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Several studies have demonstrated diverse pathological effects of ALS' cerebrospinal fluid in different in vivo and in vitro models. The cerebrospinal fluid is very roughly similar to the lymphatic system, as it drains waste products from the brain metabolism and they are removed into the bloodstream as CSF is absorbed.

Recently an article by Jean-Pierre Julien's group was published on transmission of ALS pathogenesis by the cerebrospinal fluid and we reported it here.

This new article, from Stefan Bräuer and al, is both similar and different to those other articles. On one hand the German scientists from Dresden and Rostock tell that ALS CSF degrades motor neurons, but on the other hand it did report of proteinopathies. It is also a study done in dish versus studies done on living animals.

enter image description here

In other studies a multitude of phenotypes linked to ASL-CSF had been observed, including aggregation of transactive response DNA binding protein 43 kDA (TDP-43) in the case of ALS-frontotemporal dementia (FTLD)-CSF, neurofilament abnormalities, gliosis, endoplasmic reticulum (ER)-stress, mitochondrial dysfunction and Golgi fragmentation.

Interesting is the fact that ALS-CSF is able to induce Golgi fragmentation and the inhibition of ER-Golgi trafficking. But this study was not able to induce any proteopathy. enter image description here

The term Golgi fragmentation describes the dispersion of this cisternal structure across the cell. Golgi fragmentation in motoneurons themselves has been reported in different in vitro and in vivo ALS models. It is also present in postmortem sections of ALS patients.

Moreover, Golgi fragmentation is reported in several other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. There is convincing evidence that Golgi fragmentation is an early event in the disease process and not only a consequence of apoptosis but rather inducing it.

Thus, similar to other neurodegenerative disease conditions, Golgi fragmentation in ALS could be an event that takes place before seeding of the aggregates, axon degeneration and manifestation of clinical symptoms occurs.

This new study aimed at learning how ALS-CSF derived from sporadic ALS patients, induces motor neuronal degeneration in human patient-derived induced pluripotent stem cell (iPSC)-derived motoneurons. Only one aspect of ALS (namely a model for spinal cord degeneration), and thus there might be differences when analyzing other neuronal cell populations affected, e.g., cortical neurons.

CSF was collected from 19 patients. The ALS group consisted of 11 patients (3 women and 8 men) with a mean age of 63 years. The group of 8 control patients (3 women and 5 men) had a mean age of 47 years.

The authors did not observe significant neuronal network degeneration, motoneurons-loss or protein aggregates containing SOD1, FUS or TDP-43, which is a bit surprising Since Golgi fragmentation is expected to be an early event in the pathophysiological cascade, it is plausible that it occurs prior to further changes, which could develop either later or under additional stress conditions.

Additionally they did not observed pathological protein mislocalization or aggregate formation when treating monogenetic ALS-patient-derived motoneurons with ALS-CSF

A major concern regards the cellular age. Because iPSC-derived neurons do resemble fetal neurons and are not as old as the ones normally affected in ALS patients, human development takes much longer.

This study does not explain what is the pathologic agent in the CSF. However it is another study that hints that the etiology of ALS is of extracellular origin.

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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.

Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish

Mounir El Maï, Marta Marzullo, Inês Pimenta de Castro, Miguel Godinho Ferreira

Here is an interesting article from the point of view of neurodegenerative diseases. There are terms that resonate with those we are familiar with: ROS, SOD, insulin resistance. Although this article does not apply to neurons (as they do not divide) it could provide a key to ALS and other neurodegenerative diseases. enter image description here * Source: https://elifesciences.org/articles/54935/figures*

Indeed it presents the idea that in a young organism, a defective cell commits suicide and is easily replaced, while in an aged organism a defective cell seeks to subsist despite everything, and that damages the tissue where it is inserted. The determining factor for this change in behavior is the quality control of DNA.

Whenever a chromosome in a eukaryotic cell is replicated, DNA polymerase is unable to copy the last nucleotides. To overcome this problem, the DNA of a chromosome is equipped with a telomer at each end. It is a DNA region at the end of a chromosome, which is without genetic information. During each cell division, the telomeres erode until reaching a critical size.

Stopping the cell cycle allows the cell to stimulate its repair mechanisms, some of which are directly activated by the p53 pathway. When the repair is done, the p53 level returns to normal and the cell cycle resumes. If the damage to the cell cannot be repaired, the cell goes into apoptosis, which leads to its elimination.

Cell proliferation is however possible by inactivation of the p53 pathway. Cells entering proliferation after inactivation of the p53 pathway undergo gross chromosomal rearrangements and genome instability.

In this article, the authors study the effect of reducing telomeres in a model animal (zebrafish) where this reduction is accelerated.

In most eukaryotes, shortening of telomeres is counteracted by telomerase, although its expression is limited in most human somatic cells. As a result, telomeres shorten considerably during human aging. But, and this is not explained in the article, this is only true for cells that are subject to frequent replacement.

Curiously, while neurodegenerative diseases are linked to age, neurons are not subject to the Hayflick limit, even if there is one for glial cells. Perhaps the mechanism described in this article induces neurodegenerative diseases by its action on glial cells ?.

