1. The Vagus nerve: a window on
consciousness and disease
Chris Pomfrett
Clinical Scientist
The University of Manchester
Edited from my Royal Institution Friday Evening Discourse
11 April 2008
5. Neural Coding
• Action potentials conducted along many
parallel fibres (axons) within the nerve
– Sensory (afferent) to the brain
– Motor (efferent) from the brain to the organ
• Frequency coding
– bursts of activity (phasic) code fast changes
– sustained activity (tonic) codes long term
activity
6. Neural coding
Linder TM & Palka J. A student apparatus for recording action potentials in cockroach legs. Am. J.
Physiol. 262 (Adv. Physiol. Educ. 7): SlS-S22, 1992.
7. Neural coding in the vagus nerve
DM O'Leary and JF Jones Discharge
patterns of preganglionic neurones with
axons in a cardiac vagal branch in the rat
Exp. Physiol. (2003) 88: 711-723
9. Depth of
anaesthesia
A continuum
• ? One is either conscious or
unconscious
• There is a physiological depth of
anaesthesia
– Sedation leading to loss of
consciousness
– Cognitive function impaired
– Sensation increasingly impaired
– Deep surgical anaesthesia:
movement impaired
1 in 500 people become aware
during anaesthesia
• Due to inadequate depth of
anaesthesia
• Incidence can be reduced by
physiological monitoring
EEG
ECG
11. 0 6 seconds
Electrocardiogram (ECG or EKG)
P
R
T
Q
1mV
Heart rate = 60 beats per minute
Heart rate variability (HRV) beat to beat0.03
0.00
-0.03
HF
(Hz)
0.3
0.0
-0.3
LF
(Hz)
Time0 300 seconds
HIGH FREQUENCY
(HF)
LOW FREQUENCY
(LF)
13. Burnstock G (1969) Evolution of
the autonomic innervation of
visceral and cardiovascular
systems in vertebrates
Pharmacological Reviews 31(4):
247-324
Vagus
Vagus
Vagus
Vagus
Evolution has conserved
vagal control of the heart
15. Otto Loewi (1873-1961)
• “A drug is a substance that, when injected into a rabbit,
produces a paper”
The Oxford Dictionary of Scientific Quotations. Ed. Bynum & Porter. Oxford University Press, 2006
• Loewi discovered that a chemical produced by the stimulated
vagus nerve of one frog slowed the unstimulated, dennervated
heart from another frog (1921)
– “Vagusstoff” later shown to be acetylcholine
– First evidence for neurotransmitters at chemical synapses
• Loewi shared the 1936 Nobel prize with Sir Henry H. Dale
(director of Davy-Faraday research laboratory 1942-46) for
pharmacology of the autonomic nervous system
James FAJL The Common Purposes of Life 2002
17. From:
Sigurdson et al (2001) J.Gen.Virol. 82: 2327-34
Vagus nerve
gut – brainstem
Obex section
medulla oblongata
18. Modified from: Diamond, Scheibel & Elson “The
Human Brain Coloring Book” 1985 Harper Collins
19. Fight or flight
Vagal control adapted to behaviour
Porges Polyvagal Theory
• Mammalian
– Homeothermic & ready to move at short notice
– increase in heart rate (tachycardia)
• Sympathetic excitation
• Vagus inhibited
• Reptilian
– Poikilothermic & needs external warmth
– Threat response to conserve resources and remain
still until warm
– Reduce heart rate (bradycardia) to levels dangerous
to mammals
• Vagus activated
20. The Vagus comprises multiple
control circuits
• Vagal ‘brake’ comprising two parallel systems
– Fast, myelinated axons
• Originate in nucleus ambiguus (well developed in mammals)
• B fibres (Cat 10-30 m s-1
Jones 2001)
• beat to beat control of heart rate
– Slower, unmyelinated axons
• Originate in the dorsal vagal nucleus (present in all vertebrates)
• C fibres (Cat <2 m s-1
