A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.

Learning Curves during Implementation of Robotic Stereotactic Surgery.

INTRODUCTION: Adoption of robotic techniques is increasing for neurosurgical applications. Common cranial applications include stereoelectroencephalography (sEEG) and deep brain stimulation (DBS). For surgeons to implement robotic techniques in these procedures, realistic learning curves must be anticipated for surgeons to overcome the challenges of integrating new techniques into surgical workflow. One such way of quantifying learning curves in surgery is cumulative sum (CUSUM) analysis. METHODS: Here, the authors present retrospective review of stereotactic cases to perform a CUSUM analysis of operative time for robotic cases at a single institution performed by 2 surgeons. The authors demonstrate learning phase durations of 20 and 16 cases in DBS and sEEG, respectively. RESULTS: After plateauing of operative time, mastery phases started at cases 132 and 72 in DBS and sEEG. A total of 273 cases (188 DBS and 85 sEEG) were included in the study. The authors observed a learning plateau concordant with change of location of surgery after exiting the learning phase. CONCLUSION: This study demonstrates the learning curve of 2 stereotactic workflows when integrating robotics as well as being the first study to examine the robotic learning curve in DBS via CUSUM analysis. This work provides data on what surgeons may expect when integrating this technology into their practice for cranial applications.

Thoracic canal morphology on preoperative magnetic resonance imaging in spinal cord stimulation patients.

INTRODUCTION: In high-frequency spinal cord stimulation anatomic placement targeting of the T9-10 disc space is based on "empiric" results that are best replicated with coverage broadly from T8 to T10. This study contains the largest cohort of patients evaluating low thoracic morphology and seeks to address the lack of MRI morphological analysis in literature. METHODS: This study was a retrospective review of a database of 101 consecutive patients undergoing permanent implant of thoracic SCS for chronic pain. Measurements were carried out on preoperative MRI imaging. Anteroposterior (AP) and lateral dimensions of the spinal cord as well as dural sac were measured. In addition, dorsal cerebrospinal fluid thickness and paddle depression distance were also measured. RESULTS: When comparing morphological dimensions by level, dorsal CSF thickness was smaller at T9-10 than T7-8 (p = 0.018). In addition, lateral dural and spinal cord diameters were larger at T10-11 than T9-10, contributing to larger dural surface area at T10-11 (p = 0.028). While trends of dorsal CSF thickness tend to decrease with lower thoracic levels, the ratio of surface area of spinal cord to dural sac appeared to remain relatively constant. CONCLUSIONS: Dorsal CSF thickness is smaller at T9-10 than T7-8 in chronic pain patients in this cohort. More ellipsoid, cord, and spinal canal diameter measurements were noted at lower levels of the thoracic spinal cord, particularly at T10-11. This may correlate with anatomical SCS placement. Future studies should evaluate efficacy of SCS therapy for pain based on these anatomical considerations.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Stimulation better targets fast-ripple generating networks in super responders to the responsive neurostimulator system.

How responsive neurostimulation (RNS) decreases seizure frequency is unclear. Stimulation may alter epileptic networks during inter-ictal epochs. Definitions of the epileptic network vary but fast ripples (FRs) may be an important substrate. We, therefore, examined whether stimulation of FR-generating networks differed in RNS super responders and intermediate responders. In 10 patients, with subsequent RNS placement, we detected FRs from stereo-electroencephalography (SEEG) contacts during pre-surgical evaluation. The normalized coordinates of the SEEG contacts were compared with those of the eight RNS contacts, and RNS-stimulated SEEG contacts were defined as those within 1.5 cm3 of the RNS contacts. We compared the post-RNS placement seizure outcome to (1) the ratio of stimulated SEEG contacts in the seizure-onset zone (SOZ stimulation ratio [SR]); (2) the ratio of FR events on stimulated contacts (FR SR); and (3) the global efficiency of the FR temporal correlational network on stimulated contacts (FR SGe). We found that the SOZ SR (p = .18) and FR SR (p = .06) did not differ in the RNS super responders and intermediate responders, but the FR SGe did (p = .02). In super responders, highly active desynchronous sites of the FR network were stimulated. RNS that better targets FR networks, as compared to the SOZ, may reduce epileptogenicity more.

