Neurological Insult Research Articles

Pain or Weakness? An Immunocompromised Patient Presenting with Inability to Walk

IntroductionErythema nodosum (EN) appears as tender erythematous nodules, mainly on the pretibial areas. The causes are varied including medication side effects, infections, autoimmune conditions, malignancy, and is idiopathic in 50% of cases. The pathophysiology is not completely understood but may involve an immunologic response or hypersensitivity reaction to various stimuli, leading to immune complex deposition in the venules of septae in subcutaneous fat. Case Presentation17-year-old male with right mandible ameloblastoma (positive for BRAF V600E mutation), who was diagnosed in May 2022, and has been semi-compliant with dabrafenib, BRAF V600E mutation kinase inhibitor, for the previous 6 months and was off for about 1 week when he presented with fever, followed by painful rash of extremities, including soles and palms, and ascending weakness with inability to walk, concerning for neurological insult. The rash was confluent, macular patches, non-pruritic, blanching with a needle-like tenderness. We questioned whether the inability to walk was neurological or related to pain. Brain Magnetic Resonance Imaging (MRI) was unremarkable. Extensive infectious disease testing yielded rhinovirus/enterovirus positive Polymerase Chain Reaction (PCR) but was negative for all other pathogens, including Streptococcus A infection. Rheumatologic workup was negative. He was treated with Non-Steroidal Anti-Inflammatory Drugs and triamcinolone cream which provided improvement of rash and presenting symptoms. Skin biopsy showed granulomatous panniculitis compatible with EN. Dabrafenib was discontinued. DiscussionPatient’s initial presentation was concerning for acute onset of ascending weakness in an immunocompromised patient, suggestive of Guillain-Barré syndrome. Muscular strength was difficult to examine upon initial physical exam likely due to patient effort versus experienced symptoms and patient’s need for assistance to ambulate. However, detailed neurological examination and having normal brain MRI led to the conclusion that the acute change was EN-related pain, rather than weakness. After extensive infectious and rheumatological work up, we concluded that the patient’s EN was likely secondary to Dabrafenib use even if adherence was suboptimal. Clinicians should be aware that EN is an adverse reaction which has been reported in relation to Dabrafenib, as evidenced by a retrospective chart review and case report.

Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study.

Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.

RGS14 limits seizure-induced mitochondrial oxidative stress and pathology in hippocampus

RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. In these neurons, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies showed that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity, possibly affording protection to CA2 PCs. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show that the loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Our proteomics data show that the loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found that RGS14 KO dramatically increased 3- nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we unexpectedly found no differences in neuronal injury in CA2 PCs. However, we observed a striking and surprising lack of microgliosis in CA1 and CA2 of RGS14 KO compared to WT. Together, our data demonstrate a newly appreciated role for RGS14 in limiting intense seizure activity and pathology in hippocampus. Our findings are consistent with a model where RGS14 limits seizure onset and mortality and, after seizure, is upregulated to support mitochondrial function, prevent oxidative stress in CA2 PCs, and promote microglial activation in hippocampus.

Endoscopic Fenestration of an Intra-ventricular Arachnoid Cyst in a Young Male – A Rare Entity

Introduction: Among intracranial space-occupying lesions, arachnoid cysts compromise 1% only. Abnormal collection of cerebrospinal fluid occurs in these types of cysts leading to pressure symptoms. Developmental abnormalities of cerebrospinal structures in early fetal life lead to the primary type of arachnoid cysts, while the second type of arachnoid cyst is formed after some neurological insult like head injury, tumor, meningitis, or brain surgery. In 60 – 90% of cases, the primary type predominates and presents with pressure symptoms before the age of 20 years. The adjudged incidence is 1.4% in adults, the least frequent being intraventricular location. Clinical Case: A 23-year-old male presented with a long-standing left-sided cranial vault headache, right-sided focal seizures, and progressive right- hemiparesis. Neurological evaluation revealed upper motor neuron signs on the right side of the body. A computerized axial tomography raised the suspicion of an arachnoid cyst for which magnetic resonance imaging was done which revealed a large intraventricular cyst of lateral ventricles causing mass effect over the ipsilateral hemisphere and mild obstructive hydrocephalous. Surgical intervention was required as per symptomology (intractable headache, seizures, and hemiparesis) and large cyst size. Conclusion: Cerebrospinal fluid accumulation in the brain's arachnoid layer causes non-cancerous arachnoid cysts. Larger cysts may push on brain tissue and cause neurological difficulties. MRI may diagnose arachnoid cysts, and treatment options include cystoperitoneal shunt, craniotomy, and neuro-endoscopic fenestration, the least invasive. Cyst size and location determine therapy. In this example, endoscopic treatment reduced symptoms and consequences.

