Institut du Cerveau https://institutducerveau-icm.org Thu, 20 Jan 2022 09:50:30 +0000 https://wordpress.org/?v=4.9.13 hourly 1 https://wordpress.org/?v=4.9.13 A SYNAPTIC RECEPTOR INVOLVED IN THE EMERGENCE OF ABERRANT BELIEFS https://institutducerveau-icm.org/en/actualite/a-synaptic-receptor-involved-in-the-emergence-of-aberrant-beliefs/ https://institutducerveau-icm.org/en/actualite/a-synaptic-receptor-involved-in-the-emergence-of-aberrant-beliefs/#respond Thu, 20 Jan 2022 09:47:45 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22917 Why are we sometimes inclined to believe in the improbable against all odds? A study conducted at the École Normale Supérieure and Hôpital Sainte-Anne by a team For more information ]]> Why are we sometimes inclined to believe in the improbable against all odds? A study conducted at the École Normale Supérieure and Hôpital Sainte-Anne by a team of neuroscientists and psychiatrists from Inserm, the University of Paris and the Paris Brain Institute, points to a specific synaptic receptor. Its blockage induces premature and aberrant decisions, as well as symptoms resembling those reported in the early stages of psychosis. The results have just been published in Nature Communications.

 

When the world around us becomes unpredictable and uncertain, we become more likely to believe the improbable – such as conspiracy theories during a pandemic. This type of reaction to uncertainty is seen most acutely during the early stages of psychosis: a general sense of strangeness precedes the emergence of delusional beliefs. These early stages of psychosis are difficult to study, as patients only access care when delusional beliefs are already established.

 

The team, led by Valentin Wyart, Inserm research director at the Cognitive and Computational Neuroscience Laboratory (Inserm/ENS-PSL) and Professor Raphaël Gaillard of the University of Paris at Hôpital Sainte-Anne-GHU Paris, studied the role of a specific synaptic receptor called NMDA (N-methyl-D-aspartate) in the emergence of these aberrant beliefs. In the brain, synaptic receptors regulate communication at synapses, the areas of contact between neurons. The researchers did not become interested in this receptor by chance. Indeed, encephalitis caused by an autoimmune reaction against the NMDA receptor is known to give rise to psychotic symptoms.

 

To understand whether an abnormality of this receptor favours the emergence of aberrant beliefs, the team asked a group of healthy volunteers to make decisions based on uncertain visual information while being administered a very low dose of ketamine, a molecule that temporarily blocks the NMDA receptor. By comparing the effects of ketamine with those of a placebo on the behaviour and brain activity of the volunteers tested, the researchers were able to determine the effect of ketamine on the behaviour of the volunteers.

 

In comparing the effects of ketamine with those of a placebo on the behaviour and brain activity of the volunteers tested, the researchers observed that the administration of ketamine produced not only a heightened sense of uncertainty, but also premature decisions.

 

A blockade of the NMDA receptor destabilises decision-making, favouring information that confirms our opinions to the detriment of information that invalidates them,” explains Valentin Wyart. “It is this reasoning bias that produces premature and often erroneous decisions.

 

It is this type of bias that is particularly blamed on social networks, which offer users a selection of information based on their opinions.

 

The team went further by showing that this reasoning bias compensates for the high feeling of uncertainty experienced under ketamine.

This result suggests that the premature decisions we observe are not the consequence of overconfidence,” continues Valentin Wyart. “On the contrary, these decisions seem to be the result of high uncertainty, and provoke the emergence of ideas that are highly improbable, and which are self-reinforcing without being invalidated by external information”

 

These results open up new avenues for the management of patients with psychosis.

Our treatments act on the delusions, but do little to influence what causes them,” explains Raphaël Gaillard. “Clinical trials should therefore be carried out to determine how to increase patients’ tolerance of uncertainty in the early stages of psychosis.”

 

 

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Spinocerebellar ataxia type 2: a therapeutic trial opens new avenues https://institutducerveau-icm.org/en/actualite/spinocerebellar-ataxia-type-2-a-therapeutic-trial-opens-new-avenues/ https://institutducerveau-icm.org/en/actualite/spinocerebellar-ataxia-type-2-a-therapeutic-trial-opens-new-avenues/#respond Wed, 19 Jan 2022 08:39:04 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22897 A clinical trial conducted by Prof. Alexandra Durr's team (Sorbonne University.AP-HP) at the Paris Brain Institute and the Pitié-Salpêtrière Hospital AP-HP shows For more information ]]> A clinical trial conducted by Prof. Alexandra Durr’s team (Sorbonne University.AP-HP) at the Paris Brain Institute and the Pitié-Salpêtrière Hospital AP-HP shows that despite the hopes raised in recent years, riluzole does not improve the clinical or radiological symptoms of patients suffering from spinocerebellar ataxia type 2. However, these results could provide valuable biomarkers for future trials. The results are published in Lancet Neurology.

 

Spinocerebellar ataxias are a group of genetic neurodegenerative diseases, heterogeneous from a clinical and genetic point of view. At present, more than 50 genes have been implicated. The main symptoms are impaired coordination, difficulties with gait balance, dysarthria and impaired ocular movements. There is currently little drug treatment for these conditions.

 

In recent years, positive results of riluzole, a therapeutic molecule already used against amyotrophic lateral sclerosis, had been reported for cerebellar ataxias. However, its effectiveness had not been proven, depending on the different subtypes of this disease. As ataxias differ greatly from one type to another, from one patient to another according to the stage of the disease, precise studies by subtype of ataxia were necessary.

 

Professor Alexandra Durr’s team (Sorbonne University.AP-HP) at the Paris Brain Institute and the Pitié-Salpêtrière University Hospital AP-HP, took up the challenge for spinocerebellar ataxia type 2. The clinical trial ATRIL was conducted on 45 patients at a moderate stage of the disease, in eight reference centers, gathered within the French Neurogene network, a national reference center for rare diseases. In parallel with the treatment, researchers and clinicians acquired MRI data and clinical scores of ataxic symptoms.

 

The results of the study do not report any improvement in clinical or radiological signs in patients with spinocerebellar ataxia type 2, despite a good tolerance and the absence of adverse effects. However, the follow-up of patients during this trial provided valuable clinical and brain imaging data on the progression of the disease. This information could provide new biomarkers of the disease, which are essential for the evaluation of potential new treatments.

 

This result does not exclude a possible beneficial effect in other forms of ataxia but underlines the importance of evaluating treatments in homogeneous groups of patients, including in rare diseases.

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Julia SLIWA and Leonie KOBAN, two researchers from the Paris Brain Institute rewarded by the ERC Starting grant. https://institutducerveau-icm.org/en/actualite/julia-sliwa-and-leonie-koban-two-researchers-from-the-paris-brain-institute-rewarded-by-the-erc-starting-grant/ https://institutducerveau-icm.org/en/actualite/julia-sliwa-and-leonie-koban-two-researchers-from-the-paris-brain-institute-rewarded-by-the-erc-starting-grant/#respond Tue, 11 Jan 2022 09:33:54 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22747

“Letting young talent thrive in Europe and go after their most innovative ideas - this is the best investment in our future, not least with the ever-growing For more information ]]>

“Letting young talent thrive in Europe and go after their most innovative ideas – this is the best investment in our future, not least with the ever-growing competition globally. We must trust the young and their insights into what areas will be important tomorrow. So, I am thrilled to see these new ERC Starting Grant winners ready to cut new ground and set up their own teams.”

Pr Maria Leptin, President of the European Research Council

 

Julia SLIWA, CNRS researcher, develops a project on the neural and neuronal mechanisms that enable transformation of social percepts into social concepts named NEUROSOCIETY.

Dr. Julia Sliwa’s website

 

Leonie KOBAN, CNRS researcher, is interested in how social information, such as other people’s ratings or social feedback and social relationships modulate decision making through the SOCIALCRAVING project.

Dr. Leonie Koban’s website

 

Since its creation in 2010, the Paris Brain Institute hosted 17 ERC grants which encourage the highest quality research in Europe through competitive funding and support investigators for scientific excellence.

