Multi‑mechanical waves against Alzheimer’s disease pathology: a systematic review

Alzheimer’s disease (AD) is the most common cause of dementia, affecting approximately 40 million people worldwide. The ineffectiveness of the available pharmacological treatments against AD has fostered researchers to focus on alternative strategies to overcome this challenge. Mechanical vibrations delivered in different stimulation modes have been associated with marked improvements in cognitive and physical performance in both demented and nondemented elderly. Some of the mechanical-based stimulation modalities in efforts are earlier whole-body vibration, transcranial ultrasound stimulation with microbubble injection, and more recently, auditory stimulation. However, there is a huge variety of treatment specifications, and in many cases, conflicting results are reported. In this review, a search on Scopus, PubMed, and Web of Science databases was performed, resulting in 37 papers . These studies suggest that mechanical vibrations delivered through different stimulation modes are effective in attenuating many parameters of AD pathology including functional connectivity and neuronal circuit integrity deficits in the brains of AD patients, as well as in subjects with cognitive decline and non-demented older adults. Despite the evolving preclinical and clinical evidence on these therapeutic modalities, their translation into clinical practice is not consolidated yet. Thus, this comprehensive and critical systematic review aims to address the most important gaps in the reviewed protocols and propose optimal regimens for future clinical application.FCT (Fundação para a Ciência e Tecnologia) through the grant with reference SFRH/BD/09375/2020, and in the scope of the projects UIDB/04436/2020, UIDP/04436/2020, and NORTE-01- 0145-FEDER-000023, funded by the European Fund for Regional Development (FEDER) of the Operational Programme for Competitiveness and Internationalization (POCI), by Portugal 2020

The year in review: progress in brain barriers and brain fluid research in 2018

Abstract This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.https://deepblue.lib.umich.edu/bitstream/2027.42/147737/1/12987_2019_Article_124.pd

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour : a Pilot Numerical Simulation Study

Funding: This research received no external funding. Acknowledgments: The author would like to acknowledge the supports of the Imperial College London Central Library and the Maxwell Compute Cluster funded by the University of Aberdeen.Peer reviewedPublisher PD

Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model

BACKGROUND AND PURPOSE: Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO). METHODS: Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model. RESULTS: Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model. CONCLUSIONS: Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models

İNMEDE BEYİN ÖDEMİ VE KAFA İÇİ BASINÇ ARTIŞI: TÜRK BEYİN DAMAR HASTALIKLARI DERNEĞİ UZMAN GÖRÜŞÜ

Beyin ödemi inmeden sonra sık karşılaşılan bir sorundur. İntrakranial basınç artışı serebral perfüzyonu bozarak veserebral herniasyona yol açarak mortalite ve morbiditeyi artırır. İnme hastası takip eden nörologların, hangi inmedensonra beyin ödemi gelişeceğini kestirebilmesi, beyin ödemi gelişmemesi için önlemler alabilmesi, gelişirse intrakranialbasınç artışı ve serebral herniasyonu klinik ve radyolojik olarak tanıyabilmesi, ve önlenemezse beyin ödemi veintrakranial basınç artışını hızlı ve etkin şekilde tedavi edebilmesi gerekir. Bu uzman görüşü Türk Beyin DamarHastalıkları Derneği bünyesinde aktif olarak çalışan 60 uzmanın ortak görüşü ile hazırlanmış bir klinik rehberniteliğindedir

Neuroenhancement in Military Personnel::Conceptual and Methodological Promises and Challenges

Military personnel face harsh conditions that strain their physical and mental well-being, depleting resources necessary for sustained operational performance. Future operations will impose even greater demands on soldiers in austere environments with limited support, and new training and technological approaches are essential. This report highlights the progress in cognitive neuroenhancement research, exploring techniques such as neuromodulation and neurofeedback, and emphasizes the inherent challenges and future directions in the field of cognitive neuroenhancement for selection, training, operations, and recovery