Systematic Innominate Artery Cannulation Strategy in Acute Type A Aortic Dissection: Better Perfusion, Better Results.

(1) Background: Arterial cannulation in type A acute aortic dissection (TAAAD) is still subject to debate. We describe a systematic approach of using the innominate artery for arterial perfusion (2) Methods: The hospital records of 110 consecutive patients with acute TAAAD operated on between January 2014 and December 2022 were retrospectively analyzed. The effect of the cannulation site on early and late mortality, as well as on cardio-pulmonary perfusion indices (lactate and base excess levels, and cooling and rewarming speed) were investigated. (3) Results: There was a significant difference in early mortality (8.82% vs. 40.79%, p < 0.01) but no difference in long-term survival beyond the first 30 days. Using the innominate artery enabled the use of approximately 20% higher CPB flows (2.73 ± 0.1 vs. 2.42 ± 0.06 L/min/m2 BSA, p < 0.01), which resulted in more rapid cooling (1.89 ± 0.77 vs. 3.13 ± 1.62 min/°C/m2 BSA, p < 0.01), rewarming (2.84 ± 1.36 vs. 4.22 ± 2.23, p < 0.01), lower mean base excess levels during CPB (-5.01 ± 2.99 mEq/L vs. -6.66 ± 3.37 mEq/L, p = 0.01) and lower lactate levels at the end of the procedure (4.02 ± 2.48 mmol/L vs. 6.63 ± 4.17 mmol/L, p < 0.01). Postoperative permanent neurologic insult (3.12% vs. 20%, p = 0.02) and acute kidney injury (3.12% vs. 32.81%, p < 0.01) were significantly reduced. (4) Conclusions: systematic use of the innominate artery enables better perfusion and superior results in TAAAD repair.

The Role of Speech-Language Pathologists in Expanding Delivery of Teen Online Problem Solving for Adolescents With Acquired Brain Injury: A Quality Improvement Project.

Teen Online Problem Solving (TOPS) is an evidence-based teletherapy program designed to promote neurocognitive, behavioral, and psychosocial recovery following brain injury through family-centered training. To date, TOPS has been primarily administered by neuropsychologists and clinical psychologists. This clinical focus article discusses a quality improvement project to adapt the TOPS training and manual for use by speech-language pathologists (SLPs) and reports feedback from SLPs following TOPS training and after delivering the program with adolescents who experienced neurological insults. SLPs were invited to participate in TOPS training. Trainees were asked to complete posttraining surveys, active therapist questionnaires, and follow-up surveys directed to SLPs who had completed the intervention with at least one patient. To date, a total of 38 SLPs completed TOPS training, 13 have implemented TOPS with at least one adolescent. Eight SLPs and 16 psychologists/trainees responded to follow-up surveys to share their perspectives on the program. Perceptions of clinicians delivering the program did not differ significantly in most respects. SLPs rated the ease of understanding nonverbal communication higher than psychologists. Seven SLPs responded to an SLP-specific survey about their experiences administering TOPS, noting a range of advantages and some limitations in their open-ended responses. Training SLPs to deliver TOPS has the potential to increase service provision to adolescents with acquired brain injury who have cognitive communication difficulties and their families. https://doi.org/10.23641/asha.22357327.

Virtual Reality Application for Vestibular/Ocular Motor Screening: Current Clinical Protocol Versus a Novel Prototype.

