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Oxford Textbook of Neuroscience and Anaesthesiology
Oxford Textbook of Neuroscience and Anaesthesiology
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Edited by Graeme McLeod, Colin McCartney, and Tony Wildsmith
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Edited by R. Peter Alston, Paul S. Myles, and Marco Ranucci
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Edited by Ernesto A. Pretto, Jr., Gianni Biancofiore, Andre DeWolf, John R. Klinck, Claus Niemann, Andrew Watts, and Peter D. Slinger
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Edited by Vicki Clark, Marc Van de Velde, Roshan Fernando
Oxford Textbook of Neuroscience and Anaesthesiology
Edited by George A. Mashour and Kristin Engelhard
Oxford Textbook of Neuroscience and Anaesthesiology
Edited by George A. Mashour
Bert N. La Du Professor of Anesthesiology Research
Professor of Anesthesiology and Neurosurgery
Faculty, Neuroscience Graduate Program
Director, Center for Consciousness Science
Director, Michigan Institute for Clinical & Health Research
Associate Dean for Clinical and Translational Research
University of Michigan Medical School
Ann Arbor, Michigan, USA
Kristin Engelhard
Professor of Anesthesiology
Vice-Chair of the Department of Anesthesiology
University Medical Center of the Johannes Gutenberg-University Mainz, Germany
Great Clarendon Street, Oxford, OX2 6DP, United Kingdom
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Dedication
George A. Mashour
Dedicated to my wonderful children, Alexander Fulgens Mashour and Anna Luise Mashour—may they live long, healthy, and joyful lives, and reach the fullest potential of their beautiful minds.
Kristin Engelhard
Dedicated to my mentors and teachers Eberhard Kochs and Christian Werner, who always encouraged and supported me throughout my academic career.
Preface-the three pillars of Neuroanaesthesiology
While serving as the President of the Society for Neuroscience in Anesthesiology and Critical Care, I espoused a vision for neuroanaesthesiology that was supported by three ‘pillars’. The traditional pillar of neuroanaesthesiology relates to the care of neurosurgical and neurological patients. The clinical care of individuals with neurologic compromise is incredibly rewarding and represents a true opportunity to make a positive difference in the lives of others. However, the specialty of anaesthesiology is itself a form of clinical neuroscience. On a daily basis, even as anaesthetists for non-neurosurgical cases, we modulate peripheral nerves, the spinal cord, subcortical arousal systems, thalamocortical and corticocortical networks supporting consciousness, pain networks, memory systems in the medial temporal lobe, the neuromuscular junction, and the autonomic nervous system. From this perspective, ‘neuroanaesthesiology’ is more a compression of ‘neuroscience in anaesthesiology’ than ‘neurosurgical anaesthesiology’. The mechanistic study of our therapeutic interventions, which represents another pillar, is exciting neuroscience in its own right, and has profound implications for nervous system function. Finally, the question of how the peri-operative period might negatively impact the brain is the new frontier of outcomes studies and has been a major priority for the field of anaesthesiology in the past decade. Questions related to anaesthetic neurotoxicity, cognitive dysfunction, stroke, and other neurologic outcomes of non-neurosurgical interventions represent a critically important third pillar for the subspecialty.
The Oxford Textbook of Neuroscience and Anaesthesiology is the first book of its kind to comprehensively address all three pillars related to neuroscience in anaesthesiology. The first section treats the neuroscientific foundations of anaesthesiology, including the neural mechanisms of general anaesthetics, cerebral physiology, the neurobiology of pain, and more. The second section represents the traditional pillar related to the care of patients with neurologic disease in the operating room or intensive care unit, with a focus on clinical neuroanaesthesia. These chapters systematically treat the peri-operative considerations of both brain and spine surgery, and provide introductions to neurocritical care and pediatric neuroanaesthesia. Finally, the last section examines some connections of neurology and anaesthesiology, examining how conditions such as dementia, stroke, or epilepsy interface with the peri-operative period.
This international textbook gathers the best available expertise of authors and leaders in the field from Canada, Germany, Italy, New Zealand, Spain, Switzerland, the UK, and the US. They have done an outstanding job of crafting concise yet highly informative chapters describing the cutting edge of neuroscience and neuroanaesthesia. It is my hope that this textbook is itself a ‘chapter’ in the evolution of the field, creating a lasting foundation and appreciation for the three pillars of neuroscience in anaesthesiology.
George A. Mashour, M.D., Ph.D.
Abbreviations xi
Contributors xv
Digital media accompanying the book xvii SECTION 1
Neuroscience in Anaesthetic Practice
1 Neural Mechanisms of Anaesthetics 3
Andrew McKinstry-Wu and Max B. Kelz
2 Intracranial Pressure 17
Harald Stefanits, Andrea Reinprecht, and Klaus Ulrich Klein
3 Cerebral Physiology 27
Stefan Bittner, Kerstin Göbel, and Sven G. Meuth
4 Introduction to Electroencephalography 35
Michael Avidan and Jamie Sleigh
5 The Autonomic Nervous System 47
David B. Glick, Gerald Glick†, and Erica J. Stein
6 Neuromuscular Junction: Anatomy and Physiology, Paralytics, and Reversal Agents 61
Christiane G. Stäuble, Heidrun Lewald, and Manfred Blobner
7 Principles of Neuroprotection 77
Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel
8 Neurotoxicity of General Anaesthetics 93
Margaret K. Menzel Ellis and Ansgar Brambrink
9 Neurobiology of Acute and Chronic Pain 111
Adrian Pichurko and Richard E. Harris
10 Neurologic Emergencies 125
Ross P. Martini and Ines P. Koerner 11 Neurophysiologic Monitoring for Neurosurgery 137
Antoun Koht, Laura B. Hemmer, J. Richard Toleikis, and Tod B. Sloan
12 Brain Trauma 149
Anne Sebastiani and Kristin Engelhard
13 Supratentorial Craniotomy for Mass Lesion 161
Shaun E. Gruenbaum and Federico Bilotta
14 The Posterior Fossa 173
Tasha L. Welch and Jeffrey J. Pasternak
15 Cerebrovascular Surgery 189
Deepak Sharma and David R. Wright
16 Interventional Neuroradiology 201
Nathan Manning, Katherine M. Gelber, Michael Crimmins, Philip M. Meyers, and Eric J. Heyer
17 Pituitary and Neuroendocrine Surgery 213
Douglas A. Colquhoun and Edward C. Nemergut
18 Hydrocephalus and Associated Surgery 225
Paola Hurtado and Neus Fàbregas
19 Awake Craniotomy for Tumour, Epilepsy, and Functional Neurosurgery 235
Lashmi Venkatraghavan and Pirjo Manninen
20 Anaesthesia for Complex Spine Surgeries 245
Ehab Farag and Zeyd Ebrahim
21 Spine Trauma 255
Timur M. Urakov and Michael Y. Wang
22 Paediatric Neuroanaesthesia 263
Sulpicio G. Soriano and Craig D. McClain
23 Basics of Neurocritical Care 273
Magnus Teig and Martin Smith
Neurologic Patients Undergoing
Non-Neurologic Surgery
24 Cerebrovascular Disease 289 Corey Amlong and Robert D. Sanders
25 Peri-Operative Considerations of Dementia, Delirium, and Cognitive Decline 297
Phillip E. Vlisides and Zhongcong Xie
26 Epilepsy 303 Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp
27 Parkinson’s Disease 309 M. Luke James and Ulrike Hoffmann
28 Treatment of Psychiatric Diseases with General Anaesthetics 315 Laszlo Vutskits
Index 323
Abbreviations
133Xe Xenon
3D Three-dimensional
AANS American Association of Neurological Surgeons
ABC Airway, breathing, circulation
ABCB-1 ATP-binding cassette subfamily B member 1
ABI Acute brain injury
ABP Arterial blood pressure
ABR Auditory brain stem responses
ACA Anterior cerebral artery
ACC Anterior cingulate cortex
ACDF Anterior cervical discectomy with fusion
ACh Acetylcholine
