Direct Stimulation Therapy Research Articles

Pre-implant modeling of depth lead placement in white matter for maximizing the extent of cortical activation during direct neurostimulation therapy

Introduction: The objective of this work was to predict preoperatively the maximum extent to which direct stimulation therapy can propagate through an epileptic circuit for stabilizing refractory focal-onset epilepsy. A pre-surgical workflow is presented which comprises a computationally intensive process for calculating the volume of cortical activation (VOCA) surrounding cylindrical depth contacts virtually placed in white matter. The process employs an activation function (AF) derived from cable modeling of an axon. The AF was extrapolated to describe the three-dimensional activation of axon bundles facilitated by patient-specific diffusion tensor imaging (DTI).Methods: The modeling process consisted of the following steps: (1) acquisition of structural MRI and DTI; (2) computation of the electric potential using the finite element method; (3) analysis of the effect of the modeled electric field on depolarizing axon bundles using the AF; (4) predicting distant cortical activation by strategically placing the AF seeds for creating a modulated circuit tractography (MCT) map; and finally, (5) post-implant in vivo validation using Subtracted Activated SPECT (SAS).Results: The pre-implant simulation calculated non-spherical volumetric regions around the contacts representing areas of hyperpolarization and depolarization. Furthermore, the generated MCT map predicted the extent to which white matter connected epileptic sources were influenced during direct stimulation therapy. Validation of this map was demonstrated post-implantation employing RNS electrocorticography and SAS. The latter technique captured transient alterations in blood flow synched to neural metabolism potentially distant to the stimulated contacts.Conclusion: This pre-implant modeling system offers the potential for predicting optimal depth lead implant sites with a limited set of contacts for modulating the maximal extent of a refractory epileptogenic network.

On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.

The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.