Virtual reality (VR) has been explored to improve baseline and postinjury assessments in sport-related concussion (SRC). Some experience symptoms related to VR, unrelated to concussion. This may deter use of vestibular/ocular motor screening (VOMS) using VR. Baseline VR VOMS symptomatology differentiates baseline from overall symptomatology. There will be no difference between current clinical manual VOMS (MAN), a clinical prototype (PRO), and VR for symptom provocation change score (SPCS) and near point of convergence (NPC) average score in a healthy population and sex differences among the 3 modes of administration. Cohort study. Level 3. A total of 688 National Collegiate Athletic Association Division I student-athletes completed VOMS using 3 methods (MAN, N = 111; female athletes, N = 47; male athletes, N = 64; average age, 21 years; PRO, N = 365; female athletes, N = 154; male athletes, N = 211; average age, 21 years; VR, N = 212; female athletes, N = 78; male athletes, N = 134; average age = 20 years) over a 3-year period (2019-2021) during annual baseline testing. Exclusion criteria were as follows: self-reported motion sickness in the past 6 months, existing or previous neurological insult, attention deficit hyperactivity disorder, learning disabilities, or noncorrected vision impairment. Administration of MAN followed the current clinical protocols, PRO used a novel prototype, and VR used an HTC Vive Pro Eye head mounted display. Symptom provocation was compared using Mann-Whitney U tests across each VOMS subtest with total SPCS and NPC average by each method. MAN had significantly (P < 0.01) more baseline SPCS (MAN = 0.466 ± 1.165, PRO = 0.163 ± 0.644, VR = 0.161 ± 0.933) and significantly (P < 0.01) and more SPCS (MAN = 0.396 ± 1.081, PRO = 0.128 ± 0.427, VR = 0.48 ± 0.845) when compared with PRO and VR. NPC average measurements for VR (average, 2.99 ± 0.684 cm) were significantly greater than MAN (average, 2.91 ± 3.35 cm; P < 0.01; Cohen's d = 0.03) and PRO (average, 2.21 ± 1.81 cm; P < 0.01; Cohen's d = 0.57). For sex differences, female athletes reported greater SPCS with PRO (female athletes, 0.29 ± 0.87; male athletes, 0.06 ± 0.29; P < 0.01) but not in VR or MAN. Using a VR system to administer the VOMS may not elicit additional symptoms, resulting in fewer false positives and is somewhat stable between sexes. VOMS may allow for standardization among administrators and reduce possible false positives.

Caregivers matter: Neurological vulnerability for pediatric brain tumor survivors.

Pediatric brain tumor survivors (PBTS) are at risk of worse quality of life (QOL) due to the impact of neurotoxic treatments on the developing nervous system. Parenting factors such as protectiveness have been linked to worse QOL in childhood cancer survivors generally, but have yet to be explored for PBTS. We examined whether parenting behaviors moderated the association between neurotoxic treatment and QOL for PBTS. PBTS (n = 40; ages 10-25) and their caregivers (n = 47) completed measures of parenting behaviors including warmth (support/connectedness) and psychological control (protectiveness) and QOL. We divided the sample into moderate/high and low neurotoxicity groups based on chart review using the Pediatric Neuro-Oncology Rating of Treatment Intensity and examined moderator effects. Survivor-reported primary caregiver warmth moderated the relationship between neurotoxicity and caregiver-reported QOL. Moderate/high neurotoxicity was associated with lower caregiver-reported QOL only when survivor-reported primary caregiver warmth was low, P = .02. Similar results were found for survivor-reported QOL. Caregiver-reported psychological control moderated the association between neurotoxicity and caregiver-reported QOL such that neurotoxicity only affected QOL at high levels of psychological control, P = .01. Heightened associations between parenting and QOL in the context of neurotoxic treatments underscore the need to better support PBTS. Findings are consistent with research suggesting that family factors may be particularly important for children with other neurological insults. Limitations include cross-sectional design and a small/heterogeneous clinical sample with low ethnic/racial diversity. Prospective studies are needed to refine evidence-based screening and develop psychosocial intervention strategies to optimize QOL for PBTS and their families.

