The Brain in the Operating Room: Understanding the Loss of Consciousness During General Anesthesia

Written By Katerina Hristova

Katerina Hristova

Illustrations by Anna Bishop & Iris Li

Imagine that you are being wheeled into the operating room for surgery, your mind racing with anxious questions. Will you remember anything? Will you feel pain? Will you be able to see or hear the doctors and nurses? Amidst your swirling thoughts, the nurse attaches an IV to the top of your hand. She tells you to begin counting down from ten. You feel drowsy and begin counting: ten, nine, eight, seven. When you open your eyes, the operation is over. You have no recollection of falling asleep at all. Most people have no sense that any time has passed between the moments of anesthesia administration and waking up [1, 2, 3]. General anesthesia is a drug-induced loss of consciousness that is characterized by amnesia, immobility, hypnosis, unresponsiveness to painful stimuli, and the absence of reflexes [4]. Anesthetics, such as propofol, are medications used to put people in a controlled state of unconsciousness so that invasive surgical procedures may be completed without physical or psychological discomfort [5]. While people are sedated under anesthesia, their heart rate, blood pressure, oxygen levels, and other vital signs must be  monitored because some bodily functions temporarily slow down [6]. At the end of a surgical procedure, the sedation is reversed and the person wakes up. What occurs inside the brain when someone is under general anesthesia remains enigmatic, however the neurological mechanisms behind how anesthesia operates have been explored [7]. 

Not Just a Nap: The Sleeping Brain vs. The Unconscious Brain 

You may think that you were ‘put to sleep’ for your surgery, but a myriad of neurological and physiological differences between sleep and anesthesia-induced unconsciousness exist [8]. Both states are characterized by immobility and one’s reduced responsiveness to their environment [9]. However, while sleep is a naturally altered state of consciousness, anesthesia is drug-induced, and is considered a reversible loss of consciousness [4, 10]. Additionally, sleep is a restorative and active process that is vital to maintaining optimal brain function, facilitating hormonal and metabolic regulation as well as memory consolidation processes [11]. Via consolidating memories, we cement the knowledge and experiences we gain while we are awake into our long-term memory [11]. In contrast, anesthetics block the use of working-memory, which is the temporary storage of limited information [12, 13]. Undergoing general anesthesia is therefore not the same as just falling asleep.

Flipping the Switch: How Propofol Dims Neurons

Before you start to feel drowsy, propofol has to find its way to where consciousness arises: the brain. For this to happen, the drug must pass through the blood-brain barrier, which regulates the movement of blood and other fluids into the brain [14]. Once past the blood-brain barrier and into the brain, propofol can begin to affect neurons, or communicative brain cells [15]. In order to transmit information, neurons utilize chemical and electrical signaling [16]. At rest, the inside of a neuron is negatively charged relative to the outside of the cell, a difference called membrane potential [17]. An increase in the movement of positively charged particles called ions into the cell changes the membrane potential. When the interior charge of a neuron is increased to a certain threshold, the neuron is able to fire signals to other neurons [17]. GABA is a neurotransmitter that generally inhibits neuronal activity; when GABA binds to its respective receptor, negatively charged ions will enter the neurons. An influx of negative ions causes the charge of the cell to become more negative, which prevents activation and therefore communication with other neurons [18]. GABA can bind to a variety of receptors, including the GABAA receptor subtype [19, 20]. GABAA receptors play a key role in facilitating the loss of spinal and muscle reflexes and amnesia in general anesthesia [21, 22]. Propofol imitates GABA and binds directly to the GABAA receptor, allowing negative ions to enter the cell. The increasingly negative membrane potential prevents the neuron from being activated. Therefore, propofol prevents neurons from sending electrical signals to communicate with other cells [9]. Propofol can also bind to another part of the GABAA receptor and enhance the existing activity of GABA [20, 23]. Unlike other modulators that potentiate, or intensify, the response of the GABAA receptor, propofol binds to a subunit that is seen in all GABAA subtypes, allowing it to bind to GABAA receptors, quickly and efficiently targeting various regions of the brain where the receptor is abundant [19].

Targeting the Thalamus: How Propofol Induces Unconsciousness

Propofol, likely through its action on GABA receptors, significantly decreases overall activity in the brain [24, 25]. One way to measure levels of brain activity is to measure rates of metabolism in the brain known as cerebral metabolic rate (CMR) [26]. Metabolism is the process by which food is transformed into a form of energy that our body can use to fuel its functions [27]. Therefore, a higher cerebral metabolic rate can be indicative of higher brain activity [26]. The injection of propofol has been shown to decrease CMR in every region of the brain by amounts ranging from 30-70% [24, 25]. Metabolic suppression is also observed with other anesthetic agents, and may be responsible for unconsciousness [28, 29]. However, ketamine, which is another agent known to disrupt consciousness, has been shown to increase the CMR in several brain regions [24, 30]. 

