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iii
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
1
ii
1
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v
Dedication
While serving as the President of the Society for Neuroscience The Oxford Textbook of Neuroscience and Anaesthesiology is the
in Anesthesiology and Critical Care, I espoused a vision for first book of its kind to comprehensively address all three pillars
neuroanaesthesiology that was supported by three ‘pillars’. The related to neuroscience in anaesthesiology. The first section treats
traditional pillar of neuroanaesthesiology relates to the care of the neuroscientific foundations of anaesthesiology, including the
neurosurgical and neurological patients. The clinical care of indi- neural mechanisms of general anaesthetics, cerebral physiology,
viduals with neurologic compromise is incredibly rewarding and the neurobiology of pain, and more. The second section represents
represents a true opportunity to make a positive difference in the the traditional pillar related to the care of patients with neuro-
lives of others. However, the specialty of anaesthesiology is itself a logic disease in the operating room or intensive care unit, with a
form of clinical neuroscience. On a daily basis, even as anaesthe- focus on clinical neuroanaesthesia. These chapters systematically
tists for non-neurosurgical cases, we modulate peripheral nerves, treat the peri-operative considerations of both brain and spine
the spinal cord, subcortical arousal systems, thalamocortical and surgery, and provide introductions to neurocritical care and pedi-
corticocortical networks supporting consciousness, pain networks, atric neuroanaesthesia. Finally, the last section examines some
memory systems in the medial temporal lobe, the neuromuscular connections of neurology and anaesthesiology, examining how
junction, and the autonomic nervous system. From this perspective, conditions such as dementia, stroke, or epilepsy interface with the
‘neuroanaesthesiology’ is more a compression of ‘neuroscience in peri-operative period.
anaesthesiology’ than ‘neurosurgical anaesthesiology’. The mech- This international textbook gathers the best available expertise of
anistic study of our therapeutic interventions, which represents authors and leaders in the field from Canada, Germany, Italy, New
another pillar, is exciting neuroscience in its own right, and has pro- Zealand, Spain, Switzerland, the UK, and the US. They have done an
found implications for nervous system function. Finally, the ques- outstanding job of crafting concise yet highly informative chapters
tion of how the peri-operative period might negatively impact the describing the cutting edge of neuroscience and neuroanaesthesia.
brain is the new frontier of outcomes studies and has been a major It is my hope that this textbook is itself a ‘chapter’ in the evolution
priority for the field of anaesthesiology in the past decade. Questions of the field, creating a lasting foundation and appreciation for the
related to anaesthetic neurotoxicity, cognitive dysfunction, stroke, three pillars of neuroscience in anaesthesiology.
and other neurologic outcomes of non-neurosurgical interventions
represent a critically important third pillar for the subspecialty. George A. Mashour, M.D., Ph.D.
ix
Contents
David B. Glick, Gerald Glick†, and Erica J. Stein Douglas A. Colquhoun and Edward C. Nemergut
Margaret K. Menzel Ellis and Ansgar Brambrink Ehab Farag and Zeyd Ebrahim
Adrian Pichurko and Richard E. Harris Timur M. Urakov and Michael Y. Wang
22 Paediatric Neuroanaesthesia 263
x contents
Neurologic Patients Undergoing Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp
Non-Neurologic Surgery 27 Parkinson’s Disease 309
M. Luke James and Ulrike Hoffmann
24 Cerebrovascular Disease 289
Corey Amlong and Robert D. Sanders 28 Treatment of Psychiatric Diseases
with General Anaesthetics 315
25 Peri-Operative Considerations of Dementia,
Laszlo Vutskits
Delirium, and Cognitive Decline 297
Phillip E. Vlisides and Zhongcong Xie
Index 323
xi
Abbreviations
xii a bbreviations
abbreviations xiii
xiv a bbreviations
Contributors
Corey Amlong, Department of Anesthesiology, University of Gerald Glick†, Department of Medicine, Rush Medical
Wisconsin School of Medicine and Public Health, USA College, USA
Michael Avidan, Department of Anesthesiology, Washington David B. Glick, Department of Anesthesia & Critical Care,
University School of Medicine, USA University of Chicago, USA
Federico Bilotta, Department of Anesthesiology, Critical Care and Kerstin Göbel, Department of Neurology, University Hospital
Pain Medicine, Sapienza University of Rome, Italy Münster, Germany
Stefan Bittner, Department of Neurology, Johannes Gutenberg Shaun E. Gruenbaum, Department of Anesthesiology, Yale
University Mainz, Germany University School of Medicine, USA
Manfred Blobner, Klinik für Anaesthesiologie der Technischen Richard E. Harris, Department of Anesthesiology, University of
Universität München, Klinikum rechts der Isar, Germany Michigan Medical School, USA
Ansgar Brambrink, Department of Anesthesiology, Columbia Laura B. Hemmer, Department of Anesthesiology and
University, USA Neurological Surgery, Northwestern University, Feinberg School
of Medicine, USA
Douglas A. Colquhoun, Department of Anesthesiology, University
of Michigan Medical School, USA Eric J. Heyer, Departments of Anesthesiology and Neurology,
Columbia University, USA
Michael Crimmins, Walter Reed National Military Medical Center,
Department of Neurology, Neurosurgery and Critical Care, USA Ulrike Hoffmann, Department of Anesthesiology, Duke
University, USA
Zeyd Ebrahim, Department of General Anesthesiology,
Anesthesiology Institute, Cleveland Clinic, USA Paola Hurtado, Anesthesiology Department, Hospital Clìnic de
Barcelona, Spain.
Margaret K. Menzel Ellis, Portland VA Medical Center,
Assistant Professor of Anesthesiology, Oregon Health & Science Adam K. Jacob, Department of Anesthesiology and Perioperative
University, USA Medicine, Mayo Clinic College of Medicine, USA
Kristin Engelhard, Department of Anesthesiology, University M. Luke James, Departments of Anesthesiology and Neurology,
Medical Center of the Johannes Gutenberg-University Mainz, Duke University, USA
Germany
Max B. Kelz, Department of Anesthesiology and Critical Care,
Neus Fàbregas, Anesthesiology Department, Hospital Clìnic de University of Pennsylvania Perelman School of Medicine, USA
Barcelona, Spain
Klaus Ulrich Klein, Department of Anesthesia, General Intensive
Ehab Farag, Department of General Anesthesia and Outcomes Care and Pain Management, Medical University of Vienna,
Research, Anesthesiology Institute, Cleveland Clinic, USA Austria
Heidrun Lewald, Klinik für Anaesthesiologie der Technischen Ines P. Koerner, Department of Anesthesiology & Perioperative
Universität München, Klinikum rechts der Isar, Germany Medicine, Department of Neurological Surgery, Oregon Health &
Science University, USA
Katherine M. Gelber, Department of Anesthesiology, Cedars-Sinai
Medical Center, USA
xvi
xvi c ontributors
Antoun Koht, Department of Anesthesiology, Neurological Jamie Sleigh, Department of Anaesthesia and Pain Medicine,
Surgery, and Neurology, Northwestern University, Feinberg School Waikato Clinical Campus, University of Auckland, New Zealand
of Medicine, USA
Tod B. Sloan, Department of Anesthesia, University of Colorado
Sandra L. Kopp, Department of Anesthesiology and Perioperative School of Medicine, USA
Medicine, Mayo Clinic College of Medicine, USA
Martin Smith, Department of Neuroanaesthesia and Neurocritical
Brian P. Lemkuil, Department of Anesthesiology, University of Care, The National Hospital for Neurology and Neurosurgery,
California San Diego, USA University College London Hospitals, UK
Pirjo Manninen, Department of Anesthesia, Toronto Sulpicio G. Soriano, Department of Anesthesiology, Perioperative
Western Hospital University Health Network, University of and Pain Medicine, Boston Children's Hospital, Harvard Medical
Toronto, Canada School, USA
Nathan Manning, Departments of Neurosurgery and Christiane G. Stäuble, Klinik für Anaesthesiologie der
Radiology, Columbia University Medical Centre, New York Technischen Universität München, Klinikum rechts der Isar,
Presbyterian, USA Germany
Ross P. Martini, Department of Anesthesiology and Perioperative Harald Stefanits, Department of Neurosurgery, Medical
Medicine, Oregon Health & Science University, USA University of Vienna, Austria
Craig D. McClain, Department of Anesthesiology, Perioperative Erica J. Stein, Department of Anesthesiology, The Ohio State
and Pain Medicine, Boston Children's Hospital, Harvard Medical University, USA
School, USA
Magnus Teig, Department of Anesthesiology, University of
Andrew McKinstry-Wu, Department of Anesthesiology and Michigan Medical School, USA
Critical Care, University of Pennsylvania, USA
J. Richard Toleikis, Department of Anesthesiology, Rush
Sven G. Meuth, Department of Neurology, Institute of University School of Medicine, USA
Translational Neurology, Westfälische-Wilhelms University
Münster, Germany Timur M. Urakov, Department of Neurosurgery, University of
Miami, Jackson Memorial Hospital, USA
Philip M. Meyers, Departments of Radiology and Neurological
Surgery, Columbia University, USA Lashmi Venkatraghavan, Department of Anesthesia, Toronto
Western Hospital, University of Toronto, Canada
Edward C. Nemergut, Department of Anesthesiology, University
of Virginia Health System, USA Phillip E. Vlisides, Department of Anesthesiology, University of
Michigan Medical School, USA
Adam D. Niesen, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic College of Medicine, USA Laszlo Vutskits, Department of Anesthesiology, Pharmacology
and Intensive Care, University Hospitals of Geneva, Department
Jeffrey J. Pasternak, Department of Anesthesiology and of Basic Neuroscience, University of Geneva Medical School,
Perioperative Medicine, Mayo Clinic College of Medicine, USA Switzerland
Piyush Patel, VA Medical Center, University of California San Michael Y. Wang, University of Miami, Miller School of
Diego, USA Medicine, USA
Adrian Pichurko, Department of Anesthesiology, Northwestern Tasha L. Welch, Department of Anesthesiology and Perioperative
University, Feinberg School of Medicine, USA Medicine, Mayo Clinic College of Medicine, USA
Andrea Reinprecht, Department of Neurosurgery, Medical David R. Wright, Departments of Anesthesiology & Pain Medicine
University of Vienna, Austria and Neurological Surgery, University of Washington, USA
Robert D. Sanders, Department of Anesthesiology, University of Zhongcong Xie, Department of Anesthesia, Critical Care and
Wisconsin, USA Pain Medicine, Massachusetts General Hospital, Harvard Medical
School, USA
Anne Sebastiani, Department of Anesthesiology, University
Medical Center of the Johannes Gutenberg University Mainz, Sophia C. Yi, Department of Anesthesiology, University of
Germany California San Diego, USA
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Q Cases and multiple-choice questions
1
SECTION 1
Neuroscience
in Anaesthetic Practice
CHAPTER 1
Neural Mechanisms
of Anaesthetics
Andrew McKinstry-Wu and Max B. Kelz
Mt
KV1 HCN K2P NaV NMDA Glycine GABA mAch nAch TTCa RTCa Complex
I
Ethers
Halothane
Propofol
Etomidate
Barbiturates
Ketamine
Nitrous
Oxide/
Xenon
Dexmedeto-
midine
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.
Kv1.1: Shaker-related voltage-gated potassium channel HCN: Hyperpolarization-activated cyclic nucleotide-gated channel, K2P: Two-pore potassium channels, NMDA: N-
methyl D-aspartate receptor, Glycine: Glycine receptor, GABA: gamma-aminobutyric acid receptor, mAch: muscarinic acetylcholine receptor, nAch: nicotinic acetylcholine
receptor, TTCa: T-type calcium channel, RTCa: R-type calcium channel, Mt complex I: Complex I of the electron transport chain (NADH: ubiquinone oxidoreductase).