AGING, A PATHOLOGICAL FACTOR IN NEUROLOGICAL INJURY

One of the main reasons for CNS drugs to fail in clinical development is not considering age as a risk factor while studying chronic age-related neurological/neurodegenerative diseases in preclinical studies. We first set out to gain a comprehensive understanding of the impact of age on various aspects (anatomical, immunological, and biochemical) in rodents that play a key role in determining the onset, progression, and evolution of disease severity. With advancing age, the vascular structure and function are compromised which is hypothesized to accelerate cognitive decline. The initial step toward developing novel therapeutics is to characterize the age-related vascular modifications. Utilizing a vessel painting technique, we labelled the surface cortical vessels of young and aged Sprague-Dawley rats and analyzed for classical angiographic features (junctions, lengths, end points, density, etc). We found significant decrease in vascular components while vascular complexity and lacunarity were significantly increased in the aged brain compared to young brain. These age-dependent changes were prominent at the level of right and left middle cerebral artery (MCA) as well as on a global scale. Next, we investigated the changes on the peripheral immune response following lipopolysaccharide (LPS) induced acute systemic inflammation in young and aged Sprague Dawley rats. We observed age-related immunosuppression in the splenic leukocytes indicative of reduced ability of the spleen to retain the immune cells. We also found dysregulated cytokine/chemokine expression in the plasma following LPS stimulation in aged and young animals. Interestingly, we noticed significant increase in circulatory neutrophil population in the aged animals compared to young animals in response to LPS at 24h. Taken together, these studies confirm the presence of age-related modifications in the vasculature as well as immune system suggesting altered response to injury/infection and thus emphasizing the need to utilize age-appropriate models when studying diseases of the elderly. Lastly, we wanted to test the therapeutic effect of a novel agent in case of brain injury model in aged rodents. Previous studies by our lab and others have showed that targeting mitoNEET using NL-1 was neuroprotective following brain injury models. We wanted to investigate if administration of NL-1 could improve functional outcomes following stroke in an aged rodent model of cerebral ischemia reperfusion injury. We found significant decrease in infarct volume and edema index at 24h post stroke. We also saw enhanced survival and reduced behavior deficits. Moreover, we showed improved BBB integrity, reduced oxidative stress and apoptosis at 72h post stroke. Interestingly, PLGA encapsulated NL-1 at 0.25mg/kg (which is 40-fold lesser dose than NL-1 at 10mg/kg) produced better therapeutic effects. Future studies should focus on understanding the mechanism underlying the biology of aging thus enabling the development of novel therapeutic targets for neurological disorders/diseases

A study on cholinergic signal transduction pathways involved in short term and long term memory formation in the rat hippocampus

Neurodegenerative processes alter neuronal and glial physiology and cause cognitive and mnemonic impairments. Aim of this PhD thesis is to investigate the involvement of the cholinergic system and the role of mTOR pathway in the mechanisms of memory encoding in the hippocampus and to study the pathophysiological processes at the base of the cognitive impairments in different experimental models of neurodegeneration: in particular normal brain aging, neuroinfiammation and chronic cerebral hypoperfusion. These mechanisms are studied focusing on the morpho-functional alterations in the neuron-astrocytemicroglia triad

