"Mail-slot" Technique for Minimally Invasive Placement of Subdural Grid Electrodes: A Single-institution Experience.

BACKGROUND: In the management of multi-drug-resistant focal epilepsies, intracranial electrode implantation is used for precise localization of the ictal onset zone. In select patients, subdural grid electrode implantation is utilized. Subdural grid placement traditionally requires large craniotomies to visualize the cortex prior to mapping. However, smaller craniotomies may enable shorter operations and reduced risks. We aimed to compare surgical outcomes between patients undergoing traditional large craniotomies with those undergoing tailored "mini" craniotomies (the "mail-slot" technique) for subdural grid placement. METHODS: This retrospective cohort study included 23 patients who underwent subdural electrode implantation for epilepsy monitoring between 2014 and 2020. Patients were categorized into mini-craniotomies (n = 9) and traditional large craniotomies (n = 14) groups. Demographics, operative details, and outcomes were reviewed. Craniotomy size and number of electrodes were determined via post hoc radiographs. RESULTS: Of the 23 patients studied, the mini group had smaller craniotomy sizes (mean: 22.71 cm2 vs. 65.17 cm2, P < 0.001) and higher electrode-to-size ratios (mean: 4.25 vs. 1.71, P < 0.0001). The mini group had slightly fewer total electrodes (mean: 88.67 vs. 107.43, P = 0.047). No significant differences were found in operative duration, blood loss, invasive electroencephalography duration, complications, or Engel scores between the groups. One patient per group required further invasive epilepsy monitoring for localization; all patients underwent therapeutic surgery. CONCLUSIONS: Our findings suggest that mini-craniotomies for subdural grid placement in epilepsy monitoring offer significant advantages, including smaller craniotomy sizes and shorter operation durations, without compromising safety or efficacy. These results support the trend towards minimally invasive, patient-tailored surgical approaches in epilepsy treatment.

Intracranial Arterial Calcifications: Potential Biomarkers of Stroke Risk and Outcome.

Intracranial artery calcifications (IAC), a common and easily identifiable finding on computed tomorgraphy angiography (CTA), has gained recognition as a possible risk factor for ischemic stroke. While atherosclerosis of intracranial arteries is believed to be a mechanism that commonly contributes to ischemic stroke, and coronary artery calcification is well-established as a predictor of both myocardial infarction (MI) and ischemic stroke risk, IAC is not currently used as a prognostic tool for stroke risk or recurrence. This review examines the pathophysiology and prevalence of IAC, and current evidence suggesting that IAC may be a useful tool for prediction of stroke incidence, recurrence, and response to acute ischemic stroke therapy.

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

BACKGROUND: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression. OBJECTIVE: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. METHODS: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. RESULTS: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. CONCLUSION: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.

Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.

The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. This article has an associated First Person interview with the first author of the paper.

Head impact exposure and concussion in women's collegiate club lacrosse.

This study sought to describe head impact exposure in women's collegiate club lacrosse. Eleven women's collegiate club lacrosse players wore head impact sensors during eight intercollegiate competitions. Video recordings of competitions were used to verify impact data. Athletes completed questionnaires detailing their concussion history and perceived head impact exposure. During the monitored games, no diagnosed concussions were sustained. Three athletes reported sustaining head impacts (median = 0; range: 0-3 impacts per game). Six impacts registered by the sensors were verified on video across a total of 81 athlete-game exposures. Verified impacts had a median peak linear acceleration of 21.0 g (range: 18.3 g - 48.3 g) and peak rotational acceleration of 1.1 krad/s2 (range: 0.7 krad/s2 - 5.7 krad/s2). Women competing in collegiate club lacrosse are at a low risk of sustaining head impacts, comparable to previous reports of the high school and collegiate varsity levels of play.

Pigmented ependymoma, a tumor with predilection for the middle-aged adult: case report with methylation classification and review of 16 literature cases.

Ependymomas have rarely been described to contain pigment other than melanin, neuromelanin, lipofuscin or a combination. In this case report, we present a pigmented ependymoma in the fourth ventricle of an adult patient and review 16 additional cases of pigmented ependymoma from the literature. A 46-year-old female showed up with hearing loss, headaches, and nausea. Magnetic resonance imaging revealed a 2.5 cm contrast-enhancing cystic mass in the fourth ventricle, which was resected. Intraoperatively, the tumor appeared grey-brown, cystic, and was adherent to the brainstem. Routine histology revealed a tumor with true rosettes, perivascular pseudorosettes and ependymal canals consistent with ependymoma, but also showed chronic inflammation and abundant distended pigmented tumor cells that mimicked macrophages in frozen and permanent sections. The pigmented cells were positive for GFAP and negative for CD163 consonant with glial tumor cells. The pigment was negative for Fontana-Masson, positive for Periodic-acid Schiff and autofluorescent, which coincide with characteristics of lipofuscin. Proliferation indices were low and H3K27me3 showed partial loss. H3K27me 3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates the tri-methylation of lysine 27 on histone H3 protein. This methylation classification was compatible with a posterior fossa group B ependymoma (EPN_PFB). The patient was clinically well without recurrence at three-month post-operative follow-up appointment. Our analysis of all 17 cases, including the one presented, shows that pigmented ependymomas are most common in the middle-aged with a median age of 42 years and most have a favorable outcome. However, one patient that also developed secondary leptomeningeal melanin accumulations died. Most (58.8%) arise in the 4th ventricle, while spinal cord (17.6%) and supratentorial locations (17.6%) were less common. The age of presentation and generally good prognosis raise the question of whether most other posterior fossa pigmented ependymomas may also fall into the EPN_PFB group, but additional study is required to address that question.

