Miller, Kai J.

Abstract Despite the growing interest in network-guided neuromodulation for epilepsy, uncertainty about the safety and long-term efficacy of thalamocortical stimulation persists. Our evaluation focused on the use of a four-lead open-loop implantable pulse generator for thalamocortical network neuromodulation. We retrospectively reviewed seven patients with diverse seizure networks—poorly localized, regional, or multifocal—undergoing thalamocortical neuromodulation. Employing a four-lead system, electrodes targeted both thalamic and cortical seizure network nodes. We assessed seizure severity, life satisfaction and sleep quality on a 10-point scale, and seizure frequency was assessed via telephone interviews and chart review. Outcomes were assessed by the Wilcoxon sign-rank test at the 0.05 significance level. Seven patients with a median age at implant of 22 years (range 14–42 years) had a median disabling seizure reduction of 93% (range 50–100%, P = 0.0156), with 100% responder rate (≥50% reduction in seizure frequency) after a median of 17 months post-implantation (range 13–60). The median improvement in seizure severity was 3.5 out of 10 points (P = 0.0312), life satisfaction 4.5 points (P = 0.0312) and quality of sleep 3 points (P = 0.062). No perioperative complications occurred. Transient seizure exacerbations (n = 2) and stimulation-related sensory/motor side-effects (n = 2) quickly resolved with parameter adjustments. One patient required surgical revision due to delayed infection. Six patients had permanent electrode placement refined by intracranial EEG trial stimulation; five patients had >90% reduction in seizure frequency during trial stimulation. Thalamocortical network neuromodulation using a four-lead open-loop system is safe and associated with significant improvements in seizure control and patient quality of life. Trial stimulation during intracranial EEG shows promise for enhancing seizure network engagement and parameter optimization but requires further study. Prospective controlled trials are needed to further characterize and validate the efficacy and side-effect profile of thalamocortical network neuromodulation for epilepsy.

BACKGROUND AND OBJECTIVES: Upper limb motor recovery is limited and affects functional outcomes in stroke survivors. Recent randomized controlled trials have assessed the role of combining vagus nerve stimulation with standard neurorehabilitation. The aim of this review was to evaluate the effectiveness of pairing implanted vagus nerve stimulation (I-VNS) with rehabilitation therapy in ischemic stroke patients and to provide a framework for its integration into standard clinical practice. METHODS: We searched PubMed, Scopus, CINAHL Plus, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles published from inception to July 2024. Randomized controlled trials and follow-up studies assessing the efficacy and/or safety of I-VNS in stroke rehabilitation were included. The outcomes included upper limb motor function and adverse events related to intervention. The risk of bias was assessed using the Cochrane risk-of-bias tool, and a random-effects model was generated for the meta-analysis using the Meta package in R. RESULTS: The final analysis included 8 studies, with a cumulative sample size of n = 498 patients who underwent I-VNS–paired rehabilitation for upper extremity weakness in unilateral supratentorial stroke. The intervention group (I-VNS) included 245 patients (49.1%) whereas the control group had 252 patients (50.6%). The mean age was 59.0 ± 10.01 years in the intervention group and 61.0 ± 9.7 years in the control group. The intervention group included 155 male patients (63.2%), and the control group had 165 male patients (64.4%). The meta-analyses showed statistically significant improvement in upper limb motor function in the I-VNS–paired rehabilitation group with a mean difference of 2.73 (95% CI: 1.32-4.13; P = .04) in the Fugl-Meyer Assessment for Upper Extremity score. Only one study reported a serious adverse event. CONCLUSION: A systematic review and meta-analysis of the current literature provides high-level evidence that I-VNS–paired rehabilitation improves functional outcomes and has a favorable safety profile in patients with poststroke upper extremity weakness.

