Archive for: April 2020 - Padirac Innovations' blog

A new study aimed to determine the effect that learning to walk on a treadmill with a rhythm provided by an external signal, could then have on walking on the floor in people with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) studies have shown decreased activation in many locomotor areas of the brain in people with Parkinson's disease. This decreased activation impairs the ability to change the pace of walking. The use of external signals reduces the pressure on the internal regulation of walking timing.

The use of rhythmic auditory signals improves gait parameters in people with Parkinson's disease. Rhythmic auditory signals presumably serve as an external stimulus and alleviate the alteration of internal synchronization in Parkinson's disease.

It is important to note that the literature is closely focused on the use of faster tempo. This is probably due to the fact that most investigators seek to increase the speed of walking in order to increase the motor capacity of the sick. In addition, it has been suggested that the use of slower frequencies increases the risk of falls.

The walking speed is a function of both the cadence and the length of the step. Thus, when walking on the floor, the cadence changes induced by the auditory signals can increase the speed of walking, but without requiring a patient to increase the length of his steps.

The authors hypothesize that on a treadmill, people with Parkinson's disease will increase the step length with a slow-tempo metronome signal (85% of normal tempo) due to the fixed speed of the treadmill, and will keep this length of their step on the ground with a fast-tempo metronome signal (which increases the perception of their speed).

Indeed, the authors observed that the stride lengths were longer when walking with slow time signals on the treadmill only, while the stride length was unchanged during walking on the floor.

These results probably come from a mixture of biomechanical and neuroanatomical mechanisms. The combined use of treadmill learning and rhythmic auditory signals can therefore improve the mechanics of walking on the floor, in a way that the patient could not have achieved independently.

Une nouvelle étude avait pour but de déterminer l'effet qu’un apprentissage de la marche sur tapis roulant avec un rythme fourni par un signal externe, pourrait avoir ensuite sur la marche sur le sol chez les personnes atteintes de la maladie de Parkinson.

Les études d'imagerie par résonance magnétique fonctionnelle (IRMf) ont démontré une diminution de l'activation dans de nombreuses zones locomotrices du cerveau chez les personnes atteintes de maladie de Parkinson. Cette activation diminuée, nuit à la capacité de modifier le rythme de la marche. L'utilisation de signaux externes diminue la pression sur la régulation interne du timing de la marche.

L'utilisation de signaux auditifs rythmiques permet d'améliorer les paramètres de démarche chez les personnes atteintes de maladie de Parkinson. Les signaux auditifs rythmiques servent vraisemblablement de stimulus externe et soulage l’altération de la synchronisation interne dans la maladie de Parkinson.

Il est important de noter que la littérature est étroitement axée sur l'utilisation de tempo plus rapide. Ceci est probablement dû au fait que la plupart des enquêteurs cherchent à augmenter la vitesse de la marche afin d’ugmenter la capacité motrice des malades. En outre, il a été suggéré que l'utilisation de fréquences plus lentes augmentait le risque de chutes.

La vitesse de marche est fonction à la fois de la cadence et de la longueur du pas. Ainsi, lorsqu'il marche sur le sol, les changements de cadence induits par les signaux auditifs peuvent augmenter la vitesse de la marche, mais sans obliger un patient à augmenter la longueur de ses pas.

Les auteurs émettent l'hypothèse que sur tapis roulant, les personnes atteintes de maladie de Parkinson augmenteront la longueur de pas avec un signal de métronome à tempo lent (85 % du tempo normal) en raison de la vitesse fixe du tapis, et conserveront cette longueur de leur pas sur le sol avec un signal de métronome à tempo rapide (ce qui augmente la perception de leur vitesse).

En effet, les auteurs ont observé que les longueurs de pas étaient plus longues lors de la marche avec des signaux de tempo lents sur le tapis roulant uniquement, tandis que la longueur de pas était inchangée pendant la marche sur le sol.

Ces résultats proviennent probablement d'un mélange de mécanismes biomécaniques et neuroanatomiques. L'utilisation combinée d'un apprentissage sur tapis roulant et de signaux auditifs rythmiques peut donc améliorer la mécanique de la marche sur le sol, d’une manière que le patient n’aurait pas pu obtenir de manière indépendante.

A preprint on BioRxiv tells interesting things about Cu II-ATSM.

