Publications by authors named "Nicholas Schiff"

127 Publications

Quantitative Electroencephalographic Markers of Delirium in the Pediatric Intensive Care Unit: Insights From a Heterogenous Convenience Sample.

J Neuropsychiatry Clin Neurosci 2021 Mar 24:appineuropsych20070184. Epub 2021 Mar 24.

Departments of Rehabilitation Medicine (Shah, Lowder), Pediatrics (Traube), and Population Health Sciences (Mauer, Gerber), Cornell University Joan and Sanford I Weill Medical College, New York; Clinical and Translational Science Center, Cornell University Joan and Sanford I Weill Medical College, New York (Gautam); Department of Pediatrics, New York-Presbyterian Hospital, New York (Carullo, Parlatore, Traube); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (Shah, Schiff); Department of Neurology, Weill Cornell Medicine, New York (Schiff); and Rockefeller University Hospital, New York (Schiff).

Objective: Little is known about the underlying neurophysiology of pediatric delirium. In adult patients, the sensitivity of EEG to clinical symptoms of delirium has been noted, with a slowing of background activity (alpha) and an increase in slow-wave activity (delta-theta). In this pilot study, the authors extended this investigation to a pediatric cohort.

Methods: In a convenience sample, 23 critically ill children were screened for delirium, using the Cornell Assessment for Pediatric Delirium (CAPD), every 12 hours throughout their pediatric intensive care unit stay as part of standard intensive care unit procedure, and EEGs were performed as part of their clinical care. After hospital discharge, EEGs were reviewed using quantitative analysis, and the maximum delta-alpha ratio (DAR; eyes closed) was derived for each 12-hour period. DAR values were compared between delirious and nondelirious episodes, and the linear relationship between DAR and CAPD was assessed.

Results: Higher DARs were associated with episodes of delirium. The DAR also positively correlated with CAPD assessments, with higher DARs relating to higher delirium scores.

Conclusions: Future prospective studies may further investigate this relationship in a more homogeneous and larger sample, and the DAR should be considered to track delirium and assess the effectiveness of therapeutic interventions.
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http://dx.doi.org/10.1176/appi.neuropsych.20070184DOI Listing
March 2021

Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies.

Nat Rev Neurol 2021 Mar 14;17(3):135-156. Epub 2020 Dec 14.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15-20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC.
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http://dx.doi.org/10.1038/s41582-020-00428-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734616PMC
March 2021

Objective and graded calibration of recovery of consciousness in experimental models.

Curr Opin Neurol 2021 Feb;34(1):142-149

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.

Purpose Of Review: Experimental preclinical models of recovery of consciousness (ROC) and anesthesia emergence are crucial for understanding the neuronal circuits restoring arousal during coma emergence. Such models can also potentially help to better understand how events during coma emergence facilitate or hinder recovery from brain injury. Here we provide an overview of current methods used to assess ROC/level of arousal in animal models. This exposes the need for objective approaches to calibrate arousal levels. We outline how correlation of measured behaviors and their reestablishment at multiple stages with cellular, local and broader neuronal networks, gives a fuller understanding of ROC.

Recent Findings: Animals emerging from diverse coma-like states share a dynamic process of cortical and behavioral recovery that reveals distinct states consistently sequenced from low-to-high arousal level and trackable in nonhuman primates and rodents. Neuronal activity modulation of layer V-pyramidal neurons and neuronal aggregates within the brainstem and thalamic nuclei play critical roles at specific stages to promote restoration of a conscious state.

Summary: A comprehensive, graded calibration of cortical, physiological, and behavioral changes in animal models is undoubtedly needed to establish an integrative framework. This approach reveals the contribution of local and systemic neuronal circuits to the underlying mechanisms for recovering consciousness.
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http://dx.doi.org/10.1097/WCO.0000000000000895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866679PMC
February 2021

Delayed reemergence of consciousness in survivors of severe COVID-19.

Neurocrit Care 2020 12 10;33(3):627-629. Epub 2020 Nov 10.

Feil Family Brain and Mind Research Institute, Weill Cornell Medical Center, New York, NY, USA.