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Nicolas Renier (Inserm) receives the FENS EJN Young Investigator Prize 2022 https://institutducerveau-icm.org/en/actualite/nicolas-renier-young-investigator-prize/ https://institutducerveau-icm.org/en/actualite/nicolas-renier-young-investigator-prize/#respond Wed, 05 Jan 2022 13:34:33 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22660 Nicolas Renier (Inserm), head of the "Structural Dynamics of Networks" team at the Paris Brain Institute, is one of the four laureates of the 2022 Young Investigator For more information ]]> Nicolas Renier (Inserm), head of the “Structural Dynamics of Networks” team at the Paris Brain Institute, is one of the four laureates of the 2022 Young Investigator prize of the Federation of European Neuroscience Societies (FENS) and European Journal of Neuroscience

 

Every two years, the FENS and the EJN present their Young Investigator Award to researchers in recognition of their contribution to neuroscience.

 

Among the four winners this year is Nicolas Renier, team leader at the Paris Brain Institute. Since 2017, he and his team have been developing research to understand the mechanisms and impact of brain plasticity during development and adult life. In 2020, he published the first complete mapping of cerebral vasculature in mice, paving the way for research into the role of the blood network in the evolution of many neurological and psychiatric pathologies.

 

For more information: https://institutducerveau-icm.org/en/actualite/the-first-complete-mapping-of-cerebral-vasculature/

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Is falling asleep a creativity booster? https://institutducerveau-icm.org/en/actualite/sleep-and-creativity/ https://institutducerveau-icm.org/en/actualite/sleep-and-creativity/#respond Fri, 10 Dec 2021 11:05:09 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22553 What if a few minutes of sleep could act as a trigger for creativity? This is what a study conducted by researchers from Inserm and Sorbonne University at the Paris For more information ]]> What if a few minutes of sleep could act as a trigger for creativity? This is what a study conducted by researchers from Inserm and Sorbonne University at the Paris Brain Institute and the sleep pathology department at the Pitié-Salpêtrière Hospital (AP-HP) suggests. The results are published in Science Advances.

 

A legend about the inventor Thomas Edison says that he used to take short naps to stimulate his creativity. During these naps, he held a metal ball in his hand. The ball would fall noisily when he fell asleep and wake him up just in time to record his creative flashes. Other famous people were also proponents of using short phases of sleep to stimulate their creative ability, such as Albert Einstein and Salvador Dali.

Inserm researcher Delphine Oudiette and her collaborator Célia Lacaux at the Institut du Cerveau and the Pitié-Salpêtrière Hospital (AP-HP) were inspired by this story and wanted to explore this very particular phase of sleep. The scientists wanted to determine whether this phase did indeed have an effect on creativity.

To do this, the team proposed mathematical problems to 103 participants, all of which could be solved almost instantly using the same rule, which was of course unknown to the participants at the start of the test. The subjects tried to solve the problems a first time. All those who had not found the hidden rule were invited to take a twenty-minute nap under the same conditions as Edison, with an object in their hand, before taking the mathematical tests again.

“Spending at least 15 seconds in this very first phase of sleep after falling asleep tripled the chances of finding this hidden rule, through the famous “Eureka! This effect disappeared if the subjects went deeper into sleep,” explains Célia Lacaux, the study’s first author. At the same time, the researchers highlighted several key neurophysiological markers of this creativity-generating sleep phase.

 

There is therefore a phase conducive to creativity at the time of falling asleep. To activate it, we need to find the right balance between falling asleep quickly and not falling asleep too deeply. These “creative naps” could be an easy and accessible way to stimulate our creativity in everyday life.

“The sleep phase has been relatively neglected by cognitive neuroscience until now. This discovery opens up an extraordinary new field for future studies, especially of the brain mechanisms of creativity. Sleep is also often seen as a waste of time and productivity. By showing that it is in fact essential to our creative performance, we hope to reiterate its importance to the public,” concludes Delphine Oudiette, Inserm researcher and final author of the study.

Sources

Sleep onset is a creative sweet spot

Célia Lacaux1, Thomas Andrillon1, Céleste Bastoul1, Yannis Idir1, Alexandrine Fonteix-Galet1, Isabelle Arnulf1,2, Delphine Oudiette1,2*

1 Sorbonne University, Paris Brain Institute – ICM, Inserm, CNRS, Paris 75013, France

2 AP-HP, Hôpital Pitié-Salpêtrière, Service des Pathologies du Sommeil, National Reference Centre for Narcolepsy, Paris 75013, France

Science Advances, December 2021

Contact researcher

Delphine Oudiette

E-mail: delphine.oudiette@icm-institute.org

Telephone on request

Press contact: presse@inserm.fr

Go to the Inserm press room

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Prof. Catherine Lubetzki, winner of the Prize Pasteur-Weizmann / Servier 2021 https://institutducerveau-icm.org/en/actualite/prof-catherine-lubetzki-winner-of-the-prize-pasteur-weizmann-servier-2021/ https://institutducerveau-icm.org/en/actualite/prof-catherine-lubetzki-winner-of-the-prize-pasteur-weizmann-servier-2021/#respond Thu, 09 Dec 2021 16:46:27 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22549 Prof. Catherine Lubetzki, winner of the Prize Pasteur-Weizmann / Servier 2021 for her work on myelin regeneration in the treatment of multiple sclerosis

Awarded For more information ]]> Prof. Catherine Lubetzki, winner of the Prize Pasteur-Weizmann / Servier 2021 for her work on myelin regeneration in the treatment of multiple sclerosis

Awarded every three years, the Prize Pasteur-Weizmann / Servier rewards an internationally recognised researcher, doctor or scientist and/or his or her team for a major contribution to a biomedical discovery leading to a therapeutic application.

The Prize Pasteur-Weizmann / Servier dedicated this year to neurodegenerative pathologies has been awarded to Professor Catherine Lubetzki, Head of the Neuroscience Department of AP-HP Sorbonne University and Medical Director of the Brain Institute. It honours the career of a clinical researcher mainly dedicated to MS who has constantly combined basic research with her clinical activity of therapeutic management and support for many MS patients.

The Paris Brain Institut is delighted to receive this award, which recognises the work of Catherine Lubetzki and her team in developing experimental models, understanding the mechanisms involved and identifying therapeutic targets, leading to the initiation of therapeutic trials in patients with multiple sclerosis. In addition, the imaging work carried out under the supervision of Prof. Bruno Stankoff, who co-leads the research team, has made it possible to quantify demyelination and remyelination in humans and has thus highlighted inter-individual heterogeneity in myelin repair capacities.

The prize of 250,000 euros will be awarded to the research team “Remyelination in multiple sclerosis: from biology to clinical translation” co-directed by Professors Catherine Lubetzki and Bruno Stankoff at the Paris Brain Institute.

 

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Cardiac investigations in genetic epilepsy https://institutducerveau-icm.org/en/actualite/cardiac-investigations-in-genetic-epilepsy/ https://institutducerveau-icm.org/en/actualite/cardiac-investigations-in-genetic-epilepsy/#respond Wed, 24 Nov 2021 10:24:13 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22477 A rare and tragic consequence of epilepsy is Sudden Unexpected Death in Epilepsy (SUDEP), which occurs after a seizure. The mechanisms involved, whether respiratory, For more information ]]> A rare and tragic consequence of epilepsy is Sudden Unexpected Death in Epilepsy (SUDEP), which occurs after a seizure. The mechanisms involved, whether respiratory, cardiac or cerebral, are not yet fully understood. However, this risk is very low, about 1 per 1000 patients with epilepsy. A study led by Alexandre Bacq in Stéphanie Baulac’s (Inserm) “Genetics and Pathophysiology of Epilepsy” team at the Institut du Cerveau, looked at cardiac functions in a cohort of patients at risk of SUDEP and using mouse models of SUDEP. The results, published in Annals of Neurology, have a direct impact on the management of patients, suggesting that certain heavy cardiac examinations could be avoided, and pave the way for new research on the brain mechanisms in SUDEP.

In 2019, Stéphanie Baulac’s team at the Brain Institute had highlighted that the risk of sudden death is higher in drug-resistant epilepsy linked to mutations in the DEPDC5 gene, a player in the mTOR signalling pathway. Other epilepsy genes are associated with SUDEP, including those coding for ion channels. Mutations in these genes result in cardiac defects. Is this the case in patients with a DEPDC5 mutation?

To answer this question, Alexandre Bacq and colleagues assembled a cohort of patients with a DEPDC5 mutation – considered to be at risk of SUDEP – and collected electrocardiogram (ECG), holter (24-hour ECG up to 8 days), and structural investigations by transthoracic echography. No major cardiac abnormalities were identified in the 16 patients studied. Three of these patients subsequently died of SUDEP. The researchers had access to the post-mortem heart tissue of one of them and did not observe any abnormalities such as fibrosis or thrombosis.