Glycine receptors are the other significant inhibitory, anionic Excitatory Ligand-Gated Ion Channel Inhibition
LGICs in the CNS. This receptor family is found mostly in the Many general anaesthetics act to inhibit excitatory LGICs, a
brainstem and spinal cord. Like GABAA-receptors, glycine re- complementary effect to their potentiation of inhibitory LGICs.
ceptors are heteropentameric chlorine channels, and are directly Glutamate is the primary excitatory neurotransmitter of the CNS.
activated or potentiated by volatile and many intravenous anaes- Among glutamate’s targets is the NMDA receptor (where it has gly-
thetics (13–16). Evidence for the functional importance of gly- cine as a co-receptor). NMDA receptors are the functional target for
cine receptors to anaesthetic action is not as robust as that for the a significant number of general anaesthetics. Like the extrasynapic
GABAA-receptor. Glycine receptor mutations can produce diver- GABA receptors responsible for tonic currents, NMDA receptors
gent responses to anaesthetic endpoints. Site-specific mutations do not produce the fast postsynaptic transmission responsible
of the glycine receptor that alter in vitro receptor sensitivity to for excitatory postsynaptic potentials, but acts presynaptically,
volatile and potent intravenous anaesthetics do not always pro- postsynaptically, and extrasynaptically, and can affect synaptic plas-
duce associated changes in immobility or hypnotic sensitivity in ticity (21). All known noncompetitive NMDA antagonists severely
vivo (6, 17). Specifically with propofol, the glycine receptor may disturb consciousness, with many acting as general anaesthetics at
not contribute to immobility. A structural analogue of propofol sufficient concentrations (22). The gas anaesthetics nitrous oxide
that potentiates glycine (but not GABA) receptor signalling, 2,6 and xenon, as well as the intravenous agent ketamine, all act pri-
di-tert-butylphenol, lacks any immobilizing effects in vivo (7, marily as NMDA receptor antagonists, while many of the volatile
18, 19). Similarly, a Q266I point mutation introduced into the anaesthetics possess NMDA antagonist activity in addition to their
α1 subunit of the glycine receptor that decreases receptor sen- effects on other putative anaesthetic targets (23–26).
sitivity to isoflurane unexpectedly conferred hypersensitivity to The nicotinic acetylcholine receptor, a ligand-gated nonspecific
the immobilizing properties of both isoflurane and enflurane in cation channel, is inhibited by volatile anaesthetics at clinically
mice. These results suggest that glycine receptors containing the relevant concentrations. While that inhibition does not mediate
α1 subunit are unlikely to mediate immobilizing properties of anaesthetic hypnosis, it may mediate amnesia and analgesic ef-
anaesthetics (20). fects of volatile anaesthetics (27–30). Moreover, central cholinergic
5
signalling via nicotinic receptors appears important for anaesthetic historically inhibition had only been seen at higher concentrations
emergence. Although blockade of cholinergic signalling may not (42). The role of sodium channels in volatile anaesthetic hypnosis
be sufficient to alter loss-of-righting-reflex or Minimum alveolar is demonstrated by hypersensitivity to isoflurane and sevoflurane
concentration (MAC) concentration, it can still be sufficient to re- in mice with reduced activity in one voltage-gated sodium channel
tard emergence from anaesthetic hypnosis (discussed later in this subtype, NaV1.6 (43).
chapter). Presynaptic voltage-gated calcium channels are critical for neuro-
transmitter release and inhibited by general anaesthetics, making
Constitutively Active and Voltage-Gated Ion Channels them likely anaesthetic targets. Low-voltage-activated T-type
Members of the two-pore-domain potassium channel family calcium channels, which modulate cellular excitability through
(K2P) produce a continuous non-inactivatable current that modi- regulating burst firing and pacemaker activity, are inhibited by
fies resting membrane potential and thus affects neuronal excit- clinically relevant concentrations of volatile and intravenous anaes-
ability (31). Volatile and gaseous anaesthetics directly activate thetics (44–46). In vivo knockouts of T-type calcium channels do
members of this family, including TREK-1, TREK-2, TASK-1, not show changes in anaesthetic sensitivity to the loss of righting
TASK-2, and TASK-3. Anaesthetic activation of these K2P chan- reflex (LoRR), a traditional rodent equivalent endpoint to loss of
nels causes an increase in potassium efflux out of the cell leading to consciousness in humans, though they do have altered speed of in-
hyperpolarization. However, not every member of the K2P family duction and reaction to noxious stimuli (46, 47). This suggests that
is activated by anaesthetic exposure. Several members are insensi- the effects of anaesthetics upon these channels modulate the anaes-
tive to anaesthetics, while THIK-1, TWIK-2, TALK-1, and TALK-2 thetized state, rather than cause it. High-voltage-activated calcium
are actually closed by anaesthetic exposure. Mutations of two-pore- channels (R-type) are also sensitive to inhibition by volatile anaes-
domain potassium channels can abrogate sensitivity to activation thetics, and contribute to rhythmicity of thalamocortical circuits. R-
by volatile and gaseous anaesthetics. Distinct gene mutations alter type knockouts display less electroencephalographic suppression at
volatile sensitivity versus sensitivity to gaseous anaesthetics (32). 1% isoflurane than their wild-type counterparts. This suggests that
An in vivo knockout of one K2P, TREK-1, caused an impressive 40% thalamic calcium channels are involved in isoflurane-induced thal-
resistance to halothane and more modest resistance to other inhaled amic suppression, thought to contribute to unconsciousness (48).
anaesthetics, while leaving barbiturate sensitivity unchanged (33).
Hyperpolarization-activated cyclic nucleotide- gated (HCN) G-Protein-Coupled Receptors
channels are tetrameric, relatively nonspecific cation channels that G-protein-coupled receptors make up the largest and most di-
activate with cell hyperpolarization (as opposed to depolarization.) verse family of membrane receptors. They comprise 4% of the en-
The Ih current, produced by HCN activation, is involved in pro- tire coding human genome and are the target for over a quarter
ducing long-term potentiation, dendritic integration, control of of all current pharmaceuticals (49). Drugs that affect this receptor
working memory, and thalamocortical oscillations (34). Of the four superfamily are an integral part of anaesthetic practice, including
HCN isoforms, HCN1 is both abundant in the CNS and inhibited such diverse classes as opioids, vasopressors, and anticholinergics.
by volatile and intravenous agents. Agents as diverse as isoflurane, So, while these receptors are known targets for producing analgesia
ketamine, and propofol inhibit HCN1 at clinically relevant doses. and amnesia, there is little direct evidence that volatile-anaesthetic-
In in vivo models, this HCN1 inhibition plays a direct role in the induced hypnosis is primarily mediated via this superfamily of
hypnotic potency of these agents (35–38). There is even debate that receptors. This is despite the fact that volatile anaesthetics do select-
NMDA receptor antagonists producing hypnosis do so not through ively activate G-protein-coupled receptors at pharmacologically-
actions at the NMDA receptor itself, but through their inhibition relevant concentrations (50, 51). Ketamine very specifically
of HCN1 (37). The involvement of HCN channels in critical CNS interacts with a subset of olfactory receptors, which are a subgroup
processes and their inhibition by diverse anaesthetic agents suggest of G-protein-coupled receptors, though it is unclear if these inter-
a significant role for this channel in anaesthetic-induced hypnosis. actions are in any way related to its anaesthetic actions (52).
Voltage-gated potassium channels of the Kv1 family are recently
identified targets of volatile anaesthetics that contribute to suppres- Electron Transport Chain
sion of arousal. Flies with mutations in a gene coding for a member Unlike the previously discussed membrane-bound proteins in the
of the Kv1.2 family (shaker) exhibit altered sensitivity to volatile an- cell’s outer membrane, components of complex I, a multi-subunit
aesthetics, requiring higher doses than wild-type controls to cease member of the respiratory chain, are putative anaesthetic targets lo-
movement (39). Sevoflurane enhances currents in members of the cated in the inner mitochondrial membrane. Animal models with
Kv1 family, with other clinically used volatiles also affecting Kv1 mutations in specific subunits of complex I, GAS-1 in C. elegans
currents, suppressing firing in the central medial thalamus (40). and Ndufs4 in mice, are hypersensitive to volatile anaesthetics. This
Kv1 channel inhibitors infused into the central medial thalamus hypersensitivity phenotype is strictly mirrored across evolution up
are able to reverse continuous low-dose sevoflurane anaesthesia in to and including humans with complex I mutations (53–55). The
animal models, as are antibodies against Kv channels (41). anaesthetic hypersensitivity phenotype is not present in all com-
Voltage-gated sodium channels are a requisite for normal exci- plex I gene mutations, nor is it present with other electron transport
tatory neuronal function, as they are key to initiating and propa- chain mutations, indicating a specific interaction between volatile
gating action potentials. Their inhibition by volatile anaesthetics anaesthetics and precise complex I subunits. While halogenated
presynaptically results in a decreased likelihood of action poten- ethers and alkanes inhibit complex I function though interaction
tial propagation and decreased presynaptic neurotransmitter re- with the distal portion of the complex, volatile anaesthetics do not
lease. Several sodium channel subtypes are inhibited by volatile appear to disproportionately decrease ATP production in complex
anaesthetics in pharmacologically relevant concentrations, though I mutants. This dissociation suggests volatile anaesthetic hypnotic
6
action is not solely a result of disproportionate mitochondrial ener- anaesthetic depth can also distinguish wakefulness from sleep (59–
getic disruption in those mutants, begging the persistent question 65). During anaesthesia and sleep, thalamic nuclei and wake-active
of how these mutations cause anaesthetic hypersensitivity (56–58). nuclei, collectively known as the reticular activating system, are
similarly inhibited (46, 66–70). Parallels between the states extend
Systems Neuroscience and Anaesthetic to their functional effects—in some cases anaesthesia can substi-
tute for sleep. Sleep debt does not accrue during prolonged periods
Effects: Discrete Nuclei and Local Networks of propofol-induced unconsciousness, while propofol hypnosis ap-
There is incontrovertible evidence for anaesthetic drugs interacting pears to relieve previously incurred sleep debt (71–73). Conversely,
with multiple molecular targets to affect behaviour, but anaesthetic sleep deprivation or administration of endogenous somnogens
hypnosis is impossible to explain by mere examination of molecular reduce the dose of anaesthetic required for hypnosis. In a parallel
binding events in isolation. The imperfect connection between vein, induction and maintenance of anaesthesia itself alters levels
molecular action and larger-scale brain phenomena must be in- of endogenous somnogens (72, 74). Together, these data support
terpreted in light of relevant neuroanatomy. Complexities are intro- the theory that anaesthetic-induced hypnosis stems in part from
duced by circuit-level interactions—neuronal hyperpolarization actions of anaesthetics on the neural circuits involved with en-
that reduces firing of a presynaptic inhibitory input can increase dogenous sleep-wake control.
activity for the postsynaptic neuron resulting in a net increase of
circuit output. Evaluating the net contribution of anaesthetics on Arousal-Promoting Nuclei of the Reticular
discrete brain regions to hypnosis provides a way to simplify the Activating System
massive complexity encountered at the molecular and neuronal The ascending reticular activating system, extending rostrally from
level without ignoring the fundamental circuitry of the CNS. the mid pons to the hypothalamus, basal forebrain, and thalamus,
was first identified more than half a century ago. Stimulation of the
Sleep and Arousal Pathways brain stem reticular formation causes cortical arousal during an-
General anaesthetics alter the activity of endogenous arousal cir- aesthetic states (75). Subsequently, discrete interacting neuronal
cuits. Such actions directly contribute to their hypnotic effects populations were found to be the arousal-promoting components
(Figure 1.2). Anaesthetic-induced unconsciousness is a non- of the activating system, including cholinergic, histaminergic, ad-
arousable behavioural state that shares many commonalities with renergic, serotonergic, dopaminergic, and orexinergic centres.
slow-wave sleep (SWS) There is a functional loss in cortical con-
nectivity during both NREM sleep and anaesthetic hypnosis. Laterodorsal Tegmentum (LDT) and Pedunculopontine
Moreover, over much of the anaesthetic dose response range, the Tegmentum (PPT)
cortical electroencephalography (EEG) exhibits striking simi- These nuclei comprise two major cholinergic populations in the
larities, such that processed EEG measures developed to assess brainstem with the ability to regulate arousal state and promote
Frontal cortex
Mesial parietal cortex
Precuneus
Posterior cingulate cortex
Thalamus
Hippocampus
Mesopontine tegmental area
Amygdala
Ox
TMN
(HA) VTA
(DA)
DpMe
(Glut)
BF
(Ach/Glut/GABA) PPT/LDT
RN
(ACh)
(5-HT)
POA
(GABA/Gal)
vPAG
LC (Ne)/PB
(DA)
(Glut)
PZ
(GABA) Pno
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.
