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Tools assaying the neural networks that modulate consciousness may facilitate tracking of recovery after acute severe brain injury. The ABCD framework classifies resting-state EEG into categories reflecting levels of thalamocortical network function that correlate with outcome in post-cardiac arrest coma. In this longitudinal cohort study, we applied the ABCD framework to 20 patients with acute severe traumatic brain injury requiring intensive care (12 of whom were also studied at ≥6-months post-injury) and 16 healthy controls. We tested four hypotheses: 1) EEG ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioral recovery; 3) ABCD classifications correlate with behavioral level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol yields improved ABCD classifications. Channel-level EEG power spectra were classified based on spectral peaks within pre-defined frequency bands: 'A' = no peaks above delta (4 Hz) range (complete thalamocortical disruption); 'B' = theta (4-8 Hz) peak (severe thalamocortical disruption); 'C' = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or 'D' = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). Acutely, 95% of patients demonstrated 'D' signals in at least one channel but exhibited within-session temporal variability and spatial heterogeneity in the proportion of different channel-level ABCD classifications. By contrast, healthy participants and patients at follow-up consistently demonstrated signals corresponding to intact thalamocortical network function. Patients demonstrated longitudinal improvement in ABCD classifications (p .05) and ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (p .01). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (p .05) but did not correspond with behavioral level of consciousness. These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

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 phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.

SummarySubanesthetic 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 involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

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 well as their known functional roles, suggest multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.

Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma.We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework: ‘A’ = no peaks above delta (Acutely, 95% of patients demonstrated ‘D’ signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent ‘D’ signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent ‘D’ signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (PPPThese findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

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-time tracking of unconscious state during anesthesia-induced unconsciousness. We used cross-validation to select and train the best performing models using 33,159 2s segments of EEG data recorded from 7 healthy volunteers who received increasing infusions of propofol while responding to stimuli to directly assess unconsciousness. Cross-validated models of unconsciousness performed very well when tested on 13,929 2s EEG segments from 3 left-out volunteers collected under the same conditions (median volunteer AUCs 0.99-0.99). Models showed strong generalization when tested on a cohort of 27 surgical patients receiving solely propofol collected in a separate clinical dataset under different circumstances and using different hardware (median patient AUCs 0.95—0.98), with model predictions corresponding with actions taken by the anesthesiologist during the cases. Performance was also strong for 17 patients receiving sevoflurane (alone or in addition to propofol) (median AUCs 0.88—0.92). These results indicate that EEG spectral features can predict unconsciousness, even when tested on a different anesthetic that acts with a similar neural mechanism. With high performance predictions of unconsciousness, we can accurately monitor anesthetic state, and this approach may be used to engineer infusion pumps to intelligibly respond to patients’ neural activity.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5–2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug’s pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

Background We investigated the effect of delirium burden in mechanically ventilated patients, beginning in the ICU and continuing throughout hospitalization, on functional neurologic outcomes up to 2.5 years following critical illness. Methods Prospective cohort study of enrolling 178 consecutive mechanically ventilated adult medical and surgical ICU patients between October 2013 and May 2016. Altogether, patients were assessed daily for delirium 2941days using the Confusion Assessment Method for the ICU (CAM-ICU). Hospitalization delirium burden (DB) was quantified as number of hospital days with delirium divided by total days at risk. Survival status up to 2.5 years and neurologic outcomes using the Glasgow Outcome Scale were recorded at discharge 3, 6, and 12 months post-discharge. Results Of 178 patients, 19 (10.7%) were excluded from outcome analyses due to persistent coma. Among the remaining 159, 123 (77.4%) experienced delirium. DB was independently associated with >4-fold increased mortality at 2.5 years following ICU admission (adjusted hazard ratio [aHR], 4.77; 95% CI, 2.10–10.83; P < .001), and worse neurologic outcome at discharge (adjusted odds ratio [aOR], 0.02; 0.01–0.09; P < .001), 3 (aOR, 0.11; 0.04–0.31; P < .001), 6 (aOR, 0.10; 0.04–0.29; P < .001), and 12 months (aOR, 0.19; 0.07–0.52; P = .001). DB in the ICU alone was not associated with mortality (HR, 1.79; 0.93–3.44; P = .082) and predicted neurologic outcome less strongly than entire hospital stay DB. Similarly, the number of delirium days in the ICU and for whole hospitalization were not associated with mortality (HR, 1.00; 0.93–1.08; P = .917 and HR, 0.98; 0.94–1.03, P = .535) nor with neurological outcomes, except for the association between ICU delirium days and neurological outcome at discharge (OR, 0.90; 0.81–0.99, P = .038). Conclusions Delirium burden throughout hospitalization independently predicts long term neurologic outcomes and death up to 2.5 years after critical illness, and is more predictive than delirium burden in the ICU alone and number of delirium days.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

