“Some of the patients remembered the sound of their limb dropping to the ground, or the saw going through their sinew and bones. The smell of their own body being cut into. Usually, a surgeon would employ six burly men to hold a patient down. And instead of having an operation, some people committed suicide before they would face going into an operating room, which were usually located on the top floor of a hospital, in part because the hospital really didn’t do itself a lot of good to have the screams heard by passers-by.” [1]
This grim reality characterised the everyday theatrics of the surgical theatre prior to October 16th, 1846. On this day, the esteemed surgeon Dr John Warren was due to operate on Gilbert Abbot, a young printer with a vascular neck tumour. This operation would be different, as the first to use ether as a general anaesthetic.
Warren had a week prior met the dentist William T. G Morton, a moustache cladden man toting a mysterious bag of gas, who had convinced the surgeon that ether was an effective means of erasing pain during surgery. Morton had successfully tried ether as an anaesthetic on his dental patients, himself and his pet dog and goldfish. Warren noted that “the general properties of ether have been known for more than a century, and the effect of its inhalation in producing exhilaration and insensibility has been known for many years” [2], but no one had previously thought to use ether to reduce consciousness and relieve pain during surgical procedures.
In the packed surgical amphitheatre of Massachusetts General Hospital, Warren prepared for the operation whilst Morton fumbled with a valve mask on Abbot’s face that he had only just constructed and never tested before, administering ether by manually operating the valves with each inhale and exhale. After 3 minutes, Abbott was fully unconscious. Warren brought down the scalpel to Abbot’s neck to make the first incision, and for the first time in history in an operating theatre there was complete silence.
The experience of undergoing anaesthetic is the complete absence of selfhood and time, a call to the oblivion from which we have come from and where we may go. Through anaesthetics, consciousness can be temporarily and reversibly altered without completely halting brain activity. While the exact mechanism of how individual anaesthetic agents induce unconsciousness and impair awareness is not completely understood, the pharmacokinetics of anaesthetic agents can be broadly categorised by their effects: those which upregulate inhibitor neuronal activity (e.g propofol and halogenated vapours working on GABA receptors) and those which inhibit excitatory neuronal activity (e.g ketamine on NMDA receptors). Anaesthetics affect almost all living organisms – bacteria become sluggish, whilst mimosa plants are rendered unresponsive to touch.
The art of anaesthetics lies in keeping a patient in a steady state of unconsciousness whilst they are paralysed by a neuromuscular blockade. If the patient is underdosed, they will drift into a new consciousness state with the potential catastrophic consequence of accidental awareness during the procedure. An excessive dose, meanwhile, can cause significant physiological sequelae during the procedure, increase postoperative nausea, vomiting and delirium and neurocognitive disorders (NCDs) [3].
Monitoring the depth of anaesthesia typically involves processed electroencephologram (EEG). Electrodes are placed over the scalp and record the activity of cortical neurons closer to the surface of the skull – the amplitude and frequency of these neural activities are then sub-categorised and can correlate to states of both wakefulness and consciousness [4]. An EEG recorded inadvertently on an 87 year old who experienced a fatal heart attack showed oscillations consisting of gamma waves, a form of brain activity involved in memory retrieval and suggestive that the final act of brain activity in death may be a recall of important life events [5].
[4] Abhang PA, Gawali BW, Mehrotra SC. Technological basics of EEG recording and operation of apparatus. Introduction to EEG-and speech-based emotion recognition. 2016 Jan:19-50.
EEG monitors assimilate the data from frequency and amplitude of waveforms of brain activity to create a single continuously updated number between 0-100, the Bispectral Index (BIS). Generally speaking, loss of consciousness occurs at a BIS value of 70 to 80, while an optimal range for general anaesthesia is between 40-60 [6]. BIS can be a problematic metric as the algorithm which generates scores from EEG data are still hidden behind patent, and there have been cases of poor correlation between BIS number and behavioural signs of consciousness such as eye opening, indicating that BIS may not be sensitive enough to differentiate between different possible states of consciousness under anaesthesia [7,8,9].
[9] Bonhomme V, Staquet C, Montupil J, Defresne A, Kirsch M, Martial C, Vanhaudenhuyse A, Chatelle C, Larroque SK, Raimondo F, Demertzi A. General anesthesia: a probe to explore consciousness. Frontiers in Systems Neuroscience. 2019 Aug 14;13:36.
Transcranial magnetic stimulation (TMS) offers additional insights into brain function through different states of consciousness, in combination with proton emission tomography (PET) and functional magnetic resonance imaging (fMRI) techniques to monitor changes in regional cerebral blood flow. TMS pulsing involves monitoring the effect of firing a short transcranial magnetic pulse on neuronal activity. Like observing the ripples generated from throwing a stone into a water, the complexity of the neural chatter in response to a TMS pulse is analysed and indexed as a perturbational complexity index (PCI). Under a general anaesthetic, there is a strong initial response to a TMS pulse but this is not sustained, resulting in a lower PCI value. Whereas in a conscious state, the ripples from a TMS pulse re-appear in multiple complex and intricate patterns long after the initial response, resulting in a higher PCI value. In clinical studies PCI values correlate highly with clinical diagnosis of the severity of brain injury made by neurologists on patients. Through PCI metrics a dividing line can be drawn between minimally conscious states and those suggesting its absence such as persistent vegetative states, despite their similar clinical appearance [10, 11].