Exoscope improves visualization and extent of hippocampal resection in temporal lobectomy.

INTRODUCTION: Anterior temporal lobectomy (ATL) is a safe and well-validated procedure in the treatment of temporal lobe epilepsy (TLE), but is a challenging technique to master and still confers a risk of morbidity and mortality due to the complex anatomy of the mesial temporal lobe structures. Automated robotic 3D exoscopes have been developed to address limitations traditionally associated with microscopic visualization, allowing for ergonomic, high-definition 3D visualization with hands-free control of the robot. Given the potential advantages of using such a system for visualization of complex anatomy seen during mesial structure resection in ATL, this group sought to investigate impact on the percentage of hippocampal resection in both exoscope and microscope guided procedures. METHODS: We conducted a retrospective analysis of 20 consecutive patients undergoing standard ATL for treatment of medically refractory TLE at our institution. Using pre-operative and post-operative imaging, the coronal plane cuts in which either the head, body, or tail of the hippocampus appeared were counted. The number of cuts in which the hippocampus appeared were multiplied by slice thickness to estimate hippocampal length. RESULTS: Mean percentage of hippocampal resection was 61.1 (SD 13.1) and 76.5 (SD 6.5) for microscope and exoscope visualization, respectively (p = 0.0037). CONCLUSION: Use of exoscope for mesial resection during ATL has provided good visualization for those in the operating room and the potential for a safe increase in hippocampal resection in our series. Further investigation of its applications should be evaluated to see if it will improve outcomes.

Delta oscillation coupled propagating fast ripples precede epileptiform discharges in patients with focal epilepsy.

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p < 0.05). Propagating FR had a distinct frequency and larger power (p < 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p < 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p < 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep.

Single-Center Retrospective Analysis of Device-Related Complications Related to Dorsal Root Ganglion Stimulation for Pain Relief in 31 Patients.

INTRODUCTION: Dorsal root ganglion (DRG) stimulation is a form of neuromodulation used to treat neuropathic pain due to a myriad of etiologies. Though this relatively new therapy has been shown to be quite effective, complications associated with the implantation of this therapy have not been well documented. OBJECTIVES: The primary objective of this study was to describe the device-related complications associated with DRG stimulator implantations. MATERIALS AND METHODS: This was a single-center retrospective analysis of 31 patients who underwent full implantation of neuromodulation hardware marketed for DRG stimulation. The predefined endpoints included device-related complications associated with DRG implantations, such as hardware failure, explantation procedures, and revision surgery. Additional endpoints included percentage of patients receiving therapy and pain as measured using the visual analog scale (VAS) pain scale at initial, six-month, and 12-month follow-up after hardware implantation. RESULTS: Thirty-one patients were included out of 42 patients trialed. Baseline VAS in patients was 7.7 (31 patients). At initial follow-up, six-month follow-up, and one-year follow-up, VAS scores were 4.7 (31 patients), 5.3 (20 patients), and 5.5 (13 patients), respectively. Paired t-test between preoperative VAS (mean 7.3) and one-year follow-up VAS (5.5) demonstrated statistical significance (p = 0.027). At initial, six-month, and one-year follow-up, 30/31 (97%), 19/24 (79%), and 18/23 (78%) patients were confirmed to be receiving DRG stimulation therapy after permanent implant. Of the 31 patients who were implanted with a permanent system, 8 (26%) were explanted and an additional 10 (29%) required revision surgery. CONCLUSION: In this study, we examine the various device-related complications associated with DRG stimulation requiring repeat surgery. High rates of hardware failure, revision surgery, and explantation of stimulators illustrate the need for hardware optimization to improve patient outcomes.

Reactivated Spatial Context Guides Episodic Recall.

