Interictal epileptiform discharges affect memory in an Alzheimer's disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.

Current application of cannabidiol (CBD) in the management and treatment of neurological disorders.

Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.

NMDAR-mediated activation of pannexin1 channels contributes to the detonator properties of hippocampal mossy fiber synapses.

Pannexins are large-pore ion channels expressed throughout the mammalian brain that participate in various neuropathologies; however, their physiological roles remain obscure. Here, we report that pannexin1 channels (Panx1) can be synaptically activated under physiological recording conditions in rodent acute hippocampal slices. Specifically, NMDA receptor (NMDAR)-mediated responses at the mossy fiber to CA3 pyramidal cell synapse were followed by a slow postsynaptic inward current that could activate CA3 pyramidal cells but was absent in Panx1 knockout mice. Immunoelectron microscopy revealed that Panx1 was localized near the postsynaptic density. Further, Panx1-mediated currents were potentiated by metabotropic receptors and bidirectionally modulated by burst-timing-dependent plasticity of NMDAR-mediated transmission. Lastly, Panx1 channels were preferentially recruited when NMDAR activation enters a supralinear regime, resulting in temporally delayed burst-firing. Thus, Panx1 can contribute to synaptic amplification and broadening the temporal associativity window for co-activated pyramidal cells, thereby supporting the auto-associative functions of the CA3 region.

Interictal epileptiform discharges affect memory in an Alzheimer's Disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimer's Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory. Significant Statement: Prevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.

Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-ß in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-ß 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.

Multilayer Arrays for Neurotechnology Applications (MANTA): Chronically Stable Thin-Film Intracortical Implants.

Flexible implantable neurointerfaces show great promise in addressing one of the major challenges of implantable neurotechnology, namely the loss of signal connected to unfavorable probe tissue interaction. The authors here show how multilayer polyimide probes allow high-density intracortical recordings to be combined with a reliable long-term stable tissue interface, thereby progressing toward chronic stability of implantable neurotechnology. The probes could record 10-60 single units over 5 months with a consistent peak-to-peak voltage at dimensions that ensure robust handling and insulation longevity. Probes that remain in intimate contact with the signaling tissue over months to years are a game changer for neuroscience and, importantly, open up for broader clinical translation of systems relying on neurotechnology to interface the human brain.

Single Center Retrospective Analysis of Cerebral Aneurysms from a Patient Sample Data Collection at a Comprehensive Stroke Center.

INTRODUCTION: Institutional self-monitoring of cerebral aneurysm data should occur regularly. The objective of this retrospective single center study was to examine the reproducibility of a data collection and analytic method to examine cerebral aneurysm characteristics and trends. METHODS: A single center retrospective analysis was performed from 2018 to 2021 of the most recent 100 patient presentations with a newly diagnosed cerebral aneurysm. Data collection included patient demographics, radiographic features, ruptured or unruptured status, location, grading scale, treatment strategy, survival, and length of stay, which were extracted and presented in tabular form and analyzed for overall trends. RESULTS: Of the collected 100 patients meeting ICD-10 criteria, 10 (10%) patients were excluded due to having been previously diagnosed at the institution and not meeting the criteria of a new discovery of cerebral aneurysm for inclusion. The remaining 90 sample patients presented with newly diagnosed aneurysms to the authors' Emergency Department between 2018 and 2021. Most patients were between the ages of 25 and 65 with 55 (61%) patients identifying themselves as female sex. Of the 90 eligible sample patients, 59 (66%) had aneurysms that were not ruptured. Eighty-eight (97.7%) patients had cerebral aneurysms that were < 7mm in size. The most common location for aneurysms was in the anterior cerebral circulation, with identification of 27 middle cerebral artery aneurysms. Length of stay (LOS) ranged from 0-171 days with a mean of 11.97 days (SD = 19.9). Of the seven (7.7%) patients who expired, four (57%) experienced spontaneous subarachnoid hemorrhages, with two (29%) occurring in the anterior communicating artery and one (14%) in the left middle cerebral artery and basilar artery respectively. CONCLUSIONS: The typical presentation of a cerebral aneurysm is unruptured with a pre-dominance in middle-aged females. Our findings are congruent with the literature regarding the location of the aneurysm originating in the anterior circulation. However, most aneurysms in our clinical cohort were located on the MCA/ICA in contrast to the literature reported (i.e., most anterior communicating artery). Of those patients who presented unruptured, outpatient follow-up and routine monitoring were appropriate with medical management in the setting of small aneurysms. The risk of progression and subsequent rupture was relatively small in this patient cohort. Multi-year examinations of single institution comprehensive stroke centers regarding cerebral aneurysms would enable researchers to conduct regional analyses and comparisons to national and international trends.

