Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli.

Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions1,2; however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC neurons3-6, where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here we demonstrate that dopamine increases the signal-to-noise ratio of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal grey (dPAG). Using an electrochemical approach, we reveal the precise time course of pinch-evoked dopamine release in the mPFC, and show that mPFC dopamine biases behavioural responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviours. mPFC-dPAG neurons display robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of dopamine terminals in the mPFC reveals an increase in the signal-to-noise ratio in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how dopamine in the mPFC can selectively route sensory information to specific downstream circuits, representing a potential circuit mechanism for valence processing.

Learned Motor Patterns Are Replayed in Human Motor Cortex during Sleep.

Consolidation of memory is believed to involve offline replay of neural activity. While amply demonstrated in rodents, evidence for replay in humans, particularly regarding motor memory, is less compelling. To determine whether replay occurs after motor learning, we sought to record from motor cortex during a novel motor task and subsequent overnight sleep. A 36-year-old man with tetraplegia secondary to cervical spinal cord injury enrolled in the ongoing BrainGate brain-computer interface pilot clinical trial had two 96-channel intracortical microelectrode arrays placed chronically into left precentral gyrus. Single- and multi-unit activity was recorded while he played a color/sound sequence matching memory game. Intended movements were decoded from motor cortical neuronal activity by a real-time steady-state Kalman filter that allowed the participant to control a neurally driven cursor on the screen. Intracortical neural activity from precentral gyrus and 2-lead scalp EEG were recorded overnight as he slept. When decoded using the same steady-state Kalman filter parameters, intracortical neural signals recorded overnight replayed the target sequence from the memory game at intervals throughout at a frequency significantly greater than expected by chance. Replay events occurred at speeds ranging from 1 to 4 times as fast as initial task execution and were most frequently observed during slow-wave sleep. These results demonstrate that recent visuomotor skill acquisition in humans may be accompanied by replay of the corresponding motor cortex neural activity during sleep.SIGNIFICANCE STATEMENT Within cortex, the acquisition of information is often followed by the offline recapitulation of specific sequences of neural firing. Replay of recent activity is enriched during sleep and may support the consolidation of learning and memory. Using an intracortical brain-computer interface, we recorded and decoded activity from motor cortex as a human research participant performed a novel motor task. By decoding neural activity throughout subsequent sleep, we find that neural sequences underlying the recently practiced motor task are repeated throughout the night, providing direct evidence of replay in human motor cortex during sleep. This approach, using an optimized brain-computer interface decoder to characterize neural activity during sleep, provides a framework for future studies exploring replay, learning, and memory.

Associations between early in-hospital medications and the development of delirium in patients with stroke.

OBJECTIVES: Patients hospitalized with stroke develop delirium at higher rates than general hospitalized patients. While several medications are associated with existing delirium, it is unknown whether early medication exposures are associated with subsequent delirium in patients with stroke. Additionally, it is unknown whether delirium identification is associated with changes in the prescription of these medications. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients admitted to a comprehensive stroke center, who were assessed for delirium by trained nursing staff during clinical care. We analyzed exposures to multiple medication classes in the first 48 h of admission, and compared them between patients who developed delirium >48 hours after admission and those who never developed delirium. Statistical analysis was performed using univariate testing. Multivariable logistic regression was used further to evaluate the significance of univariately significant medications, while controlling for clinical confounders. RESULTS: 1671 unique patients were included in the cohort, of whom 464 (27.8%) developed delirium >48 hours after admission. Delirium was associated with prior exposure to antipsychotics, sedatives, opiates, and antimicrobials. Antipsychotics, sedatives, and antimicrobials remained significantly associated with delirium even after accounting for several clinical covariates. Usage of these medications decreased in the 48 hours following delirium identification, except for atypical antipsychotics, whose use increased. Other medication classes such as steroids, benzodiazepines, and sleep aids were not initially associated with subsequent delirium, but prescription patterns still changed after delirium identification. CONCLUSIONS: Early exposure to multiple medication classes is associated with the subsequent development of delirium in patients with stroke. Additionally, prescription patterns changed following delirium identification, suggesting that some of the associated medication classes may represent modifiable targets for future delirium prevention strategies, although future study is needed.