The copper compound Cu II-ATSM is in phase 2/3 for the treatment of ALS. It reproducibly improves neurodegeneration in SOD1 mouse models of ALS mutants.

enter image description here Copper(II) hydroxide, source: Vano3333 via Wikipedia

Cu II (atsm) or Copper-64 (64Cu) is an oxidized isotope of copper, with applications for molecular radiotherapy and positron emission tomography. It has a half life of 12 hours and decays in nickel 64 and zinc 64. There are many kind of copper compounds, the one pictured above is a copper(II) hydroxide.

It is not so surprising that copper may be useful for patients with SOD1 ALS, as copper is found in many superoxide dismutases (SOD), proteins that catalyze the decomposition of superoxides by converting it to oxygen and hydrogen peroxide. Indeed SOD1 is pivotal in mitigating reactive oxygen species (ROS) release during oxidative stress.

However, SOD1 mutations cause only 2% of ALS cases, most of the cases being of unknown etiology. And recent studies on Cu II (atsm) have not been very clear as to why Cu II (atsm) should be useful for sporadic cases.

Recent studies about Cu II in ALS have been mired in controversies regarding conflicts of interest or simply the use of questionable methodologies such as using BMAA poisoned mice as ALS models.

The therapeutic relevance of Cu II (atsm) for sporadic ALS is therefore unclear. This article describes an attempt to find out why it is useful in sporadic cases.

Because of its role in facilitating iron uptake, copper deficiency can produce anemia-like symptoms, neutropenia.

The authors analyzed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper manipulation, and the activities of cuproenzymes.

They discovered that the natural distribution of copper is disrupted in sporadic ALS.

The tissue affected by ALS has a molecular signature consistent with an insatiable need for copper and cupro enzyme activity is affected. Copper proteins have diverse roles in biological electron transport and oxygen transportation, processes that exploit the easy interconversion of Cu(I) and Cu(II). Copper is essential in the aerobic respiration of all eukaryotes.

Copper levels are decreased in the ventral gray matter where the motor neuron bodies reside, the main anatomical site of neuronal loss in ALS.

The factors that lead to the localized accumulation observed in ALS are not yet confirmed. However, a redox imbalance involving a hyper-reducing state is involved. In short, the cellular retention of copper from copperII compounds such as CuII (atsm) is dictated, in part, by an intra-cellular reduction of copper followed by its dissociation from the ligand.

The insatiable requirement for copper which is evident in these mice is a biochemical target for Cu II (atsm). The evidence provided here for the disturbed bioavailability of copper in human cases of sporadic ALS indicates that a therapeutic mechanism for Cu II (atsm) involving the bioavailability of copper is relevant for sporadic cases of ALS, not just those involving SOD1 mutant.

Indeed more work is needed to understand why there is an intracellular deficiency in copper.

Another question is, if there is an intracellular reduction of copper, why using something as unstable as Cu II ATSM, when there are so many copper II compounds? Some that are known to be innocuous?

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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.

Introduction:

Human cognition is characterized by its extreme flexibility, such as the ability to integrate already memorized events into new contexts and thus to form abstract thoughts, such as analogies and inferences.

When an animal moves in its environment, the individual hippocampal neurons are active when the animal occupies specific regions or specific situations. Crossing a given environment leads to the sequential activation of a series of these neuronal cells.

During sleep or awake rest, the hippocampal neural circuits replay spatial experiences (the situations with which the brain is confronted) on several levels in the form of action potentials organized in sharp waves and ripples.

enter image description here

Scientists propose in an article in "pre-print" on BioRxiv, that the variability of the temporal organization of these wavelets, could constitute a selective mechanism of memory associations.

Some context

These cellular activation sequences, which can be observed via an EEG, are similar to sequences which had occurred during activity, but their replay is done on a much faster timescale. This rereading can be done in the same order but also in reverse.

The phenomenon has been mainly observed in the hippocampus, a region of the brain associated with memory and space navigation. The first study to explore this phenomenon was carried out in 1989. It showed that the neuronal activity of cells during sleep resembled activity during the awake state. Subsequent studies have shown that other groups of cells also demonstrate this same type of increased activity during sleep.

There are three main patterns of oscillation in the hippocampus: theta waves, sharp waves and ripples and gamma waves. Gamma oscillations are found in all major brain structures, while theta and sharp waves and ripples are specific to the hippocampus and its neighboring regions. Sharp waves and ripples are composed of large amplitude waves and associated rapid oscillations.

enter image description here

Altered gamma activity has been observed in many mood and cognitive disorders such as Alzheimer's disease, epilepsy, and schizophrenia.

