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Assessing the integrity of neural functions in coma after cardiac arrest remains an open challenge. Prognostication of coma outcome relies mainly on visual expert scoring of physiological signals, which is prone to subjectivity and leaves a considerable number of patients in a ‘grey zone’, with uncertain prognosis. Quantitative analysis of EEG responses to auditory stimuli can provide a window into neural functions in coma and information about patients’ chances of awakening. However, responses to standardized auditory stimulation are far from being used in a clinical routine due to heterogeneous and cumbersome protocols. Here, we hypothesize that convolutional neural networks can assist in extracting interpretable patterns of EEG responses to auditory stimuli during the first day of coma that are predictive of patients’ chances of awakening and survival at 3 months. We used convolutional neural networks (CNNs) to model single-trial EEG responses to auditory stimuli in the first day of coma, under standardized sedation and targeted temperature management, in a multicentre and multiprotocol patient cohort and predict outcome at 3 months. The use of CNNs resulted in a positive predictive power for predicting awakening of 0.83 ± 0.04 and 0.81 ± 0.06 and an area under the curve in predicting outcome of 0.69 ± 0.05 and 0.70 ± 0.05, for patients undergoing therapeutic hypothermia and normothermia, respectively. These results also persisted in a subset of patients that were in a clinical ‘grey zone’. The network’s confidence in predicting outcome was based on interpretable features: it strongly correlated to the neural synchrony and complexity of EEG responses and was modulated by independent clinical evaluations, such as the EEG reactivity, background burst-suppression or motor responses. Our results highlight the strong potential of interpretable deep learning algorithms in combination with auditory stimulation to improve prognostication of coma outcome.

Both the brain and the bodily activity shape how we react to the external world (Azzalini et al., 2019). As an example, cardio-audio synchrony is the phenomenon by which heart and brain responses depend on the synchronization of auditory stimuli with the cardiac rhythm (Pfeiffer & De Lucia, 2017 ; Banellis & Cruse, 2020). However, the mechanisms supporting this kind of synchronization remain debated (Palmer & Demos, 2022): surprise response proposes that bodily signals are reacting to deviations from sensory predictions, active inference proposes that bodily rhythms are regulated to reduce the mismatch between sensory and bodily signals and dynamical coupling argues that bodily rhythms depend on the coupling between oscillators at the brain and cardiac level (Palmer & Demos, 2022). Because these different mechanistic interpretations of the phenomenon make different predictions that could not be resolved in the literature so far, we designed a protocol to test which mechanism underlies cardio-audio synchrony. To do so, we aim first to replicate the fact that physiological responses depend on the synchronization between external sound and cardiac activity and will then directly compare predictions of theories by manipulating: - The type of deviations - The expectancy of deviations Surprise response proposes that bodily signals are reacting to deviations from sensory predictions, active inference proposes that bodily rhythms are regulated to reduce the mismatch between sensory and bodily signals and dynamical coupling argues that bodily rhythms depend on the coupling between oscillators at the brain and cardiac level (Palmer & Demos, 2022).

Early prognostication of long-term outcome of comatose patients after cardiac arrest remains challenging. Electroencephalography-based power spectra after cardiac arrest have been shown to help with the identification of patients with favourable outcome during the first day of coma. Here, we aim at comparing the power spectra prognostic value during the first and second day after coma onset following cardiac arrest and to investigate the impact of sedation on prognostication. In this cohort observational study, we included comatose patients (N = 91) after cardiac arrest for whom resting-state electroencephalography was collected on the first and second day after cardiac arrest in four Swiss hospitals. We evaluated whether the average power spectra values at 4.6-15.2 Hz were predictive of patients' outcome based on the best cerebral performance category score at 3 months, with scores ranging from 1 to 5 and dichotomized as favourable (1-2) and unfavourable (3-5). We assessed the effect of sedation and its interaction with the electroencephalography-based power spectra on patient outcome prediction through a generalized linear mixed model. Power spectra values provided 100% positive predictive value (95% confidence intervals: 0.81-1.00) on the first day of coma, with correctly predicted 18 out of 45 favourable outcome patients. On the second day, power spectra values were not predictive of patients' outcome (positive predictive value: 0.46, 95% confidence intervals: 0.19-0.75). On the first day, we did not find evidence of any significant contribution of sedative infusion rates to the patient outcome prediction (P > 0.05). Comatose patients' outcome prediction based on electroencephalographic power spectra is higher on the first compared with the second day after cardiac arrest. Sedation does not appear to impact patient outcome prediction.