Common Data Elements for Disorders of Consciousness: Recommendations from the Electrophysiology Working Group.

BACKGROUND: Electroencephalography (EEG) has long been recognized as an important tool in the investigation of disorders of consciousness (DoC). From inspection of the raw EEG to the implementation of quantitative EEG, and more recently in the use of perturbed EEG, it is paramount to providing accurate diagnostic and prognostic information in the care of patients with DoC. However, a nomenclature for variables that establishes a convention for naming, defining, and structuring data for clinical research variables currently is lacking. As such, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups composed of experts in the field to construct common data elements (CDEs) to provide recommendations for DoC, with the main goal of facilitating data collection and standardization of reporting. This article summarizes the recommendations of the electrophysiology DoC working group. METHODS: After assessing previously published pertinent CDEs, we developed new CDEs and categorized them into "disease core," "basic," "supplemental," and "exploratory." Key EEG design elements, defined as concepts that pertained to a methodological parameter relevant to the acquisition, processing, or analysis of data, were also included but were not classified as CDEs. RESULTS: After identifying existing pertinent CDEs and developing novel CDEs for electrophysiology in DoC, variables were organized into a framework based on the two primary categories of resting state EEG and perturbed EEG. Using this categorical framework, two case report forms were generated by the working group. CONCLUSIONS: Adherence to the recommendations outlined by the electrophysiology working group in the resting state EEG and perturbed EEG case report forms will facilitate data collection and sharing in DoC research on an international level. In turn, this will allow for more informed and reliable comparison of results across studies, facilitating further advancement in the realm of DoC research.

Habitat isolation interacts with top-down and bottom-up processes in a seagrass ecosystem.

Habitat loss is accelerating at unprecedented rates, leading to the emergence of smaller, more isolated habitat remnants. Habitat isolation adversely affects many ecological processes independently, but little is known about how habitat isolation may interact with ecosystem processes such as top-down (consumer-driven) and bottom-up (resource-driven) effects. To investigate the interactive influence of habitat isolation, resource availability and consumer distribution and impact on community structure, we tested two hypotheses using invertebrate and algal epibionts on temperate seagrasses, an ecosystem of ecological and conservation importance. First, we hypothesized that habitat isolation will change the structure of the seagrass epibiont community, and isolated patches of seagrass will have lower epibiont biomass and different epibiont community composition than contiguous meadows. Second, we hypothesized that habitat isolation would mediate top-down (i.e., herbivory) and bottom-up (i.e., nutrient enrichment) control for algal epibionts. We used observational studies in natural seagrass patches and experimental artificial seagrass to examine three levels of habitat isolation. We further manipulated top-down and bottom-up processes in artificial seagrass through consumer reductions and nutrient additions, respectively. We indeed found that habitat isolation of seagrass patches decreased epibiont biomass and modified epibiont community composition. This pattern was largely due to dispersal limitation of invertebrate epibionts that resulted in a decline in their abundance and richness in isolated patches. Further, habitat isolation reduced consumer abundances, weakening top-down control of algal epibionts in isolated seagrass patches. Nutrient additions, however, reversed this pattern, and allowed a top-down effect on algal richness to emerge in isolated habitats, demonstrating a complex interaction between patch isolation and top-down and bottom-up processes. Habitat isolation may therefore shape the relative importance of central processes in ecosystems, leading to changes in community composition and food web structure in marine habitats.

An evaluation of surrogate decision maker health literacy in the neurology ward and neuroscience ICU.

PURPOSE: There has been little investigation into surrogate comprehension of education provided by the neuroscience healthcare team. We sought to evaluate 1) surrogate understanding about a patient's clinical condition and 2) the relationship between how surrogates and the neuroscience team perceive surrogate comprehension of a patient's condition. METHODS: We prospectively surveyed surrogates of patients who lacked decision making capacity while admitted to the neurology ward or neuroscience ICU for >48 h from 10/2018-05/2021. The survey investigated the surrogate's communication with the neuroscience team and understanding of the hospitalization. A member of the neuroscience team was asked to provide clinical data about the patient and indicate how well they perceived the surrogate understood the situation. RESULTS: We surveyed 50 surrogates at a median of 10 (IQR 5-17) days after hospitalization. There were 38 (76%) surrogates who correctly identified the reason for admission, and 21 (42%) who correctly identified all the assessments/interventions performed. Nearly all surrogates rated their understanding of the patient's medical condition as excellent (47%) or good (49%). There was no to slight agreement (kappa = 0.133) between surrogate self-perception of understanding and neuroscience team perception of the surrogate's understanding. Although only 20% of surrogates used institutional electronic education materials, 74% discussed the hospitalization with friends/family who work in healthcare. CONCLUSION: Objective and subjective assessments of surrogate comprehension demonstrate that there is a need to improve communication with the surrogates of patients with neurological conditions. Neuroscience healthcare teams must be taught how to educate surrogates and assess their understanding.

