the vagus nerve
TRANSCRIPT
The Vagus nerve: a window on consciousness and disease
Chris PomfrettClinical Scientist
The University of Manchester
Edited from my Royal Institution Friday Evening Discourse11 April 2008
From: www.winkingskull.com
© 2007 Thieme
The vagus is cranial nerve X (ten)
Named from “the wanderer” (latin)
Connects the viscera below the neck to the brainstem
X
From: www.winkingskull.com
© 2007 Thieme
Paired vagus nerves
Extensively branched
XX
Kandel, Schwartz & Jessell
Principles of Neural Science (3rd ed.)
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
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.
Neural coding in the vagus nerveDM 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
Kandel, Schwartz & Jessell
Principles of Neural Science (3rd ed.)
Clinically diagnostic signs
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 impaired1 in 500 people become aware
during anaesthesia• Due to inadequate depth of
anaesthesia• Incidence can be reduced by
physiological monitoring
EEG
ECG
Baseline
Propofol Induction
0.65MAC Isoflurane
1.2MAC Isoflurane
Recovery
100µV6s
Brain activity before, during and after anaesthesia
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)
Copyright ©1996 American Heart Association
Electrophysiology, T. F. o. t. E. S. o. C. t. N. A. S. o. P. Circulation 1996;93:1043-1065
Example of an estimate of power spectral density obtained from the entire 24-hour interval of a long-term Holter recording
Respiratory
Vagus
Baroreflex(blood pressure)
Vagus & Sympathetic
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
Kandel, Schwartz & Jessell
Principles of Neural Science (3rd ed.)
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
Kandel, Schwartz & Jessell
Principles of Neural Science (3rd ed.)
From:
Sigurdson et al (2001) J.Gen.Virol. 82: 2327-34
Vagus nervegut – brainstem
Obex section
medulla oblongata
Modified from: Diamond, Scheibel & Elson “The Human Brain Coloring Book” 1985 Harper Collins
Fight or flightVagal 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
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
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
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
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
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
Human Heart Rate Variability (HRV) during isoflurane anaesthesia
Respiratory sinus
arrhythmia (RSA)
ECG R timing after
inspiration (s)
RSA
RSA
Time (s)
0
0.1
0.2
0.3
0.4
0.5
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0.7
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0.9
1
0 1000 2000 3000 4000 5000 6000
Isof
lura
ne (E
T%)
Isoflurane (ET%)
0
10
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30
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BIS
BIS (v3.0 A1000)
ECG ElectrodesOff
Hypothesis: Could respiratory sinus arrhythmia be an index of anaesthetic depth?
RSA during propofol intravenous anaesthesia failure
0.07
02000 4400
Pump on
RSA
Predicted
Time (s)
RS
A
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
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 anaesthesiaStatistical map (SPM) of Global Metabolic Rate,
Respiratory sinus arrhythmia (mean circular resultant),
and ET Isoflurane (p<0.01)
ASA 1997
Some diseases associated with the vagus nerve
• SIDS– Abnormal bradycardia– Increased vagal activity
• Heart disease– Reduced heart rate variability
• Diabetes– Vagal neuropathy– Reduced heart rate variability
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
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…”
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
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
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
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)
Vagal modulation of inflammatory cytokinesOke S.L & Tracey K.J (2007) J.Leukocyte Biol.
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)
BSE in cattlevariant 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)
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
BSE post mortem tests
Brainstem
Medulla oblongata
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
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.
L. J. M. VAN KEULEN, M. E. W. VROMANS and F. G. VAN ZIJDERVELD APMIS 110: 23–32, 2002
Lucien J.M. van Keulen*, Alex Bossers, Fred van Zijderveld
TSE pathogenesis in cattle and sheep
Vet. Res. (2008) 39:24-35
Lucien J.M. van Keulen*, Alex Bossers, Fred van Zijderveld
TSE pathogenesis in cattle and sheep
Vet. Res. (2008) 39:24-35
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
HRV measurements in cattleUses 3 ECG electrodes & takes 5 minutes
LHFA
XH
R
-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.
+veFieldControl
Bovine Heart Rate Variability
Frequency Domain Analysis
200 Field controls v 4 field symptomatic cases
1.3
1.2
1.1
1.0
0.9
140 150 160 170Time (s)
1.3
1.2
1.1
1.0
0.9
Tac
hygr
am (H
z)
0.2
0.1
0.0
-0.1
-0.2
EC
G (m
V)
0.00030
0.00020
0.00010
0.000000 0.10 0.20 0.30 0.40
Frequency (Hz)
0.00030
0.00020
0.00010
0.000000 0.10 0.20 0.30 0.40
Frequency (Hz)
50
40
30
20
10
0
EC
G R
wav
e in
terv
als
(n)
0 0.5 1.0 1.5 1.9Time (s)
50
40
30
20
10
00 0.5 1.0 1.5 1.9
Time (s)R Wave
0.2
0.1
0.0
-0.1
-0.2
EC
G (
mV
)
114 120 130
Tac
hygr
am (H
z)
0.3
1.4 55
EC
G R
wav
e in
terv
als
(n) 55
Power (Hz²)
Power (Hz²)
a
R waveb
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
2.00E-06
2.50E-06
3.00E-06
Hig
h Fr
eque
ncy
0 1 100Oral challenge (g) =
1.40E-04
1.50E-04
1.60E-04
1.70E-04
1.80E-04
1.90E-04
Low
Fre
quen
cy
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
Reduction in LF HRV in presymptomatic sheep with scrapie
D G Glover, B J Pollard, L González, S Sisó, D Kennedy and M JeffreyA non-invasive screen for infectivity in transmissible spongiform encephalopathies Gut 2007;56;1329-1331
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
Wireless ECG system5-minute test for human volunteers
ECG R
0.03
0.00
-0.03
HF (Hz)
0.3
0.0
-0.3
LF (Hz)
0.5
0.0
-0.5
ECG (mV)
ECG R
0.03
0.00
-0.03
HF (Hz)
0.3
0.0
-0.3
LF (Hz)
0.5
0.0
-0.5
ECG (mV)
0 300 sTime
Control dhopha.smr
vCJD d0mfpha.smr
0.0005
00 0.20Frequency (Hz)
80
00
80
00 2
2ECG R-R Interval (s)
0.0005
00 0.20Frequency (Hz)
Power (Hz² )
ECG R-R Interval (s)
Power (Hz² )
n
n
vCJD Time Domain AnalysisECG R-R interval histograms
Woolfson, L.A.M., Glover D.G., Pollard B.J., Pomfrett C.J.D. (2003) Symptomatic vCJD alters heart rate variability. J. Physiol. 551P: C47 Dublin meeting 10 July 2003
Healthy Control
vCJD symptomatic
0
0.000025Hz²
0.000006Hz²
Pent
osan
pol
ysul
phat
e in
fusi
on c
omm
ence
d
LF HF
1s
260
0
ECG R-Rintervals
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
1 s
ECG R-Rintervals
n
LF
HF
Stimulus
Heart Rate
Control
vCJD repeated measures of heart rate variabilitySame day; response to verbal instruction
0
0.00008
11:18 12:18 13:18 14:18
Pow
er (H
z²)
0
110
Hea
rt R
ate
(BPM
+- 1
SD)
0
260
vCJD is still a risk factor
• Cross Infection– Blood transfusion– Instruments
• Surgical• Dental• Ophthalmic
• Earlier diagnosis allows faster treatment with putative therapeutics
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
Thank You1996 – 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