7
wakefulness or REM sleep. These cholinergic neurons densely systemic effects (92, 93). Clearly, a more complex local microcir-
innervate the midline and intralaminar thalamic nuclei and thal- cuitry awaits discovery.
amic reticular nucleus and alter thalamic activity from bursting to
Deep Mesencephalic Reticular Formation (DpMe)
spiking (76). Direct effects of these nuclei on anaesthetic-induced
hypnosis are unknown. Despite this, the PPT is in a region that is Over the decades, many studies have demonstrated that electrical
associated with pain-induced movement, the inactivation of which stimulation in the DpMe reliably induces cortical activation in an-
leads to a significant decrease of isoflurane MAC (77). aesthetized animals. These presumptively glutamatergic neurons
project to the thalamus, hypothalamus, and basal forebrain, where
Locus Coeruleus (LC) they increase their firing rates prior to the onset of wakefulness,
The Locus Coeruleus is the site of the brain’s largest collection of and fire more slowly during SWS (94). These glutamatergic neurons
noradrenergic neurons. As with many of the other monoaminergic are possibly part of a previously poorly recognized arm of the as-
systems, the LC diffusely innervates the brain by projecting directly cending arousal system that potentially includes the parabrachial
to the cortex, thalamus, hypothalamus, basal forebrain, amygdala, nucleus as well.
hippocampus, and other subcortical systems. State-dependent
modulation of activity within the LC has long been proposed as Hypocretin/Orexinergic Neurons
an essential means of regulating arousal. Changes in the activity The orexin signalling system exerts potent wake-promoting and
of LC neurons occur before, and are predictive of, changes in an wake-stabilizing effects, and plays an important role in modulating
organism’s behavioural state (78). Through its actions on alpha1 and anaesthetic emergence. As with the monoaminergic wake-active
beta receptors, firing of LC neurons promotes wakefulness through systems, the orexin system displays state-dependent firing pat-
actions on the medial septum, the medial preoptic area, and the terns with maximal activity during active wakefulness and silence
substantia innominata within the basal forebrain. Activity in the during SWS (95). Anatomically, these neurons project to all of the
LC modulates thalamocortical circuits, switching the tone of thal- monoaminergic groups along with extending to the basal forebrain,
amocortical neurons from the burst pattern of slow-wave sleep to midline thalamic nuclei, and other regions known to participate in
a spiking pattern that characterizes wakefulness. Consequently, the regulation of arousal. When signalling of these neurons is im-
optogenetically driven LC activity causes transitions from SWS to paired, narcolepsy with cataplexy ensues (96). Local application of
wakefulness (79). Under deep isoflurane anaesthesia, artificially orexin excites target neurons expressing either of the two orexin Gq-
driven LC activity has been shown to cause EEG desynchron- coupled neurotransmitter receptors, including the LDT, LC, RN,
ization. Similarly, artificially induced firing of the LC speeds emer- basal forebrain (BF), and thalamocortical neurons. Halogenated
gence from isoflurane anaesthesia (80). However, the LC is not the ethers, propofol, and pentobarbital inhibit orexinergic neuronal
sole source of adrenergically driven arousal. Noradrenergic popu- activity, and genetic knockout of these neurons results in delayed
lations outside of the LC, such as the A1 and A2 brainstem groups, emergence from isoflurane and sevoflurane anaesthesia without
also may contribute to the regulation of sleep, wakefulness, and an- affecting sensitivity to anaesthetic induction (97–99). In the case
aesthesia (81–83). of barbiturate anaesthesia, the pharmacologic inverse is true as
well: intracerebroventricular injection of orexin speeds emergence,
Pontine Reticular Nucleus, Oral Part (PnO) and orexin1-receptor blockade negates this effect (100). The case
Neurons in this large region (which includes the sublaterodorsal of delayed emergence without altered induction in orexinergic de-
nucleus) receive cholinergic, orexinergic, and GABAergic inputs ficient animals highlights the intriguing possibility that distinct
and include wakefulness-promoting and REM-on populations. populations of neurons may unilaterally and differentially impact
PnO activity also modifies anaesthetic action. GABAergic activity the process of entering into or exiting from the anaesthetic state.
at the PnO produces resistance to induction without significant
effects on emergence (84–87). Electrical stimulation at the PnO Wake-Promoting Neurons of the Basal Forebrain
causes an increase in functional connectivity under continuous The BF encompasses heterogeneous populations of neurons ac-
isoflurane anaesthesia, similarly suggesting anaesthetic antag- tive in arousal and sleep that modify anaesthetic state and sensi-
onist actions (88). This region highlights the critical importance tivity. GABA agonists microinjected at the BF potentiate systemic
of neuroanatomic and neurochemical compartments: unlike most intravenous and volatile anaesthetic effect and duration, as do
other regions of brain, increased GABA levels in the PnO pro- electrolytic lesions of the medial septum within the BF (101, 102).
mote wakefulness. Other seemingly paradoxical effects occur in The BF sits atop the ventral extrathalamic relay and receives inte-
this region: wakefulness is actually impaired by local delivery of grated arousal inputs from caudal structures. Within the BF, there
adenosine or acetylcholine into PnO, or alternatively, promoted are wake-active cholinergic neurons, wake-active glutamatergic
by local delivery of orexin or GABA (89–91). Cholinergic input to neurons, wake- a ctive parvalbumin- c ontaining GABAergic
the PnO originates from the LDT and PPT, while the orexinergic neurons, and sleep-active somatostatin-containing GABAergic
input arises from the hypothalamus. Divergent responses to adeno- neurons (103). The cholinergic neurons receive afferents from the
sine and GABA suggest that simple disinhibition of a single popu- LC, DpMe, Tuberomamillary nucleus (TMN), orexinergic neurons,
lation of PnO neurons is not sufficient to understand the actions parabrachial neurons, and glutamatergic neurons of the BF, and
of these neuromodulators. Further clouding the picture, micro- send widespread efferent projections to the cortex and hippo-
injections of pentobarbital within a region that has been termed campus, as well as back to the hypothalamus. Selective lesion of
the mesopontine tegmental area, which overlaps with a significant cholinergic neurons within the nucleus basalis of the BF prolongs
portion of the PnO and some neighbouring structures, have been behavioural effects of propofol and pentobarbital (104). Increased
shown to induce hypnosis similar to systemic administration of a cholinergic activity of the basal forebrain during wakefulness is re-
larger general anaesthetic dose, while nearby injections lack any sponsible for the fluctuations in cortical acetylcholine levels. The
8
cholinergic neurons stimulate cortical activation, and the resultant CNS serotonin. The median raphe contributes little to producing
increased discharge frequency, along with increased activity of or modulating anaesthetic actions. In contrast, when the DR is si-
cortically projecting parvalbumin-containing GABAergic neurons, lenced by calcium blockage or by lesion, sensitivity is increased to
underlies the desynchronized EEG that typifies wakefulness as well pentobarbital or halothane and cyclopropane, respectively (124,
as REM sleep (103, 105). 125). The raphe nuclei (RN) do display state-dependent firing
similar to noradrenergic or histaminergic centres. Single unit re-
Parabrachial Nucleus
cordings, however, demonstrate that firing rates of serotonergic
Neurons in the parabrachial nuclei belong to a recently identi- neurons do not anticipate spontaneous changes in arousal state
fied glutamatergic arm of the anterior branch of the ascending (126). This suggests that activity of the DR is not causally linked to
arousal system and can themselves modify the anaesthetic state. changes in behavioural state.
Lesion of the parabrachial nuclei induces coma, while the sleep- Within the vPAG, there is a population of dopaminergic neurons
active parafacial zone (see Sleep-active Neurons of the Basal that are wake-active. This is in contrast to dopaminergic neurons of
Forebrain and Parafacial Zone) promotes SWS through inhibition the VTA or substantia nigra, which do not display state-dependent
of glutamatergic parabrachial neurons that, in turn, project to the activity. However, the vPAG dopaminergic neurons appear not to
BF (106–109). Electrical stimulation of the parabrachial nucleus is contribute to anaesthetic hypnosis. Instead, they modulate anal-
able to antagonize continuous low-dose isoflurane administration gesia, with lesions of these neurons causing decreased reaction to
(110). This observed direct effect on anaesthetic sensitivity, as well noxious stimuli under general anaesthesia (127, 128).
as the parabrachial’s known anatomic and functional connection
with sleep-active nuclei and other CNS regions that affect anaes- Sleep-Active Neurons and Nuclei
thetic sensitivity and emergence, suggests a significant role for the
When compared to the large numbers of known arousal-
parabrachial nucleus in maintaining or emerging from an anaes-
promoting, wake-active nuclei, there are few neural populations
thetic state. However, this has yet to be fully explored.
that are predominantly active during SWS or REM sleep with de-
Ventral Tegmental Area (VTA) creased activity during wakeful states. Neurons with sleep-active
A midbrain dopaminergic and GABAergic region associated with firing patterns are most commonly found in the preoptic area and
both arousal and reward, the VTA receives diverse inputs and has BF (though populations do exist elsewhere, including in the pons
widespread outputs, including the prefrontal cortex, cingulate and cortex.) These populations act as a network counterbalance to
gyrus, hippocampus, amygdala, and nucleus acumbens. Reflecting many of the arousal-promoting populations discussed previously.
those widespread connections, it is functionally diverse, with roles Just as there are many examples of anaesthetics depressing those
in motivation, cognition, and arousal (111). Dopaminergic neurons arousal centres, there is evidence for sleep-active neurons being
of the VTA do not appear to change their firing rate across sleep– directly and indirectly activated by certain anaesthetics.
wake. Consequently, VTA dopamine neurons have not been linked Preoptic Area: Ventrolateral Preoptic Nucleus (VLPO) and
to modulation of spontaneous arousal. Nevertheless, dopamin- Median Preoptic Nucleus (MnPO)
ergic neurons are suppressed by GABA, and other neurons within
In the earliest attempts to identify specific populations of sleep-
the VTA have circadian-dependent activity (112–116). Artificially
promoting neurons, a definitive role was assigned to the preoptic
driving dopamine release from the VTA, administration of methyl-
anterior hypothalamus. This broad region encompasses the VLPO,
phenidate, or more selective pharmacologic agents that act on D1-
which lies within the anterior hypothalamus on the ventral floor
like receptors, will all accelerate anaesthetic emergence, and can
at the level of the optic chiasm, as well as the MnPO, which strad-
even reverse anaesthesia produced by continuous administrations
dles the decussation of the anterior commissure. Neurons with
of propofol or isoflurane (117–120).
heightened activity during SWS are found throughout the preoptic
Tuberomamillary Nucleus (TMN) area, with the greatest concentration found in VLPO. Neurons of
The sole source for histamine in the CNS, the histaminergic neurons the VLPO are more active during SWS and REM sleep. Changes
of the TMN have widespread projection throughout the brain and in VLPO activity precede the changes in an organism’s behavioural
have activity tightly correlated with arousal state (121). Though state. Retrograde and anterograde labelling studies show the VLPO
centrally administered histamine causes potent arousal, and central is reciprocally interconnected with many wake-promoting nuclei,
H1 antagonists produce sedation, the role of the TMN in modifying including the histaminergic TMN, serotonergic RN, noradrenergic
general anaesthesia is circumscribed. Lesions of the TMN increase LC, and the cholinergic LDT and PPT, as well as the orexinergic
sensitivity to isoflurane-induced LoRR, but leave propofol, keta- neurons of the hypothalamus. VLPO neurons contain the inhibi-
mine, and barbiturate sensitivity unchanged (122). Cell-specific tory neurotransmitters GABA and galanin and are thus ideally
knockout of GABAA receptors in histaminergic cells likewise positioned to coordinate and reciprocally inhibit wake-active as-
produced no change in propofol hypnotic sensitivity. These phe- cending reticular activating nuclei.
nomena were observed despite the fact that histaminergic neurons The role of the preoptic area in promoting and modulating the
lacking GABAA receptors were resistant to hyperpolarization by anaesthetic state appears connected to its regulation of sleep and
propofol—strong evidence that histaminergic neurons are not crit- wake. Destructive lesions of VLPO cause long-lasting insomnia.
ical to induction or maintenance of propofol hypnosis (123). Bilateral lesions of the VLPO also cause a biphasic change in an-
aesthetic sensitivity that possibly relates to insomnia: at six days
Dorsal Raphe (DR) and Ventral Periaqueductal Gray (vPAG) post-destruction, animals showed resistance to isoflurane LoRR,
The serotonergic neurons of the raphe nuclei have diffuse pro- while 24 days post-lesion, subjects showed hypersensitivity to
jections throughout the brain and comprise the largest source of isoflurane LoRR. Such changes have been hypothesized to arise
9
due to accumulating sleep pressure as VLPO lesioned animals The central thalamus has long been known to be critical
fail to sleep (129, 130). Isoflurane directly depolarizes GABAergic to arousal, with small lesions of the area leading to gross dis-
neurons in VLPO. Acute resistance to isoflurane induction seen orders of consciousness (136). The anterior intralaminar nuclei,
following VLPO lesions suggests that in normal conditions, an- of which the central medial thalamus (CMT) is a part, receive
aesthetic activation of VLPO contributes to induction. Except for significant ascending cholinergic innervation from the BF and
ketamine, every other general anaesthetic appears to depolarize brainstem. Microinjection of nicotine into the CMT is suffi-
and recruit putative sleep-active VLPO neurons. The population cient to reverse continuous systemic sevoflurane anaesthesia in
of neurons throughout the preoptic area (including the VLPO, animal models. This effect is replicated with an infusion of anti-
MnPO, and surrounding area) that are active during recovery SWS bodies against potassium channels in the Kv1 family (41, 137).