AChE acetylcholinesterase
ACSNSQIP American College of Surgeons National Surgical Quality Improvement Program
SIADH Syndrome of inappropriate antidiuretic hormone secretion
sICH Symptomatic intracerebral haemorrhage
SII Secondary somatosensory cortex
SjvO2 Supra normal jugular venous oxygen saturation
SMA Supplemental motor area
SMT Spinomesencephalic tract
SNACC Society for Neuroscience in Anesthesiology and Critical Care
SNAPs Synaptosomal-associated protein
SNARE Soluble NSF receptor
SNS Sympathetic nervous system
SPECT Single-photon emission CT
SRT Spinoreticular tract
SSEP Somatosensory evoked potentials
SSRIs Selective serotonin and norepinephrine reuptake inhibitors
STAIR Stroke Therapy Academic Industry Roundtable
STN Subthalamic nucleus
STT Spinothalamic tract
SVS Slit ventricle syndrome
SWS Slow-wave sleep
TBI Traumatic brain injury
TCA Tricyclic antidepressant
TCD Transcranial Doppler sonography
TCS Transcranial stimulation
TDF Thermal diffusion flowmetry
TEE Transoesophageal echocardiogram
THx High temporal resolution
THx Therapeutic hypothermia
TIVA Total intravenous anaesthetic
TMN Tuberomamillary nucleus
TNF-α Tumour necrosis factor α
tPA Tissue plasminogen activator
TRP Transient receptor potential
TRPM TRP melastatin receptor
TRPV TRP vanilloid receptor
TSH Thyroid stimulating hormone
VAE Venous air embolism
VEP Visual Evoked Potentials
VIP Vasoactive intestinal protein
VLPO Ventrolateral preoptic nucleus
vPAG Ventral periaqueductal gray
VPL Ventroposterolateral
VPS Ventriculoperitoneal shunt
VR-1 Vanilloid receptor
VRL-1 Vanilloid-like receptor 1
VTA Ventral tegmental area
WDR Wide dynamic range
WFNS World Federation of Neurological Surgeons
ZO Zona occludens
β-ARK
β-adrenergic receptor
Contributors
Corey Amlong, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, USA
Michael Avidan, Department of Anesthesiology, Washington University School of Medicine, USA
Federico Bilotta, Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Italy
Stefan Bittner, Department of Neurology, Johannes Gutenberg University Mainz, Germany
Manfred Blobner, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany
Ansgar Brambrink, Department of Anesthesiology, Columbia University, USA
Douglas A. Colquhoun, Department of Anesthesiology, University of Michigan Medical School, USA
Michael Crimmins, Walter Reed National Military Medical Center, Department of Neurology, Neurosurgery and Critical Care, USA
Zeyd Ebrahim, Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, USA
Margaret K. Menzel Ellis, Portland VA Medical Center, Assistant Professor of Anesthesiology, Oregon Health & Science University, USA
Kristin Engelhard, Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Germany
Neus Fàbregas, Anesthesiology Department, Hospital Clìnic de Barcelona, Spain
Ehab Farag, Department of General Anesthesia and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, USA
Heidrun Lewald, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany
Katherine M Gelber, Department of Anesthesiology, Cedars-Sinai Medical Center, USA
Gerald Glick† , Department of Medicine, Rush Medical College, USA
David B. Glick, Department of Anesthesia & Critical Care, University of Chicago, USA
Kerstin Göbel, Department of Neurology, University Hospital Münster, Germany
Shaun E. Gruenbaum, Department of Anesthesiology, Yale University School of Medicine, USA
Richard E. Harris, Department of Anesthesiology, University of Michigan Medical School, USA
Laura B. Hemmer, Department of Anesthesiology and Neurological Surgery, Northwestern University, Feinberg School of Medicine, USA
Eric J. Heyer, Departments of Anesthesiology and Neurology, Columbia University, USA
Ulrike Hoffmann, Department of Anesthesiology, Duke University, USA
Paola Hurtado, Anesthesiology Department, Hospital Clìnic de Barcelona, Spain.
Adam K. Jacob, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA
M. Luke James, Departments of Anesthesiology and Neurology, Duke University, USA
Max B. Kelz, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, USA
Klaus Ulrich Klein, Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Austria
Ines P. Koerner, Department of Anesthesiology & Perioperative Medicine, Department of Neurological Surgery, Oregon Health & Science University, USA
Antoun Koht, Department of Anesthesiology, Neurological Surgery, and Neurology, Northwestern University, Feinberg School of Medicine, USA
Sandra L. Kopp, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA
Brian P. Lemkuil, Department of Anesthesiology, University of California San Diego, USA
Pirjo Manninen, Department of Anesthesia, Toronto Western Hospital University Health Network, University of Toronto, Canada
Nathan Manning, Departments of Neurosurgery and Radiology, Columbia University Medical Centre, New York Presbyterian, USA
Ross P. Martini, Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, USA
Craig D. McClain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, USA
Andrew McKinstry-Wu, Department of Anesthesiology and Critical Care, University of Pennsylvania, USA
Sven G. Meuth, Department of Neurology, Institute of Translational Neurology, Westfälische-Wilhelms University Münster, Germany
Philip M. Meyers, Departments of Radiology and Neurological Surgery, Columbia University, USA
Edward C. Nemergut, Department of Anesthesiology, University of Virginia Health System, USA
Adam D. Niesen, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA
Jeffrey J. Pasternak, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA
Piyush Patel, VA Medical Center, University of California San Diego, USA
Adrian Pichurko, Department of Anesthesiology, Northwestern University, Feinberg School of Medicine, USA
Andrea Reinprecht, Department of Neurosurgery, Medical University of Vienna, Austria
Robert D. Sanders, Department of Anesthesiology, University of Wisconsin, USA
Anne Sebastiani, Department of Anesthesiology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
Deepak Sharma, Department of Anesthesiology & Pain Medicine, University of WashingtonUSA
Jamie Sleigh, Department of Anaesthesia and Pain Medicine, Waikato Clinical Campus, University of Auckland, New Zealand
Tod B. Sloan, Department of Anesthesia, University of Colorado School of Medicine, USA
Martin Smith, Department of Neuroanaesthesia and Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, UK
Sulpicio G. Soriano, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, USA
Christiane G. Stäuble, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany
Harald Stefanits, Department of Neurosurgery, Medical University of Vienna, Austria
Erica J. Stein, Department of Anesthesiology, The Ohio State University, USA
Magnus Teig, Department of Anesthesiology, University of Michigan Medical School, USA
J. Richard Toleikis, Department of Anesthesiology, Rush University School of Medicine, USA
Timur M. Urakov, Department of Neurosurgery, University of Miami, Jackson Memorial Hospital, USA
Lashmi Venkatraghavan, Department of Anesthesia, Toronto Western Hospital, University of Toronto, Canada
Phillip E. Vlisides, Department of Anesthesiology, University of Michigan Medical School, USA
Laszlo Vutskits, Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Department of Basic Neuroscience, University of Geneva Medical School, Switzerland
Michael Y. Wang, University of Miami, Miller School of Medicine, USA
Tasha L. Welch, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA
David R. Wright, Departments of Anesthesiology & Pain Medicine and Neurological Surgery, University of Washington, USA
Zhongcong Xie, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, USA
Sophia C. Yi, Department of Anesthesiology, University of California San Diego, USA
Digital media accompanying the book
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Q Cases and multiple-choice questions
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If you are interested in access to the complete online edition, please consult with your librarian.