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http://dx.doi.org/10.1007/s12028-020-01133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654564PMC
December 2020

Predicting task performance from biomarkers of mental fatigue in global brain activity.

J Neural Eng 2020 Oct 27. Epub 2020 Oct 27.

Cornell University College of Engineering, Ithaca, New York, 14853-2201, UNITED STATES.

Objective Detection and early prediction of mental fatigue (i.e., shifts in vigilance), could be used to adapt neuromodulation strategies to effectively treat patients suffering from brain injury and other indications with prominent chronic mental fatigue. Approach In this study, we analyzed electrocorticography (ECoG) signals chronically recorded from two healthy non-human primates (NHP) as they performed a sustained attention task over extended periods of time. We employed a set of spectrotemporal and connectivity biomarkers of the ECoG signals to identify periods of mental fatigue and a gradient boosting classifier to predict performance, up to several seconds prior to the behavioral response. Main results Wavelet entropy and the instantaneous amplitude and frequency were among the best single features across sessions in both NHPs. The classification performance using higher order spectral-temporal (HOST) features was significantly higher than that of conventional spectral power features in both NHPs. Across the 99 sessions analyzed, average F1 scores of 77.5%±8.2% and 91.2%±3.6%, and accuracy of 79.5%±8.9% and 87.6%±3.9% for the classifier were obtained for each animal, respectively. Significance Our results here demonstrate the feasibility of predicting performance and detecting mental fatigue by analyzing ECoG signals, and that this general approach, in principle, could be used for closed-loop control of neuromodulation strategies.
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http://dx.doi.org/10.1088/1741-2552/abc529DOI Listing
October 2020

Intensive Care Admission and Early Neuro-Rehabilitation. Lessons for COVID-19?

Front Neurol 2020 25;11:880. Epub 2020 Aug 25.

Acute Neuro-Rehabilitation Unit and Neurology Unit, Department of Clinical Neurosciences, Lausanne University Hospital-CHUV, Lausanne, Switzerland.

Coronavirus disease 2019 (COVID-19) requires admission to intensive care (ICU) for the management of acute respiratory distress syndrome in about 5% of cases. Although our understanding of COVID-19 is still incomplete, a growing body of evidence is indicating potential direct deleterious effects on the central and peripheral nervous systems. Indeed, complex and long-lasting physical, cognitive, and functional impairments have often been observed after COVID-19. Early (defined as during and immediately after ICU discharge) rehabilitative interventions are fundamental for reducing the neurological burden of a disease that already heavily affects lung function with pulmonary fibrosis as a possible long-term consequence. In addition, ameliorating neuromuscular weakness with early rehabilitation would improve the efficiency of respiratory function as respiratory muscle atrophy worsens lung capacity. This review briefly summarizes the polymorphic burden of COVID-19 and addresses possible early interventions that could minimize the neurological and systemic impact. In fact, the benefits of early multidisciplinary rehabilitation after an ICU stay have been shown to be advantageous in several clinical conditions making an early rehabilitative approach generalizable and desirable to physicians from a wide range of different specialties.
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http://dx.doi.org/10.3389/fneur.2020.00880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477378PMC
August 2020

Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior.

J Neurosci 2020 09 21;40(38):7343-7354. Epub 2020 Aug 21.

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy. The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy.
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http://dx.doi.org/10.1523/JNEUROSCI.1370-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534908PMC
September 2020

The Curing Coma Campaign: Framing Initial Scientific Challenges-Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting.

Neurocrit Care 2020 08;33(1):1-12

Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.
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http://dx.doi.org/10.1007/s12028-020-01028-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392933PMC
August 2020

Central Lateral Thalamic Nucleus Stimulation Awakens Cortex via Modulation of Cross-Regional, Laminar-Specific Activity during General Anesthesia.

Neuron 2020 04;106(1):1-3

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

Experiments identify cortical layer specific effects during induced arousal from general anesthesia. In this issue of Neuron, Redinbaugh et al. (2020) find evidence that central lateral thalamic nucleus electrical stimulation reactivates the cortex by restoring deep-layer firing rates and modulating feedforward and feedback connectivity.
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http://dx.doi.org/10.1016/j.neuron.2020.02.016DOI Listing
April 2020

Recovery in cognitive motor dissociation after severe brain injury: A cohort study.