Sharp waves and ripples and associated wavelets have been observed in the brains of many mammals, mice, rats, rabbits, monkeys and humans. In all these species, it has been shown that these waves are mainly involved in the consolidation of recently acquired memories.

The characteristics of these oscillations provide indications of their role in the consolidation of memory. Certain direct indications concerning their role come from studies on the effects of their removal. Animal studies have thus indicated that the exhaustion of the wavelet by electrical stimulation, hinders the formation of new memories in the rat.

What was studied:

To study these problems, the authors of the article examined the temporal organization of events on an event-to-event basis during locomotion and awake immobility in male Long-Evans rats. They learned to perform a task where they have to use their memory.

The data were obtained from a network of independent mobile tetrodes, targeting the CA1 and CA3 areas of the hippocampus. There are four regions named CA in the hippocampus, after the initials of Cornu Ammonis, an earlier name for the hippocampus. A tetrode is a type of electrode used in neuroscience to analyze extracellular action potentials.

Scientists recount that action potential events of varying frequency could represent similar spatial experiences and, surprisingly, that variability increases rather than decreases as the environment becomes more familiar, perhaps because that the complexity of these is better understood.

The wide time range that is punctuating these wavelets events, is apparent in new environments where sharp waves and ripples are very widespread and is even increased in more familiar environments. On the other hand, no change of this type was present for the action potentials associated with locomotion.

The great variability in the temporal organization of sharp waves and ripples linked to situations rather than movements, suggests that this higher variability serves a function.

Conclusion:

Humans have the ability to remember past experiences with varying degrees of specificity, and it is possible that this degree of specificity corresponds physiologically to different timings in repetition of groups of action potentials.

The analyzes narrated in this article suggest that a similar spatial experience can be replayed in different temporal configurations of groups of action potentials. This variability is increased in more familiar environments.

The authors therefore hypothesize that the variability of the temporal organization of the hippocampus leads to a mechanism for recovering the experiences memorized with various degrees of specificity.

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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.

Introduction:

La cognition humaine se caractérise par son extrême flexibilité, comme la capacité d'intégrer des évènements déjà mémorisés à de nouveaux contextes et ainsi de former des pensées abstraites, telles que des analogies et des inférences.

Lorsqu'un animal se déplace dans son environnement, les neurones hippocampiques individuels sont actifs lorsque l'animal occupe des régions spécifiques ou des situations spécifiques. Une traversée d'un environnement donné entraîne l'activation séquentielle d'une série de ces cellules neuronales.

Pendant le sommeil ou le repos éveillé, les circuits neuronaux hippocampiques rejouent les expériences spatiales (les situations auxquels le cerveau est confronté) à plusieurs niveaux sous la forme de potentiels d'action organisés en ondelettes transitoires.

enter image description here

Des scientifiques proposent dans un article en "pré-print" sur BioRxiv, que la variabilité de l'organisation temporelle de ces ondelettes, puisse constituer un mécanisme sélectif d'associations mémorielles.

Ces séquences d'activations cellulaires, qui peuvent être observées via un EEG, elles sont similaires à des séquences qui s'étaient produites pendant l'activité, mais leur relecture se fait a une échelle de temps beaucoup plus rapide. Cette relecture peut être effectuée dans le même ordre mais aussi en sens inverse.

Le phénomène a été principalement observé dans l'hippocampe, une région du cerveau associée à la mémoire et à la navigation spatiale. La première étude ayant exploré ce phénomène a été effectué en 1989. Elle a montré que l'activité neuronale des cellules pendant le sommeil ressemblait à l'activité pendant l'état éveillé. Des études ultérieures ont montré que d'autres groupes de cellules démontraient également ce même type d'activité accrue pendant le sommeil.

Il existe trois principaux modèles d'oscillation dans l'hippocampe: les ondes thêta, les ondelettes transitoires et les ondes gamma. Les oscillations gamma se trouvent dans toutes les principales structures cérébrales, tandis que les ondes thêta et transitoires sont spécifiques à l'hippocampe et à ses régions voisines. les ondelettes transitoires sont composées d'ondes de grande amplitude et d'oscillations rapides associées appelées ondelettes.

enter image description here

Une altération de l'activité gamma a été observée dans de nombreux troubles de l'humeur et cognitifs tels que la maladie d'Alzheimer, l'épilepsie, et la schizophrénie.

Des ondes transitoires et des ondelettes associées ont été observées dans le cerveau de nombreux mammifères, les souris, les rats, les lapins, les singes et les humains. Dans toutes ces espèces, il a été démontré que ces ondes étaient principalement impliquées dans la consolidation des souvenirs récemment acquis.

