Neural origin of evoked potentials during thalamic deep brain

49 Closed-loop deep brain stimulation (DBS) systems could provide automatic adjustment of stimulation 50 parameters and improve outcomes in the treatment of Parkinson's disease and essential tremor. The 51 evoked compound action potential (ECAP), generated by activated neurons near the DBS electrode, may 52 provide a suitable feedback control signal for closed-loop DBS. The objectives of this work were to 53 characterize the ECAP across stimulation parameters and determine the neural elements contributing to 54 the signal. We recorded ECAPs during thalamic DBS in anesthetized cats and conducted computer 55 simulations to calculate the ECAP of a population of thalamic neurons. The experimental and 56 computational ECAPs were similar in shape and had characteristics that were correlated across 57 stimulation parameters (R=0.80-0.95, P<0.002). The ECAP signal energy increased with larger DBS 58 amplitudes (P<0.0001) and pulse widths (P<0.002), and the signal energy of secondary ECAP phases was 59 larger at 10 Hz than 100 Hz DBS (P<0.002). The computational model indicated that these changes 60 resulted from a greater extent of neural activation and an increased synchronization of post-synaptic 61 thalamocortical activity, respectively. Administration of tetrodotoxin, lidocaine, or isoflurane abolished or 62 reduced the magnitude of the experimental and computational ECAPs, glutamate receptor antagonists 63 CNQX and APV reduced secondary ECAP phases by decreasing post-synaptic excitation, and the 64 GABAA receptor agonist muscimol increased the latency of the secondary phases by augmenting post65 synaptic hyperpolarization. This study demonstrates that the ECAP provides information about the type 66 and extent of neural activation generated during DBS, and the ECAP may serve as a feedback control 67 signal for closed-loop DBS. 68 69