PLoS One 2020 5;15(2):e0228474. Epub 2020 Feb 5.

Department of Clinical Neurosciences, Neurology Service, Acute Neurorehabilitation Unit, University Hospital Lausanne, Lausanne, Switzerland.

Objective: To investigate the functional and cognitive outcomes during early intensive neurorehabilitation and to compare the recovery patterns of patients presenting with cognitive motor dissociation (CMD), disorders of consciousness (DOC) and non-DOC.

Methods: We conducted a single center observational cohort study of 141 patients with severe acquired brain injury, consecutively admitted to an acute neurorehabilitation unit. We divided patients into three groups according to initial neurobehavioral diagnosis at admission using the Coma Recovery Scale-Revised (CRS-R) and the Motor Behavior Tool (MBT): potential clinical CMD, [N = 105]; DOC [N = 19]; non-DOC [N = 17]). Functional and cognitive outcomes were assessed at admission and discharge using the Glasgow Outcome Scale, the Early Rehabilitation Barthel Index, the Disability Rating Scale, the Rancho Los Amigos Levels of Cognitive Functioning, the Functional Ambulation Classification Scale and the modified Rankin Scale. Confirmed recovery of conscious awareness was based on CRS-R criteria.

Results: CMD patients were significantly associated with better functional outcomes and potential for improvement than DOC. Furthermore, outcomes of CMD patients did not differ significantly from those of non-DOC. Using the CRS-R scale only; approximatively 30% of CMD patients did not recover consciousness at discharge.

Interpretation: Our findings support the fact that patients presenting with CMD condition constitute a separate category, with different potential for improvement and functional outcomes than patients suffering from DOC. This reinforces the need for CMD to be urgently recognized, as it may directly affect patient care, influencing life-or-death decisions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228474PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001945PMC
April 2020

Independent Functional Outcomes after Prolonged Coma following Cardiac Arrest: A Mechanistic Hypothesis.

Ann Neurol 2020 04 11;87(4):618-632. Epub 2020 Feb 11.

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.

Objective: Survivors of prolonged (>2 weeks) post-cardiac arrest (CA) coma are expected to remain permanently disabled. We aimed to investigate 3 outlier patients who ultimately achieved independent functional outcomes after prolonged post-CA coma to identify electroencephalographic (EEG) markers of their recovery potential. For validation purposes, we also aimed to evaluate these markers in an independent cohort of post-CA patients.

Methods: We identified 3 patients with late recovery from coma (17-37 days) following CA who recovered to functionally independent behavioral levels. We performed spectral power analyses of available EEGs during prominent burst suppression patterns (BSP) present in all 3 patients. Using identical methods, we also assessed the relationship of intraburst spectral power and outcomes in a prospectively enrolled cohort of post-CA patients. We performed chart reviews of common clinical, imaging, and EEG prognostic variables and clinical outcomes for all patients.

Results: All 3 patients with late recovery from coma lacked evidence of overwhelming cortical injury but demonstrated prominent BSP on EEG. Spectral analyses revealed a prominent theta (~4-7Hz) feature dominating the bursts during BSP in these patients. In the prospective cohort, similar intraburst theta spectral features were evident in patients with favorable outcomes; patients with BSP and unfavorable outcomes showed either no features, transient burst features, or decreasing intraburst frequencies with time.

Interpretation: BSP with theta (~4-7Hz) peak intraburst spectral power after CA may index a recovery potential. We discuss our results in the context of optimizing metabolic substrate availability and stimulating the corticothalamic system during recovery from prolonged post-CA coma. ANN NEUROL 2020;87:618-632.
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http://dx.doi.org/10.1002/ana.25690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393600PMC
April 2020

Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Brain 2019 07;142(7):1887-1893

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.
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http://dx.doi.org/10.1093/brain/awz118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598636PMC
July 2019

Therapeutic interventions in patients with prolonged disorders of consciousness.

Lancet Neurol 2019 06 16;18(6):600-614. Epub 2019 Apr 16.

Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium.