Abstract Cortico‐cortical evoked potentials (CCEPs) are an active electrophysiological technique used during intracranial electroencephalography to evaluate the effective connectivity and influence of therapeutic stimulation between distinct cortical regions and pinpoint epileptogenic zones (EZs) in patients with epilepsy. Various methodologies have been implemented to analyze CCEPs and characterize the epileptogenic networks for EZ localization. Despite its promise, their interpretation remains challenging due to the large volumes of spatially and temporally complex data generated. Early studies focused largely on qualitative descriptors and predefined, semi‐quantitative features such as waveform morphology and peak latencies. However, these methods are limited by the significant heterogeneity in CCEP waveform conformations across patients and cortical regions. The specific technique used for extraction of features, such as the spectral band power and root mean squared values, remains open to empirical refinement, as does choice of appropriate latency windows, with no consensus reached regarding the optimal approach. Graph theoretical metrics such as degree centrality, betweenness centrality, and clustering coefficients can provide a rich representation of epileptogenic network connectivity. However, these metrics are often abstract and difficult to interpret in a clinical setting or to the non‐expert, and their neuroscientific substrates remains poorly understood. The lack of standardization in stimulation protocol and data‐processing pipelines has further contributed to inconsistency in reported findings. Emerging machine learning approaches have been increasingly applied to CCEP data, offering a more data‐driven and potentially generalizable way to identify electrophysiological biomarkers of the epileptogenic effective connectivity. In this article, we discuss qualitative, quantitative, and spectral features; network‐analytical metrics; and more recently, data driven methodologies aimed at improving the interpretability and clinical utility of CCEP data.

Abstract Electrical stimulation is increasingly used to modulate brain networks for clinical purposes. The basic unit of neurostimulation, a single electrical pulse, can travel through white matter to influence connected neuronal populations. However, the mechanisms by which it influences connected populations is not well understood: stimulation may excite, inhibit, or add noise to neuronal population activity. In this study, we investigated how single pulses modulate the neuronal processing of images in a well-controlled visual paradigm. In two human subjects implanted with iEEG electrodes for clinical purposes, single pulses were delivered to electrodes in white matter tracts connected to measurement electrodes in visual cortex. Images appeared on-screen at 0, 100, or 200 ms after each pulse. Using finite impulse response modeling, we decomposed the broadband and evoked potential responses into separate components induced by electrical stimulation and by visual processing. Single pulses induced transient broadband increases followed by suppression, but they did not modulate the visual broadband responses (i.e., stimulation response was additive to visual response). In contrast, single pulses elicited prominent brain stimulation evoked potentials and they modulated the visual evoked potentials. Specifically, visual evoked potentials were larger when stimulation occurred closer to visual onset. This indicates that a single electrical pulse can increase the strength or synchrony of visual inputs. Overall, these findings suggest that the effects of electrical stimulation in the visual system are two-fold: stimulation induces additive effects on broadband power, possibly by adding noise, and it interacts with synchronous visual inputs to amplify them.

AbstractObjectiveNeuromodulation for pediatric refractory epilepsy (PRE) is preferred when the seizure onset zone is not amenable to surgical resection, due to multifocal onset or involvement of eloquent cortex. Given its rapidly evolving landscape, we describe our institutional experience with neurostimulation therapies including deep brain stimulation (DBS) of the anterior nucleus (DBS‐ANT), the centromedian nucleus (DBS‐CM), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS) to treat PRE.MethodsA retrospective chart review was conducted to identify pediatric patients (≤18 years of age) who presented to our institution with PRE. Patients were included who had at least 1 year of follow‐up after neurostimulation was started. Patients with ≥50% seizure frequency reduction at last follow‐up compared to baseline were classified as responders.ResultsA total of 35 patients (21 females) were included in the series. Nine patients underwent DBS‐ANT, 9 underwent DBS‐CM (+ ANT in 7 patients), 5 underwent RNS, and 12 underwent CSS. The median age at seizure onset and surgery was 8 and 16 years, respectively. Structural lesions were the most common etiology of epilepsy (54%). Eighteen patients had prior interventions and 13 received invasive EEG. Post‐operative complications following neurostimulation implantation were noted in three patients (9%). However, no permanent deficits were noted. Median follow‐up time was 46 months (range 13–162 months). Twenty‐three patients (59%) were responders (3/9 DBS‐ANT; 7/9 DBS‐CM; 4/5 RNS; 9/12 CSS). Further, median seizure reduction was 25% (DBS‐ANT), 89% (DBS‐CM), 87% (RNS), and 88% (CSS) across the cohort. Six patients (17%) had improved subjective neurocognitive outcomes while the other 29 had stable neurocognitive outcomes.SignificanceDBS, RNS, and CSS are safe and effective options for PRE. An understanding of treatment approaches can optimize results by tailoring therapy to individual patients.Plain Language SummaryThis study investigates the use of various neurostimulation therapies for treating pediatric refractory epilepsy (PRE) including deep brain stimulation (DBS), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS). Overall, neuromodulation was found to be effective in reducing seizures in most patients, with 59% of patients showing at least a 50% reduction in seizure frequency. Additionally, the treatments were generally safe, with few complications and no instances of permanent deficits.

