Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

Abstract

General anesthesia (GA) is a reversible drug-induced state of altered arousal required for more than 60,000 surgical procedures each day in the United States alone. Sedation and unconsciousness under GA are associated with stereotyped electrophysiological oscillations that are thought to reflect profound disruptions of activity in neuronal circuits that mediate awareness and cognition. Computational models make specific predictions about the role of the cortex and thalamus in these oscillations. In this paper, we provide in vivo evidence in rats that alpha oscillations (10-15 Hz) induced by the commonly used anesthetic drug propofol are synchronized between the thalamus and the medial prefrontal cortex. We also show that at deep levels of unconsciousness where movement ceases, coherent thalamocortical delta oscillations (1-5 Hz) develop, distinct from concurrent slow oscillations (0.1-1 Hz). The structure of these oscillations in both cortex and thalamus closely parallel those observed in the human electroencephalogram during propofol-induced unconsciousness. During emergence from GA, this synchronized activity dissipates in a sequence different from that observed during loss of consciousness. A possible explanation is that recovery from anesthesia-induced unconsciousness follows a "boot-up" sequence actively driven by ascending arousal centers. The involvement of medial prefrontal cortex suggests that when these oscillations (alpha, delta, slow) are observed in humans, self-awareness and internal consciousness would be impaired if not abolished. These studies advance our understanding of anesthesia-induced unconsciousness and altered arousal and further establish principled neurophysiological markers of these states.

Keywords: anesthesia; coherence; prefrontal cortex; propofol; thalamus.

Conflict of interest statement

Conflict of interest statement: E.N.B. and P.L.P. have patents pending on anesthesia monitoring.

Figures

Fig. S1.

Histological localization of electrodes targeting prelimbic cortex and higher-order thalamic nuclei. (A, Left) Example of electrode locations in prelimbic cortex (PL) in a coronal slice. The probes left a clear track in the tissue. (A, Right) Summary of prelimbic electrode locations (red circles) across all rats, projected into a coronal slice +3.00 mm anterior to Bregma. (B, Left) Example of electrode locations in the thalamus in a coronal slice. The tracks left by the probes can be easily observed. (B, Right) Summary of thalamic electrode locations across all rats, projected into a coronal slice −3.12 mm from Bregma. (C) Example of assignment of different shanks to different layers of prelimbic cortex. (D) Example of assignment of different shanks to different nuclei of dorsal thalamus. All slices were stained with the Nissl procedure. CL, central lateral thalamic nucleus; LDDM, laterodorsal thalamic nucleus, dorsomedial part; LDVL, laterodorsal thalamic nucleus, ventrolateral part; MDC, mediodorsal thalamic nucleus, central part; MDL, mediodorsal thalamic nucleus, lateral part; MDM, mediodorsal thalamic nucleus, medial part; Po, posterior thalamic nuclear group.

Fig. S2.

Temporal correlations between behavioral events during induction of and recovery from anesthesia. (A) Latencies of the main behavioral events observed during induction of anesthesia. The horizontal black bar represents the median (n = 11, eight rats). (B) Correlation between the latency to pica and the latency to LORR within experiments. No correlation exists between these two sates (slope: −0.29, 95% CI = [−0.99, 0.41]). (C) Correlation between the latency to LORR and the latency to LOM. The latencies of these events are significantly correlated within experiments. (D) Latencies of the main behavioral events observed during emergence from anesthesia. (E) Correlation between the latency to ROM and the latency to RORR during recovery of consciousness. The latencies to these events are significantly correlated within experiments. Shaded area in B, C, and E represents 95% CIs of the regression estimates.

Fig. 1.

Sequence of changes in the prelimbic LFP during induction of and emergence from anesthesia. (A) Representative trace from a single electrode, recorded during baseline, and located in layer 6 of prelimbic cortex. Recordings from this electrode are used in examples throughout this figure. (B) Group spectra observed during baseline in prelimbic cortex across all layers and subjects (n = 27, eight rats). The shaded area represent 99% confidence intervals. (C) Representative spectrogram observed during induction of unconsciousness. Propofol dosing starts at t = 0, and the vertical black lines mark behavioral events (LORR and LOM). (D) Same spectrogram as in C, normalized by its own baseline (Materials and Methods). (E) Representative raw traces recorded during each of the behavioral events observed during induction. Vertical scale: 1,000 μV. Horizontal scale: 1 s. (F) Peri-event, normalized group spectra corresponding to the same behavioral events shown in E. The horizontal lines mark the frequencies at which power is significantly different from baseline. (G) Representative spectrogram during emergence from unconsciousness. Propofol dosing stopped at t = 0 (not shown). The vertical black lines mark behavioral events (ROM and RORR). (H) Same spectrogram as in G, but normalized by its own baseline. (I) Representative raw traces recorded during each of the behavioral events observed during emergence. (J) Peri-event, normalized group spectra corresponding to the same behavioral events shown in I.

