ryan A Tesh, Colin Magdamo, Sarah I Collens, Wolfgang Ganglberger, Ingrid V Bassett, James B Meigs, Jayashree Kalpathy-Cramer, Matthew D Li, Jacqueline T Chu, Michael L Dougan, Lawrence W Stratton, Jonathan Rosand, Bruce Fischl, Sudeshna Das, Shibani S Mukerji, Gregory K Robbins, and Brandon M Westover. 10/24/2020. “CoVA: An Acuity Score for Outpatient Screening that Predicts COVID-19 Prognosis.” The Journal of infectious diseases, Pp. jiaa663. Publisher's VersionAbstract

Background
We sought to develop an automatable score to predict hospitalization, critical illness, or death for patients at risk for COVID-19 presenting for urgent care.

Methods
We developed the COVID-19 Acuity Score (CoVA) based on a single-center study of adult outpatients seen in respiratory illness clinics (RICs) or the emergency department (ED). Data was extracted from the Partners Enterprise Data Warehouse, and split into development (n = 9381, March 7-May 2) and prospective (n = 2205, May 3-14) cohorts. Outcomes were hospitalization, critical illness (ICU or ventilation), or death within 7 days. Calibration was assessed using the expected-to-observed event ratio (E/O). Discrimination was assessed by area under the receiver operating curve (AUC).

Results
In the prospective cohort, 26.1%, 6.3%, and 0.5% of patients experienced hospitalization, critical illness, or death, respectively. CoVA showed excellent performance in prospective validation for hospitalization (expected-to-observed ratio (E/O): 1.01, AUC: 0.76); for critical illness (E/O 1.03, AUC: 0.79); and for death (E/O: 1.63, AUC=0.93). Among 30 predictors, the top five were age, diastolic blood pressure, blood oxygen saturation, COVID-19 testing status, and respiratory rate.

Conclusions
CoVA is a prospectively validated automatable score for the outpatient setting to predict adverse events related to COVID-19 infection.

Algorithm for automatic detection of self-similarity and prediction of residual central respiratory events during CPAP
Eline Oppersma, Wolfgang Ganglberger, Haoqi Sun, Robert J. Thomas, and M. Brandon Westover. 10/15/2020. “Algorithm for automatic detection of self-similarity and prediction of residual central respiratory events during CPAP.” Sleep, zsaa215. Publisher's VersionAbstract

Study objectives
Sleep disordered breathing is a significant risk factor for cardiometabolic and neurodegenerative diseases. High loop gain is a driving mechanism of central sleep apnea or periodic breathing. This study presents a computational approach that identifies “expressed/manifest” high loop gain via a cyclical self-similarity feature in effort-based respiration signals.

Methods
Working under the assumption that high loop gain increases the risk of residual central respiratory events during continuous positive airway pressure (CPAP), the full night similarity, computed during diagnostic non-CPAP polysomnography (PSG), was used to predict residual central events during CPAP (REC), which we defined as central apnea index (CAI)>10. Central apnea labels are obtained both from manual scoring by sleep technologists, and from an automated algorithm developed for this study. The Massachusetts General Hospital (MGH) sleep database was used, including 2466 PSG pairs of diagnostic and CPAP titration PSG recordings.

Results
Diagnostic CAI based on technologist labels predicted REC with an AUC of 0.82 ±0.03. Based on automatically generated labels, the combination of full night similarity and automatically generated CAI resulted in an AUC of 0.85 ±0.02. A subanalysis was performed on a population with technologist labeled diagnostic CAI>5. Full night similarity predicted REC with an AUC of 0.57 ±0.07 for manual and 0.65 ±0.06 for automated labels.

Conclusions
The proposed self-similarity feature, as a surrogate estimate of expressed respiratory high loop gain and computed from easily accessible effort signals, can detect periodic breathing regardless of admixed obstructive features such as flow-limitation, and can aid prediction of REC.

Association of Sleep Electroencephalography-Based Brain Age Index With Dementia
Elissa Ye, Haoqi Sun, Michael J. Leone, Luis Paixao, Robert J. Thomas, Alice D. Lam, and M. Brandon Westover. 9/28/2020. “Association of Sleep Electroencephalography-Based Brain Age Index With Dementia.” JAMA Network Open, 3, 9, Pp. e2017357. Publisher's VersionAbstract

Importance  Dementia is an increasing cause of disability and loss of independence in the elderly population yet remains largely underdiagnosed. A biomarker for dementia that can identify individuals with or at risk for developing dementia may help close this diagnostic gap.

Objective  To investigate the association between a sleep electroencephalography-based brain age index (BAI), the difference between chronological age and brain age estimated using the sleep electroencephalogram, and dementia.

Design, Setting, and Participants  In this retrospective cross-sectional study of 9834 polysomnograms, BAI was computed among individuals with previously determined dementia, mild cognitive impairment (MCI), or cognitive symptoms but no diagnosis of MCI or dementia, and among healthy individuals without dementia from August 22, 2008, to June 4, 2018. Data were analyzed from November 15, 2018, to June 24, 2020.