SECTION 1 Neuroscience in Anaesthetic Practice
1 Neural Mechanisms of Anaesthetics 3
Andrew McKinstry-Wu and Max B. Kelz
2 Intracranial Pressure 17
Harald Stefanits, Andrea Reinprecht, and Klaus Ulrich Klein
3 Cerebral Physiology 27
Stefan Bittner, Kerstin Göbel, and Sven G. Meuth
4 Introduction to Electroencephalography 35
Michael Avidan and Jamie Sleigh
5 The Autonomic Nervous System 47
David B. Glick, Gerald Glick†, and Erica J. Stein
6 Neuromuscular Junction: Anatomy and Physiology, Paralytics, and Reversal Agents 61
Christiane G. Stäuble, Heidrun Lewald, and Manfred Blobner
7 Principles of Neuroprotection 77
Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel
8 Neurotoxicity of General Anaesthetics 93
Margaret K. Menzel Ellis and Ansgar Brambrink
9 Neurobiology of Acute and Chronic Pain 111
Adrian Pichurko and Richard E. Harris
Neural Mechanisms of Anaesthetics
Andrew McKinstry-Wu and Max B. Kelz
Introduction
The first public demonstration of general anaesthesia took place in 1846. Over 170 years later, a majority of the estimated 234 million annual surgical procedures worldwide are performed under general anaesthesia (1). Nevertheless, general anaesthetics remain poorly understood as a unique class of drug that has infallible clinical efficacy with a narrow therapeutic window. Despite their pervasive use, there is a lack of basic knowledge of where and how anaesthetics produce both their desirable and unintended side effects.
Apparent similarities in dose- dependent behavioural effects among gaseous, volatile, and intravenous general anaesthetics led to the historical belief that all general anaesthetics shared a single molecular mechanism of action. Older theories of anaesthetic action relied on common chemical properties of the anaesthetics to explain their common effects, such as the association of lipid solubility with anaesthetic potency (the MeyerOverton rule). Ultimately, these early theories fell out of favour with the realization that anaesthetics could exert their actions in lipid-free protein preparations. Subsequently, many molecular targets of individual anaesthetics have been identified. With the discovery of each new molecular target, the fallacy of a unitary molecular mechanism of anaesthesia becomes more apparent. The past twenty years have demonstrated that knowledge of both the specific molecular targets, as well as their location in discrete neural circuits, is a prerequisite to any real understanding of anaesthetic hypnosis. Hence, the molecular, neuronal, circuit, and network targets of anaesthetics are all critical to our neuroscientific framework of how these agents produce reversible unconsciousness.
Molecular Mechanisms of Anaesthetic Hypnosis
The breadth of molecular targets of general anaesthetics highlights the diversity of molecular mechanisms sufficient to produce anaesthetic hypnosis. Inhaled and intravenous anaesthetics act on diverse protein targets to exert their hypnotic effects: ion channels, G-protein coupled receptors, and constituents of the electron transport chain, among others (Figure 1.1).
Ligand-Gated Ion Channels
Ligand-gated ion channels (LGICs) are common targets for volatile, gaseous, and potent intravenous agents. They provide an easily understood mechanism for modulating individual neural activity and offer a plausible method for altering large-scale neural effects. General anaesthetics variously affect multiple LGICs, the two most common being potentiation of inhibitory anionic channels and inhibition of excitatory cationic channels. In fact, the vast majority of general anaesthetics demonstrate specific actions at one or both of two LGICs: potentiation of the anionic gamma-aminobutyric acid (GABA)-gated GABAA receptor, and inhibition of the cationic glutamate- and- glycine- gated N- methyl- D- aspartate (NMDA) receptor.
Inhibitory Ligand-Gated Ion Channel Potentiation
GABA is the most common inhibitory neurotransmitter in the central nervous system (CNS.) The GABAA-receptor, an abundant GABA effector site, is a heteropentameric ligand-gated chlorineselective ion channel responsible for GABA’s inhibitory effects in the CNS. Importantly, it is also a crucial functional target of most potent intravenous agents and volatile anaesthetics (2–7). Volatile and intravenous anaesthetics that affect the GABAA-receptor enhance endogenous GABAergic signalling at pharmacologically relevant concentrations, and at higher concentrations can directly open the channel (5–10). Synaptic potentiation of GABAA-receptors affects size and duration of rapid, phasic, inhibitory postsynaptic potentials. Potentiation at extrasynaptic receptors, in contrast, alters baseline membrane potential through tonic chloride currents (11). The net effect of these actions is to decrease the chance that the postsynaptic neuron will fire an action potential in the presence of pharmacologically relevant concentrations of many general anaesthetics. Mounting evidence suggests that it is the extrasynaptic, tonic inhibition that is the primary method through which general anaesthetics produce their effects (12). Specific mutations in GABAA-receptor subunits at known anaesthetic binding sites produce attenuation to anaesthetic effects of specific agents, both in vitro and in vivo. Mutations in the alpha subunit of the GABAA-receptor reduce the effect of volatile anaesthetics and benzodiazepines, while beta subunit mutations attenuate the effects of intravenous and volatile anaesthetics (3, 5). This suggests a critical role for action at the GABAA-receptor in producing on-target anaesthetic effects.
Figure 1.1 Summary of the effect of anaesthetic drugs on molecular targets relevant to anaesthetic hypnosis.
Light blue circles represent activation or potentiation, dark blue circles indicate inhibition, and white circles indicate no effect. Circles with more than one colour are present where different agents of a single anaesthetic class have differing effects. Where interactions have not been explored in the literature, no circle is present.
Glycine receptors are the other significant inhibitory, anionic LGICs in the CNS. This receptor family is found mostly in the brainstem and spinal cord. Like GABAA - receptors, glycine receptors are heteropentameric chlorine channels, and are directly activated or potentiated by volatile and many intravenous anaesthetics (13–16). Evidence for the functional importance of glycine receptors to anaesthetic action is not as robust as that for the GABAA -receptor. Glycine receptor mutations can produce divergent responses to anaesthetic endpoints. Site-specific mutations of the glycine receptor that alter in vitro receptor sensitivity to volatile and potent intravenous anaesthetics do not always produce associated changes in immobility or hypnotic sensitivity in vivo (6, 17). Specifically with propofol, the glycine receptor may not contribute to immobility. A structural analogue of propofol that potentiates glycine (but not GABA) receptor signalling, 2,6 di- tert- butylphenol, lacks any immobilizing effects in vivo (7, 18, 19). Similarly, a Q266I point mutation introduced into the α1 subunit of the glycine receptor that decreases receptor sensitivity to isoflurane unexpectedly conferred hypersensitivity to the immobilizing properties of both isoflurane and enflurane in mice. These results suggest that glycine receptors containing the α 1 subunit are unlikely to mediate immobilizing properties of anaesthetics (20).