An individual’s required anaesthetic dose varies significantly. In one study 16 subjects received a slow infusion of an increasing dose of propofol under EEG monitoring [12]. Shortly after a loss of behavioural response to sensory stimulation all patients recorded mounting “slow wave activity”, marked by low frequency (1Hz) waves which did not vary with any further increase in propofol concentration. The concentration of propofol required to induce slow wave activity varied significantly among patients, suggesting personalised dosing could optimise therapeutic effects. fMRI studies at the same time of the transition to slow wave activity showed the thalamocortical network – the central brain network for sensory processing and perception, becomes an island unresponsive to external sensory stimuli whilst its own internal signalling is preserved. Interestingly, during the transition to slow waves the neural activity within the cortical network – an alternative network within the cerebral cortex, is fully preserved and remains responsive to sensory stimuli and is able to generate its own alpha waves. When music is played to a patient under anaesthetic, this is still “heard” and processed by the auditory cortex within the cortical network but this cannot be communicated to other regions of the brain [13].
The slow oscillation appears to occur asynchronously across different regions of the brain. For an individual neuron, there is still a small window during the 1Hz slow wave in which neuronal activity re-appears at the same intensity as the conscious state (neuronal spiking), but outside of this window the neuron is silent [14]. The timing of neuronal spiking is fragmented across different areas of the brain due to the asynchronous nature of the disruptive slow wave, preventing functional connectivity between cortical areas. Imagine being a member of a crowd for a ninety minute football match trying to start a Mexican Wave, except you can only stand and wave your arms for one random minute of the ninety (during which no one else notices you), and for the remaining eighty nine minutes of the game you are completely oblivious to the crowd around you. That is how it feels to be a neuron under the effects of propofol.
Our growing understanding of anaesthetics indicates they are able to exert a dose-dependent effect which allows internal consciousness to be sustained without globally suppressing brain activity. The input of anaesthetics produces a sudden interruption to our subjective experience, and the outcome of blissful unawareness of traumatic surgery – yet the details of the black box between remains elusive. As the science of consciousness continues to evolve; anaesthetics and consciousness remain entangled whilst the former can temporarily abolish the latter. Through exploring the disruptive effects of anaesthetics on the brain’s delicate electrochemical imbalance, we may bring ourselves closer towards understanding just what it is to ‘be’.
References
- Fenster JM. Ether day: the strange tale of America’s greatest medical discovery and the haunted men who made it. (No Title). 2001 Aug.
- Warren JC. Etherization; with surgical remarks. William D. Ticknor & Company; 1849.
- Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, et al., Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018. Anesthesiology. 2018 Nov 1;129(5):872-9.
- Abhang PA, Gawali BW, Mehrotra SC. Technological basics of EEG recording and operation of apparatus. Introduction to EEG-and speech-based emotion recognition. 2016 Jan:19-50.
- Greyson B, Pim van Lommel MD, Fenwick P. Recent report of electroencephalogram of a dying human brain. Journal of Near-Death Studies. 2022 Mar 1;40(1):5-11.
- Mathur S, Patel J, Goldstein S, Hendrix JM, Jain A. Bispectral index. InStatPearls [Internet] 2023 Nov 6. StatPearls Publishing.
- Ferreira AL, Nunes C, Mendes JG, Amorim P. Do we have today a reliable method to detect the moment of loss of consciousness during induction of general anaesthesia?. Revista Española de Anestesiología y Reanimación (English Edition). 2019 Feb 1;66(2):93-103.
- Seth A. Being you: A new science of consciousness. Penguin; 2021 Oct 19.
- Bonhomme V, Staquet C, Montupil J, Defresne A, Kirsch M, Martial C, et al. General anesthesia: a probe to explore consciousness. Frontiers in Systems Neuroscience. 2019 Aug 14;13:36.
- Casali AG, Gosseries O, Rosanova M, Boly M, Sarasso S, Casali KR, et al. A theoretically based index of consciousness independent of sensory processing and behavior. Science translational medicine. 2013 Aug 14;5(198):198ra105-.
- Casarotto S, Comanducci A, Rosanova M, Sarasso S, Fecchio M, Napolitani M, et al. Stratification of unresponsive patients by an independently validated index of brain complexity. Annals of neurology. 2016 Nov;80(5):718-29.
- Ní Mhuircheartaigh R, Warnaby C, Rogers R, Jbabdi S, Tracey I. Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans. Science translational medicine. 2013 Oct 23;5(208):208ra148-.
- Krom AJ, Marmelshtein A, Gelbard-Sagiv H, Tankus A, Hayat H, Hayat D, et al. Anesthesia-induced loss of consciousness disrupts auditory responses beyond primary cortex. Proceedings of the National Academy of Sciences. 2020 May 26;117(21):11770-80.
- Lewis LD, Weiner VS, Mukamel EA, Donoghue JA, Eskandar EN, Madsen JR, et al. Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness. Proceedings of the National Academy of Sciences. 2012 Dec 4;109(49):E3377-86.[2] Warren JC. Etherization; with surgical remarks. William D. Ticknor & Company; 1849.
