Emery N. Brown's research while affiliated with Massachusetts Institute of Technology and other places
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Publications (562)
Over the past 30 years, there have been significant advances in the understanding of the mechanisms associated with loss and recovery of consciousness following severe brain injury. This work has provided a strong grounding for the development of novel restorative therapeutic interventions. Although all interventions are aimed at modulating and the...
Every day, hundreds of thousands of people undergo general anesthesia. One hypothesis is that anesthesia disrupts dynamic stability, the ability of the brain to balance excitability with the need to be stable and thus controllable. We tested this hypothesis using a new method for quantifying population-level dynamic stability in complex systems, De...
Findings by our labs and others demonstrate that 40 Hz frequency sensory stimulation induces electrophysiological responses and attenuates pathology in mouse models of Alzheimer's disease (AD). A recent study in Nature Neuroscience concluded that the stimulation does not affect endogenous gamma oscillations or amyloid burden. We welcome research in...
Research in human volunteers and surgical patients has shown that unconsciousness under general anesthesia can be reliably tracked using real-time electroencephalogram processing. Hence, a closed-loop anesthesia delivery (CLAD) system that maintains precisely specified levels of unconsciousness is feasible and would greatly aid intraoperative patie...
A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cog...
Recording and modulating neural activity in vivo enables investigations of the neurophysiology underlying behavior and disease. However, there is a dearth of translational tools for simultaneous recording and localized receptor-specific modulation. We address this limitation by translating multifunctional fiber neurotechnology previously only avail...
The recent publication of practice guidelines for management of patients with disorders of consciousness (DoC) in the United States and Europe was a major step forward in improving the accuracy and consistency of terminology, diagnostic criteria, and prognostication in this population. There remains a pressing need for a more precise brain injury c...
The implementation of multimodality monitoring in the clinical management of patients with disorders of consciousness (DoC) results in physiological measurements that can be collected in a continuous and regular fashion or even at waveform resolution. Such data are considered part of the “Big Data” available in intensive care units and are potentia...
Predictive coding is a fundamental function of the cortex. The predictive routing model proposes a neurophysiological implementation for predictive coding. Predictions are fed back from deep-layer cortex via alpha/beta (8-30Hz) oscillations. They inhibit the gamma (40-100Hz) and spiking that feed sensory inputs forward. Unpredicted inputs arrive in...
Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a...
Consciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data from ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesl...
The effects of critical illness on electroencephalographic (EEG) signatures of sedatives have not been described, limiting the use of EEG-guided sedation in the intensive care unit (ICU). We report the case of a 36-year-old man recovering from acute respiratory distress syndrome (ARDS). Severe ARDS was characterized by slow-delta (0.1-4 Hz) and the...
A critical component of anesthesia is the loss sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential (LFP) and spiking recorded from Utah arrays in auditory cortex, associative cortex, and...
Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical tha...
Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produce...
During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phe...
Background:
Conscious states are typically inferred through responses to auditory tasks and noxious stimulation. We report the use of a stimulus-free behavioural paradigm to track state transitions in responsiveness during dexmedetomidine sedation. We hypothesised that estimated dexmedetomidine effect-site (Ce) concentrations would be higher at lo...
Background
The delirium-sparing effect of nighttime dexmedetomidine has not been studied after surgery. We hypothesised that a nighttime dose of dexmedetomidine would reduce the incidence of postoperative delirium as compared to placebo.
Methods
This single-centre, parallel-arm, randomised, placebo-controlled superiority trial evaluated whether a...
Non-invasive G amma EN trainment U sing S ensory stimulation (GENUS) at 40Hz reduces Alzheimer’s disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitive...
The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cogni...
Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep-wake state and associated behaviors, such as changes in posture, light levels, fasting or eating, rest or activity and social interactions; thus, it is often important to quantify the relative...
Recording and modulating neural activity in vivo enables investigations of neural circuits during behavior. However, there is a dearth of tools for simultaneous recording and localized receptor modulation in large animal models. We address this limitation by translating multifunctional fiber-based neurotechnology previously only available for roden...
Objective:
Electrodermal activity (EDA) reflects sympathetic nervous system activity through sweating-related changes in skin conductance and could be used in clinical settings in which patients cannot self-report pain, such as during surgery or when in a coma. To enable EDA data to be used robustly in clinical settings, we need to develop artifac...
The role of the prefrontal cortex (PFC) in the mechanism of consciousness is a matter of active debate. Most theoretical and empirical investigations have focused on whether the PFC is critical for the content of consciousness (i.e., the qualitative aspects of conscious experience). However, there is emerging evidence that, in addition to its well-...