(after sleep deprivation) significantly overlap with the population In slice recordings of neurons of the CMT, sevoflurane reduces
of neurons activated with systemic administration of hypnotic firing, which is, in turn, reversed by administration of a Kv1 in-
doses of dexmedetomidine. This reinforces earlier findings sug- hibitor (40). Activity of the CMT appears to be critical for both
gesting dexmedetomidine acts on native preoptic sleep circuits to sleep and anaesthesia, as changes in high-f requency oscillations
produce hypnosis (131, 132). that occur at both the onset of sleep and anaesthetic-induced
Similar to the VLPO, MnPO sleep- a ctive neurons are loss of consciousness occur first in the CMT, rapidly followed
GABAergic and fire more rapidly several seconds prior to sleep by cortical changes (68). More generally, thalamic inactiva-
onset. Although not as broadly activated by anaesthetics as the tion as measured by reduced blood flow has been associated
VLPO, some inhaled anaesthetics also appear to activate putative with anaesthetic-induced unconsciousness, although whether
sleep-active MnPO neurons (133). Microinjection of benzodi- this is causal or secondary to unconsciousness itself remains
azepines, propofol, and pentobarbital into the MnPO has been unclear (138).
shown to induce SWS (72, 134, 135). Due to the state-dependent
firing pattern of MnPO neurons, they have been assigned an im- Neocortex and Limbic Cortex
portant role in the initiation of sleep. The MnPO is known to send
The effects of anaesthetics are particularly heterogeneous across the
inhibitory projections to multiple arousal systems, including the
neocortex, in stark contrast to the largely antiquated ‘wet blanket’
orexinergic neurons in the hypothalamus, in a manner similar to
theory of anaesthetic action as a general neuronal depressant. The
the VLPO.
extent to which the primary sensory cortices are affected by many
Sleep-active Neurons of the Basal Forebrain and Parafacial general anaesthetics remains unclear. These primary processing
Zone (PZ) areas are still able to maintain normal or near-normal responses
While arousal-promoting neurons of the BF and pons are well es- to evoked potentials while longer-latency potentials are inhibited.
tablished and their effects on anaesthetic states detailed, it is only In contrast, the function of higher-order association cortices and
recently that sleep-active groups in these structures were identi- portions of the entorhinal cortex are markedly impaired by general
fied. Although they interact with arousal centres known to influ- anaesthetics. The mesial parietal cortex, the anterior and posterior
ence anaesthetic actions, the effects of these newly detailed groups cingulate cortices, and the precuneus are deactivated in sleep and
on the anaesthetic state and the effects of anaesthetics on their ac- anaesthesia, as measured indirectly by changes in cerebral blood
tion remain to be investigated. Parvalbumin-positive GABAergic flow (139–141). Given the variability of anaesthetic effect on in-
neurons of the BF are wake-active and strongly promote arousal, dividual cortical areas, hypnotic effects of anaesthetics may either
while another subset of GABAergic neurons expressing somato- prove to be a result of direct actions upon the cortex or could be a
statin in the BF comprise a sleep-active group. Somatostatin posi- result of network-level perturbations that include cortical and sub-
tive, GABAergic neurons of the BF exhibit specific increases in cortical interactions.
local unit activity during SWS. Optogenetic stimulation of these
neurons can induce SWS (103). The parafacial zone is a pontine re-
gion lateral to the seventh nerve containing SWS-active GABAergic Brain Networks and Anaesthesia
neurons. Those sleep-active, inhibitory neurons project directly The specific molecular target(s) of an anaesthetic may not yield
onto arousal-promoting glutamatergic neurons of the parabrachial immediate insight into mechanisms by which the drug pro-
nucleus, which, in turn, project to arousal-promoting neurons of duces unconsciousness. Complete understanding requires de-
the BF. Artificial stimulation of those PZ GABAergic neurons pro- tailed knowledge of drug effects on their molecular targets, as
duces SWS (108). Anaesthetic effects on the PZ and sleep-active well as how ensuing changes in the activity of neurons and glia
neurons of the BF await further study. affect local and distant circuits in addition to the global impact
on networks. The relevant actions of anaesthetics, and hence their
Thalamus common mechanism, may thus be their ultimate disruption of
The thalamus is a critical structure that plays at least three major network function-decreasing functional information integration.
roles in wakefulness and consciousness. First, in terms of levels of Understanding discrete effects of anaesthetics on receptors, indi-
consciousness, the thalamus is an important conduit for arousal vidual neurons, and brain nuclei are necessary but not sufficient
pathways from the brainstem. Second, in terms of the content of in isolation. To investigate anaesthetic disruption of network level
consciousness, it is a major relay station for sensory information en processes, large-scale brain activity studies employ functional
route to the cortex. Third, in terms of the organization of conscious magnetic resonance imaging (fMRI), positron emission tomog-
experience, the higher-order nuclei of the thalamus play a critical raphy (PET), magnetoencephalography (MEG), or high-density
role in facilitating corticocortical coherence and communication. electroencephalography (EEG).
01
Summary 6. Mascia M, Trudell JR, Harris AR. Specific binding sites for alcohols and
anesthetics on ligand-gated ion channels. Proceedings of the National
◆ Anaesthetics act upon a variety of protein targets to exert their Academy of Sciences. 2000;97(16):9305–10.
hypnotic effects. 7. Hemmings HC, Akabas MH, Goldstein PA. Emerging molecular
mechanisms of general anesthetic action. Trends in Pharmacological
◆ Relevant hypnotic molecular targets of general anaesthetics in- Sciences. 2005;26(10):503–10.
clude ligand-gated ion channels (examples: GABA and NMDA 8. Jenkins A, Greenblatt EP, Faulkner HJ, Bertaccini E, Light A, Lin
receptors), voltage-gated ion channels (examples: Kv1 and A,, et al. Evidence for a common binding cavity for three general
Nav1.6), constitutively active ion channels (example: K2P), G- anesthetics within the GABAA receptor. The Journal of Neuroscience.
protein-coupled receptors, and respiratory complex I. 2001;21(6):RC136.
9. Li, X, Pearce, RA. Effects of halothane on GABA(A) receptor
◆ Anaesthetics elicit circuit-level effects not readily predicted by kinetics: evidence for slowed agonist unbinding. The Journal of
their effects on single neurons of a given circuit. Neuroscience. 2000;20(3):899–907.
10. Bieda M, MacIver B. Major role for tonic GABAA conductances in
◆ Anaesthetics can affect endogenous neural systems regulating anesthetic suppression of intrinsic neuronal excitability. Journal of
sleep and arousal, and such actions may produce or potentiate Neurophysiology. 2004;92(3):1658–67.
their hypnotic effects. 11. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and
tonic activation of GABAA receptors. Nature Reviews Neuroscience.
◆ The thalamus is part of the ascending arousal system, serves as a
2005;6(3):215–29.
relay for sensory information, and facilitates corticocortical com- 12. Bonin R, Orser B. GABAA receptor subtypes underlying
munication. While thalamic inactivation does not invariably lead general anesthesia. Pharmacology Biochemistry and Behavior.
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nosis during continuous anaesthetic administration, presumably 13. Mascia M, Machu T, Harris A. Enhancement of homomeric glycine
through the ascending arousal pathways. receptor function by longchain alcohols and anaesthetics. British
Journal of Pharmacology. 1996;119(7):1331–6.
◆ Disruption of function in cortical association areas by anaes- 14. Harrison NL, Kugler JL, Jones MV, Greenblatt EP, Pritchett DB.
thetics corresponds with changes of global network properties Positive modulation of human gamma-aminobutyric acid type A and
during hypnosis, where long-range connections decline and glycine receptors by the inhalation anesthetic isoflurane. Molecular
the total capacity for information integration decreases. It is Pharmacology. 1993;44(3):628–32.
not yet clear whether direct action at those association centres 15. Beckstead M, Phelan R, Trudell J, Bianchini M, Mihic J. Anesthetic and
ethanol effects on spontaneously opening glycine receptor channels.
directly underlies network adaptations or whether the primary
Journal of Neurochemistry. 2002;82(6):1343–51.
change occurs elsewhere and propagates to impair cortical 16. Yamakura T, Mihic SJ, Harris RA. Amino acid volume and
activity. hydropathy of a transmembrane site determine glycine and anesthetic
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of connectivity are altered with anaesthetic hypnosis. Changes in
17. Quinlan JJ, Ferguson C, Jester K, Firestone LL, Homanics GE. Mice
both of these networks may reflect a final common marker or with glycine receptor subunit mutations are both sensitive and resistant
mediator of anaesthetic-induced unconsciousness. to volatile anesthetics. Anesthesia and Analgesia. 2002;95(3):578–82.
18. Ahrens J, Haeseler G, Leuwer M, Mohammadi B, Krampfl K, Dengler
Multiple-Choice Questions R, et al. 2,6 di-tert-butylphenol, a nonanesthetic propofol analog,
modulates alpha1beta glycine receptor function in a manner distinct
Q Interactive multiple-choice questions to test your knowledge from propofol. Anesthesia and Analgesia. 2004; 99(1):91–6.
on this chapter can be found in the online appendix at www. 19. Krasowski MD, Jenkins A, Flood P, Kung AY. General anesthetic
oxfordmedicine.com/otneuroanesthesiology. potencies of a series of propofol analogs correlate with potency
for potentiation of gamma-aminobutyric acid (GABA) current at
the GABAA receptor but not with lipid solubility. The Journal of
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71
CHAPTER 2
Intracranial Pressure
Harald Stefanits, Andrea Reinprecht,
and Klaus Ulrich Klein
Blood
brainstem towards the foramen magnum. The cranial nerves III to The cerebral blood volume makes up 5% of the ICV, mainly con-
XII originate from the brainstem. The brain parenchyma has to be sisting of venous vessels. Cerebral blood flow (CBF) and associ-
considered a rather static volume that is easily adaptive to chronic ated cerebral blood volume (CBV) are regulated by mechanisms
compression up to a certain extent (in cases of slowly growing tu- influencing cerebral resistance (i.e., constriction or dilation of ves-
mours, such as meningiomas), but very sensitive to acute com- sels, static autoregulation) over time (dynamic autoregulation). The
pression such as intracranial bleeding. Volume expansion of the pressure reactivity index (PRx) is described as a correlation coef-
parenchyma might be caused by tumour, abscess, intracranial ficient between (e.g., ten-second average) ICP and mean arterial
haemorrhage (ICH), or oedema. The latter can be focal (e.g., in blood pressure (MAP) over a time window (e.g., five minutes). In
cases of tumour, bleeding, infection, stroke, venous stasis) or gen- severe brain injury patients, impaired autoregulation contributes to
eral (e.g., in SAH, global infarctions, traumatic brain injury, or as- unfavourable outcome. CPP is calculated as a difference between
sociated with systemic diseases). A natural atrophy of the brain can the MAP at head level and the ICP. The concept of the ‘optimal
be observed during ageing, which provides more buffer space for CPP’ should be followed, since values beyond the CPP level opti-
volume expansion in elderly people. mizing cerebral autoregulation are associated with fatal outcome or
increased disability. The optimal CPP is between 50 and 95 mmHg,
Cerebrospinal Fluid
but it is patient-and time-dependent, and thus needs continuous
The CSF space makes up 10% of the ICV, equalling a total of 120–200 monitoring. In cases of acutely elevated ICP, decreasing the IBV
ml. CSF is a low-protein, glucose-containing liquid that contains is a short-term strategy to decrease ICP. This can be achieved by
few cells, mostly lymphocytes (up to 4/µl). It is mainly produced by moderate (short-term) hyperventilation leading to hypocapnia
and associated cerebral vasoconstriction. Special caution has to be
undertaken in patients suffering from vasospasm after SAH.