In order to further explore the mechanisms at play during SUDEP and to ‘counteract’ the limitations of the human study, the researchers turned to the study of the heart and brain of a genetic mouse model of DEPDC5 deficiency. To do this, they generated a new model of epilepsy and SUDEP that mimics the human genetic etiology. As in patients, the rodents show no cardiac predisposition or variations in heart rate in the basal state. During the fatal seizure, the cardiac arrhythmia classically found during an epileptic seizure is not present at the beginning of the cerebral crisis.

These findings have a first direct consequence on the management of patients with a DEPDC5 gene mutation at high risk of SUDEP, by suggesting that burdensome cardiac examinations for patients could be limited. If the DEPDC5 gene mutation is not associated with cardiac dysfunction, what is the origin of SUDEP? The answer may lie in the brain, for example in the brainstem, which controls cardiorespiratory functions. Future research on brain activity during SUDEP should help to elucidate the mechanisms behind this tragic consequence of epilepsy.

Source

Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I, Picard F, Navarro V, Sisodiya S and Baulac. Cardiac investigations in sudden unexpected death in DEPDC5-related epilepsy. Annals of Neurology. Oct 24. doi: 10.1002/ana.26256

Translated with www.DeepL.com/Translator (free version)

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Detecting the occurrence of auditory hallucinations from brain activity in schizophrenia https://institutducerveau-icm.org/en/actualite/detecting-the-occurrence-of-auditory-hallucinations/ https://institutducerveau-icm.org/en/actualite/detecting-the-occurrence-of-auditory-hallucinations/#respond Thu, 18 Nov 2021 11:12:27 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22420 A study conducted by Renaud Jardri, Professor at the University of Lille and child psychiatrist at the University Hospital of Lille (Inserm Unit U-1172, University For more information ]]> A study conducted by Renaud Jardri, Professor at the University of Lille and child psychiatrist at the University Hospital of Lille (Inserm Unit U-1172, University of Lille, University Hospital of Lille – Lille Neuroscience & Cognition), Dr Philippe Domenech at the Brain Institute, and their collaborators, shows that it is possible to predict the occurrence of auditory hallucinations in schizophrenia patients thanks to the combination of functional MRI and artificial intelligence algorithms. These results, published in Biological Psychiatry, pave the way for the development of new neuromodulation and closed-loop neurofeedback therapies to treat these hallucinations.

Abstract

Functional magnetic resonance imaging (fMRI) capture aims at detecting auditory-verbal hallucinations (AVHs) from continuously recorded brain activity. Establishing efficient capture methods with low computational cost that easily generalize between patients remains a key objective in precision psychiatry. To address this issue, we developed a novel automatized fMRI-capture procedure for AVHs in patients with schizophrenia (SCZ).

We used a previously validated but labor-intensive personalized fMRI-capture method to train a linear classifier using machine learning techniques. We benchmarked the performances of this classifier on 2320 AVH periods versus resting-state periods obtained from SCZ patients with frequent symptoms (n = 23). We characterized patterns of blood oxygen level-dependent activity that were predictive of AVH both within and between subjects. Generalizability was assessed with a second independent sample gathering 2000 AVH labels (n = 34 patients with SCZ), while specificity was tested with a nonclinical control sample performing an auditory imagery task (840 labels, n = 20).

Our between-subject classifier achieved high decoding accuracy (area under the curve = 0.85) and discriminated AVH from rest and verbal imagery. Optimizing the parameters on the first schizophrenia dataset and testing its performance on the second dataset led to an out-of-sample area under the curve of 0.85 (0.88 for the converse test). We showed that AVH detection critically depends on local blood oxygen level-dependent activity patterns within Broca’s area.

Our results demonstrate that it is possible to reliably detect AVH states from fMRI blood oxygen level-dependent signals in patients with SCZ using a multivariate decoder without performing complex preprocessing steps. These findings constitute a crucial step toward brain-based treatments for severe drug-resistant hallucinations.

Source

https://pubmed.ncbi.nlm.nih.gov/34742546/

 

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A new model for therapeutic research in Creutzfeldt-Jakob disease https://institutducerveau-icm.org/en/actualite/a-new-model-for-therapeutic-research-in-creutzfeldt-jakob-disease/ https://institutducerveau-icm.org/en/actualite/a-new-model-for-therapeutic-research-in-creutzfeldt-jakob-disease/#respond Wed, 17 Nov 2021 10:59:21 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22398 What if a worm allowed a quantum leap in research on prion diseases such as Creutzfeldt-Jakob disease? A recent study by Nicolas Bizat (University of Paris) and For more information ]]> What if a worm allowed a quantum leap in research on prion diseases such as Creutzfeldt-Jakob disease? A recent study by Nicolas Bizat (University of Paris) and Stéphane Haïk (Inserm) at the Paris Brain Institute, published in the journal Brain, suggests the potential of this model for therapeutic research and identifies five promising molecules for these diseases.

 

Abstract

 

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival.

Image of a nematode (C. elegans) expressing the human prion protein in the mechanosensory system (green)

Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system.

Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental

system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood–brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals.

 

This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.

 

Source

An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases. Bizat N, Parrales V, Laoues S, Normant S, Levavasseur E, Roussel J, Privat N, Gougerot A, Ravassard P, Beaudry P, Brandel JP, Laplanche JL, Haïk S.Brain. 2021 Oct 22;144(9):2745-2758.

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ANR 2021 call for projects: a record success rate for researchers at the Paris Brain Institute https://institutducerveau-icm.org/en/actualite/anr-2021/ https://institutducerveau-icm.org/en/actualite/anr-2021/#respond Fri, 29 Oct 2021 08:00:53 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22196 Once again, this year, the researchers at the Paris Brain Institute have met with great success in the generic call for projects of the Agence nationale de la For more information ]]> Once again, this year, the researchers at the Paris Brain Institute have met with great success in the generic call for projects of the Agence nationale de la Recherche (ANR, French National Research Agency).

 

The call for projects of the French National Research Agency funds innovative research projects from all actors of the scientific community, according to four categories: JCJC (Young Researcher), PRC (Collaborative Research Project), PRCE (Collaborative Research Project – Company), PRCI (Collaborative Research Project – International).

 

19 projects were selected this year, a record rate of 38% for Paris Brain Institute’s researchers.

 

Congratulations to all the winners for this record success rate, which underlines the quality and innovative nature of the projects conducted at the Institute. This funding is essential for the continuation of our research and is a real gas pedal for the progress of knowledge on the brain and its pathologies.” Prof. Alexis Brice, Director General of the Paris Brain Institute.

 

The Paris Brain Institute’s projects selected by the ANR 2021 Generic Call for Projects:

 

ASCENTS PRC Investigating a newly identified structural asymmetry of the vertebrate Claire Wyart
BBDMI PRCE Brain Body Digital Musical Instruments Vincent NAVARRO
CADICI JCJC An endocannabinoid-induced switch in cortical disinhibitory circuits Joana LOUENCO
DecoSensoMoL1 PRC Decoding sensorimotor integration through cortical Layer 1 microcircuits Nelson REBOLA
DISCOMMODE PRC Dissection of molecular and neural circuits underlying impulse control disorders: A translational approach Jean-Christophe CORVOL
DUALTRACK JCJC Adaptation vs Interruption: the dual nature of the human medial prefrontal cortex Philippe DOMENECH
EPIDEV PRC Cortical defects: from mTOR activation to neuronal hyperexcitability Stéphanie BAULAC
FAB PRC Non-invasive gene therapy for Parkinson disease: Improve delivery of AAV vectors by single Intravenous delivery combined with Focused UltraSound (FUS). Françoise PIGUET
FIBERSHAPE JCJC Understanding how Reissner’s fiber in cerebrospinal fluid contributes to posterior axis shape acquisition Yasmine CANTAUT BELARIF
IMMUNE-PARK PRCI Exploring immune-related pathways in familial forms of Parkinson’s disease Olga CORTI
KETABELIEF JCJC Ketamine and belief updating: Neurocognitive mechanisms in the treatment of depressive disorder. Liane SCHMIDT
MOTOMYO PRC Matching motoneuron and myofiber subtypes: from embryonic development to pathogenesis Claire Wyart
NeuroNPP PRC Control of neuronal cell number and fate by the interplay of temporal regulation of Notch activity and post-translational modification of Proneural Proteins Bassem HASSAN
PREDITOC PRC Detection, prediction and monitoring of compulsions Eric BURGUIERE
RADIO-AIDE PRCE RADIation-induced neurOtoxicity assessed by spatio-temporal modelling combined with Artificial Intelligence after brain raDiothErapy Nadya PYATIGORSKAYA
RELATIVE PRC Relative value learning: computational processes and neural foundations Sébastien BOURET
RESTORE PRC Development of kallikrein-related peptidase 6 inhibitors to treat MS Brahim NAIT OUMESMAR
SocialNeuroNet PRC Neuroimaging of social networks in semi-free ranging monkeys Julia SLIWA
VAMPHEARS PRC Development and Plasticity of the Auditory Cerebrovasculature Nicolas RENIER