To explore the potential value of heart rate variability features for automated monitoring of sedation levels in mechanically ventilated ICU patients.Multicenter, pilot study.Several ICUs at Massachusetts General Hospital, Boston, MA.Electrocardiogram recordings from 40 mechanically ventilated adult patients receiving sedatives in an ICU setting were used to develop and test the proposed automated system.Richmond Agitation-Sedation Scale scores were acquired prospectively to assess patient sedation levels and were used as ground truth. Richmond Agitation-Sedation Scale scores were grouped into four levels, denoted "unarousable" (Richmond Agitation- Sedation Scale = -5, -4), "sedated" (-3, -2, -1), "awake" (0), "agitated" (+1, +2, +3, +4). A multiclass support vector machine algorithm was used for classification. Classifier training and performance evaluations were carried out using leave-oneout cross validation. An overall accuracy of 69% was achieved for discriminating between the four levels of sedation. The proposed system was able to reliably discriminate (accuracy = 79%) between sedated (Richmond Agitation-Sedation Scale0) and nonsedated states (Richmond Agitation-Sedation Scale0).With further refinement, the methodology reported herein could lead to a fully automated system for depth of sedation monitoring. By enabling monitoring to be continuous, such technology may help clinical staff to monitor sedation levels more effectively and to reduce complications related to over- and undersedation.

Objective : This study was performed to evaluate how well states of deep sedation in ICU patients can be detected from the frontal electroencephalogram (EEG) using features based on the method of atomic decomposition (AD). Methods : We analyzed a clinical dataset of 20 min of EEG recordings per patient from 44 mechanically ventilated adult patients receiving sedatives in an intensive care unit (ICU) setting. Several features derived from AD of the EEG signal were used to discriminate between awake and sedated states. We trained support vector machine (SVM) classifiers using AD features and compared the classification performance with SVM classifiers trained using standard spectral and entropy features using leave-one-subject-out validation. The potential of each feature to discriminate between awake and sedated states was quantified using area under the receiver operating characteristic curve (AUC). Results : The sedation level classification system using AD was able to reliably discriminate between sedated and awake states achieving an average AUC of 0.90, which was significantly better ( $p ) than performance achieved using spectral (AUC = 0.86) and entropy (AUC = 0.81) domain features. A combined feature set consisting of AD, entropy, and spectral features provided better discrimination (AUC = 0.91, $p ) than any individual feature set. Conclusions : Features derived from the atomic decomposition of EEG signals provide useful discriminative information about the depth of sedation in ICU patients. Significance : With further refinement and external validation, the proposed system may be able to assist clinical staff with continuous surveillance of sedation levels in mechanically ventilated critically ill ICU patients.

