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The Vagus Nerve

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The Vagus Nerve

  1. 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
  2. 2. 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
  3. 3. From: www.winkingskull.com © 2007 Thieme Paired vagus nerves Extensively branched XX
  4. 4. Kandel, Schwartz & Jessell Principles of Neural Science (3rd ed.)
  5. 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. 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. 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
  8. 8. Kandel, Schwartz & Jessell Principles of Neural Science (3rd ed.) Clinically diagnostic signs
  9. 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
  10. 10. Baseline Propofol Induction 0.65MAC Isoflurane 1.2MAC Isoflurane Recovery 100µV 6s Brain activity before, during and after anaesthesia
  11. 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)
  12. 12. 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
  13. 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
  14. 14. Kandel, Schwartz & Jessell Principles of Neural Science (3rd ed.)
  15. 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
  16. 16. Kandel, Schwartz & Jessell Principles of Neural Science (3rd ed.)
  17. 17. From: Sigurdson et al (2001) J.Gen.Virol. 82: 2327-34 Vagus nerve gut – brainstem Obex section medulla oblongata
  18. 18. Modified from: Diamond, Scheibel & Elson “The Human Brain Coloring Book” 1985 Harper Collins
  19. 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. 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. 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. 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. 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. 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. 25. Human Heart Rate Variability (HRV) during isoflurane anaesthesia Respiratory sinus arrhythmia (RSA) ECG R timing after inspiration (s)
  26. 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. 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. 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)
  29. 29. ASA 1997
  30. 30. 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
  31. 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. 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. 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. 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. 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. 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)
  37. 37. Vagal modulation of inflammatory cytokines Oke S.L & Tracey K.J (2007) J.Leukocyte Biol.
  38. 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. 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. 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
  41. 41. BSE post mortem tests Brainstem Medulla oblongata
  42. 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. 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. 44. L. J. M. VAN KEULEN, M. E. W. VROMANS and F. G. VAN ZIJDERVELD APMIS 110: 23–32, 2002
  45. 45. Lucien J.M. van Keulen*, Alex Bossers, Fred van Zijderveld TSE pathogenesis in cattle and sheep Vet. Res. (2008) 39:24-35
  46. 46. Lucien J.M. van Keulen*, Alex Bossers, Fred van Zijderveld TSE pathogenesis in cattle and sheep Vet. Res. (2008) 39:24-35
  47. 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
  48. 48. HRV measurements in cattle Uses 3 ECG electrodes & takes 5 minutes
  49. 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. 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. 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. 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. 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
  54. 54. Wireless ECG system 5-minute test for human volunteers
  55. 55. 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 0 0 0.20 Frequency (Hz) 80 0 0 80 0 0 2 2 ECG R-R Interval (s) 0.0005 0 0 0.20 Frequency (Hz) Power (Hz² ) ECG R-R Interval (s) Power (Hz² ) n n
  56. 56. vCJD Time Domain Analysis ECG 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
  57. 57. Healthy Control
  58. 58. vCJD symptomatic
  59. 59. 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
  60. 60. 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
  61. 61. vCJD is still a risk factor • Cross Infection – Blood transfusion – Instruments • Surgical • Dental • Ophthalmic • Earlier diagnosis allows faster treatment with putative therapeutics
  62. 62. 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
  63. 63. 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

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