Amyotrophic lateral sclerosis: a new avenue for improving patient diagnosis and follow-up

Neurones noradrénergiques présents dans le locus coeruleus de sourisNoradrenergic neurons in the mouse locus coeruleus whose dysfunction contributes to cortical hyperexcitability in ALS. © Caroline Rouaux

Amyotrophic lateral sclerosis or Charcot’s disease is a neurodegenerative disease that results in progressive paralysis and subsequent death. Diagnosing it is difficult and no curative treatment exists to date, making these challenges for research. In a new study, Inserm researcher Caroline Rouaux and her team at the Strasbourg Biomedical Research Centre (Inserm-Université de Strasbourg), in collaboration with researchers from Ludwig Maximilian University in Munich, CNRS and Sorbonne Université, show that electroencephalography could become a diagnostic and prognostic tool for the disease. Thanks to this type of examination, the scientists were able to reveal an atypical brain wave profile that could prove to be specific to the disease. Through this research, published in Science Translational Medicine, a potential therapeutic target has also been discovered. Fundamental advances that could ultimately benefit patients.

Amyotrophic lateral sclerosis (ALS), otherwise known as Charcot’s disease, remains a veritable challenge for clinicians. This neurodegenerative disease, which most often develops between the ages of 50 and 70, leads to progressive paralysis and death within just two to five years. It is caused by the death of the motor neurons – the nerve cells that control the muscles, both in the brain (central motor neurons) and in the spinal cord (peripheral motor neurons).

Diagnosing ALS is difficult because its initial signs vary from person to person: weakness or cramps in an arm or leg, trouble swallowing or slurred speech, etc. In addition, there is no biomarker specific to the disease. Therefore it is diagnosed by ruling out other conditions that can lead to motor disorders, which usually takes one to two years after the onset of symptoms, delaying the deployment of therapeutic measures and reducing the chances of inclusion in clinical trials at an early stage.

It was with the aim of shortening this time frame that Caroline Rouaux’s team at the Strasbourg Biomedical Research Centre, in collaboration with the teams of Sabine Liebscher in Munich and Véronique Marchand-Pauvert, Inserm researcher in Paris, tested the use of electroencephalography1. This inexpensive and easy-to-use technique involves placing electrodes on the surface of the skull to record brain activity in the form of waves.

The examination performed in subjects with ALS and in corresponding animal models revealed an imbalance between two types of waves associated with excitatory and inhibitory neuron activity, respectively. This imbalance, in favour of greater excitatory neuron activity to the detriment of inhibitory neurons, reflects cortical hyperexcitability.

This phenomenon is no surprise and had already been described with other investigation methods, but these are rarely used due to being difficult to implement and only work at the very beginning of the disease. Electroencephalography, however, is minimally invasive, very inexpensive, and can be used at different times during the disease. In addition, the atypical brain wave profile revealed by electroencephalography could prove to be specific to the disease,’ explains Rouaux, Inserm researcher and last author of the study.

Indeed, analysis of the electroencephalographic recording of the brain’s electrical activity reveals various types of brain waves of differing amplitudes and frequencies. One of these, called the theta wave, reflects the activity of the excitatory neurons that transmit messages stimulating neurons, while another wave, gamma, reflects that of the inhibitory neurons that block the transmission of nerve messages.

The study reveals that in humans and animals with ALS, the interaction between these two wave types is atypical, revealing an imbalance between the excitatory and inhibitory activities. Not only was this imbalance found in all the subjects tested, but the scientists also showed that the more the symptoms of the disease progress, the greater the imbalance. In addition, this atypical wave pattern was detected in animals even before the onset of the first motor symptoms.

If these initial findings are confirmed, electroencephalography could in the future serve as a prognostic tool for already-diagnosed patients in order to evaluate, for example, the response to a medication, or even as a diagnostic tool in the event of symptoms suggestive of the disease.

In the second part of this research, the scientists were able to study, in patients and mice, the mechanisms behind the hyperexcitability observed. First, they measured the levels of the different neuromodulators produced by the neurons to communicate with each other, and found a deficiency in one of them: noradrenaline was present in smaller amounts in the brains of the patients and mice with ALS compared to healthy brains.