Physiological Assessment of Delirium Severity: The Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S).

OBJECTIVES: Delirium is a common and frequently underdiagnosed complication in acutely hospitalized patients, and its severity is associated with worse clinical outcomes. We propose a physiologically based method to quantify delirium severity as a tool that can help close this diagnostic gap: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S). DESIGN: Retrospective cohort study. SETTING: Single-center tertiary academic medical center. PATIENTS: Three-hundred seventy-three adult patients undergoing electroencephalography to evaluate altered mental status between August 2015 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed the E-CAM-S based on a learning-to-rank machine learning model of forehead electroencephalography signals. Clinical delirium severity was assessed using the Confusion Assessment Method Severity (CAM-S). We compared associations of E-CAM-S and CAM-S with hospital length of stay and inhospital mortality. E-CAM-S correlated with clinical CAM-S (R = 0.67; p < 0.0001). For the overall cohort, E-CAM-S and CAM-S were similar in their strength of association with hospital length of stay (correlation = 0.31 vs 0.41, respectively; p = 0.082) and inhospital mortality (area under the curve = 0.77 vs 0.81; p = 0.310). Even when restricted to noncomatose patients, E-CAM-S remained statistically similar to CAM-S in its association with length of stay (correlation = 0.37 vs 0.42, respectively; p = 0.188) and inhospital mortality (area under the curve = 0.83 vs 0.74; p = 0.112). In addition to previously appreciated spectral features, the machine learning framework identified variability in multiple measures over time as important features in electroencephalography-based prediction of delirium severity. CONCLUSIONS: The E-CAM-S is an automated, physiologic measure of delirium severity that predicts clinical outcomes with a level of performance comparable to conventional interview-based clinical assessment.

Electroencephalographic Abnormalities are Common in COVID-19 and are Associated with Outcomes.

OBJECTIVE: The aim was to determine the prevalence and risk factors for electrographic seizures and other electroencephalographic (EEG) patterns in patients with Coronavirus disease 2019 (COVID-19) undergoing clinically indicated continuous electroencephalogram (cEEG) monitoring and to assess whether EEG findings are associated with outcomes. METHODS: We identified 197 patients with COVID-19 referred for cEEG at 9 participating centers. Medical records and EEG reports were reviewed retrospectively to determine the incidence of and clinical risk factors for seizures and other epileptiform patterns. Multivariate Cox proportional hazards analysis assessed the relationship between EEG patterns and clinical outcomes. RESULTS: Electrographic seizures were detected in 19 (9.6%) patients, including nonconvulsive status epilepticus (NCSE) in 11 (5.6%). Epileptiform abnormalities (either ictal or interictal) were present in 96 (48.7%). Preceding clinical seizures during hospitalization were associated with both electrographic seizures (36.4% in those with vs 8.1% in those without prior clinical seizures, odds ratio [OR] 6.51, p = 0.01) and NCSE (27.3% vs 4.3%, OR 8.34, p = 0.01). A pre-existing intracranial lesion on neuroimaging was associated with NCSE (14.3% vs 3.7%; OR 4.33, p = 0.02). In multivariate analysis of outcomes, electrographic seizures were an independent predictor of in-hospital mortality (hazard ratio [HR] 4.07 [1.44-11.51], p < 0.01). In competing risks analysis, hospital length of stay increased in the presence of NCSE (30 day proportion discharged with vs without NCSE: HR 0.21 [0.03-0.33] vs 0.43 [0.36-0.49]). INTERPRETATION: This multicenter retrospective cohort study demonstrates that seizures and other epileptiform abnormalities are common in patients with COVID-19 undergoing clinically indicated cEEG and are associated with adverse clinical outcomes. ANN NEUROL 2021;89:872-883.

Associations Between Stroke Localization and Delirium: A Systematic Review and Meta-Analysis.