Jones 2001)
• Slow control of heart rate, gut motility
• Vagal sensory system
– Terminates in the solitary nucleus
• Stretch reflexes
• Chemoreception
– e.g. Pulmonary chemoreflex
21. Brainstem damage
• Damage to the vagal complex of the
brainstem will affect vagus nerve function
• Partial dysfunction
– Damage to nucleus ambiguus
• Wallenberg’s syndrome
• Difficulty in swallowing, hoarseness
• Complete ablation
– Destruction of the solitary nucleus & tract
• Disorders of consciousness e.g. coma
22. Respiratory sinus arrhythmia
• heart rate variability coincident with
breathing or forced ventilation of the lungs
• when lying down, heart rate speeds up
during inspiration
• reduced during anaesthesia in humans
• predominately controlled by the right
vagus
• high frequency component of HRV
23. Respiratory sinus arrhythmia
(RSA)
Awake (Subject MK1); BIS=99; RSA = 0.624
0
1.5
10
0.4% ET Isoflurane (Subject MK1); BIS = 70; RSA = 0.386
0
R-wave tachygram (Hz)
Time (s)
SA node of heart
Vagal efferents
Nucleus ambiguus
(Medulla oblongata)
Solitary nucleus
(Medulla oblongata)
Vagal afferents
Stretch Receptors
(e.g. Lungs)
Vagally-mediated respiratory sinus arrhythmia falls with
increasing depth of anaesthesia
24. a b c d
0 6 seconds
0 180 360 degrees
a b c d
InspirationInspiration
a
b
c
d Inspiration
Pomfrett patent 1991 inspired by Weinberg & Pfeifer (metronome breathing)
Electrocardiogram (ECG)
Calculation of respiratory sinus arrhythmia
normal or ventilator-assisted breathing
25. Human Heart Rate Variability (HRV)
during isoflurane anaesthesia
Respiratory
sinus
arrhythmia
(RSA)
ECG R
timing
after
inspiration
(s)
26. RSA
RSA
Time (s)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 1000 2000 3000 4000 5000 6000
Isoflurane(ET%)
Isoflurane (ET%)
0
10
20
30
40
50
60
70
80
90
100
BIS
BIS (v3.0 A1000)
ECG Electrodes
Off
Hypothesis: Could respiratory sinus arrhythmia be an index of anaesthetic depth?
27. RSA during propofol intravenous
anaesthesia failure
0.07
0
2000 4400
Pump on
RSA
Predicted
Time (s)
RSA
99% CI
99% CI
4 min
Syringe pump off
Pomfrett CJD, Barrie JR, Healy TEJ. (1993) Respiratory sinus arrhythmia: an index of
light anaesthesia. Br J Anaesth. 71(2):212-7
28. n=6 volunteers: Coronal n=6 volunteers: Transverse
Pomfrett & Alkire (1999) Respiratory sinus arrhythmia as an index of anaesthetic depth: evidence from
functional imaging studies. Journal of Physiology 518P: 180
Functional imaging of vagal control during anaesthesia
Statistical map (SPM) of Global Metabolic Rate,
Respiratory sinus arrhythmia (mean circular resultant),
and ET Isoflurane (p<0.01)
31. Vagal control of the gut
• Relays expansion of stomach
• Controls contraction of stomach
• Regulates release of gastric acid
• Signals emptying of stomach into small
intestine
• Regulates release of pancreatic enzymes
• Involved in feelings of hunger, satisfaction
or fullness
32. Science Fiction
• Movie “Minority Report” Spielberg 2002
– Police used a “sick stick” to incapacitate
suspects with a touch to the neck
• Novel “Diplomatic Immunity” Bujold 2002
Simon & Schuster, Sydney, p.37
– “…I used to have this nifty bio-chip on my
vagus nerve that kept me from losing my
lunch in free-fall…”
33. Science Fact:
Vagal stimulation for treatment of obesity
• Electrodes implanted adjacent to the
sensory vagal nerve at the stomach
• Emulates feelings of fullness
• EnteroMedics™VBLOC therapy
34. Vagal treatment for epilepsy