Neurostimulation of the Rat Motor System

Ce document fait la synthèse d'un ensemble de travaux concernant la nature de la plasticité neuronale et la manière dont la neurostimulation peut être utilisée pour améliorer la récupération motrice après une atteinte neurologique. Nous commençons par les principes fondamentaux généraux des neurosciences, la structure du système nerveux moteur chez l'homme et le rat, ainsi qu'une brève discussion sur les lésions neurologiques. Les sujets sont vastes et couverts avec la brièveté nécessaire, mais ils fournissent un contexte essentiel pour les chapitres suivants, présentés sous forme d'articles scientifiques. Dans le premier article, nous passons en revue le domaine de la neurostimulation sous ses aspects fondamental et clinique avec l'Accident Vasculaire Cerebral (AVC) en tant que maladie modèle pour les lésions neurologiques. Nous classifions les interventions de stimulation en trois modèles différents d'induction de la plasticité. Notre thèse centrale est qu'une meilleure compréhension des règles sous-jacentes de la plasticité, accompagnée de progrès dans une plus grande précision spatio-temporelle, est nécessaire pour faire avancer le domaine de la neurostimulation. Dans le deuxième article, nous décrivons, étape par étape, un nouveau protocole pour évaluer l'excitabilité corticospinale chez le rongeur éveillé pendant le comportement libre, ainsi que les plateformes matérielles et logicielles associées que notre équipe a développées à cette fin. L'une de ses principale caractéristique est la possibilité d'évaluer l'excitabilité corticomotrice en boucle fermée, en fonction de l'EMG, une nouvelle façon d'accroître l'uniformité des mesures sur des animaux en comportement. Cette plateforme de développement sera utile aux neuroscientifiques intéressés par l'évaluation de l'excitabilité du système nerveux chez les rongeurs éveillés par le biais d'une interrogation électrique ou optogénétique, un intermédiaire important avant les essais chez les primates non humains et éventuellement chez les humains. Dans le troisième article, nous avons utilisé cette plateforme prototype pour étudier la stimulation électrique associative appariée et le rôle de la plasticité dépendant de la synchronisation des potentiels d'action chez des rats implantés de façon chronique, sans l'influence de l'anesthésie. Nous nous sommes concentrés sur la variation systématique de l'intervalle entre la stimulation corticale et musculaire dans notre cohorte d'animaux afin de révéler l'effet de la synchronisation relative de l'activité aux niveaux cortical et spinal. Nous n'avons pas observé de potentialisation significative dans tous les intervalles de stimulation testés, mais plutôt des tendances vers des effets de type LTD dans la plupart des conditions de synchronisation. Nous discutons des raisons possibles pour lesquelles nous avons observé ces résultats. Dans le dernier article et dans le projet en cours, nous décrivons les premiers travaux prometteurs impliquant la neurostimulation optogénétique et électrique, ainsi que la réadaptation post-AVC comme tremplin pour des recherches futures. Nous concluons par une discussion générale et nous nous projetons dans l'avenir, tant à moyen qu'à long terme. La poursuite scientifique, tant sur le plan personnel que sur celui du domaine, se poursuivra, comme il se doit. Bien que ce travail soit conçu pour être lu dans un ordre séquentiel, chaque chapitre est indépendant. Collectivement, les travaux de cette thèse posent les bases et plaident en faveur d'une meilleure compréhension de la plasticité neuronale, du développement d'outils pour l'évaluer et de l'étude de ses applications pratiques pour parvenir à une meilleure récupération motrice après une lésion neurologique.This document synthesizes a body of work concerning the nature of neural plasticity and how neurostimulation may be used to improve motor recovery after neurological insult. We begin with general foundational principles in neuroscience, the structure of the nervous and motor systems in humans and rats, and a brief discussion of neurological injury. The topics are broad and covered with the necessary brevity, but provides critical context for the following chapters. In the first paper, we review the fields of neurostimulation across the clinical and basic science domains in the service of stroke as a model disease for neurological injury, framing the field in terms of three different models of plasticity induction. Our central thesis here is that enhanced understanding of the underlying rules of plasticity, accompanied with advances in greater spatiotemporal precision is necessary to move the field of neurostimulation forward. In the second paper we describe a stable, novel step-by-step protocol to assess corticospinal excitability in the awake, freely behaving rodent, and the associated hardware and software platforms that our team has developed for this purpose. A core feature enables corticomotor excitability assessment in a closed-loop, Electromyogram (EMG)-dependent manner, a novel way of increasing consistency during free behavior in untrained animals. This development platform will be of use to neuroscientists interested in assessing the excitability of the nervous system in awake, unrestrained rodents via electrical or optogenetic interrogation, an important intermediary before trials in non-human primates and eventually humans. In the third paper, we used this prototype platform to investigate electrical paired associative stimulation and the role of spike-timing-dependent plasticity in chronically implanted rats, without the influence of anaesthesia. Our focus was on systematically varying the Inter-Stimulus Interval (ISI) between cortical and muscle stimulation in our animal cohort in order to reveal the effect of relative activity timing at both the cortical and spinal levels. We did not observe significant potentiation across all of the stimulus intervals we tested, but instead observed trends towards Long-Term Depression (LTD)-like effects in the short term across most timing conditions. We discuss possible reasons why we observed these results. In the final paper and project currently in progress, we describe early promising work involving optogenetic and electrical neurostimulation, and stroke recovery as a launchpad for future investigations. We conclude with a general discussion and peer into the future, both in the medium term and the long term. The scientific pursuit, both personally and as a field will continue, as it should. Although this work is designed to be read in sequential order, each chapter stands alone. Collectively, the work in this thesis lays the groundwork and argues for a greater understanding of neural plasticity, development of tools to assess it, and study of its practical applications to achieve enhanced motor recovery after neurological injury