Oculomotor nerve cavernous malformation: case report and operative video.

BACKGROUND: Cavernous malformations (CMs) are clusters of thin-walled sinusoidal vessels without well-defined walls. Though they can occur anywhere in the neuroaxis, cranial nerve (CN) CMs are rare. METHOD: We report a 47-year-old male with gradual CN III palsy. Initial imaging showed no significant findings, but a follow-up MRI revealed a growing lesion along CN III. Intraoperative findings confirmed a CN III CM. Diagnosing and treating CN III CM are complex. Radiological findings lack specificity, requiring consideration of various diagnoses for patients with isolated CN III palsy and abnormal radiological findings. CONCLUSION: Surgery is the gold standard, aiming for complete lesion removal while minimizing neurological complications.

Evidence supporting deep brain stimulation of the medial septum in the treatment of temporal lobe epilepsy.

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial.

Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity.

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space.Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters.Main results.We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly 'artificial' (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity.Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization.

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson's disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico ( p < 0.0056 , N = 1000 ) and in vivo ( p = 0.0036 , N = 20 ) . This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization.

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson's disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico (p<0.0056, N=1,000) and in vivo (p=0.0036, N=20). This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

Identifying the Sources of Racial Disparity in the Treatment of Parkinson's Disease With Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficacious treatment for appropriately selected patients with advanced, medically refractory Parkinson's disease (PD). It is severely underutilized in Black patients-constituting a major treatment gap. The source of this disparity is unknown, but its identification and correction are necessary to provide equitable care. OBJECTIVE: To identify sources of racial disparity in DBS for PD. METHODS: We predicted the demographics of potential DBS candidates by synthesizing published data on PD and race. We retrospectively examined the clinical course of a cohort including all patients with PD evaluated for DBS at our center from 2016 to 2020, testing whether the rate of DBS use and time from evaluation to surgery differed by race. We also tested whether the geographic distribution of patient catchment was biased relative to racial demographics. RESULTS: Far fewer Black patients were evaluated for DBS than would be expected, given regional demographics. There was no significant difference in the rate at which Black patients evaluated in our clinic were treated with DBS, compared with White patients. Fewer patients were recruited from portions of the surrounding area with larger Black populations. CONCLUSION: The known underuse of DBS in Black patients with PD was replicated in this sample from a center in a racially diverse metropolitan area, but was not attributable to the presurgical workup. Future work should examine the transition from medical management to surgical evaluation where drivers of disparity are potentially situated. Surgical practices should increase outreach to physicians managing PD in underserved areas.

Complication rate of overlapping versus nonoverlapping functional and stereotactic surgery: a retrospective cohort study.

OBJECTIVE: Overlapping surgery, in which one attending surgeon manages two overlapping operating rooms (ORs) and is present for all the critical portions of each procedure, is an important policy that improves healthcare access for patients and case volumes for surgeons and surgical trainees. Despite several studies demonstrating the safety and efficacy of overlapping neurosurgical operations, the practice of overlapping surgery remains controversial. To date, there are no studies that have investigated long-term complication rates of overlapping functional and stereotactic neurosurgical procedures. The primary objective of this study was to investigate the 1-year complication rates and OR times for nonoverlapping versus overlapping functional procedures. The secondary objective was to gain insight into what types of complications are the most prevalent and test for differences between groups. METHODS: Seven hundred eighty-three functional neurosurgical cases were divided into two cohorts, nonoverlapping (n = 342) and overlapping (n = 441). The American Society of Anesthesiologists (ASA) scale score was used to compare the preoperative risk for both cohorts. A complication was defined as any surgically related reason that required readmission, reoperation, or an unplanned emergency department or clinic visit that required intervention. Complications were subdivided into infectious and noninfectious. Chi-square tests, independent-samples t-tests, and uni- and multivariable logistic regressions were used to determine significance. RESULTS: There were no significant differences in mean ASA scale score (2.7 ± 0.6 for both groups, p = 0.997) or overall complication rates (8.8% nonoverlapping vs 9.8% overlapping, p = 0.641) between the two cohorts. Infections accounted for the highest percentage of complications in both cohorts (46.6% vs 41.8%, p = 0.686). There were no statistically significant differences between mean in-room OR time (187.5 ± 141.7 minutes vs 197.1 ± 153.0 minutes, p = 0.373) or mean open-to-close time (112.2 ± 107.9 minutes vs 121.0 ± 123.1 minutes, p = 0.300) between nonoverlapping and overlapping cases. CONCLUSIONS: There was no increased risk of 1-year complications or increased OR time for overlapping functional and stereotactic neurosurgical procedures compared with nonoverlapping procedures.