• Nerve stimulator implanted near the left
vagus nerve
– Avoids inducing heart rate changes
– Gives a direct route to the brainstem
• Vagal stimuli altered to suit the patient
using a remote control
• Significantly reduces the incidence of
seizure in some drug-resistant patients
• Cyberonics Vagal nerve stimulator
35. Henry, T. R. Neurology 2002;59:3-14S
Vagus nerve stimulation
Schema of ascending bilateral vago-solitario-parabrachial pathways of the
central autonomic, reticular activating, and limbic systems
36. Vagus nerve stimulation (VNS) reduces
experimental pain in humans
A. Kirchner, F. Birklein, H. Stefan, H.O. Handwerker (2000) Left vagus nerve
stimulation suppresses experimentally induced pain. Neurology 55: 1167-1171
Mean curves show pain during pinching in
patients.. Baseline session is indicated by
squares, second session by triangles (vagus
nerve stimulation [VNS], 0.7 mA), and third
session by diamonds (VNS, 1.4 mA). At
baseline, there was no difference. VNS,
however, reduced pain in the patient group ( p
< 0.03) by flattening the pain response curves,
especially during the second minute of
pinching ( p < 0.001).
Time of pinching (s)
38. More diseases associated with the
vagus nerve
• Transmissible Spongiform
Encephalopathies
– Bovine Spongiform Encephalopathy (cattle)
– Chronic Wasting Disease (deer)
– Scrapie (sheep)
– variant Creutzfeld Jacob Disease (humans)
39. BSE in cattle
variant Creutzfeld Jacob Disease (vCJD) in humans
• 1997 Ri FED by Professor Roy Anderson
– “The epidemic of mad cow disease (BSE) in the UK”
• 163 probable deaths in the UK
• Peak 28 deaths in 2000
• Most cases probably from eating BSE-infected cattle
products
– 2 cases probably due to blood transfusion
• Also 1 non-symptomatic blood recipient tested positive with
infectious prion in tissue
• In UK cannot donate blood if received transfusion since 1980
• 3 still alive
– Jonathan Simms is the longest survivor (7 years post symptoms)
40. Obex section of brainstem
Cattle Brain
From Philips Inquiry
Dorsal motor nucleus of the vagus
(DMNX; always PrPres
+ve)
Nucleus tractus solitarii (NTS; often
PrPres
+ve)
Nucleus ambiguus (NA; sometimes
PrPres
+ve)
Post-mortem diagnosis of BSE =
Abnormal prions in vagal brainstem
42. Chronic Wasting Disease (CWD)
Epidemic in cervids (e.g. deer) of USA & Canada
From:
Sigurdson et al (2001) PrPcwd
in the myenteric plexus, vasosympathetic trunk and endocrine
glands of deer with chronic wasting disease. J.Gen.Virol. 82: 2327-34
Vagus nerve stained positive for disease-
associated prion protein
43. Vagus nerves of cattle
• Positive for disease-associated prion
• Infectious when subsequently used to
innoculate mice
• Masujin K, Matthews D, Wells GAH, Mohri S,
Yokoyama T (2007) Prions in the peripheral nerves
of bovine spongiform encephalopathy-affected
cattle. J.Gen.Virol. 88: 1850-1858.
44. L. J. M. VAN KEULEN, M. E. W. VROMANS and F. G. VAN ZIJDERVELD
APMIS 110: 23–32, 2002
45. Lucien J.M. van Keulen*, Alex
Bossers, Fred van Zijderveld
TSE pathogenesis in cattle and sheep
Vet. Res. (2008) 39:24-35
46. Lucien J.M. van Keulen*, Alex
Bossers, Fred van Zijderveld
TSE pathogenesis in cattle and sheep
Vet. Res. (2008) 39:24-35
47. HRV & TSE
• Observation: Brainstem is diagnostic for
infectious prion in symptomatic cattle, sheep &
deer brainstem post mortem
– 12 biochemical tests validated by the EU
• Hypothesis: Is brainstem function viewed by
heart rate variability affected by TSEs in vivo?