 

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A X-linked modifier of the age at onset in the C9orf72 frontotemporal lobar degeneration https://institutducerveau-icm.org/en/actualite/xlinked-lobardegeneration/ https://institutducerveau-icm.org/en/actualite/xlinked-lobardegeneration/#respond Wed, 27 Oct 2021 10:22:22 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22214 In the September issue of Brain, Mathieu Barbier and Isabelle Le Ber from Paris Brain Institute report the finding of a X-linked modifier of the age at onset in the For more information ]]> In the September issue of Brain, Mathieu Barbier and Isabelle Le Ber from Paris Brain Institute report the finding of a X-linked modifier of the age at onset in the C9orf72 disease “SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration”.

The pathogenic G4C2 repeats expansion is a major cause of hereditary frontotemporal dementia (FTD) as well as amyotrophic lateral sclerosis (ALS). Carriers of this expansion often present with a highly variable phenotype including heterogeneous clinical picture and variable age at onset. Indeed, patients can develop symptoms from the third decade of life to nearly incomplete penetrance in elderly carriers. To date, this phenotypical variability is poorly understood.

In this work, Mathieu Barbier and Dr. Isabelle Le Ber (Durr/Stevanin’ team) pursued their investigations in the field through Genome Wide Association Studies (GWAS). To get around the problematic of rare diseases which subsequently limits the size of cohorts, they included relatives, all carriers of the C9orf72 pathogenic expansion, with either highly concordant or discordant age at onset. This design was actually used in pioneer genetic studies in which the inclusion of highly informative relatives was privileged. Through this discovery cohort and multiple waves of replications with unrelated individuals from different international consortia, and the use of different statistical methodologies, the authors highlighted a polymorphism robustly associated with the age at onset. This polymorphism (rs1009776) lies on chromosome X, upstream of the gene SLITRK2 encoding for a post-synaptic transmembrane protein involved in the development of excitatory synapses.

In addition, they performed functional studies on brain tissue from C9orf72 expansion carriers with different rs1009776 genotypes. In particular the synaptic vesicular pathway, which is known to be affected in the C9orf72 pathology seems to be more preserved in patients carrying the allele associated with a late onset conversely to the others.

Thus, this work is original in several ways:

  • First, the original GWAS design including highly informative relatives. This design could be of interest especially in the context of rare diseases.
  • Second, the highlighting of an X-linked modifier (the X-chromosome being often neglected in GWAS although it carries about 800 genes).
  • Third, from the identification of this modifier and subsequent functional investigations, results suggest that preservation synaptic vesicular pathway may delay the appearance of symptoms in C9orf72 expansion carriers.

 

Source

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration. Mathieu Barbier, et al. Brain, Volume 144, Issue 9, September 2021, Pages 2798–2811

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Thinking collectively to understand the social intelligence of animals https://institutducerveau-icm.org/en/actualite/thinking-collectively/ https://institutducerveau-icm.org/en/actualite/thinking-collectively/#respond Fri, 22 Oct 2021 08:45:32 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22163 What if, in order to understand the social intelligence of animals, including humans, we had to study the brain at the group level and not only at  the individual For more information ]]> What if, in order to understand the social intelligence of animals, including humans, we had to study the brain at the group level and not only at  the individual level? This is a perspective put forward by Julia Sliwa, a CNRS researcher at the Paris Brain Institute, in the journal Science.

All animals evolving in social groups, from ants to humans, birds and monkeys, adapt their behaviour to the group. The group represents a considerable evolutionary advantage for many species. It allows them to find solutions or accomplish tasks that are impossible to achieve alone: from reducing predation to building habitats, from ant hills to human cities. These behaviours arise from social interaction, be it verbal or non-verbal communication, mimicry, memorisation, or other signalling processes.

 

From ethology to social neuroscience

Research in ethology has already revealed collective decision-making within social groups of animals. These decisions are made by individuals without them realising that it is a collective effort, but simply by having one-to-one interactions that gradually guide the whole group in the same direction. This is for example the case with some birds such as starlings when they fly. By computer modelling interactions, it is even possible to simulate what type of collective behaviour would emerge from these interactions, by varying the skills of the individuals in the group, such as memory and the ability to signal information to others.

But what happens in the brains of these individuals when they interact and make individual decisions within groups? Until now, neuroscience has mainly studied animal intelligence at the level of an individual brain in isolation. However, it is quite possible that the brain of this animal changes its functioning when it evolves within a group. Technological advances in brain imaging now make it possible to make electroencephalographic recordings, i.e. of the brain’s electrical activity, using portable machines. The study of social cognition has thus been able to move out of the laboratory and into ‘real life’. We now know that in humans, within a group, the electrical activity of the brains of the individuals that make up the group can be synchronised during various social interactions, from communication to learning.

 

Towards a collective approach of social intelligence

Two recent publications in the journal Science focus not only on how animals perceive the social interactions of others but also on how they experience them, i.e. how they interact with others. The other major novelty of their approach is that they look not only at two-to-two interactions but also at all interactions within the group, potentially a very large number of interactions at the same time. The synchronisation phenomenon already observed in humans also exists in other primates and bats, suggesting a mechanism that is conserved at least in mammals. Moreover, while humans and several primates are individually able to represent group decisions, many other animals, especially insects, are not. How this ability is encoded in the brain is a new field of research that these publications started to uncover.

Finally, could the key to social intelligence lie in the synchronisation of the brains, allowing group interactions to be made? If so, should social neuroscience now focus on the group rather than the individual? Above all, this work suggests the importance of studying social intelligence at both scales. Another perspective would be to extend group interaction from the real to the virtual, to explore the new collective dynamics resulting from the use of social networks on the internet.

Source

Sliwa J. Toward collective animal neuroscience. Science. 2021 Oct 22;374(6566):397-398. doi: 10.1126/science.abm3060. Epub 2021 Oct 21. PMID: 34672744.

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New data on inflammation in multiple sclerosis using PET-MRI https://institutducerveau-icm.org/en/actualite/news-data-sclerosis/ https://institutducerveau-icm.org/en/actualite/news-data-sclerosis/#respond Wed, 20 Oct 2021 18:00:54 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22117
Several studies by Prof. Bruno Stankoff's team "Remyelination in multiple sclerosis: from biology to clinical translation", highlight new mechanisms of brain For more information ]]>

Several studies by Prof. Bruno Stankoff’s team “Remyelination in multiple sclerosis: from biology to clinical translation”, highlight new mechanisms of brain inflammation in multiple sclerosis, thanks to new imaging tools based on the combination of magnetic resonance imaging (MRI) and positron emission tomography (PET).

Using PET-MRI, Prof. Stankoff’s team has just published in the journal Radiology the results of a study of 97 MS patients and 44 healthy controls showing abnormalities (increased volume and inflammation) in the choroid plexuses of the patients. The choroid plexuses are structures located in the cerebral ventricles responsible for the production of cerebrospinal fluid, and act as a barrier between the nervous system and the immune system.

These choroidal plexus abnormalities were correlated with brain inflammation, indicating disease activity. These results open a new avenue for the application of imaging of this structure as a marker of the immune response in the brain and point to the choroid plexus as an important player in the pathophysiology of the disease.

The choroïd plexuses (circled in red) of MS patients with a remitting form are larger (on the right) than healthy controls’ (on the left)

 

Work by the same team published in the journal Neurology, shows activation of innate immune cells associated with white matter micro-lesions in MS patients with worsening disability, and that this immune activation follows a gradient centered around the cerebral ventricles, which contain cerebrospinal fluid.