Excitatory Ligand-Gated Ion Channel Inhibition
Many general anaesthetics act to inhibit excitatory LGICs, a complementary effect to their potentiation of inhibitory LGICs. Glutamate is the primary excitatory neurotransmitter of the CNS. Among glutamate’s targets is the NMDA receptor (where it has glycine as a co-receptor). NMDA receptors are the functional target for a significant number of general anaesthetics. Like the extrasynapic GABA receptors responsible for tonic currents, NMDA receptors do not produce the fast postsynaptic transmission responsible for excitatory postsynaptic potentials, but acts presynaptically, postsynaptically, and extrasynaptically, and can affect synaptic plasticity (21). All known noncompetitive NMDA antagonists severely disturb consciousness, with many acting as general anaesthetics at sufficient concentrations (22). The gas anaesthetics nitrous oxide and xenon, as well as the intravenous agent ketamine, all act primarily as NMDA receptor antagonists, while many of the volatile anaesthetics possess NMDA antagonist activity in addition to their effects on other putative anaesthetic targets (23–26).
The nicotinic acetylcholine receptor, a ligand-gated nonspecific cation channel, is inhibited by volatile anaesthetics at clinically relevant concentrations. While that inhibition does not mediate anaesthetic hypnosis, it may mediate amnesia and analgesic effects of volatile anaesthetics (27–30). Moreover, central cholinergic
HCN NaV NMDA Glycine GABAmAch nAch TTCa RTCa Mt Complex I
signalling via nicotinic receptors appears important for anaesthetic emergence. Although blockade of cholinergic signalling may not be sufficient to alter loss-of-righting-reflex or Minimum alveolar concentration (MAC) concentration, it can still be sufficient to retard emergence from anaesthetic hypnosis (discussed later in this chapter).
Constitutively Active and Voltage-Gated Ion Channels
Members of the two- pore- domain potassium channel family (K2P) produce a continuous non-inactivatable current that modifies resting membrane potential and thus affects neuronal excitability (31). Volatile and gaseous anaesthetics directly activate members of this family, including TREK- 1, TREK- 2, TASK- 1, TASK-2, and TASK-3. Anaesthetic activation of these K2P channels causes an increase in potassium efflux out of the cell leading to hyperpolarization. However, not every member of the K2P family is activated by anaesthetic exposure. Several members are insensitive to anaesthetics, while THIK-1, TWIK-2, TALK-1, and TALK-2 are actually closed by anaesthetic exposure. Mutations of two-poredomain potassium channels can abrogate sensitivity to activation by volatile and gaseous anaesthetics. Distinct gene mutations alter volatile sensitivity versus sensitivity to gaseous anaesthetics (32).
An in vivo knockout of one K2P, TREK-1, caused an impressive 40% resistance to halothane and more modest resistance to other inhaled anaesthetics, while leaving barbiturate sensitivity unchanged (33).
Hyperpolarization- activated cyclic nucleotide- gated (HCN) channels are tetrameric, relatively nonspecific cation channels that activate with cell hyperpolarization (as opposed to depolarization.) The Ih current, produced by HCN activation, is involved in producing long-term potentiation, dendritic integration, control of working memory, and thalamocortical oscillations (34). Of the four HCN isoforms, HCN1 is both abundant in the CNS and inhibited by volatile and intravenous agents. Agents as diverse as isoflurane, ketamine, and propofol inhibit HCN1 at clinically relevant doses. In in vivo models, this HCN1 inhibition plays a direct role in the hypnotic potency of these agents (35–38). There is even debate that NMDA receptor antagonists producing hypnosis do so not through actions at the NMDA receptor itself, but through their inhibition of HCN1 (37). The involvement of HCN channels in critical CNS processes and their inhibition by diverse anaesthetic agents suggest a significant role for this channel in anaesthetic-induced hypnosis.
Voltage-gated potassium channels of the Kv1 family are recently identified targets of volatile anaesthetics that contribute to suppression of arousal. Flies with mutations in a gene coding for a member of the Kv1.2 family (shaker) exhibit altered sensitivity to volatile anaesthetics, requiring higher doses than wild-type controls to cease movement (39). Sevoflurane enhances currents in members of the Kv1 family, with other clinically used volatiles also affecting Kv1 currents, suppressing firing in the central medial thalamus (40). Kv1 channel inhibitors infused into the central medial thalamus are able to reverse continuous low-dose sevoflurane anaesthesia in animal models, as are antibodies against Kv channels (41).
Voltage-gated sodium channels are a requisite for normal excitatory neuronal function, as they are key to initiating and propagating action potentials. Their inhibition by volatile anaesthetics presynaptically results in a decreased likelihood of action potential propagation and decreased presynaptic neurotransmitter release. Several sodium channel subtypes are inhibited by volatile anaesthetics in pharmacologically relevant concentrations, though
historically inhibition had only been seen at higher concentrations (42). The role of sodium channels in volatile anaesthetic hypnosis is demonstrated by hypersensitivity to isoflurane and sevoflurane in mice with reduced activity in one voltage-gated sodium channel subtype, NaV1.6 (43).
Presynaptic voltage-gated calcium channels are critical for neurotransmitter release and inhibited by general anaesthetics, making them likely anaesthetic targets. Low- voltage- activated T- type calcium channels, which modulate cellular excitability through regulating burst firing and pacemaker activity, are inhibited by clinically relevant concentrations of volatile and intravenous anaesthetics (44–46). In vivo knockouts of T-type calcium channels do not show changes in anaesthetic sensitivity to the loss of righting reflex (LoRR), a traditional rodent equivalent endpoint to loss of consciousness in humans, though they do have altered speed of induction and reaction to noxious stimuli (46, 47). This suggests that the effects of anaesthetics upon these channels modulate the anaesthetized state, rather than cause it. High-voltage-activated calcium channels (R-type) are also sensitive to inhibition by volatile anaesthetics, and contribute to rhythmicity of thalamocortical circuits. Rtype knockouts display less electroencephalographic suppression at 1% isoflurane than their wild-type counterparts. This suggests that thalamic calcium channels are involved in isoflurane-induced thalamic suppression, thought to contribute to unconsciousness (48).
G-Protein-Coupled Receptors
G-protein-coupled receptors make up the largest and most diverse family of membrane receptors. They comprise 4% of the entire coding human genome and are the target for over a quarter of all current pharmaceuticals (49). Drugs that affect this receptor superfamily are an integral part of anaesthetic practice, including such diverse classes as opioids, vasopressors, and anticholinergics. So, while these receptors are known targets for producing analgesia and amnesia, there is little direct evidence that volatile-anaestheticinduced hypnosis is primarily mediated via this superfamily of receptors. This is despite the fact that volatile anaesthetics do selectively activate G-protein-coupled receptors at pharmacologicallyrelevant concentrations (50, 51). Ketamine very specifically interacts with a subset of olfactory receptors, which are a subgroup of G-protein-coupled receptors, though it is unclear if these interactions are in any way related to its anaesthetic actions (52).