One may wonder to what extent the senescence of neurons and other glial cells leads to proteopathies. For example, if there is not enough energy, the endoplasmic reticulum will not be able to fulfill its role of protein conformation, and similarly the Golgi apparatus will not be able to deliver these proteins to their normal destination. This could lead to proteopathy. enter image description here * Source: Magnus Manske via Wikipedia *

But what motivates this article is that the molecular mechanism determining cell fate (apoptosis or senescence) remains uncertain.

In the present study, the authors describe young zebrafish (3 months old), which are deficient in telomerase already show DNA damage and activation of p53. At this stage, apoptosis is the predominant cellular fate. Even though DNA damage is present in proliferative tissues, such as the intestine and testes, no signs of cellular senescence could be detected. In this study, early activation of p53 in the zebrafish does not affect the function of the mitochondria.

However, there is an obvious change between apoptosis and senescence in older fish. In these animals, senescence becomes the most widespread cellular response. This observation highlights the fact that the same types of cells can undergo different cellular destinies in vivo depending on the age of the animal.

Unlike young fish, the gut and testes of older zebrafish exhibit mitochondrial dysfunction accompanied by a significant reduction in ATP levels (ATP provides the energy necessary for the chemical reactions of cellular metabolism) and an accumulation of ROS (while they are byproducts of normal oxygen metabolism, their concentration can increase significantly in times of stress and damage cell structures).

The study reveals that mitochondrial defects are associated with a reduction in mitochondrial defenses. The authors observe that with age, the expression of SOD2 is reduced in response to activation of AKT pathway.

In humans, there are 3 genes from the Akt family: Akt1, Akt2, and Akt3. These enzymes belong to the family of protein kinases. Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that plays a key role in several cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. AKT is activated on pro-proliferative extracellular signals. The mTOR / AKT pathway is triggered by growth factor receptors, including the insulin growth factor receptor (IGFR).

The anti-proliferative p53 and pro-survival mTOR / AKT pathways interact in complex ways. Depending on the context, the interaction of these pathways modulates cell fate by stopping the cell cycle, apoptosis or senescence. Consistent with these in vitro data, scientists show that activation of AKT in aged mutant zebrafish is concomitant with suppression of apoptosis and activation of mechanisms leading to senescence.

What is the mechanism that switches the cell fate from apoptosis to senescence? A high rate of apoptosis among tissue cells increases the demand for cell proliferation of surrounding cells in a process called compensatory proliferation induced by apoptosis.

On the contrary, the restrictions on cell proliferation cause tissue degeneration which becomes apparent in aging zebrafish.

In tissues where stem cells are not readily available or where tissue-intrinsic genetic programs limit cell division, cell hypertrophy is an alternative strategy to tissue homeostasis.

ProMIS Neurosciences is a biotechnology company focused on the discovery and development of antibody therapeutics intended for neurodegenerative diseases. This biotech has just released an update on several new programs including using intrabodies.

Until now their vaccine platform could rapidly and cost-effectively identify peptide antigens (MHC) and create specifically tailored antibody drugs, diagnostic tools and vaccines. They had work on such a vaccine for SOD1 ALS on the premise that ALS is a prion like disease where a prion like protein moves from cell to cell.

A vaccine is not really applicable to neurons as it would accelerate the progression of the disease, by making the immune system kill any defective neuron. Indeed from birth to death we use the same neurons. As most neurons do not reproduce, if they die, the host would die. So such a vaccine could only apply to the glial cells which are cells that reproduce every few hours.

We can see that making a vaccine for ALS is even more difficult than designing a molecular drug that targets a cell receptor.

Clearly any vaccine designer that wants to address the ALS has to experience a paradigm shift. The problem then is no more to kill the defective cell, but how to heal it.

Intrabodies are somewhat similar to antibodies.

An intrabody (from intracellular and antibody) works within the cell to bind to an intracellular protein. The antibody then activates some cellular mechanism, for example moving the binded protein from one place in the cell to another place, operating some transformation upon it or signaling it as to be recycled.

Intrabodies could be designed to promote degradation of toxic species of TDP-43 while preserving normal forms of the protein. Normal TDP-43 is essential for proper cell function.

One problem is how to introduce the intrabody in the cell. An intrabody is too huge to enter a cell via one cellular pore. A classical solution is to modify the DNA of cells to make the cell produce the intrabodies themselves. Many articles have described the use of gene therapy vectors to introduce intrabodies in a cell and at least two have described this technology for ALS.

An alternative solution is to use a cell penetrating peptide that, when inside the cell, has similar properties to intrabodies.

We have proposed a gene therapy against misfolded TDP-43 early in 2019, following articles by several teams in this area.

This therapy is also presented in our book on ALS research. An alternative with Cell Penetrating Peptides has been presented by the end of 2019.

We had the chance to discuss briefly such mechanisms in a few emails exchanged with Dr. Neil Cashman, ProMIS Neurosciences’ Co-Founder and Chief Science Officer in late November 2019.