Local aberration control to improve efficiency in multiphoton holographic projections.

Optical aberrations affect the quality of light propagating through a turbid medium, where refractive index is spatially inhomogeneous. In multiphoton optical applications, such as two-photon excitation fluorescence imaging and optogenetics, aberrations non-linearly impair the efficiency of excitation. We demonstrate a sensorless adaptive optics technique to compensate aberrations in holograms projected into turbid media. We use a spatial light modulator to project custom three dimensional holographic patterns and to correct for local (anisoplanatic) distortions. The method is tested on both synthetic and biological samples to counteract aberrations arising respectively from misalignment of the optical system and from samples inhomogeneities. In both cases the anisoplanatic correction improves the intensity of the stimulation pattern at least two-fold.

Impact of the COVID-19 pandemic on people with epilepsy: findings from the US arm of the COV-E study.

OBJECTIVES: As part of the COVID-19 and Epilepsy (COV-E) global study, we aimed to understand the impact of COVID-19 on the medical care and well-being of people with epilepsy (PWE) in the United States, based on their perspectives and those of their caregivers. METHODS: Separate surveys designed for PWE and their caregivers were circulated from April 2020 to July 2021; modifications in March 2021 included a question about COVID-19 vaccination status. RESULTS: We received 788 responses, 71% from PWE (n = 559) and 29% (n=229) from caregivers of persons with epilepsy. A third (n = 308) of respondents reported a change in their health or in the health of the person they care for. Twenty-seven percent (n = 210) reported issues related to worsening mental health. Of respondents taking ASMs (n = 769), 10% (n= 78) reported difficulty taking medications on time, mostly due to stress causing forgetfulness. Less than half of respondents received counseling on mental health and stress. Less than half of the PWE reported having discussions with their healthcare providers about sleep, ASMs and potential side effects, while a larger proportion of caregivers (81%) reported having had discussions with their healthcare providers on the same topics. More PWE and caregivers reported that COVID-19 related measures caused adverse impact on their health in the post-vaccine period than during the pre-vaccine period, citing mental health issues as the primary reason. SIGNIFICANCE: Our findings indicate that the impact of the COVID-19 pandemic in the US on PWE is multifaceted. Apart from the increased risk of poor COVID-19 outcomes, the pandemic has also had negative effects on mental health and self-management. Healthcare providers must be vigilant for increased emotional distress in PWE during the pandemic and consider the importance of effective counseling to diminish risks related to exacerbated treatment gaps.

How innovations in methodology offer new prospects for volume electron microscopy.

Detailed knowledge of biological structure has been key in understanding biology at several levels of organisation, from organs to cells and proteins. Volume electron microscopy (volume EM) provides high resolution 3D structural information about tissues on the nanometre scale. However, the throughput rate of conventional electron microscopes has limited the volume size and number of samples that can be imaged. Recent improvements in methodology are currently driving a revolution in volume EM, making possible the structural imaging of whole organs and small organisms. In turn, these recent developments in image acquisition have created or stressed bottlenecks in other parts of the pipeline, like sample preparation, image analysis and data management. While the progress in image analysis is stunning due to the advent of automatic segmentation and server-based annotation tools, several challenges remain. Here we discuss recent trends in volume EM, emerging methods for increasing throughput and implications for sample preparation, image analysis and data management.