Neuroinflammatory mediators in acquired epilepsy: an update.

Epilepsy is a group of chronic neurological disorders that have diverse etiologies but are commonly characterized by spontaneous seizures and behavioral comorbidities. Although the mechanisms underlying the epileptic seizures mostly remain poorly understood and the causes often can be idiopathic, a considerable portion of cases are known as acquired epilepsy. This form of epilepsy is typically associated with prior neurological insults, which lead to the initiation and progression of epileptogenesis, eventually resulting in unprovoked seizures. A convergence of evidence in the past two decades suggests that inflammation within the brain may be a major contributing factor to acquired epileptogenesis. As evidenced in mounting preclinical and human studies, neuroinflammatory processes, such as activation and proliferation of microglia and astrocytes, elevated production of pro-inflammatory cytokines and chemokines, blood-brain barrier breakdown, and upregulation of inflammatory signaling pathways, are commonly observed after seizure-precipitating events. An increased knowledge of these neuroinflammatory processes in the epileptic brain has led to a growing list of inflammatory mediators that can be leveraged as potential targets for new therapies of epilepsy and/or biomarkers that may provide valued information for the diagnosis and prognosis of the otherwise unpredictable seizures. In this review, we mainly focus on the most recent progress in understanding the roles of these inflammatory molecules in acquired epilepsy and highlight the emerging evidence supporting their candidacy as novel molecular targets for new pharmacotherapies of acquired epilepsy and the associated behavioral deficits.

Granule Cell Layer Morphology and Wnt Signaling in Temporal Lobe Epilepsy

Background and Hypothesis: Temporal lobe epilepsy (TLE) is the most common human seizure disorder and can develop after neurologic insults such as trauma or infection. No treatment exists to prevent the development of epilepsy during this critical period. Epileptogenesis is characterized by pathological neuronal network remodeling in the hippocampal dentate gyrus (DG). Previously, we found that Wnt pathway signaling is dysregulated in the kainate (KA) mouse model of TLE, such that Wnt antagonism exacerbated epileptogenic DG remodeling. We hypothesize that Wnt agonism will mitigate pathological DG remodeling of the granule cell layer (GCL) during epileptogenesis.Project Methods: TLE was induced by unilateral intrahippocampal KA injection in POMC-eGFP transgenic mice, while controls received saline. Mice received injections of vehicle or Wnt agonist Chir99021 daily. eGFP+ immature dentate granule cells were characterized by confocal microscopy. GCL width and immature dentate granule neuronal migration in the ictal/ipsilateral and peri-ictal/contralateral DG were quantified. Quantitative analyses were performed to compare means of the 4 groups.Results: We found that GCL width significantly increased in the ictal zone 2 weeks after seizure induction in both KA groups and was not mitigated by Chir treatment. Immature dentate granule cell migration also increased in the ictal zone in the KA groups and was not altered by Chir treatment. In the peri-ictal zone, GCL width and cell migration were unchanged across KA and saline control mice.Conclusion and Potential Impact: The Wnt agonist Chir99201 did not appear to alter GCL morphology in control or KA mice. It is likely that Wnt signaling may impact neuronal functioning rather than morphology in DG remodeling, and this will be explored through future electrophysiological studies. The Wnt pathway remains a potential therapeutic target in the prevention of the development of epilepsy.&#x0D;

Investigation of neurobiological responses to theta burst stimulation during recovery from mild traumatic brain injury (mTBI)