Electron Transport Chain
Unlike the previously discussed membrane-bound proteins in the cell’s outer membrane, components of complex I, a multi-subunit member of the respiratory chain, are putative anaesthetic targets located in the inner mitochondrial membrane. Animal models with mutations in specific subunits of complex I, GAS-1 in C. elegans and Ndufs4 in mice, are hypersensitive to volatile anaesthetics. This hypersensitivity phenotype is strictly mirrored across evolution up to and including humans with complex I mutations (53–55). The anaesthetic hypersensitivity phenotype is not present in all complex I gene mutations, nor is it present with other electron transport chain mutations, indicating a specific interaction between volatile anaesthetics and precise complex I subunits. While halogenated ethers and alkanes inhibit complex I function though interaction with the distal portion of the complex, volatile anaesthetics do not appear to disproportionately decrease ATP production in complex I mutants. This dissociation suggests volatile anaesthetic hypnotic
action is not solely a result of disproportionate mitochondrial energetic disruption in those mutants, begging the persistent question of how these mutations cause anaesthetic hypersensitivity (56–58).
Systems Neuroscience and Anaesthetic Effects: Discrete Nuclei and Local Networks
There is incontrovertible evidence for anaesthetic drugs interacting with multiple molecular targets to affect behaviour, but anaesthetic hypnosis is impossible to explain by mere examination of molecular binding events in isolation. The imperfect connection between molecular action and larger-scale brain phenomena must be interpreted in light of relevant neuroanatomy. Complexities are introduced by circuit-level interactions—neuronal hyperpolarization that reduces firing of a presynaptic inhibitory input can increase activity for the postsynaptic neuron resulting in a net increase of circuit output. Evaluating the net contribution of anaesthetics on discrete brain regions to hypnosis provides a way to simplify the massive complexity encountered at the molecular and neuronal level without ignoring the fundamental circuitry of the CNS.
Sleep and Arousal Pathways
General anaesthetics alter the activity of endogenous arousal circuits. Such actions directly contribute to their hypnotic effects (Figure 1.2). Anaesthetic- induced unconsciousness is a nonarousable behavioural state that shares many commonalities with slow-wave sleep (SWS) There is a functional loss in cortical connectivity during both NREM sleep and anaesthetic hypnosis. Moreover, over much of the anaesthetic dose response range, the cortical electroencephalography (EEG) exhibits striking similarities, such that processed EEG measures developed to assess
anaesthetic depth can also distinguish wakefulness from sleep (59–65). During anaesthesia and sleep, thalamic nuclei and wake-active nuclei, collectively known as the reticular activating system, are similarly inhibited (46, 66–70). Parallels between the states extend to their functional effects—in some cases anaesthesia can substitute for sleep. Sleep debt does not accrue during prolonged periods of propofol-induced unconsciousness, while propofol hypnosis appears to relieve previously incurred sleep debt (71–73). Conversely, sleep deprivation or administration of endogenous somnogens reduce the dose of anaesthetic required for hypnosis. In a parallel vein, induction and maintenance of anaesthesia itself alters levels of endogenous somnogens (72, 74). Together, these data support the theory that anaesthetic-induced hypnosis stems in part from actions of anaesthetics on the neural circuits involved with endogenous sleep-wake control.
Arousal-Promoting Nuclei of the Reticular Activating System
The ascending reticular activating system, extending rostrally from the mid pons to the hypothalamus, basal forebrain, and thalamus, was first identified more than half a century ago. Stimulation of the brain stem reticular formation causes cortical arousal during anaesthetic states (75). Subsequently, discrete interacting neuronal populations were found to be the arousal-promoting components of the activating system, including cholinergic, histaminergic, adrenergic, serotonergic, dopaminergic, and orexinergic centres.
Laterodorsal Tegmentum (LDT) and Pedunculopontine Tegmentum (PPT)
These nuclei comprise two major cholinergic populations in the brainstem with the ability to regulate arousal state and promote
Frontal cortex
Mesial parietal cortex
Precuneus
Posterior cingulate cortex alamus
Hippocampus
Mesopontine tegmental area
Amygdala BF (Ach/Glut/GABA) POA (GABA/Gal)
(5-HT) vPAG
Figure 1.2 Cortical and subcortical (inset) structures affected by anaesthetic agents and potentially contributing to hypnosis. Arrows indicate the ascending reticular activating system, both the anterior branch passing through the basal forebrain before ascending to the cortex and the posterior branch extending into the cortex via the thalamus. The primary neurotransmitters associated with their respective subcortical structures are listed in parentheses. BF: basal forebrain, Ox: orexin field, TMN: tuberomamillary nucleus, VTA: ventral tegmental area, DpMe: deep mesencephalic reticular formation, PPT/ LDT: pedunculopontine tegmentum/laterodorsal tegmentum, LC/PB: locus coeruleus/parabrachial nucleus, PnO: pontine oralis, PZ: parafacial nucleus, vPAG: ventral periaqueductal grey, RN: raphe nucleus, POA: preoptic area. HA: histamine, DA: dopamine, Glut: glutamate, Ach: acetylcholine, GABA: gamma-aminobutyric acid, 5-HT: serotonin, Gal: galanin.
wakefulness or REM sleep. These cholinergic neurons densely innervate the midline and intralaminar thalamic nuclei and thalamic reticular nucleus and alter thalamic activity from bursting to spiking (76). Direct effects of these nuclei on anaesthetic-induced hypnosis are unknown. Despite this, the PPT is in a region that is associated with pain-induced movement, the inactivation of which leads to a significant decrease of isoflurane MAC (77).
Locus Coeruleus (LC)
The Locus Coeruleus is the site of the brain’s largest collection of noradrenergic neurons. As with many of the other monoaminergic systems, the LC diffusely innervates the brain by projecting directly to the cortex, thalamus, hypothalamus, basal forebrain, amygdala, hippocampus, and other subcortical systems. State- dependent modulation of activity within the LC has long been proposed as an essential means of regulating arousal. Changes in the activity of LC neurons occur before, and are predictive of, changes in an organism’s behavioural state (78). Through its actions on alpha1 and beta receptors, firing of LC neurons promotes wakefulness through actions on the medial septum, the medial preoptic area, and the substantia innominata within the basal forebrain. Activity in the LC modulates thalamocortical circuits, switching the tone of thalamocortical neurons from the burst pattern of slow-wave sleep to a spiking pattern that characterizes wakefulness. Consequently, optogenetically driven LC activity causes transitions from SWS to wakefulness (79). Under deep isoflurane anaesthesia, artificially driven LC activity has been shown to cause EEG desynchronization. Similarly, artificially induced firing of the LC speeds emergence from isoflurane anaesthesia (80). However, the LC is not the sole source of adrenergically driven arousal. Noradrenergic populations outside of the LC, such as the A1 and A2 brainstem groups, also may contribute to the regulation of sleep, wakefulness, and anaesthesia (81–83).
Pontine Reticular Nucleus, Oral Part (PnO) Neurons in this large region (which includes the sublaterodorsal nucleus) receive cholinergic, orexinergic, and GABAergic inputs and include wakefulness- promoting and REM- on populations. PnO activity also modifies anaesthetic action. GABAergic activity at the PnO produces resistance to induction without significant effects on emergence (84–87). Electrical stimulation at the PnO causes an increase in functional connectivity under continuous isoflurane anaesthesia, similarly suggesting anaesthetic antagonist actions (88). This region highlights the critical importance of neuroanatomic and neurochemical compartments: unlike most other regions of brain, increased GABA levels in the PnO promote wakefulness. Other seemingly paradoxical effects occur in this region: wakefulness is actually impaired by local delivery of adenosine or acetylcholine into PnO, or alternatively, promoted by local delivery of orexin or GABA (89–91). Cholinergic input to the PnO originates from the LDT and PPT, while the orexinergic input arises from the hypothalamus. Divergent responses to adenosine and GABA suggest that simple disinhibition of a single population of PnO neurons is not sufficient to understand the actions of these neuromodulators. Further clouding the picture, microinjections of pentobarbital within a region that has been termed the mesopontine tegmental area, which overlaps with a significant portion of the PnO and some neighbouring structures, have been shown to induce hypnosis similar to systemic administration of a larger general anaesthetic dose, while nearby injections lack any
systemic effects (92, 93). Clearly, a more complex local microcircuitry awaits discovery.
