OBJECTIVE:To investigate whether local lesions created by stereo-electroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) affect distant brain connectivity and excitability in patients with focal, drug-resistant epilepsy (DRE). METHODS:Ten patients with focal DRE underwent SEEG implantation and subsequently 1 Hz bipolar repetitive electrical stimulation (RES) for 30 s before and after RFTC. Root mean square (RMS) of cortico-cortical evoked potentials (CCEPs) was calculated for 15 ms to 300 ms post-stimulation with baseline correction. Contact pairs were categorized as both coagulated, hybrid, or both non-coagulated. The data were divided into nine categories based on the stimulating and recording contact pair combinations. RMS of CCEPs was compared before and after (<12 h) RFTC using a two-sample t test (Hochberg corrected, p < 0.05) for each patient. Boost score, indicating power increase during seizures before RFTC relative to baseline, was analyzed in 4 s windows with 1 s overlap during seizure duration. RESULTS:RFTC altered connectivity across all categories. Of interest, decreases and increases in RMS were observed in connections between non-coagulated contacts distant from coagulation site (range: 1.09-85 mm, median = 17.7 mm, interquartile range [IQR] 10.1-32.3). Contact pairs involved in significantly altered non-coagulated connections showed a higher boost score correlation in the theta, beta, and gamma bands, as well as a stronger maximum correlation with coagulated sites in the delta band than contacts for which connectivity did not change after RFTC. SIGNIFICANCE:This study highlights how local lesions alter distant brain connectivity, providing insights for future research on epilepsy network changes and seizure outcomes following RFTC.

Error recognition is fundamental to adaptive behavior, enabling rapid compensatory action when outcomes deviate from expectations. Central to this function are neural circuits for performance monitoring, encoding cognitive signals that could support more reliable neural interfaces. Here, we recorded intracranial electroencephalography (iEEG) in epilepsy patients to enable a motor brain-computer interface (BCI) while sampling error-related activity across a distributed network. Our work reveals high-frequency population dynamics emerging in the anterior insula and propagating to the prefrontal cortex as the interface fails to follow the user’s intention. We identify spatially organized insular responses to error processing and movement feedback, highlighting it as a heterogeneous hub linking action and outcome. Real-time integration of error responses enables a self-correcting neural interface that enhances usability by reducing the need for manual user intervention. Together, our work demonstrates a human intracranial BCI harnessing insular brain activity, integrating cognitive processes directly into device control. ### Competing Interest Statement The authors have declared no competing interest. NWO Crossover Programme, INTENSE consortium, 17619

Objective.Motor-related neural activity is more widespread than previously thought, as pervasive brain-wide neural correlates of motor behavior have been reported in various animal species. Brain-wide movement-related neural activity have been observed in individual brain areas in humans as well, but it is unknown to what extent global patterns exist.Approach.Here, we use a decoding approach to capture and characterize brain-wide neural correlates of movement. We recorded invasive electrophysiological data from stereotactic electroencephalographic electrodes implanted in eight epilepsy patients who performed both an executed and imagined grasping task. Combined, these electrodes cover the whole brain, including deeper structures such as the hippocampus, insula and basal ganglia. We extract a low-dimensional representation and classify movement from rest trials using a Riemannian decoder.Main results.We reveal global neural dynamics that are predictive across tasks and participants. Using an ablation analysis, we demonstrate that these dynamics remain remarkably stable under loss of information. Similarly, the dynamics remain stable across participants, as we were able to predict movement across participants using transfer learning.Significance.Our results show that decodable global motor-related neural dynamics exist within a low-dimensional space. The dynamics are predictive of movement, nearly brain-wide and present in all our participants. The results broaden the scope to brain-wide investigations, and may allow combining datasets of multiple participants with varying electrode locations or calibrationless neural decoder.