Exposure  Dementia, MCI, and dementia-related symptoms, such as cognitive change and memory impairment.

Main Outcomes and Measures  The outcome measures were the trend in BAI when moving from groups ranging from healthy, to symptomatic, to MCI, to dementia and pairwise comparisons of BAI among these groups.

Findings  A total of 5144 sleep studies were included in BAI examinations. Patients in these studies had a median (interquartile range) age of 54 (43-65) years, and 3026 (59%) were men. The patients included 88 with dementia, 44 with MCI, 1075 who were symptomatic, and 2336 without dementia. There was a monotonic increase in mean (SE) BAI from the nondementia group to the dementia group (nondementia: 0.20 [0.42]; symptomatic: 0.58 [0.41]; MCI: 1.65 [1.20]; dementia: 4.18 [1.02]; P < .001).

Conclusions and Relevance  These findings suggest that a sleep-state electroencephalography-based BAI shows promise as a biomarker associated with progressive brain processes that ultimately result in dementia.

Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo
Yingxia Liang, Frank Raven, Joseph F Ward, Sherri Zhen, Siyi Zhang, Haoqi Sun, Sean J Miller, Se Hoon Choi, Rudolph E Tanzi, and Can Zhang. 6/24/2020. “Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.” Journal of Alzheimer's Disease. Publisher's VersionAbstract
Background:The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective:Here, we aimed to investigate astrocyte-related pathological changes of Aβ and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results:Weutilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion:Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD.
Kimia Kashkooli, Samuel L Polk, Eunice Yunhee Hahm, James Murphy, Breanna R Ethridge, Jacob Gitlin, Reine Ibala, Jennifer Mekonnen, Juan C. Pedemonte, Haoqi Sun, M. Brandon Westover, Riccardo Barbieri, Oluwaseun Akeju, and Shubham Chamadia. 6/2/2020. “Improved tracking of sevoflurane anesthetic states with drug-specific machine learning models.” Journal of Neural Engineering. Publisher's VersionAbstract
Objective: The ability to monitor anesthetic states using automated approaches is expected to reduce inaccurate drug dosing and side-effects. Commercially available anesthetic state monitors perform poorly when ketamine is administered as an anesthetic-analgesic adjunct. Poor performance is likely because the models underlying these monitors are not optimized for the electroencephalogram (EEG) oscillations that are unique to the co-administration of ketamine. Approach: In this work, we designed two k-nearest neighbors algorithms for anesthetic state prediction. Main results: The first algorithm was trained only on sevoflurane EEG data, making it sevoflurane-specific. This algorithm enabled discrimination of the sevoflurane general anesthesia (GA) state from sedated and awake states (true positive rate = 0.87, [95% CI, 0.76, 0.97]). However, it did not enable discrimination of the sevoflurane-plus-ketamine GA state from sedated and awake states (true positive rate = 0.43, [0.19, 0.67]). In our second algorithm, we implemented a cross drug training paradigm by including both sevoflurane and sevoflurane-plus-ketamine EEG data in our training set. This algorithm enabled discrimination of the sevoflurane-plus-ketamine GA state from sedated and awake states (true positive rate = 0.91, [0.84, 0.98]). Significance: Instead of a one-algorithm-fits-all-drugs approach to anesthetic state monitoring, our results suggest that drug-specific models are necessary to improve the performance of automated anesthetic state monitors. Clinical trial registration number: NCT03503578.
Maurice Abou Jaoude, Haoqi Sun, Kyle R Pellerin, Milena Pavlova, Rani A Sarkis, Sydney S Cash, Brandon M Westover, and Alice D Lam. 6/1/2020. “Expert-level automated sleep staging of long-term scalp EEG recordings using deep learning.” Sleep, zsaa112. Publisher's VersionAbstract

Study Objectives
Develop a high-performing, automated sleep scoring algorithm that can be applied to long-term scalp electroencephalography (EEG) recordings.

Methods
Using a clinical dataset of polysomnograms from 6,431 patients (MGH-PSG dataset), we trained a deep neural network to classify sleep stages based on scalp EEG data. The algorithm consists of a convolutional neural network (CNN) for feature extraction, followed by a recurrent neural network (RNN) that extracts temporal dependencies of sleep stages. The algorithm’s inputs are 4 scalp EEG bipolar channels (F3-C3, C3-O1, F4-C4, C4-O2), which can be derived from any standard PSG or scalp EEG recording. We initially trained the algorithm on the MGH-PSG dataset and used transfer learning to fine-tune it on a dataset of long-term (24-72 hour) scalp EEG recordings from 112 patients (scalpEEG dataset).

Results
The algorithm achieved a Cohen’s kappa of 0.74 on the MGH-PSG holdout testing set and cross-validated Cohen’s kappa of 0.78 after optimization on the scalpEEG dataset. The algorithm also performed well on two publicly available PSG datasets, demonstrating high generalizability. Performance on all datasets was comparable to the inter-rater agreement of human sleep staging experts (Cohen’s kappa ~ 0.75±0.11). The algorithm’s performance on long-term scalp EEGs was robust over a wide age range and across common EEG background abnormalities.