 

These results obtained thanks to the combination of PET targeting innate immune cells and MRI confirm the existence of a correlation between the activation of these cells around the ventricles, privileged areas of MS lesions in contact with cerebrospinal fluid (CSF), and the worsening of the disability in patients. This suggests that molecules contained in the CSF could worsen the inflammation present in the white matter of patients and thus promote a deleterious evolution of the disease, making these molecules candidates for future research into treatments.

Activated innate immune cells in a patient with MS using PET-scan around ventricles.

 

Source

Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis. Poirion E, Tonietto M, Lejeune FX, Ricigliano VAG, Boudot de la Motte M, Benoit C, Bera G, Kuhnast B, Bottlaender M, Bodini B, Stankoff B. Neurology. 2021 Apr 6;96(14):e1865-e1875.

 

Choroid Plexus Enlargement in Inflammatory Multiple Sclerosis: 3.0-T MRI and Translocator Protein PET Evaluation. Ricigliano VAG, Morena E, Colombi A, Tonietto M, Hamzaoui M, Poirion E, Bottlaender M, Gervais P, Louapre C, Bodini B, Stankoff B. Radiology. 2021 Oct;301(1):166-177.

 

Positron emission tomogramphy in multiple sclerosis – straight to the target. Bodini B, Tonietto M, Airas L, Stankoff B. Nat Rev Neurol. 2021 Sep 20.

 

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Discover the Paris Brain Institute https://institutducerveau-icm.org/en/actualite/discover/ https://institutducerveau-icm.org/en/actualite/discover/#respond Tue, 19 Oct 2021 09:51:46 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22110 https://youtu.be/qxmBW3kNo5k

Discover our institute

Paris Brain Institute (ICM) is a research center of international dimension,  innovative in its conception as in For more information ]]>

Discover our institute

Paris Brain Institute (ICM) is a research center of international dimension,  innovative in its conception as in its organization. By bringing together patients, doctors and researchers in the same place, the objective is to enable the rapid development of treatments for nervous system injuries in order to apply them to patients as quickly as possible. Coming from all horizons and all countries, the best scientists develop the most advanced research in this field.

 

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World Mental Health Day https://institutducerveau-icm.org/en/actualite/world-mental-health-day/ https://institutducerveau-icm.org/en/actualite/world-mental-health-day/#respond Sun, 10 Oct 2021 08:06:23 +0000 Théophile Lacrampe https://institutducerveau-icm.org/?post_type=actualite&p=22059 If we need to take care of our mental health every day, World Mental Health Day, held every October 10, is an opportunity to bring this essential component of our For more information ]]> If we need to take care of our mental health every day, World Mental Health Day, held every October 10, is an opportunity to bring this essential component of our lives back into focus. The events of the Covid-19 pandemic have also had a heavy impact on our mental health. It is essential to talk about it!

 

Mental health is an essential component of our health, defined by the WHO as “a state of well-being in which a person can achieve personal fulfillment, cope with the normal stresses of life, do productive work, and contribute to his or her community. In this positive sense, mental health is the foundation for an individual’s well-being and for the proper functioning of a community.

 

This definition covers many aspects, from the development of the individual to the protection of his or her psychological balance. Mental health therefore goes far beyond the pathological dimension, but since more than one adult in four is or will be affected by a psychiatric disorder during his or her lifetime, it is important to shed light on what these conditions are and their impact on the lives of the people they affect.

 

Psychiatric disorders represent a major public health issue today. Although their therapeutic management has progressed considerably thanks to research, societal prejudices persist. These distorted views of reality, fueled by media coverage of violent but “rare” events (less than 1% of patients being potentially dangerous to others), still lead to discrimination and a significant delay in the diagnosis of patients. The association between psychiatry and madness is unfortunately still widespread in society’s beliefs. Nowadays, psychiatric disorders benefit from appropriate care and effective treatments that allow patients to continue their social, family and professional life.

 

Innovative targeted and personalized therapies

 

The treatment of patients with psychiatric disorders is multidisciplinary and must combine psychotherapy, drug treatments, and new therapeutic technologies. Clinicians and researchers at the Paris Brain Institute, in close collaboration with the adult psychiatry department of the Pitié-Salpêtrière Hospital (AP-HP), have as their main objective to develop the use of existing and effective technologies in more pathologies, but also to allow therapies to be adapted to each patient.

 

New ways to treat psychiatric disorders

 

These “new generation” therapies are generally associated with psychotherapy and drug treatments specific to each psychiatric disorder.

 

Virtual reality

The objective of this therapy is to allow the patient to gradually tame anxiety-provoking situations and to desensitize himself. Equipped with a 3D headset projecting a scene that usually provokes his disorder, the patient can progress without risk since he knows that he is only facing virtual dangers.

 

Transcranial magnetic stimulation

Transcranial magnetic stimulation consists of using a magnetic field to modify the electrical activity in the cerebral cortex. This technology has shown its effectiveness in cases of severe depressive syndromes, but also in cases of auditory hallucinations in schizophrenic patients. It is currently being evaluated for OCD and addictions.

 

Deep brain stimulation

In cases of severe depression or OCD, resistant to other therapies, deep brain stimulation is indicated. These stimulations are performed with electrodes implanted in specific regions of the brain. They deliver permanent electrical stimulation to the neurons in very specific areas of the brain. Researchers at the Paris Brain Institute are pioneers in the use of deep brain stimulation in many neurological and psychiatric pathologies, such as Parkinson’s disease or Tourette’s syndrome, for example.

 

E-psychiatry

The development of “connected” devices allowing access to clinical information in real time in the patient’s natural environment is beginning to change the way psychiatric disorders are managed. In the case of suicidal tendencies, for example, variables such as appetite and sleep appear to be very informative for the clinician in predicting and preventing a possible act.

The Covid-19 pandemic: a heavy impact on our mental health

 

The Covid-19 pandemic, the successive confinements and the multiple changes of sanitary rules, more globally the uncertainty that this crisis has generated in our lives, have had a heavy impact on our psychic well-being and repercussions on our mental health. Cases of anxiety and depression have increased in the last year and a half in the general population. Psychiatrists have identified several reasons for these disorders: anxiety about being contaminated, about contaminating one’s loved ones, uncertainty about the future, and the many constraints in daily life imposed by the health situation.

 

 

 

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Our checking behaviours deciphered by experimental psychology! https://institutducerveau-icm.org/en/actualite/our-checking-behaviours-deciphered-by-experimental-psychology/ https://institutducerveau-icm.org/en/actualite/our-checking-behaviours-deciphered-by-experimental-psychology/#respond Fri, 24 Sep 2021 12:51:43 +0000 Nicolas BRARD https://institutducerveau-icm.org/?post_type=actualite&p=21891 We engage in checking behaviours on a daily basis. In certain pathologies such as OCD, these behaviours can be exacerbated and greatly disturb the quality of life of For more information ]]> We engage in checking behaviours on a daily basis. In certain pathologies such as OCD, these behaviours can be exacerbated and greatly disturb the quality of life of patients. A study conducted by Axel Baptista (AP-HP/Sorbonne University), Maxime Maheu (UKE Hamburg), Luc Mallet (AP-HP/Université Paris-Est Créteil) and Karim N’Diaye (CNRS) at the Paris Brain Institute shows that these checking behaviours are modulated by two cognitive mechanisms: metacognition and self-beliefs. The results are published in Scientific Reports.

 

The decisions we make every day include an element of uncertainty. To reduce this uncertainty and thus facilitate our choices, we carry out verification behaviours, such as listening several times to a message on the answering machine when the sound quality is poor. In some psychiatric conditions, such as obsessive-compulsive disorder (OCD), these checks are exacerbated and greatly handicap patients in their daily lives. While we experience these behaviours all the time, their brain mechanisms and disruptions in OCD are poorly understood.

“This spontaneous behaviour is not easy to explore in the laboratory, particularly in healthy participants. To do this, we had to set up a specific computer test in which the participants would be inclined to view the same stimulus several times,” explains Karim N’Diaye, head of the PRISME core facility dedicated to behavioural studies at the Paris Brain Institute, the last author of the study.

The task in question consisted of participants giving the direction of the global movement of a cloud of animated dots. The degree of difficulty was also adapted individually. In parallel, the researchers measured obsessive-compulsive tendencies, such as the propensity to check that the gas is turned off, as well as metacognitive beliefs, such as the extent to which the participants trust their memory, using standardised questionnaires.

