Posts tagged: Neuromodulation - Padirac Innovations' blog

Flashing light and neural plasticity

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The plasticity of the central nervous system (CNS) in response to neuronal activity was suggested as early as 1894 by Cajal. Many neurodegenerative and neurological diseases are characterized by a dysfunction of the neuro-immune system, therefore, manipulation of this system has strong therapeutic potential.

For example, in humans, a link between neuronal activity and the addition of new myelin sheaths in the adult CNS has been demonstrated by studies on healthy subjects performing motor and memory tasks.

Astrocytes can further promote pro-inflammatory responses, recruit immune cells through the blood-brain barrier and modulate the number of activated microglial cells.

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Cytokines, which are extracellular signaling proteins in the immune system, provide communication between neurons, astrocytes and immune cells.

Previous work has shown that the exposure of mice to lights flashing at 40 Hz, leads to neuronal activity at gamma frequency (∼40 Hz) and the recruitment of microglia, which are the main immune cells of the brain.

However, the mechanisms of biochemical signaling between neuronal activity at 40 Hz and immune recruitment remain unknown. Here, the scientists exposed male wild-type mice at 5–60 min of 40 Hz, controlled the flicker and evaluated the networks of cytokines and phosphoproteins known to play a role in immune function. Exposing mice to LED bands flashing at 40 Hz, is known to induce gamma neural activity.

These scientists discovered that the 40 Hz flicker results in increased expression of cytokines that promote phagocytic microglial states, such as IL-6 and IL-4, and increased expression of microglial chemokines. Interestingly, the effects of cytokines differed depending on the frequency of stimulation, revealing a range of neuroimmune effects.

Scientists have discovered that 40 Hz flicker regulates NF-κB and MAPK.

  • The phospho-signaling in the NF-κB pathway was significantly upregulated after 15 min, but not 5 or 60 min, of 40 Hz compared to random flicker.

  • While the phosphorylation profiles of MAPK were similar to those of NF-κB, they had different kinetics. The MAPK phospho-signaling was significantly different between 40 Hz and the random groups after 60 min of flicker but not after 5 or 15 min.

These results are the first, to the researchers' knowledge, to show how visual stimulation rapidly induces critical neuroimmune signaling in healthy animals. Different forms of visual stimulation have induced unique cytokine profiles. Thus, flicker stimulation can be used to quickly and non-invasively manipulate the signaling and expression of genes regulating neuronal immune activity. It is important to note that all the researchers carried out their analyzes on wild type animals.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

La plasticité du système nerveux central (SNC) en réponse à l'activité neuronale a été suggérée dès 1894 par Cajal. De nombreuses maladies neurodégénératives et neurologiques sont caractérisées par un dysfonctionnement du système neuro-immunitaire, par conséquent, la manipulation de ce système a un fort potentiel thérapeutique.

Par exemple, chez l'homme, un lien entre l'activité neuronale et l'ajout de nouvelles gaines de myéline dans le SNC adulte a été démontré par des études sur des sujets sains effectuant des tâches motrices et de mémoire.

Les astrocytes peuvent favoriser davantage les réponses pro-inflammatoires, recruter des cellules immunitaires à travers la barrière hémato-encéphalique et moduler le nombre de cellules microgliales activées.

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Les cytokines, qui sont des protéines de signalisation extracellulaires du système immunitaire, assurent la communication entre les neurones, les astrocytes et les cellules immunitaires.

Des travaux antérieurs ont montré que l'exposition de souris à des lumières clignotant à 40 Hz, conduit à une activité neuronale à une fréquence gamma (∼40 Hz) et au recrutement de microglies, qui sont les principales cellules immunitaires du cerveau.

Cependant, les mécanismes de signalisation biochimique entre l'activité neuronale à 40 Hz et le recrutement immunitaire restent inconnus. Ici, les scientifiques ont exposé des souris mâles de type sauvage à 5–60 min de 40 Hz, contrôlé le scintillement et évalué les réseaux de cytokines et de phosphoprotéines connues pour jouer un rôle dans la fonction immunitaire. L'exposition de souris à des bandes LED clignotant à 40 Hz est connue pour induire une activité neuronale gamma.

Ces scientifiques ont découvert que le scintillement à 40 Hz entraîne une augmentation de l'expression des cytokines qui favorisent les états microgliaux phagocytaires, tels que l'IL-6 et l'IL-4, et une expression accrue des chimiokines microgliales. Fait intéressant, les effets des cytokines diffèrent selon la fréquence de la stimulation, révélant une gamme d'effets neuro-immunitaires.

Les scientifiques ont découvert que le scintillement à 40 Hz régule NF-κB et MAPK.

  • La phospho-signalisation dans la voie NF-κB a été significativement régulée à la hausse après 15 min, mais pas 5 ou 60 min, de 40 Hz par rapport au scintillement aléatoire.