Introduction: Periventricular nodular heterotopias (PVNH) are developmental abnormalities with neurons abnormally clustered around the cerebral ventricles. Patients frequently present with focal drug-resistant epilepsy (DRE). However, the relationship between PVNH and the seizure onset zone (SOZ) is complex. Stereo-electroencephalography (SEEG) is an invasive diagnostic procedure for patients with DRE. In selected patients, the SEEG may be converted into a therapeutic procedure, lesioning the probable (SOZ) with pulsed radiofrequency thermocoagulation (RFTC). The aim of our study was to evaluate the efficacy and safety of SEEGRFTC in a series of DRE patients with PVNH. Methods: Twenty-four patients with focal DRE related to PVNH and treated with SEEG-guided-RFTC restricted to nodules were prospectively collected between 2016 and 2023 and retrospectively analyzed after a follow-up of at least 12 months. Results: Seventeen patients (71 %) responded (ILAE class 1-4) after SEEG-guided RFTC of whom eleven (46 %) became seizure-free (class 1) at last follow up, nine (45 %) despite residual PVNH tissue on MRI. SEEG seizure onset was restricted to PVNH in eleven patients (class 1 in 45 %) and simultaneously in PVNH and other cortical areas in thirteen patients (class 1 in 46 %). Out of 31 SEEG-RFTC procedures in twenty-four patients, adverse events, related to RFTC, were recorded in eight (26 %), of which two patients (8 %) had predicted permanent visual complaints whilst the other five had transient complaints. Significance: This study demonstrates that a considerable percentage of patients, even with bilateral, multiple PVNH and involvement of adjacent cortical regions can be rendered seizure-free with SEEG-guided-RFTC restricted to the nodules. Furthermore, this study delivers evidence that the complete destruction of the entire nodule is not necessary to render a patient seizure free. This justifies the use of SEEG in patients with single, multiple or bilateral PVNHs to provide insight into the epileptogenic organization in and around these lesions.

Background and ObjectivesThe aim of this study was to evaluate whether people living with severe medically refractory epilepsy (PSRE) benefit from a seizure dog.MethodsAn individual-level stepped-wedge randomized controlled trial was conducted. The study was conducted in the Netherlands among adults with daily to weekly seizures. All participants were included simultaneously (on June 1, 2019) while receiving usual care. Then, during the 36-month follow-up, they received a seizure dog in a randomized sequence. Participants kept a seizure diary and completed 3-monthly surveys. Seizure frequency was the primary outcome. Secondary outcomes included seizure-free days, seizure severity, health-related quality of life (HRQoL), and well-being. Data were analyzed using generalized linear mixed modeling (GLMM). The models assumed a delayed intervention effect, starting when the seizure dog reached an advanced stage of training. Effects were calculated as changes per 28-day period with the intervention.ResultsData were collected from 25 participants, of whom 20 crossed over to the intervention condition. The median follow-up was 19 months with usual care and 12 months with the intervention. On average, participants experienced 115 (SD 164) seizures per 28-day period in the usual care condition and 73 (SD 131) seizures in the intervention condition. Seven participants achieved a reduction of 50% or more at the end of follow-up. GLMM indicated a 3.1% decrease in seizure frequency for each consecutive 28-day period with the intervention (0.969, 95% CI 0.960-0.977). Furthermore, an increase in the number of seizure-free days was observed (1.012, 95% CI 1.009, 1.015), but no effect on seizure severity measured with the NHS3. Generic HRQoL scores improved, as reflected in the decrease in EQ-5D-5L utility decrement (0.975, 95% CI 0.954-0.997). Smaller improvements were observed on overall self-rated HRQoL, epilepsy-specific HRQoL, and well-being, measured with the EQ VAS, QOLIE-31-P, and ICECAP-A, respectively.DiscussionSeizure dogs reduce seizure frequency, increase the number of seizure-free days, and improve the quality of life of PSRE. The magnitude of the effect on generic HRQoL indicates that seizure dogs benefit PSRE beyond the impact on seizure frequency alone. Early discontinuation of seizure dog partnerships suggests that this intervention is not suitable for all PSRE and requires further study.Trial Registration InformationThis study was registered in the Dutch Trial Register (NL6682) on November 28, 2017. Participants were enrolled on June 1, 2019.Classification of EvidenceThis study provides Class III evidence that seizure dogs are associated with a decrease in seizure frequency in adult patients with medically refractory epilepsy.

