Ince, Nuri F.

Abstract High-frequency oscillations (HFOs) are clinically established biomarkers of epileptogenic tissue, yet their translation from hospital-based recording systems to implantable neural interfaces remains a major barrier to their utilization in adaptive neuromodulation in epilepsy. Here, we established a bedside translational framework using a benchtop implementation of a wireless implantable neural interface (Brain Interchange, BIC) to evaluate whether clinically meaningful HFO can be preserved under implant-grade sensing constraints. Ten patients with drug resistant epilepsy underwent simultaneous 24-hour intracranial EEG recordings using synchronized BICs and a clinical-grade amplifier. A sensitive detector identified candidate HFOs, while sparse signal processing and machine learning methods removed artifact related pseudo-HFOs. Despite its lower sampling rate, narrower analog bandwidth, and higher noise floor, the integrated sensing and computational intelligence framework preserved approximately 82% of clinical amplifier HFOs and maintained nearly identical spatial distribution of pathological activity. After pseudo-HFO elimination, BIC derived HFOs localized the seizure onset zone with 84% sensitivity and 90% specificity, comparable to the clinical amplifier despite lower fast ripple detection. These findings demonstrate that implant-grade neural sensing, when integrated with artifact resilient computational intelligence, can preserve clinically relevant HFO biomarkers and their spatial fidelity without reproducing every individual electrophysiological event. More broadly, this work establishes a translational framework for chronic tracking of evolving epileptogenic networks and future biomarker-guided adaptive neuromodulation.

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 For implantable closed loop neuromodulation systems, real-time neural sensing, biomarker detection, and targeted stimulation are essential components for delivering personalized therapy. Current limitations in sampling rate and the number of available recording channels in implantable systems may pose significant challenges, especially in epilepsy research where high-frequency biomarkers and multi-site monitoring are essential. The Brain Interchange (BIC) system of CorTec is an externally powered, wireless implantable system that enables sensing and stimulation up to 32 channels at 1 kHz addressing the current limitations in the field. In this study, we present a modular closed loop neuromodulation environment developed for the BIC, enabling real-time data streaming, event detection, and flexible stimulation control. The framework integrates a Simulink-based processing pipeline, real-time communication, and a graphical user interface supporting both open and closed loop paradigms. System performance was evaluated through impedance measurement, latency assessment across three stimulation modes, and real-time closed loop stimulation using electrocardiogram (ECG) for in-lab demonstration. This modular environment provides a flexible platform for developing and validating neuromodulation algorithms and can be extended to incorporate advanced biomarker detection and multi-channel neural interfaces for future clinical research.