Utility of ventriculogallbladder shunts in complex cases of hydrocephalus related to extreme prematurity.

OBJECTIVE: The management of hydrocephalus resulting from intraventricular hemorrhage related to extreme prematurity remains demanding. Given the complexities of controlling hydrocephalus in this population, less commonly used procedures may be required. The authors examined the utility of ventriculogallbladder (VGB) shunts in a series of such children. METHODS: The authors retrospectively reviewed the medical records of all children who underwent surgery for hydrocephalus in the period from 2011 through 2019 at Children's Healthcare of Atlanta. Six patients who underwent VGB shunt placement were identified among a larger cohort of 609 patients who had either a new shunt or a newly changed distal terminus site. The authors present an analysis of this series, including a case of laparoscopy-assisted distal VGB shunt revision. RESULTS: The mean age at initial shunt placement was 5.1 months (range 3.0-9.4 months), with patients undergoing a mean of 11.8 shunt procedures (range 5-17) prior to the initial VGB shunt placement at a mean age of 5.3 years (range 7.9 months-12.8 years). All 6 patients with VGB shunt placement had hydrocephalus related to extreme prematurity (gestational age < 28 weeks). At the time of VGB shunt placement, all had complex medical and surgical histories, including poor venous access due to congenital or iatrogenic thrombosis or thrombophlebitis and a peritoneum hostile to distal shunt placement related to severe necrotizing enterocolitis. VGB complications included 1 case of shunt infection, identified at postoperative day 6, and 2 cases of distal shunt failure due to retraction of the distal end of the VGB shunt. In all, there were 3 conversions back to ventriculoperitoneal or ventriculoatrial shunts due to the 2 previously mentioned complications, plus 1 patient who outgrew their initial VGB shunt. Three of 6 patients remain with a VGB shunt, including 1 who underwent laparoscopy-assisted distal shunt revision 110.5 months after initial VGB shunt insertion. CONCLUSIONS: Placement of VGB shunts should be considered in the armamentarium of procedures that may be used in the particularly difficult cohort of children with hydrocephalus related to extreme prematurity. VGB shunts show utility as both a definitive treatment and as a "bridge" procedure until the patient is larger and comorbid abdominal and/or vascular issues have resolved sufficiently to allow conversion back to ventriculoperitoneal or ventriculoatrial shunts, if needed.

A framework for designing data-driven optimization systems for neural modulation.

Objective.Neural modulation is a fundamental tool for understanding and treating neurological and psychiatric diseases. However, due to the high-dimensional space, subject-specific responses, and variability within each subject, it is a major challenge to select the stimulation parameters that have the desired effect. Data-driven optimization provides a range of different algorithms and tools for addressing this challenge, but each of these algorithms has specific strengths and limitations, and therefore must be carefully designed for a given neural modulation problem. Here we present a framework for designing data-driven optimization algorithms for neural modulation.Approach.We develop this framework using an optogenetic medial septum stimulation model, where the goal is to find the stimulation parameters that modulate hippocampal gamma power to a desired value. This framework proceeds in four steps: (a) collecting stimulation data, (b) creating high-throughput simulation models, (c) prototyping a range of different data-driven optimization algorithms and evaluating their performance, and (d) deploying the best performing algorithmin vivo. Main results.Following this framework, we prototype and design an algorithm specifically for finding the medial septum optogenetic stimulation parameters that maximize hippocampal gamma power. Building on this, we then change our objective function to find the stimulation parameters that modulate gamma to a specific setpoint, use the framework to understand and anticipate the results before deployingin vivo. Significance.We show that this framework can be used to design an effective optimization solution for a specific neural modulation problem, and discuss how it can potentially be applied beyond the optogenetic medial septum stimulation model.

