Deep brain stimulation that regularizes neural activity alleviates parkinsonian motor symptoms.

Alan D. Dorval II, Alexis M. Kuncel, Merrill J. Birdno, Dennis A. Turner and Warren M. Grill

Deep brain stimulation (DBS) treats the motor symptoms of Parkinson's disease (PD), reducing tremor, bradykinesia and rigidity and enabling persons with advanced PD to walk again. The mechanisms of DBS are not understood, limiting therapy to a small patient population and requiring trial and error application to novel brain regions. We hypothesize that PD symptoms are alleviated by the regularity of stimulation. We present a computational network model that reproduces the electrophysiological effects of PD: as the disease progresses, neural activity becomes disordered and neurons in motor thalamus lose the ability to relay cortical signals. In the model, DBS regularizes network activity and thalamic neurons regain the ability to relay signals.

We tested this regularization hypothesis in nine human volunteers undergoing battery replacement surgery for their DBS implantable generators. In subjects with PD and clinically effective DBS leads, we replaced the regular stimulation (rDBS) they normally receive with irregular stimulation (iDBS) with the same average high pulse frequency (130Hz). We quantified bradykinesia with a finger tapping task in the absence (OFF) and presence of rDBS and iDBS. In response to rDBS, the average and variability of the time between finger taps decreased from the OFF case, suggesting that subjects can move more quickly and regularly in the presence of rDBS. In contrast, symptomatic responses to iDBS were unchanged from the OFF case. Thus, a DBS frequency of 130Hz did not treat bradykinesia unless the pulses were regularly spaced. These findings suggest that clinical DBS alleviates symptoms by regularizing neural activity, a mechanism that may be useful to apply in other brain regions for other disease or disorder states.