The effects of anesthetics, including propofol, on consciousness also vary across regions of the brain [24, 31, 32, 33]. Propofol’s impact on the thalamus, a region in the brain responsible for relaying sensory and motor information from the body to the brain for processing, has been well studied [31, 34]. The thalamus plays an important role in regulating alertness and consciousness [34, 35]. Nuclei, or clusters of neurons, each with different functions, can be found throughout the thalamus [36, 37]. Notably, thalamic nuclei can be either specific or nonspecific [34, 38]. Most sensory information, like the chirping of birds or the taste of coffee, initially passes through specific thalamic nuclei and is then sent on to the other areas in the brain for processing [39]. Meanwhile, nonspecific thalamic nuclei transmit information between the thalamus and the cerebral cortex, the outermost layer of the brain that contains several distinct sub-regions involved in a variety of processes such as attention and cognition [38, 40]. Nonspecific thalamic nuclei are important in regulating cortical arousal, the level of neural activity within the cerebral cortex [38]. Additionally, nonspecific nuclei  are vital for integrating information across the different functional regions that make up the cortex [34, 41]. Unlike specific thalamic nuclei, which solely relay sensory information, nonspecific thalamic nuclei synchronize information between different brain regions, allowing the thalamus to modulate and coordinate neural activity across brain regions [38]. 

The effect of propofol on the activity of specific and nonspecific nuclei can be measured using a blood oxygen level-dependent (BOLD) fMRI, which measures changes in blood oxygenation [42]. When neurons in a particular brain region become more active, they expend more energy and, therefore, consume more oxygen [43]. To meet this increased demand, blood flow to the active area increases, and BOLD fMRI signals reflect an  increase in the concentration of oxygenated blood [42]. BOLD fMRI can be used to analyze changes in functional connectivity, or the temporal connection — how in sync or coordinated the activity is — between brain regions [34] When distant brain regions synchronize their activity, they are said to be functionally connected, indicating substantial communication between those regions [44]. Propofol decreases the functional connectivity of both specific and nonspecific nuclei [31, 45, 41]. While functional connectivity in specific thalamic nuclei is moderately reduced by propofol, propofol significantly suppresses functional connectivity in nonspecific thalamic nuclei [31, 34]. The significant decrease in the functional connectivity of nonspecific nuclei, and subsequent disruption of arousal and information integration, may be how propofol results in a loss of consciousness [34, 41]. Specific thalamic nuclei, however, remain mostly active after propofol is administered. In fact, during propofol-induced unconsciousness, the sensory cortices — or the parts of the brain responsible for processing sensory information — are still reactive. Therefore, the brain can still receive information during propofol-induced unconsciousness, but it cannot consciously perceive this sensory information. As shocking as it may seem, you can hear during anesthesia, but your brain is unable to consciously recall auditory signals. A lack of conscious perception of sensory stimuli may be due to a decrease of functional activity in nonspecific thalamic nuclei, since information across sensory systems is unable to be integrated and utilized to support higher cognitive functions [34, 41]. A disruption in functional connectivity within nonspecific thalamic nuclei may explain why sensory input continues to reach the cortex during anesthesia, yet we are not consciously aware of it. 

Lifting the Veil on Going Under: What Anesthesia Can Tell Us

The study of anesthesia-induced unconsciousness, particularly through the lens of propofol's effects on the brain, offers a valuable perspective on the mechanisms underlying consciousness itself [46]. The suppression of functional connectivity in nonspecific thalamic nuclei provides critical insights into how the brain orchestrates integrated states of awareness, highlighting the importance of dynamic communication between brain regions in maintaining consciousness [34, 41, 47]. Furthermore, understanding how anesthetics like propofol interfere with these processes could not only advance medical practices by improving anesthetic techniques and safety, but also deepen our understanding of what it means to be conscious [46, 48]. Moreover, by identifying the specific neural circuits that underlie conscious experience, we may uncover new avenues of research for further understanding other conditions, such as coma [47]. Anesthesia-induced unconsciousness serves as a compelling tool for unraveling the complex neurological basis of consciousness, offering both clinical and philosophical avenues for our understanding of the mind [47].

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Katerina Hristova
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