You’re getting sleepy: Brain mechanisms of anesthesia and natural sleep

Posted by Susan Lubejko on May 30, 2019 in Neuroscience, Sleep | Leave a comment

[En español]

“Take a deep breath and count backwards from 10…” “10…9…8…7….”

If you are one of the many people that have had surgery under general anesthesia, you may remember these words from your anesthesiologist, beginning the countdown yourself, then probably ….nothing. When you awoke later, you were already out of surgery and in a recovery room with no memory of the procedure and no perception of the pain your body must’ve endured during the process.

General anesthesia can take a lot of forms, from inhaled gases to liquid drugs introduced to your bloodstream through an intravenous (IV) infusion, but the results follow the same basic principles: pain relief, amnesia, the inability to move, and, most notably, the loss of consciousness. When administered by a certified anesthesia expert, the process is safe, effective, and reversible.

While the administration of general anesthesia is something we now often take for granted, the advent of modern anesthesia completely revolutionized medicine and surgery. While other drugs such as alcohol and even simple distraction of the patient have been used throughout history to dull pain during procedures, surgery was a decidedly unpleasant experience for the fully awake patient. The development of modern general anesthesia is often credited to William T.G. Morton, a Boston dentist who was the first to deliver controlled inhaled ether to a patient undergoing a tumor removal from his neck at Massachusetts General Hospital in 1846. He had created a glass and wood apparatus to manage the delivery of the ether to patients during surgery. While other physicians had previously used ether and nitrous oxide during procedures, they lacked control over the administration of the anesthesia, greatly increasing the risk of overdose on the anesthetic [1].

Undoubtedly, our implementation of general anesthesia has improved with the invention of the endotracheal tube which is inserted into the airways to induce inhaled anesthesia and support breathing during surgical procedures, a variety of other anesthetic induction technologies, and newer and safer inhaled and injected anesthetic drugs [2]. So, you might be surprised to learn that neuroscientists and medical professionals aren’t exactly sure how these drugs cause the hallmark signs of general anesthesia, particularly the reversible loss of consciousness.

Brain targets of general anesthesia

The current hypotheses about how general anesthetic drugs cause these effects has been studied at two different levels of the nervous system: how the activity of individual cells in the brain changes and how activity in larger brain areas changes.

In terms of the individual neurons in the brain, general anesthetics seem to cause some major alterations in how the brain is able to send signals from cell to cell. Typically, neurons can be “excited” by incoming messages from other neurons and will pass that signal along to others. However, neurons can also be “inhibited” by other neurons, which makes them less likely to send signals along to excite the next cell in the chain. General anesthesia seems to quiet neuronal communication by opening channels in the cell membrane that cause neurons to be inhibited, while at the same time blocking receptors that usually would cause neurons to be excited and spread their signals to the next neuron. To complicate this matter, however, different anesthetic drugs use these approaches differently, making it difficult to determine general mechanisms of drug action that apply to all anesthesia [3].

Using human subjects, scientists aim to answer the second question of how activity in larger brain areas changes. PET scans (a method of imaging blood flow to certain areas of the brain) show that overall, there is a decrease in blood flow to most parts of the brain during the loss of consciousness from general anesthesia. While different anesthetic drugs change the identity of the areas that are deactivated the most, areas of the cerebral cortex involved in sharing sensory information, the thalamus (which sends sensory information to the cerebral cortex), and the cerebellum (which coordinates movement) seem to be hit the hardest by general anesthetics [3].

Sleep and anesthesia

For a variety of reasons, scientists have long questioned whether general anesthesia and natural sleep share any mechanisms of action. The most obvious reason to suggest this is the unmistakable loss of consciousness that is a hallmark for both sleep and drug-induced anesthesia. Additionally, propofol anesthesia can cause the same amount of recovery from 24 hours of sleep deprivation in rats as natural sleep for the same time period after sleep deprivation. This suggests that sleep and anesthesia may share some mechanisms and propofol may be able to help make up for a lack of natural sleep [4]. Furthermore, while most patients report a loss of time while under anesthesia, more recent scientific studies in which patients were roused from light anesthesia at a variety of intervals indicate that patients can dream and understand external stimuli under certain phases of general anesthesia, but the drugs usually cause memory loss of these events [5,6].