• Commercially-funded studies on cattle
– TSEnse Diagnostics
– Licensed by the University of Manchester
– Using DEFRA/ADAS herds of infected cattle
49. LHFAXHR
-200
-300
-400
-500
-600
-700
-800
Box plots
Summary plot based on the median, quartiles, and extreme values. The box represents the interquartile range which contains the 50% of
values. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers. A line across the box indicates
the median.
+veField
Control
Bovine Heart Rate
Variability
Frequency Domain
Analysis
200 Field controls v
4 field symptomatic
cases
50. 1.3
1.2
1.1
1.0
0.9
140 150 160 170
Time (s)
1.3
1.2
1.1
1.0
0.9
Tachygram(Hz)
0.2
0.1
0.0
-0.1
-0.2
ECG(mV)
0.00030
0.00020
0.00010
0.00000
0 0.10 0.20 0.30 0.40
Frequency (Hz)
0.00030
0.00020
0.00010
0.00000
0 0.10 0.20 0.30 0.40
Frequency (Hz)
50
40
30
20
10
0
ECGRwaveintervals(n)
0 0.5 1.0 1.5 1.9
Time (s)
50
40
30
20
10
0
0 0.5 1.0 1.5 1.9
Time (s)
R Wave
0.2
0.1
0.0
-0.1
-0.2
ECG(mV)
114 120 130
Tachygram(Hz)
0.3
1.4 55
ECGRwaveintervals(n)
55
Power (Hz²)
Power (Hz²)
a
R wave
b
Control Bovine
High Dose Bovine (100g oral challenge, 36 months earlier)
1.4
c
d
e
f
g
h
i
j
0.0
0.0
0.3
Pomfrett et al Veterinary Record (2004) 154: 687-691
Time
domain
Frequency
domain
51.
2.00E-06
2.50E-06
3.00E-06
HighFrequency
0 1 100Oral challenge (g) =
1.40E-04
1.50E-04
1.60E-04
1.70E-04
1.80E-04
1.90E-04
LowFrequency
N = 264 423 248 N = 264 423 248
0 1 100Oral challenge (g) =
From: Pomfrett C.J.D., Glover D.G., Bollen B.G., Pollard B.J. Perturbation of heart rate variability in cattle fed BSE-infected material
Veterinary Record (2004) 154: 687-691
Dose of BSE infection apparent in heart rate
variability of cattle
Presymptomatic, 29 to 41 months post-infection, pooled data
DMV NA
52. Reduction in LF HRV in
presymptomatic sheep with scrapie
D G Glover, B J Pollard, L González, S Sisó, D Kennedy and M Jeffrey
A non-invasive screen for infectivity in transmissible spongiform
encephalopathies Gut 2007;56;1329-1331
53. Hypothesis:
Is brainstem function viewed by heart rate
variability affected in human cases of vCJD?