OBJECTIVES: Delirium is common among patients with acute stroke and associated with worse outcomes. However, it is unclear which stroke locations or types are most associated with delirium. MATERIALS AND METHODS: We systematically reviewed studies of patients with acute stroke that reported stroke locations and types by delirium status. We included papers in any language, through a combined search from January 2010 to June 2021. Case studies with less than 20 patients, case-control studies, and randomized controlled trials were excluded. MEDLINE, EMBASE, PsycINFO, CINAHL, and Alois databases were searched. Pooled relative risks were calculated using bivariate random effects models or network meta-analysis. Methodological quality was assessed across 8 factors. RESULTS: 31 patient samples representing 8329 patients were included. Delirium was more common in patients with supratentorial lesions than infratentorial (RR [Relative Risk] 2.01, CI [Confidence Interval] 1.49-2.72); anterior circulation lesions than posterior (RR 1.41, CI 1.13-1.78); and cortical lesions than subcortical (RR 1.54, CI 1.25-1.89). Stroke side was not associated with delirium (right vs. left: RR 0.99, CI 0.77-1.28). Delirium was more common in patients with hemorrhagic strokes than ischemic (RR 1.74, CI 1.42-2.11) and patients with preexisting qualitative atrophy (RR 1.66, CI 1.21-2.27). CONCLUSION: Several brain localizations and types of strokes were associated with delirium. Conclusions were in part limited by the heterogeneity of studies and broad or qualitative lesion descriptions. These results may assist in anticipating the risk of delirium in acute stroke and highlight brain networks and pathologies that may be involved in the pathophysiology of delirium.

Evaluation and Management of Delirium.

Delirium, sometimes referred to as encephalopathy, is an acute confusional state that is both common in hospitalized patients and associated with poor outcomes. For patients, families, and caregivers, delirium can be a traumatic experience. While delirium is one of the most common diagnoses encountered by the consulting neurologist, the majority of the time it will have been previously unrecognized as such by the care team. Neurologic syndromes such as dementia or aphasia can either be misdiagnosed as delirium or may coexist with it, necessitating careful neurologic assessment. Once the diagnosis of delirium has been established, a careful evaluation for predisposing and precipitating factors can help uncover modifiable contributors, which should be addressed as part of a multicomponent, primarily nonpharmacologic intervention. Importantly, delirium management, which begins with comprehensive prevention, should emphasize the humanity of the delirious patient and the challenges of caring for this vulnerable population. When considered, delirium represents an important opportunity for the neurologist to substantially enhance patient care.

Accurate detection of spontaneous seizures using a generalized linear model with external validation.

OBJECTIVE: Seizure detection is a major facet of electroencephalography (EEG) analysis in neurocritical care, epilepsy diagnosis and management, and the instantiation of novel therapies such as closed-loop stimulation or optogenetic control of seizures. It is also of increased importance in high-throughput, robust, and reproducible pre-clinical research. However, seizure detectors are not widely relied upon in either clinical or research settings due to limited validation. In this study, we create a high-performance seizure-detection approach, validated in multiple data sets, with the intention that such a system could be available to users for multiple purposes. METHODS: We introduce a generalized linear model trained on 141 EEG signal features for classification of seizures in continuous EEG for two data sets. In the first (Focal Epilepsy) data set consisting of 16 rats with focal epilepsy, we collected 1012 spontaneous seizures over 3 months of 24/7 recording. We trained a generalized linear model on the 141 features representing 20 feature classes, including univariate and multivariate, linear and nonlinear, time, and frequency domains. We tested performance on multiple hold-out test data sets. We then used the trained model in a second (Multifocal Epilepsy) data set consisting of 96 rats with 2883 spontaneous multifocal seizures. RESULTS: From the Focal Epilepsy data set, we built a pooled classifier with an Area Under the Receiver Operating Characteristic (AUROC) of 0.995 and leave-one-out classifiers with an AUROC of 0.962. We validated our method within the independently constructed Multifocal Epilepsy data set, resulting in a pooled AUROC of 0.963. We separately validated a model trained exclusively on the Focal Epilepsy data set and tested on the held-out Multifocal Epilepsy data set with an AUROC of 0.890. Latency to detection was under 5 seconds for over 80% of seizures and under 12 seconds for over 99% of seizures. SIGNIFICANCE: This method achieves the highest performance published for seizure detection on multiple independent data sets. This method of seizure detection can be applied to automated EEG analysis pipelines as well as closed loop interventional approaches, and can be especially useful in the setting of research using animals in which there is an increased need for standardization and high-throughput analysis of large number of seizures.