The management of patients with severe brain injuries and prolonged disorders of consciousness raises important issues particularly with respect to their therapeutic options. The scarcity of treatment options is challenged by new clinical and neuroimaging data indicating that some patients with prolonged disorders of consciousness might benefit from therapeutic interventions, even years after the injury. Most studies of interventions aimed at improving patients' level of consciousness and functional recovery were behavioural and brain imaging open-label trials and case reports, but several randomised controlled trials have been done, particularly focused on the effects of drugs or use of non-invasive brain stimulation. However, only two studies on amantadine and transcranial direct current stimulation provided class II evidence. Although new therapeutic approaches seem to be valuable for patients with prolonged disorders of consciousness, optimised stimulation parameters, alternative drugs, or rehabilitation strategies still need to be tested and validated to improve rehabilitation and the quality of life of these patients.
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http://dx.doi.org/10.1016/S1474-4422(19)30031-6DOI Listing
June 2019

Treating Disorders of Consciousness With Apomorphine: Protocol for a Double-Blind Randomized Controlled Trial Using Multimodal Assessments.

Front Neurol 2019 19;10:248. Epub 2019 Mar 19.

GIGA Consciousness, University of Liège, Liège, Belgium.

There are few available therapeutic options to promote recovery among patients with chronic disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects and safety of use in small-sample pilot studies. The true efficacy of the drug and its neural mechanism are still unclear. Apomorphine may act through a modulation of the anterior forebrain mesocircuit, but neuroimaging and neurophysiological investigations to test this hypothesis are scarce. This clinical trial aims to (1) assess the treatment effect of subcutaneous apomorphine infusions in patients with DOC, (2) better identify the phenotype of responders to treatment, (3) evaluate tolerance and side effects in this population, and (4) examine the neural networks underlying its modulating action on consciousness. This study is a prospective double-blind randomized parallel placebo-controlled trial. Forty-eight patients diagnosed with DOC will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, using standardized behavioral scales (Coma Recovery Scale-Revised, Nociception Coma Scale-Revised), neurophysiological measures (electroencephalography, body temperature, actigraphy) and brain imaging (magnetic resonance imaging, positron emission tomography). Behavioral follow-up will be performed up to 2 years using structured phone interviews. Analyses will look for changes in behavioral status, circadian rhythmicity, brain metabolism, and functional connectivity at the individual level (comparing before and after treatment) and at the group level (comparing apomorphine and placebo arms, and comparing responder and non-responder groups). This study investigates the use of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal assessments. The results will contribute to define the role of dopamine agonists for the treatment of these challenging conditions and identify the neural correlates to their action. Results will bring objective evidence to further assess the modulation of the anterior forebrain mesocircuit by pharmacological agents, which may open new therapeutic perspectives. EudraCT n°2018-003144-23; Clinicaltrials.gov n°NCT03623828 (https://clinicaltrials.gov/ct2/show/NCT03623828).
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http://dx.doi.org/10.3389/fneur.2019.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433751PMC
March 2019

Daytime Central Thalamic Deep Brain Stimulation Modulates Sleep Dynamics in the Severely Injured Brain: Mechanistic Insights and a Novel Framework for Alpha-Delta Sleep Generation.

Front Neurol 2019 4;10:20. Epub 2019 Feb 4.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.