Spontaneous and evoked high-frequency oscillations in the tetanus toxin model of epilepsy.

PURPOSE: High-frequency oscillations (HFOs) are an emerging biomarker for epileptic tissue. Yet the mechanism by which HFOs are produced is unknown, and their rarity makes them difficult to study. Our objective was to examine the occurrence of HFOs in relation to action potentials (APs) and the effect of microstimulation in the tetanus toxin (TT) model of epilepsy, a nonlesional model with a short latency to spontaneous seizures. METHODS: Rats were injected with TT into dorsal hippocampus and implanted with a 16-channel (8 × 2) multielectrode array, one row each in CA3 and CA1. After onset of spontaneous seizures (3-9 days), recordings were begun of APs and local field potentials, analyzed for the occurrence of interictal spikes and HFOs. Recordings were made during microstimulation of each electrode using customized, open-source software. RESULTS: Population bursts of APs during interictal spikes were phase-locked with HFOs, which were observable almost exclusively with high-amplitude interictal spikes. Furthermore, HFOs could reliably be produced by microstimulation of the hippocampus, providing evidence that these oscillations can be controlled temporally by external means. DISCUSSION: We show for the first time the occurrence of HFOs in the TT epilepsy model, an attractive preparation for their experimental investigation and, importantly, one with a different etiology than that of status models, providing further evidence of the generality of HFOs. The ability to provoke HFOs with microstimulation may prove useful for better understanding of HFOs by directly evoking them in the lab, and designing high-throughput techniques for presurgical localization of the epileptic focus.

Endovascular sacrifice of the proximal posterior inferior cerebellar artery for treatment of ruptured intracranial aneurysms.

BACKGROUND: Ruptured aneurysms of the intracranial vertebral artery (VA) or posterior inferior cerebellar artery (PICA) are challenging to treat as they are often dissecting aneurysms necessitating direct sacrifice of the diseased segment, which is thought to carry high morbidity due to brainstem and cerebellar stroke. However, relatively few studies evaluating outcomes following VA or proximal PICA sacrifice exist. We sought to determine the efficacy and outcomes of endovascular VA/PICA sacrifice. METHODS: A retrospective series of ruptured VA/PICA aneurysms treated by endovascular sacrifice of the VA (including the PICA origin) or proximal PICA is reviewed. Collected data included demographic, radiologic, clinical, and disability information. RESULTS: Twenty-one patients were identified. Median age was 57 years (IQR 11); 15 were female. The Hunt and Hess grade was mostly 3 and 4 (18/21). Seven cases (33%) involved VA-V4 at the PICA take-off, and 14 cases (67%) involved the PICA exclusively. For VA pathology, V4 was sacrificed in all cases, while for PICA pathology, sacrificed segments included anterior medullary (4/14), lateral medullary (7/14), and tonsillomedullary (3/14) segments. Four patients went to hospice (19%). Twelve patients (57%) had evidence of stroke on follow-up imaging: cerebellar (8), medullary (1), and both (3). One patient required suboccipital decompression for brainstem compression. No aneurysm re-rupture occurred. Median discharge modified Rankin Scale score was 2.0 (IQR 2), which decreased to 1.0 (IQR 1) at median follow-up of 6.5 months (IQR 23). CONCLUSIONS: Endovascular sacrifice of V4 or PICA aneurysms may carry less morbidity than previously thought, and is a viable alternative for poor surgical candidates or those with good collateral perfusion.

Accuracy of frameless image-guided implantation of depth electrodes for intracranial epilepsy monitoring.