Les caractéristiques de ces oscillations, fournissent des indications sur leur rôle dans la consolidation de la mémoire. Certaines indications directes concernant leur rôle, proviennent d'études sur les effets de leur suppression. Des études animales ont ainsi indiqué que l'épuisement de l'ondelette par stimulation électrique, entravait la formation de nouveaux souvenirs chez le rat.

L'objet de l'article:

Pour étudier ces problèmes, les auteurs de l'article ont examiné l'organisation temporelle des événements sur une base événement à événement pendant la locomotion et l'immobilité éveillée chez des rats Long-Evans mâles Ceux ci ont appris à effectuer une tâche en se basant sur leur mémoire.

Les données ont été obtenus d'un réseau de tétrodes mobiles indépendentes, ciblant les zones CA1 et CA3 de l'hippocampe. Il y a quatre régions nommées CA dans l'hippocampe, d'après les initiales de Cornu Ammonis, un nom antérieur de l'hippocampe. Une tétrode est un type d'électrode utilisé en neuroscience pour analyser les potentiels d'action extracellulaires.

Les scientifiques expliquent qu'ils ont constatés que des événements neuronaux de périodicité variable pourraient représenter des expériences spatiales similaires et, de façon surprenante, que la variabilité augmentait plutôt qu'elle ne diminuait à mesure que l'environnement devenait plus familier, peut-être parce que la complexité de ceux-ci est mieux appréhendée.

La large gamme temporelle rythmant ces ondelettes était clairement visible dans de nouveaux environnements où les ondelettes transitoires sont très répandues et même augmenté dans des environnements plus familiers. Par contre aucun changement de ce type n'était présent pour les potentiels d'action associé à la locomotion.

La grande variabilité dans l'organisation temporelle des ondelettes transitoires liées à des situations plutôt que des mouvements, suggère que cette variabilité plus élevée sert une fonction.

Conclusion:

Les humains ont la capacité de se souvenir d'expériences passées avec divers degrés de spécificité, et il est possible que ce degré de spécificité corresponde sur le plan physiologique à différents niveaux temporels de répétitions de groupes de potentiels d'action.

Les analyses narrées dans cet article suggèrent qu'une expérience spatiale similaire peut être rejouée dans différentes configurations temporelles de groupes de potentiels d'actions. Cette variabilité est accrue dans des environnements plus familiers.

Les auteurs émettent donc l'hypothèse que la variabilité de l'organisation temporelle de l'hippocampe entraîne un mécanisme de récupération des expériences mémorisées avec divers degrés de spécificité.

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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.

The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson’s disease (PD). Minor hallucinations or delusions occur in approximately 50% of people with PD over the course of the illness, and may herald the emergence of dementia.

Patients say that the presences are not distressing, are short-lasting, and often are felt beside or behind them, while at home.

Such sensations have given rise to numerous literary and religious accounts. The first description of feeling of a presence by a psychologist was probably that of William James in 1902: “It often happens that an hallucination is imperfectly developed: the person affected will feel a ‘ presence ’ in the room, definitely localized, ( ... ) and yet neither seen, heard, touched, nor cognized in any of the usual ‘ sensible ’ ways .

Jaspers described the same phenomenon in 1913 under the name leibhaftige Bewusstheit : “There are patients who have a certain feeling or awareness that someone is close by, behind them or above them, someone that they can in no way perceive with the external senses, yet whose actual and concrete presence is clearly experienced ”.

Bleuler called “ extracampine ” a type of visual or tactile hallucination that occurs outside the limits of the sensory field. For example, a patient felt, on his skin, mice running on a wall, while another one “saw” birds or persons in a garden while seated in a room with his back to the window.

In a recent publication, the authors asked to 25 patients who endorsed presence phenomena, to complete a semi-structured interview about their experiences. The cognitive profiles of these patients were then compared to those of age- and education-matched patients who denied presence phenomena.

Patients described the presence as mostly that of an unknown human but without much interactions. Patients who described it as unpleasant were noted to also demonstrate elevated anxiety. Those patients who identified the presence as a known person, described it as touching them, or interacted with the presence emotionally or physically demonstrated reduced insight.

Presence phenomena were frequently associated impairments in visual processing, executive function and speed of processing and they may involve the posterior cortical functions. The experience is shaped by the patient's emotional state and level of understanding.

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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.

Flashing light and neural plasticity

- Posted in English by

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.

enter image description here

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.

entrez la description de l'image ici

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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