Decoding brain activity from non-invasive electroencephalography (EEG) is crucial for brain-computer interfaces (BCIs) and the study of brain disorders. Notably, end-to-end EEG decoding has gained widespread popularity in recent years owing to the remarkable advances in deep learning research. However, the sample sizes in many EEG studies are often...
Electrodermal activity (EDA), which tracks sweat gland activity as a proxy for sympathetic activation, has the potential to be a biomarker of physiological and psychological changes in the clinic. To show this, in this study, we demonstrate that the tonic component of EDA responds consistently and robustly during induction of anesthesia in the oper...
Objective
The objective of this study was to develop a portable and modular brain–computer interface (BCI) software platform independent of input and output devices. We implemented this platform in a case study of a subject with cervical spinal cord injury (C5 ASIA A).
Background
BCIs can restore independence for individuals with paralysis by usin...
Significance
Deep brain stimulation (DBS) in the subthalamic nucleus (STN) is highly effective for treating the motor symptoms of Parkinson’s disease (PD). However, the neural mechanisms by which DBS acts are unknown. PD symptoms are tied to altered brain rhythms in basal ganglia (BG) and particularly the striatum. We develop a biophysical model of...
Subanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involv...
This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six maj...
Oscillatory dynamics in cortex seem to organize into traveling waves that serve a variety of functions. Recent studies show that propofol, a widely used anesthetic, dramatically alters cortical oscillations by increasing slow-delta oscillatory power and coherence. It is not known how this affects traveling waves. We compared traveling waves across...
During propofol-induced general anesthesia, alpha rhythms undergo a striking shift from posterior to anterior, termed anteriorization. We combined human intracranial recordings with diffusion imaging to show that anteriorization occurs with opposing dynamics in two distinct thalamocortical subnetworks. The cortical and thalamic anatomy involved, as...
Objective:
Estimate time to recovery of command-following and associations between hypoxemia with time to recovery of command-following METHODS: In this multi-center, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kap...
Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical tha...
Short-time Fourier transform (STFT) is the most common window-based approach for analyzing the spectrotemporal dynamics of time series. To mitigate the effects of high variance on the spectral estimates due to finite-length, independent STFT windows, state-space multitaper (SSMT) method used a state-space framework to introduce dependency among the...
Oscillatory dynamics in cortex seem to organize into traveling waves that serve a variety of functions. Recent studies show that propofol, a widely used anesthetic, dramatically alters cortical oscillations by increasing slow-delta oscillatory power and coherence. It is not known how this affects traveling waves. We compared traveling waves across...
Background
Non‐invasive gamma frequency light and sound stimulation at 40Hz reduced Alzheimer’s disease (AD) pathology and improved performance during behavioral testing in mouse models of AD (Iaccarino et al., Nature , 2016; Martorell et al., Cell , 2019; Adaikkan et al., Neuron , 2019). Sensory stimulation inducing 40Hz entrainment reduced amyloi...
Purpose
Anesthesiologists simultaneously manage several aspects of patient care during general anesthesia. Automating administration of hypnotic agents could enable more precise control of a patient's level of unconsciousness and enable anesthesiologists to focus on the most critical aspects of patient care. Reinforcement learning (RL) algorithms c...
Short-time Fourier transform (STFT) is the most common window-based approach for analyzing the spectrotemporal dynamics of time series. To mitigate the effects of high variance on the spectral estimates due to finite-length, independent STFT windows, state-space multitaper (SSMT) method used a state-space framework to introduce dependency among the...
Purpose
To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in formulations suitable for administration in hospitalized patients in the presence of complex comorbid conditions is paramount. The purpose of this study is to evaluate the...
Artifact detection and removal is a crucial step in all data preprocessing pipelines for physiological time series data, especially when collected outside of controlled experimental settings. The fact that such artifact is often readily identifiable by eye suggests that unsupervised machine learning algorithms may be a promising option that do not...
Objective
Electrodermal activity (EDA) reflects sympathetic nervous system activity through sweating-related changes in skin conductance. To enable EDA data to be used robustly in clinical settings, we need to develop artifact detection and removal frameworks that can handle the types of interference experienced in clinical settings.
Methods
We co...
Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in one 21 year-old male subject with complete cervical quadriplegia (C5 American Spinal Injury Association Impairment Scale A) using a portable fully implanted brain-computer interface...
Multimodal general anesthesia (MMGA) is a strategy that utilizes the well-known neuroanatomy and neurophysiology of nociception and arousal control in designing a rational and clinical practical paradigm to regulate the levels of unconsciousness and antinociception during general anesthesia while mitigating side effects of any individual anesthetic...
Background:
Intraoperative electroencephalography (EEG) signatures related to the development of postoperative delirium (POD) in older patients are frequently studied. However, a broad analysis of the EEG dynamics including preoperative, postinduction, intraoperative and postoperative scenarios and its correlation to POD development is still lacki...