Reward contingency gates selective cholinergic suppression of amygdala neurons.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward - even prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex. Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling, while also facilitating firing in BLA GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

Scaling behaviours of deep learning and linear algorithms for the prediction of stroke severity.

Deep learning has allowed for remarkable progress in many medical scenarios. Deep learning prediction models often require 105-107 examples. It is currently unknown whether deep learning can also enhance predictions of symptoms post-stroke in real-world samples of stroke patients that are often several magnitudes smaller. Such stroke outcome predictions however could be particularly instrumental in guiding acute clinical and rehabilitation care decisions. We here compared the capacities of classically used linear and novel deep learning algorithms in their prediction of stroke severity. Our analyses relied on a total of 1430 patients assembled from the MRI-Genetics Interface Exploration collaboration and a Massachusetts General Hospital-based study. The outcome of interest was National Institutes of Health Stroke Scale-based stroke severity in the acute phase after ischaemic stroke onset, which we predict by means of MRI-derived lesion location. We automatically derived lesion segmentations from diffusion-weighted clinical MRI scans, performed spatial normalization and included a principal component analysis step, retaining 95% of the variance of the original data. We then repeatedly separated a train, validation and test set to investigate the effects of sample size; we subsampled the train set to 100, 300 and 900 and trained the algorithms to predict the stroke severity score for each sample size with regularized linear regression and an eight-layered neural network. We selected hyperparameters on the validation set. We evaluated model performance based on the explained variance (R2) in the test set. While linear regression performed significantly better for a sample size of 100 patients, deep learning started to significantly outperform linear regression when trained on 900 patients. Average prediction performance improved by ∼20% when increasing the sample size 9× [maximum for 100 patients: 0.279 ± 0.005 (R2, 95% confidence interval), 900 patients: 0.337 ± 0.006]. In summary, for sample sizes of 900 patients, deep learning showed a higher prediction performance than typically employed linear methods. These findings suggest the existence of non-linear relationships between lesion location and stroke severity that can be utilized for an improved prediction performance for larger sample sizes.

Potentiated cholinergic and corticofugal inputs support reorganized sensory processing in the basolateral amygdala during auditory threat acquisition and retrieval.

Reappraising neutral stimuli as environmental threats reflects rapid and discriminative changes in sensory processing within the basolateral amygdala (BLA). To understand how BLA inputs are also reorganized during discriminative threat learning, we performed multi-regional measurements of acetylcholine (ACh) release, single unit spiking, and functional coupling in the mouse BLA and higher-order auditory cortex (HO-AC). During threat memory recall, sounds paired with shock (CS+) elicited relatively higher firing rates in BLA units and optogenetically targeted corticoamygdalar (CAmy) units, though not in neighboring HO-AC units. Functional coupling was potentiated for descending CAmy projections prior to and during CS+ threat memory recall but ascending amygdalocortical coupling was unchanged. During threat acquisition, sound-evoked ACh release was selectively enhanced for the CS+ in BLA but not HO-AC. These findings suggest that phasic cholinergic inputs facilitate discriminative plasticity in the BLA during threat acquisition that is subsequently reinforced through potentiated auditory corticofugal inputs during memory recall.

Potentiation of cholinergic and corticofugal inputs to the lateral amygdala in threat learning.

The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.

Giant Cell Arteritis Presenting With Multiple Cranial Neuropathies - Case Report.

