Electrical Stimulation of Cranial Nerves in Cognition and Disease Devin Adair a , Dennis Truong a , Zeinab Esmaeilpour a , Nigel Gebodh a , Helen Borges a , Libby Ho a , J. Douglas Bremner b , Bashar W. Badran c , Vitaly Napadow d , Vincent P. Clark e , Marom Bikson a a Department of Biomedical Engineering, City College of New York, New York, NY, USA b Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, GA, USA; Atlanta VA Medical Center, Decatur, GA, USA c Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston SC d Martinos Center for Biomedical Imaging, Department of Radiology, MGH, Harvard Medical School e Psychology Clinical Neuroscience Center, Dept. Psychology, MSC03-2220, University of New Mexico, Albuquerque, NM, 87131, USA; Department of Psychology, University of New Mexico, Albuquerque, NM, 87131, USA; The Mind Research Network of the Lovelace Biomedical Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM, 87106, USA Abstract The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author manuscript Brain Stimul. Author manuscript; available in PMC 2021 May 01. Published in final edited form as: Brain Stimul. 2020 ; 13(3): 717–750. doi:10.1016/j.brs.2020.02.019. Author Manuscript Author Manuscript Author Manuscript Author Manuscript