Loss of organized sleep electrophysiology is a characteristic finding following severe brain injury. The return of structured elements of sleep architecture has been associated with positive prognosis across injury etiologies, suggesting a role for sleep dynamics as biomarkers of wakeful neuronal circuit function. In a continuing study of one minimally conscious state patient studied over the course of ~8½ years, we sought to investigate whether changes in daytime brain activation induced by central thalamic deep brain stimulation (CT-DBS) influenced sleep electrophysiology. In this patient subject, we previously reported significant improvements in sleep electrophysiology during 5½ years of CT-DBS treatment, including increased sleep spindle frequency and SWS delta power. We now present novel findings that many of these improvements in sleep electrophysiology regress following CT-DBS discontinuation; these regressions in sleep features correlate with a significant decrease in behavioral responsiveness. We also observe the re-emergence of alpha-delta sleep, which had been previously suppressed by daytime CT-DBS in this patient subject. Importantly, CT-DBS was only active during the daytime and has been proposed to mediate recovery of consciousness by driving synaptic activity across frontostriatal systems through the enhancement of thalamocortical output. Accordingly, the improvement of sleep dynamics during daytime CT-DBS and their subsequent regression following CT-DBS discontinuation implicates wakeful synaptic activity as a robust modulator of sleep electrophysiology. We interpret these findings in the context of the "synaptic homeostasis hypothesis," whereby we propose that daytime upregulation of thalamocortical output in the severely injured brain may facilitate organized frontocortical circuit activation and yield net synaptic potentiation during wakefulness, providing a homeostatic drive that reconstitutes sleep dynamics over time. Furthermore, we consider common large-scale network dynamics across several neuropsychiatric disorders in which alpha-delta sleep has been documented, allowing us to formulate a novel mechanistic framework for alpha-delta sleep generation. We conclude that the bi-directional modulation of sleep electrophysiology by daytime thalamocortical activity in the severely injured brain: (1) emphasizes the cyclical carry-over effects of state-dependent circuit activation on large-scale brain dynamics, and (2) further implicates sleep electrophysiology as a sensitive indicator of wakeful brain activation and covert functional recovery in the severely injured brain.
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http://dx.doi.org/10.3389/fneur.2019.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369150PMC
February 2019

A Neurologic Examination for Anesthesiologists: Assessing Arousal Level during Induction, Maintenance, and Emergence.

Anesthesiology 2019 03;130(3):462-471

From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (E.R.R.) the Feil Family Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, New York, New York (N.D.S.) the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (E.N.B) the Department of Brain and Cognitive Science, the Institute for Medical Engineering and Sciences, the Picower Institute for Learning and Memory, and the Institute for Data, Systems and Society, Massachusetts Institute of Technology, Cambridge, Massachusetts (E.N.B).

Anesthetics have profound effects on the brain and central nervous system. Vital signs, along with the electroencephalogram and electroencephalogram-based indices, are commonly used to assess the brain states of patients receiving general anesthesia and sedation. Important information about the patient's arousal state during general anesthesia can also be obtained through use of the neurologic examination. This article reviews the main components of the neurologic examination focusing primarily on the brainstem examination. It details the components of the brainstem examination that are most relevant for patient management during induction, maintenance, and emergence from general anesthesia. The examination is easy to apply and provides important complementary information about the patient's arousal level that cannot be discerned from vital signs and electroencephalogram measures.
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http://dx.doi.org/10.1097/ALN.0000000000002559DOI Listing
March 2019

Cortical Response to the Natural Speech Envelope Correlates with Neuroimaging Evidence of Cognition in Severe Brain Injury.

Curr Biol 2018 12 21;28(23):3833-3839.e3. Epub 2018 Nov 21.

Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College, New York, NY 10065, USA; The Rockefeller University Hospital, Rockefeller University, New York, NY 10065 USA. Electronic address:

Recent studies identify severely brain-injured patients with limited or no behavioral responses who successfully perform functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG) mental imagery tasks [1-5]. Such tasks are cognitively demanding [1]; accordingly, recent studies support that fMRI command following in brain-injured patients associates with preserved cerebral metabolism and preserved sleep-wake EEG [5, 6]. We investigated the use of an EEG response that tracks the natural speech envelope (NSE) of spoken language [7-22] in healthy controls and brain-injured patients (vegetative state to emergence from minimally conscious state). As audition is typically preserved after brain injury, auditory paradigms may be preferred in searching for covert cognitive function [23-25]. NSE measures are obtained by cross-correlating EEG with the NSE. We compared NSE latencies and amplitudes with and without consideration of fMRI assessments. NSE latencies showed significant and progressive delay across diagnostic categories. Patients who could carry out fMRI-based mental imagery tasks showed no statistically significant difference in NSE latencies relative to healthy controls; this subgroup included patients without behavioral command following. The NSE may stratify patients with severe brain injuries and identify those patients demonstrating "cognitive motor dissociation" (CMD) [26] who show only covert evidence of command following utilizing neuroimaging or electrophysiological methods that demand high levels of cognitive function. Thus, the NSE is a passive measure that may provide a useful screening tool to improve detection of covert cognition with fMRI or other methods and improve stratification of patients with disorders of consciousness in research studies.
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http://dx.doi.org/10.1016/j.cub.2018.10.057DOI Listing
December 2018

Spectral Content of Electroencephalographic Burst-Suppression Patterns May Reflect Neuronal Recovery in Comatose Post-Cardiac Arrest Patients.