A key concept in biology is that the structure of tissues, cells and their components (cell organelles) often relates to their function. With electron microscopy (EM), it is possible to reveal this structure with nanometre resolution and therefore infer about its function. Electron microscopy of tissues knows a long history of method development, starting in the 1940s. Method development has largely determined the possibilities and scope of electron microscopy. In the 2000s, innovative techniques were developed that allowed routine imaging of tissues in 3D with a higher degree of automation. Nevertheless, conventional electron microscopy techniques remain unsuited for imaging of tissue with nanometre resolution on a millimetre scale because of their low inherent throughput. Here we analyse trends in volume electron microscopy (EM of tissues in 3D) by reviewing the application, acquisition parameters and data information from over 100 publications in the field. We see an expansion of interest from the conventional applications in neuroscience to other fields, such as cell biology. Additionally, the size of data sets is growing rapidly. From here, we review in detail how certain developments in methodology from the past 10 years have tried to overcome the low acquisition throughput of electron microscopes, by making these techniques more robust during long acquisitions, but also much faster by parallelisation. We find that these new developments have big implications for sample preparation, processing and analysis of the images and data management. We therefore also describe the new developments in these separate domains. We illustrate how novel sample preparation protocols have been developed specifically for larger volumes, how the introduction of machine learning has accelerated automated segmentation of volume EM data and that there is an ongoing transition from local to remote data storage and management. We also touch upon the tools that researchers use to analyse and annotate EM data. We conclude that the potential of volume EM remains high and the new developments open up possibilities for novel biological studies. We promote the sharing of resources and tools between researchers and institutions to maximise the potential from the new developments in volume electron microscopy.

Microscopic modulation and analysis of islets of Langerhans in living zebrafish larvae.

Microscopic analysis of molecules and physiology in living cells and systems is a powerful tool in life sciences. While in vivo subcellular microscopic analysis of healthy and diseased human organs remains impossible, zebrafish larvae allow studying pathophysiology of many organs using in vivo microscopy. Here, we review the potential of the larval zebrafish pancreas in the context of islets of Langerhans and Type 1 diabetes. We highlight the match of zebrafish larvae with the expanding toolbox of fluorescent probes that monitor cell identity, fate and/or physiology in real time. Moreover, fast and efficient modulation and localization of fluorescence at a subcellular level, through fluorescence microscopy, including confocal and light sheet (single plane illumination) microscopes tailored to in vivo larval research, is addressed. These developments make the zebrafish larvae an extremely powerful research tool for translational research. We foresee that living larval zebrafish models will replace many cell line-based studies in understanding the contribution of molecules, organelles and cells to organ pathophysiology in whole organisms.

Neuroprognostication after Cardiac Arrest: Who Recovers? Who Progresses to Brain Death?

Approximately 15% of deaths in developed nations are due to sudden cardiac arrest, making it the most common cause of death worldwide. Though high-quality cardiopulmonary resuscitation has improved overall survival rates, the majority of survivors remain comatose after return of spontaneous circulation secondary to hypoxic ischemic injury. Since the advent of targeted temperature management, neurologic recovery has improved substantially, but the majority of patients are left with neurologic deficits ranging from minor cognitive impairment to persistent coma. Of those who survive cardiac arrest, but die during their hospitalization, some progress to brain death and others die after withdrawal of life-sustaining treatment due to anticipated poor neurologic prognosis. Here, we discuss considerations neurologists must make when asked, "Given their recent cardiac arrest, how much neurologic improvement do we expect for this patient?"

GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage.

GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.

Systemic Inflammatory Response Syndrome is Associated with Hematoma Expansion in Intracerebral Hemorrhage.

OBJECTIVES: Systemic inflammatory response syndrome (SIRS) and hematoma expansion are independently associated with worse outcomes after intracerebral hemorrhage (ICH), but the relationship between SIRS and hematoma expansion remains unclear. MATERIALS AND METHODS: We performed a retrospective review of patients admitted to our hospital from 2013 to 2020 with primary spontaneous ICH with at least two head CTs within the first 24 hours. The relationship between SIRS and hematoma expansion, defined as ≥6 mL or ≥33% growth between the first and second scan, was assessed using univariable and multivariable regression analysis. We assessed the relationship of hematoma expansion and SIRS on discharge mRS using mediation analysis. RESULTS: Of 149 patients with ICH, 83 (56%; mean age 67±16; 41% female) met inclusion criteria. Of those, 44 (53%) had SIRS. Admission systolic blood pressure (SBP), temperature, antiplatelet use, platelet count, initial hematoma volume and rates of infection did not differ between groups (all p>0.05). Hematoma expansion occurred in 15/83 (18%) patients, 12 (80%) of whom also had SIRS. SIRS was significantly associated with hematoma expansion (OR 4.5, 95% CI 1.16 - 17.39, p= 0.02) on univariable analysis. The association remained statistically significant after adjusting for admission SBP and initial hematoma volume (OR 5.72, 95% CI 1.40 - 23.41, p= 0.02). There was a significant indirect effect of SIRS on discharge mRS through hematoma expansion. A significantly greater percentage of patients with SIRS had mRS 4-6 at discharge (59 vs 33%, p=0.02). CONCLUSION: SIRS is associated with hematoma expansion of ICH within the first 24 hours, and hematoma expansion mediates the effect of SIRS on poor outcome.

