Neural Correlates of Anesthesia in Newborn Mice and Humans

Abstract

Monitoring the hypnotic component of anesthesia during surgeries is critical to prevent intraoperative awareness and reduce adverse side effects. For this purpose, electroencephalographic (EEG) methods complementing measures of autonomic functions and behavioral responses are in use in clinical practice. However, in human neonates and infants existing methods may be unreliable and the correlation between brain activity and anesthetic depth is still poorly understood. Here, we characterized the effects of different anesthetics on brain activity in neonatal mice and developed machine learning approaches to identify electrophysiological features predicting inspired or end-tidal anesthetic concentration as a proxy for anesthetic depth. We show that similar features from EEG recordings can be applied to predict anesthetic concentration in neonatal mice and humans. These results might support a novel strategy to monitor anesthetic depth in human newborns.

Keywords: EEG; LFP; anesthesia; development; human; machine learning; mouse; network dynamics.

Figure 1

Frequency-unspecific dampening of neuronal activity during urethane anesthesia in neonatal mice. (A) Schematic representation of experimental paradigm and recording sites as well as characteristic local field potential (LFP) recordings of discontinuous activity in the prefrontal cortex (PFC), HP, lateral entorhinal cortex (LEC), and olfactory bulb (OB) of neonatal mice (P8–10) during non-anesthetized and urethane-anesthetized state. Time windows of active periods are marked by red lines. (B) Line plots displaying the relative occurrence of active periods normalized to total recording time in PFC, HP, OB and LEC before and after urethane injection. (C) Color-coded MI of power spectra for full signal (top) and active periods (bottom) recorded in PFC, HP, LEC and OB of neonatal mice before and after urethane injection. (D) Violin plots displaying the MI of power in delta (2–4 Hz), theta-alpha (4–12 Hz), beta (12–30 Hz) and gamma (30–100 Hz) frequency bands for full signal (blue) and active periods (red) recorded in the PFC, HP, LEC and OB. (E) Line plots displaying multi-unit activity (MUA) rates during full signal (blue) and active periods (red). In (B,C,E) green lines correspond to the time point of urethane injection.

Figure 2

Suppression of active periods in relationship with the depth of isoflurane anesthesia in neonatal mice. (A) Schematic representation of experimental protocol for LFP recordings without anesthesia and during increasing levels of isoflurane anesthesia in neonatal mice (P8–10). (B) Line plots displaying the relative occurrence of active periods in PFC and HP during increasing levels of isoflurane anesthesia. (C) Color-coded MI of power spectra for full signal (top) and active periods (bottom) during increasing levels of isoflurane anesthesia. (D) Violin plots displaying the MI of power in delta (2–4 Hz), theta (4–12 Hz), beta (12–30 Hz) and gamma (30–100 Hz) frequency bands for full signal (blue) and active periods (red). (E) Line plots displaying MUA firing rates during full signal (blue) and active periods (red). In (B,C,E) green lines correspond to the time points of increasing isoflurane anesthesia. (F) Visualization of anesthesia depth prediction by t-sne plots. Background color codes for predicted anesthesia depth, while the color of the dots represents the actual anesthesia level in the training (left) and test set (right). (G) Scatter plots displaying anesthesia depth predictions with support vector regression (left) and absolute errors between anesthesia depth prediction and actual anesthesia depth (right).

Figure 3

Age-dependent switch from broadband suppression to frequency-specific effects of general anesthesia on electroencephalographic (EEG) activity in human neonates and infants. (A) Scatter plots displaying the median EEG amplitude as a function of anesthetic concentration for representative examples of 0–2, 2–4 and 4–6 months of age. (B) Scatter plot displaying the correlation coefficient of median EEG amplitude and anesthetic concentration in relation to birth age for sevoflurane (black), isoflurane (red), and desflurane (blue). (C) Line plots displaying normalized EEG amplitude as a function of anesthetic concentration. (D) Color-coded MI of median EEG amplitudes in different frequency bands as a function of anesthetic concentration for human babies of 0–2 months (left), 2–4 months (middle) and 4–6 months (right).

Figure 4

EEG activity is predictive for anesthetic concentration in human infants. (A) Scatter plots displaying measured anesthetic concentration and predicted anesthetic concentration of support vector regression for all predictions (left) and absolute difference between measured and predicted anesthetic concentration (right) for human neonates of 0–2 months. (B) Same as (A) for human infants of 2–4 months. (C) Same as (A) for human infants of 4–6 months. (D) Same as (A) for human neonates and infants of 0–6 months.