PROJECT SUMMARY Antiepileptic drugs are the primary treatment option for individuals with epilepsy. However, many are refractory to this approach and require other therapeutics such as resective surgery. Unfortunately, few undergo this procedure due to low candidacy or referral rates and ~35% still have seizures even after surgery. Therefore, there’s an urgent unmet need to provide seizure freedom for refractory individuals using alternative approaches. Neuromodulation, and in particular deep brain stimulation (DBS), may accomplish this goal, but current options such as vagus nerve stimulation (VNS), responsive neurostimulation (RNS) and anterior thalamus deep brain stimulation (ANT-DBS) provide limited seizure-freedom. Therefore, current neuromodulatory options fall short of potently treating refractory epilepsy. Recently, our data revealed that DBS of the ventral pallidum (VP), a basal ganglia structure, prevented partial and secondarily generalized forebrain seizures and brainstem seizures in the pilocarpine rat model of temporal lobe epilepsy (TLE). Conversely, VNS, RNS and ANT-DBS reduce or delay seizures in comparable preclinical studies. While compelling, our findings are from animals with acute seizures and not spontaneous recurrent seizures (SRSs). Therefore, it remains to be determined whether VP-DBS possess similar efficacy in rats with seizures that more closely resemble human epilepsy. In light of this and keeping in mind VP-DBS potent efficacy in preventing brainstem seizures, we formulate an overarching hypothesis that ventral pallidum deep brain stimulation prevents spontaneous recurrent seizures and mitigate cardio-respiratory dysfunction by inhibiting electrographic seizures in specific epileptic foci and preserving functional fidelity in autonomic brainstem areas, respectively. To test this, we employ video-electroencephalogram (EEG) monitoring, in vivo and in vitro electrophysiology, electrocardiogram (ECG)-telemetry and whole-body plethysmography technology and immunocycto-histochemistry to accomplish the following specific aims: 1) determine if VP-DBS prevents spontaneous recurrent seizures; 2) identify specific epileptic foci inhibited by VP-DBS responsible for preventing spontaneous recurrent seizures; and lastly, 3) determine if VP-DBS mitigate cardio-respiratory dysfunction by preserving functional fidelity of neurons in brainstem autonomic centers controlling their activity; specifically in the nucleus of solitary tract (NTS) and pre-botzinger complex (PBC). Altogether, findings from our study will underscore VP-DBS as a potent neuromodulatory approach for controlling seizures in epilepsy and reveal potential underlying neural substrates contributing to this efficacy. Lastly, it will show that VP-DBS has provocative utility in mitigating cardio-respiratory dysfunction during generalized seizures by preserving functional fidelity of brainstem areas that control these functions.