Fig. 2.

Differential effects of propofol in deep and superficial layers. (A and B) Difference in power between layers during induction of anesthesia. (A) Example raw traces observed during LORR from electrodes located in layers 2/3 (blue), 5 (green), and 6 (red). (B) Baseline-normalized, difference group spectra between layers, at each behavioral event. Shaded area represents 99% confidence intervals. (C and D) Difference in power between layers during emergence from anesthesia. (C) Example raw traces observed during preROM from electrodes located in layers 2/3, 5, and 6. Color code is the same as in A. (D) Baseline-normalized, difference group spectra at each behavioral event. Color code is the same as in B. In A and C, the yellow squares highlight portions of the raw traces where deep layers display bigger amplitude than superficial layers. The shaded area in all group spectra represents 99% confidence intervals, and the horizontal lines mark the frequencies at which power is significantly different from baseline beyond the spectral resolution (3 Hz). Vertical scale: 1,000 μV. Horizontal scale: 1 s.

Fig. 3.

Sequence of changes in the higher-order thalamic LFP during induction and emergence from anesthesia. (A) Representative trace from a single electrode, recorded during baseline, and located in the mediodorsal thalamic nucleus. Recordings from this electrode are used in examples throughout this figure. (B) Group spectra observed during baseline in thalamus across all nuclei and subjects (n = 27, eight rats). The shaded area represents 99% confidence intervals. (C) Representative spectrogram observed during induction of unconsciousness. Propofol dosing starts at t = 0. The vertical black lines mark behavioral events (LORR and LOM). (D) Same spectrogram as in C, normalized by its own baseline (Materials and Methods). (E) Representative raw traces recorded during each of the behavioral events observed during induction. Vertical scale: 1,000 μV. Horizontal scale: 1 s. (F) Peri-event, normalized group spectra corresponding to the same behavioral events shown in E. The horizontal lines mark the frequencies at which power is significantly different from baseline. (G) Representative spectrogram during emergence from unconsciousness. Propofol dosing stopped at t = 0 (not shown for clarity). The vertical black lines mark behavioral events (ROM and RORR). (H) Same spectrogram as in G, but normalized by its own baseline. (I) Representative raw traces recorded during each of the behavioral events observed during emergence. (J) Peri-event, normalized group spectra corresponding to the same behavioral events shown in I.

Fig. S3.

Schema of anatomical thalamocortical connections.

Fig. S4.

Differential effects of propofol within higher-order thalamic nuclei. (A and B) Difference in power between nuclei during induction of anesthesia. (A) Example raw traces observed during LORR from electrodes located in M (blue), C (green), and S (red) nuclei. (B) Baseline-normalized, group difference spectra at each behavioral event. The horizontal lines at the bottom signify the frequencies at which power is significantly different between nuclei. (C and D) Difference in power between nuclei during emergence from anesthesia. (C) Example raw traces observed during preROM from electrodes located in M, C, and S nuclei. Color code is the same as in A. (D) Baseline-normalized group spectra at each behavioral event. Color code is the same as in B. Shaded areas in all difference spectra represent 99% CIs. In the raw traces, the vertical scale corresponds to 1,000 μV and the horizontal scale to 1 s.

Fig. 4.

Changes in thalamocortical coherence with respect to baseline in the δ and α bands. (A and B) Strength of synchronization between deep layers (DL) or superficial layers (SL) of prelimbic cortex and the mediodorsal (M), central lateral (C), and sensory-motor (S) nuclei, within two frequency bands (δ and α, rows) and the three different behavioral states (columns) observed during induction (A) and emergence (B). The arrows depict the establishment of significant changes in coherence between cortical and thalamic nuclei with respect to baseline. The color of the arrows exemplifies the size of the increase (red shades) in coherence.

Fig. S5.

Thalamocortical coherence difference with baseline across all behavioral states. In this plot matrix, the rows correspond to the different combinations of SLs and DLs and M, C, and S thalamic nuclei. The columns correspond the different behavioral states (main text). The coherence difference is a dimensional.

Fig. S6.

Changes in thalamocortical coherence with respect to baseline in the slow, θ, and β bands. (A and B) Strength of synchronization between DLs or SLs of prelimbic cortex and the M, C, and S thalamic nuclei, within three different frequency bands (slow, θ, and β, rows) and the three different behavioral states (columns) observed during induction (A) and emergence (B). The arrows depict the establishment of significant changes in synchronization between cortical regions with respect to baseline. The color of the arrows exemplifies the size of the increase (red shades) or decrease (blue shades) in coherence.