title: Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment.
abstract: OBJECTIVE
  The vagus nerve has gained a role in the treatment of certain diseases by the use of vagus nerve stimulation (VNS). This study provides detailed morphological information regarding the human cervical vagus nerve at the level of electrode implant.
  
  
  RESULTS
  Eleven pairs of cervical vagus nerves and four pairs of intracranial vagus nerves were analysed by the use of computer software. It was found that the right cervical vagus nerve has an 1.5 times larger effective surface area on average than the left nerve [1,089,492 ± 98,337 vs 753,915 ± 102,490 μm(2), respectively, (P < 0.05)] and that there is broad spreading within the individual nerves. At the right side, the mean effective surface area at the cervical level (1,089,492 ± 98,337 μm(2)) is larger than at the level inside the skull base (630,921 ± 105,422) (P < 0.05). This could imply that the vagus nerve receives anastomosing and 'hitchhiking' branches from areas other than the brainstem. Furthermore, abundant tyrosine hydroxylase (TH)- and dopamine ß-hydroxylase (DBH)-positive staining nerve fibres could be identified, indicating catecholaminergic neurotransmission. In two of the 22 cervical nerves, ganglion cells were found that also stained positive for TH and DBH. Stimulating the vagus nerve may therefore induce the release of dopamine and noradrenaline. A sympathetic activation could therefore be part of mechanism of action of VNS. Furthermore, it was shown that the right cervical vagus nerve contains on average two times more TH-positive nerve fibres than the left nerve (P < 0.05), a fact that could be of interest upon choosing stimulation side. We also suggest that the amount of epineurial tissue could be an important variable for determining individual effectiveness of VNS, because the absolute amount of epineurial tissue is widely spread between the individual nerves (ranging from 2,090,000 to 11,683,000 μm(2)).
  
  
  CONCLUSIONS
  We conclude by stating that one has to look at the vagus nerve as a morphological entity of the peripheral autonomic nervous system, a composite of different fibres and (anastomosing and hitchhiking) branches of different origin with different neurotransmitters, which can act both parasympathetic and sympathetic. Electrically stimulating the vagus nerve therefore is not the same as elevating the 'physiological parasympathetic tone', but may also implement catecholaminergic (sympathetic) effects.
authors.affiliation: Department of Anatomy & Embryology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
authors.forename: T J M
authors.initials: TJ
authors.lastname: Verlinden
authors.affiliation: Department of Neurosurgery, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.|Department of Neurosurgery, Zuyderland Hospital, Heerlen, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Rijkers
authors.affiliation: Department of Neurosurgery, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Hoogland
authors.affiliation: Department of Anatomy & Embryology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Herrler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001341:Autonomic Nervous System / Q000033:anatomy & histology; D002574:Cervical Vertebrae; D003238:Connective Tissue / Q000033:anatomy & histology; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004567:Electrodes, Implanted; D005260:Female; D007839:Functional Laterality; D006801:Humans; D008297:Male; D009186:Myelin Sheath / Q000648:ultrastructure; D009412:Nerve Fibers; D009638:Norepinephrine / Q000378:metabolism; D019291:Skull Base / Q000033:anatomy & histology / Q000502:physiology; D009435:Synaptic Transmission; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014630:Vagus Nerve / Q000033:anatomy & histology* / Q000503:physiopathology; D055536:Vagus Nerve Stimulation / Q000379:methods*
chemical_list: D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine
keywords: dopamine ß-hydroxylase; morphology; morphometric analysis; osmium tetroxide; peripheral autonomic nervous system; tyrosine hydroxylase; vagus nerve stimulation