OBJECTIVE: Various techniques are available for stereotactic implantation of depth electrodes for intracranial epilepsy monitoring. The goal of this study was to evaluate the accuracy and effectiveness of frameless MRI-guided depth electrode implantation. METHODS: Using a frameless MRI-guided stereotactic approach (Stealth), depth electrodes were implanted in patients via burr holes or craniotomy, mostly into the medial temporal lobe. In all cases in which it was possible, postoperative MR images were coregistered to planning MR images containing the marked targets for quantitative analysis of intended versus actual location of each electrode tip. In the subset of MR images done with sufficient resolution, qualitative assessment of anatomical accuracy was performed. Finally, the effectiveness of implanted electrodes for identifying seizure onset was retrospectively examined. RESULTS: Sixty-eight patients underwent frameless implantation of 413 depth electrodes (96% to mesial temporal structures) via burr holes by one surgeon at 2 institutions. In 36 patients (203 electrodes) planning and postoperative MR images were available for quantitative analysis; an additional 8 procedures with 19 electrodes implanted via craniotomy for grid were also available for quantitative analysis. The median distance between intended target and actual tip location was 5.19 mm (mean 6.19 ± 4.13 mm, range < 2 mm-29.4 mm). Inaccuracy for transtemporal depths was greater along the electrode (i.e., deep), and posterior, whereas electrodes inserted via an occipital entry deviated radially. Failure to localize seizure onset did not result from implantation inaccuracy, although 2 of 62 patients (3.2%)-both with electrodes inserted occipitally-required reoperation. Complications were mostly transient, but resulted in long-term deficit in 2 of 68 patients (3%). CONCLUSIONS: Despite modest accuracy, frameless depth electrode implantation was sufficient for seizure localization in the medial temporal lobe when using the orthogonal approach, but may not be adequate for occipital trajectories.

A Machine Learning Approach to Characterize the Modulation of the Hippocampal Rhythms Via Optogenetic Stimulation of the Medial Septum.

The medial septum (MS) is a potential target for modulating hippocampal activity. However, given the multiple cell types involved, the changes in hippocampal neural activity induced by MS stimulation have not yet been fully characterized. We combined MS optogenetic stimulation with local field potential (LFP) recordings from the hippocampus and leveraged machine learning techniques to explore how activating or inhibiting multiple MS neuronal subpopulations using different optical stimulation parameters affects hippocampal LFP biomarkers. First, of the seven different optogenetic viral vectors used for modulating different neuronal subpopulations, only two induced a substantial change in hippocampal LFP. Second, we found hippocampal low-gamma band to be most effectively modulated by the stimulation. Third, the hippocampal biomarkers were sensitive to the optogenetic virus type and the stimulation frequency, establishing those parameters as the critical ones for the regulation of hippocampal biomarker activity. Last, we built a Gaussian process regression model to describe the relationship between stimulation parameters and activity of the biomarker as well as to identify the optimal parameters for biomarker modulation. This new machine learning approach can further our understanding of the effects of neural stimulation and guide the selection of optimal parameters for neural control.

Predicting the stimulation effectiveness using pre-stimulation neural states via optogenetic activation of the medial septum glutamatergic neurons modulating the hippocampal neural activity.

In this study, we explored the role of pre-stimulation neural states on the effectiveness of optogenetic stimulation. Optogenetic stimulation was applied to the medial septum glutamatergic neurons to modulate the hippocampal neural activity in a rat tetanus toxin seizure model. The hippocampal local field potential was recorded using a multi electrode array in an awake and behaving rat. Optical stimulation with a 465nm light source was applied at 35Hz in a 20 seconds off / 20 seconds on pattern with simultaneous recording from the hippocampus. Both the baseline and the stimulation period recordings were divided into 2 second segments and used for the further analysis. In the first experiment, a support vector machine (SVM) model classified the neural states by using spectral features between 0 and 50Hz. 447 out of 545 segments (82.02%) were correctly labeled as `Baseline' while only 326 out of 544 (59.93%) segments from the stimulation period were correctly labeled as `Stimulation.' As the ratio of mislabels is significantly higher for the stimulation period (chi-squared, p<;0.01), we concluded that the stimulation was not always effective. In the second experiment, an SVM model predicted the stimulation effectiveness using the spectral features of the pre-stimulation segments. The classification result shows that 63.7% of the pre-stimulation segments correctly predicted the stimulation effectiveness. These findings suggest that the prediction of the stimulation effectiveness may improve the stimulation efficacy by implementing a state-based stimulation protocol.

Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials.

Deep brain stimulation (DBS) has proven remarkably safe and effective in the treatment of movement disorders. As a result, it is being increasingly applied to a range of neurologic and psychiatric disorders, including medically refractory epilepsy. This review will examine the use of DBS in epilepsy, including known targets, mechanisms of neuromodulation and seizure control, published clinical evidence, and novel technologies. Cortical and deep neuromodulation for epilepsy has a long experimental history, but only recently have better understanding of epileptogenic networks, precise stereotactic techniques, and rigorous trial design combined to improve the quality of available evidence and make DBS a viable treatment option. Nonetheless, underlying mechanisms, anatomical targets, and stimulation parameters remain areas of active investigation.

Real-time in vivo optogenetic neuromodulation and multielectrode electrophysiologic recording with NeuroRighter.

Optogenetic channels have greatly expanded neuroscience's experimental capabilities, enabling precise genetic targeting and manipulation of neuron subpopulations in awake and behaving animals. However, many barriers to entry remain for this technology - including low-cost and effective hardware for combined optical stimulation and electrophysiologic recording. To address this, we adapted the open-source NeuroRighter multichannel electrophysiology platform for use in awake and behaving rodents in both open and closed-loop stimulation experiments. Here, we present these cost-effective adaptations, including commercially available LED light sources; custom-made optical ferrules; 3D printed ferrule hardware and software to calibrate and standardize output intensity; and modifications to commercially available electrode arrays enabling stimulation proximally and distally to the recording target. We then demonstrate the capabilities and versatility of these adaptations in several open and closed-loop experiments, demonstrate spectrographic methods of analyzing the results, as well as discuss artifacts of stimulation.

Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy.

BACKGROUND: Open surgery effectively treats mesial temporal lobe epilepsy, but carries the risk of neurocognitive deficits, which may be reduced with minimally invasive alternatives. OBJECTIVE: To describe technical and clinical outcomes of stereotactic laser amygdalohippocampotomy with real-time magnetic resonance thermal imaging guidance. METHODS: With patients under general anesthesia and using standard stereotactic methods, 13 adult patients with intractable mesial temporal lobe epilepsy (with and without mesial temporal sclerosis [MTS]) prospectively underwent insertion of a saline-cooled fiberoptic laser applicator in amygdalohippocampal structures from an occipital trajectory. Computer-controlled laser ablation was performed during continuous magnetic resonance thermal imaging followed by confirmatory contrast-enhanced anatomic imaging and volumetric reconstruction. Clinical outcomes were determined from seizure diaries. RESULTS: A mean 60% volume of the amygdalohippocampal complex was ablated in 13 patients (9 with MTS) undergoing 15 procedures. Median hospitalization was 1 day. With follow-up ranging from 5 to 26 months (median, 14 months), 77% (10/13) of patients achieved meaningful seizure reduction, of whom 54% (7/13) were free of disabling seizures. Of patients with preoperative MTS, 67% (6/9) achieved seizure freedom. All recurrences were observed before 6 months. Variances in ablation volume and length did not account for individual clinical outcomes. Although no complications of laser therapy itself were observed, 1 significant complication, a visual field defect, resulted from deviated insertion of a stereotactic aligning rod, which was corrected before ablation. CONCLUSION: Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy is a technically novel, safe, and effective alternative to open surgery. Further evaluation with larger cohorts over time is warranted.