Gregg, Nicholas M

Abstract To characterize invasive neuromodulation for insular drug‐resistant epilepsy, we retrospectively evaluated 22 patients treated with responsive neurostimulation (RNS; n = 14) or chronic subthreshold stimulation (CSS; n = 8). Stereoelectroencephalography was performed in 20 cases (91%). Median baseline seizure frequency was 10.5/month. Forty‐one percent had prior epilepsy surgery. At year 3, median seizure reduction (MSR) was 83% ( p = .01, Wilcoxon signed‐rank test), with a responder rate (RR) of 77%; MSR was 92% for CSS and 75% for RNS. There were no significant differences in MSR ( p ≥ .4) or RR ( p > .9) when comparing RNS versus CSS. Three patients achieved seizure freedom by year 3. Patients undergoing combined insular–thalamic stimulation ( n = 5) demonstrated an MSR of 84%, 86%, and 88% at 1, 2, and 3 years; seizure reduction in thalamocortical versus cortical‐only stimulation was not different ( p ≥ .1). Parasagittal lead trajectories achieved closer insular proximity than transopercular trajectories ( p < .0001, Mann–Whitney U ‐test). Median charge density at last follow‐up was 1.3 μC/cm 2 . There were no acute surgical complications and all stimulation‐related side effects resolved with programming adjustments. This study expands the limited literature on insular neuromodulation by demonstrating effectiveness of RNS and CSS, suggesting potential benefit from combined thalamocortical targeting, and defining parasagittal trajectories as a surgical approach for optimal lead proximity.

Abstract Objective Interictal epileptiform spikes (IESs) are widely used biomarkers of epileptogenic tissue in presurgical epilepsy evaluation. However, their reliability for seizure onset zone (SOZ) localization in high‐density intracranial electroencephalography (iEEG) remains inconsistent. It is underexplored whether this variability reflects methodological differences across detection algorithms or a limitation of IESs as a biomarker. This study evaluates whether IES detection alone provides sufficient spatial specificity for accurate SOZ localization in iEEG. Methods We systematically benchmarked eight established IES detection algorithms using iEEG recordings from 35 patients with drug‐resistant focal epilepsy. To provide a clinically meaningful reference, algorithm performance was evaluated against the clinically defined SOZ. To refine detection outputs and move beyond only IES detection, we applied masking strategies to isolate informative IES subsets based on rate, amplitude, frequency, and co‐occurrence with high‐frequency oscillations (HFOs). Conceptually, masking acts as a spatial refinement strategy that progressively restricts diffuse IES activity to more focal, pathologically relevant event populations. Results Despite substantial variability in detection characteristics, SOZ localization performance (ratio of events originating from SOZ divided by total number of events) converged within a narrow range (.23–.51), suggesting that IESs exhibit an intrinsic ceiling in SOZ localization performance when used alone. Amplitude‐based masking yielded modest improvements, whereas frequency‐based masking reduced performance. In contrast, IES‐HFO co‐occurrence markedly improved localization, particularly when combined with rate‐based masking, achieving a median SOZ localization ratio of .89, exceeding IESs (.37) and HFOs (.63) evaluated independently. Significance These findings demonstrate that IES‐based SOZ localization may require moving beyond detection‐only approaches. The integration of informed, biomarker‐driven masking strategies provides a more robust framework for identifying the activity most relevant to the epileptogenic network and paves the way for future incorporation into the clinical decision‐making pipeline.

Abstract Objective Anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) is an effective therapy for frontotemporal and limbic drug‐resistant focal epilepsies. The pulvinar nucleus (PUL) is an emerging neuromodulation target for seizure networks involving the posterior quadrant and temporal lobe. This study evaluates the safety and effectiveness of combined bilateral ANT plus PUL DBS for posterior quadrant and temporal lobe epilepsies. Methods We conducted a single‐center retrospective cohort study of patients receiving combined ANT/PUL DBS between 2021 and 2025. Outcomes included median seizure rate reduction (MSR), responder rate (RR; >50% seizure frequency reduction), and stimulation‐related side effects, assessed across ANT, PUL, and concurrent ANT/PUL stimulation settings. Acute surgical complications were evaluated. Statistical significance was assessed using two‐sided Wilcoxon signed‐rank tests with Holm–Bonferroni correction. Results Nine patients with combined ANT/PUL DBS were identified, and eight patients had sufficient follow‐up for inclusion (median follow‐up = 20 months). Posterior predominant structural abnormalities were present in eight of nine patients. There were no acute surgical complications. Three instances of transient stimulation‐related side effects resolved with parameter adjustments, whereas one patient required rescue antiseizure medication in addition to programming changes. Eight patients received periods of ANT stimulation, six PUL stimulation, and seven combined ANT/PUL stimulation. Regarding overall outcome, at last follow‐up, there was a significant 80.8% MSR ( p = .0078) and 87.5% RR, with two patients receiving ANT and six ANT/PUL stimulation. Regarding target‐specific MSR, concurrent ANT/PUL DBS (68.8% MSR) showed a trend toward superior performance relative to ANT (43.3%) and PUL DBS (17.5%) alone, although subgroup analysis of target‐specific performance did not reach statistical significance. Significance Combined four‐lead ANT/PUL DBS appears safe and effective for patients with drug‐resistant posterior quadrant and temporal lobe epilepsies. Dual‐network neuromodulation may provide greater flexibility to individually optimize neuromodulation for complex seizure networks.

