Background: Vagus nerve stimulation (VNS) is a promising therapy for many neurologic and psychiatric conditions. However, determining stimulus parameters for individual patients is a major challenge. The traditional method of titrating stimulus intensity based on patient perception produces highly variable responses. This study explores using the vagal response to measure stimulation dose and predict physiological effect. Clinicians are investigating the use of VNS for heart failure management, and this work aims to correlate cardiac measures with vagal fiber activity.Results: By recording vagal activity during VNS in rats and using regression analysis, we found that cardiac activity across all animals was best correlated to the activation of a specific vagal fiber group. With conduction velocities ranging from 5 to 10 m/s, these fibers are classified as B fibers (using the Erlanger-Gasser system) and correspond to vagal parasympathetic efferents. Conclusions: B fiber activation can serve as a standardized, objective measure of stimulus dose across all subjects. Tracking fiber activation provides a more systematic way to study the effects of VNS and in the future, may lead to a more consistent method of therapy delivery.

Object There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. Methods In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ–aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8–10 rats/group), after which the animals were placed in operant chambers containing 2 levers—one used to administer water and the other to administer 15% EtOH—to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat’s left AcbSh. The animals then received 100 or 200 μA (3–4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. Results In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. Conclusions Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism.

Abstract-Electrical vagus nerve stimulation is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. However, the fixed stimulus, open loop dosing mechanism limits its efficacy and precludes major advances in the quality of therapy. A real-time, responsive form of vagus nerve stimulation is needed to control nerve activation according to therapeutic need. This personalized approach to therapy will improve efficacy and reduce the number and severity of side effects. We present autonomous neural control, a responsive, biofeedbackdriven approach that uses the degree of measured nerve activation to control stimulus delivery. We demonstrate autonomous neural control in rats, showing that it rapidly learns how to most efficiently activate any desired proportion of vagal A, B, and/or C fibers over time. This system will maximize efficacy by minimizing patient response variability and by minimizing therapeutic failures resulting from longitudinal decreases in nerve activation with increasing durations of treatment. The value of autonomous neural control equally applies to other applications of electrical nerve stimulation.

We demonstrate an alternative method of designing electrical stimuli-termed burst modulation--for producing different patterns of nerve fiber recruitment. By delivering electrical charge in bursts of "pulsons"--miniature pulses-instead of as long continuous pulses, our method can optimize the waveform for stimulation efficiency and fiber selectivity. In our in vivo validation experiments, while maintaining C fibers of the rat vagus nerve at ∼ 50% activation with different waveforms, the burst-modulated waveform produced 11% less A fiber activation than the standard rectangular pulse waveform (rectangular: 50.8±1.5% of maximal A response, mean ± standard error of the mean; burst-modulated: 39.8 ±1.3%), which equates to a 20% reduction in A fiber response magnitude. In addition, the burst-modulated waveform required 45% less stimulus charge per phase to maintain 50% C fiber activation (rectangular: 20.7 ±0.86 μC; burst-modulated: 11.3 ±0.41 μC ). Burst-modulated waveforms produced consistent patterns of fiber recruitment within and across animals, which indicate that our methods of stimulus design and response analysis provide a reliable way to study neurostimulation and deliver therapy.