 

“We put a lot of effort into the methodological rigour and then the statistical analysis of the data to show that the subjective evaluation of our degree of uncertainty does modulate the tendency to check, but that this seems to be relatively limited to the uncertainty that we apprehend explicitly, i.e. the uncertainty that we become aware of when we are asked to evaluate our confidence in a decision,” explains Axel Baptista, first author of the publication.

 

The link between subjective uncertainty and verification behaviour is also modulated by negative metacognitive beliefs – the fact of not trusting one’s “cognitive abilities”. These beliefs tend to decouple verification behaviour from the degree of uncertainty. Finally, the researchers show in this study that obsessive-compulsive tendencies, in these healthy participants, exacerbate the link between uncertainty and checking. This may seem paradoxical insofar as OCD patients spontaneously report suffering from feeling compelled to check, while being aware that it is probably unnecessary.

This study will allow further work to confirm these mechanisms, and to study them in populations of patients with neuropsychiatric disorders like OCD. Indeed, it is suspected that these mechanisms are altered in this condition. Overall, this work could lead to a better understanding of the link between uncertainty, metacognition and OCD.

 

 

Source

Baptista A, Maheu M, Mallet L, N’Diaye K (2021). Joint contributions of metacognition and self-beliefs to uncertainty-guided checking behaviorSci Rep, 2021. doi: 10.1038/s41598-021-97958-1

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ECOCAPTURE@HOME: assessing apathy and its consequences in everyday life https://institutducerveau-icm.org/en/actualite/ecocapturehome-assessing-apathy-and-its-consequences-in-everyday-life/ https://institutducerveau-icm.org/en/actualite/ecocapturehome-assessing-apathy-and-its-consequences-in-everyday-life/#respond Thu, 23 Sep 2021 11:16:46 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21824 Apathy, a pathological absence of motivation and emotion, is a common symptom of many neurological and psychiatric diseases, such as dementia or depression. The For more information ]]> Apathy, a pathological absence of motivation and emotion, is a common symptom of many neurological and psychiatric diseases, such as dementia or depression. The ECOCAPTURE@HOME program, developed by researchers and clinicians at the Paris Brain Institute, aims to establish a precise diagnosis of apathy and to set up personalised care for patients.

 

Apathy is the most common neuropsychiatric symptom in neurodegenerative diseases such as Alzheimer’s, Parkinson’s or fronto-temporal degeneration. It is associated with greater cognitive impairment and an overall deterioration in the quality of life of patients and their carers. Indeed, this pathological loss of motivation makes daily activities a real challenge.

Drug treatments for apathy, mainly antidepressants, show only moderate effects. Non-medicinal approaches such as psychotherapy require a very precise assessment of the degree of apathy in each patient in order to propose personalised treatment and hope for an improvement in symptoms.

“Define and assess apathy is far from obvious. Apathy can take many different forms and clinical assessment scales are biased by the subjectivity of the evaluator, usually the patient themselves or their carer“ explains Valérie Godefroy, first author of the study and post-doctoral fellow under the supervision of Bénédicte Batrancourt (Inserm) and Richard Lévy (AP-HP/Sorbonne University) at the Paris Brain Institute’s Frontlab.

The ECOCAPTURE programme, led at the Paris Brain Institute by Bénédicte Batrancourt (Inserm) and Richard Lévy (AP-HP/Sorbonne University), aims to develop new approaches to measuring apathy. It has recently defined several forms of the behavioural variant of frontotemporal dementia (FTD), through evaluation in the functional exploration room of the PRISME core facility.

In order to be as close as possible to the real-life conditions of patients, one of the objectives of ECOCAPTURE is to bring its assessment tools directly to their homes. This study, ECOCAPTURE@HOME, has been set up to validate a method for monitoring apathy at a distance. To do this, the researchers and clinicians at the Brain Institute wish to recruit 40 patient-caregiver pairs, 20 for Alzheimer’s disease, 20 for the behavioural variant of FTD, and 20 control subjects without pathology. The data will be acquired using a connected watch and questionnaires on a smartphone application.

“Our objective is to validate the relevance of our measurement method based on three behavioural markers of apathy: daytime activity, sleep quality and the emergence of emotions. If the results are positive, ECOCAPTURE@HOME could enable a better diagnosis of apathy in order to implement personalised management in the daily lives of patients,” concludes Bénédicte Batrancourt, the study’s last author.

 

The Paris Brain Institute thanks the Malakoff Humanis group for its support of the Ecocapture project.

Source

ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences. Godefroy V, Levy R, Bouzigues A, Rametti-Lacroux A, Migliaccio R, Batrancourt B. Int J Environ Res Public Health. 2021 Jul 2

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Discovery of the association between two key cellular mechanisms of Alzheimer’s disease https://institutducerveau-icm.org/en/actualite/discovery-of-the-association-between-two-key-cellular-mechanisms-of-alzheimers-disease/ https://institutducerveau-icm.org/en/actualite/discovery-of-the-association-between-two-key-cellular-mechanisms-of-alzheimers-disease/#respond Wed, 15 Sep 2021 15:18:48 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21864 A study by Bassem Hassan's team (Inserm) at the Paris Brain Institute shows for the first time the direct link between two key mechanisms of Alzheimer's disease: the For more information ]]> A study by Bassem Hassan’s team (Inserm) at the Paris Brain Institute shows for the first time the direct link between two key mechanisms of Alzheimer’s disease: the amyloid precursor protein (APP) defect and the Wnt signalling defect. In collaboration with Marie Claude Potier’s team (CNRS), they also show a direct effect of this interaction on the production of amyloid, one of the proteins that becomes pathological in the disease. The results are published in eLife.

 

 

Mutations in the APP gene, which produces the amyloid precursor protein, are one of the main familial causes of Alzheimer’s disease. These share most of their clinical features with the sporadic forms of the disease, which account for 95% of cases. The biological mechanisms between the two forms should also share a number of similarities between the two forms. The study of the genetic forms is therefore essential for a better understanding of this pathology as a whole.

Results have been accumulating for years, in Alzheimer’s disease models and in patients, on another cell signalling pathway that is very important in brain development and physiology, the Wnt pathway. This pathway has been shown to be associated with both more severe and milder forms of the disease.

A study conducted by Bassem Hassan’s team (Inserm) looked at the link between these two pathways and how they interact in normal and pathological conditions in the case of Alzheimer’s disease.

Using the fruit fly (Drosophila melanogaster) and mouse neurons, the researchers show that APP is in fact a receptor for the Wnt pathway, and that there is therefore a direct link between these two mechanisms. Wnt regulates APP levels and the way APP is processed in neurons.

APP is the precursor of the amyloid-beta peptide, known to be one of the major pathological proteins in Alzheimer’s disease. In collaboration with Marie-Claude Potier’s team (CNRS), the researchers wanted to evaluate the impact of the interaction between Wnt and APP on the production of beta-amyloid. They thus confirmed that the regulation of APP levels by the Wnt pathway affects amyloid production.

Taken together, these results provide important insights into the pathological mechanisms of Alzheimer’s disease at the molecular level, and their consequences for the production of beta amyloid.

Source The amyloid precursor protein is a conserved Wnt receptor. Liu T, Zhang T, Nicolas M, Boussicault L, Rice H, Soldano A, Claeys A, Petrova I, Fradkin L, De Strooper B, Potier MC, Hassan BA.Elife. 2021 Sep 9;10:e69199.

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Inter-subject heart rate synchronization: a new sign for monitoring consciousness https://institutducerveau-icm.org/en/actualite/inter-subject-heart-rate-synchronization/ https://institutducerveau-icm.org/en/actualite/inter-subject-heart-rate-synchronization/#respond Tue, 14 Sep 2021 15:38:31 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21844 When we listen to a story being told, our attention might be reflected in the inter-subject synchronisation of our heart rate. This is shown by a study carried by For more information ]]> When we listen to a story being told, our attention might be reflected in the inter-subject synchronisation of our heart rate. This is shown by a study carried by Pauline Perez (co-first author) from Jacobo Sitt’s group (Inserm) in the “PICNIC – physiological investigation of clinically normal and impaired cognition” team at Paris Brain Institute, which also reports that this synchronisation could constitute a new biomarker of states of consciousness. The results are published in Cell Reports.