Novel Methods of Necroptosis Inhibition for Spinal Cord Injury Using Translational Research to Limit Secondary Injury and Enhance Endogenous Repair and Regeneration.

Spinal cord injuries (SCIs) pose an immense challenge from a clinical perspective as current treatments and interventions have been found to provide marginal improvements in clinical outcome (with varying degrees of success) particularly in areas of motor and autonomic function. In this review, the pathogenesis of SCI will be described, particularly as it relates to the necroptotic pathway which has been implicated in limiting recovery of SCI via its roles in neuronal cell death, glial scarring, inflammation, and axonal demyelination and degeneration. Major mediators of the necroptotic pathway including receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domainlike will be described in detail regarding their role in facilitating necroptosis. Additionally, due to the rapid accumulation of reactive oxygen species and inflammatory markers, the onset of necroptosis can begin within hours following SCI, thus developing therapeutics that readily cross the blood-brain barrier and inhibit necroptosis during these critical periods of inflammation are imperative in preventing irreversible damage. As such, current therapeutic interventions regarding SCI and targeting of the necroptotic pathway will be explored as will discussion of potential future therapeutics that show promise in minimizing long-term or permanent damage to the spinal cord following severe injury.

Implications of 3-Dimensional Printed Spinal Implants on the Outcomes in Spine Surgery.

Three-dimensional printing (3DP) applications possess substantial versatility within surgical applications, such as complex reconstructive surgeries and for the use of surgical resection guides. The capability of constructing an implant from a series of radiographic images to provide personalized anatomical fit is what makes 3D printed implants most appealing to surgeons. Our objective is to describe the process of integration of 3DP implants into the operating room for spinal surgery, summarize the outcomes of using 3DP implants in spinal surgery, and discuss the limitations and safety concerns during pre-operative consideration. 3DP allows for customized, light weight, and geometrically complex functional implants in spinal surgery in cases of decompression, tumor, and fusion. However, there are limitations such as the cost of the technology which is prohibitive to many hospitals. The novelty of this approach implies that the quantity of longitudinal studies is limited and our understanding of how the human body responds long term to these implants is still unclear. Although it has given surgeons the ability to improve outcomes, surgical strategies, and patient recovery, there is a need for prospective studies to follow the safety and efficacy of the usage of 3D printed implants in spine surgery.

Special Considerations to Improve Clinical Outcomes in Patients with Osteoporosis Undergoing Spine Surgery.

BACKGROUND: Osteoporosis is a condition that is commonly encountered, with increasing diagnosis by the medical community with the aging population. Osteoporosis leaves patients susceptible to fragility fractures in the vertebrae and is also associated with degenerative changes, both of which may require intervention from a spine surgeon. The goal of this review is to concisely outline special nonoperative adjuncts, as well as preoperative, intraoperative, and postoperative considerations of osteoporotic patients undergoing spine intervention. METHODS: A literature analysis was completed for this narrative review. A database search of PubMed and Google Scholar was conducted using "osteoporosis" combined with "spine," "spine surgery," and "spinal fusion" without exclusion based on publication date. Articles were screened to exclude duplicate articles and screened for their full text and English language availability. RESULTS: The database search yielded recent publications from which the narrative review was completed. CONCLUSIONS: Preoperatively, screening is traditionally completed with dual-energy x-ray absorptiometry (DEXA). Pharmacological therapy modalities currently include teriparatide, raloxifene, denosumab, bisphosphonates, and calcitonin. In order to prevent operative complications associated with osteoporosis, surgeons have found success in increasing the diameter and the length of pedicle screws, limiting pedicle tapping, achieving bicortical or even tricortical purchase, augmenting with polymethyl methacrylate, using iliosacral stabilization, preventing positive sagittal balance, and using adequate fusion products when necessary. Postoperatively, it is important to implant a care plan that includes adequate pain control and necessary care, and to understand risks associated with falls may increase risk of postoperative fragility fractures as well as instrumentation displacement. At this time there are no recommendations in regard to bracing in the postoperative setting. CLINICAL RELEVANCE: This review article outlines the most current evidence-based medicine with regard to considerations in spine surgery of the osteoporotic patient, and aims to bring about new questions to be investigated in that paradigm.