ProMIS has now generated several highly selective intrabodies that bind to toxic TDP-43 protein aggregates within cells and promote their degradation without affecting normal TDP-43. This represent a promising first step in the eventual development of a safe and effective therapy for ALS, FTD and other TDP-43-driven disorders. Indeed those intrabodies still need to be introduced in the target cell with some gene therapy vector.

Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins.

Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission.

The authors review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders.

They highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation.

Go here for the section about ALS.

The scientific corpus of medicine has been gradually developed by classifying diseases according to clinical signs, in order to differentiate the treatments. The interpretation of clinical signs is itself relatively subjective. This way of proceeding, differentiating treatments according to clinical signs has been particularly fruitful since the discovery of the concept of pathogen. The causative agent of the disease being capable of being detected by a technological process, of a greater reliability than the interpretation of clinical signs. However, at the end of the 1970s it was noted that progress on non-communicable diseases was slower. As past advances were linked to the introduction of technology into the diagnostic process, there was great hope at the end of the 20th century that genetic technologies could take over. Unfortunately, it is clear that at the start of the 20th century that the announced revolution did not take place.

A striking example concerns ALS (Charcot or Lou Gehrig's disease). The diagnosis of ALS is very slow and the etiology remains absolutely unknown.

ALS is not a homogeneous disease despite a very characteristic phenotype. First, many other diseases have a similar phenotype, some of which are contagious. Some of those that are non-contagious may resemble less acute forms of ALS, for example SCA36.

Among the non-contagious forms, there are those that can be obtained by poisoning, such as BMAA poisoning.

In addition, there are also forms of ALS linked to the patient's genetics (C9orf72, SOD1). These forms have things in common with other diseases such as FTD. We are talking now about spectrum of diseases rather than of different diseases. So the methodology of differentiating treatments according to clinical signs, is no more applicable.

But even obviously different diseases have something in common with ALS, for example a third of Alzheimer's forms show aggregates of the TDP-43 protein, like 95% of cases of ALS.

We therefore have a very murky picture of the clinical signs of ALS, but also of their etiology. For some patients the disease could be of viral or microbial origin, for others it could result from poisoning for still others there could be a genetic origin. Finally aging seems to have an important part in the etiology.

However, researchers have rarely worked on metabolism in the case of ALS. Yet it is known that half of the cases of ALS have an increased metabolism and that also half of the cases of ALS have developed insulin insensitivity. It is estimated that the daily energy deficit of ALS patients is around 400 to 500 kcal. So it could also be possible for neurologists to differentiate ALS patients depending on metabolic dysfunctions, even if this is not done today. A realistic strategy would be to identify treatments and nutritional interventions to improve the survival of ALS patients based on metabolism characteristics.

Many studies have shown a decrease in fat storage and an acceleration of lipolysis in ALS. At the asymptomatic stage, the effect of body fat on the delay in neurodegeneration could be interpreted as a protective effect on the risk of ALS in the population. Compelling observational studies have provided evidence of the time relationship between lifetime body mass index (BMI) and ALS and have suggested that a higher BMI is associated with a lower risk of ALS. Longitudinal cohort studies and case-control studies have consistently indicated that a higher premorbid BMI contributes to a decreased risk of ALS decades later, suggesting that early adiposity, such as birth weight (MI) and childhood BMI can be a factor delaying the onset of ALS in the long term.

But alas a higher consumption of premorbid fat contributes to an increased risk of ALS. This could be explained as follows: A high fat intake leads to dyslipidemia, subsequently increasing the risk of ALS. Studies have shown that higher low density lipoprotein increases the risk of ALS.

However, these observational studies are influenced by the possibility of confounding factors wrongly attributing adiposity to a causal role.

A new study has confirmed the protective nature of early adiposity: Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study. Zhang, Tang, Huang and Fan of Peking University.

A widely used genetic epidemiological method, called Mendelian randomization, has been proposed by the authors to assess the causal relationship between exposures and outcomes, in particular by exploiting significant genetic variants associated with high exposure as instrumental variables. This approach is less likely to lead to biased results resulting from the confusion or reverse causation that exist in observational studies. In addition, the availability of gigantic databases makes this type of study very easy to carry out.

Mononucleotide polymorphisms significantly associated with adiposity during life were used as instrumental variables to estimate the causal effects on ALS. The scientists used summary data from a cohort of 20,806 cases and 59,804 controls for this Mendelian randomization study.

The genetically predicted increase in body fat percentage was associated with a lower risk of ALS. A genetically higher BMI in children was genetically associated with a lower risk of ALS. The weighted median method indicated a suggestive association between BMI and ALS. Neither a genetically predicted increase in birth weight, nor the BMI and the waist / hip ratio adjusted for BMI were associated with ALS.

There are several strengths in this study, including the assessment of lifelong adiposity in relation to ALS, the use of data from large GWAS of adiposity, and the Mendelian randomization design. This design technique minimizes the confusion of known and unknown factors and avoids reverse causation.

Hopefully with the wealth of studies in this field, neurologists and doctors will now explore metabolism dysfunctions in ALS, in order to better diagnose patients and adjust treatments.

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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.

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.

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.

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.

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