Eeshan Sharma, Ahir Datta
This project is a meta analysis of all of the meaningful studies and literature on the topic of anesthesia and how it relates to other states of unconsciousness. For a long period of time, there was a great deal of mystery regarding the mechanism of general anesthetics and its unique ability to chemically induce a "reversible loss of consciousness." Over time, we have come to a basic understanding.
A brief explanation of the general mechanism of anesthesia is as follows. Lipid solubility directly correlates with anesthetic potency, with sites for absorption being the cell membrane bilayer and the respective proteins in the bilayer. Anesthetics have a role in altering the voltage-gated ion channel, but its effects are present when greater anesthetic doses are administered, which is usually not done due to lower doses being necessary to induce the anesthetic state. Ligand-gated ion channels, a neurotransmitter receptor, are particularly sensitive to anesthetic agents. Two receptors of importance seem to be the NMDA receptor and GABA-A receptor, which are the receptors that are seemingly directly involved in producing the anesthetic state.
We have primarily focused on the general anesthetic "propofol," which is the most common anesthetic administered in the clinical setting, and part of a class of drugs known as GABA-A agonists. In general, propofol binds to GABA binding sites and inhibits neural activity. This is because inhibitory neurons in these locations act as “routers,” controlling excitatory neurons with a ratio of 1:8 or 1:10, so if a drug controls these inhibitory neurons, there lies a lot of potential for controlling specific areas of brain activity.
In addition, anesthetics have the ability to produce many different states of unconsciousness. We have considered three different states of altered arousal: traditional coma states, drug-induced coma states, and sleep. This can tell us a lot about what specific portions of the brain must be turned off to induce unconsciousness, the role of sleep and its relationship with other forms of unconsciousness, and even more.
For this project, we have provided a meta-analysis of various forms of literature describing the theorized mechanisms of propofol, its effects in relation to other anesthetic compounds from a systems neuroscience perspective, a comparison of sleep, coma, and a drug-induced coma, and possible theories that may link these unconscious states. More specifically, we have looked at oscillation disruptions between the thalamus and frontal cortex and comparing alpha (fast) and delta (slow) oscillations and their roles in inducing sleep, the role of the brain stem in all forms of unconsciousness, and other specific dynamics of the brain.
From the computational perspective, we have compared and contrasted the findings of each of those studies, using higher-level EEG data, global coherence analysis, and other computational techniques to evaluate the accuracy of these various perspectives on anesthetic mechanisms. We have modeled and outlined similarities and differences between the onset and duration of anesthesia versus other unconscious states. We will also develop a more rigorous understanding of the oscillations and changes of state within the unconscious level.
Before delving into the methodology of the project, our understanding of the current literature was that the unconscious states induced by anesthesia would be different from the unconscious states of sleep and coma, due to the targeted nature of propofol. By viewing EEG data and chemical/biological/physical models of how propofol interacts with the brain, our hypothesis was that we should theoretically be able to distinguish between a state induced by anesthesia and sleep/etc. There are several pieces of literature, studies, models, and other concepts that cover this topic of general anesthetics and their role in influencing states of unconsciousness and it is worth mentioning the main pieces here.
The first study of importance is “General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis” by Emery Brown. It “performs a systems neuroscience analysis of the altered arousal states induced by the five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act.” The important portion of the study for our purposes is the GABAA agonist portion, which includes propofol and some other drugs, like etomidate, thiopental, and methohexital. All GABAA- agonist drugs act at GABAA receptors to enhance inhibition. Their effects depend on how much and how rapidly they are administered. A small dose of a GABAA- agonist drug induces sedation, which when increased slowly, can induce a state of “paradoxical excitation or disinhibition defined by euphoria or dysphoria, incoherent speech, purposeless or defensive movements, and increased electroencephalogram (EEG) oscillations in the beta range (13–25 Hz).” This excerpt introduces two important concepts, which is the role of paradoxical excitation (and other common EEG patterns) with EEG oscillations within the brain as a metric of mapping brain activity. Paradoxical excitation is relevant because it is something observed primarily in this GABAA-agonist class of drugs, and it occurs only in low doses of propofol administration. We will dive deeper into paradoxical excitation and other patterns later. EEG oscillations are relevant because different oscillations of frequency ranges can induce different physiological and neural responses. We will discuss more on EEG oscillations later. Below is a chart taken from the study outlining the different effects of administering a GABAA-agonist drug.
We can see that there are some distinct responses. The main things to note are that the drug targets the GABAA receptor and that the basic mechanism of propofol inducing unconsciousness is when the hypnotic rapidly reaches the GABAergic neurons in the respiratory centers in the pons and medulla, and the arousal centers in the pons, midbrain, hypothalamus and basal forebrain.