 

Our heart rate fluctuates greatly depending on the information we receive. Physical activity causes it to speed up, but just thinking about it could also change our heartbeat. Meditation, on the other hand, can slow it down. Mental processes could therefore play an important role in our body rhythms. Jacobo Sitt’s group at the Paris Brain Institute sought to understand whether and how awareness of a stimulus could synchronize our body rhythms across individuals (EEG, heart rate, etc.) and in particular cardiac activity, which has the advantage of being easily measured. To do this, they used a new type of stimulus, the narration of a story, audio or audiovisual. They show that when subjects listen to a story, their cardiac activity synchronizes, i.e. it increases and decreases at the same moments.

The study was conducted in collaboration with British and American teams on four groups of subjects. The first group recorded in Birmingham, UK (lead by Damian Cruse) measured only heart timing while listening to a story.

A second group in New York (Lucas Parra – co-senior author – and Jens Madsen – co-first author of the study) tested two conditions: in one they attentively watch educational videos, in the other they watch the same video while doing a simultaneous task (counting backwards in steps of 7) in order to disrupt their attention. In this case, there was a significant difference between subjects who were attentive to the story, who were synchronized in their heart activity, and those who were distracted and did not synchronize.

The third group was evaluated by the Paris Brain Institute team. The stories presented to them were audio only. This was necessary in order to be able to carry out this experiment with patients with impaired consciousness, who are not able to watch a video. He followed a similar test pattern to the New York group. At the end of the story, the subjects were also asked to fill in a questionnaire about the story in question. The results obtained were identical to those of New York. The addition of the questionnaire also allowed the team to show that the subjects’ levels of synchronization with the group were predictive of their ability to memorise the story. Thus, subjects with very high levels of synchronization remembered the story much better than subjects with low levels of heart synchronization.

Finally, the last group consisted of subjects with impaired consciousness. The researchers show that the synchronization levels between patients and healthy subjects are still very low. However, some patients showed a higher synchronization with the healthy subjects. This was associated with a better recovery of consciousness.

“While we don’t know for sure if these patients are fully conscious, they can react in the same way as healthy subjects. This response appears to be predictive of recovery of consciousness. This result suggests a new approach to assessing consciousness, easy to implement in the clinic and complementary to other methods of measuring consciousness” explains Jacobo SITT (Inserm)

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A major role for PIK3CA gene mutations in sporadic cavernoma https://institutducerveau-icm.org/en/actualite/a-major-role-for-pik3ca-gene-mutations-in-sporadic-cavernoma/ https://institutducerveau-icm.org/en/actualite/a-major-role-for-pik3ca-gene-mutations-in-sporadic-cavernoma/#respond Fri, 10 Sep 2021 15:49:34 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21837 Teams from the Paris Brain Institute and Pitié-Salpêtrière Hospital AP-HP, coordinated by Dr Matthieu Peyre and Prof Michel Kalamarides, have studied the presence For more information ]]> Teams from the Paris Brain Institute and Pitié-Salpêtrière Hospital AP-HP, coordinated by Dr Matthieu Peyre and Prof Michel Kalamarides, have studied the presence of mutations in the PIK3CA gene in cavernomas. This work is published in the New England Journal of Medicine.

Cavernomas are low-flow cerebral vascular malformations consisting of abnormally enlarged capillary cavities without intervening brain parenchyma; the condition affects 1 in 200 to 250 people. Although mainly characterised by subclinical bleeding, cavernomas can lead to epileptic seizures and haemorrhagic strokes with significant neurological complications, particularly when they are located in the brainstem.

Cavernomas can occur in isolation or as part of a familial genetic disease. Mutations occurring in a familial context concern in 80% of cases the CCM genes. The genetics of sporadic cavernomas, which account for up to 90% of cases, is poorly understood.

In order to study meningeal tumorigenesis and meningiomas (the most frequent tumour of the central nervous system, of which they are experts), Dr Peyre and Prof Kalamarides have generated two new genetically modified mouse models of meningiomas by activating mutation of the PIK3CA and AKT1 genes in the PI3K-AKT-mTOR pathway.

The unexpected observation of typical cavernomas identical to human lesions prompted them to investigate the possible involvement of PIK3CA and AKT1 mutations in sporadic human cavernomas. They identified 39% PIK3CA mutations in a series of 88 sporadic cavernomas. Furthermore, their results shed new light on the potential cell of origin of cerebral cavernous malformations that was previously considered to be of endothelial lineage. They have shown that it is in fact PGDS-positive pericytes that cause cavernomas in their models by disorganisation of the neurovascular unit.

Their results may provide a better understanding of the biology of sporadic cerebral cavernous malformations by highlighting the major role of PIK3CA mutations in them, rather than that of the CCM genes, initially considered to be predominant.

This result, which was corroborated by a preclinical model, opens new perspectives, still to be validated, for the development of targeted therapies for the treatment of sporadic human PIK3CA-mutated cavernomas that are refractory to surgery and radiotherapy or radiosurgery and lead to frequent complications. PIK3CA inhibitors have indeed shown promising results in patients with CLOVES syndrome (PIK3CA-related hypergrowth syndrome) as well as in patients with a wide range of tumours.

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Discovery of a new way for our brain cells to communicate https://institutducerveau-icm.org/en/actualite/discovery-of-a-new-way-for-our-brain-cells-to-communicate/ https://institutducerveau-icm.org/en/actualite/discovery-of-a-new-way-for-our-brain-cells-to-communicate/#respond Thu, 09 Sep 2021 09:31:43 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21815 A study conducted by Anne Desmazières, Rémi Ronzano and Thomas Roux in Catherine Lubetzki’s team at Paris Brain Institute, shows for the first time a new For more information ]]> A study conducted by Anne Desmazières, Rémi Ronzano and Thomas Roux in Catherine Lubetzki’s team at Paris Brain Institute, shows for the first time a new interaction between neurons and microglia, immune cells present in the brain. This hitherto unknown mode of communication could be key to a better understanding of brain repair mechanisms and pathologies such as multiple sclerosis. The results are published in Nature Communications.

In our nervous system, the transmission of nerve impulses (nerve messages) takes place via the extensions of neurons, the axons, surrounded by an insulating sheath called myelin. The nodes of Ranvier, small domains interspersed between the myelin segments, are essential for the rapid diffusion of information, but they are also a hub of cellular interactions in the brain.

 

 

Previous studies have already shown that certain types of brain cells, such as oligodendrocytes and astrocytes, form contacts with neurons at these nodes of Ranvier. However, interactions with another essential brain cell type, microglia, had not been explored. These immune cells play a key role in protecting the brain and in regenerative processes such as remyelination, the reformation of the myelin sheath, which is affected in diseases such as multiple sclerosis.

A study conducted at the Paris Brain Institute by Anne Desmazières and her colleagues Rémi Ronzano and Thomas Roux in Catherine Lubetzki’s team shows for the first time that contacts and communication exist between neurons and microglial cells at the level of the nodes of Ranvier.

Thanks to studies carried out on ex-vivo (tissue culture) and in-vivo mouse models, in particular using real-time imaging approaches to observe the dynamics of these contacts, but also on human tissue, the researchers revealed a particularly stable interaction between these two types of cells, and a reinforced dialogue in a context of myelin regeneration. They also identified the mechanisms underlying this dialogue. Neuronal activity mediates and reinforces the interaction. Microglia are able to ‘read’ the information arriving at the nodes of Ranvier in the form of an ionic signal, thus modulating their state and their interaction with the neuron. Alteration of this ionic signal can keep microglia in a pro-inflammatory state, preventing them from playing their pro-regenerative and pro-remyelinating role.

In the case of multiple sclerosis, this discovery opens up several avenues of research to better understand the disease, in particular the impact of inflammatory signals in this disease on the neuron-microglia dialogue and the pro-remyelinating potential of microglia. The discovery of this dialogue is all the more interesting as therapies being tested in multiple sclerosis are now trying to act on the physiology of these microglia in order to promote their pro-regenerative character.

This new mode of communication also raises the question of the impact of neuronal activity on the behaviour of microglia. Indeed, many neurological pathologies, including epilepsy, are associated with alterations in neuronal activity, and the consequences of this alteration on microglial cells are still unknown.

