Direct nose to the brain nanomedicine delivery presents a formidable challenge

: NeuroAIDS, a disease incorporating both infectious and neurodegenerative pathways, is still a formidable challenge for the researchers to deal with. The primary concern for the treatment of neuroAIDS still remains the inaccessibility of the viral reservoir, making it indispensable for novel techniques to be continuously innovated. Since the brain serves as a reservoir for viral replication, it is pragmatic and a prerequisite to overcome the related barriers in order to improve the drug delivery to the brain. The current treatment ideology is based on the combinatorial approach of a mocktail of antiretroviral drugs. However, complete eradication of the disease could not be achieved. Thereby the arena of gene-based cellular delivery is trending and has created a niche for itself in the present scenario. To establish the supremacy of gene delivery, it is advisable to have a better understanding of the molecular mechanism involved in the due process. The mechanism associated with the activity of the anti-HIV gene lies in their intrinsic property to impart resistance to the HIV infection by targeting the viral entry channels. This review principally emphasizes on different types of gene therapies explored so far for the management of AIDS and its associated neurological conditions. Therefore it could rightly be said that we are at the crossroad where the need of the hour is to develop novel strategies for curbing AIDS and its associated neurological conditions.

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Saccade Adaptation in Response to Altered Arm Dynamics

Journal of Neurophysiology ◽

10.1152/jn.00430.2003 ◽

2003 ◽

Vol 90 (6) ◽

pp. 4016-4021 ◽

Cited By ~ 19

Author(s):

Thrishantha Nanayakkara ◽

Reza Shadmehr

Keyword(s):

Feedback Control ◽

Real Time ◽

Internal Model ◽

Proprioceptive Feedback ◽

Hand Position ◽

Formidable Challenge ◽

Random Direction ◽

Intact Brain ◽

Saccade Adaptation ◽

The Brain

The delays in sensorimotor pathways pose a formidable challenge to the implementation of stable error feedback control, and yet the intact brain has little trouble maintaining limb stability. How is this achieved? One idea is that feedback control depends not only on delayed proprioceptive feedback but also on internal models of limb dynamics. In theory, an internal model allows the brain to predict limb position. Earlier we had found that during reaching, the brain estimates hand position in real-time in a coordinate system that can be used for generating saccades. Here we tested the idea that the estimate of hand position, as expressed through saccades, depends on an internal model that adapts to dynamics of the arm. We focused on the behavior of the eyes as perturbations were applied to the unseen hand. We found that when the hand was perturbed from stable posture with a 100-ms force pulse of random direction and magnitude, a saccade was generated on average at 182 ms postpulse onset to a position that was an unbiased estimate of real-time hand position. To test whether planning of saccades depended on an internal model of arm dynamics, arm dynamics were altered either predictably or unpredictably during the postpulse period. When arm dynamics were predictable, saccade amplitudes changed to reflect the change in the arm's behavior. We suggest that proprioceptive feedback from the arm is integrated into an adaptable internal model that computes an estimate of current hand position in eye-centered coordinates.

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Diagnosis and Treatment of Recurrent High-Grade Astrocytoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.7522 ◽

2006 ◽

Vol 24 (8) ◽

pp. 1273-1280 ◽

Cited By ~ 127

Author(s):

Nicholas A. Butowski ◽

Patricia K. Sneed ◽

Susan M. Chang

Keyword(s):

Imaging Techniques ◽

Intensity Modulated Radiotherapy ◽

Systemic Exposure ◽

Clinical Trial Design ◽

Cytotoxic Agents ◽

Resonance Spectroscopy ◽

High Grade ◽

Convection Enhanced Delivery ◽

Formidable Challenge ◽

The Brain

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

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Convection-Enhanced Delivery in silico study for personalized brain cancer treatment

10.21203/rs.3.rs-998895/v1 ◽

2021 ◽

Author(s):

Chryso Lambride ◽

Vasileios Vavourakis ◽

Triantafyllos Stylianopoulos

Keyword(s):

Brain Cancer ◽

In Silico ◽

Drug Transport ◽

Drug Distribution ◽

Local Drug Delivery ◽

Patient Specific ◽

Convection Enhanced Delivery ◽

Formidable Challenge ◽

The Impact ◽

The Brain

Abstract Brain cancer therapy remains a formidable challenge in oncology. Convection-enhanced delivery (CED) is an innovative and promising local drug delivery method for the treatment of brain cancer, overcoming the challenges of the systemic delivery of drugs to the brain. To improve our understanding about CED efficacy and drug transport, we present an in silico methodology for brain cancer CED treatment simulation. To achieve this, a three-dimensional finite element biomechanics formulation is utilized which employs patient-specific brain model representation and is used to predict the drug deposition in CED regimes. The model encompasses nonlinear biomechanics and the transport of drugs in the brain parenchyma. Drug distribution was studied under various patho-physiological conditions of the tumor, in terms of tumor vessel wall pore size and tumor tissue hydraulic conductivity as well as for drugs of various sizes, spanning from small molecules to nanoparticles. Our contribution reports for the first time the impact of the size of the vascular wall pores and that of the therapeutic agent on drug distribution during and after CED. The in silico findings provide useful insights of the spatio-temporal distribution and average drug concentration in the tumor towards an effective treatment of brain cancer.