Table 2.1 The contents of the cranial vault are divided into three
compartments. Proportions of intracranial volume are given in %.
Intracranial Compliance
Contents of the intracranial vault The pressure-volume relationship between ICP, ICV, and CPP
pressure is known as the Monro-Kellie doctrine, which states that
Brain parenchyma 85% i) the brain is enclosed in the non-expandable cranium; ii) brain
Cerebrospinal fluid 10% parenchyma is nearly incompressible; iii) the blood volume of the
Blood 5% intracranial vault is nearly constant; and iv) a continuous outflow of
venous blood from the intracranial vault is required to make room
91
(a) 14 P2
13
12
11
ICP (mmHg)
10
9 P1
8
7
6
5
4
3
0 50 100 150 200 250 300 350 400
Time (ms)
(b) 14
P2
13
12
11 P1
P3
ICP (mmHg)
10
Pressure
9
8
7
6
5
4
3
0 50 100 150 200 250 300 350 400
∆p Time (ms)
(c) 10 P1
9
ICP (mmHg)
8 P2
7 P3
6
5
∆p
4
3
∆V Volume ∆V 0 50 100 150 200 250 300 350 400
Time (ms)
low, leaving only P2, although P2 and P3 are not changed by this. changes, for example, during intracerebral vasodilation or
A prominent P2 wave may occur when intracerebral compliance vasoconstriction.
has decreased (e.g., increasing ICP) or during inspiratory breath
hold. During hyperventilation, P2 and P3 waves might diminish. Lundberg A–C Waves
A rounded ICP waveform with reduced peaks from P1–3 might
occur when ICP is critically high. A number of pathological waves Lundberg A-waves (plateau waves) are clearly pathological and de-
have been described so far. Modern extended ICP pulse waveform fined as a sudden ICP increase up to 50–100 mmHg lasting 5–20
analysis (e.g., morphological clustering and analysis of ICP, or minutes (Figure 2.4). During A-waves, it is common to develop
MOCAIP) potentially may allow for detection of cerebrovascular clinical signs and symptoms of early herniation, including brady-
cardia and hypertension. Although the underlying mechanism
remains unknown, it has been postulated that CPP cannot meet
cerebral metabolic demand, thereby triggering cerebral vasodila-
Table 2.2 Typical ICP values during different activities and sleep tion and subsequent increase in CBV and ICP. This, in return,
in babies and adults. causes additional CPP decrease, ultimately resulting in a vicious
cycle. Atypical Lundberg A-waves do not exceed an elevation of
Activity Baby [mmHg] Adult [mmHg] 50 mmHg and are an early indicator of neurological deterioration.
Lying supine 6±1 10±5 Lundberg B-waves are oscillating waves defined as a short modest
ICP increase of 10–20 mmHg lasting 0.5–2 minutes. It has been
Standing up –5±5 –5±5
postulated that B-waves might be caused by vasomotor centre
Non-REM-sleep 7±2 12±5 instability when CPP is unstable or at the lower limit of cerebro-
REM-sleep 19–22 15–25 vascular autoregulation. Lundberg C-waves are rapid sinusoidal
fluctuations of up to 20 mmHg of ICP lasting for 7–15 seconds
Coughing, sneezing 20–40 30–110
(about 0.1 Hz). These waves correspond to Mayer fluctuations in
12
Lundberg A waves
60
50
40
ICP (mmHg)
30
20
10
0
0 10 20 30 40 50 60 70 80
Time (min)
60 Lundberg B waves
50
ICP (mmHg)
40
30
20
10
0
0 10 20 30 40 50 60 70 80
Time (min)
60
Lundberg C waves
50
ICP (mmHg)
40
30
20
10
0
0 10 20 30 40 50 60 70 80
Time (min)
Figure 2.4 Lundberg A waves (5–50 mmHg, 5–20 minutes), Lundberg B waves (10–20 mmHg, 0.5–2 minutes) and Lundberg C waves (several mmHg, about 0.1 Hz).
MAP that have been documented in healthy individuals and poten- in terms of mortality. When measured over time at different CPP
tially are caused by cardiovascular interactions. thresholds, PRx demonstrates a U-shaped curve, suggesting a spe-
cific relationship of individual autoregulation. This approach can
be used to tailor individual CPP management in order to optimize
Cerebrovascular Pressure Reactivity the patient’s autoregulation. As ABP and ICP routinely are meas-
CBF autoregulation describes the ability of the cerebral vasculature ured continuously in patients at risk, this index is readily available
to maintain a stable CBF despite fluctuations in CPP. With intact when using appropriate software. Notably, the underlying prin-
autoregulation, a rise in arterial blood pressure (ABP) produces ciple of PRx also works for cerebral variables other than the ICP,
cerebral vasoconstriction, a decrease in CBV, and a fall in ICP (7, such as cross-correlating MAP and CBF velocity determined by
8). A fall in ABP produces the opposite effects. With disturbed transcranial Doppler sonography (Mx) or regional frontal haemo-
autoregulation, a rise in ABP is transmitted to the intracranial com- globin oxygen saturation determined by near-infrared spectros-
partment and produces a rise in ICP as a passive pressure effect. copy (ORx, THx) ideally determined at high temporal resolution.
Cerebral autoregulation can be determined by investigating the
moving Pearson correlation coefficient between changes in ABP ICP Measurement
and ICP, i.e., PRx. In fact, waveforms of ABP and ICP are correl-
ated at higher temporal resolution. PRx is negative (e.g., between Intraventricular Catheters
0 and –1) when cerebral vessels are pressure reactive and aim to Direct measurement of ICP in the lateral ventricle is still con-
counteract changes in ABP. Instead, PRx is positive (e.g., between sidered the ‘gold standard’ for ICP measurement (Figure 2.5 and
0.3 and 1) when cerebral vessels are not pressure reactive and alter- Box 2.2) (9). The measurement is performed at the level of the me-
ations in MAP are mostly directly transmitted to ICP. PRx has been atus acusticus externus corresponding to the foramen of Monro.
identified as a predictor of outcome after traumatic brain injury Advantages of this measurement include the possibility of external
2
calibration and CSF drainage. However, placement of the catheter ventricular drain (EVD) or a lumbar drain (LD). The latter can only
may be difficult or even impossible in case of severe brain swelling be applied in communicating hydrocephalus, and an open passage
with collapsed ventricles. Furthermore, the risk of infection is re- through the aqueduct and the outlet of the fourth ventricle is man-
ported to be between 3.5% to more than 20% according to different datory, which can be estimated by radiologic imaging (i.e., to check
larger clinical studies. Many authors report an increase of infection for mass lesions and ventricular diameter gradients). Blockage of
risk with prolonged usage (10). In clinical practice it is important to CSF pathways could lead to transtentorial or transforaminal her-
be aware that ICP recordings are representative only with a closed niation (see Herniation Syndromes).
drainage system (4, 11, 12, 13, 14). In many cases, an external ventricular drainage is the first choice.
It can be implanted in a sterile surrounding at the intensive care
Intraparenchymal Probes unit (ICU) or in the operating theatre by a neurosurgeon and com-
ICP can be recorded by inserting a probe into the brain paren- bines draining of CSF with measurement of ICP. The EVD is a sili-
chyma. Usually, these probes are inserted in a non-eloquent brain cone catheter that is inserted into the lateral ventricle, usually by a
area, although the exact placement, especially in focal pathologies, frontal and rarely by an occipital or temporal approach, through a
is a matter of ongoing debate. Measurement of ICP is local and does burr hole and a small incision of the dura (15, see Table 2.3). The
not necessarily represent CSF pressure. The risk for parenchymal most common variant is a frontal burr hole over Kocher’s point,
bleeding or infection is <1%. Microtransducers cannot be recali- which is 1 cm anterior to the coronary suture and 3 cm lateral from
brated after insertion and drift from zero might occur during long- the midline (Figure 2.6). The target point is the entrance of the for-
term measurement. amen of Monro which is situated at the crossing of virtual lines
through the medial canthus of the eye (anterior-posterior) and the
Drainage of CSF external acoustic meatus (left-right). The EVD can be attached to
the bone via a bolt system or tunnelled subcutaneously. The ven-
In cases of acute hydrocephalus, drainage of CSF has to be per- tricular catheter is secured by suturing it to the skin, although it
formed promptly. This can be done by insertion of an external may also be connected to a second distal silicone catheter with a
‘Vienna connector’ to prevent accidental removal by the patient or
during nursing procedures. The CSF drainage system includes a
Box 2.2 Reasons for Performing ICP Monitoring drip chamber that is positioned according to the patient’s head, at a
certain level above reference points such as the radix nasi or the ex-
◆ Severe brain trauma (GCS 3–8) ternal acoustic meatus (point where the tip of the ventricular cath-
eter is estimated to be, i.e. the opening of the foramen of Monro).
◆ Severe subarachnoid haemorrhage (traumatic, vascular) The level of the drip chamber can be adjusted according to a re-
◆ Severe cerebral ischaemia sistance for the drained CSF target amount (principle of commu-
nicating vessels). It is typically placed between 0 and 15 cm above
◆ Diagnostic (hydrocephalus, shunt insufficiency)
the reference points and adapted to ICP (normal values between
32
the EVD functioning, a cranial computed tomography (CCT) scan compression of the oculomotor nerve. This complements to the
should be considered to check for ventricular size or dislocation stretching of the nerve over the clivus (due to downward shift of
of the ventricle catheter. The ICP should only be measured by the its origination), resulting in ipsilateral mydriasis at an early stage.
transducer when the distal drainage system is closed. A lumbar CSF This is an absolute alert sign—immediate lowering of ICP has to
drain is inserted intradurally under sterile conditions between ver- be achieved.
tebrae L4/5, L3/4, or L2/3. The level of L4/5 can easily be found by ◆ Subfalcine: Parts of the hemisphere inheriting the mass lesion
connecting the palpable rims of the anterior iliac crests. The drain may herniate below the falx cerebri, possibly compressing the
is also connected to a drip chamber and a distal drainage system. pericallosal and callosomarginal arteries, leading to brain in-
However, ICP measurement is not reliable. From both types of farcts of the medial frontal lobe (gyrus cinguli, gyrus frontalis
drainages, CSF should be analysed at regular intervals (e.g., every superior) down to the precuneus. On CCT, a midline shift can
second day). The following parameters may be evaluated (Table be seen (measured at the level of the septum pellucidum or the
2.4). Additionally, microbiological cultures should be performed pineal gland). Greater than 5 mm of midline shift may lead to
regularly. stupor, and greater than 9 mm to coma.
