The Vagus Nerve

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

http://www.winkingskull.com/

From: www.winkingskull.com

© 2007 Thieme

Paired vagus nerves

Extensively branched

XX

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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



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



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



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

0.6

0.7

0.8

0.9

1

0 1000 2000 3000 4000 5000 6000

Isof

lura

ne (E

T%)

Isoflurane (ET%)

0

10

20

30

40

50

60

70

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90

100

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

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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)

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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

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ysul

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e in

fusi

on c

omm

ence

d

LF HF

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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

Documents

The Vagus Nerve