To verify the role of noradrenaline, they blocked the production of this neuromodulator in healthy animals, and showed that doing so causes cortical hyperexcitability, such as that observed in the disease. And conversely, by administering molecules that stimulate the action of noradrenaline in a mouse model of ALS, the scientists reduced the hyperexcitability and restored brain activity equivalent to that of healthy mice.

This discovery could mark the opening of a new therapeutic avenue in ALS provided that cortical hyperexcitability is indeed associated with disease progression. Indeed, while we have seen an association between the two in our study, no causal link has been established for the moment. This is what we will be checking in the coming months.’ concludes Rouaux.


1 Electroencephalography is commonly used for research purposes in neurology but also in clinical practice. The examination provides information on brain activity in the event of sleep disorders, after a stroke, or even in the case of coma. It can also be used to diagnose encephalitis, epilepsy or confirm brain death.

Physical and mental well-being of older adults: a positive impact of meditation and health education

Méditation_personnes âgéesLearning mindfulness meditation improves self-compassion, while health education promotes an increase in physical activity. © AdobeStock

A team from Inserm and Université de Caen Normandie, in collaboration with researchers from the University of Jena (Germany) and University College London (UK), has studied the potential benefits of meditation and health education interventions in people who feel that their memory is in decline. This research was performed as part of the European H2020 Silver Santé Study programme coordinated by Inserm[1]. It shows that learning mindfulness meditation improves self-compassion, while health education promotes an increase in physical activity. These findings, published in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, propose new avenues to support healthier ageing.

‘Subjective cognitive decline’ is when people feel that their cognitive faculties have deteriorated without this being apparent in standard cognitive tests. Studies have shown that such people have a higher risk of developing actual cognitive decline.

Previous studies had concluded that mindfulness meditation and health education (a practice in which people implement preventive measures and actions that are beneficial for their health) had a positive impact, which was still present six months later, on anxiety in people reporting subjective cognitive decline.

More generally, self-compassion (feeling of kindness toward oneself, having a sense of common humanity, and having an awareness of negative thoughts and feelings without over-identification) and exercise have previously been associated with better mental health, itself associated with improved general health, well-being, and quality of life.

A European research group coordinated by Julie Gonneaud, Inserm researcher at the Physiopathology and Imaging of Neurological Disorders laboratory (Inserm/Université de Caen Normandie), Olga Klimecki, researcher at the University of Jena (Germany), and Nathalie Marchant, researcher at University College London (UK), studied the impact of eight weeks of mindfulness meditation and health education courses on self-compassion and physical activity in people reporting subjective cognitive decline.

The trial included 147 patients from memory clinics in France, Spain, Germany and the UK. One group took meditation classes for eight weeks, while the other took health education classes. The impact of the interventions was evaluated using blood tests, cognitive assessments and questionnaires.

The researchers observed that the participants who did the mindfulness meditation training showed an improvement in their self-compassion. The participants who did the health education training showed an increase in their physical activity. These changes were still present six months later.

These findings support complementary effects of mindfulness meditation and participation in health education programmes on certain factors contributing to improved mental well-being and lifestyle in older adults reporting subjective cognitive decline.

The fact that these improvements appear to be sustained after six months of follow-up suggests that these new skills and habits have been incorporated into the participants’ lives.

According to Marchant, who led the trial, ‘more and more people are living to an advanced age, and it is crucial that we find ways to support the mental and physical health of older adults.’

‘Self-compassion can be of great importance to the elderly. It could improve psychological well-being in order to promote healthy ageing,’ adds Klimecki. ‘Our findings are an encouraging first step towards a mindfulness-based intervention that could be used to strengthen self-compassion in older adults. ‘

Gonneaud adds: ‘Although physical activity has been scientifically associated with better physical, cognitive and mental health, how to promote it in everyday life remains a challenge. Given the particularly harmful effect of a sedentary lifestyle on the health of ageing populations, showing that health education intervention programmes can strengthen commitment to physical activity among the elderly is particularly promising for promoting healthy ageing,‘ she concludes.