J Clin Neurophysiol 2019 Mar;36(2):119-126

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, U.S.A.

Purpose: To assess the potential biologic significance of variations in burst-suppression patterns (BSPs) after cardiac arrest in relation to recovery of consciousness. In the context of recent theoretical models of BSP, bursting frequency may be representative of underlying network dynamics; discontinuous activation of membrane potential during impaired cellular energetics may promote neuronal rescue.

Methods: We reviewed a database of 73 comatose post-cardiac arrest patients who underwent therapeutic hypothermia to assess for the presence of BSP and clinical outcomes. In a subsample of patients with BSP (n = 14), spectral content of burst and suppression periods were quantified using multitaper method.

Results: Burst-suppression pattern was seen in 45/73 (61%) patients. Comparable numbers of patients with (31.1%) and without (35.7%) BSP regained consciousness by the time of hospital discharge. In addition, in two unique cases, BSP initially resolved and then spontaneously reemerged after completion of therapeutic hypothermia and cessation of sedative medications. Both patients recovered consciousness. Spectral analysis of bursts in all patients regaining consciousness (n = 6) showed a prominent theta frequency (5-7 Hz) feature, but not in age-matched patients with induced BSP who did not recover consciousness (n = 8).

Conclusions: The prognostic implications of BSP after hypoxic brain injury may vary based on the intrinsic properties of the underlying brain state itself. The presence of theta activity within bursts may index potential viability of neuronal networks underlying recovery of consciousness; emergence of spontaneous BSP in some cases may indicate an innate neuroprotective mechanism. This study highlights the need for better characterization of various BSP patterns after cardiac arrest.
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http://dx.doi.org/10.1097/WNP.0000000000000536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399070PMC
March 2019

Resolving the role of the paramedian thalamus in forebrain arousal mechanisms.

Ann Neurol 2018 12;84(6):812-813

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.

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http://dx.doi.org/10.1002/ana.25378DOI Listing
December 2018

Comprehensive Systematic Review Update Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Arch Phys Med Rehabil 2018 09 8;99(9):1710-1719. Epub 2018 Aug 8.

Department of Neurology, University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.

Methods: Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.

Results: No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
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http://dx.doi.org/10.1016/j.apmr.2018.07.002DOI Listing
September 2018

Practice Guideline Update Recommendations Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Arch Phys Med Rehabil 2018 09 8;99(9):1699-1709. Epub 2018 Aug 8.

Department of Neurology, University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC).

Methods: Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended.

Recommendations: Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/ unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale-Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100-200 mg bid) for adults with traumatic VS/UWS or MCS (4-16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.
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http://dx.doi.org/10.1016/j.apmr.2018.07.001DOI Listing
September 2018

Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Neurology 2018 09 8;91(10):450-460. Epub 2018 Aug 8.

From the Department of Physical Medicine and Rehabilitation (J.T.G.), Spaulding Rehabilitation Hospital and Harvard Medical School; Department of Psychiatry (J.T.G.), Massachusetts General Hospital, Boston; Department of Neurology (D.I.K.), Boston University School of Medicine; Braintree Rehabilitation Hospital (D.I.K.), MA; Department of Neurology and Neuroscience (N.D.S.), Weill Cornell Medical College, New York, NY; Moss Rehabilitation Research Institute (J.W.), Elkins Park, PA; Bronson Neuroscience Center (E.J.A.), Bronson Methodist Hospital, Kalamazoo, MI; Department of Pediatrics, Division of Child Neurology (S.A.), Loma Linda University School of Medicine, CA; Department of Neurology (R.B.), University of Rochester Medical Center, NY; Indiana University Department of Physical Medicine & Rehabilitation (F.M.H.), University of Indiana School of Medicine, Indianapolis; Coma Science Group-GIGA Research and Department of Neurology (S.L.), Sart Tillman Liège University & University Hospital, Liège, Belgium; Department of Neurology (G.S.F.L.), Uniformed Services University of Health Sciences, Bethesda; Department of Neurology (G.S.F.L.), Johns Hopkins University, Baltimore, MD; James A. Haley Veterans' Hospital (R.N.-R.), US Department of Veterans Affairs, Tampa, FL; Crawford Research Institute (R.T.S.), Shepherd Center, Atlanta, GA; Center for Rehabilitation Science and Engineering, Department of Physical Medicine & Rehabilitation (R.T.S.), Virginia Commonwealth University School of Medicine, Richmond; Division of Physical Medicine & Rehabilitation (S.Y.), University of Mississippi School of Medicine; Brain Injury Program (S.Y.), Methodist Rehabilitation Center, Jackson, MS; Heart Rhythm Society (T.S.D.G.), Washington, DC; Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City; and Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC).