• Human studies
– Department of Health funded 2002-2004
(£112k)
– n=4 vCJD victims and 50 controls, including
GSS, repeated measures where possible
– Human cases are all symptomatic and
beyond the stage of disease encountered in
cattle and other animal models
60. 0
0.000025
Hz²
0.000006
Hz²
Pentosanpolysulphateinfusioncommenced
LF HF
1s
260
0
ECG R-R
intervals
n
LF
HF
Feb-03 Apr-03 Jul-03
Oct-
03
Jan-
04
Apr-04
0
HF
LF
Controls
vCJD repeated measures of heart rate variability
Pomfrett CJD, et al., The vagus nerve as a conduit for neuroinvasion, a diagnostic tool, and a therapeutic pathway for transmissible
spongiform encephalopathies, including variant Creutzfeld Jacob disease. Med Hypotheses (2006) doi:10.1016/j.mehy.2006.10.047
61. 1 s
ECG R-R
intervals
n
LF
HF
Stimulus
Heart Rate
Control
vCJD repeated measures of heart rate variability
Same day; response to verbal instruction
0
0.00008
11:18 12:18 13:18 14:18
Power(Hz²)
0
110
HeartRate(BPM+-1SD)
0
260
62. vCJD is still a risk factor
• Cross Infection
– Blood transfusion
– Instruments
• Surgical
• Dental
• Ophthalmic
• Earlier diagnosis allows faster treatment
with putative therapeutics
63. Conclusions
• Vagal function opens a window on
consciousness & disease
• Brainstem dysfunction quantified:
– Reversibly e.g. during anaesthesia
– Pathologically e.g. during prion disease
• Ideally suited to repeated measures
• A potential index of therapeutic effect
64. Thank You
1996 – present
Collaborators/funders in chronological order
• Professor Tom Healy FRCA
• Professor Brian Pollard FRCA
• VLA/ADAS/DEFRA
• Mr Tony Austin B.Sc.
• Mr Barrie Bollen B.Sc.
• BTG
• TSEnse Diagnostics Ltd.
• Department of Health
• Mr David Glover B.Sc.
• Mrs Laura Woolfson B.Sc.
• Families of vCJD cases
Editor's Notes
The brain uses both sensory and motor nerves to interact with the outside world. We are all quite familiar with the senses of vision, touch, smell, taste and hearing, and voluntary control of movement by our muscles.
We are less familiar with a specialised and very important subset of nerves comprising the autonomic nervous system, which deals with control of bodily function and maintenance of the internal environment. Much of this interaction is done at an involuntary, automatic level, with little or no conscious thought. We are only aware of this autonomic nervous system when something is wrong, and then it can make our lives very unpleasant.
I wish to review some of the functions of one of the autonomic nervous system’s evolutionarily oldest and most important nerves: the Vagus – meaning the wanderer
The human vagus and its position in the wiring of the central nervous system. Only a subset of motor, efferent (leading from the brain) wiring is shown here.
There are two main divisions to the autonomic nervous system. Sympathetic (on the left in this diagram) and parasympathetic (on the right).
The vagus is the tenth cranial nerve, and innervates the lung, heart and gut with parallel and separate connections. There are two, paired vagus nerves, and the one on the left has some different function to the right. In the cat there are around 30,000 vagal fibres, of which around a fifth are myelinated. Each efferent fibre has a cell body in the brainstem, and innervates a ganglia of local neurones closely associated with an organ. It is at the brainstem and at the organ that phamaceuticals can intervene to enhance or inhibit the actions of the nerve.
The cranial nerves, comprising part of the parasympathetic nervous system control tear formation, pupilllary diameter, airway contractility, heart rate and gut motility, in balance with the sympathetic nervous system modulated via the spinal cord. Such control is of particular interest to one group of clinicians.
The human vagus and its position in the wiring of the central nervous system. Only a subset of motor, efferent (leading from the brain) wiring is shown here.
There are two main divisions to the autonomic nervous system. Sympathetic (on the left in this diagram) and parasympathetic (on the right).
The vagus is the tenth cranial nerve, and innervates the lung, heart and gut with parallel and separate connections. There are two, paired vagus nerves, and the one on the left has some different function to the right. In the cat there are around 30,000 vagal fibres, of which around a fifth are myelinated. Each efferent fibre has a cell body in the brainstem, and innervates a ganglia of local neurones closely associated with an organ. It is at the brainstem and at the organ that phamaceuticals can intervene to enhance or inhibit the actions of the nerve.
The cranial nerves, comprising part of the parasympathetic nervous system control tear formation, pupilllary diameter, airway contractility, heart rate and gut motility, in balance with the sympathetic nervous system modulated via the spinal cord. Such control is of particular interest to one group of clinicians.