The second study of note is a deeper exploration of some of the concepts mentioned in the previous study. It is called “Modeling the Dynamical Effects of Anesthesia on Brain Circuits,” also by Emery Brown. The study documents EEG activity on patients administered with propofol; there is a highly regular, rhythmic structure that correlates strongly with the patient’s arousal. This analysis is applied to all of the important concepts required to delineate specific EEG patterns commonly associated with drug-induced anesthetic states, like paradoxical excitation, strong frontal alpha oscillations, anteriorization, and burst suppression. The study concludes with suggesting that brain dynamics occurring at the GABAergic networks in the cortex, thalamus, brain stem, basal forebrain, and other sites with GABAA receptors is the “likely mechanism through which propofol induces altered arousal states from sedation to unconsciousness.” To understand this study and its importance, EEG oscillations become relevant because different oscillations of frequency ranges can induce different physiological and neural responses. These oscillations change systematically with anesthetic drug class, drug dose, and patient age. There are four frequency ranges of oscillations to define. Alpha oscillations (8–12 Hz) produced by GABAergic anesthetics (not propofol) depend critically on excitatory and inhibitory connections between the thalamus and the cortex. Beta/gamma oscillations (15–50 Hz) produced by NMDA receptor agonists “depend on blocking the NMDA receptors of inhibitory and excitatory neurons in the cortex.” Lastly, “slow” or delta oscillations are produced by GABA- agonists. These oscillations dramatically alter when neurons can spike and impede communication between brain regions that play a role in consciousness. The first EEG pattern discussed in the study is paradoxical excitation; “propofol is well-known to induce paradoxical behavioral and electrophysiological manifestations of excitation, rather than sedation, at low doses.” A common EEG marker for this paradoxical excitation is higher levels of activity in the beta (12.5–25Hz) frequency band. The theorized cause of paradoxical excitation in this specific circumstance involves the interaction of pyramidal neurons with two types of inhibitory interneurons. The main one is “M-current, a slow potassium current, in low-threshold spiking (LTS) interneurons.” The essential dynamical mechanism is the creation of post-inhibitory rebound spiking in LTS interneurons. The second point of emphasis in the study is the high alpha oscillation activity in thalamocortical networks that becomes highly regular when unconsciousness occurs. In traditional unconscious states, low-frequency delta (1–4 Hz) activity in the EEG is linked to unconsciousness. This study shows that the point at which propofol induces unconsciousness is well-characterized by the appearance of a highly coherent alpha (9–13 Hz) rhythm in frontal cortices.
In this image, we can see the EEG activity change as dosage of propofol is increased. Part A shows a higher activity of beta and alpha-band oscillations as dosage increases. Part B is a thalamocortical model that matches the pattern in part A. Part C is a coherence analysis mapped on the actual data, which matches closely with part D which is a theorized model comparing the hypothesized output to the real data in part C. The process seen above links to the next concept delineated in the study, known as anteriorization. High alpha oscillations activity has a distinct “spatial structure,” which also manifests in frontal regions of the brain. During conscious states, there is an alpha rhythm in the occipital region of the brain when the eye is closed. As the brain moves into the unconscious state, there is a higher prevalence of alpha oscillations that emerges in frontal regions instead of occipital regions; this movement of the oscillations towards the front of the brain is known as anteriorization. The last concept of the study is known as burst suppression. This is when high amplitude activity alternates with periods of “isoelectric quiescence,” which is a transitional state that occurs between the levels of propofol described above and a state of complete EEG flatline. “The amount of suppression increases as a function of anesthetic depth this flatline is achieved. The electrophysiological properties of burst suppression include a broad spatial expression across the cortex and quasiperiodicity in the onset and offset of bursts.” This EEG pattern is also highly regular. All in all, the study describes important concepts and adds credence to the theory that reversible, drug-induced unconscious states induced by propofol are “strongly coupled to highly structured EEG oscillations.” This is because “administering propofol for general anesthesia or sedation is equivalent to applying simultaneously strong inhibitory inputs to the brainstem, thalamus and cortex,” and giving multiple brain regions a large dose of an inhibitory drug should have meaningful effects on the pattern activity of those corresponding regions. This idea leads us into some of the more technical approaches of describing EEG activity and its corresponding pattern analyses.
Before diving deeper into a computational discussion, I want to mention some of the studies that map and compare EEG patterns in drug-induced unconscious states, sleep states, and the coma state. This is done in “General Anesthesia, Sleep, and Coma,” also by Emery Brown.
In the above image, we can see some of the concepts discussed in the previous study in action. We can see the EEG activity that propofol induces on the brain and body. There is a region-specific and dose-dependent effect that propofol has on the brain; studies have shown that it diminishes the randomness of the spontaneous and evoked EEG signal. “Panel A on the bottom shows the EEG patterns when the patient is awake, with eyes open (left) and the alpha rhythm (10 Hz) with eyes closed (right). Panel B shows the EEG patterns during the states of general anesthesia: paradoxical excitation, phases 1 and 2, burst suppression, and the isoelectric tracing. Panel C shows the EEG patterns during the stages of sleep: rapid-eye-movement (REM) sleep; stage 1 non-REM sleep; stage 2 non-REM sleep, and stage 3 non-REM (slow-wave) sleep. The EEG patterns during recovery from coma — coma, vegetative state, and minimally conscious state — resemble the patterns during general anesthesia, sleep, and the awake state. We can see that there are profound differences between all three states of unconsciousness.” This image, at the very least, bolsters the support of our initial inclination on the matter, in which we believed that there would be marked differences in the EEG activity of different unconscious states brought about by different stimuli.
Other studies were also used to strengthen our discussion, but the topics integrated in those papers are covered by the discussion above. Other studies include “Sleep and Anesthesia – Common mechanisms of action” by Susana Vacas, “Neural oscillations demonstrate that general anesthesia and sedative states are neurophysiologically distinct from sleep,” by Emery Brown, “Potential Network Mechanisms Mediating Electroencephalographic Beta Rhythm Changes during Propofol-Induced Paradoxical Excitation” by Emery Brown, “Cognitive Unbinding: A Neuroscientific Paradigm of General Anesthesia and Related States of Unconsciousness,” by George Mashour, and “Tracking brain states under general anesthesia by using global coherence analysis,” by Aylin Cemenser. These studies either set forth the mathematical and computational component of analysis of the topics discussed previously, or dive deeper into some of the previously discussed topics to discover relationships between ostensibly unrelated phenomena in EEG activity or physical models.