Emerging approaches in neurostimulation for epilepsy.

PURPOSE OF REVIEW: Neurostimulation is a quickly growing treatment approach for epilepsy patients. We summarize recent approaches to provide a perspective on the future of neurostimulation. RECENT FINDINGS: Invasive stimulation for treatment of focal epilepsy includes vagus nerve stimulation, responsive neurostimulation of the cortex and deep brain stimulation of the anterior nucleus of the thalamus. A wide range of other targets have been considered, including centromedian, central lateral and pulvinar thalamic nuclei; medial septum, nucleus accumbens, subthalamic nucleus, cerebellum, fornicodorsocommissure and piriform cortex. Stimulation for generalized onset seizures and mixed epilepsies as well as increased efforts focusing on paediatric populations have emerged. Hardware with more permanently implanted lead options and sensing capabilities is emerging. A wider variety of programming approaches than typically used may improve patient outcomes. Finally, noninvasive brain stimulation with its favourable risk profile offers the potential to treat increasingly diverse epilepsy patients. SUMMARY: Neurostimulation for the treatment of epilepsy is surprisingly varied. Flexibility and reversibility of neurostimulation allows for rapid innovation. There remains a continued need for excitability biomarkers to guide treatment and innovation. Neurostimulation, a part of bioelectronic medicine, offers distinctive benefits as well as unique challenges.

Electrical brain stimulation and continuous behavioral state tracking in ambulatory humans.

Objective.Electrical deep brain stimulation (DBS) is an established treatment for patients with drug-resistant epilepsy. Sleep disorders are common in people with epilepsy, and DBS may actually further disturb normal sleep patterns and sleep quality. Novel implantable devices capable of DBS and streaming of continuous intracranial electroencephalography (iEEG) signals enable detailed assessments of therapy efficacy and tracking of sleep related comorbidities. Here, we investigate the feasibility of automated sleep classification using continuous iEEG data recorded from Papez's circuit in four patients with drug resistant mesial temporal lobe epilepsy using an investigational implantable sensing and stimulation device with electrodes implanted in bilateral hippocampus (HPC) and anterior nucleus of thalamus (ANT).Approach.The iEEG recorded from HPC is used to classify sleep during concurrent DBS targeting ANT. Simultaneous polysomnography (PSG) and sensing from HPC were used to train, validate and test an automated classifier for a range of ANT DBS frequencies: no stimulation, 2 Hz, 7 Hz, and high frequency (>100 Hz).Main results.We show that it is possible to build a patient specific automated sleep staging classifier using power in band features extracted from one HPC iEEG sensing channel. The patient specific classifiers performed well under all thalamic DBS frequencies with an average F1-score 0.894, and provided viable classification into awake and major sleep categories, rapid eye movement (REM) and non-REM. We retrospectively analyzed classification performance with gold-standard PSG annotations, and then prospectively deployed the classifier on chronic continuous iEEG data spanning multiple months to characterize sleep patterns in ambulatory patients living in their home environment.Significance.The ability to continuously track behavioral state and fully characterize sleep should prove useful for optimizing DBS for epilepsy and associated sleep, cognitive and mood comorbidities.

Anterior Nucleus of the Thalamus Deep Brain Stimulation with Concomitant Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

BACKGROUND: The Food and Drug Administration approved the deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) as an adjunctive therapy for drug-resistant epilepsy (DRE) in the United States in 2018. The DBS Therapy for Epilepsy Post-Approval Study is further evaluating the safety and effectiveness of ANT-DBS among different patients' groups. For this study, devices for vagus nerve stimulation (VNS) must be removed prior to enrolment. OBJECTIVE: To investigate the outcomes of concomitant ANT-DBS and VNS treatment for DRE. METHODS: A retrospective analysis was performed for 33 patients who underwent ANT-DBS using previous VNS to define distinct subgroups: standard ANT-DBS (9 subjects), ANT-DBS with functional VNS (12 subjects), and ANT-DBS with the VNS implantable pulse generator explanted or turned off at the time of the DBS (12 subjects). Effectiveness and safety data were analyzed across the whole population and among subgroups. RESULTS: A mean decrease in seizure frequency of 55% was observed after a mean follow-up of 25.5 mo. Approximately 67% of patients experienced ≥50% reduction in seizure frequency. Seizure reduction percentage was not significantly different among groups. Approximately 50% of subjects with no appreciable improvement and 75% of those who showed benefit after VNS (including improvement in seizure frequency, seizure severity, and seizure duration or quality of life) achieved a seizure reduction ≥50% after ANT-DBS surgery. There were no complications related to concomitant VNS and ANT-DBS. CONCLUSION: ANT-DBS for DRE provides excellent results despite previous and ongoing VNS therapy. Removal of VNS does not appear to be necessary before ANT-DBS.

Chronic subthreshold cortical stimulation: a therapeutic and potentially restorative therapy for focal epilepsy.

INTRODUCTION: Approximately one third of patients with focal epilepsy continue to have ongoing seizures despite adequate trials of anti-seizure medications. Surgery to remove the epileptogenic zone remains the most efficacious treatment option for focal drug-resistant epilepsy. However, when cortical areas are eloquent or there are multiple epileptogenic zones, surgical resection is not an ideal approach. Cortical stimulation provides an attractive alternative. Area covered: Here, the authors describe Chronic Subthreshold Cortical Stimulation (CSCS), which uses continuous intracranial electrical stimulation applied near the epileptogenic zone to lower seizure probability. The authors review literature related to CSCS. One challenge is finding the most efficacious set of stimulation parameters for each patient. Expert commentary: Data supporting CSCS are limited but promising for the treatment of patients with focal drug resistant epilepsy who are not surgical candidates. Additional electrophysiological biomarkers to estimate cortical excitability are needed.

Multiple timescale encoding of slowly varying whisker stimulus envelope in cortical and thalamic neurons in vivo.

Adaptive processes over many timescales endow neurons with sensitivity to stimulus changes over a similarly wide range of scales. Although spike timing of single neurons can precisely signal rapid fluctuations in their inputs, the mean firing rate can convey information about slower-varying properties of the stimulus. Here, we investigate the firing rate response to a slowly varying envelope of whisker motion in two processing stages of the rat vibrissa pathway. The whiskers of anesthetized rats were moved through a noise trajectory with an amplitude that was sinusoidally modulated at one of several frequencies. In thalamic neurons, we found that the rate response to the stimulus envelope was also sinusoidal, with an approximately frequency-independent phase advance with respect to the input. Responses in cortex were similar but with a phase shift that was about three times larger, consistent with a larger amount of rate adaptation. These response properties can be described as a linear transformation of the input for which a single parameter quantifies the phase shift as well as the degree of adaptation. These results are reproduced by a model of adapting neurons connected by synapses with short-term plasticity, showing that the observed linear response and phase lead can be built up from a network that includes a sequence of nonlinear adapting elements. Our study elucidates how slowly varying envelope information under passive stimulation is preserved and transformed through the vibrissa processing pathway.