When recording the activity in the brain during sleep and anesthesia, other similarities arise. Electroencephalography (EEG) recordings from electrodes on the scalp, which can track the global changes in electrical activity in human brains, reveal that the patterns in how the electrical activity changes over short time periods during anesthesia looks a lot like it does during different stages of REM (rapid eye movement) and non-REM sleep (for more information on sleep, check out this 2014 NeuWrite article!). Similar to the brain areas affected by anesthesia in the previous section, brain imaging shows that non-REM deep sleep causes major deactivation of the thalamus and certain cerebral cortex areas that combine different types of sensory information [3].

Evidence of neurons in the brain that connect different anesthetic drugs and sleep

As you read above, general anesthesia probably works through really complicated changes in the brain that differ between different types of anesthetic drugs. But they all cause such similar loss of consciousness and can similarly be compared to sleep, so might there be some shared mechanisms between these distinct general anesthetics?

A 2019 scientific article [7] from researchers at Duke University Medical Center set out to answer just that. These scientists found that there is a small collection of neurons in the hypothalamus of the mouse brain that are active during general anesthesia of many different types. The hypothalamus is a brain region that is closely connected with the pituitary gland to send chemical signals to the rest of the body and controls things like sleep, hunger, fatigue, and body temperature to name just a few. The same hypothalamic neurons increased their electrical activity in the presence of isoflurane (an inhaled drug), ketamine or propofol (both injected anesthetics). Interestingly, they determined that the neurons started increasing their activity before the loss of consciousness, and quieted their activity before the subject recovered from the anesthesia, which suggests that these neurons probably control the loss of consciousness typical of general anesthesia of inhaled *and* injectable kinds.

Next, the researchers wanted to prove that there is a definitive connection between the neurons that are responsible for controlling general anesthesia and sleep processes. When they activated the specific hypothalamic neurons that turned on during anesthesia using light (see this awesome 2015 NeuWrite article on this method of controlling neurons!), sleep was improved during the time period after light stimulation due to an increase in the duration of non-REM sleep and a decrease in duration of awake periods. Correspondingly, when those same neurons were destroyed, natural REM and non-REM sleep declined over time in mouse subjects. Excitingly, this study provides us with specific brain mechanisms that help explain why general anesthesia resembles sleep and can promote recovery from sleep deprivation.

The evolution of general anesthesia

It’s pretty clear that we have come a long way from the days of William T.G. Morton in terms of the safety and efficacy of general anesthesia and that modern medicine would look very different without it. While neuroscientists have discovered a lot about how anesthetic drugs do their job and how these mechanisms are related to sleep in terms of cellular and whole brain activity, we will continue to refine the anesthesia process through a better understanding of specific neuron players and studying the challenging topic of how the brain creates consciousness. For now, continue to thank those early pioneers and those that have worked on this question since for your comfortable surgery experience.

References

1. Markel H (2013) The Painful Story Behind Modern Anesthesia. PBS NewsHour. Retrieved May 20, 2019 from https://www.pbs.org/newshour/health/the-painful-story-behind-modern-anesthesia
2. Robinson DH, Toledo AH (2012) Historical development of modern anesthesia. Journal of Investigative Surgery, 25:3 141-149
3. Franks NP (2008) General anesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nature Reviews Neuroscience, 9: 370-386
4. Tung A, Bergmann BM, Herrera S, Cao D, Mendelson WB (2004) Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology, 100:1419-26
5. University of Turku. (2018, July 3). Consciousness is partly preserved during general anesthesia. ScienceDaily. Retrieved May 28, 2019 from http://www.sciencedaily.com/releases/2018/07/180703105631.htm
6. Scheinin A, Kallionpaa RE, Li D, Kallioinen M, Kaisti K, Langsjo J, Maksimow A, Vahlberg T, Valli K, Mashour GA, Revonsuo A, Scheinin H (2018) Differentiating drug-related and state-related effects of dexmedetomidine and propofol on the electroencephalogram. Anesthesiology, 129:22-36
7. Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F (2019) A common neuroendocrine substrate for diverse general anesthetics and sleep. Neuron, 102:1-13