The medial temporal lobe (MTL) is known as the locus of spatial coding and episodic memory, but the interaction between these cognitive domains as well as the extent to which they rely on common neurophysiological mechanisms is poorly understood. Here, we use intracranial electroencephalography and a hybrid spatial-episodic memory task (29 subjects, 15 female) to determine how spatial information is dynamically reactivated in subregions of the human MTL and how this reactivation guides recall of episodic information. Our results implicate theta oscillations across the MTL as a common neurophysiological substrate for spatial coding in navigation and episodic recall. We further show that our index of retrieved spatial context is high in the hippocampus (HC) in an early time window preceding recall. Closer to recall, it decreases in the HC and increases in the parahippocampal gyrus. Finally, we demonstrate that hippocampal theta phase modulates parahippocampal gamma amplitude during retrieval of spatial context, suggesting a role for cross-frequency coupling in coding and transmitting retrieved spatial information.SIGNIFICANCE STATEMENT By recording from the human medial temporal lobe (MTL) while subjects recall items experienced in a virtual environment, we establish a direct relation between the strength of theta activity during memory search and the extent to which memories are organized by their spatial locations. We thereby pinpoint a role for theta oscillations in accessing the "cognitive map" during episodic retrieval and further highlight the dynamic interplay of hippocampus and extrahippocampal MTL in representing retrieved spatial context. Our results provide an important step toward a unified theory of MTL function encompassing its role in spatial navigation and episodic memory.

Contribution of left supramarginal and angular gyri to episodic memory encoding: An intracranial EEG study.

The role of the left ventral lateral parietal cortex (VPC) in episodic memory is hypothesized to include bottom-up attentional orienting to recalled items, according to the dual-attention model (Cabeza et al., 2008). However, its role in memory encoding could be further clarified, with studies showing both positive and negative subsequent memory effects (SMEs). Furthermore, few studies have compared the relative contributions of sub-regions in this functionally heterogeneous area, specifically the anterior VPC (supramarginal gyrus/BA40) and the posterior VPC (angular gyrus/BA39), on a within-subject basis. To elucidate the role of the VPC in episodic encoding, we compared SMEs in the intracranial EEG across multiple frequency bands in the supramarginal gyrus (SmG) and angular gyrus (AnG), as twenty-four epilepsy patients with indwelling electrodes performed a free recall task. We found a significant SME of decreased theta power and increased high gamma power in the VPC overall, and specifically in the SmG. Furthermore, SmG exhibited significantly greater spectral tilt SME from 0.5 to 1.6 s post-stimulus, in which power spectra slope differences between recalled and unrecalled words were greater than in the AnG (p = 0.04). These results affirm the contribution of VPC to episodic memory encoding, and suggest an anterior-posterior dissociation within VPC with respect to its electrophysiological underpinnings.

Consequences of mesial temporal sparing temporal lobe surgery in medically refractory epilepsy.

OBJECTIVE: We compared long-term seizure outcome, neuropsychological outcome, and occupational outcome of anterior temporal lobectomy (ATL) with and without sparing of mesial structures to determine whether mesial sparing temporal lobectomy prevents memory decline and thus disability, with acceptable seizure outcome. METHODS: We studied patients (n = 21) and controls (n = 21) with no evidence of mesial temporal sclerosis (MTS) on MRI who had surgery to treat drug-resistant epilepsy. Demographic and pre- and postsurgical clinical characteristics were compared. Patients had neuropsychological assessment before and after surgery. Neuropsychological analyses were limited to patients with left-sided surgery and available data (n = 14 in each group) as they were at risk of verbal memory impairment. The California Verbal Learning Test II (CVLT-II) (sum of trials 1-5, delayed free recall) and the Logical Memory subtest of the Wechsler Memory Scale III or IV (WMS-III or WMS-IV) (learning and delayed recall of prose passages) were used to assess verbal episodic learning and memory. Seizure and occupational outcomes were assessed. RESULTS: The chance of attaining seizure freedom was similar in the two groups, so sparing mesial temporal structures did not lessen the chance of stopping seizures. Sparing mesial temporal structures mitigated the extent of postoperative verbal memory impairment, though some of these individuals suffered decline as a consequence of surgery. Occupational outcome was similar in both groups. SIGNIFICANCE: Mesial temporal sparing resections provide a similar seizure outcome as ATL, while producing a better memory outcome. Anterior temporal lobectomy including mesial structure resection did not increase the risk of postoperative disability.