OBJECTIVES:The Epilepsy Support Dog Evaluation study was commissioned by the Dutch Ministry of Health, Welfare and Sports to inform a reimbursement decision on seizure dogs. The randomized trial found that seizure dogs reduce seizure frequency and improve health-related quality of life of persons with severe refractory epilepsy (PSREs). This article examined the cost-effectiveness (CE) of adding seizure dogs to usual care for PSREs in The Netherlands. METHODS:A microsimulation model was developed, informed by generalized linear mixed models using patient-level trial data from the Epilepsy Support Dog Evaluation study. The model adopted a 10-year time horizon and took a societal perspective. Seizure frequency was predicted as a function of time with the seizure dog. Patient utilities, caregiver utilities, and costs were predicted as a function of seizure frequency and time with the seizure dog. RESULTS:Quality-adjusted life-years (QALYs) of PSREs with a seizure dog and usual care alone were estimated at 6.28 and 5.65, respectively (Δ 0.63). For caregivers, estimated QALYs were 6.94 and 6.52, respectively (Δ 0.42). Total costs were respectively €228 691 and €226 261 (Δ €2430). Intervention costs were largely offset by savings in informal care and healthcare. The incremental CE ratio was €2314/QALY. Probabilistic sensitivity analysis indicated a 91% probability of seizure dogs being cost-effective at the €50 000/QALY threshold. The incremental CE ratio fell well below this threshold in scenario analyses. CONCLUSIONS:Seizure dogs are likely to be a cost-effective addition to usual care for PSREs in The Netherlands.

BACKGROUND AND PURPOSE:Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS:Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS:SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS:The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Introduction Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. Methods and analysis A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. Ethics and dissemination The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019–1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. Trial registration NL8278; Pre-results.

Using brain activity directly as input for assistive tool control can circumventmuscular dysfunction and increase functional independence for physically impaired people. The motor cortex is commonly targeted for recordings, while growing evidence shows that there exists decodable movement-related neural activity outside of the motor cortex. Several decoding studies demonstrated significant decoding from distributed areas separately. Here, we combine information from all recorded non-motor brain areas and decode executed and imagined movements using a Riemannian decoder. We recorded neural activity from 8 epilepsy patients implanted with stereotactic-electroencephalographic electrodes (sEEG), while they performed an executed and imagined grasping tasks. Before decoding, we excluded all contacts in or adjacent to the central sulcus. The decoder extracts a low-dimensional representation of varying number of components, and classified move/no-move using a minimum-distance-to-geometric-mean Riemannian classifier. We show that executed and imagined movements can be decoded from distributed non-motor brain areas using a Riemannian decoder, reaching an area under the receiver operator characteristic of 0.83 ± 0.11. Furthermore, we highlight the distributedness of the movement-related neural activity, as no single brain area is the main driver of performance. Our decoding results demonstrate a first application of a Riemannian decoder on sEEG data and show that it is able to decode from distributed brain-wide recordings outside of the motor cortex. This brief report highlights the perspective to explore motor-related neural activity beyond the motor cortex, as many areas contain decodable information.

Insulaire epilepsie wordt vaak gezien als imitator van andere focale epilepsieën zoals temporaalkwab-, pariëtaalkwabof frontaalkwabepilepsie. Bepaalde klinische verschijnselen, vooral in het begin van een aanval, zoals een stik-gevoel, paresthesieën in het gelaat, smaak hallucinaties of pijn kunnen aanwijzingen zijn voor een insulair focus van de epilepsie. Met uitgebreidere kennis op het gebied van klinische semiologie, functionele anatomie en connectiviteit kunnen patiënten met een insulaire epilepsie in een eerder stadium de juiste zorg (vaak epilepsiechirurgie) krijgen.

Het Academisch Centrum voor Epileptologie, een samenwerking van Kempenhaeghe en Maastricht UMC+, heeft een informatieve filmserie ontwikkeld over epilepsiechirurgie. De films belichten alle fases van het epilepsiechirurgietraject: van voorbereiding, onderzoeken, de hersenoperatie tot nazorg. Dit om patiënten beter voor te bereiden op het traject naar epilepsiechirurgie en steun te bieden voor hen die overwegen om het traject in te gaan. Vooral de ervaringen en afwegingen van patiënten staan in deze filmserie centraal.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