Background Anaesthetic drugs act at sites within the brain that undergo profound changes during typical ageing. We postulated that anaesthesia-induced brain dynamics observed in the EEG change with age. Methods We analysed the EEG in 155 patients aged 18–90 yr who received propofol (n=60) or sevoflurane (n=95) as the primary anaesthetic. The EEG spectrum and coherence were estimated throughout a 2 min period of stable anaesthetic maintenance. Age-related effects were characterized by analysing power and coherence as a function of age using linear regression and by comparing the power spectrum and coherence in young (18- to 38-yr-old) and elderly (70- to 90-yr-old) patients. Results Power across all frequency bands decreased significantly with age for both propofol and sevoflurane; elderly patients showed EEG oscillations ∼2- to 3-fold smaller in amplitude than younger adults. The qualitative form of the EEG appeared similar regardless of age, showing prominent alpha (8–12 Hz) and slow (0.1–1 Hz) oscillations. However, alpha band dynamics showed specific age-related changes. In elderly compared with young patients, alpha power decreased more than slow power, and alpha coherence and peak frequency were significantly lower. Older patients were more likely to experience burst suppression. Conclusions These profound age-related changes in the EEG are consistent with known neurobiological and neuroanatomical changes that occur during typical ageing. Commercial EEG-based depth-of-anaesthesia indices do not account for age and are therefore likely to be inaccurate in elderly patients. In contrast, monitoring the unprocessed EEG and its spectrogram can account for age and individual patient characteristics.

An automated patient-specific system to classify the level of sedation in ICU patients using heart rate variability signal is presented in this paper. ECG from 70 mechanically ventilated adult patients with administered sedatives in an ICU setting were used to develop a support vector machine based system for sedation depth monitoring using several heart rate variability measures. A leave-one-subject-out cross validation was used for classifier training and performance evaluations. The proposed patient-specific system provided a sensitivity, specificity and an AUC of 64%, 84.8% and 0.72, respectively. It is hoped that with the help of additional physiological signals the proposed patient-specific sedation level prediction system could lead to a fully automated multimodal system to assist clinical staff in ICUs to interpret the sedation level of the patient.

Neurons communicate with each other dynamically; how such communications lead to consciousness remains unclear. Here, we present a theoretical model to understand the dynamic nature of sensory activity and information integration in a hierarchical network, in which edges are stochastically defined by a single parameter p representing the percolation probability of information transmission. We validate the model by comparing the transmitted and original signal distributions, and we show that a basic version of this model can reproduce key spectral features clinically observed in electroencephalographic recordings of transitions from conscious to unconscious brain activities during general anesthesia. As p decreases, a steep divergence of the transmitted signal from the original was observed, along with a loss of signal synchrony and a sharp increase in information entropy in a critical manner; this resembles the precipitous loss of consciousness during anesthesia. The model offers mechanistic insights into the emergence of information integration from a stochastic process, laying the foundation for understanding the origin of cognition.

To develop a personalizable algorithm to discriminate between sedation levels in ICU patients based on heart rate variability.Multicenter, pilot study.Several ICUs at Massachusetts General Hospital, Boston, MA.We gathered 21,912 hours of routine electrocardiogram recordings from a heterogenous group of 70 adult ICU patients. All patients included in the study were mechanically ventilated and were receiving sedatives.As "ground truth" for developing our method, we used Richmond Agitation Sedation Scale scores grouped into four levels denoted "comatose" (-5), "deeply sedated" (-4 to -3), "lightly sedated" (-2 to 0), and "agitated" (+1 to +4). We trained a support vector machine learning algorithm to calculate the probability of each sedation level from heart rate variability measures derived from the electrocardiogram. To estimate algorithm performance, we calculated leave-one-subject out cross-validated accuracy. The patient-independent version of the proposed system discriminated between the four sedation levels with an overall accuracy of 59%. Upon personalizing the system supplementing the training data with patient-specific calibration data, consisting of an individual's labeled heart rate variability epochs from the preceding 24 hours, accuracy improved to 67%. The personalized system discriminated between light- and deep-sedation states with an average accuracy of 75%.With further refinement, the methodology reported herein could lead to a fully automated system for depth of sedation monitoring. By enabling monitoring to be continuous, such technology may help clinical staff to monitor sedation levels more effectively and to reduce complications related to over- and under sedation.