The Therapeutic Frequency Profile of Subthalamic Nucleus Deep Brain Stimulation in Rats Is Shaped by Antidromic Spike...

The therapeutic mechanisms of subthalamic nucleus (STN) deep brain stimulation (DBS) may depend on antidromic activation of cortex via the hyperdirect pathway. However, hyperdirect pathway neurons cannot reliably follow high-stimulation frequencies, and the spike failure rate appears to correlate with symptom relief as a function of stimulation frequency. We hypothesized that antidromic spike failure contributes to the cortical desynchronization caused by DBS. We measured in vivo evoked cortical activity in female Sprague Dawley rats and developed a computational model of cortical activation from STN DBS. We modeled stochastic antidromic spike failure to determine how spike failure affected the desynchronization of pathophysiological oscillatory activity in cortex. We found that high-frequency STN DBS desynchronized pathologic oscillations via the masking of intrinsic spiking through a combination of spike collision, refractoriness, and synaptic depletion. Antidromic spike failure shaped the parabolic relationship between DBS frequency and cortical desynchronization, with maximum desynchronization at ∼130 Hz. These findings reveal that antidromic spike failure plays a critical role in mediating the dependency of symptom relief on stimulation frequency.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is a highly effective neuromodulation therapy, yet it remains uncertain why conventionally used stimulation frequencies (e.g., ∼130 Hz) are optimal. In this study, we demonstrate a potential explanation for the stimulation frequency dependency of DBS through a combination of in vivo experimental measurements and computational modeling. We show that high-frequency stimulation can desynchronize pathologic firing patterns in populations of neurons by inducing an informational lesion. However, sporadic spike failure at these high frequencies limits the efficacy of the informational lesion, yielding a parabolic profile with optimal effects at ∼130 Hz. This work provides a potential explanation for the therapeutic mechanism of DBS, and highlights the importance of considering spike failure in mechanistic models of DBS.