Abstracts

Rationale: Deep Brain Stimulation (DBS) of the substantia nigra pars reticulata (SNr) is a potential treatment for refractory neocortical epilepsy [1,2]. Despite demonstrated therapeutic efficacy, very little is known about how this treatment influences neural circuitry, particularly at the high stimulation frequencies commonly employed in the clinical setting. Identification of modulated downstream circuitry may shed light on the neurobiological underpinnings of SNr-DBS, a prerequisite for further advancing this important therapy. Functional magnetic resonance imaging (fMRI) provides sensitive measurements of neural circuit activity on a whole-brain scale, thus making it an ideal tool for preclinical DBS studies. In the present study, we employed fMRI with simultaneous DBS in a preclinical healthy rat model to investigate neural circuit modulation by SNr-DBS. [1] H. Guo, et al., “Electrical Stimulation of the Substantia Nigra Pars Reticulata (SNr) Suppresses Chemically Induced Neocortical Seizures in Rats”, J Mol Neurosc, 2014, 53, pp546-52. [2] C. Wille, et al., “Chronic high-frequency deep-brain stimulation in progressive myoclonic epilepsy in adulthood--report of five cases”, Epilepsia, 2011, 52, pp489-96.Methods: Four Sprague-Dawley rats were stereotactically implanted with a custom-made MR-compatible DBS electrode in the right SNr. Stimulation was applied using a block-design paradigm (20sOFF/10sON/60sOFF), with a stimulation intensity of 300μA, a pulse duration of 0.5ms, and 6 different stimulation frequencies: 10Hz, 40Hz, 70Hz, 130Hz, 200Hz and 400Hz. Each frequency was repeated five times, leading up to a total of 30 fMRI acquisitions for each rat. All data were acquired on a 9.4T Bruker Biospec MRI and realigned, coregistered, and averaged per stimulation frequency. The group-average data were processed by means of voxel-wise general linear model analysis. Cluster significance was defined as p≤0.05 following correction for multiple comparisons.Results: Our data indicate that SNr-DBS evokes positive CBV responses in the SNr, hypothalamus, subthalamic nucleus and pons, and a negative CBV response in the bilateral dorsal striatum and cortical structures. CBV responses were larger at 130Hz than lower tested frequencies. The activation map of the group-averaged data and corresponding timeseries are shown in fig. 1 and 2 resp., at 130Hz.Conclusions: This study employed fMRI with simultaneous SNr-DBS to evaluate the circuit modulation profile of this therapy on a whole-brain scale. Our data suggests that SNr-DBS may potentially recruit both cortical and subcortical regions, including both cognitive and motor regions. This modulation is fully present from a stimulation frequency of 130Hz. Modulation of these diverse circuits may contribute to therapeutic efficacy, DBS side effects, or both. Identification of additional therapeutic regions is clinically paramount, as there are still non-responders to DBS at canonical brain targets. Our future studies will examine how circuit modulation by SNr-DBS therapy correlates with therapeutic outcomes in neocortical epileptic disease models.