Methods: Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended.

Recommendations: Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale-Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100-200 mg bid) for adults with traumatic VS/UWS or MCS (4-16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.
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http://dx.doi.org/10.1212/WNL.0000000000005926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139814PMC
September 2018

Comprehensive systematic review update summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Neurology 2018 09 8;91(10):461-470. Epub 2018 Aug 8.

From the Department of Physical Medicine and Rehabilitation (J.T.G.), Spaulding Rehabilitation Hospital and Harvard Medical School; Department of Psychiatry (J.T.G.), Massachusetts General Hospital, Boston; Department of Neurology (D.I.K.), Boston University School of Medicine; Braintree Rehabilitation Hospital (D.I.K.), MA; Department of Neurology and Neuroscience (N.D.S.), Weill Cornell Medical College, New York, NY; Moss Rehabilitation Research Institute (J.W.), Elkins Park, PA; Bronson Neuroscience Center (E.J.A.), Bronson Methodist Hospital, Kalamazoo, MI; Department of Pediatrics, Division of Child Neurology (S.A.), Loma Linda University School of Medicine, CA; Department of Neurology (R.B.), University of Rochester Medical Center, NY; Indiana University Department of Physical Medicine & Rehabilitation (F.M.H.), University of Indiana School of Medicine, Indianapolis; Coma Science Group-GIGA Research and Department of Neurology (S.L.), Sart Tillman Liège University & University Hospital, Liège, Belgium; Department of Neurology (G.S.F.L.), Uniformed Services University of Health Sciences, Bethesda; Department of Neurology (G.S.F.L.), Johns Hopkins University, Baltimore, MD; James A. Haley Veterans' Hospital (R.N.-R.), US Department of Veterans Affairs, Tampa, FL; Crawford Research Institute (R.T.S.), Shepherd Center, Atlanta, GA; Center for Rehabilitation Science and Engineering, Department of Physical Medicine & Rehabilitation (R.T.S.), Virginia Commonwealth University School of Medicine, Richmond; Division of Physical Medicine & Rehabilitation (S.Y.), University of Mississippi School of Medicine; Brain Injury Program (S.Y.), Methodist Rehabilitation Center, Jackson, MS; Heart Rhythm Society (T.S.D.G.), Washington, DC; Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City; and Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.

Methods: Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.

Results: No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
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http://dx.doi.org/10.1212/WNL.0000000000005928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139817PMC
September 2018

A method for decomposing multivariate time series into a causal hierarchy within specific frequency bands.

J Comput Neurosci 2018 10 30;45(2):59-82. Epub 2018 Jul 30.

Weill Cornell Medical College, New York, NY, 10065, USA.

We propose a method - Frequency extracted hierarchical decomposition (FEHD) - for studying multivariate time series that identifies linear combinations of its components that possess a causally hierarchical structure - the method orders the components so that those at the "top" of the hierarchy drive those below. The method shares many of the features of the "hierarchical decomposition" method of Repucci et al. (Annals of Biomedical Engineering, 29, 1135-1149, 2001) but makes a crucial advance - the proposed method is capable of determining this causal hierarchy over arbitrarily specified frequency bands. Additionally, a novel minimization strategy is used to generate the decomposition resulting in an increase in stability, reliability, and an improvement in the sensitivity to model parameters. We demonstrate the utility of the method by applying it to both artificial time series constructed to have specific causal graphs, and to the EEG of healthy volunteers and patient subjects who are recovering from a severe brain injury.
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http://dx.doi.org/10.1007/s10827-018-0691-yDOI Listing
October 2018

Characterization of EEG signals revealing covert cognition in the injured brain.