ObjectiveThe ability of the brain to recover following neurological insult is of interest for mild traumatic brain injury (mTBI) populations. Investigating whether non-invasive brain stimulation (NIBS) can modulate neurophysiology and cognition may lead to the development of therapeutic interventions post injury. The purpose of this study was to investigate neurobiological effects of one session of intermittent theta burst stimulation (iTBS) to the dorsolateral prefrontal cortex (DLPFC) in participants recovering from mTBI. MethodChanges to neurophysiology were assessed with electroencephalography (EEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG). Digit span working memory accuracy assessed cognitive performance. 30 patients were assessed within one-month of sustaining a mTBI and 26 demographically matched controls were assessed. Participants were also assessed at 3-months (mTBI: N = 21, control: N = 26) and 6-months (mTBI: N = 15, control: N = 24). ResultsAnalyses demonstrated iTBS did not reliably modulate neurophysiological activity, and no differences in cognitive performance were produced by iTBS at any assessment time-point. ConclusionsFactors responsible for our null results are unclear. Possible limitations to our experimental design are discussed. SignificanceOur findings suggest additional research is required to establish the effects of iTBS on plasticity following mTBI, prior to therapeutic application. Data and Code Availability StatementWe do not have ethical approval to make this data publicly available, as our approval predated our inclusion of such approvals (which we now do routinely).

Prognosis of adults and children following a first unprovoked seizure.

Prognosis of adults and children following a first unprovoked seizure.

Role of Orbital Ultrasound in the Monitoring of Children with Raised Intracranial Pressure—Prospective Observational Study Conducted in Tertiary Care Centre

AbstractOur objective was to evaluate the role of optic nerve sheath diameter measurement by orbital ultrasound in monitoring children with nontraumatic coma and increased intracranial pressure (ICP). A single-center prospective observational study was conducted in the pediatric intensive care unit (PICU) of a tertiary care teaching hospital in Puducherry, India. Children admitted to the PICU with features of raised ICP were enrolled. Baseline characteristics and raised ICP characteristics were recorded. Optic nerve sheath diameter (ONSD) measurements were taken in all children in the supine position using bedside ultrasound with a 12 MHz linear probe. The probe was initially placed in the axial plane, and measurements were taken at a distance of 3 mm posterior to the site at which the optic nerve enters the globe. Measurements were recorded sequentially 8th hourly till ICP features got resolved or the patient died. Along with each measurement, clinical parameters were recorded. The ONSD measurements were compared with clinical features. We also recruited children admitted to the PICU for other conditions without features of raised ICP as controls. We compared ONSD measurements of cases with controls. In total, 185 children were recruited, of which 81 had features of raised ICP and 104 were without increased ICP. The ONSD measurements in children with raised ICP were significantly higher as compared with those without ICP. Among children with raised ICP, there was a negative correlation between ONSD and Glasgow Coma Scale scores (r = −0.739, p ≤ 0.0001). In children with raised ICP, there was a significant difference in ONSD at different intervals, demonstrating a falling trend from admission to 32nd-hour readings. ONSD measurements were higher in children with clinical signs of increased ICP compared with controls, thereby suggesting that this noninvasive measure may be helpful in the neuromonitoring of children with neurologic insults.

Pädiatrische Neurointensivmedizin

Pediatric neurocritical care requires multidisciplinary expertise for the care of critically ill children. Approximately 14-16% of critically ill children in pediatric intensive care suffer from a primary neurological disease, whereby cardiac arrest and severe traumatic brain injury play major roles in Europe. The short-term goal of interventions in the pediatric intensive care unit is to stabilize vital functions, whereas the overarching goal is to achieve survival without neurological damage that enables fulfillment of the individual developmental physiological potential. For this reason, evidence-based methods for brain monitoring during the acute phase and recovery are necessary, which can be performed clinically or with technical devices. This applies to critically ill children with primary neurological diseases and for all children at risk for secondary neurological insults. Patients with diseases of the peripheral nervous system are also treated in pediatric intensive care medicine. In these patients, the primary aim frequently consists of bridging the time until recovery after acute deterioration, for example during an infection. In these patients, monitoring the cerebral function can be especially challenging, because due to the underlying disease the results of the examination cannot be interpreted in the same way as for previously neurologically healthy children. This article summarizes the complexity of pediatric neurocritical care by presenting examples of diagnostic and therapeutic approaches in the context of various neurological diseases that can be routinely encountered in the pediatric intensive care unit and can only be successfully treated by multidisciplinary teams.

Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells Attenuates Heat Stress-Induced Exacerbation of Neuropathology Following Brain Blast Injury.