Transtentorial: When the supratentorial ICP increases, structures
Herniation Syndromes ◆
shift further downwards, leading to transtentorial herniation. It is
There are different reasons for causes of impairment of conscious- a rather late, often terminal event, leading to direct compression of
ness in neurological and neurosurgical patients, and conscious- the brainstem. The oculomotor nuclei are damaged on the contra-
ness is dependent on the functioning of the ascending reticular lateral side, resulting in mydriasis and loss of light reaction of the
activating system (ARAS), a network of neurons with connections contralateral (in addition to the ipsilateral) pupil. Bilateral mydriasis
from the pons up to the cerebral cortex. The following three terms and decerebrate posturing (flexion of upper, extension of lower ex-
are often used to describe impairment of consciousness, but all tremities) are signs of a late phase of herniation. Furthermore, the
terms used should be complemented by detailed clinical descrip- posterior cerebral artery (PCA) is at risk—its compression leads to
tions of the patient. parietooccipital brain infarcts (visual impairments, blindness).
1) Somnolence is a sleep-like state that can be disrupted easily by ◆ Tonsillar: Raised pressure in the posterior fossa leads to her-
speaking to the patient. Wakefulness and awareness are im- niation of the cerebellar tonsils through the foramen magnum.
paired and attention cannot be sustained. Compression of the medulla oblongata leads to respiratory arrest
2) Stuporous patients may be roused only by strong stimuli, such and compression of the outflow of the fourth ventricle to acute
as pain. hydrocephalus.
3) Coma is characterized by a loss of consciousness with an Besides impairment of consciousness, other signs of increasing ICP
unarousable patient, even to strong stimuli. Motor responses have to be considered, such as headache, altered brain function
are possible. (sensory or motor deficits, speech impairment, cognitive dysfunc-
tion), seizures, and visual disturbances. Conservative measures
Different grading scales such as the Glasgow Coma Scale or the Full should be undertaken before aiming at surgical interventions (Box
Outline of Unresponsiveness score are used to describe these states 2.3). There should at least be a consideration of surgical intervention
in more detail. Increase of ICP leads to compression of the struc- for intracranial lesions with mass effect leading to clinical symp-
tures relevant for the ARAS by ‘herniation’ through the tentorial toms. Extra-axial and intra-axial tumours, intracranial bleedings
notch and the foramen magnum or the facial and tentorial edges: (especially epidural and subdural haematoma, but in some cases
◆ Uncal and Central: Unilateral, supratentorial mass lesions shift also intracerebral haemorrhage), as well as large abscesses often re-
the brain downwards and towards the contralateral side, leading quire surgical intervention. Mass lesions in the posterior fossa—
to compression of the diencephalon and the brainstem in the including intraparenchymal bleeds—have to be surgically treated
tentorial notch and at the tentorial edge, thus leading to im- when compression of the fourth ventricle is suspected or expected
pairment of consciousness. Also, temporal structures, especially due to swelling. In cases of strokes, conservative management
the uncus, herniate around the tentorial edge, leading to direct should be aimed at, except from large cerebellar strokes. However,
Table 2.4 The following parameters of the cerebrospinal fluid are important for the differential diagnosis of infection and haemorrhage.
CHAPTER 3
Cerebral Physiology
Stefan Bittner, Kerstin Göbel, and Sven G. Meuth
These mechanisms are necessary to regulate the cerebral intake principle. For an experimental assessment, non-physiological gas
of compounds very carefully. For example, the BBB glucose car- (e.g., nitrous oxide [N2O] or radioactive gas) is inhaled. Thereafter,
rier that also transports other hexoses, such as galactose, mannose, the absorbed amount of gas in the CNS and its concentration in the
or deoxyglucose, was identified as the glucose transporter type 1 arterial and cerebral venous blood is recorded. The arterial concen-
(GLUT-1). The density of GLUT-1 is higher at the abluminal side tration (Ca) of foreign gas can be measured in any artery. For meas-
than at the luminal side, thereby providing a homeostatic control urement of the brain venous concentration (Cv), blood is taken
of D-glucose influx to the CNS. The expression of GLUT-1 is con- from the jugular vein by puncture or catheter.
trolled by the hypoxia-inducible factor 1 alpha (HIF-1α) and can be
modulated by astrocytes.
CBF = volume / time
The BBB phenylalanine carrier that also transports other large
and, to a lesser extent, small neutral amino acids, has been shown = absorbed amount of indicator / time * (Ca − Cv )
to be the large neutral amino-acid transporter type 1 (LAT-1). The
BBB arginine carrier that also transports other cationic amino The brain is supplied with blood by the circle of Willis. Potential
acids (ornithine, lysine), was identified as the cationic amino-acid collateral pathways exist between the internal and external ca-
transporter type 1 (CAT-1). The BBB lactate carrier that also trans- rotid arteries via the meningeal and ophthalmic vessels. Although
ports other monocarboxylic acids (ketone bodies, acetoacetate, the brain is only 2% of the total body weight, CBF is about 50 ml/
β-hydroxybutyrate and pyruvate), is the monocarboxylic acid 100 g tissue per minute under physiological conditions, which re-
transport type 1 (MCT-1). The BBB adenosine carrier that also sembles 15% of the cardiac output, and is required to maintain a
transports the pyrimidine nucleoside uridine and other purine nu- blood flow of 700–900 ml/min. However, there are large regional
cleosides (inosine, guanosine) has been shown to be the concentra- differences overall. For example, values for blood flow in the white
tive nucleoside transporter type 2 (CNT-2). matter are about 20 ml/100 g tissue per minute, while in the grey
Different receptor-mediated carriers complement this system. matter, values from 80 to 140 ml/100 g tissue per minute are meas-
For example, both transferrin and insulin can be found in the brain, ured. As the CBF hardly ever fluctuates, a constant intracranial
but there is no mRNA in the CNS. Therefore, both substances are blood volume of 100–150 ml can be measured. This relatively con-
produced outside the CNS and are transported to brain by receptor- stant blood supply is perpetuated by the so-called autoregulation.
mediated carriers. This concept includes the cerebral ability to sustain a constant CBF,
These different transport systems allow a selective extraction of despite changes in the CPP. Autoregulation is present in many vas-
compounds from the blood into the brain. In addition, there are cular beds, but is particularly well-developed in the brain, likely
carriers available to transport compounds from the brain to the due to the need for a constant blood supply and water homeostasis.
blood to protect the CNS from potentially dangerous substances. In normotensive adults, the CBF remains constant, provided the
One of these classic active efflux transporters is P-glycoprotein, CPP is in the range of 60–160 mmHg, independent of the MAP
which is a product of the multidrug resistance gene (MDR-1), also and cardiac output. Therefore, autoregulation is the mechanism
named the ATP-binding cassette subfamily B member 1 (ABCB- that protects the CBF in physiological situations, such as exercise
1) and is located on both the luminal and abluminal endothelial and in pathological conditions, such as cardiogenic shock. Below
membranes, thereby mediating rapid removal of ingested toxic and above this limit, autoregulation is lost and the CBF becomes
lipophilic metabolites and reducing drug penetration into the brain dependent on the MAP in a linear fashion. When the CPP falls
(6). The expression and functional activity can be modulated by below the lower limit of autoregulation, reduction in the CBF is first
astrocytes and pericytes. Different enzymes expressed within the compensated by an increased oxygen extraction from the blood
BBB complement the active efflux transporter system. Both systems and, subsequently, cerebral ischaemia ensues. Pressures above the
are subject to modulation. upper limit may result in oedema, haemorrhage, seizures, and pos-
terior leukoencephalopathy. The normal autoregulatory curve may
Basics Principles of the Blood-cerebrospinal Fluid Barrier
be shifted towards higher pressures in chronically hypertensive
The CSF is mainly produced at the choroid plexus of the ventricles patients.
(about 500 ml per day), moves over the surface of the brain, and is The mechanisms of autoregulation in the CNS are not completely
constantly absorbed into the general circulation across the arach- understood and likely differ with increases versus decreases in pres-
noid villi into the superior sagittal sinus of the venous bloodstream, sure. The autoregulation mechanism starts within two seconds after
so that a constant volume of 120–160 ml is constantly present. changes in the CPP. Decreasing the CPP leads to a dilatation, while
In this way, a rapid equilibrium occurs between the CSF and increasing the CPP causes a constriction of the cerebral resistance
blood. Substances that should reach brain tissue from the CSF can vessels.
diffuse. However, the differential rates create a paradox that sub- The CBF is dependent on two dimensions: the CPP, and the cere-
stances injected into the CSF distribute easily to the blood and brovascular resistance (CVR). The CPP and CVR can be calculated:
poorly to the brain. Parts of the hypothalamus and pituitary use
this process, which allows the transfer of hormones produced in
the brain to the blood. CPP = MAP − ICP
reductions in the CBF occur. The three major components of the Functional Analyses by Determination of Local Blood Flow and
intracranial cavity are the brain tissue, CSF, and CBV. If one compo- Metabolism Parameters
nent increases its volume, it must be compensated for by a decrease Blood flow and metabolism differ in individual brain structures, but
in another to prevent the ICP from increasing. are closely interconnected. For adaptation to alternating demand
Activity of the brain and CBF has a close correlation with cere- that is preset by changing metabolism, blood flow must be adjusted.
bral metabolism. If the cerebral concentrations of oxygen and This so-called hyperaemia is the mechanism by which microscopic
metabolic substrates are measured in the arterial and cerebral blood flow is regulated at a local level, ensuring that the delivery
venous blood, oxygen consumption and substrate utilization can of nutrients and oxygen fits the changes in activity at a local level.
be calculated: Local metabolism is dependent on the function of the respective
Cerebral metabolic oxygen consumption (CMRO2) or substrate brain structure (see Figure 3.2). The hyperaemia mechanism is ac-
utilization = CBF * (Ca − Cv) tivated, for example, in physiological situations: with increasing
The physiological oxygen consumption is about 3 ml/100 g visual strain, the metabolism in the visual cortex increases. As indi-
brain tissue per minute. Oxygen consumption differs per region cated, the neurovascular unit accomplishes the coupling of changes
with the highest values in the cortex. As the brain weight is about in the blood supply. The result of this metabolism augmentation is
1400 g, the cerebral energy requirement is about 15% of the total an increase in blood flow that can be measured more simply than
organism demand. With increasing oxygen demand, the CBF in- local metabolism.
creases, while oxygen difference in the arterial and venous blood Local Blood Flow Regulation in the Brain
remains constant. Different factors can influence cerebral me-
The connection of functional activity, metabolism, and blood flow
tabolism, e.g., body temperature. An increase in body tempera-
in the brain results from a release of functional and metabolic de-
ture of 1°C leads to an enhanced oxygen consumption of about
pendent factors from cells in the interstitial space, and is regulated
10–15%.
by the neurovascular unit. With the help of this mechanism, the
Glucose is the almost exclusive substrate of cerebral metabolism.
vessel tone can be regulated. An important function-dependent
Alternatively, ketones can be metabolized in cases of high plasma
factor is potassium that is released into the cerebral extracellular
concentrations. However, ketones can cover only half of the cere-
space after the generation of an action potential. Therefore, an in-
bral energy requirement. Under physiological conditions, an appre-
crease in interstitial potassium concentration is the result of en-
ciable amount of ketones is metabolized by the brain after several
hanced neuronal activity leading to an elevated cerebral blood flow.
days of fasting. Typical pathophysiological conditions include, for
Metabolic factors are hydrogen, lactate, prostaglandins (especially
example, diabetic ketoacidosis.
prostaglandin E), nitrogen monoxide, and adenosine. Generation
Local Cerebral Blood Flow and Local Cerebral Metabolism of these factors is augmented by a discrepancy between oxygen de-
mand and offer. An increased interstitial concentration of potas-
Method for Local Measurements
sium, hydrogen, lactate, and adenosine leads to a dilatation of the
As physiological and pathophysiological changes in the metabolic
cerebral vessels. While potassium allows a fast regulation, fine ad-
state rarely affect the whole brain, but only specific anatomical re-
justment occurs by metabolic factors (see Figure 3.3).
gions, local methods for taking measurements were developed to
These local factors act on the outer surface of cerebral vessels
register regional changes in the CBF and metabolism. A common
and regulate their tone. In the blood stream, they have almost no
method for taking measurements is the application of a radioactive
physiological influence, as the BBB of endothelial cells does not
indicator by inhalation or injection. Thereafter, the indicator’s con-
allow an extensive impact of circulating substances on the muscu-
centration is determined in the arterial blood and cerebral tissue
lature of vessels. Exempt are blood gases, especially carbon dioxide,
over time. For measurement in the brain, γ-detectors that detect
that can pass the BBB. Thus, an alteration of arterial carbon dioxide
tissue radiation are placed around the head. For measurement of
pressure (e.g., hyper-and hypoventilation) leads to a change of
the regional cerebral blood flow, well-diffusible indicators, such as
133Xe, are used. The accumulation of these indicators in the brain pH value in the CSF and in the interstitial fluid that surrounds the
cerebral vessels. Modification of pH value is the triggering factor
and their elution are dependent on the level of local CBF. Local
for a constriction (by a reduction in carbon dioxide [hypocapnia],
oxygen consumption can be measured with the help of 15O. For
interstitial alkalosis) or a dilatation (by an increase in carbon di-
measurement of regional glucose consumption, the glucose ana-
oxide [hypercapnia], interstitial acidosis, see also Figure 3.3).
logue 2-deoxyglucose that is labelled with 18F is commonly used.
