Neural signal data collection and analysis of Percept™ PC BrainSense recordings for thalamic stimulation in epilepsy.

Deep brain stimulation (DBS) using Medtronic's Percept™ PC implantable pulse generator is FDA-approved for treating Parkinson's disease (PD), essential tremor, dystonia, obsessive compulsive disorder, and epilepsy. Percept™ PC enables simultaneous recording of neural signals from the same lead used for stimulation. Many Percept™ PC sensing features were built with PD patients in mind, but these features are potentially useful to refine therapies for many different disease processes. When starting our ongoing epilepsy research study, we found it difficult to find detailed descriptions about these features and have compiled information from multiple sources to understand it as a tool, particularly for use in patients other than those with PD. Here we provide a tutorial for scientists and physicians interested in using Percept™ PC's features and provide examples of how neural time series data is often represented and saved. We address characteristics of the recorded signals and discuss Percept™ PC hardware and software capabilities in data pre-processing, signal filtering, and DBS lead performance. We explain the power spectrum of the data and how it is shaped by the filter response of Percept™ PC as well as the aliasing of the stimulation due to digitally sampling the data. We present Percept™ PC's ability to extract biomarkers that may be used to optimize stimulation therapy. We show how differences in lead type affects noise characteristics of the implanted leads from seven epilepsy patients enrolled in our clinical trial. Percept™ PC has sufficient signal-to-noise ratio, sampling capabilities, and stimulus artifact rejection for neural activity recording. Limitations in sampling rate, potential artifacts during stimulation, and shortening of battery life when monitoring neural activity at home were observed. Despite these limitations, Percept™ PC demonstrates potential as a useful tool for recording neural activity in order to optimize stimulation therapies to personalize treatment.

Electrical stimulation of the endopiriform nucleus attenuates epilepsy in rats by network modulation.

OBJECTIVE: Neuromodulatory anterior thalamic deep brain stimulation (DBS) is an effective therapy for intractable epilepsy, but few patients achieve complete seizure control with thalamic DBS. Other stimulation sites may be considered for anti-seizure DBS. We investigated bilateral low-frequency stimulation of the endopiriform nuclei (LFS-EPN) to control seizures induced by intracortically implanted cobalt wire in rats. METHODS: Chronic epilepsy was induced by cobalt wire implantation in the motor cortex unilaterally. Bipolar-stimulating electrodes were implanted into the EPN bilaterally. Continuous electroencephalography (EEG) was recorded using electrodes placed into bilateral motor cortex and hippocampus CA1 areas. Spontaneous seizures were monitored by long-term video-EEG, and behavioral seizures were classified based on the Racine scale. Continuous 1-Hz LFS-EPN began on the third day after electrode implantation and was controlled by a multi-channel stimulator. Stimulation continued until the rats had no seizures for three consecutive days. RESULTS: Compared with the control and sham stimulation groups, the LFS-EPN group experienced significantly fewer seizures per day and the mean Racine score of seizures was lower due to fewer generalized seizures. Ictal discharges at the epileptogenic site had significantly reduced theta band power in the LFS-EPN group compared to the other groups. INTERPRETATION: Bilateral LFS-EPN attenuates cobalt wire-induced seizures in rats by modulating epileptic networks. Reduced ictal theta power of the EEG broadband spectrum at the lesion site may be associated with the anti-epileptogenic mechanism of LFS-EPN. Bilateral EPN DBS may have therapeutic applications in human partial epilepsies.

VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms.

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy System has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.

Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. prolonged effects at high and low levels of stimulation.

PURPOSE: To measure vagus nerve stimulation (VNS)-induced cerebral blood flow (CBF) effects after prolonged VNS and to compare these effects with immediate VNS effects on CBF. METHODS: Ten consenting partial epilepsy patients had positron emission tomography (PET) with intravenous [15O]H2O. Each had three control scans without VNS and three scans during 30 s of VNS, within 20 h after VNS began (immediate-effect study), and repeated after 3 months of VNS (prolonged study). After intrasubject subtraction of control from stimulation scans, images were anatomically transformed for intersubject averaging and superimposed on magnetic resonance imaging (MRI) for anatomic localization. Changes on t-statistical maps were considered significant at p < 0.05 (corrected for multiple comparisons). RESULTS: During prolonged studies, CBF changes were not observed in any regions that did not have CBF changes during immediate-effect studies. During both types of studies, VNS-induced CBF increases were similarly located in the bilateral thalami, hypothalami, inferior cerebellar hemispheres, and right postcentral gyrus. During immediate-effect studies, VNS decreased bilateral hippocampal, amygdalar, and cingulate CBF and increased bilateral insular CBF; no significant CBF changes were observed in these regions during prolonged studies. Mean seizure frequency decreased by 25% over a 3-month period between immediate and prolonged PET studies, compared with 3 months before VNS began. CONCLUSIONS: Seizure control improved during a period over which some immediate VNS-induced CBF changes declined (mainly over cortical regions), whereas other VNS-induced CBF changes persisted (mainly over subcortical regions). Altered synaptic activities at sites of persisting VNS-induced CBF changes may reflect antiseizure actions.

Therapeutic mechanisms of vagus nerve stimulation.

Experiments in acute and chronic animal models of epilepsy provide mechanistic insight into the acute abortive, acute prophylactic, and chronic progressive prophylactic, anti-seizure effects of vagus nerve stimulation (VNS) observed in human epilepsies, and demonstrate antiepileptogenic effects of VNS in the kindling model. Anatomic-physiologic studies, experimental epilepsy studies, and human imaging, EEG, and CSF studies suggest that multiple mechanisms underlie the antiseizure effects of VNS and that alterations of vagal parasympathetic efferent activities do not underlie these antiseizure effects. Putative antiseizure mechanisms are mediated by altered vagal afferent activities, and probably include altered activities in the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. Anatomic-physiologic studies fully account for the common and rare adverse effects of VNS. Current understandings of antiepileptic drug (AED) and VNS therapeutic mechanisms strongly support the "common sense" interpretation of the clinical studies: i.e., adjunctive VNS can add antiseizure effect to any AED regimen, with no interactive toxicity and no effect on drug distribution and elimination.