Corticothalamic Connectivity in Aneurysmal Subarachnoid Hemorrhage: Relationship with Disordered Consciousness and Clinical Outcomes.

BACKGROUND: We present an exploratory analysis of the occurrence of early corticothalamic connectivity disruption after aneurysmal subarachnoid hemorrhage (SAH) and its correlation with clinical outcomes. METHODS: We conducted a retrospective study of patients with acute SAH who underwent continuous electroencephalography (EEG) for impairment of consciousness. Only patients undergoing endovascular aneurysm treatment were included. Continuous EEG tracings were reviewed to obtain artifact-free segments. Power spectral analyses were performed, and segments were classified as A (only delta power), B (predominant delta and theta), C (predominant theta and beta), or D (predominant alpha and beta). Each incremental category from A to D implies greater preservation of corticothalamic connectivity. We dichotomized categories as AB for poor connectivity and CD for good connectivity. The modified Rankin Scale score at follow-up and in-hospital mortality were used as outcome measures. RESULTS: Sixty-nine patients were included, of whom 58 had good quality EEG segments for classification: 28 were AB and 30 were CD. Hunt and Hess and World Federation of Neurological Surgeons grades were higher and the initial Glasgow Coma Scale score was lower in the AB group compared with the CD group. AB classification was associated with an adjusted odds ratio of 5.71 (95% confidence interval 1.61-20.30; p < 0.01) for poor outcome (modified Rankin Scale score 4-6) at a median follow-up of 4 months (interquartile range 2-6) and an odds ratio of 5.6 (95% confidence interval 0.98-31.95; p = 0.03) for in-hospital mortality, compared with CD. CONCLUSIONS: EEG spectral-power-based classification demonstrates early corticothalamic connectivity disruption following aneurysmal SAH and may be a mechanism involved in early brain injury. Furthermore, the extent of this disruption appears to be associated with functional outcome and in-hospital mortality in patients with aneurysmal SAH and appears to be a potentially useful predictive tool that must be validated prospectively.

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

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.

Incidence, Implications, and Management of Seizures Following Ischemic and Hemorrhagic Stroke.

PURPOSE OF REVIEW: In this review, we summarize the recent literature regarding the incidence and treatment of seizures arising after ischemic and hemorrhagic strokes. Additionally, we identify open questions in guidelines and standard clinical care to aid future studies aiming to improve management of seizures in post-stroke patients. RECENT FINDINGS: Studies demonstrate an increasing prevalence of seizures following strokes, probably a consequence of advances in post-stroke management and expanding use of continuous EEG monitoring. Post-stroke seizures are associated with longer hospitalization and increased mortality; therefore, prevention and timely treatment of seizures are important. The standard of care is to treat recurrent seizures with anti-epileptic drugs (AEDs) regardless of the etiology. However, there are no established guidelines currently for prophylactic use of AEDs following a stroke. The prevalence of post-stroke seizures is increasing. Further studies are needed to determine the risk factors for recurrent seizures and epilepsy after strokes and optimal treatment strategies.

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

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.

Association of Seizure Occurrence with Aneurysm Treatment Modality in Aneurysmal Subarachnoid Hemorrhage Patients.