[1] This research is funded by the European Union and forms part of the SCD-Well study of the H2020 Silver Santé programme (, which has received 7 million euros in funding and is coordinated by Inserm. The Silver Santé study, funded for a five-year period, examines whether mental training techniques, such as mindfulness meditation, health education, or language learning, can help improve the mental health and the well-being of the ageing population.

The brain mechanisms behind our desire to dance

Groove- envie de danser© AdobeStock

Why does some music make us want to dance more than others? This is the question that a research team from Inserm and Aix-Marseille Université tried to answer by studying the desire to dance (also called the ‘groove’) and the brain activity of 30 participants who were asked to listen to music. Their findings show that the groove sensation is highest for a moderately complex rhythm and that the desire to move is reflected in the brain by an anticipation of the music’s rhythm. This research, to be published in Science Advances also designates the left sensorimotor cortex[1] as being the centre of coordination between the auditory and motor systems.

Dancing means action. But to dance to the sound of a melody, you still have to coordinate your actions with the rhythm of the music. Previous studies have already shown that the motor system (consisting of the motor cortex[2] and all the brain structures and nerve pathways which, under its control, participate in the execution of movement) plays a crucial role in the brain’s processing of musical rhythms.

‘Groove’ is the spontaneous desire to dance to music. But while some music has us immediately heading for the dance floor, others leaves us indifferent. So what is it that makes some music more ‘groovy’ than others?

A research team led by Benjamin Morillon, Inserm researcher at the Institute of Systems Neurosciences (Inserm/Aix-Marseille Université), looked at the neural dynamics (i.e. the interactions between neurons resulting from the electrical activity of the brain) of 30 participants when they listened to pieces of music whose rhythms were of greater or lesser complexity. This was to determine the brain mechanisms involved in the emergence of the groove sensation.

To do this, the team started by creating 12 short melodies comprised of a rhythm of 120 beats per minute – or 2 Hz, the average rhythm generally found in music. Each melody was then modified in order to obtain three variants with an increasing degree of syncopation[3] (low, medium, high) – i.e. with an increasingly complex rhythm, but without changing either the speed of the rhythm or the other musical characteristics of the melody.

The researchers then asked the participants to listen to these melodies while recording their brain activity in real time using a magnetoencephalography (MEG) device. At the end of each melody, the participants were asked to score the level of groove felt.

They also created a so-called ‘neurodynamic’ mathematical model of the neural network that describes in a simple way the brain calculations required for the emergence of the groove.

The experience of the groove as reported by the participants – and reproduced by the neurodynamic model – appeared to be correlated with the rate of syncopation. As observed in previous studies, the desire to move to music was highest for a rhythm with an intermediate level of syncopation, i.e. not too simple or too complex.

‘These findings show that the motor engagement linked to the groove is materialised by a temporal anticipation of the tempo. At brain level, this is based on a dynamic balance between the temporal predictability of the rhythm (the less complex the rhythm, the better it is) and the listener’s temporal prediction errors (the more complex the rhythm, the more errors they make),’ explains Arnaud Zalta, first author of the study and post-doctoral fellow at ENS-PSL.

Analysis of the participants’ brain activity then enabled the researchers to highlight the role of the left sensorimotor cortex as coordinator of the neural dynamics involved in both auditory temporal prediction and the planning and execution of movement.

The brain region which is the site of the left sensorimotor cortex is currently considered to be the potential cornerstone of sensorimotor integration, essential for the perception of both music and speech. The fact that it appears in our study as necessary for ‘cooperation’ between the auditory and motor systems reinforces this hypothesis, especially as we are using natural stimuli here,’ concludes Morillon.


[1]In the brain, the sensorimotor cortex consists of the motor cortex and the sensory cortex (postcentral gyrus, at the front of the parietal lobe), separated by the central fissure. Involved in the coordination of movements, it receives sensory information from the different parts of the body and integrates it to adjust and refine the movements generated by the motor cortex.

[2]The motor cortex consists of the regions of the cerebral cortex that participate in the planning, control and execution of voluntary muscle movements. It is located in the posterior part of the brain’s frontal lobe, in the precentral gyrus.

