Miller, Kai J.

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 General anesthesia increasingly facilitates asleep deep brain stimulation (DBS) surgery but suppresses spontaneous electrophysiological signals used to guide lead placement. Here, we investigated whether evoked resonant neural activity (ERNA), a stimulation-evoked biomarker of basal ganglia circuitry, remains informative during asleep DBS. We analyzed intraoperative recordings from a multisite cohort of 45 patients (86 hemispheres) undergoing subthalamic nucleus or globus pallidus internus DBS under awake and anesthetized conditions. Anesthesia markedly attenuated spontaneous beta and high-frequency oscillatory activity. Although ERNA amplitude was reduced at matched stimulation intensities, increasing stimulation current restored high-amplitude, spatially localized responses while preserving anatomical specificity. Across both targets, ERNA spatial distributions remained stable across awake and anesthetized states, co-localized with established motor-network biomarkers, and retrospectively identified electrode levels associated with the greatest postoperative therapeutic window. These retrospective findings position stimulation-evoked circuit interrogation as a complement to imaging for physiology-guided asleep DBS and as a candidate signal for contact prioritization. Prospective studies are warranted to determine whether ERNA-guided decisions improve placement, programming efficiency and clinical outcomes.

ABSTRACT Introduction The insula is an increasingly important target for functional neurosurgery given its involvement in a range of neurological and neuropsychiatric disorders, including epilepsy and chronic pain. As this practice evolves, optimal targeting will require standardized outcome measures that relate electrode or laser trajectory to postprocedural outcome. Traditional whole- brain registration approaches fail to capture the substantial person-to-person variability in insular gyral configuration, including the relative internal rotation of the insular gyri with respect to standard stereotactic space. Objective We propose and validate a stereotactic coordinate system based on local anatomical landmarks to facilitate surgical planning and standardized outcome assessment within the insular cortex. Methods Our approach transforms brain MRI first into standard AC-PC space, and then into an insular-specific space defined by five anatomical landmarks: four points along the central sulcus of the insula and one point at the middle cerebral artery (MCA) bifurcation (at the limen insulae). The system calculates two angles - θ (axial) and φ (sagittal) - between the AC-PC line and the insular axis, and the brain volume undergoes sequential rotation through these angles followed by translation to place the coordinate system’s origin along the insular axis. Results In a sample of 32 patients, the angle between the AC-PC line and the insular axis ranged from -17° to 17° in the axial plane (θ) and 31° to 69° in the sagittal plane (φ). In the resulting coordinate system, the insular axis defines z = 0 and the MCA turning point defines y = 0. We developed a custom, open-access MATLAB graphical interface that allows intuitive implementation of this system for both surgical planning and postoperative analysis; implanted electrodes, laser fiber position, and ablation geometry can each be localized within this common space. As a demonstration of its utility for pooling data across subjects, we applied the transformation to a previously acquired intracranial electrophysiology dataset and found that anatomically consistent, effector-specific motor representations emerged across 18 subjects once electrode positions were expressed in insular-specific coordinates. Conclusion As stereotactic surgery for insular targets becomes more common with expanding scientific inquiry, an insular-specific coordinate system may facilitate operative planning and functional mapping, and may help standardize outcome assessment across patients and institutions. SIGNIFICANCE STATEMENT The insular cortex represents an increasingly important surgical target for therapeutic interventions, yet substantial person-to-person anatomical variability hampers standardized targeting and outcome comparison. The insula is simultaneously the subject of expanding scientific inquiry — into interoception, pain, autonomic regulation, salience processing, and sensorimotor representation — much of it now pursued through intracranial recording and stimulation in humans, where cohorts are small, electrode sampling is idiosyncratic, and progress therefore depends on pooling data across patients in a frame that respects insular gyral architecture. We present “ Insulotaxy ,” a stereotactic coordinate system built from consistent, easily identifiable local anatomical landmarks that accounts for the insula’s unique rotational relationship to standard brain coordinates. An open-source MATLAB tool transforms imaging into insular-specific coordinates, facilitating surgical planning for ablation and electrode placement while enabling standardized outcome reporting across institutions. By providing locally anchored, anatomically aligned coordinates rather than relying on whole-brain registration, this framework addresses a practical gap in functional neurosurgery and lays a foundation for pooling clinical and electrophysiological data as insular interventions become more prevalent.

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 Prediction errors (PEs) drive perceptual learning by updating internal models of the sensory environment, yet it remains unclear how attention reshapes their representation across distributed thalamocortical circuits. Using intracranial stereoelectroencephalography (sEEG) from 17 patients performing a roving auditory oddball task under attended and unattended conditions, we quantified PE encoding using mutual information and co-information to capture redundant and synergistic PE representations. Attention modulated PE encoding in both the thalamus and the temporal cortex, but with distinct informational dynamics. Thalamic encoding showed a stable reduction of PE information during distraction, consistent with state-dependent thalamocortical gating. In contrast, the temporal cortex expressed two opposing learning trajectories during attended listening that converged once attention was diverted, revealing distinct cortical learning regimes rather than a uniform attentional effect. Attention further reorganized the informational content of cortical PE representations by altering the balance between redundant and synergistic information. A biologically constrained neural network showed that attention-dependent changes in inhibition and long-range connectivity reproduced these dynamics through Hebbian learning. Together, these findings suggest that attention regulates predictive learning not simply by changing the strength of PE responses, but by reshaping how distributed thalamocortical circuits represent and integrate sensory evidence over time.