BACKGROUND: Data on new-onset seizures after treatment of aneurysmal subarachnoid hemorrhage (aSAH) patients are limited and variable. We examined the association between new-onset seizures after aSAH and aneurysm treatment modality, as well their relationship with initial clinical severity of aSAH and outcomes. METHODS: This is a retrospective cohort study of all aSAH patients admitted to our institution over a 6-year period. 'Seizures' were defined as any observed clinical seizure or electrographic seizure on continuous electroencephalogram (cEEG) recordings, as determined by the reviewing neurophysiologist. Subgroup analyses were performed in low-grade (Hunt-Hess 1-3) and high-grade (Hunt-Hess 4-5) patients. Outcomes measures were Glasgow Coma Score (GCS) at intensive care unit (ICU) discharge and modified Rankin Scale (mRS) at outpatient follow-up. RESULTS: There were 282 patients with aSAH; 203 (72.0%) suffered low-grade and 79 (28%) high-grade aSAH. Patients were treated with endovascular coiling (N = 194, 68.8%) or surgical clipping (N = 66, 23.4%). Eighteen (6.4%) patients had seizures, of whom 10 (5.5%) had aneurysm coiling and 7 (10.6%) underwent clipping (p = 0.15). In low-grade patients, seizures occurred less frequently (p = 0.016) and were more common after surgical clipping (p = 0.0089). Seizures correlated with lower GCS upon ICU discharge (p < 0.001), in clipped (p = 0.011) and coiled (p < 0.001) patients and in low-grade aSAH (p < 0.001). Seizures correlated with higher mRS on follow-up (p < 0.001), in clipped (p = 0.032) and coiled (p = 0.004) patients and in low-grade aSAH (p = 0.003). CONCLUSIONS: New-onset seizures after aSAH occurred infrequently, and their incidence after aneurysm clipping versus coiling was not significantly different. However, in low-grade patients, new seizures were more frequently associated with clipping than coiling. Additionally, non-convulsive seizures did not occur in low-grade patients treated with coiling. These findings may explain, in part, previous work suggesting better outcomes in coiled patients and encourage physicians to have a lower threshold for cEEG utilization in low-grade patients suspected to have acute seizures after surgical clipping.

Preservation of electroencephalographic organization in patients with impaired consciousness and imaging-based evidence of command-following.

OBJECTIVE: Standard clinical characterization of patients with disorders of consciousness (DOC) relies on observation of motor output and may therefore lead to the misdiagnosis of vegetative state or minimally conscious state in patients with preserved cognition. We used conventional electroencephalographic (EEG) measures to assess a cohort of DOC patients with and without functional magnetic resonance imaging (fMRI)-based evidence of command-following, and correlated the findings with standard clinical behavioral evaluation and brain metabolic activity. METHODS: We enrolled 44 patients with severe brain injury. Behavioral diagnosis was established using standardized clinical assessments. Long-term EEG recordings were analyzed to determine wakeful background organization and presence of elements of sleep architecture. A subset of patients had fMRI testing of command-following using motor imagery paradigms (26 patients) and resting brain metabolism measurement using (18) fluorodeoxyglucose positron emission tomography (31 patients). RESULTS: All 4 patients with fMRI evidence of covert command-following consistently demonstrated well-organized EEG background during wakefulness, spindling activity during sleep, and relative preservation of cortical metabolic activity. In the entire cohort, EEG organization and overall brain metabolism showed no significant association with bedside behavioral testing, except in a few cases when EEG was severely abnormal. INTERPRETATION: These findings suggest that conventional EEG is a simple strategy that complements behavioral and imaging characterization of DOC patients. Preservation of specific EEG features may be used to assess the likelihood of unrecognized cognitive abilities in severely brain-injured patients with very limited or no motor responses.

EEG Pattern With Spectral Analysis Can Prognosticate Good and Poor Neurologic Outcomes After Cardiac Arrest.

PURPOSE: To investigate the prognostic value of a simple stratification system of electroencephalographical (EEG) patterns and spectral types for patients after cardiac arrest. METHODS: In this prospectively enrolled cohort, using manually selected EEG segments, patients after cardiac arrest were stratified into five independent EEG patterns (based on background continuity and burden of highly epileptiform discharges) and four independent power spectral types (based on the presence of frequency components). The primary outcome is cerebral performance category (CPC) at discharge. Results from multimodal prognostication testing were included for comparison. RESULTS: Of a total of 72 patients, 6 had CPC 1-2 by discharge, all of whom had mostly continuous EEG background without highly epileptiform activity at day 3. However, for the same EEG background pattern at day 3, 19 patients were discharged at CPC 3 and 15 patients at CPC 4-5. After adding spectral analysis, overall sensitivity for predicting good outcomes (CPC 1-2) was 83.3% (95% confidence interval 35.9% to 99.6%) and specificity was 97.0% (89.5% to 99.6%). In this cohort, standard prognostication testing all yielded 100% specificity but low sensitivity, with imaging being the most sensitive at 54.1% (36.9% to 70.5%). CONCLUSIONS: Adding spectral analysis to qualitative EEG analysis may further improve the diagnostic accuracy of EEG and may aid developing novel measures linked to good outcomes in postcardiac arrest coma.

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

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.

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.

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.

Dynamic regimes of neocortical activity linked to corticothalamic integrity correlate with outcomes in acute anoxic brain injury after cardiac arrest.