Brain 2018 05;141(5):1404-1421

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, NY, USA.

See Boly and Laureys (doi:10.1093/brain/awy080) for a scientific commentary on this article.Patients with severe brain injury are difficult to assess and frequently subject to misdiagnosis. 'Cognitive motor dissociation' is a term used to describe a subset of such patients with preserved cognition as detected with neuroimaging methods but not evident in behavioural assessments. Unlike the locked-in state, cognitive motor dissociation after severe brain injury is prominently marked by concomitant injuries across the cerebrum in addition to limited or no motoric function. In the present study, we sought to characterize the EEG signals used as indicators of cognition in patients with disorders of consciousness and examine their reliability for potential future use to re-establish communication. We compared EEG-based assessments to the results of using similar methods with functional MRI. Using power spectral density analysis to detect EEG evidence of task performance (Two Group Test, P ≤ 0.05, with false discovery rate correction), we found evidence of the capacity to follow commands in 21 of 28 patients with severe brain injury and all 15 healthy individuals studied. We found substantial variability in the temporal and spatial characteristics of significant EEG signals among the patients in contrast to only modest variation in these domains across healthy controls; the majority of healthy controls showed suppression of either 8-12 Hz 'alpha' or 13-40 Hz 'beta' power during task performance, or both. Nine of the 21 patients with EEG evidence of command-following also demonstrated functional MRI evidence of command-following. Nine of the patients with command-following capacity demonstrated by EEG showed no behavioural evidence of a communication channel as detected by a standardized behavioural assessment, the Coma Recovery Scale - Revised. We further examined the potential contributions of fluctuations in arousal that appeared to co-vary with some patients' ability to reliably generate EEG signals in response to command. Five of nine patients with statistically indeterminate responses to one task tested showed a positive response after accounting for variations in overall background state (as visualized in the qualitative shape of the power spectrum) and grouping of trial runs with similar background state characteristics. Our findings reveal signal variations of EEG responses in patients with severe brain injuries and provide insight into the underlying physiology of cognitive motor dissociation. These results can help guide future efforts aimed at re-establishment of communication in such patients who will need customization for brain-computer interfaces.
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http://dx.doi.org/10.1093/brain/awy070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917770PMC
May 2018

Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank.

Front Neurosci 2017 24;11:734. Epub 2018 Jan 24.

Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, United States.

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.
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http://dx.doi.org/10.3389/fnins.2017.00734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787550PMC
January 2018

Divergent neural responses to narrative speech in disorders of consciousness.

Ann Clin Transl Neurol 2017 11 27;4(11):784-792. Epub 2017 Sep 27.

City College of New York New York New York.

Objective: Clinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ intersubject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls.

Methods: Electroencephalographic data were recorded from 20 subjects with disorders of consciousness and 14 healthy controls during of two narrative audio stimuli, presented both forwards and time-reversed. Intersubject correlation of evoked electroencephalography signals were calculated, comparing responses of both groups to those of the healthy control subjects. This analysis was performed blinded and subsequently compared to the diagnostic status of each patient based on the Coma Recovery Scale-Revised.

Results: Subjects with disorders of consciousness exhibit significantly lower intersubject correlation than healthy controls during narrative speech. Additionally, while healthy subjects had higher intersubject correlation values in forwards versus backwards presentation, neural responses did not vary significantly with the direction of playback in subjects with disorders of consciousness. Increased intersubject correlation values in the backward speech condition were noted with improving disorder of consciousness diagnosis, both in cross-sectional analysis and in a subset of patients with longitudinal data.

Interpretation: Intersubject correlation of neural responses to narrative speech audition differentiates healthy controls from patients and appears to index clinical diagnoses in disorders of consciousness.
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http://dx.doi.org/10.1002/acn3.470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682119PMC
November 2017