Using Objective Structured Clinical Exams (OSCE) to Teach Neurology Residents to Disclose Prognosis after Hypoxic Ischemic Brain Injury.

BACKGROUND: Neurologists need to be adept at disclosing prognosis and breaking bad news. Objective structured clinical examinations (OSCE) allow trainees to practice these skills. METHODS: In 2017, in conjunction with the NYU School of Medicine Simulation Center, neurology faculty designed an OSCE case in which a resident had to inform a standardized patient (SP) her father had severe global hypoxic ischemic injury. The residents were surveyed on the experience using a Likert scale from 1 (worst) to 5 (best). The SP completed a behavioral anchored checklist and marked items as "not done," "partly done," or "well done". RESULTS: 57 third and fourth year neurology residents completed the case from 2018 to 2020, 54 (95%) of whom completed the post-OSCE survey. Residents reported feeling moderately prepared for the simulation (mean Likert score 3.7/5), and thought their performance was average (3.4/5). Overall, they found the case to be very helpful (4.6/5). The residents performed well in the realms of maintaining professionalism (64% rated "well done"), developing a relationship (62% rated "well done"), and information gathering (61% rated "well done"). There was room for improvement in the realms of providing education and presenting the bad news (39% and 37% rated "partly/not done," respectively). CONCLUSIONS: OSCE cases can be used to teach neurology trainees how to discuss prognosis and break bad news. Feedback about this simulation was positive, though its efficacy has yet to be evaluated and could be a future direction of study.

Cerebrospinal fluid findings in patients with seizure in the setting of COVID-19: A review of the literature.

We reviewed the literature on cerebrospinal fluid (CSF) studies in patients who had a seizure in the setting of COVID-19 infection to evaluate for evidence of viral neuroinvasion. We performed a systematic review of Medline and Embase to identify publications that reported one or more patients with COVID-19 who had a seizure and had CSF testing preformed. The search ranged from December 1st 2019 to November 18th 2020. We identified 56 publications which described 69 unique patients who met our inclusion criteria. Of the 54 patients whose past medical history was provided, 2 (4%) had epilepsy and 1 (2%) had a prior seizure in the setting of hyperglycemia, but the remaining 51 (94%) had no history of seizures. Seizure was the initial symptom of COVID-19 for 15 (22%) patients. There were 26 (40%) patients who developed status epilepticus. SARS-CoV-2 PCR testing was performed in the CSF for 45 patients; 6 (13%) had a positive CSF SARS-CoV-2 PCR, only 1 (17%) of whom had status epilepticus. The cycle thresholds were not reported. Evaluation for CSF SARS-CoV-2 antibodies (directly or indirectly, via testing for CSF oligoclonal bands or immunoglobulins) was performed in 26 patients, only 2 (8%) of whom had evidence of intrathecal antibody synthesis. Of the 11 patients who had CSF autoimmune antibody panels tested, 1 had NMDA antibodies and 1 had Caspr-2 antibodies. Detection of SARS-CoV-2 in the CSF of patients with seizures who have COVID-19 is uncommon. Our review suggests that seizures in this patient population are not likely due to direct viral invasion of the brain.

Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.

Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.

Experience, circuit dynamics, and forebrain recruitment in larval zebrafish prey capture.

Experience influences behavior, but little is known about how experience is encoded in the brain, and how changes in neural activity are implemented at a network level to improve performance. Here we investigate how differences in experience impact brain circuitry and behavior in larval zebrafish prey capture. We find that experience of live prey compared to inert food increases capture success by boosting capture initiation. In response to live prey, animals with and without prior experience of live prey show activity in visual areas (pretectum and optic tectum) and motor areas (cerebellum and hindbrain), with similar visual area retinotopic maps of prey position. However, prey-experienced animals more readily initiate capture in response to visual area activity and have greater visually-evoked activity in two forebrain areas: the telencephalon and habenula. Consequently, disruption of habenular neurons reduces capture performance in prey-experienced fish. Together, our results suggest that experience of prey strengthens prey-associated visual drive to the forebrain, and that this lowers the threshold for prey-associated visual activity to trigger activity in motor areas, thereby improving capture performance.

Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.