[3]In rhythmic solfège, if we consider the 4/4 measure, beats 1 and 3 are ‘strong’ and beats 2 and 4 are ‘weak’. Syncopation is a rhythm in which a note (or a chord) is started on a weak beat and prolonged over the next strong beat. For the listener, this creates a shift in the expected accent, perceived as a kind of musical ‘hiccup’ that disrupts the regularity of the rhythm. These musical motifs are particularly present in funk or jazz.

Prefer natural light to avoid age-related sleep disorders

© Adobe stock

One in three French adults is thought to have a sleep disorder. While the prevalence of these disorders increases with age, the biological mechanisms at play are relatively unknown, leaving scientists in doubt as to their origin. In a new study, Inserm researcher Claude Gronfier and his team at the Lyon Neuroscience Research Center (Inserm/CNRS/Université Claude-Bernard Lyon 1) hypothesised that their onset during ageing was linked to a desynchronisation of the biological clock caused by decreased light perception. In the course of their research, they identified a new adaptive mechanism of the retina during ageing that enables older individuals[1] to remain sensitive to light. These findings are also of clinical relevance in encouraging older people to have more exposure to daylight, rather than artificial light, to avoid developing sleep disorders. These results have been published in the Journal of Pineal Research.

Almost all biological functions are subject to the circadian rhythm, which is a 24-hour cycle. The secretion of the night hormone melatonin is typically circadian. Its production increases at the end of the day shortly before bedtime, helping us to fall asleep, and falls before we wake up.

Previous studies have shown that its secretion by the brain is blocked by light, to which it is very sensitive. This sensitivity to light can manifest as desynchronisation of the circadian clock, which can lead to sleep disorders. Other studies have also revealed the important role, in the control of melatonin production, of melanopsin – a photoreceptor present in certain cells of the retina which, being highly sensitive to light (mainly blue light), regulates pupillary reflex and circadian rhythm. Therefore, when exposed to light, melanopsin becomes a driver of melatonin suppression and biological clock synchronisation.

While sleep disorders are already common in adults, they increase with age: nearly one third of people over 65 chronically consume sleeping pills[2]. Yet there are no previous studies specifically focusing on the biological mechanism at work in age-related sleep disorders. Are we talking about the consequence of a problem of light perception? If so, at what level? And what is the role of melanopsin in this specific case?

A team at the Lyon Neuroscience Research Center tried to elucidate this mystery. The scientists observed the effects of light on melatonin secretion in a group of adults. The participants were all exposed to 9 different coloured lights (corresponding to 9 very precise wavelengths) to enable the scientists to identify the mechanisms involved via the photoreceptors concerned.

The participants were divided into two distinct groups, with mean ages of 25 and 59. This experiment was performed in the middle of the night, when the body normally releases the most melatonin.

The results show that, out of the lights tested, blue light (with a wavelength of approximately 480 nm) is very effective in suppressing melatonin production in the youngest individuals. More specifically, the scientists observed that in the young subjects exposed to blue light, melanopsin was the only photoreceptor driving melatonin suppression. Conversely, in the older participants, photoreceptors other than melanopsin appear to be involved, such as the S and M cones – photoreceptors that enable the world to be perceived in colour, and which are located in the outer retina.

These data suggest that while ageing is accompanied by decreased melanopsin involvement in visual perception, the retina is able to compensate for this loss through an increase in the sensitivity of other photoreceptors that were previously not known to be involved in melatonin suppression.

These observations enable the scientists to conclude that light perception – and light requirements – change with age.

While for young people, in whom only the melanopsin receptor is involved, exposure to blue light[3] is sufficient to synchronise their circadian clock over a 24-hour day, older people require exposure to light that is richer in wavelengths (colours) – a light whose characteristics are those of sunlight.

‘This is the discovery of a new adaptive mechanism of the retina during ageing – enabling older subjects to remain sensitive to light despite yellowing of the lens. These findings are also clinically relevant, encouraging older people to have more exposure to daylight, which is richer in wavelengths, rather than artificial light, in order to avoid developing sleep disturbances or mood or metabolism disorders, for example. Finally, they offer new possibilities for the optimal personalisation of phototherapies/light therapies for older people‘, explains Claude Gronfier, Inserm researcher and last author of the study.