OBJECTIVE: Recognition of potential for neurological recovery in patients who remain comatose after cardiac arrest is challenging and strains clinical decision making. Here, we utilize an approach that is based on physiological principles underlying recovery of consciousness and show correlation with clinical recovery after acute anoxic brain injury. METHODS: A cohort study of 54 patients admitted to an Intensive Care Unit after cardiac arrest who underwent standardized bedside behavioral testing (Coma Recovery Scale - Revised [CRS-R]) during EEG monitoring. Blinded to all clinical variables, artifact-free EEG segments were selected around maximally aroused states and analyzed using a multi-taper method to assess frequency spectral content. EEG spectral features were assessed based on pre-defined categories that are linked to anterior forebrain corticothalamic integrity. Clinical outcomes were determined at the time of hospital discharge, using Cerebral Performance Categories (CPC). RESULTS: Ten patients with ongoing seizures, myogenic artifacts or technical limitations obscuring recognition of underlying cortical dynamic activity were excluded from primary analysis. Of the 44 remaining patients with distinct EEG spectral features, 39 (88%) fit into our predefined categories. In these patients, spectral features corresponding to higher levels of anterior forebrain corticothalamic integrity correlated with higher levels of consciousness and favorable clinical outcome at the time of hospital discharge (P = 0.014). INTERPRETATION: Predicted transitions of neocortical dynamics that indicate functional integrity of anterior forebrain corticothalamic circuitry correlate with clinical outcomes in postcardiac-arrest patients. Our results support a new biologically driven approach toward better understanding of neurological recovery after cardiac arrest.

Isolation Syndrome after Cardiac Arrest and Therapeutic Hypothermia.

Here, we present the first description of an isolation syndrome in a patient who suffered prolonged cardiac arrest and underwent a standard therapeutic hypothermia protocol. Two years after the arrest, the patient demonstrated no motor responses to commands, communication capabilities, or visual tracking at the bedside. However, resting neuronal metabolism and electrical activity across the entire anterior forebrain was found to be normal despite severe structural injuries to primary motor, parietal, and occipital cortices. In addition, using quantitative electroencephalography, the patient showed evidence for willful modulation of brain activity in response to auditory commands revealing covert conscious awareness. A possible explanation for this striking dissociation in this patient is that altered neuronal recovery patterns following therapeutic hypothermia may lead to a disproportionate preservation of anterior forebrain cortico-thalamic circuits even in the setting of severe hypoxic injury to other brain areas. Compared to recent reports of other severely brain-injured subjects with such dissociation of clinically observable (overt) and covert behaviors, we propose that this case represents a potentially generalizable mechanism producing an isolation syndrome of blindness, motor paralysis, and retained cognition as a sequela of cardiac arrest and therapeutic hypothermia. Our findings further support that highly-preserved anterior cortico-thalamic integrity is associated with the presence of conscious awareness independent from the degree of injury to other brain areas.

Perisaccadic parietal and occipital gamma power in light and in complete darkness.

Our objective was to determine perisaccadic gamma range oscillations in the EEG during voluntary saccades in humans. We evaluated occipital perisaccadic gamma activity both in the presence and absence of visual input, when the observer was blindfolded. We quantified gamma power in the time periods before, during, and after horizontal saccades. The corresponding EEG was evaluated for individual saccades and the wavelet transformed EEG averaged for each time window, without averaging the EEG first. We found that, in both dark and light, parietal and occipital gamma power increased during the saccade and peaked prior to reaching new fixation. We show that this is not the result of muscle activity and not the result of visual input during saccades. Saccade direction affects the laterality of gamma power over posterior electrodes. Gamma power recorded over the posterior scalp increases during a saccade. The phasic modulation of gamma by saccades in darkness--when occipital activity is decoupled from visual input--provides electrophysiological evidence that voluntary saccades affect ongoing EEG. We suggest that saccade-phasic gamma modulation may contribute to short-term plasticity required to realign the visual space to the intended fixation point of a saccade and provides a mechanism for neuronal assembly formation prior to achieving the intended saccadic goal. The wavelet-transformed perisaccadic EEG could provide an electrophysiological tool applicable in humans for the purpose of fine analysis and potential separation of stages of 'planning' and 'action'.