Deep Mesencephalic Reticular Formation (DpMe)
Over the decades, many studies have demonstrated that electrical stimulation in the DpMe reliably induces cortical activation in anaesthetized animals. These presumptively glutamatergic neurons project to the thalamus, hypothalamus, and basal forebrain, where they increase their firing rates prior to the onset of wakefulness, and fire more slowly during SWS (94). These glutamatergic neurons are possibly part of a previously poorly recognized arm of the ascending arousal system that potentially includes the parabrachial nucleus as well.
Hypocretin/Orexinergic Neurons
The orexin signalling system exerts potent wake-promoting and wake-stabilizing effects, and plays an important role in modulating anaesthetic emergence. As with the monoaminergic wake-active systems, the orexin system displays state-dependent firing patterns with maximal activity during active wakefulness and silence during SWS (95). Anatomically, these neurons project to all of the monoaminergic groups along with extending to the basal forebrain, midline thalamic nuclei, and other regions known to participate in the regulation of arousal. When signalling of these neurons is impaired, narcolepsy with cataplexy ensues (96). Local application of orexin excites target neurons expressing either of the two orexin Gqcoupled neurotransmitter receptors, including the LDT, LC, RN, basal forebrain (BF), and thalamocortical neurons. Halogenated ethers, propofol, and pentobarbital inhibit orexinergic neuronal activity, and genetic knockout of these neurons results in delayed emergence from isoflurane and sevoflurane anaesthesia without affecting sensitivity to anaesthetic induction (97–99). In the case of barbiturate anaesthesia, the pharmacologic inverse is true as well: intracerebroventricular injection of orexin speeds emergence, and orexin1-receptor blockade negates this effect (100). The case of delayed emergence without altered induction in orexinergic deficient animals highlights the intriguing possibility that distinct populations of neurons may unilaterally and differentially impact the process of entering into or exiting from the anaesthetic state.
Wake-Promoting Neurons of the Basal Forebrain
The BF encompasses heterogeneous populations of neurons active in arousal and sleep that modify anaesthetic state and sensitivity. GABA agonists microinjected at the BF potentiate systemic intravenous and volatile anaesthetic effect and duration, as do electrolytic lesions of the medial septum within the BF (101, 102).
The BF sits atop the ventral extrathalamic relay and receives integrated arousal inputs from caudal structures. Within the BF, there are wake-active cholinergic neurons, wake- active glutamatergic neurons, wake- active parvalbumin- containing GABAergic neurons, and sleep- active somatostatin- containing GABAergic neurons (103). The cholinergic neurons receive afferents from the LC, DpMe, Tuberomamillary nucleus (TMN), orexinergic neurons, parabrachial neurons, and glutamatergic neurons of the BF, and send widespread efferent projections to the cortex and hippocampus, as well as back to the hypothalamus. Selective lesion of cholinergic neurons within the nucleus basalis of the BF prolongs behavioural effects of propofol and pentobarbital (104). Increased cholinergic activity of the basal forebrain during wakefulness is responsible for the fluctuations in cortical acetylcholine levels. The
cholinergic neurons stimulate cortical activation, and the resultant increased discharge frequency, along with increased activity of cortically projecting parvalbumin-containing GABAergic neurons, underlies the desynchronized EEG that typifies wakefulness as well as REM sleep (103, 105).
Parabrachial Nucleus
Neurons in the parabrachial nuclei belong to a recently identified glutamatergic arm of the anterior branch of the ascending arousal system and can themselves modify the anaesthetic state. Lesion of the parabrachial nuclei induces coma, while the sleepactive parafacial zone (see Sleep- active Neurons of the Basal Forebrain and Parafacial Zone) promotes SWS through inhibition of glutamatergic parabrachial neurons that, in turn, project to the BF (106–109). Electrical stimulation of the parabrachial nucleus is able to antagonize continuous low-dose isoflurane administration (110). This observed direct effect on anaesthetic sensitivity, as well as the parabrachial’s known anatomic and functional connection with sleep-active nuclei and other CNS regions that affect anaesthetic sensitivity and emergence, suggests a significant role for the parabrachial nucleus in maintaining or emerging from an anaesthetic state. However, this has yet to be fully explored.
Ventral Tegmental Area (VTA)
A midbrain dopaminergic and GABAergic region associated with both arousal and reward, the VTA receives diverse inputs and has widespread outputs, including the prefrontal cortex, cingulate gyrus, hippocampus, amygdala, and nucleus acumbens. Reflecting those widespread connections, it is functionally diverse, with roles in motivation, cognition, and arousal (111). Dopaminergic neurons of the VTA do not appear to change their firing rate across sleep–wake. Consequently, VTA dopamine neurons have not been linked to modulation of spontaneous arousal. Nevertheless, dopaminergic neurons are suppressed by GABA, and other neurons within the VTA have circadian-dependent activity (112–116). Artificially driving dopamine release from the VTA, administration of methylphenidate, or more selective pharmacologic agents that act on D1like receptors, will all accelerate anaesthetic emergence, and can even reverse anaesthesia produced by continuous administrations of propofol or isoflurane (117–120).
Tuberomamillary Nucleus (TMN)
The sole source for histamine in the CNS, the histaminergic neurons of the TMN have widespread projection throughout the brain and have activity tightly correlated with arousal state (121). Though centrally administered histamine causes potent arousal, and central H1 antagonists produce sedation, the role of the TMN in modifying general anaesthesia is circumscribed. Lesions of the TMN increase sensitivity to isoflurane-induced LoRR, but leave propofol, ketamine, and barbiturate sensitivity unchanged (122). Cell-specific knockout of GABAA receptors in histaminergic cells likewise produced no change in propofol hypnotic sensitivity. These phenomena were observed despite the fact that histaminergic neurons lacking GABAA receptors were resistant to hyperpolarization by propofol—strong evidence that histaminergic neurons are not critical to induction or maintenance of propofol hypnosis (123).
Dorsal Raphe (DR) and Ventral Periaqueductal Gray (vPAG)
The serotonergic neurons of the raphe nuclei have diffuse projections throughout the brain and comprise the largest source of
CNS serotonin. The median raphe contributes little to producing or modulating anaesthetic actions. In contrast, when the DR is silenced by calcium blockage or by lesion, sensitivity is increased to pentobarbital or halothane and cyclopropane, respectively (124, 125). The raphe nuclei (RN) do display state-dependent firing similar to noradrenergic or histaminergic centres. Single unit recordings, however, demonstrate that firing rates of serotonergic neurons do not anticipate spontaneous changes in arousal state (126). This suggests that activity of the DR is not causally linked to changes in behavioural state.
Within the vPAG, there is a population of dopaminergic neurons that are wake-active. This is in contrast to dopaminergic neurons of the VTA or substantia nigra, which do not display state-dependent activity. However, the vPAG dopaminergic neurons appear not to contribute to anaesthetic hypnosis. Instead, they modulate analgesia, with lesions of these neurons causing decreased reaction to noxious stimuli under general anaesthesia (127, 128).