Physiological oxygen partial pressures have no influence on blood
Brain cells absorb and phosphorylate 2-deoxyglucose, but cannot
flow. The blood flow only increases if the oxygen partial pressure is
further metabolize this substance. Subsequently, 2-deoxyglucose ac-
below 50 mmHg.
cumulates in the cerebral tissues over time, depending on its phos-
Nitrogen monoxide is produced by cerebral endothelial cells and
phorylation rate, which is similar to that of glucose. Accumulation
by different cells in the cerebral tissue, such as astrocytes, muscle
of radioactive tracers is higher in those brain regions with a high
cells, and specific neurons. In the brain, nitrogen monoxide mostly
cerebral metabolism than in areas with low rates. 15O and 18F are
leads to a basal dilatation of the vessels and strengthens the effect of
positron-emitting substances and can be detected by PET. This nu-
other vasoactive substances (see Figure 3.3).
clear medical method can detect disturbances in the local CBF and
metabolism and is the gold standard for the measurement of cere- Other Mechanisms of Vascular Regulation
bral perfusion and oxygen metabolism. However, due to its logistic, In the brain, an innervation of vessels is less important for blood
time and personnel consuming effort, the technique is challenging flow than in other organs. The sympathetic noradrenergic con-
to implement in routine diagnostics. For this purpose, the method stricting nerve fibres in the cerebral vessels are mostly activated
of choice remains computer tomography. during rising blood pressure. They reduce a pressure-induced
13
thalamus
visual
cortex
Eyes
OPEN/CLOSED
60%
20% 23%
Glucose
8%
metabolism
Figure 3.2 Analyses of brain function via measurement of local blood flow.
Dependency of local cerebral metabolism on stimulus intensity: with increasing intensity and complexity of a visual stimulus, cerebral metabolism rises in the visual
cortex. The complex scene was the view of a quite busy park in New York.
increase in blood flow and tighten the BBB to decrease fluid in- nitric oxide. A direct relationship of endothelial cells with astrocytes
flux to the cerebral tissue. The importance of parasympathetic is also being researched. Vessel contraction or dilatation would
cholinergic dilating innervation is not yet completely understood. then depend on numerous factors, ranging from the intensity of
The same is true for the function of vasoactive peptides. However, neuronal stimulation, the intrinsic characteristics of the endothelial
signals not only influence endothelial cells and musculature of cell, pericyte, and muscle cells. It most likely also depends on the
cerebral vessels but also indirectly act on astrocytes, neurons, or area of the CNS in which the neurovascular unit is located. Among
pericytes. Under physiological conditions with an adequate supply all the factors that seem to be relevant in the regulation of brain
of nutrients and oxygen, myocytes and pericytes remain in a state hyperaemia, intra-astrocyte calcium concentration may play an im-
of basal contractility. This tone is the result of the balance between portant role that does not seem to be only regulated by neuronal
vasodilator and vasoconstrictor signals determined by neurons. In activity. Furthermore, calcium influx can also lead to vasoconstric-
these circumstances, the neuron is able to communicate with the tion or vasodilation in the same group in different neuronal situ-
astrocytes, either directly or indirectly, through interneurons after ations. This means that astrocytes are not only influenced on the
the release of glutamate. Figure 3.3 shows one example. Following metabolic pathway but also according to the neuronal information
the release of glutamate during synaptic transmission, postsynaptic and the surrounding environment, depending on several factors,
receptors are stimulated on both the downstream neurons and the such as neuropeptides, ATP, or nitric oxide. There is evidence that
astrocytic processes localized on synapses. Activation of these re- the bipolar response of vasoconstriction versus vasodilation is de-
ceptors on astrocytic processes increases the calcium concentration pendent on the bioavailability of nitric oxide that is not only pro-
in astrocytes, thereby causing a chain reaction. This gain induces a duced by endothelial cells, but also by neurons.
release of different vasoactive substances, such as prostaglandins, Apart from astrocytes, neurons can be stimulated by glutamate,
which are released by the astrocyte end-feet directly into the muscle which leads to a release of, for example, nitrogen monoxide and
cells or pericytes, resulting in cell contraction. In the process, in- adenosine, both known vasoactive factors. Furthermore, pericytes
creases in calcium concentrations can be dispersed in a wave-like can play an important part in the regulation of blood flow as they
manner in the astrocytes and reach other astrocytes via the gap can modulate the diameter of vessels by specialized proteins, such
junctions. Through this connection, vasoactive substances reach as actin.
other distant cerebral vessels. Vasoactive substances, such as pros-
taglandins, ATP, or nitrogen monoxide released by astrocytes can Age Dependency of Cerebral Blood Flow and Metabolism
lead to a dilatation and a constriction of the vessels. The cerebral metabolism and blood flow varies considerably from
Endothelial cells may also modulate the vascular tone, as birth to old age. In the first months of life, cerebral metabolism and
they produce both a number of vasoconstrictive agents, such as blood flow rise rapidly during the period of cerebral growth and de-
endothelin and thromboxane, and vasodilator substances, such as velopment and reach a maximal level at about the time maturation
23
is completed; values (per gram of cerebral tissue) are higher in neuronal tissue, and is therefore of utmost importance during an-
children than in adults. The rate of blood flow in different cerebral aesthetic procedures. Pharmacological modulation of the CBF can
structures peaks at different times, depending on the maturation be mediated either by a direct impact on the CNS blood vessels
rate of the particular area. The peak is reached during adolescence. or indirectly by modulating the cerebral metabolism or breathing
With increasing age, CBF and probably cerebral metabolism only frequency. As described previously, arterial O2 (PaO2) and CO2
decline to the levels characteristic of adulthood. CBF and oxygen (PaCO2) concentrations have important influences on the CBF.
consumption normally remain unchanged between young adult-
hood and older age, but can distinctly decrease if arteriosclerotic
changes in the cerebral vessels or neurodegenerative disorders de-
Table 3.1 Normal values for cerebral metabolism.
velop. As plasma concentrations of ketones increase in the elderly,
they can additionally be metabolized. The increase in ketones is
Parameter Normal Value
caused by reduced utilization of ketones by the skeletal muscula-
ture that decreases with age. Brain weight 1,400 g
ICP 10–15 mmHg
Effects of Anaesthetics on Cerebral Physiology
CBF 45–60 ml/100 g/min
Anaesthetics and other peri-operative drugs have important influ-
ences on brain physiology by modulating the CMRO2, CBF, or ICP CMRO2 3.0–3.8 ml/100 g/min
(see Table 3.1 for normal values) (7). A constant regulation of the CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen consumption; ICP,
CBF levels ensures a constant delivery of glucose and oxygen to the intracranial pressure.
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before; and, beholding him thus moved, her breath quickened and
she glanced away lest he should read the triumph in her face.
“Can such love truly be?” she asked softly.
“So long as thou art Rose,” he answered.
“And what o’ poor Herminia?”
“Do but love me, Rose, and I will strive to love her for thy dear
sake.”
“Will this be so hard a matter? Must you strive so extremely?” she
questioned, and glanced at him over her shoulder, languorous-eyed,
vivid lips up-curving, conscious of and assured in her beauty; and,
reading this look, he laughed a little bitterly.
“O Coquetry!” he exclaimed, “that turn o’ the neck and shoulder,
that languishing droop o’ the eyes become you vastly.... Egad, I
protest you are monstrous bewitching so, my Lady Herminia!”
At this she flushed angrily and knit black brows at him.
“Faith, sir,” she retorted, “by your vast knowledge o’ feminine arts I
perceive you to be merely Sir John Dering!”
“Who is extreme hungry!” he added. “And there doth await him a
Sir Loin o’ beef—hot! So, shall we go on, my lady?”
On they went accordingly, my lady with head proudly averted, and
yet he knew her eyes were tearful, but, noting how passionately her
white hand clenched itself, knew these for tears of anger only.
“Alas,” sighed he at last, “to-day poor John Derwent’s wooing doth
not prosper, it seems. Love hath fled awhile on soaring pinions.”
“I never hated you more!” said she in low, steady voice.
“Wouldst break thy John’s heart, girl?”
To this she deigned no answer; but when he had repeated the
question three or four times with as many different modulations, she
broke out angrily:
“Aye, I would—I would, if ever I find it!”
“Couldst be so cruel, child?” he questioned lightly; and then, more
seriously, “Could you stoop to such baseness? I wonder!”
“Nay,” she retorted bitterly, “’twere impossible! You have no heart
... never did have ... never will!”
“And yet it beats for thee, Rose. Reach me thy hand and feel.”
“Then ’tis the heart of a stock-fish!” she cried. “Cold, cold—
infinitely cold and sluggish!”
“Stock-fish!” he repeated mournfully—“O ye gods—a stock-fish!
Alas, sweet soul, what strange mistake is here? A stock-fish. I that
am by nature so ardent yet so humble, of impulses so kindly, of
passions so fiery, of sentiments so very infinite tender! I that am thy
predestined mate, thy man——”
“Aye, thou,” she cried fiercely—“thou that art no more than a fine-
gentlemanly thing as humble as Lucifer, as kindly as an east wind,
as fiery as a lump of lead, as tender as that savage monster who
nigh broke my wrists for me!”
“Gad’s my life, child,” said he, noting her flashing eyes and
glowing cheek, “thy so splendid theme endows thee with new
splendour, thou handsome wench! Though thou dost sadly
embarrass thy modest John——”
“Would I might, indeed!”
“But ’tis very well thou shouldst justly appreciate me as well before
as after marriage! And now, for thy poor, pretty wrists——”
“Why are you here, Sir John, wasting yourself in the country?” she
demanded mockingly. “Your true place is that same heartless, selfish
world o’ modish idleness whence you came! What do you here
among these kindly Sussex folk who, at the least, live to some
purpose? Why are you here, you who live for no purpose but
yourself?”
“Mayhap,” he answered, “’tis because you once minded me o’ the
scabious flowers, child. See where they bloom all around us, sweet
things! Do not tread too hastily, Herminia, lest you crush and end
their blooming. Haste not so, for here is a stile for you to climb, and
yonder, bosomed i’ the green, is Alfriston spire.”
“Aye, I thank heaven!” cried she.
“And wherefore thy so fervent gratitude, child?”
“To be rid of thy hated presence!”
“Ah, Rose,” he sighed. “Alas, Herminia, how heavy thy foot is! See
this poor flower you trample—’tis my heart!” And speaking, he
stooped, put by her foot very gently, and plucked one of the scabious
flowers she had trodden; fingering it tenderly, he placed it in her
hand. “Take it, child!” he sighed; “cherish it for its own sweet sake.
And for me and my so hated presence, I will deliver you, here and
now.... But first, thy poor, pretty wrists? Show ’em to me!”
“No!” she answered; “never to you, Sir John!”
“Indeed, child, ’tis thy Derwent pleadeth, thy John o’ Gentleness....
Suffer me to see!” And, taking her hands, he lifted them whether she
would or no.
“I see no wounds,” quoth he, “nor mark or bruise; and yet who am
I to judge the pretty things? And if they endured hurt, let this witness
my sorrow.” So saying, he stooped and kissed them tenderly. “Thus,
sweet Rose, thy Derwent leaveth thee. Now, had I been the ‘Wicked
Dering’ and thou the proud Lady Barrasdaile, it had been ... thy
hands, thine arms, thy lips ... thy very self! And now, farewell awhile,
my Rose o’ love.”
