Neural oscillations track recovery of consciousness in acute traumatic brain injury patients.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

Sedation-Induced Burst Suppression Predicts Positive Outcome Following Traumatic Brain Injury.

While electroencephalogram (EEG) burst-suppression is often induced therapeutically using sedatives in the intensive care unit (ICU), there is hitherto no evidence with respect to its association to outcome in moderate-to-severe neurological patients. We examined the relationship between sedation-induced burst-suppression (SIBS) and outcome at hospital discharge and at 6-month follow up in patients surviving moderate-to-severe traumatic brain injury (TBI). For each of 32 patients recovering from coma after moderate-to-severe TBI, we measured the EEG burst suppression ratio (BSR) during periods of low responsiveness as assessed with the Glasgow Coma Scale (GCS). The maximum BSR was then used to predict the Glasgow Outcome Scale extended (GOSe) at discharge and at 6 months post-injury. A multi-model inference approach was used to assess the combination of predictors that best fit the outcome data. We found that BSR was positively associated with outcomes at 6 months (P = 0.022) but did not predict outcomes at discharge. A mediation analysis found no evidence that BSR mediates the effects of barbiturates or propofol on outcomes. Our results provide initial observational evidence that burst suppression may be neuroprotective in acute patients with TBI etiologies. SIBS may thus be useful in the ICU as a prognostic biomarker.

The subcortical basis of outcome and cognitive impairment in TBI: A longitudinal cohort study.

OBJECTIVE: To understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at 6 months after injury. METHODS: For this longitudinal analysis, clinical and MRI data were collected in a tertiary neurointensive care setting in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient, we collected T1- and T2-weighted MRI data acutely and at the 6-month follow-up, as well as acute measures of injury severity (Glasgow Coma Scale), follow-up measures of functional impairment (Glasgow Outcome Scale-extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory. RESULTS: In the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first 6 months after injury across the brain. However, only atrophy within subcortical regions, particularly in the left thalamus, was associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good from bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could achieve only 20% accuracy. CONCLUSION: Despite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute event and the longer-term disease of traumatic brain injury.

Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study.

BACKGROUND: Traumatic brain injury (TBI) causes early seizures and is the leading cause of post-traumatic epilepsy. We prospectively assessed structural imaging biomarkers differentiating patients who develop seizures secondary to TBI from patients who do not. DESIGN: Multicentre prospective cohort study starting in 2018. Imaging data are acquired around day 14 post-injury, detection of seizure events occurred early (within 1 week) and late (up to 90 days post-TBI). RESULTS: From a sample of 96 patients surviving moderate-to-severe TBI, we performed shape analysis of local volume deficits in subcortical areas (analysable sample: 57 patients; 35 no seizure, 14 early, 8 late) and cortical ribbon thinning (analysable sample: 46 patients; 29 no seizure, 10 early, 7 late). Right hippocampal volume deficit and inferior temporal cortex thinning demonstrated a significant effect across groups. Additionally, the degree of left frontal and temporal pole thinning, and clinical score at the time of the MRI, could differentiate patients experiencing early seizures from patients not experiencing them with 89% accuracy. CONCLUSIONS AND RELEVANCE: Although this is an initial report, these data show that specific areas of localised volume deficit, as visible on routine imaging data, are associated with the emergence of seizures after TBI.

Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study.

OBJECTIVE: Injury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (PTE). However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE. METHODS: We assessed early seizure incidence (n = 90) and longitudinal development of PTE (n = 46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2 years post-injury. RESULTS: Early seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n = 90). Within the cohort of subjects who had evidence of early seizures (n = 24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n = 46), 45.7% of patients developed PTE within a minimum of 2 years post-injury. Within the cohort of subjects who developed PTE (n = 21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n = 21) were more likely than patients who did not develop PTE (n = 25) to have a hemorrhagic temporal lobe injury (p < 0.001), worse functional recovery (p = 0.003), and greater temporal lobe atrophy (p = 0.029). CONCLUSION: Our results indicate that in a cohort of patients with a moderate-severe TBI, 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of PTE, 2) early seizures, whether convulsive or non-convulsive in nature, are associated with an increased risk for PTE development, and 3) patients who develop PTE have greater chronic temporal lobe atrophy and worse functional outcomes, compared to those who do not develop PTE, despite matched injury severity characteristics. This study provides the foundation for a future prospective study focused on elucidating the mechanisms and risk factors for epileptogenesis.

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.