  • Alors que les profils de phosphorylation de MAPK étaient similaires à ceux de NF-κB, ils avaient une cinétique différente. La phospho-signalisation MAPK était significativement différente entre 40 Hz et les groupes aléatoires après 60 min de scintillement mais pas après 5 ou 15 min.

Ces résultats sont les premiers, à la connaissance des chercheurs, à montrer comment la stimulation visuelle induit rapidement une signalisation neuro-immune critique chez des animaux en bonne santé. Différentes formes de stimulation visuelle ont induit des profils de cytokines uniques. Ainsi, la stimulation par scintillement peut être utilisée pour manipuler rapidement et de manière non invasive la signalisation et l'expression de gènes régulants l'activité immunitaire neuronale. Il est important de noter que tous les chercheurs ont effectué leurs analyses sur des animaux de type sauvage.

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Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Fecal incontinence is a lack of control over defecation, leading to involuntary loss of bowel contents, including gas. Incontinence can result from different causes and might occur with either constipation or diarrhea. It is estimated that 2% to 10% of adults are affected, particularly women, often because of childbirth trauma to that area of the body, as well as the elderly, including about half of nursing home residents. enter image description here Dr. Satish S.C. Rao providing TNT therapy for fecal incontinence

There is often reduced self-esteem, shame, humiliation, depression, a need to organize life around easy access to a toilet and avoidance of enjoyable activities. fecal incontinence is an example of a stigmatized medical condition. People may be too embarrassed to seek medical help, and attempt to self-manage the symptom in secrecy from others.

Fecal incontinence management may be achieved through an individualized mix of dietary, pharmacologic, and surgical measures. The goals of treatment are to decrease the frequency and severity of episodes and improve quality of life. The decision of which treatment to employ is based on the severity of symptoms and integrity of the anal sphincter.

Patients with more severe disease or sphincter defects will require more invasive procedures which can be categorized into methods that, repair, augment, replace or neuromodulate bowel function.

The mechanism of neuromodulation is still unclear. Indeed activation of a muscle is not the result of a simple volitional act that would result in activation of the muscle through an action potential sent to a chain of motor neurons. On contrary it is the result of a delicate balance and interactions between stimulating and inhibitory signals from different parts of the brain and the spine.

New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation.

Translumbosacral neuromodulation therapy, or TNT, has shown early promise in strengthening connections between nerves and muscles that enable us to control stool release

"People have been applying brain (transcranial) magnetic stimulation to improve depression and nerve function, and we have demonstrated that patients with fecal incontinence have significant anal and rectal neuropathy," says Dr. Satish S.C. Rao. Dr Rao is director of neurogastroenterology/motility and the Digestive Health Clinical Research Center at MCG. He is also project director and principal investigator on the new studies funded by a five-year, $4.2 million grant (R21DK104127-02) from the National Institute of Diabetes and Digestive and Kidney Diseases.

"We were therefore keen to study whether magnetic stimulation applied to the nerves in the back that control bowels would improve fecal incontinence," says Rao, who pioneered a special device and technology to enable these first in the world studies in fecal incontinence.

The investigators theorize and have evidence that magnetic stimulation, particularly at the higher dose of 3,600, helps correct what is wrong with the nerve-muscle connection.

The investigators will examine 88 patients again at 12, 24 and 48 weeks and assess whether the actual treatment, rather than the placebo or sham, improves leakage.

Dr Rao and his colleagues are giving the painless TNT sessions once a week over six weeks to 88 patients at a dose of either 2,400 or 3,600 magnetic stimulations at 1 hertz and performing the lookalike sham on 44 others.

While many therapies have focused on strengthening muscles, or surgically repairing torn muscles, Rao has increasing evidence that for many a major problem is that the nerves which control the muscle have been damaged, and this nerve injury, or neuropathy, is a significant factor in fecal incontinence. Rao uses the analogy of a malfunctioning lightbulb: Replacing the bulb is not helpful if it is an electrical problem.

Part of the problem has been lack of an easily usable, accurate and objective method to assess and/or improve nerve function, Rao says. For example, one technique requires putting a needle in the anal muscle.

Rao first developed a comparatively benign yet comprehensive method with a probe in the rectum and an external coil placed on the back to deliver magnetic stimulations to related nerves and watch the response. His team found that 70-80% of patients with fecal incontinence had anal or rectal neuropathy using this novel test, called the translumbosacral anorectal magnetic stimulation test, or TAMS, pioneered in his lab.

Finding that nerve function was definitely an issue, Rao and his team then decided to apply the external magnet on relevant nerves in the back area as a potential treatment. They looked at different frequencies, knowing that higher frequencies worked better on the brain, but found the low frequency 1 hertz worked best on these nerves with about 90% of the first patients experiencing improvement. While these patients were not asked to do exercises to strengthen anal muscles, they also experienced an improvement in muscle function and sensory awareness for stooling.

The $18.8 million five-year study, also funded by the National Institutes of Health's NIDDK, also is underway at MCG and AU Health as well as three other sites nationally that are referral centers for fecal incontinence.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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