Abstract White matter bundles play a crucial role in cognitive functions by rapidly transmitting information between brain regions. Inter-areal conduction guides the integration of information and conduction velocity is a fundamental parameter in theories and models of brain function. However, distributions of conduction velocity remain difficult to characterize in vivo in humans. In this work, we integrated diffusion magnetic resonance imaging (dMRI) tractography with intracranial electrical stimulation during clinical stereo-electroencephalography (sEEG) monitoring in 17 subjects to measure conduction velocity within four major white matter bundles. Our findings reveal that human brain conduction is characterized by high variability both within and between bundles, reflecting a predominance of slow connections alongside rare high-speed connections. Because conduction velocity in myelinated fibers follows an approximately linear relationship with axon diameter, we derive underlying axon diameter distributions and show that these estimates are comparable to previous post-mortem studies. These findings demonstrate a heavily skewed distribution of human neural conduction velocities and show that structural heterogeneity shapes the timing and integration of information in large-scale networks.

Objective Lennox–Gastaut syndrome (LGS) is a severe treatment‐resistant epilepsy. Although vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are established therapies, comparative data and the impact of dual neuromodulation remain limited. We compared seizure outcomes across VNS, DBS, and combined DBS + VNS therapy in LGS. Methods This retrospective cohort study at Mayo Clinic (2005–2024) included LGS patients treated with VNS and/or DBS . Seizure frequency was assessed at 6, 12, and 24 months post‐stimulation. Responder was defined as 50% or more seizure reduction. Results Forty patients were included (42% female, median, 150 seizures/month). Eleven patients underwent sequential VNS followed by DBS and contributed data to 2 treatment epochs, yielding 3 treatment groups: VNS alone (n = 29), DBS alone (n = 12), and DBS + VNS (n = 10). At 24 months, median seizure reduction rate was comparable between VNS (50%; 95% confidence interval [ CI], 44–75%) and the overall DBS cohort (59%, 95% CI, 33–86%) ( p = 0.54). However, a significant difference emerged when comparing the 3 treatment arms ( p = 0.027). Specifically, DBS + VNS therapy yielded significantly greater median reduction rate (81%, 95% CI, 60–99%) than DBS alone (43%, 95% CI, 0–58%) ( p adj = 0.027) or VNS alone (50%, 95% CI, 44.4–75.0%) ( p adj = 0.048). Four patients attained sustained seizure freedom above 1 year at last follow‐up. Interpretation VNS and DBS provide comparable seizure reduction in LGS over a 2‐year follow‐up period. DBS + VNS was associated with further improvements in seizure reduction in this small, retrospective dataset. This possibility warrants further investigation. ANN NEUROL 2026

Abstract Drug-resistant epilepsy affects tens of millions of people worldwide and is associated with considerable morbidity and mortality. Thalamic deep brain stimulation and cortical responsive neurostimulation are proven treatments for focal epilepsy. Both have been used to target a range of thalamic nuclei; yet, the roles of these thalamic nuclei in focal seizure generation remain incompletely understood. Thirteen patients with drug-resistant focal epilepsy undergoing intracranial EEG were consented to undergo investigation of thalamocortical networks. Sampled regions included cortical, mesial temporal, and thalamic brain regions. Visual and spectral analyses were performed to identify seizure onset patterns and correlate thalamic and cortical seizure activity. Thalamic ictal discharges were observed in 89% of seizures. Of these, 56% demonstrated synchronous thalamocortical activity with distinct patterns. These onset patterns included hypersynchronous spiking, low-voltage fast activity, ictal baseline shifts, and broadband suppression. Multiple thalamic nuclei were involved in ictal organization and propagation, with the specific nuclei depending on the cortical seizure network. The thalamus plays a crucial role in focal onset seizure generation and propagation, with distinct seizure onset patterns and nuclei involved. These findings support exploring a broader range of thalamic nuclei in epilepsy neurostimulation and have implications for seizure detection settings in intracranial sensing devices.

Understanding motor representation in the human brain requires mapping beyond the primary motor cortex, into the distributed networks that coordinate complex movements. The insular cortex, a multifunctional hub buried within the Sylvian fissure, has been implicated in motor control through clinical observations and neuroimaging. Yet its precise relation to primary sensorimotor processing remains one of the least understood aspects of motor neurophysiology. To address this gap, we quantified electrophysiological changes from implanted depth electrodes in patients performing simple movement tasks combined with single-pulse electrical stimulation (SPES) to map effective connectivity. The movement data reveal somatotopically specific representation bilaterally, as well as intereffector regions that are active for different movement types. Hand representation is centered along the contralateral ventral aspect of the middle and posterior short gyri bilaterally, while tongue/mouth tuned sites cluster in the dorsal posterior short gyrus and the dorsal long gyri. Insular activity temporally follows the primary motor cortex (M1) and precedes movement onset. SPES revealed somatotopically specific connectivity between corresponding sites in M1 and insula (hand-to-hand, tongue-to-tongue) and between bilateral insulae. These observations establish that somatotopy is a conserved property of distributed motor control incorporating the insular representations and connectivity.

Miller et al. maintain that thalamic SEEG can now be considered a cornerstone of standard clinical practice in individualized epilepsy care, helping to define seizure onset and spread, assess therapeutic stimulation, map connectivity, and identify target-specific biomarkers for responsive neurostimulation.

Objective The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single‐pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation. Methods Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier. Results Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus‐ventral anterior nucleus junction. DBS delivered for >1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well‐connected seizure networks. Interpretation BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large‐scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748–760