Implant- and anesthesia-related factors affecting threshold intensities for vagus nerve stimulation

Vagus nerve stimulation (VNS) is used as therapy in epilepsy and depression and is tested as a potential treatment for several chronic disorders. Typically, VNS is delivered at increasing stimulus intensity until a response is observed (threshold intensity). Factors that affect threshold intensities for engagement of different fiber types and concomitant physiological responses have not been studied. We determined neural and physiological responses to increasing stimulus intensities of VNS in anesthetized and awake animals, and examined the effect of implant- and anesthesia-related factors on threshold intensities in a rodent model of VNS. In acute and long-term cervical vagus nerve implants (53 and 14 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake at different intensities. Stimulus-evoked compound action potentials (eCAPs) were recorded, elicited physiological responses were registered, including changes heart rate (HR), breathing, and blood pressure (BP), and threshold intensities were determined. The intensity that elicits eCAPs ("neural threshold") is significantly lower than what elicits a physiological response ("physiological threshold", PT) (25 A {+/-}1.8 vs. 70 A {+/-}5.2, respectively; Mean {+/-}SEM). Changes in BP occur at the lowest stimulus intensities (80 A {+/-}7), followed by changes in HR (105 A {+/-}8.4) and finally in breathing (310 A {+/-}32.5). PT is lower with than without electrode insulation (60 A {+/-}12, vs. 700 A {+/-}123). PT and electrode impedance are correlated in long-term (r=0.47; p<0.001) but not in acute implants (r=-0.34; p NS); both PT and impedance increase with implant age (Pearson correlation r=0.44; p<0.001 and r=0.64; p<0.001, respectively). PT is lowest when animals are awake (210 A {+/-}33; Mean {+/-}SEM), followed by ketamine-xylazine (630 A {+/-}154), and isoflurane (1075 A {+/-}131). The sequence of physiological responses with increasing VNS intensity is similar in both anesthetized and awake states. Implant age, electrical impedance and the type of anesthesia affect VNS threshold and should be accounted for when determining stimulation dose.