APOE4 dysregulates autophagy in cultured cells.

Human APOE4 (apolipoprotein E4 isoform) is a powerful genetic risk factor for late-onset Alzheimer disease (AD). Many groups have investigated the effect of APOE4 on the degradation of amyloid ß (Aß), the main component of plaques found in the brains of AD patients. However, few studies have focused on the degradation of APOE itself. We investigated the lysosomal trafficking of APOE in cells and found that APOE from the post-Golgi compartment is degraded through an autophagic process requiring the lysosomal membrane protein LAMP2A. We found that APOE4 accumulates in enlarged lysosomes, alters autophagic flux, and changes the proteomic contents of lysosomes following internalization. This dysregulated lysosomal trafficking may represent one of the mechanisms that contributes to AD pathogenesis.

Second opinion in spine surgery: A scoping review.

BACKGROUND: As a growing number of patients seek consultations for increasingly complex and costly spinal surgery, it is of both clinical and economic value to investigate the role for second opinions (SOs). Here, we summarized and focused on the shortcomings of 14 studies regarding the role and value of SOs before proceeding with spine surgery. METHODS: Utilizing PubMed, Google Scholar, and Scopus, we identified 14 studies that met the inclusion criteria that included: English, primary articles, and studies published in the past 20 years. RESULTS: We identified the following findings regarding SO for spine surgery: (1) about 40.6% of spine consultations are SO cases; (2) 61.3% of those received a discordant SO; (3) 75% of discordant SOs recommended conservative management; and (4) SO discordance applied to a variety of procedures. CONCLUSION: The 14 studies reviewed regarding SOs in spine surgery showed that half of the SOs differed from those given in the initial consultation and that SOs in spine surgery can have a substantial impact on patient care. Absent are prospective studies investigating the impact of following a first versus second opinion. These studies are needed to inform the potential benefit of universal implementation of SOs before major spine operations to potentially reduce the frequency and type/extent of surgery.

Head impacts sustained by male collegiate water polo athletes.

Water polo is a contact sport that is gaining popularity in the United States and carries a risk of repeated head impacts and concussion. The frequency and magnitude of sport-related head impacts have not been described for water polo. We aimed to compare patterns of empirically measured head impact exposure of male collegiate water polo players to patterns previously reported by a survey of current and former water polo athletes. Participants wore water polo caps instrumented with head impact sensors during three seasons of collegiate water polo. Peak linear acceleration (PLA) and peak rotational acceleration (PRA) were recorded for head impacts. Athlete positions were recorded by research staff at the occurrence of each head impact. Head impacts were sustained by athletes in offensive positions more frequently than in defensive and transition positions (246, 59.9% vs. 93, 22.6% vs. 72, 17.5%). 37% of all head impacts during gameplay were sustained by athletes playing the offensive center position. Impact magnitude (means ± SD: PLA = 36.1±12.3g, PRA = 5.0±2.9 krads/sec2) did not differ between position or game scenario. Among goalies, impact frequency and magnitude were similar between games (means ± SD: 0.54±.51 hits/game, PLA = 36.9±14.2g, PRA = 4.3±4.2 krads/sec2) and practices (means ± SD: 0.96±1.11 hits/practice, PLA = 43.7±14.5g, PRA = 3.9±2.5 krads/sec2). We report that collegiate water polo athletes are at risk for sport-related head impacts and impact frequency is dependent on game scenario and player position. In contrast, magnitude does not differ between scenarios or across positions.

The Effectiveness of Protective Headgear in Attenuating Ball-to-Forehead Impacts in Water Polo.

Recent reports have demonstrated that there is a serious risk of head impact and injury in water polo. The use of protective headgear in contact sports is a commonly accepted strategy for reducing the risk of head injury, but there are few available protective headgears for use in water polo. Many of those that are available are banned by the sport's governing bodies due to a lack of published data supporting the effectiveness of those headgears in reducing head impact kinematics. To address this gap in knowledge, we launched a water polo ball at the forehead of an anthropomorphic testing device fitted with either a standard water polo headgear or one of two protective headgears. We selected a range of launch speeds representative of those observed across various athlete ages. Mixed-model ANOVAs revealed that, relative to standard headgear, protective headgears reduced peak linear acceleration (by 10.8-21.6%; p < 0.001), and peak rotational acceleration (by 24.5-48.5%; p < 0.001) induced by the simulated ball-to-forehead impacts. We discuss the possibility of using protective headgears in water polo to attenuate head impact kinematics.

iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aß fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function.

The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in ß-amyloid (Aß) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aß clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress.

Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala (BLA) in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both ß2 subunit-containing (ß2*) and α7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated downregulation of the ß2 or α7 nAChR subunit in the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only ß2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, α7, but not ß2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through ß2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through ß2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior.

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.