Background: Vision loss accounts for most ophthalmic presentations of giant cell arteritis (GCA), but an important minority of patients present with diplopia and other cranial neuropathies. Case study: Here we present the case of an 84-year-old woman with a prior history of multiple cancers who was admitted to our hospital after developing double vision. She was found to have mydriasis, ptosis, and ophthalmoplegia in the right eye (OD) consistent with a combined R CNIII/CNVI neuropathy, as well as highly elevated inflammatory markers. Given her cancer history, the patient was initially worked up for various neoplastic, paraneoplastic, inflammatory, and infectious causes of multiple cranial neuropathies; however, as these results were negative, GCA became a more likely contender as a possible rare cause of multiple cranial neuropathies. The patient underwent temporal artery biopsy which showed pathology consistent with giant cell arteritis, and she was treated with steroids with eventual improvement in ophthalmoplegia and ptosis. Conclusions: This case illustrates the importance of recognizing GCA as a rare possible cause of multiple cranial neuropathies, including the indispensable role of temporal artery biopsy.

Thalamus sends information about arousal but not valence to the amygdala.

RATIONALE: The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. OBJECTIVES: We seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. METHODS: Here, we use optogenetics and in vivo electrophysiological recordings to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. RESULTS: We find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. CONCLUSION: We conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified.

Automated detection of immune effector cell-associated neurotoxicity syndrome via quantitative EEG.

OBJECTIVE: To develop an automated, physiologic metric of immune effector cell-associated neurotoxicity syndrome among patients undergoing chimeric antigen receptor-T cell therapy. METHODS: We conducted a retrospective observational cohort study from 2016 to 2020 at two tertiary care centers among patients receiving chimeric antigen receptor-T cell therapy with a CD19 or B-cell maturation antigen ligand. We determined the daily neurotoxicity grade for each patient during EEG monitoring via chart review and extracted clinical variables and outcomes from the electronic health records. Using quantitative EEG features, we developed a machine learning model to detect the presence and severity of neurotoxicity, known as the EEG immune effector cell-associated neurotoxicity syndrome score. RESULTS: The EEG immune effector cell-associated neurotoxicity syndrome score significantly correlated with the grade of neurotoxicity with a median Spearman's R2 of 0.69 (95% CI of 0.59-0.77). The mean area under receiving operator curve was greater than 0.85 for each binary discrimination level. The score also showed significant correlations with maximum ferritin (R2 0.24, p = 0.008), minimum platelets (R2 -0.29, p = 0.001), and dexamethasone usage (R2 0.42, p < 0.0001). The score significantly correlated with duration of neurotoxicity (R2 0.31, p < 0.0001). INTERPRETATION: The EEG immune effector cell-associated neurotoxicity syndrome score possesses high criterion, construct, and predictive validity, which substantiates its use as a physiologic method to detect the presence and severity of neurotoxicity among patients undergoing chimeric antigen receptor T-cell therapy.

VE-CAM-S: Visual EEG-Based Grading of Delirium Severity and Associations With Clinical Outcomes.

To develop a physiologic grading system for the severity of acute encephalopathy manifesting as delirium or coma, based on EEG, and to investigate its association with clinical outcomes. DESIGN: This prospective, single-center, observational cohort study was conducted from August 2015 to December 2016 and October 2018 to December 2019. SETTING: Academic medical center, all inpatient wards. PATIENTS/SUBJECTS: Adult inpatients undergoing a clinical EEG recording; excluded if deaf, severely aphasic, developmentally delayed, non-English speaking (if noncomatose), or if goals of care focused primarily on comfort measures. Four-hundred six subjects were assessed; two were excluded due to technical EEG difficulties. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A machine learning model, with visually coded EEG features as inputs, was developed to produce scores that correlate with behavioral assessments of delirium severity (Confusion Assessment Method-Severity [CAM-S] Long Form [LF] scores) or coma; evaluated using Spearman R correlation; area under the receiver operating characteristic curve (AUC); and calibration curves. Associations of Visual EEG Confusion Assessment Method Severity (VE-CAM-S) were measured for three outcomes: functional status at discharge (via Glasgow Outcome Score [GOS]), inhospital mortality, and 3-month mortality. Four-hundred four subjects were analyzed (mean [sd] age, 59.8 yr [17.6 yr]; 232 [57%] male; 320 [79%] White; 339 [84%] non-Hispanic); 132 (33%) without delirium or coma, 143 (35%) with delirium, and 129 (32%) with coma. VE-CAM-S scores correlated strongly with CAM-S scores (Spearman correlation 0.67 [0.62-0.73]; p < 0.001) and showed excellent discrimination between levels of delirium (CAM-S LF = 0 vs ≥ 4, AUC 0.85 [0.78-0.92], calibration slope of 1.04 [0.87-1.19] for CAM-S LF ≤ 4 vs ≥ 5). VE-CAM-S scores were strongly associated with important clinical outcomes including inhospital mortality (AUC 0.79 [0.72-0.84]), 3-month mortality (AUC 0.78 [0.71-0.83]), and GOS at discharge (0.76 [0.69-0.82]). CONCLUSIONS: VE-CAM-S is a physiologic grading scale for the severity of symptoms in the setting of delirium and coma, based on visually assessed electroencephalography features. VE-CAM-S scores are strongly associated with clinical outcomes.