Blast brain injury (bBI) following explosive detonations in warfare is one of the prominent causes of multidimensional insults to the central nervous and other vital organs injury. Several military personnel suffered from bBI during the Middle East conflict at hot environment. The bBI largely occurs due to pressure waves, generation of heat together with release of shrapnel and gun powders explosion with penetrating and/or impact head trauma causing multiple brain damage. As a result, bBI-induced secondary injury causes breakdown of the blood-brain barrier (BBB) and edema formation that further results in neuronal, glial and axonal injuries. Previously, we reported endocrine imbalance and influence of diabetes on bBI-induced brain pathology that was significantly attenuated by nanowired delivery of cerebrolysin in model experiments. Cerebrolysin is a balanced composition of several neurotrophic factors, and active peptide fragment is capable of neuroprotection in several neurological insults. Exposure to heat stress alone causes BBB damage, edema formation and brain pathology. Thus, it is quite likely that hot environment further exacerbates the consequences of bBI. Thus, novel therapeutic strategies using nanodelivery of stem cell and cerebrolysin may further enhance superior neuroprotection in bBI at hot environment. Our observations are the first to show that combined nanowired delivery of mesenchymal stem cells (MSCs) and cerebrolysin significantly attenuated exacerbation of bBI in hot environment and induced superior neuroprotection, not reported earlier. The possible mechanisms of neuroprotection with MSCs and cerebrolysin in bBI are discussed in the light of current literature.

Integrin binding peptides facilitate growth and interconnected vascular-like network formation of rat primary cortical vascular endothelial cells in vitro.

Neovascularization and angiogenesis in the brain are important physiological processes for normal brain development and repair/regeneration following insults. Integrins are cell surface adhesion receptors mediating important function of cells such as survival, growth and development during tissue organization, differentiation and organogenesis. In this study, we used an integrin-binding array platform to identify the important types of integrins and their binding peptides that facilitate adhesion, growth, development, and vascular-like network formation of rat primary brain microvascular endothelial cells. Brain microvascular endothelial cells were isolated from rat brain on post-natal day 7. Cells were cultured in a custom-designed integrin array system containing short synthetic peptides binding to 16 types of integrins commonly expressed on cells in vertebrates. After 7 days of culture, the brain microvascular endothelial cells were processed for immunostaining with markers for endothelial cells including von Willibrand factor and platelet endothelial cell adhesion molecule. 5-Bromo-2'-dexoyuridine was added to the culture at 48 hours prior to fixation to assess cell proliferation. Among 16 integrins tested, we found that α5β1, αvβ5 and αvβ8 greatly promoted proliferation of endothelial cells in culture. To investigate the effect of integrin-binding peptides in promoting neovascularization and angiogenesis, the binding peptides to the above three types of integrins were immobilized to our custom-designed hydrogel in three-dimensional (3D) culture of brain microvascular endothelial cells with the addition of vascular endothelial growth factor. Following a 7-day 3D culture, the culture was fixed and processed for double labeling of phalloidin with von Willibrand factor or platelet endothelial cell adhesion molecule and assessed under confocal microscopy. In the 3D culture in hydrogels conjugated with the integrin-binding peptide, brain microvascular endothelial cells formed interconnected vascular-like network with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Monitoring an unconscious patient in the Intensive Care Unit

Monitoring an unconscious patient is complex and involves continuous clinical, haemodynamic and neurological assessment aided by various tools. This article discusses the various methods of monitoring a patient with and without a primary neurological insult. Regardless of the tools employed, monitoring, in itself, does not change the outcome. Processing the information obtained along with sound clinical judgment can, however, have a significant impact.