Sleep-Active Neurons and Nuclei
When compared to the large numbers of known arousalpromoting, wake-active nuclei, there are few neural populations that are predominantly active during SWS or REM sleep with decreased activity during wakeful states. Neurons with sleep-active firing patterns are most commonly found in the preoptic area and BF (though populations do exist elsewhere, including in the pons and cortex.) These populations act as a network counterbalance to many of the arousal-promoting populations discussed previously. Just as there are many examples of anaesthetics depressing those arousal centres, there is evidence for sleep-active neurons being directly and indirectly activated by certain anaesthetics.
Preoptic Area: Ventrolateral Preoptic Nucleus (VLPO) and Median Preoptic Nucleus (MnPO)
In the earliest attempts to identify specific populations of sleeppromoting neurons, a definitive role was assigned to the preoptic anterior hypothalamus. This broad region encompasses the VLPO, which lies within the anterior hypothalamus on the ventral floor at the level of the optic chiasm, as well as the MnPO, which straddles the decussation of the anterior commissure. Neurons with heightened activity during SWS are found throughout the preoptic area, with the greatest concentration found in VLPO. Neurons of the VLPO are more active during SWS and REM sleep. Changes in VLPO activity precede the changes in an organism’s behavioural state. Retrograde and anterograde labelling studies show the VLPO is reciprocally interconnected with many wake-promoting nuclei, including the histaminergic TMN, serotonergic RN, noradrenergic LC, and the cholinergic LDT and PPT, as well as the orexinergic neurons of the hypothalamus. VLPO neurons contain the inhibitory neurotransmitters GABA and galanin and are thus ideally positioned to coordinate and reciprocally inhibit wake-active ascending reticular activating nuclei.
The role of the preoptic area in promoting and modulating the anaesthetic state appears connected to its regulation of sleep and wake. Destructive lesions of VLPO cause long-lasting insomnia. Bilateral lesions of the VLPO also cause a biphasic change in anaesthetic sensitivity that possibly relates to insomnia: at six days post-destruction, animals showed resistance to isoflurane LoRR, while 24 days post-lesion, subjects showed hypersensitivity to isoflurane LoRR. Such changes have been hypothesized to arise
due to accumulating sleep pressure as VLPO lesioned animals fail to sleep (129, 130). Isoflurane directly depolarizes GABAergic neurons in VLPO. Acute resistance to isoflurane induction seen following VLPO lesions suggests that in normal conditions, anaesthetic activation of VLPO contributes to induction. Except for ketamine, every other general anaesthetic appears to depolarize and recruit putative sleep-active VLPO neurons. The population of neurons throughout the preoptic area (including the VLPO, MnPO, and surrounding area) that are active during recovery SWS (after sleep deprivation) significantly overlap with the population of neurons activated with systemic administration of hypnotic doses of dexmedetomidine. This reinforces earlier findings suggesting dexmedetomidine acts on native preoptic sleep circuits to produce hypnosis (131, 132).
Similar to the VLPO, MnPO sleep- active neurons are GABAergic and fire more rapidly several seconds prior to sleep onset. Although not as broadly activated by anaesthetics as the VLPO, some inhaled anaesthetics also appear to activate putative sleep- active MnPO neurons (133). Microinjection of benzodiazepines, propofol, and pentobarbital into the MnPO has been shown to induce SWS (72, 134, 135). Due to the state-dependent firing pattern of MnPO neurons, they have been assigned an important role in the initiation of sleep. The MnPO is known to send inhibitory projections to multiple arousal systems, including the orexinergic neurons in the hypothalamus, in a manner similar to the VLPO.
Sleep-active Neurons of the Basal Forebrain and Parafacial Zone (PZ)
While arousal-promoting neurons of the BF and pons are well established and their effects on anaesthetic states detailed, it is only recently that sleep-active groups in these structures were identified. Although they interact with arousal centres known to influence anaesthetic actions, the effects of these newly detailed groups on the anaesthetic state and the effects of anaesthetics on their action remain to be investigated. Parvalbumin-positive GABAergic neurons of the BF are wake-active and strongly promote arousal, while another subset of GABAergic neurons expressing somatostatin in the BF comprise a sleep-active group. Somatostatin positive, GABAergic neurons of the BF exhibit specific increases in local unit activity during SWS. Optogenetic stimulation of these neurons can induce SWS (103). The parafacial zone is a pontine region lateral to the seventh nerve containing SWS-active GABAergic neurons. Those sleep-active, inhibitory neurons project directly onto arousal-promoting glutamatergic neurons of the parabrachial nucleus, which, in turn, project to arousal-promoting neurons of the BF. Artificial stimulation of those PZ GABAergic neurons produces SWS (108). Anaesthetic effects on the PZ and sleep- active neurons of the BF await further study.
Thalamus
The thalamus is a critical structure that plays at least three major roles in wakefulness and consciousness. First, in terms of levels of consciousness, the thalamus is an important conduit for arousal pathways from the brainstem. Second, in terms of the content of consciousness, it is a major relay station for sensory information en route to the cortex. Third, in terms of the organization of conscious experience, the higher-order nuclei of the thalamus play a critical role in facilitating corticocortical coherence and communication.
The central thalamus has long been known to be critical to arousal, with small lesions of the area leading to gross disorders of consciousness (136). The anterior intralaminar nuclei, of which the central medial thalamus (CMT) is a part, receive significant ascending cholinergic innervation from the BF and brainstem. Microinjection of nicotine into the CMT is sufficient to reverse continuous systemic sevoflurane anaesthesia in animal models. This effect is replicated with an infusion of antibodies against potassium channels in the Kv1 family (41, 137). In slice recordings of neurons of the CMT, sevoflurane reduces firing, which is, in turn, reversed by administration of a Kv1 inhibitor (40). Activity of the CMT appears to be critical for both sleep and anaesthesia, as changes in high-frequency oscillations that occur at both the onset of sleep and anaesthetic- induced loss of consciousness occur first in the CMT, rapidly followed by cortical changes (68). More generally, thalamic inactivation as measured by reduced blood flow has been associated with anaesthetic- induced unconsciousness, although whether this is causal or secondary to unconsciousness itself remains unclear (138).
Neocortex and Limbic Cortex
The effects of anaesthetics are particularly heterogeneous across the neocortex, in stark contrast to the largely antiquated ‘wet blanket’ theory of anaesthetic action as a general neuronal depressant. The extent to which the primary sensory cortices are affected by many general anaesthetics remains unclear. These primary processing areas are still able to maintain normal or near-normal responses to evoked potentials while longer-latency potentials are inhibited. In contrast, the function of higher-order association cortices and portions of the entorhinal cortex are markedly impaired by general anaesthetics. The mesial parietal cortex, the anterior and posterior cingulate cortices, and the precuneus are deactivated in sleep and anaesthesia, as measured indirectly by changes in cerebral blood flow (139–141). Given the variability of anaesthetic effect on individual cortical areas, hypnotic effects of anaesthetics may either prove to be a result of direct actions upon the cortex or could be a result of network-level perturbations that include cortical and subcortical interactions.
