EEG to detect early recovery of consciousness in amantadine-treated acute brain injury patients

Alkhachroum, Ayham; Eliseyev, Andrey; Rubiños, Clio; Kromm, Julie; Mathews, Elizabeth; Bauerschmidt, Andrew; Doyle, Kevin; Velasquez, Angela; Egbebike, Jennifer; Calderon, Anna R; Roh, David; Park, Soo‐Jin; Agarwal, Sachin; Connolly, E. Sander; Claassen, Jan

doi:10.1136/jnnp-2019-322645

Cited by 28 publications

(26 citation statements)

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“…Initial results suggest that amantadine is well-tolerated in patients in the ICU with acute DoC 197 , but evidence for efficacy is lacking 195 , 196 . Reproducible EEG measures, that is, the hierarchical ABCD model, might detect changes in cerebral cortical function prior to clinical changes in patients with acute DoC treated with amantadine and could serve as early biomarkers to measure treatment effects in future clinical trials 198 . A potential association between early stimulant therapy and risk of seizures or excitotoxicity in patients with acute DoC remains a hypothetical concern, but is not supported by current evidence.…”

Section: Acute Disorders Of Consciousnessmentioning

confidence: 99%

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

et al. 2020

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Section: Acute Disorders Of Consciousnessmentioning

confidence: 99%

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

et al. 2020

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“…This conceptual framework will help guide the development of surrogate end points, or pharmacodynamic biomarkers, of therapeutic efficacy in early-stage clinical trials (i.e., phases 1 and 2). When testing whether a new therapy is engaging its target, it is likely that subclinical responses will be detectable before behavioral responses [17,[141][142][143]223]. Pharmacodynamic biomarkers derived from EEG [17,183,223,224], fMRI [17,225], positron emission tomography [225], TMS-EEG [141][142][143], or near-infrared spectroscopy [226] can thus be used to measure brain responses to new therapies, identify optimal dosing regimens, and inform the design of phase 3 trials that aim to detect behavioral and functional responses.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions

et al. 2021

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Background/Objective For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis. Methods We consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development. Results Knowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints. Conclusions This personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC.

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“…For each rest block, we assigned each channel's EEG recording to a pre-defined ABCD category via visual inspection of its spectrum. 2,7,36 The criteria were as follows: an 'A'-type spectrum either lacked any spectral peaks or contained a delta (<4 Hz) frequency peak; a 'B'type spectrum contained only a theta (4-8 Hz) frequency peak; a 'C'-type spectrum contained both theta and beta (13-24 Hz) frequency peaks; and a 'D'-type spectrum contained both alpha (8-13 Hz) and beta frequency peaks. For spectra that met multiple requirements, the most favorable category (D>C>B>A) was assigned.…”

Section: Eeg Spectral Analysis and Abcd Classificationmentioning

confidence: 99%

“…To date, this approach has only been studied in post-cardiac arrest coma 7 and a heterogeneous sample of patients with acute non-hypoxic-ischemic brain injury. 36 Moreover, its utility in analyzing EEG topography has not been explored in prior studies wherein each participant was assigned to a single ABCD category based on visual inspection of either all EEG channels simultaneously 7 or a single channel. 36 While these approaches may be suitable for patients with uniform injury burden across the cerebrum (such as in hypoxic-ischemic injury), patients with traumatic brain injury (TBI) present with heterogeneous, multifocal disruptions of the thalamocortical network caused by axonal shearing injury.…”

Section: Introductionmentioning

confidence: 99%

“…36 Moreover, its utility in analyzing EEG topography has not been explored in prior studies wherein each participant was assigned to a single ABCD category based on visual inspection of either all EEG channels simultaneously 7 or a single channel. 36 While these approaches may be suitable for patients with uniform injury burden across the cerebrum (such as in hypoxic-ischemic injury), patients with traumatic brain injury (TBI) present with heterogeneous, multifocal disruptions of the thalamocortical network caused by axonal shearing injury. 37 As a result, portions of the thalamocortical network are often preserved, even in patients with severe injuries who present in coma.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

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Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma. We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework: A = no peaks above delta (<4 Hz) range (complete thalamocortical disruption); B = theta (4-8 Hz) peak (severe thalamocortical disruption); C = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or D = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). We assessed behavioural level of consciousness with the Coma Recovery Scale-Revised or neurological examination and, in 12 patients, performed repeat EEG and behavioural assessments at ≥6-months post-injury. Acutely, 95% of patients demonstrated D signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent D signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent D signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (P<0.05), providing electrophysiological evidence for the effectiveness of this commonly performed technique. ABCD classification did not correspond with behavioural level of consciousness acutely, where patients demonstrated substantial within-session temporal variability in ABCD classifications. However, ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (P<0.01). Patients also demonstrated significant longitudinal improvement in EEG dynamics along the ABCD scale (median change in D signals: 37%, P<0.05). These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

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EEG to detect early recovery of consciousness in amantadine-treated acute brain injury patients

Cited by 28 publications

References 5 publications

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

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

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions

Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

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