Foundations of Human Consciousness: Imaging the Twilight Zone

Abstract

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (experiment 1, n = 39), and during sleep-deprived wakefulness and non-rapid eye movement sleep (experiment 2, n = 37). In experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected versus unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices, and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration, and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness.SIGNIFICANCE STATEMENT Trying to understand the biological basis of human consciousness is currently one of the greatest challenges of neuroscience. While the loss and return of consciousness regulated by anesthetic drugs and physiological sleep are used as model systems in experimental studies on consciousness, previous research results have been confounded by drug effects, by confusing behavioral "unresponsiveness" and internally generated consciousness, and by comparing brain activity levels across states that differ in several other respects than only consciousness. Here, we present carefully designed studies that overcome many previous confounders and for the first time reveal the neural mechanisms underlying human consciousness and its disconnection from behavioral responsiveness, both during anesthesia and during normal sleep, and in the same study subjects.

Keywords: anesthesia mechanisms; consciousness; dexmedetomidine; positron emission tomography; propofol; sleep.

Figure 1.

Design of Experiments 1 and 2. Behavioral states of interest in the anesthesia study are abbreviated as follows: W, wakeful baseline; SED_light, light sedation; SED_mod, moderate sedation state. Note the fixed-dose anesthetic level (UR dose) with steady-state infusion in UR, R, UR2, and R2. For details, see Materials and Methods. Behavioral states of interest in the sleep study are abbreviated as follows: SDW, sleep-deprived wakefulness; N1, N2, N3, NREM sleep stages N1, N2 and N3. For details, see Materials and Methods.

Figure 2.

Relative rCBF suppression at different anesthetic levels, sleep stages, and behavioral states. A, B, Images showing the global pattern of rCBF changes in association with different levels of propofol or dexmedetomidine (A) and different sleep stages (B). All states are compared with a non-sleep-deprived awake baseline with no drug. Cool colors show the largest relative suppression and warm colors the smallest relative suppression (p < 0.01; color bars depict bootstrap ratios in PLS). Light and moderate sedation indicate responsive levels during escalating drug exposure. UR dose refers to drug concentration titrated individually to induce unresponsiveness, and 1.5× UR dose refers to 50% higher doses. The states of consciousness (connected or disconnected) during UR and 1.5× UR levels could not be verified because of a lack of immediate interviews in unarousable subjects and/or after terminating the infusion, and are therefore marked as “(disconnected?)”. Maximal suppression is seen in frontal and parietal cortical areas as well as in subcortical structures, and the pattern is evident already during light sedation, resembling the awake sleep-deprived state. The intensity of suppression increases with drug dose level and depth of sleep, regardless of the behavioral state. Light sedation (SED_light; propofol, n = 14; dexmedetomidine, n = 6), moderate sedation (SED_mod; propofol, n = 19; dexmedetomidine, n = 20), UR dose and UR (propofol, n = 19; dexmedetomidine, n = 20), UR dose and R forced awakening during anesthetic infusion (propofol, n = 9; dexmedetomidine, n = 16), 1.5× UR dose (propofol, n = 15; dexmedetomidine, n = 16); sleep-deprived wakefulness (SDW; n = 22); NREM sleep stages N1 (n = 14), N2 (n = 24), and N3 (n = 14); all targeted states were not achieved in all subjects.

Figure 3.

Differences in relative rCBF between connected and disconnected states of consciousness. A central core network of consciousness was revealed by imaging anesthetic-induced and sleep-induced state transitions. Cool colors show the largest relative suppression on becoming disconnected and warm colors the smallest (left); and warm colors show the largest relative activation on becoming connected and cool colors the smallest (right; p < 0.01, corrected; color bars depict bootstrap ratios in PLS). A, During infusions of both propofol (top) and dexmedetomidine (middle), state-specific analyses between connected and disconnected conditions revealed that a network of core midline structures was activated and deactivated in a reciprocal manner, with minimal effects seen on the cortical surface. Activity of the thalamus, anterior and posterior cingulate cortices, precuneal area, and bilateral angular gyri showed the most consistent associations with the subject's state of consciousness. B, During physiological sleep (bottom), transition from sleep-deprived wakefulness to N2 sleep revealed the deactivation of the same core structures. Again, changes in cortical surfaces were inconsistent. Brain regions with statistically significant differences are listed in Extended Data Figures 3-2, 3-3, 3-4, 3-5, and 3-6, and cortical renderings are shown in Extended Data Figure 3-1. AG, Angular gyrus; dMPFC, dorsomedial prefrontal cortex; pCUN, precuneus; PHG, parahippocampal gyrus; vMPFC, ventromedial prefrontal cortex. Successful scans for within-subject comparisons were compared in 19 (SED_mod → UR), 14 (R → UR2), and 9 (SDW → N2) propofol, dexmedetomidine, and sleep subjects (left: connected → disconnected), and in 9 (UR → R) and 16 (UR → R) propofol and dexmedetomidine subjects (right: disconnected → connected), respectively.