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Cerebrospinal Fluid, Brain Electrolytes Balance, and the Unsuspected Intrinsic Property of Melanin to Dissociate the Water Molecule

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180904093430 ◽

2018 ◽

Vol 17 (10) ◽

pp. 743-756 ◽

Cited By ~ 2

Author(s):

Arturo Solís Herrera ◽

Ghulam Md Ashraf ◽

María del Carmen Arias Esparza ◽

Vadim V. Tarasov ◽

Vladimir N. Chubarev ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Extracellular Fluid ◽

Intrinsic Property ◽

Fluid Secretion ◽

Current View ◽

Formidable Challenge ◽

Fluid Production ◽

Fluid Transfer ◽

The Brain

Background & Objective: Regulation of composition, volume and turnover of fluids surrounding the brain and damp cells is vital. These fluids transport all substances required for cells and remove the unwanted materials. This regulation tends to act as barrier to prevent free exchange of materials between the brain and blood. There are specific mechanisms concerned with fluid secretion of the controlled composition of the brain, and others responsible for reabsorption eventually to blood and the extracellular fluid whatever their composition is. The current view assumes that choroidal plexuses secrete the major part of Cerebrospinal Fluid (CSF), while the Blood-Brain Barrier (BBB) has a much less contribution to fluid production, generating Interstitial Fluid (ISF) that drains to CSF. The skull is a rigid box; thereby the sum of volumes occupied by the parenchyma with its ISF, related connective tissue, the vasculature, the meninges and the CSF must be relatively constant according to the Monroe-Kellie dogma. This constitutes a formidable challenge that normal organisms surpass daily. The ISF and CSF provide water and solutes influx and efflux from cells to these targeted fluids in a quite precise way. Microvessels within the parenchyma are sufficiently close to every cell where diffusion areas for solutes are tiny. Despite this, CSF and ISF exhibit very similar compositions, but differ significantly from blood plasma. Many hydrophilic substances are effectively prevented from the entry into the brain via blood, while others like neurotransmitters are extremely hindered from getting out of the brain. Anatomical principle of the barrier and routes of fluid transfer cannot explain the extraordinary accuracy of fluids and substances needed to enter or leave the brain firmly. There is one aspect that has not been deeply analyzed, despite being prevalent in all the above processes, it is considered a part of the CSF and ISF dynamics. This aspect is the energy necessary to propel them properly in time, form, space, quantity and temporality. Conclusion: The recent hypothesis based on glucose and ATP as sources of energy presents numerous contradictions and controversies. The discovery of the unsuspected intrinsic ability of melanin to dissociate and reform water molecules, similar to the role of chlorophyll in plants, was confirmed in the study of ISF and CSF biology.

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Neuronal Causes and Behavioural Effects: a Review on Logical, Methodological, and Technical Issues With Respect to Causal Explanations of Behaviour in Neuroscience

10.31234/osf.io/zk2dy ◽

2019 ◽

Author(s):

Kayson Fakhar ◽

Dominic Gonschorek ◽

Lisa Schmors ◽

Natalia Z Bielczyk

Keyword(s):

Computational Models ◽

Causal Structure ◽

Human Environment ◽

Causal Explanations ◽

Behavioural Effects ◽

Formidable Challenge ◽

Artificial Neuronal Networks ◽

Modelling Studies ◽

Technical Issues ◽

The Brain

Elucidating causal, neurobiological underpinnings of behaviour is an ultimate goal of every neuroscientific study. However, due to the complexity of the brain as well as the complexity of the human environment, finding a~causal architecture that underlies behaviour remains a~formidable challenge. In this manuscript, we review the logical and conceptual issues with respect to causal research in neuroscience.First, we review the state of the art interventional and computational approaches to infer causal brain-behaviour relationships. We provide an~overview of potential issues, flaws, and confounds in these studies. We conclude that studies on the causal structure underlying behaviour should be performed by accumulating evidence coming from several lines of experimental and modelling studies. Lastly, we also propose computational models including artificial neuronal networks and simulated animats as a~potential breakthrough to causal brain-behaviour investigations.

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