Implantable Pulse Generator Site May Be Associated With Spinal Cord Stimulation Revision Surgeries.

BACKGROUND: The use of implantable pulse generators (IPG) for spinal cord stimulation (SCS) in patients with chronic pain has been well established. Although IPG-related complications have been reported on, the association between IPG site and SCS complications has not been well studied. OBJECTIVE: To investigate whether IPG placement site in buttock or flank is associated with SCS complications and, hence, revision surgeries. METHOD: A retrospective cohort study was performed that included 330 patients (52% female) treated at a single institution who underwent permanent implantation of an SCS system between 2014 and 2018. Patients ranged between 20 and 94 years of age (mean: 57.54 ± 13.25). Statistical analyses were conducted using IBM SPSS Statistics. Tests included independent samples t test, chi-square test, Mann-Whitney U test, Spearman's rank correlation coefficient, and logistic regression. RESULTS: There was a total of 93 revision surgeries (rate of 28%), where 71 out of 330 patients (rate of 21.5%) had had at least one revision surgery. Univariate tests demonstrated a significant association between IPG site and revision surgeries (p = 0.028 [chi-square test] and p = 0.031 [Mann-Whitney U test]); however, multivariate logistic regression demonstrated that neither IPG site was more likely than the other to require revision surgeries (p = 0.286). CONCLUSION: Although this study found a significant association between IPG site and revision surgeries, the effect of IPG site was not found to be predictive. The IPG site likely influences whether a patient will require revision surgery, but further investigation is required to establish this association.

How technology is driving the landscape of epilepsy surgery.

This article emphasizes the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high-intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereo-electroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; (c) addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high case load, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open-loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering the acoustic energy, further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap.

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one's own body.SIGNIFICANCE STATEMENT Spatial computations using environmental boundaries are an integral part of the brain's spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to functional neuroimaging studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions, we identified a neural marker of boundary representation in the human subiculum.

Electrical Stimulation in Hippocampus and Entorhinal Cortex Impairs Spatial and Temporal Memory.

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.SIGNIFICANCE STATEMENT Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

Neuronal phase consistency tracks dynamic changes in acoustic spectral regularity.

The brain parses the auditory environment into distinct sounds by identifying those acoustic features in the environment that have common relationships (e.g., spectral regularities) with one another and then grouping together the neuronal representations of these features. Although there is a large literature that tests how the brain tracks spectral regularities that are predictable, it is not known how the auditory system tracks spectral regularities that are not predictable and that change dynamically over time. Furthermore, the contribution of brain regions downstream of the auditory cortex to the coding of spectral regularity is unknown. Here, we addressed these two issues by recording electrocorticographic activity, while human patients listened to tone-burst sequences with dynamically varying spectral regularities, and identified potential neuronal mechanisms of the analysis of spectral regularities throughout the brain. We found that the degree of oscillatory stimulus phase consistency (PC) in multiple neuronal-frequency bands tracked spectral regularity. In particular, PC in the delta-frequency band seemed to be the best indicator of spectral regularity. We also found that these regularity representations existed in multiple regions throughout cortex. This widespread reliable modulation in PC - both in neuronal-frequency space and in cortical space - suggests that phase-based modulations may be a general mechanism for tracking regularity in the auditory system specifically and other sensory systems more generally. Our findings also support a general role for the delta-frequency band in processing the regularity of auditory stimuli.

Low-voltage fast seizures in humans begin with increased interneuron firing.