Regarding this last aspect, the research team is now looking at the quantity and quality of light necessary for each individual, and the best time for light exposure during the day, to prevent the development of sleep disorders and health problems more generally.

The research is being conducted in healthy subjects (children and adults), day and night workers, and patients (with sleep and biological rhythm disorders, genetic diseases, mood disorders and neurodegeneration)[4].


[1]In this study, the average age of the participants in the ‘older’ group was 59 years.


[3] The LED lights used are rich in blue light.


Discovery of the role of a brain regulator involved in psychiatric illnesses

It was widely accepted that families of synaptic receptors transmitted excitatory, and others inhibitory, messages to neurons. © Adobe Stock

Contrary to all expectations, GluD1 – a receptor considered to be excitatory – has been shown in the brain to play a major role in controlling neuron inhibition. Given that alterations in the GluD1 gene are encountered in a certain number of neurodevelopmental and psychiatric disorders, such as autism (ASD) and schizophrenia, this discovery opens up new therapeutic avenues to combat the imbalances between excitatory and inhibitory neurotransmissions associated with these disorders. Published in Science, this research is the result of collaborations between researchers from Inserm, CNRS and ENS at the ENS Institute of Biology (IBENS, Paris, France) with their colleagues at the MRC Laboratory of Molecular Biology in Cambridge, UK.

The complexity of the brain’s function reveals many surprises. While it was widely accepted in brain activity that families of synaptic receptors (situated at the extremity of a neuron) transmitted excitatory, and others inhibitory, messages to neurons, a study co-led by Inserm researchers Pierre Paoletti and Laetitia Mony at the ENS Institute of Biology has shed new light on this.

To understand what it is all about, we need to go back to the basics. An ‘excitatory’ synapse triggers the creation of a nerve message in the form of an electrical current if a receptor on its surface is able to bind to an excitatory neurotransmitter present in the interneuronal space, most often glutamate. This is called ‘neuronal excitation’. However, an ‘inhibitory’ synapse prevents this neuronal excitation by releasing an inhibitory neurotransmitter, often GABA. This is called ‘neuronal inhibition’. Thus, the families of glutamate receptors (iGluR) and GABA receptors (GABAAR) are considered to have opposite roles.

Toutefois, un sous-type de récepteur au glutamate appelé GluD1 intriguait les scientifiques. En effet, alors qu’il est censé avoir un rôle excitateur, celui-ci est préférentiellement retrouvé au niveau de synapses inhibitrices. Cette observation, effectuée par l’équipe de la chercheuse Inserm Cécile Charrier à l’Institut de Biologie de l’ENS en 2019, avait interpellé la communauté scientifique car le gène GluD1 est souvent associé à des troubles du neurodéveloppement comme l’autisme ou à des maladies psychiatriques de type troubles bipolaires ou schizophrénie, dans les études génétiques de population humaine. Comprendre le rôle de ce récepteur représente donc un enjeu de taille. Pour y voir plus clair, l’équipe de Pierre Paoletti a étudié ses propriétés moléculaires et sa fonction, à partir de cerveaux de souris, au niveau de l’hippocampe où il est fortement exprimé.

However, a glutamate receptor subtype called GluD1 intrigued the scientists. Although it is meant to have an excitatory role, it is preferentially found at the inhibitory synapses. This observation, made by the team of Inserm researcher Cécile Charrier at the ENS Institute of Biology in 2019, attracted the interest of the scientific community because the GluD1 gene is often associated with neurodevelopmental disorders (e.g. autism) or psychiatric conditions (e.g. bipolar disorders or schizophrenia) in human population genetic studies. Understanding the role of this receptor is therefore a major challenge. To find out more, Paoletti’s team used mouse brains to study its molecular properties and function in the hippocampus where it is strongly expressed.


An atypical role

Contrary to its name, the researchers already knew that the GluD1 receptor is unable to bind to glutamate. But in this study they were surprised to find that it bound GABA. Radu Aricescu’s team in Cambridge even described in the publication the fine atomic structure of the site where GluD1 interacts with GABA, using a technique called X-ray crystallography[1].