There have been multiple descriptions of seizures during the acute infectious period in patients with COVID-19. However, there have been no reports of status epilepticus after recovery from COVID-19 infection. Herein, we discuss a patient with refractory status epilepticus 6 weeks after initial infection with COVID-19. Extensive workup demonstrated elevated inflammatory markers, recurrence of a positive nasopharyngeal SARS-CoV-2 polymerase chain reaction, and hippocampal atrophy. Postinfectious inflammation may have triggered refractory status epilepticus in a manner similar to the multisystemic inflammatory syndrome observed in children after COVID-19.

Continuous EEG findings in patients with COVID-19 infection admitted to a New York academic hospital system.

OBJECTIVE: There is evidence for central nervous system complications of coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Encephalopathy caused by or arising from seizures, especially nonconvulsive seizures (NCS), often requires electroencephalography (EEG) monitoring for diagnosis. The prevalence of seizures and other EEG abnormalities among COVID-19-infected patients is unknown. METHODS: Medical records and EEG studies of patients hospitalized with confirmed COVID-19 infections over a 2-month period at a single US academic health system (four hospitals) were reviewed to describe the distribution of EEG findings including epileptiform abnormalities (seizures, periodic discharges, or nonperiodic epileptiform discharges). Factors including demographics, remote and acute brain injury, prior history of epilepsy, preceding seizures, critical illness severity scores, and interleukin 6 (IL-6) levels were compared to EEG findings to identify predictors of epileptiform EEG abnormalities. RESULTS: Of 111 patients monitored, most were male (71%), middle-aged or older (median age 64 years), admitted to an intensive care unit (ICU; 77%), and comatose (70%). Excluding 11 patients monitored after cardiac arrest, the most frequent EEG finding was moderate generalized slowing (57%), but epileptiform findings were observed in 30% and seizures in 7% (4% with NCS). Three patients with EEG seizures did not have epilepsy or evidence of acute or remote brain injury, although all had clinical seizures prior to EEG. Only having epilepsy (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.4-21) or seizure(s) prior to EEG (OR 4.8, 95% CI 1.7-13) was independently associated with epileptiform EEG findings. SIGNIFICANCE: Our study supports growing evidence that COVID-19 can affect the central nervous system, although seizures are unlikely a common cause of encephalopathy. Seizures and epileptiform activity on EEG occurred infrequently, and having a history of epilepsy or seizure(s) prior to EEG testing was predictive of epileptiform findings. This has important implications for triaging EEG testing in this population.

Special considerations in the assessment of catastrophic brain injury and determination of brain death in patients with SARS-CoV-2.

INTRODUCTION: The coronavirus disease 2019 (Covid-19) pandemic has led to challenges in provision of care, clinical assessment and communication with families. The unique considerations associated with evaluation of catastrophic brain injury and death by neurologic criteria in patients with Covid-19 infection have not been examined. METHODS: We describe the evaluation of six patients hospitalized at a health network in New York City in April 2020 who had Covid-19, were comatose and had absent brainstem reflexes. RESULTS: Four males and two females with a median age of 58.5 (IQR 47-68) were evaluated for catastrophic brain injury due to stroke and/or global anoxic injury at a median of 14 days (IQR 13-18) after admission for acute respiratory failure due to Covid-19. All patients had hypotension requiring vasopressors and had been treated with sedative/narcotic drips for ventilator dyssynchrony. Among these patients, 5 had received paralytics. Apnea testing was performed for 1 patient due to the decision to withdraw treatment (n = 2), concern for inability to tolerate testing (n = 2) and observation of spontaneous respirations (n = 1). The apnea test was aborted due to hypoxia and hypotension. After ancillary testing, death was declared in three patients based on neurologic criteria and in three patients based on cardiopulmonary criteria (after withdrawal of support (n = 2) or cardiopulmonary arrest (n = 1)). A family member was able to visit 5/6 patients prior to cardiopulmonary arrest/discontinuation of organ support. CONCLUSION: It is feasible to evaluate patients with catastrophic brain injury and declare brain death despite the Covid-19 pandemic, but this requires unique considerations.

Taking a Strohl Through History: Putting Strohl Back in Guillain-Barré-Strohl Syndrome.

Guillain-Barré Syndrome is a popular eponym that comes from a 1916 paper by Drs. Guillain, Barré, and Strohl. These physicians described two soldiers in the French Sixth Army during World War I who developed acute progressive motor weakness. Although Drs. Guillain and Barré have continued to be included in the syndrome's eponym, Dr. Strohl has been forgotten despite having strongly contributed to the original paper. The reasons previously mentioned for Dr. Strohl's absence appear trivial in contemporary practice and thus, his name deserves to be reintroduced to Guillain-Barré-Strohl Syndrome.