Conclusion
We developed a deep learning algorithm that achieves human expert level sleep staging performance on long-term scalp EEG recordings. This algorithm, which we have made publicly available, greatly facilitates the use of large long-term EEG clinical datasets for sleep-related research.

Mohammad Tabaeizadeh, Hassan Aboul Nour, Maryum Shoukat, Haoqi Sun, Jing Jin, Farrukh Javed, Solomon Kassa, Muhammad Edhi, Elahe Bordbar, Justin Gallagher, Valdery Junior Moura, Manohar Ghanta, Yu-Ping Shao, Andrew J. Cole, Eric S. Rosenthal, M. Brandon Westover, and Sahar F. Zafar. 4/3/2020. “Burden of Epileptiform Activity Predicts Discharge Neurologic Outcomes in Severe Acute Ischemic Stroke.” Neurocritical Care. Publisher's VersionAbstract

Background/Objectives
Clinical seizures following acute ischemic stroke (AIS) appear to contribute to worse neurologic outcomes. However, the effect of electrographic epileptiform abnormalities (EAs) more broadly is less clear. Here, we evaluate the impact of EAs, including electrographic seizures and periodic and rhythmic patterns, on outcomes in patients with AIS.

Methods
This is a retrospective study of all patients with AIS aged ≥ 18 years who underwent at least 18 h of continuous electroencephalogram (EEG) monitoring at a single center between 2012 and 2017. EAs were classified according to American Clinical Neurophysiology Society (ACNS) nomenclature and included seizures and periodic and rhythmic patterns. EA burden for each 24-h epoch was defined using the following cutoffs: EA presence, maximum daily burden < 10% versus > 10%, maximum daily burden < 50% versus > 50%, and maximum daily burden using categories from ACNS nomenclature (“rare” < 1%; “occasional” 1–9%; “frequent” 10–49%; “abundant” 50–89%; “continuous” > 90%). Maximum EA frequency for each epoch was dichotomized into ≥ 1.5 Hz versus < 1.5 Hz. Poor neurologic outcome was defined as a modified Rankin Scale score of 4–6 (vs. 0–3 as good outcome) at hospital discharge.

Results
One hundred and forty-three patients met study inclusion criteria. Sixty-seven patients (46.9%) had EAs. One hundred and twenty-four patients (86.7%) had poor outcome. On univariate analysis, the presence of EAs (OR 3.87 [1.27–11.71], p = 0.024) and maximum daily burden > 10% (OR 12.34 [2.34–210], p = 0.001) and > 50% (OR 8.26 [1.34–122], p = 0.035) were associated with worse outcomes. On multivariate analysis, after adjusting for clinical covariates (age, gender, NIHSS, APACHE II, stroke location, stroke treatment, hemorrhagic transformation, Charlson comorbidity index, history of epilepsy), EA presence (OR 5.78 [1.36–24.56], p = 0.017), maximum daily burden > 10% (OR 23.69 [2.43–230.7], p = 0.006), and maximum daily burden > 50% (OR 9.34 [1.01–86.72], p = 0.049) were associated with worse outcomes. After adjusting for covariates, we also found a dose-dependent association between increasing EA burden and increasing probability of poor outcomes (OR 1.89 [1.18–3.03] p = 0.009). We did not find an independent association between EA frequency and outcomes (OR: 4.43 [.98–20.03] p = 0.053). However, the combined effect of increasing EA burden and frequency ≥ 1.5 Hz (EA burden * frequency) was significantly associated with worse outcomes (OR 1.64 [1.03–2.63] p = 0.039).

Conclusions
Electrographic seizures and periodic and rhythmic patterns in patients with AIS are associated with worse outcomes in a dose-dependent manner. Future studies are needed to assess whether treatment of this EEG activity can improve outcomes.

Burst Suppression: Causes and Effects on Mortality in Critical Illness
Jacob Hogan, Haoqi Sun, Hassan Aboul Nour, Jin Jing, Mohammad Tabaeizadeh, Maryum Shoukat, Farrukh Javed, Solomon Kassa, Muhammad M. Edhi, Elahe Bordbar, Justin Gallagher, Valdery Moura Junior, Manohar Ghanta, Yu-Ping Shao, Oluwaseun Akeju, Andrew J. Cole, Eric S. Rosenthal, Sahar Zafar, and M. Brandon Westover. 2/24/2020. “Burst Suppression: Causes and Effects on Mortality in Critical Illness.” Neurocritical Care. Publisher's VersionAbstract

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.

2019
Excess Brain Age in the Sleep Electroencephalogram Predicts Reduced Life Expectancy
Luis Paixao, Pooja Sikka, Haoqi Sun, Aayushee Jain, Jacob Hogan, Robert J. Thomas, and M. Brandon Westover. 12/23/2019. “Excess Brain Age in the Sleep Electroencephalogram Predicts Reduced Life Expectancy.” Neurobiology of Aging. Publisher's VersionAbstract
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 = 4,877). Excess brain age (BAI > 0) was associated with reduced life expectancy (adjusted hazard ratio (aHR) 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.

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