Source

Microglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination. Ronzano R, Roux T, Thetiot M, Aigrot MS, Richard L, Lejeune FX, Mazuir E, Vallat JM, Lubetzki C, Desmazières A.Nat Commun. 2021 Se

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A Proposal to Make Biomedical Research into Alzheimer’s Disease More Democratic Following an International Survey with Researchers https://institutducerveau-icm.org/en/actualite/a-proposal-to-make-biomedical-research-into-alzheimers-disease-more-democratic-following-an-international-survey-with-researchers/ https://institutducerveau-icm.org/en/actualite/a-proposal-to-make-biomedical-research-into-alzheimers-disease-more-democratic-following-an-international-survey-with-researchers/#respond Fri, 13 Aug 2021 12:57:15 +0000 Ignacio Colmenero https://institutducerveau-icm.org/?post_type=actualite&p=21739 Background: Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting For more information ]]> Background: Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting amyloid in AD patients has not yet resulted in highly significant disease-modifying effects. Furthermore, other promising theories of AD etiology exist.

Objective: We sought to directly investigate whether the ACH still dominates the opinions of researchers working on AD and explore the implications of this question for future directions of research.

Methods: During 2019, we undertook an international survey promoted with the help of the Alzheimer’s Association with questions on theories and treatments of AD. Further efforts to promote a similar study in 2021 did not recruit a significant number of participants.

Results: 173 researchers took part in the 2019 survey, 22% of which held “pro-ACH” opinions, tended to have more publications, were more likely to be male, and over 60. Thus, pro-ACH may now be a minority opinion in the field but is nevertheless the hypothesis on which the most clinical trials are based, suggestive of a representation bias. Popular vote of all 173 participants suggested that lifestyle treatments and anti-tau drugs were a source of more therapeutic optimism than anti-amyloid treatments.

Conclusion: We propose a more democratic research structure which increases the likelihood that promising theories are published and funded fairly, promotes a broader scientific view of AD, and reduces the larger community’s dependence on a fragile economic model.

Source: https://content.iospress.com/articles/journal-of-alzheimers-disease-reports/adr210030

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Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant https://institutducerveau-icm.org/en/actualite/primary-progressive-aphasia-mutations-nonamyloid-logopenic/ https://institutducerveau-icm.org/en/actualite/primary-progressive-aphasia-mutations-nonamyloid-logopenic/#respond Tue, 20 Jul 2021 13:40:25 +0000 Ignacio Colmenero https://institutducerveau-icm.org/?post_type=actualite&p=21678 Objective: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to For more information ]]> Objective: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.

Methods: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.

Results: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).

Conclusions: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

Source

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant. Saracino D, Ferrieux S, Noguès-Lassiaille M, Houot M, Funkiewiez A, Sellami L, Deramecourt V, Pasquier F, Couratier P, Pariente J, Géraudie A, Epelbaum S, Wallon D, Hannequin D, Martinaud O, Clot F, Camuzat A, Bottani S, Rinaldi D, Auriacombe S, Sarazin M, Didic M, Boutoleau-Bretonnière C, Thauvin-Robinet C, Lagarde J, Roué-Jagot C, Sellal F, Gabelle A, Etcharry-Bouyx F, Morin A, Coppola C, Levy R, Dubois B, Brice A, Colliot O, Gorno-Tempini ML, Teichmann M, Migliaccio R, Le Ber I; French Research Network on FTD/FTD-ALS.Neurology. 2021 Jul 6;97(1):e88-e102.

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CALL FOR APPLICATIONS : GROUP LEADER POSITIONS AT THE PARIS BRAIN INSTITUTE https://institutducerveau-icm.org/en/actualite/call-for-applications/ https://institutducerveau-icm.org/en/actualite/call-for-applications/#respond Thu, 01 Jul 2021 10:09:52 +0000 Ines Haddad https://institutducerveau-icm.org/?post_type=actualite&p=21560 The Institut du Cerveau - Paris Brain Institute (ICM) is an internationally renowned neuroscience research institute located in Paris, France, on the campus of the For more information ]]> The Institut du Cerveau – Paris Brain Institute (ICM) is an internationally renowned neuroscience research institute located in Paris, France, on the campus of the Pitié-Salpêtrière hospital, providing world class expertise in basic and clinical neuroscience.

Paris Brain Institute is seeking to recruit up to 3 team leaders at the starting, junior or mid-career levels working in any area of molecular, cellular, circuit, cognitive, computational or theoretical neuroscience. Paris Brain Institute welcomes applications from talented individuals with the ambition to establish an internationally competitive research group. Successful candidates will be expected to develop an independent research program addressing challenging fundamental, translational or clinical problems in a stimulating and collaborative international environment. The new team leaders will benefit from a competitive start-up package, recurrent core funding and access to state of the art core facilities. Team leaders at the Paris Brain Institute are affiliated with the neuroscience Ph.D. program of Sorbonne University. Onboarding and skilled assistance for applications to national and international funding programs will also be provided. Successful candidates are expected to be appointed in 2023. Women and minorities are strongly encouraged to apply. Paris Brain Institute is a member of the Alba Network and endorses values of equity and diversity among all its research and support activities. ICM is committed to ensuring a safe, welcoming, and inclusive workplace, with a gender equity committee, and actively supports the local gender equity movement, the XX initiative.

Paris Brain Institute is home to 25 research teams bringing together over 700 personnel, including 150 researchers, 200 technical staff and 300 students and post-docs. Paris Brain Institute laboratories use multiscale approaches from different domains. Applicants are encouraged to consult the Paris Brain Institute description booklet available here. Paris Brain Institute is supported by a private foundation working in synergy with French public bodies, and affiliated with Sorbonne Université, CNRS and Inserm. For candidates in computational or theoretical neuroscience, neuroinformatics or digital sciences for neuroscience, partnership with Inria, the National Institute for Research in Digital Science and Technology, will provide opportunities to create a joint research team. Importantly, Paris Brain Institute is associated with clinical neuroscience departments (neurology, psychiatry, rehabilitation, …) of the Pitié-Salpêtrière hospital (APHP), as well as with a large network of public and industrial partners. Paris Brain Institute is dedicated to fundamental, translational and clinical research in Neuroscience, and fosters improved quality of care and education. Moreover, it hosts an in-house clinical neuroscience research center as well as a start-up incubator. The Paris Brain Institute is located alongside 13 National Reference Centers for rare neurological diseases at the Pitié-Salpêtrière.

Expression of interest must include a short CV, a complete list of publications highlighting up to five significant papers, and a brief description of achievements and future research (2 pages). Applications must be sent by November 15th, 2021 to: scientific.affairs@icm-institute.org

Short-listed applicants will be invited to submit a full application proposal including:

– Project/title and summary and a list of up to five of the candidate’s most significant publications (limited to 2 pages)

– CV including list of publications and invited presentations to conferences

– Description of the research project (no more than 10 pages)

– Names and contacts of three references

Full applications must be sent by February 15th, 2022 to: scientific.affairs@icm-institute.org. All applications will be reviewed by the International Scientific Advisory Board of the Institute. Shortlisted applicants will be invited for an interview and oral presentation in Paris in April 2022.

You can access to the application form here 

Expression of interest

Deadline

(2 pages maximum)

Invitation to submit full application Full application proposal Deadline Finalists’ oral presentation & Site visit
November 15th, 2021 December 15th , 2021 February 15th, 2022 April 2022
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Predicting lapses of attention with sleep-like slow waves https://institutducerveau-icm.org/en/actualite/predicting-lapses-attention-sleep-slow-waves/ https://institutducerveau-icm.org/en/actualite/predicting-lapses-attention-sleep-slow-waves/#respond Tue, 29 Jun 2021 15:17:04 +0000 Ignacio Colmenero https://institutducerveau-icm.org/?post_type=actualite&p=21574 Attentional lapses occur commonly and are associated with mind wandering, where focus is turned to thoughts unrelated to ongoing tasks and environmental demands, or For more information ]]> Attentional lapses occur commonly and are associated with mind wandering, where focus is turned to thoughts unrelated to ongoing tasks and environmental demands, or mind blanking, where the stream of consciousness itself comes to a halt. To understand the neural mechanisms underlying attentional lapses, we studied the behaviour, subjective experience and neural activity of healthy participants performing a task. Random interruptions prompted participants to indicate their mental states as task-focused, mind-wandering or mind-blanking. Using high-density electroencephalography, we report here that spatially and temporally localized slow waves, a pattern of neural activity characteristic of the transition toward sleep, accompany behavioural markers of lapses and preceded reports of mind wandering and mind blanking. The location of slow waves could distinguish between sluggish and impulsive behaviours, and between mind wandering and mind blanking. Our results suggest attentional lapses share a common physiological origin: the emergence of local sleep-like activity within the awake brain.

Source : https://www.nature.com/articles/s41467-021-23890-7

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