Abstract The pulvinar has been proposed as an effective neuromodulation target for patients with posterior quadrant and temporal epilepsies. However, the pulvinar has a large tissue volume, multiple subnuclei, and widespread cortical connections. It remains unknown whether electrical stimulation of distinct pulvinar subregions affects the temporal, occipital, and parietal areas differently. To address this gap, we delivered single-pulse electrical stimulation to the pulvinar and measured the resulting brain stimulation evoked potentials in twelve patients undergoing stereotactic EEG for drug-resistant epilepsy. Brain stimulation evoked potentials were parameterized across the occipital, temporal and parietal cortex. Stimulation of the lateral pulvinar elicited significant brain stimulation evoked potentials in striate and extrastriate areas that diminish as stimulation shifts towards the medial pulvinar. Conversely, stimulation of the ventral aspect of the medial pulvinar produced significant lateral temporal evoked potentials, which diminish with lateral pulvinar stimulation. We also found that stimulation of the dorsomedial pulvinar evoked significant parietal responses with limited striate/extrastriate and lateral temporal responses. These results demonstrate that electrical stimulation of specific pulvinar subregions influences distinct occipital, parietal and lateral temporal areas. Selective targeting of pulvinar subregions to maximize seizure network engagement may be essential for individualized treatment of posterior quadrant and temporal epilepsies.

AbstractObjectiveStereoelectroencephalography‐guided radiofrequency thermocoagulation (SEEG‐guided RFTC) has been increasingly used as diagnostic and therapeutic approach for drug‐resistant focal epilepsies (DREs). We aimed to describe seizure outcomes of RFTC before and after further neurosurgical intervention.MethodsRetrospective single‐institution case series of patients who underwent SEEG‐RFTC. The primary outcome was Engel class I–IV classification ([responders Engel I–III and non‐responders Engel IV]) at last follow‐up after RFTC and prior to further neurosurgical intervention (open surgical resection, laser ablation, and neuromodulation).ResultsTwenty‐five patients (median age 18.9 years) with DRE were included. The median follow‐up time after RFTC was 7.2 months, including 20 patients who underwent further intervention (median follow‐up time of 7.3 months) and 5 without intervention (median of 3.5 months). From the patients who had further intervention, 17 (85%) underwent surgical procedure (laser ablation 53%, open surgical resection 47%) (median 4.4 months) and 3 (15%) had responsive neurostimulators placed (median 6.9 months). Prior to further intervention (median follow‐up 3.5 months after RFTC), 12 (48%) patients were classified as responders (12% Engel class I, 16% class II, and 20% class III) and 13 (52%) as non‐responders. Following neurosurgical intervention, 17 (68%) patients were followed for a median time of 2.7 months and 3 were lost to follow‐up. Of eight initial RFTC responders, 87.5% and 12.5% had Engel classes I and III, respectively. Of nine who were non‐responders, 33% had Engel class I, 22% II and III, and 44% IV outcomes following further intervention. No neurologic complications were reported.SignificanceSEEG‐guided RFTC is a well‐tolerated procedure and a beneficial diagnostic approach prior to further neurosurgical interventions in patients with DRE.Plain Language SummarySEEG‐guided RFTC is a well‐tolerated procedure and in the patients who experienced initial seizure reduction (n = 8), subsequent neurosurgical intervention (surgery or neuromodulation) led to favorable seizure outcomes (87.5% seizure freedom and 12.5% worthwhile seizure improvement).

Abstract Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.

Abstract The cortex generates diverse neural dynamics, ranging from broadband fluctuations to narrowband oscillations at specific frequencies. Here, we investigated whether broadband and oscillatory dynamics play different roles in the encoding and transmission of visual information. We used information-theoretical measures to dissociate neural signals sharing common information (i.e., redundancy) from signals encoding complementary information (i.e., synergy). We analyzed electrocorticography (ECoG) and local field potentials (LFP) in the visual cortex of human and non-human primates (macaque) to investigate the extent to which broadband signals (BB) and narrowband gamma (NBG) oscillations conveyed synergistic or redundant information about images. In both species, the information conveyed by BB signals was highly synergistic within and between visual areas. By contrast, the information carried by NBG was primarily redundant within and between the same visual areas. Finally, the information conveyed by BB signals emerged early after stimulus onset, while NBG sustained information at later time points. These results suggest a potential dual role of BB and NBG cortical dynamics in visual processing, with broadband dynamics supporting nonlinear pattern recognition and oscillations facilitating information maintenance across the cortex.