Introduction Epilepsy is one of the most common chronic neurological disorders. Antiseizure medication (ASM) is the first choice of treatment, however, 30% of epilepsy patients are drug-resistant. For these patients, neuromodulation can be an option, especially when epilepsy surgery is not possible or did not lead to seizure freedom. Epilepsy is associated with reduced quality of life (QoL), which heavily depends on seizure control.The most recent Cochrane reviews have shown that vagus nerve stimulation and deep brain stimulation of the anterior nucleus of the thalamus, lead to a responder rate OR of, respectively, 1.93 and 1.20. The question arises if neuromodulation for drug-resistant epilepsy (DRE) will be more cost-effective than sole treatment with ASM. The current study aims to determine the change in QoL after neuromodulation. Secondarily, we will aim to study the cost-effectiveness of these treatments.Methods and analysis This prospective cohort study aims at including 100 patients aged 16 or above who will be referred for neuromodulation, from January 2021 to January 2026. After informed consent, QoL and other relevant parameters will be assessed at baseline, 6 months, 1, 2 and 5 years after surgery. Data on seizure frequency will be derived from patient charts. We expect that DRE patients will report better QoL after neuromodulation. Even if they would still report seizures, the treatment can be seen as useful. This is especially true when patients can participate in society again to a greater extent than before treatment.Ethics and dissemination The board of directors of participating centres all gave permission for this study to commence. The medical ethics committees decided that this study does not fall under the Medical Research Involving Human Subjects Act (WMO). The findings of this study will be presented at (inter)national conferences and in peer-reviewed journals.Trial registration number NL9033.

In this study we aimed to improve the 7T FLAIR image quality, especially within the temporal lobe regions which are often attenuated due to field inhomogeneities. A neural network using MP2RAGE and T 2 -weighted images as inputs was set up to generate a new FLAIR-like image. The training was performed on the extratemporal-lobe voxels of the acquired 7T FLAIR image. The deepFLAIR showed a significant improvement in the signal-to-noise ratio and contrast-to-noise ratio in the temporal lobe regions in a number of cases. This study showed the potential to generate FLAIR-like images with reduced inhomogeneity artifacts and improved image quality.

Insulaire epilepsie wordt vaak gezien als imitator van andere focale vormen van epilepsie zoals temporaalkwab-, pariëtaalkwab- of frontaalkwabepilepsie. Indien er een goede klinische hypothese bestaat, kan er gericht prechirurgische diagnostiek plaatsvinden, inclusief intracranieel onderzoek middels stereo-EEG. In deze bijdrage wordt een voorstel gedaan voor een beslisboom, als ondersteuning bij de keuze voor de meest aangewezen minimaal invasieve behandeling van een individuele patiënt met insulaire epilepsie.

In een eerdere bijdrage die verscheen in het maartnummer van ‘Epilepsie’ werd uitgaande van een tweetal casussen, de klinische semiologie passend bij insulaire epilepsie beschreven, in relatie met de anatomische gebieden van de insula. In deze bijdrage wordt ingegaan op de meest aangewezen diagnostiek en de invasieve behandeling van deze patiënten.

Ideally, decisions are made based on prior knowledge, which allows for informed choices. Real life, however, often requires us to make decisions arbitrarily, without sufficient information. Decoding decision making processes from neural activity could allow for cognitive neuroprostheses and Brain-Computer Interfaces (BCIs) to support decision processes in rapid human-machine interactions, weigh decision-making confidence, and further enable neuromodulation protocols for the treatment of reward-related dysfunctions. To understand the differences between the decision-making processes in arbitrary and informed decisions, we recorded intracranial electroencephalography in a large number of cortical and subcortical areas from 5 patients during a categorization task. We demonstrate that individual decisions can be decoded from Local Field Potentials (LFPs) before motor response, in both arbitrary and informed conditions. Our analysis revealed dissimilar spatio-temporal patterns between arbitrary and informed decision-making, with arbitrary decisions being decodable in fewer brain regions and earlier in time compared to informed decisions.

De PRECISION-trial biedt een niet-invasieve stereotactische radiotherapie behandeling voor patiënten met refractaire epilepsie die niet in aanmerking komen voor epilepsiechirurgie. De resultaten van deze behandeling vermeld in eerder internationaal onderzoek waren veelbelovend. Onze hypothese is dat stereotactische radiotherapie een superieure behandeloptie is in vergelijking met de standaardzorg, resulterend in aanvalsreductie of aanvalsvrijheid voor een deel van de patiënten.

BACKGROUND AND OBJECTIVES:The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS:MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS:Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION:The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION:MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.