In principle, its role in the brain is therefore not excitatory of neuronal activity but inhibitory. Taking this finding into account, can we still say that this receptor belongs to the glutamate receptor family?

‘While the question remains, the analyses of phylogeny (relationships between genes and proteins) and the structural data do all show that it belongs to it. However, it is possible that certain mutations acquired during the course of evolution have profoundly modified its functional properties’, explains Paoletti.

Another source of curiosity is that this receptor does not function as a ‘conventional’ glutamate receptor or as a GABA receptor. Both cause the opening of channels in the cell membrane enabling the passage of ions responsible for the excitation or inhibition of the neuron. The GluD1 receptor however does not allow any channels to be opened. Its activity results from other internal mechanisms within the cell, which remain to be clarified.

Finally, this research suggests a major regulatory role for GluD1 in relation to the inhibitory synapses. Indeed, when activated by the presence of GABA, the inhibitory synapse is more effective. This manifests as a greater inhibitory response that lasts for a few dozen minutes.

 ‘In other words, GluD1 reinforces the inhibition signal. Perhaps by promoting the recruitment of new GABA receptors at the synapse? In any case, we are talking about a key regulator’, explains Mony.

For the scientists who contributed to this research, this discovery marks a real step forward.

These findings pave the way for a better understanding of the imbalances between excitatory and inhibitory messages in the brain in neurodevelopmental and psychiatric disorders, such as ASD and schizophrenia, or in conditions characterised by neuronal hyperexcitability, such as epilepsy. Following that, it will be important to study the potential of GluD1 as a therapeutic target for restoring better balance and reducing symptoms in these disorders’, they conclude.


[1] A physicochemical analysis technique based on the diffraction of X-rays  by the matter to determine its molecular composition and 3D structure.

The very first 3D map of the embryonic human head enables new insights into its development

Image 3 D glande lacrymale d’embryon humain 3D light-sheet microscope image of a lacrimal gland of a tissue-cleared 12-week-old human embryo. The different elements of the gland were coloured using virtual reality software. © Raphael Blain/Alain Chédotal, Vision Institute (Inserm/CNRS/Sorbonne Université)

Improving our knowledge of the development of the complex structures of the human head to shed new light on the congenital abnormalities that cause malformations: this is the challenge that a team of researchers from Inserm, CNRS and Sorbonne Université at the Vision Institute, Université Claude Bernard Lyon 1 and Hospices civils de Lyon is well on its way to fulfilling. Thanks to an innovative technique in which the skull structures are made transparent and 3D photos are taken of their component cells, this team has been able to establish the very first 3D atlas of the embryonic human head. These findings, to be published in Cell, have already provided deeper insights into how certain complex structures of the head are formed, such as the lacrimal and salivary glands or the arteries of the head and neck. They pave the way for new tools to study embryonic development.

The head is the most complex structure in the human body. In addition to the muscles and skin that protect it, and the brain encased within the skull, it contains blood vessels, nerves, endocrine glands – which secrete hormones directly into the bloodstream – such as the pituitary glands, and exocrine glands – which secrete substances to the outside environment – such as the salivary glands, which produce saliva, or the lacrimal glands, which secrete tears.

Our current knowledge about the development of the human head and its complex structures is rudimentary and comes from studies mostly carried out in the first half of the XX century, using simple histological sections. As such, despite head malformations occurring in around one third of newborns with congenital defects, the mechanisms that control the development of the human head remain poorly understood.

A team led by Alain Chédotal, Inserm research director at the Vision Institute (Inserm/CNRS/Sorbonne Université) and professor at the MéLiS laboratory of Mechanisms in Integrated Life Sciences (Inserm/CNRS/Université Claude Bernard Lyon 1/Hospices civils de Lyon), and Yorick Gitton, CNRS staff scientist also at the Vision Institute, used an innovative microscopy method to shed new light on the development of the human head.

The team had previously used the same technology in the embryo to study the development of other human organs[1]. This technology is called ’tissue clearing’ because it makes organs transparent to light. The cleared sample is then imaged in 3D using a special microscope that scans with a fine sheet of laser light. This makes it possible to locate in situ the cells that make up the embryonic tissues.