OBJECTIVE: Intracellular recordings from cells in entorhinal cortex tissue slices show that low-voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial-temporal LVF seizures recorded in patients. METHODS: The seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single-unit activity during the onset of LVF seizures recorded from microelectrodes in mesial-temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K-means clustering. RESULTS: From a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial-temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p < 0.01). Excitatory neuron firing rates peaked 10 seconds after the inhibitory neurons (p < 0.01). During LVF spread to the contralateral mesial temporal lobe, an increase in inhibitory neuron firing rate was also observed (p < 0.01). INTERPRETATION: Our results suggest that seizure generation and spread during spontaneous mesial-temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution. Ann Neurol 2018;84:588-600.

Multicenter validation of automated trajectories for selective laser amygdalohippocampectomy.

OBJECTIVE: Laser interstitial thermal therapy (LITT) is a novel minimally invasive alternative to open mesial temporal resection in drug-resistant mesial temporal lobe epilepsy (MTLE). The safety and efficacy of the procedure are dependent on the preplanned trajectory and the extent of the planned ablation achieved. Ablation of the mesial hippocampal head has been suggested to be an independent predictor of seizure freedom, whereas sparing of collateral structures is thought to result in improved neuropsychological outcomes. We aim to validate an automated trajectory planning platform against manually planned trajectories to objectively standardize the process. METHODS: Using the EpiNav platform, we compare automated trajectory planning parameters derived from expert opinion and machine learning to undertake a multicenter validation against manually planned and implemented trajectories in 95 patients with MTLE. We estimate ablation volumes of regions of interest and quantify the size of the avascular corridor through the use of a risk score as a marker of safety. We also undertake blinded external expert feasibility and preference ratings. RESULTS: Automated trajectory planning employs complex algorithms to maximize ablation of the mesial hippocampal head and amygdala, while sparing the parahippocampal gyrus. Automated trajectories resulted in significantly lower calculated risk scores and greater amygdala ablation percentage, whereas overall hippocampal ablation percentage did not differ significantly. In addition, estimated damage to collateral structures was reduced. Blinded external expert raters were significantly more likely to prefer automated to manually planned trajectories. SIGNIFICANCE: Retrospective studies of automated trajectory planning show much promise in improving safety parameters and ablation volumes during LITT for MTLE. Multicenter validation provides evidence that the algorithm is robust, and blinded external expert ratings indicate that the trajectories are clinically feasible. Prospective validation studies are now required to determine if automated trajectories translate into improved seizure freedom rates and reduced neuropsychological deficits.

Effects of surgical targeting in laser interstitial thermal therapy for mesial temporal lobe epilepsy: A multicenter study of 234 patients.

OBJECTIVE: Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78% with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited three-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE. METHODS: This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively. RESULTS: Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome. SIGNIFICANCE: LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control.

First-in-human implantation of a mid-field powered neurostimulator at the sacral nerve: Results from an acute study.

INTRODUCTION: Commercially approved implantable systems for sacral neuromodulation require the implantation of a multipolar lead subcutaneously connected to an implantable pulse generator (IPG). Eliminating the need for an IPG would eliminate the need for tunneling of the lead, reduce procedure time, infection risk, and the need for IPG replacement. The objective was to demonstrate the feasibility of implanting the AHLeveeS System in the S3 Foramen to stimulate the S3 sacral nerve. MATERIALS AND METHODS: A first-in-human, prospective, single center, nonrandomized, acute feasibility clinical investigation at the Maastricht University Medical Center+. Patients with refractory overactive bladder underwent acute implantation of the AHLeveeS neurostimulator before the InterStim procedure. Outcome measurements included motor responses, procedural time and a scoring of the difficulty of the implant and explant procedure. Retrospectively, qualitative responses to the stimulation protocol were assessed by video motion analyses. Only descriptive statistics were used. RESULTS: During the stimulation a motor response to stimulation was seen in four of the five subjects. In all implantations the AHLeveeS was correctly placed. The median time for complete procedure was 24 minutes. The implant and explant procedures were successfully performed and no device or procedure related adverse events occurred. CONCLUSIONS: The results from this acute first-in-human study demonstrate the feasibility of implantation and acute stimulation of the sacral nerve with this mid-field powered system. Future clinical studies will focus on safety and efficacy of a chronically implanted device.