Brain Networks and Anaesthesia
The specific molecular target(s) of an anaesthetic may not yield immediate insight into mechanisms by which the drug produces unconsciousness. Complete understanding requires detailed knowledge of drug effects on their molecular targets, as well as how ensuing changes in the activity of neurons and glia affect local and distant circuits in addition to the global impact on networks. The relevant actions of anaesthetics, and hence their common mechanism, may thus be their ultimate disruption of network function- decreasing functional information integration. Understanding discrete effects of anaesthetics on receptors, individual neurons, and brain nuclei are necessary but not sufficient in isolation. To investigate anaesthetic disruption of network level processes, large- scale brain activity studies employ functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography (MEG), or high- density electroencephalography (EEG).
Thalamocortical Network
Thalamocortical networks are key to information integration, as they gate ascending sensory information, ascending arousal signals, and modulate corticocortical relays. Disruption of the system illustrates the importance of this network, which results in disorders of consciousness (136, 142). Shifting from cortically dominant to thalamus-dominant thalamocortical circuits during anaestheticinduced loss of consciousness corroborates a model of propofol hypnosis whereby GABAergic activation results in strengthened thalamocortical connections and an intrinsic thalamically-driven alpha (8– 12 Hz) electrical rhythm (143, 144). Evidence from animal models that changes in thalamic rhythms slightly precede related cortical rhythms at the time of anaesthetic-induced loss of consciousness also lends credence to the theory of thalamusrhythm-driven thalamocortical loop as critical to anaesthetic hypnosis (68). Other animal models using field potentials within the thalamus and cortical EEG show that ketamine/xylazine-induced loss of consciousness coincides with a shift in the dominant direction of information transfer from cortex-thalamus during consciousness to thalamus-cortex (145). Counter to the argument of a predominant thalamocortical disruption by anaesthetics, slice and chronic in vivo recordings suggest that corticocortical connections are preferentially disrupted by volatile anaesthetics, while thalamocortical connections remain intact (146),
Evidence from functional connectivity studies of the thalamus and cortex, which rely on relative blood flow as measured via PET or fMRI, rather than the electrical measurements of EEG and subcortical electrodes, do not demonstrate tight association of thalamus and cortex. Instead, their functional connectivity is eliminated with the onset of anaesthetic-induced unconsciousness, purportedly through a silencing of the thalamus (147). While this loss of functional connectivity between the cortex and thalamus was first described with isoflurane and halothane, a similar pattern was also described with dexmedetomidine-induced loss of consciousness (148). Recent studies have further solidified the pattern of reduced thalamocortical connectivity using both ketamine and sevoflurane, making it a robust finding across multiple anaesthetic classes (149, 150).
The difference in conclusions between methods using relative blood flow as a proxy for neural activity and those directly measuring electrical signatures of that activity may be a result of different temporal and spatial resolutions between the two strategies. Simultaneous measures of EEG and fMRI during a slow propofolinduced loss of consciousness addressed this disparity, and demonstrated a distinct phenomenon: isolation of the thalamocortical network from sensory input at the point of maximum slow-wave activity on EEG, and the emergence of a sensory-responsive primitive cortical network independent of the isolated thalamocortical network (151). The functional compartmentalization through thalamocortical isolation corresponds with the other EEG evidence, suggesting emergence of thalamically driven rhythms during anaesthetic-induced unconsciousness (143, 144). Only with functional isolation would the dominant rhythm driver be thalamus rather than corticocortical connections.
Corticocortical Networks
As sensory integration and processing are integral to awareness, the disruption of these functions are a predicted hallmark for
anaesthetic- induced unconsciousness. The parietal lobe contains multiple primary sensory cortices. Executive function depends upon the frontal cortex. Consequently, effective communication between the two regions is considered necessary for consciousness. It follows that disruption of that communication would serve to produce anaesthetic- induced unconsciousness (152, 153). However, rather than a simple complete breakdown of all frontal-parietal communication, anaesthetic-induced unconsciousness is associated with a specific disruption of feedback communication between the frontal and parietal cortices. Thus, although there is effective information transfer from the parietal cortex forward to the frontal cortex (feed- forward), reciprocal information transfer from the frontal cortex to the parietal (feedback) is impaired with the onset of anaestheticinduced unconsciousness (154). This pattern of feedback inhibition has proven remarkably robust over anaesthetics with varying molecular mechanisms of actions, from ketamine, to volatile agents, to propofol (155). That this pattern of feedback or top-down processing is also impaired in vegetative states suggests that this could be a general process for unconsciousness (156, 157).
Global Distance Connectivity and Information Integration Capacity
In addition to evidence that anaesthetics may exert their effects through specific networks such as those mentioned previously, anaesthetic action on large-scale brain network organization and generalized ability for information integration may be the source of their unconsciousness-inducing effects. Analyses of whole-brain networks under general anaesthesia show increased local information exchange but impaired longer distance communication (158). This change from global connectedness to a more local pattern occurs for both volatile anaesthetics and propofol, and has been seen in with the distinct measurement modalities of both EEG and fMRI (159). While not all analyses have specifically found an increase of ‘small-worldness’ of the networks (local over long-distance), decreases in network efficiency are common, and therefore the amount of information that could be transmitted and integrated by a network is diminished in the presence of a general anaesthetic (160–163).
Conclusions
While primary anaesthetic pharmacologic effects necessarily occur at the molecular level, the diversity of both general anaesthetics’ molecular targets and their subsequent cellular- level actions does not clearly translate into obvious behavioural commonalities observed in vivo. Only at the level of neural circuits can we begin to appreciate the common effects among the diverse array of individual anaesthetic drugs. Distinguishing the proximate cause and secondary effects culminating in anaesthetic hypnosis remains a significant challenge for the field. Identifying the critical anaesthetic induced network adaptations in both cortical and subcortical circuits truly responsible for loss of consciousness itself, as opposed to circuit level side effects of anaesthetic drug exposure, represents another significant challenge. Resolving these challenges will benefit both the field of anaesthesiology as well as neuroscience.
Summary
◆ Anaesthetics act upon a variety of protein targets to exert their hypnotic effects.
◆ Relevant hypnotic molecular targets of general anaesthetics include ligand-gated ion channels (examples: GABA and NMDA receptors), voltage- gated ion channels (examples: Kv1 and Nav1.6), constitutively active ion channels (example: K2P), Gprotein-coupled receptors, and respiratory complex I.
◆ Anaesthetics elicit circuit-level effects not readily predicted by their effects on single neurons of a given circuit.
◆ Anaesthetics can affect endogenous neural systems regulating sleep and arousal, and such actions may produce or potentiate their hypnotic effects.
◆ The thalamus is part of the ascending arousal system, serves as a relay for sensory information, and facilitates corticocortical communication. While thalamic inactivation does not invariably lead to loss of consciousness, artificial stimulation can reverse hypnosis during continuous anaesthetic administration, presumably through the ascending arousal pathways.
◆ Disruption of function in cortical association areas by anaesthetics corresponds with changes of global network properties during hypnosis, where long- range connections decline and the total capacity for information integration decreases. It is not yet clear whether direct action at those association centres directly underlies network adaptations or whether the primary change occurs elsewhere and propagates to impair cortical activity.
◆ Both thalamocortical networks as well as corticocortical patterns of connectivity are altered with anaesthetic hypnosis. Changes in both of these networks may reflect a final common marker or mediator of anaesthetic-induced unconsciousness.
Multiple-Choice Questions
Q Interactive multiple-choice questions to test your knowledge on this chapter can be found in the online appendix at www. oxfordmedicine.com/otneuroanesthesiology
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