Depth of anaesthesia does not correlate well with the amount given based on the age and weight of the patient. Surgical stimulation tends to waken people, and acts to oppose the hypnotic effect of the anaesthetic. Some physiological marker of the state of the nervous system is desirable.
Most equipment for measuring anaesthetic depth is based on the electroencephalograph or EEG. The most widely-used is called bispectral index, which works by detecting a number of features in the EEG corresponding with consciousness. A drawback is that the EEG indicates the conscious state of the brain retrospectively, with little advance warning.
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Much bigger than the EEG, at around 1mV, is the electrocardiogram, a spreading wave of electrical potential arising from contraction and recovery of the heart.
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Now we are looking in detail at vagal control of heart rate, and especially at the cardiac branch of the right vagus nerve. This system has been examined since early last century, and was the basis of the first experiment proving the need for neurotransmitters in neurochemical stimulation of the heart.
Loewi, Otto 1873–1961 German-born American physiologist and pharmacologistSee Dale, Henry Hallett (2). 1. The night before Easter Sunday of that year (1920) I awoke, turned on the light, and jotted down a few notes on a tiny slip of thin paper. Then I fell asleep again. It occurred to me at six o&apos;clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. The next night, at three o&apos;clock, the idea returned. It was the design of an experiment to determine whether the hypothesis of chemical transmission that I had uttered seventeen years ago was correct. I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design. I have to describe this experiment briefly since its results became the foundation of the theory of chemical transmission of the nervous impulse. The hearts of two frogs were isolated, the first with its nerves, the second without. Both hearts were attached to Straub cannulas filled with a little Ringer solution. The vagus nerve of the first heart was stimulated for a few minutes. Then the Ringer solution that had been in the first heart during the stimulation of the vagus was transferred to the second heart. It slowed and its beats diminished just as if its vagus had been stimulated. Similarly, when the accelerator nerve was stimulated and the Ringer from this period transferred, the second heart speeded up and its beats increased. These results unequivocally proved that the nerves do not influence the heart directly but liberate from their terminals specific chemical substances which, in their turn, cause the well-known modifications of the function of the heart characteristic of the stimulation of its nerves.
‘An Autobiographic Sketch’ , Perspectives in Biology and Medicine, 1960, 4, pp.17.
2. A drug is a substance which, if injected into a rabbit, produces a paper.
Quoted in Albert Szent-Gyorgyi, ‘Some Reminiscences of My Life as a Scientist’ , International Journal of Quantum Biology Symposium, 1976, 3, pp.7.
How to cite this entry:
&quot;Loewi, Otto&quot; The Oxford Dictionary of Scientific Quotations. Ed. W. F. Bynum and Roy Porter. Oxford University Press, 2006. Oxford Reference Online. Oxford University Press. Manchester University. 14 December 2007 &lt;http://www.oxfordreference.com/views/ENTRY.html?subview=Main&entry=t218.e809&gt;
The human vagus and its position in the wiring of the central nervous system.
Evolution
Vertebrates developed a dorsal spinal cord. Before vertebrates, most neural traffic was via the ventral pathway e.g. the ventral nerve cord of insects.
A vagus-like nerve is visible in certain invertebrates and all vertebrates and appears more ancient than the spinal cord.
Its purpose appears to be to link the viscera to the brain, relaying information on the internal environment and allowing the brain to control that environment. We are familiar with the conventional senses that allow us to perceive the external world – sight, hearing, smell, taste and touch. Now we are talking about the internal world and how we maintain it in the correct balance.
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1. The inflammatory reflex. Vagal
stimulation results in the release of acetylcholine.
In turn, NF-B is inhibited, and
the STAT3-suppressor of cytokine signaling
3 (SOC3) anti-inflammatory pathway is
stimulated via 7nAChR on activated macrophages
and other cytokine-producing
cells. This inhibits the release of TNF, high
mobility group box-1 (HMGB1), and other
proinflammatory cytokines implicated in inflammatory
conditions. (ref. [3]; reproduced
with permission from Blackwell Publishing).
