Temporal patterning of pulses during deep brain stimulation affects central nervous system arousal

Regulation of CNS arousal is important for a wide variety of functions, including the initiation of all motivated behaviors. Usually studied with pharmacological or hormonal tools, CNS arousal can also be elevated by deep brain stimulation (DBS), in the human brain and in animals. The effectiveness of DBS is conventionally held to depend on pulse width, frequency, amplitude and stimulation duration. We demonstrate a novel approach for testing the effectiveness of DBS to increase arousal in intact female mice: all of the foregoing parameters are held constant. Only the temporal patterning of the pulses within the stimulation is varied. To create differentially patterned pulse trains, a deterministic nonlinear dynamic equation was used to generate a series of pulses with a predetermined average frequency. Three temporal patterns of stimulation were defined: two nonlinear patterns, Nonlinear1 (NL1) and Nonlinear2 (NL2), and the conventional pattern, Fixed Frequency (FF). Female mice with bilateral monopolar electrodes were observed before, during and after hippocampal or medial thalamic stimulation. NL1 hippocampal stimulation was significantly more effective at increasing behavioral arousal than either FF or NL2; however, FF and NL2 stimulation of the medial thalamus were more effective than NL1. During the same experiments, we recorded an unpredicted increase in the spectral power of slow waves in the cortical EEG. Our data comprise the first demonstration that the temporal pattern of DBS can be used to elevate its effectiveness, and also point the way toward the use of nonlinear dynamics in the exploration of means to optimize DBS.