The role of gene therapy as a valuable treatment modality for multiple spinal pathologies.

The world of biomedical research has led to several breakthroughs in the treatment of various spinal pathologies. As we investigate chronic pathologies of the spine, we start to unravel the underlying molecular mechanisms through a careful analysis of mutated genetic sequences. Investigations have led to gene therapy being explored for its potential as a treatment modality. Despite only about 2% of current gene therapy trials being centered for spinal pathologies, spinal diseases are valuable targets in gene therapy administration. Through a comprehensive literature review, our objective is to discuss the molecular mechanisms behind gene therapy for spinal pathologies, the genetic targets, along with the outcomes, success, and possible pitfalls in gene therapy research and administration. The emerging development of robotic technologies and intelligent carriers are recognized as a promising innovative technique for increasing the efficiency of gene therapy and potentially resolving spinal pathologies.

Traumatic Spinal Injury Associated with All-Terrain Vehicle (ATV) Accidents: A 10-Year Retrospective Analysis of the Coachella Valley.

OBJECTIVE: The use of all-terrain vehicles (ATVs) and associated injuries have significantly increased in the last decade. This study aimed to determine the frequency of ATV-associated spinal cord injuries (SCIs) in the Coachella Valley, California, and provide recommendations for data reproducibility in other areas with a similarly substantial level of ATV usage and injuries. METHODS: This retrospective analysis included data obtained through screening the trauma database of a level II trauma center for ATV-related injuries between January 1, 2010 and January 1, 2020. RESULTS: Our data suggest that more than one-third of patients admitted to the trauma center over a 10-year period suffered from spinal injury. Injuries to the spine were further categorized as including the spinal cord (radiographically or clinically) or only including the bony or ligamentous elements of the spine. Injury was more common in men and predominantly located in the thoracic spine. Injuries such as epidural hematoma, vertebral artery, and cord contusion were common, with many patients requiring neurosurgical intervention. CONCLUSION: Highlighting the implicit dangers of ATV accidents on the spine could help identify outcomes and variables predictive of spinal injuries and spinal cord injuries necessary for patient management. Additionally, our study sets the framework by which legislating bodies could replicate the study for proper legislation and recommendations that may help prevent such injuries.

Gamma rhythm communication between entorhinal cortex and dentate gyrus neuronal assemblies.

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.

Distinct population code for movement kinematics and changes of ongoing movements in human subthalamic nucleus.

The subthalamic nucleus (STN) is theorized to globally suppress movement through connections with downstream basal ganglia structures. Current theories are supported by increased STN activity when subjects withhold an uninitiated action plan, but a critical test of these theories requires studying STN responses when an ongoing action is replaced with an alternative. We perform this test in subjects with Parkinson's disease using an extended reaching task where the movement trajectory changes mid-action. We show that STN activity decreases during action switches, contrary to prevalent theories. Furthermore, beta oscillations in the STN local field potential, which are associated with movement inhibition, do not show increased power or spiking entrainment during switches. We report an inhomogeneous population neural code in STN, with one sub-population encoding movement kinematics and direction and another encoding unexpected action switches. We suggest an elaborate neural code in STN that contributes to planning actions and changing the plans.

Direct N-butyl-2-cyanoacrylate injections to the head and neck for percutaneous embolized devascularization.

BACKGROUND: N-butyl-2-cyanoacrylate (NBCA) has been used for vascular malformations since the 1980s; however, few studies have looked at applications, procedural techniques, and outcome throughout many institutions. Herein, we review applications, procedural techniques, previous literature, and outcomes for the use of NBCA specifically through percutaneous technique in treating head and neck vascular pathology. METHODS: An extensive literature review using PubMed database with published literature containing "N-butyl-2-cyanoacrylate embolization," was performed. No date restrictions were used. Cross-checking of articles was conducted to exclude duplicate articles. The articles were screened for their full text and English language availability. We finalized those articles pertaining to the topic. RESULTS: The search yielded 1124 related articles. When comparing surgical resection to embolization with NBCA for cerebral AVMs, complications were similar in both groups and included hemorrhage (15%), residual AVM (6%), and cerebrospinal fluid leak (3%). Their mortality rate was 3% in both groups. Preoperative percutaneous embolization does show improved surgical outcomes. CONCLUSION: NBCA is a fast-acting liquid embolic material used in the treatment of a variety of vascular malformations and lesions of the head and neck. Investigations surrounding the use of NBCA injections as a new alternative embolic agent began in the 1980's. Administration of NBCA has been shown to be useful in minimizing intraoperative blood loss and controlling acute hemorrhage. Performing percutaneous embolization with NBCA provides a successful alternative for surgeons when transcatheter embolization techniques may prove to be too difficult to perform. Embolization using NBCA will continue to play in integral role in the treatment of malignant lesions and vascular malformations. Continued research is warranted to improve safety, outcomes, and further develop clinical applications of NBCA.