Saying which, Sir John bared his head, gave her his hand across
the stile, and seating himself thereon watched her wistfully as she
hurried away.
But, being hidden from his view, my lady paused to glance at her
wrists, flushing as though she felt his lips there yet; and finding she
still held his scabious flower, tossed it angrily away, but, marking
where it fell, took it up again, and having throned it amid the laces of
her bodice, went her way, slow of foot and with eyes a-dream.
CHAPTER XXXIII
WHICH, AMONG OTHER SMALL MATTERS,
TELLETH OF A SNUFF-BOX
And now ensued days wherein Sir John seemingly idled, the
Corporal took mysterious journeys both a-horse and afoot, and my
Lady Herminia busied herself upon Sir Hector’s comfort; for, having
visited his cottage and being horrified by his ideas of “homeliness,”
she prepared for immediate action—that is to say, with lovely head
tied up in a kerchief (laced cap, ringlets and all) against such
accidentals as spiders, cobwebs and dust, she armed herself with a
mop and Mr. William Thompson with soap, water and scrubbing-
brush, and forthwith set about cleansing the Augean Stables.
Accoutred thus, she was directing the floor-washing operations of
Mr. Thompson in the small, tiled kitchen when Sir Hector ventured to
open the door, whereupon Mr. Thompson, hitherto awed to dumb
submission by my lady’s imperious presence, cast down his
scrubbing-brush and lifted his voice in wailing protest:
“Sir ’Ector—O Sir ’Ector, will ’ee look at oi! She’s ’ad me ’ere on
me knees, a-scrubbin’ an’ a-sloshin’, this hower an’ more, she ’ave!
On me marrer-bones, sir! Crool it be! Sir ’Ector, if you ’ave an ’eart,
say a word for oi!”
“William Thompson,” quoth my lady, “William Thompson—scrub.”
“Sir ’Ector—say a word!”
“Losh, Wully man, whaur’ll be the use? Ye ken vera weel ’tis no
fau’t o’ mine. Ye ken vera weel I lo’e tae be hamely——”
“Sir Hector—silence!” commanded my lady.
“Eh, but, Rose, puir Wully an’ me are no used tae sic awfu’——”
“Enough, sir!”
“But, O lassie, ye’re fair washin’ me oot o’ hoose an’ hame——”
“Then begone, sir, and leave us to finish.”
“But Guid save us a’, d’ye no——”
“Sir Hector,” cried my lady, with a flourish of her mop, “go!”
Sir Hector went. Being in his small parlour, he glanced yearningly
upon the unwashed crockery littering the table, from this to the dusty
riding-boots upon the mantel-shelf and, sweeping a heterogeneous
collection of small oddments from the elbow-chair to the floor, sat
down with his feet among the long-dead ashes that cumbered the
hearth, sighing for that spirit of homely comfort that was, even then,
being washed and swept out of his ken.
And thus Sir John found him, a desolate soul, huddled
disconsolately over a cheerless hearth, his peruke over one mournful
eye, the very picture of woe.
“Hark till her, John!” quoth he dolefully. “O man, ’tis fair
heartrendin’! Hark till yon brushin’ an’ scrubbin’!”
“Ah, so you have a woman to clean the place for you at last,
Hector!”
“A wumman, d’ye say? Man, she’s no’ an ordinary wumman....
Wull ye hark till her!”
“William Thompson,” cried a sweet, albeit stern voice, “this corner
is not even wetted ... scrub it!”
“Rose!” exclaimed Sir John.
“Hersel’!” sighed Sir Hector. “Can ye no reason wi’ her, John, if ’tis
only for the sake o’ puir Wully Tamson?”
“Not for worlds, Hector!”
“Then what’ll I dae, Johnnie?”
“Come a-walking.”
“Na, na; I’ve no’ the sperrit, John.”
“But you’ve the legs, Hector.” So saying, Sir John straightened his
old friend’s wig, reached him his hat and, taking his arm, led him out
into the sunshine.
“Whaur awa’, Johnnie?”
“Well, I promised to visit Mr. Pym, the painter.”
“Aye, I ken him fine; wi’ rod or gun there’s nane to equal him.”
They found Mr. Pym busied in his garden, who, perceiving his
visitors, laid by his spade and hastened to make them welcome; the
better to perform which, he brought them into the house and
vanished to find the wherewithal to refresh them, only to return
empty-handed and disconsolate:
“Sirs,” quoth he, “the devil is in it for my brandy is out!” And, being
at a loss, he sought the aid of his daughter. “Elsie!” he called. “Elsie!”
A jingle of keys, a light step and Mistress Pym appeared, her
dainty, print gown girt about slender middle by a cincture whence
hung reticule and housewifely keys, her face framed in snowy mob-
cap and remarkable for a pair of handsome eyes.
“Girl,” exclaimed the painter, “my brandy’s out!”
Mistress Pym faced the so grave situation entirely undismayed:
“I told you ’twas so, days agone, sir,” she answered serenely.
“We’ve naught left in the house save my ginger wine.”
“Then that must serve,” quoth her sire. “Bring it, a heaven’s name!”
Lightly she went and lightly she was back and, steady of hand,
filled the three glasses. Sir John eyed the liquor a little askance but
tasted it bravely, and glanced at his young hostess.
“Your own making, Mistress Pym?” he inquired.
“Yes, sir,” she nodded. “’Twould be better were it older, but father
never lets it keep long enough.”
“And small wonder!” answered Sir John, bowing. “Mistress Pym, I
drink to your eyes, for sure there be few to match ’em in the South
Country.” So saying, he drank and wished his glass had been larger.
Thereupon Mistress Pym curtsied to them and jingled away about
her multifarious duties.
“Yon’s a braw wife for some lucky man, I’m thinkin’!” quoth Sir
Hector. “There’s looks till her, an’, O man, but she’s a bonny cook
whateffer! ’Tis a graund thing when a lass can appeal tae a man’s
heid, an’ heart, an’ stomach, y’ ken.”
“Mr. Pym,” said Sir John as, the ginger wine having made a duly
deliberate end, they rose to depart, “you mentioned, I mind, the first
time we met, the murder of a man on Windover.”
“I did, sir; the cruel assassination of Roger Hobden—a black
business that was never cleared up and never will be.”
“Had you any suspicions at the time?”
“Suspicions, sir? Remembering Lord Sayle and the unholy doings
in that solitary house of his, I suspected every one beneath its roof,
from Lord Sayle down.”
“Losh, man!” exclaimed Sir Hector, “ye’ve a graund gift o’
suspeecioning.”
“And suppose I have, sir?” demanded the painter argumentatively.
“There is little of good in ’Friston Manor, and evil begetteth evil. And
Sayle is a law unto himself, with bullies at hand to work his wicked
purposes.”
“Whisht, man!” exclaimed Sir Hector. “Ye’ll no be suggestin’——”
“And why not, sir? Doth the man’s rank place him above
suspicion?”
“Never heed father, Sir Hector,” said Mistress Pym at this moment,
leaning in at the open door; “he doth but seek an argument——”
“Mistress,” quoth the painter, “mind your business!” Whereat
Mistress Pym laughed and jingled away again.
“Pym—man,” said Sir Hector, “his lordship is no’ juist an archangel
nor yet a seraphim, but ye’ll no’ be suspectin’ a man o’ his quality
wad stoop tae murder a country lad o’ no condition.”
“On the contrary, Sir Hector, I say he would stoop to anything.”
“There was never any incriminating evidence found, I believe, sir?”
inquired Sir John. “No clue of any kind discovered?”
“None of importance. Though I did find a thing on the footpath that
runs above the ‘Long Man,’ near where the crime was committed—a
thing I felt it my duty to show to the law officers and was laughed at
for my pains.... I have it here somewhere.” And the painter turned to
a small, carved press in a corner where stood two or three fishing-
rods in company with a musket and a birding-piece.
“What kind o’ thing, Pym?” inquired Sir Hector.
“A snuff-box,” answered the painter, opening a drawer and turning
over a collection of small fossils, flint arrow-heads, and the like.
“A gowd snuff-box, Pym?”
“Nay, ’twas of horn—a poor thing! Ah, here ’tis!” And he held out a
clumsy horn snuff-box of battered and villainous appearance. Sir
John took it, turned it this way and that, opened and sniffed
delicately at its empty interior, and finally carrying it to the light, fell to
studying it anew.
“Now, Pym man,” said Sir Hector, “if yon had been gold or enamel,
or even siller, it might perchance justify your suspeecions; but
whaur’s the man o’ quality would carry a thing the like o’ that?”
“There, sir,” answered the painter dogmatically, “there I take issue
with ye. If that box be evidence, which I deny, mark ye—’tis precisely
the kind o’ thing your man o’ quality would purposefully leave that its
very poverty might set inquiring minds on a false scent. I further
maintain, sir, that——”
“Nay, Sir Hector,” laughed Mistress Pym, leaning in at the open
lattice at this moment, her hands full of fresh-gathered flowers, “do
but take father’s side o’ the question and he will immediately take
yours to keep the argument a-going.”
“Child,” quoth the painter, sternly grim, “I smell your bread a-
burning!”
“Sir,” she answered, throwing a flower at him, “thou’rt mighty
sharp-nosed this morning, for ’tis not yet in the oven!”
“An’ there’s for ye, man!” chuckled Sir Hector as she jingled away
once more.
“Mr. Pym, would you pray lend me this box for a few days?”
inquired Sir John.
“Nay, take it, sir,” answered the painter, “if the sorry thing hath any
interest for you, take it and welcome.”
Murmuring his thanks, Sir John slipped it into his pocket; and
shortly after, bidding Mr. Pym adieu, they left him to his gardening.
“Yon Pym-lassie,” quoth Sir Hector as they walked, “is like a
bagpipes——”
“Never in the world, Hector!”
“Aye, John; she’s sweet as a bagpipes, whilk, as a’ the warld kens,
is the sweetest and maist soothin’ of a’ instruments! ’Tis a muckle
woefu’ wight Pym’ll be if ever she marries, I’m thinkin’! But, Johnnie,
why for did ye want yon snuff-box?”
“Because I think I can find the man who lost it.”
“Losh, man! An’ suppose ye can, what then?”
“Why then, Hector, I think my Lord Sayle will cease from hunting
smugglers.”
“Eh? Sayle? Man, what d’ye mean?”
“Time will show——”
“Aye, but meanwhile, John, d’ye mean to say ye think——”
“That a mug of Mr. Bunkle’s gumboo will go very happily with
Mistress Pym’s excellent wine, so——”
“Umph-humph!” exclaimed Sir Hector; and together they entered
the hospitable portal of the ‘Market Cross Inn,’ where they were met
by the cheery Mr. Bunkle, who ushered them as honoured guests
into his five-doored holy of holies.
“Do you gin’men ’appen to ha’ seed the bill as they’ve printed an’
posted arl-on-account-o’ pore Jarge Potter? What—no, sirs? Then
bide a minute an’ I’ll show ye one o’ they bills.” Saying which, Mr.
Bunkle put aside snowy apron and from vasty pocket drew forth such
incongruous articles as: a whip lash, a fragment of tobacco, a
nutmeg, a small pistol, and finally, after laborious groping, a folded
paper which, having carefully smoothed out, he held up against the
wall and they read as follows:
“Save’s a’!” exclaimed Sir Hector, “the man Sayle is unco’ serious
an’ damnably determined.... A hundred pounds! Losh, man, ’twill be
an awfu’ temptation tae the avereecious. How think ye, Peter?”
“Why, I think, sir, as that theer hundred pound will go a-
beggin’——”
“But ... a hundred pounds, man——!”
“Aye,” nodded Mr. Bunkle as he refolded the bill, “’tis a sight o’
money, I rackon; Jarge ought to be a proud man this day! ’Twill be
the gumboo as usual, sirs?”
Now when their glasses were empty and Sir Hector had fared
unwillingly homewards, Sir John, being alone, took out the battered
snuff-box to view it once again in keen-eyed scrutiny, more
especially the lid; for there, scratched faintly on the horn, were these
two initials:
J. S.
CHAPTER XXXIV
CONCERNS ITSELF WITH ONE OF THE MANY
MYSTERIES OF THE ‘MARKET CROSS INN’