The researchers were able to apply this technique to embryos at different stages of development, obtained from the human tissue biobank created as part of the Human Developmental Cell Atlas (HuDeCA) programme coordinated by Inserm[2]. Thanks to the images obtained, they established the first 3D map of the embryonic human head[3].

Next, the team used virtual reality to analyse the 3D images and thus ‘navigate’ within the embryos.

‘This enabled us to discover previously unknown characteristics of the development of the cranial muscles, nerves, blood vessels and exocrine glands, states Chédotal. For example, it had never been possible to study the very early stages of development of the human salivary and lacrimal glands. Our research has enabled us to begin to visualise and better understand the mechanisms behind the establishment of these anatomically extremely complex structures’, he adds.


œil d’embryon humain transparisé 3D light-sheet microscope image of a 12-week-old tissue-cleared human embryo eye. The 6 oculomotor muscles responsible for eye movement and the 3 motor nerves (in white, green and red) were coloured using virtual reality software. ©Raphael Blain/Alain Chédotal, Vision Institute (Inserm/CNRS/Sorbonne Université)

The scientists have also set up a web interface ( to access not only the images obtained in this research, but also models for 3D printing and interactive 3D reconstructions of human embryos. This platform provides valuable resources that can also contribute to the training of medical students.

In future research, the team will attempt to map the various cells of certain organs, such as the retina.

‘At this stage, it is kind of as if we have mapped the continents and countries but still have to position the cities and their inhabitants’, explains Chédotal, whose team will also collaborate with physicians to apply the technology to pathological samples.

‘The new knowledge of human embryology provided by this research, as well as the new tools developed, has major implications for understanding craniofacial malformations and neurological disorders, as well as for improving diagnostic and therapeutic strategies’, concludes the researcher.


[1] See our press release of 23 March 2017:

[2] Launched in 2019, the objective of the cross-cutting HuDeCa programme coordinated by Inserm is to build the first atlas of human embryonic and foetal cells. It also aims to structure human embryology research at French level and develop databases. In the longer term, HuDeCa is expected to serve as a basis for understanding the origin of chronic diseases or congenital malformations.

[3] With the specific exception of the brain, a structure that was not covered by this research.

Major Breakthrough in the Treatment of Parkinson’s Disease: A Neuroprosthesis Restores Fluid Walking

neuroprothèseUnlike conventional Parkinson’s treatments, this neuroprosthesis targets the spinal cord region responsible for activating the leg muscles. © CHUV

Neuroscientists from Inserm, CNRS and Université de Bordeaux in France, along with Swiss researchers and neurosurgeons (EPFL/CHUV/UNIL), have designed and tested a “neuroprosthesis” to correct the gait disorders associated with Parkinson’s disease. In a study published in Nature Medicine, the scientists describe the development process of the device they used to treat a Parkinson’s disease patient for the first time, enabling him to walk fluidly, confidently, and without falling.

Disabling gait disorders occur in around 90% of people with advanced Parkinson’s disease and are often resistant to the treatments currently available. Developing new strategies that enable patients to walk fluidly again, avoiding the risk of falls, is therefore a priority for the research teams that have been studying this disease for many years.

This is the case of Erwan Bézard, a neuroscientist at Inserm, and his team at the Institute of Neurodegenerative Diseases (CNRS/Université de Bordeaux), who are working to understand the pathogenic mechanisms behind Parkinson’s and to develop strategies to restore motricity in various diseases. For several years, he has been working with a Swiss team led by neuroscientist Prof. Grégoire Courtine and neurosurgeon Prof. Jocelyne Bloch, who specialize in the development of spinal cord neuromodulation strategies.

In 2016, the Franco-Swiss team had already published research in Nature showing the effectiveness of a brain-spine interface – known as a “neuroprosthesis” – to restore the function of a limb paralyzed following a spinal cord injury. Its promising results had encouraged the scientists to pursue their efforts, suggesting beneficial effects in Parkinson’s disease with a similar device.


