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Review
. 2025 Apr;603(8):2201-2217.
doi: 10.1113/JP287164. Epub 2025 Mar 9.

The physiology, anatomy and stimulation of the vagus nerve in epilepsy

Mikaela Patros  1 , Shobi Sivathamboo  1   2   3   4 , Hugh D Simpson  1   2 , Terence J O'Brien  1   2   3   4 , Vaughan G Macefield  1   5
Affiliations
Review

The physiology, anatomy and stimulation of the vagus nerve in epilepsy

Mikaela Patros et al. J Physiol. 2025 Apr.

Abstract

The vagus nerve is the longest cranial nerve, with much of its territory residing outside the head, in the neck, chest and abdomen. Although belonging to the parasympathetic division of the autonomic nervous system, it is dominated by sensory axons originating in the heart, lungs and airways and the gastrointestinal tract. Electrical stimulation of the cervical vagus nerve via surgically implanted cuff electrodes has been used clinically for the treatment of drug-resistant epilepsy for three decades but has also shown efficacy in the treatment of drug-resistant depression and certain gastrointestinal disorders. Through consideration of the anatomical composition of the vagus nerve, its physiology and its distribution throughout the body, we review the effects of vagus nerve stimulation in the context of drug-resistant epilepsy. This narrative review is divided into two sections: part one surveys the anatomy and physiology of the vagus nerve, and part two describes what we know about how vagus nerve stimulation works.

Keywords: autonomic control; epilepsy; fibre activation; vagus nerve; vagus nerve stimulation.

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Conflict of interest statement

M.P. reports no disclosures. S.S. is the recipient of a National Health and Medical Research Council Investigator Award (APP2025610). She is supported by Research Program Grants from the National Institute of Health (1U54AT012307‐01 and 1R01NS123928‐01). She reports salary support paid to her institution from Jazz Pharmaceuticals for clinical trial‐related activities; she receives no personal income for these activities. H.D.S. is supported by a National Health and Medical Research Council (NHMRC) Medical Research Future Fund Grant (MRFF 2025695). He has received travel support for educational purposes and reports consulting fees to his institution from LivaNova. T.J.O'B. is supported by a Program Grant (APP1091593) and Investigator Grant (APP1176426) from the National Health and Medical Research Council of Australia. He reports grants and consulting fees to his institution from LivaNova, Eisai, UCB Pharma, Praxis, Biogen, ES Therapeutics and Zynerba.

Figures

Figure 1
Figure 1. Transverse histological section of a pig cervical vagus nerve, stained with Haematoxylin and Eosin
Reproduced with permission from Ottaviani and Macefield (2022).
Figure 2
Figure 2. Schematic diagram of an implanted vagus nerve stimulator device
Figure created with BioRender.
Figure 3
Figure 3. Cervical vagus nerve transverse sections
Cervical vagus nerve transverse sections at the same scale from the human, pig and rat. Reproduced with permission from Pelot et al. (2020).
Figure 4
Figure 4. Perineurium thickness of fascicles in the human, pig and rat vagus nerve
Perineurium thickness of fascicles in the human, pig and rat vagus nerve assessed using anti‐claudin‐1 immunohistochemistry for human nerves, anti‐fibronectin immunofluorescence for pig nerves, and Masson's trichrome histology for rat nerves. Pre‐segmentation images show raw segments, contrasting the perineurium with surrounding tissue. Segmented images show segmented labelling of the inner and outer boarders of the perineurium. The rat perineurium is thinnest and the human perineurium is thickest. Reproduced with permission from Pelot et al. (2020).
Figure 5
Figure 5. Vagal fibre activation thresholds
Summary of vagal fibre activation thresholds for A, B and C fibres from electrical stimulation of the human cervical vagus nerve in awake (Patros et al., 2024) and anaesthetized epilepsy patients (Evans et al., ; Koo et al., 2001). Created with BioRender.
See this image and copyright information in PMC

References

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