Continuous monitoring of electroencephalogram (EEG) recordings in humans under general anesthesia (GA) has demonstrated that changes in EEG dynamics induced by an anesthetic drug are reliably associated with the altered arousal states caused by the drug. This observation suggests that an intelligent, closed-loop anesthesia delivery (CLAD) system op...
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson's disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma and theta oscillations. These rhythms are at...
It is long hypothesized that there is a reliable, specific mapping between certain emotional states and the facial movements that express those states. This hypothesis is often tested by asking untrained participants to pose the facial movements they believe they use to express emotions during generic scenarios. Here, we test this hypothesis using,...
Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes high power gamma (25-50 Hz) oscillations alternating with slow-delta (0.1-4 Hz) oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) reco...
During general anesthesia, both behavioral and autonomic changes are caused by the administration of anesthetics such as propofol. Propofol produces unconsciousness by creating highly structured oscillations in brain circuits. The anesthetic also has autonomic effects due to its actions as a vasodilator and myocardial depressant. Understanding how...
Electrodermal activity (EDA) is a direct read-out of sweat-induced changes in the skin’s electrical conductance. Sympathetically-mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process, which yields an inverse Gaussian model as the inter-pulse interval distribution. We have previously showed that the inter-pu...
Aim
In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders.
Methods
To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the...
Burst-suppression electroencephalography (EEG) patterns of electrical activity, characterized by intermittent high-power broad-spectrum oscillations alternating with isoelectricity, have long been observed in the human brain during general anesthesia, hypothermia, coma and early infantile encephalopathy. Recently, commonalities between conditions a...
In current anesthesiology practice, anesthesiologists infer the state of unconsciousness without directly monitoring the brain. Drug- and patient-specific electroencephalographic (EEG) signatures of anesthesia-induced unconsciousness have been identified previously. We applied machine learning approaches to construct classification models for real-...
The specific circuit mechanisms through which anesthetics induce unconsciousness have not been completely characterized. We recorded neural activity from the frontal, parietal, and temporal cortices and thalamus while maintaining unconsciousness in non-human primates (NHPs) with the anesthetic propofol. Unconsciousness was marked by slow frequency...
Objective:
We present a statistical model for extracting physiologic characteristics from electrodermal activity (EDA) data in observational settings.
Methods:
We used insight about the integrate-and-fire physiology of sweat gland bursts, which predicts inverse Gaussian (IG) inter-pulse interval structure. At the core of our model-based paradigm...
Non-invasive G amma EN trainment U sing S ensory stimulation (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology such as amyloid and tau levels, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a randomized, placebo-controlled trial (n = 15) in volunteers with probable m...
Assessing directional influences between neurons is instrumental to understand how brain circuits process information. To this end, Granger causality, a technique originally developed for time-continuous signals, has been extended to discrete spike trains. A fundamental assumption of this technique is that the temporal evolution of neuronal respons...
We evaluated the incidence, distribution, and histopathologic correlates of microvascular brain lesions in patients with severe COVID-19. Sixteen consecutive patients admitted to the intensive care unit with severe COVID-19 undergoing brain MRI for evaluation of coma or neurologic deficits were retrospectively identified. Eleven patients had puncta...
Electrodermal activity (EDA) is a direct read-out of sweat-induced changes in the skin’s electrical conductance. Sympathetically-mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process, which yields an inverse Gaussian model as the inter-pulse interval distribution. We have previously showed that the inter-pu...
OBJECTIVE: We present a statistical model for extracting physiologic characteristics from electrodermal activity (EDA) data in observational settings. METHODS: We based our model on the integrate-and-fire physiology of sweat gland bursts, which predicts inverse Gaussian (IG) inter-pulse interval structure. At the core of our model-based paradigm is...
Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in a subject with complete cervical quadriplegia (C5 ASIA Impairment Scale A) using a portable fully implanted brain-computer interface (BCI) within the home environment. The BCI consi...
Burst suppression is an electroencephalography (EEG) pattern associated with profoundly inactivated brain states characterized by cerebral metabolic depression. Its distinctive feature is alternation between short temporal segments of near-isoelectric inactivity (suppressions) and relatively high-voltage activity (bursts). Prior modeling studies su...
Background
Our lab previously showed that 40 Hz sensory stimulation can modulate neural oscillations, ameliorate Alzheimer’s disease (AD) pathology, and improve cognition in AD mouse models (Iaccarino, Singer et al., Nature , 2016; Martorell, Paulson et al., Cell , 2019; Adaikkan et al., Neuron , 2019). To determine the safety and feasibility of 40...
Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes bursts of 30-50 Hz oscillations alternating with 0.1 to 10 Hz oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human...