Intramedullary spinal cord cavernous malformations in the pediatric population.

BACKGROUND: Intramedullary spinal cavernous malformations (ISCM) account for just 1% of all intramedullary pediatric spinal cord lesions. Pathologically, they are well-circumscribed vascular malformations that typically appear dark blue or reddish-brown, often coming to the spinal cord surface. With regard to the histopathology findings, ISCMs are comprised sinusoidal vascular spaces lined by a single layer of endothelial cells within a loose connective tissue stroma. As these lesions are often misdiagnosed in the pediatric population, appropriate treatment may be unduly delayed. METHODS: The authors performed an extensive review of the published literature (PubMed) focusing on ISCM in the pediatric age group. RESULTS: The search yielded 17 articles exclusively pertaining to ISCM affecting the pediatric population. CONCLUSION: Here, we reviewed the clinical, radiographic, surgical, and outcome data for the treatment of ISCM in the pediatric age groups. Notably, over 50% of pediatric patients with ISCM experienced an improvement in their neurological status after a mean postoperative follow-up duration of 4 years. Future meta-analyses are needed to highlight the potential presence of ISCM and, thereby, decrease the rate of misdiagnosis of these lesions in the pediatric population presenting with recurrent intramedullary spinal cord hemorrhages.

Nonmissile penetrating spinal injuries: Mechanisms, expectations, and management.

BACKGROUND: Nonmissile penetrating spinal injury (NMPSI) is an uncommon form of traumatic injury to the spine. Here, we present a comprehensive and contemporary literature review that provides insight into NMPSI-type injuries, their mechanisms, clinical practice, management, and expectations. METHODS: An extensive review of the published literature was conducted in PubMed, OVID Medline, and EMBASE journals for studies of nonmissile penetrating spine injuries. Terms for search included NMPSI and nonmissile penetrating spinal cord injury. No date restrictions were used. RESULTS: The search yielded only 17 related articles. Cross-checking of articles was conducted to exclude duplicate articles. The 17 articles were screened for their full text and English language availability. We finalized those articles pertaining to the topic. CONCLUSION: The mechanism of injury in NMPSI occurs in two different stages. Immediate injury is caused by direct damage to the neurological structures. The delayed injury response is caused by damage to the spinal vasculature and activated immune response pathways. Computed tomography (CT) angiograms or formal diagnostic angiograms are indicated to identify vascular injury or development of pseudoaneurysm and can be performed both preoperatively and postoperatively. Surgically, decompressive procedures include laminectomies and hemilaminectomies. Dural exploration may be indicated if a cerebrospinal fluid leak with fistula develops from dural puncture. Further research and technologies are being developed to provide patients who have suffered NMPSI with more resources for a better quality of life.

The Emerging Role of Magnetic Resonance Imaging-Guided Focused Ultrasound in Functional Neurosurgery.

Functional disorders of the central nervous system (CNS) are diverse in terms of their etiology and symptoms, however, they can be quite debilitating. Many functional neurological disorders can progress to a level where pharmaceuticals and other early lines of treatment can no longer optimally treat the condition, therefore requiring surgical intervention. A variety of stereotactic and functional neurosurgical approaches exist, including deep brain stimulation, implantation, stereotaxic lesions, and radiosurgery, among others. Most techniques are invasive or minimally invasive forms of surgical intervention and require immense precision to effectively modulate CNS circuitry. Focused ultrasound (FUS) is a relatively new, safe, non-invasive neurosurgical approach that has demonstrated efficacy in treating a range of functional neurological diseases. It can function reversibly, through mechanical stimulation causing circuitry changes, or irreversibly, through thermal ablation at low and high frequencies respectively. In preliminary studies, magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) has been shown to have long-lasting treatment effects in several disease types. The technology has been approved by the FDA and internationally for a number of treatment-resistant neurological disorders and currently clinical trials are underway for several other neurological conditions. In this review, the authors discuss the potential applications and emerging role of MRgHIFU in functional neurosurgery in the coming years.