Frequency- and circuit- specific effects of septohippocampal deep brain stimulation in mice as measured by functional ultrasound imaging.

BackgroundDeep brain stimulation (DBS) has shown remarkable success in treating neurological and psychiatric disorders such as Parkinsons disease, dystonia, epilepsy, and obsessive-compulsive disorder. Despite this success, the underlying mechanism of action remains unknown. DBS is now being explored to improve functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e. schizophrenia). While DBS for movement disorders requires high-frequency continuous stimulation, there is evidence that intermittent low-frequency stimulation in neuropsychiatric conditions may have persisting cognitive benefits, necessitating a broader exploration of how DBS alters brain networks. ObjectiveWe characterize the effects of pharmacologic NMDA antagonism on the septohippocampal network and the impact of high- and low-frequency MSN DBS on cerebral blood volume (CBV) in brain structures within and outside of the septohippocampal network. MethodsIn this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice. ResultsImaging from a sagittal plane across a variety of brain regions, we find that MSN theta-frequency (7.7Hz) DBS has a larger effect on hippocampal CBV after stimulation offset. This is observed following an intraperitoneal (i.p.) injection of either saline vehicle or MK-801 (1 mg/kg). This effect is not present using standard high-frequency DBS stimulation parameters (i.e. gamma [100Hz]). ConclusionThese results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner that continues beyond the period of electrical stimulation.