Fosgonimeton, a novel, small molecule positive modulator of the HGF/MET system is neuroprotective in primary neuron culture

AbstractBackgroundPositive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Activation of the HGF/MET system induces neuroprotective effects that counteract neurotoxicity, neuroinflammation, and oxidative stress‐induced damage, all pathological hallmarks of neurodegeneration. Herein, we investigated the in vitro neuroprotective potential of fosgonimeton (ATH‐1017), a novel, small molecule positive modulator of the HGF/MET system that has demonstrated neurotrophic and pro‐cognitive effects in vitro and in vivo. In addition, we assayed several novel compounds with related activity to fosgonimeton to establish the neuroprotective effects of a series of HGF/MET positive modulators.MethodMature rat cortical neurons were treated with the active metabolite of fosgonimeton or related HGF/MET positive modulators and subjected to a variety of neurotoxic insults including 1‐methyl‐4‐phenylpryidinium (MPP+), glutamate, lipopolysaccharide (LPS), or hydrogen peroxide (H2O2). Neuronal cell viability was determined using CellTiter Glo luminescence assay to assess relative levels of ATP. Furthermore, the effect of fosgonimeton and other test compounds on mitochondrial membrane potential (MMP) was assessed utilizing a fluorescent MMP dye.ResultCortical neurons treated with our HGF/MET positive modulators exhibited significant improvement in cell viability against MPP+ neurotoxicity, glutamate excitotoxicity, LPS‐induced cytotoxicity, and H2O2‐induced oxidative stress. For example, treatment with 1 µM fosgonimeton rescued cell viability against neurological insults with the following percent recoveries: 85% vs. MPP+, 61% vs. glutamate, 93% vs. LPS, and 144% vs. H2O2. Significant improvement in cell viability was also observed at 100 nM, 10 nM, and 1 nM fosgonimeton against all insults, highlighting its potent neuroprotective actions. Furthermore, fosgonimeton treatment led to an increase in mitochondrial membrane potential, suggesting that it may mitigate mitochondrial dysfunction associated with neurodegeneration.ConclusionOur data demonstrate the ability of fosgonimeton and related HGF/MET positive modulators to offer protection against several neurological insults that are central to neurodegeneration. The neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects, highlight its therapeutic potential to restore neuronal health and slow or reverse neurodegeneration. Fosgonimeton is currently in clinical trials for Alzheimer’s disease, Parkinson’s disease dementia, and Dementia with Lewy bodies.

Robot-aided Rehabilitation with SREx: A Smart Robotic Exoskeleton for Reducing Therapists' Physical Stress

<h3>Research Objectives</h3> Upper limb dysfunctions (ULD) are common following a neurological insult. Passive range of motion (PROM) exercise of the affected extremity is one of the critical components of current rehabilitation plans of care when treating these patients. Robot-aided rehabilitation is a promising technology for this and comes with the added advantage of reducing therapists' physical burden. This study describes the development of a robot-aided upper limb rehabilitation device, 7 degrees of freedom exoskeleton type robot named SREx. It also shows the preliminary testing results on healthy participants with emulated ULD patients. <h3>Design</h3> Experimental study. <h3>Setting</h3> In the BioRobotics Lab. <h3>Participants</h3> Five healthy male human subjects (age: 26-30 years) participated in this study. <h3>Interventions</h3> Healthy human subjects (n=5) wore the SREx on the lateral side of their right hands while being seated on chair. Isolated, composite joint PROM sessions containing slower, medium, and faster speed cycles. <h3>Main Outcome Measures</h3> Tests were carried out in three settings: (a) subject exerts no effort, (b) resistance to motion equivalent to patient with generalized spasticity resulting from ULD, and (c) sudden jerking/ perturbation during motion emulating real patients' muscle spasm. During all exercises human-robot interaction was measured with force-torque sensor. Collected ROM data was statistically analyzed. <h3>Results</h3> The robot was able to provide therapeutic PROM to all subjects' UL with a maximum ROM error of ∼3.6 degrees even under external perturbation of force at 6.8 lbs. The preliminary testing showed that the robot was able to provide PROM exercise without the need for physical intervention from anyone else, in an effective manner for emulated patient conditions. <h3>Conclusions</h3> The SREx can provide safe and measurable PROM exercises to healthy patients. The next step is to receive feedback from individuals suffering from ULD. <h3>Author(s) Disclosures</h3> The authors declare no conflict of interest.