EEG-based grading of immune effector cell-associated neurotoxicity syndrome.

CAR-T cell therapy is an effective cancer therapy for multiple refractory/relapsed hematologic malignancies but is associated with substantial toxicity, including Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Improved detection and assessment of ICANS could improve management and allow greater utilization of CAR-T cell therapy, however, an objective, specific biomarker has not been identified. We hypothesized that the severity of ICANS can be quantified based on patterns of abnormal brain activity seen in electroencephalography (EEG) signals. We conducted a retrospective observational study of 120 CAR-T cell therapy patients who had received EEG monitoring. We determined a daily ICANS grade for each patient through chart review. We used visually assessed EEG features and machine learning techniques to develop the Visual EEG-Immune Effector Cell Associated Neurotoxicity Syndrome (VE-ICANS) score and assessed the association between VE-ICANS and ICANS. We also used it to determine the significance and relative importance of the EEG features. We developed the Visual EEG-ICANS (VE-ICANS) grading scale, a grading scale with a physiological basis that has a strong correlation to ICANS severity (R = 0.58 [0.47-0.66]) and excellent discrimination measured via area under the receiver operator curve (AUC = 0.91 for ICANS ≥ 2). This scale shows promise as a biomarker for ICANS which could help to improve clinical care through greater accuracy in assessing ICANS severity.

Clinical Electroencephalography Findings and Considerations in Hospitalized Patients With Coronavirus SARS-CoV-2.

BACKGROUND AND PURPOSE: Reports have suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes neurologic manifestations including encephalopathy and seizures. However, there has been relatively limited electrophysiology data to contextualize these specific concerns and to understand their associated clinical factors. Our objective was to identify EEG abnormalities present in patients with SARS-CoV-2, and to determine whether they reflect new or preexisting brain pathology. METHODS: We studied a consecutive series of hospitalized patients with SARS-CoV-2 who received an EEG, obtained using tailored safety protocols. Data from EEG reports and clinical records were analyzed to identify EEG abnormalities and possible clinical associations, including neurologic symptoms, new or preexisting brain pathology, and sedation practices. RESULTS: We identified 37 patients with SARS-CoV-2 who underwent EEG, of whom 14 had epileptiform findings (38%). Patients with epileptiform findings were more likely to have preexisting brain pathology (6/14, 43%) than patients without epileptiform findings (2/23, 9%; p = 0.042). There were no clear differences in rates of acute brain pathology. One case of nonconvulsive status epilepticus was captured, but was not clearly a direct consequence of SARS-CoV-2. Abnormalities of background rhythms were common, as may be seen in systemic illness, and in part associated with recent sedation (p = 0.022). CONCLUSIONS: Epileptiform abnormalities were common in patients with SARS-CoV-2 referred for EEG, but particularly in the context of preexisting brain pathology and sedation. These findings suggest that neurologic manifestations during SARS-CoV-2 infection may not solely relate to the infection itself, but rather may also reflect patients' broader, preexisting neurologic vulnerabilities.

A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes.

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its rostrocaudal axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from rostral and caudal BFCNs over a 1-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Rostral BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Caudal tail BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.