Avoiding Falls and Freezing

In this new study, the team developed a similar neuroprosthesis to compensate for falls and the phenomenon of freezing – when the feet remain glued to the ground during walking – that is sometimes associated with Parkinson’s disease.

Unlike conventional treatments for Parkinson’s, which target the brain regions directly affected by the loss of dopamine-producing neurons, this neuroprosthesis targets the spinal cord region responsible for activating the leg muscles during walking, which is not believed to be directly affected by the disease. However, the spinal cord is under the voluntary control of the motor cortex, whose activity is modified by the loss of dopaminergic neurons.

Drawing on their complementary expertise, the French and Swiss teams were able to develop and test the neuroprosthesis in a non-human primate model reproducing the locomotor deficits caused by Parkinson’s disease. The system not only reduced the locomotor deficits, but also restored walking capacity in this model by reducing freezing.

“The idea of developing a neuroprosthesis that electrically stimulates the spinal cord to harmonize gait and correct the locomotor disorders of Parkinson’s patients is the result of several years of research on the treatment of paralysis caused by spinal cord lesions”, explains Erwan Bézard, Inserm research director at the Institute of Neurodegenerative Diseases (Université de Bordeaux/CNRS).

“Previous attempts to stimulate the spinal cord have failed because they provide blanket stimulation of the locomotor centers without taking physiology into account. In our case, the stimulation overlays the natural functioning of the spinal cord neurons to target, with spatiotemporal coordination, the different muscle groups responsible for walking,” add Courtine and Bloch, co-directors of NeuroRestore, the research center based in French-speaking Switzerland.

These promising results paved the way for clinical development, to test the device in a patient.


Improvement Thanks to the Neuroprosthesis

A first patient, aged 62, who has been living with the disease for three decades, underwent surgery two years ago at Vaud University Hospital (CHUV) in Lausanne. During a precision neurosurgical procedure, Marc, originally from Bordeaux, was fitted with this new neuroprosthesis, consisting of a field of electrodes placed against the region of his spinal cord that controls gait, and an electrical-impulse generator implanted under the skin of his abdomen.

Thanks to the targeted programming of spinal-cord stimulations that adapt to his movements in real time, Marc has quickly seen his gait problems improve. After a few weeks of rehabilitation with the device, his walking has almost returned to normal.

This neuroprosthesis therefore opens up new prospects for treating the gait disorders suffered by many people with Parkinson’s disease. However, at this stage, this therapeutic concept has only demonstrated its efficacy in one person, with an implant that still has to be optimized for large-scale deployment.

The scientists are therefore working to develop a commercial version of the device[1] that incorporates all the essential features for optimal daily use. Clinical trials on more patients are also due to start early next year[2].

“Our ambition is to enable widespread access to this innovative technology in order to significantly improve the quality of life of patients with Parkinson’s disease, throughout the world”, conclude the researchers.


[1] In partnership with ONWARD Medical, a company based in Switzerland that will develop these implants.

[2] Thanks to a one-million-dollar donation from the Michael J. Fox Foundation for Parkinson’s research, NeuroRestore will embark on clinical trials on six new patients early next year. These trials aim not only to validate the technology developed in collaboration with ONWARD, but also to identify the patient profiles most likely to benefit from this innovative therapy. Founded by actor Michael J. Fox (Back to the Future), who himself has Parkinson’s disease, this foundation is the leading private donor in the field of Parkinson’s disease research.

Asleep but Open to the World: We Can Still Respond to External Stimuli

Sleep is generally defined as a period during which the body and mind are at rest, as if disconnected from the world. © Nicolas Decat

When we sleep we are not completely cut off from our environment: we are still able to hear and understand words. These observations, resulting from the close collaboration between researchers from Inserm, CNRS, Sorbonne Université and AP-HP at the Brain Institute and the Department of Sleep Disorders at Pitié-Salpêtrière Hospital in Paris, call into question the very definition of sleep and the clinical criteria that distinguish between its different stages. They are detailed in a new study published in Nature Neuroscience.

Sleep is generally defined as a period during which the body and mind are resting, as if disconnected from the world. However, a new study led by Delphine Oudiette, Inserm researcher, Isabelle Arnulf (Sorbonne Université, AP-HP) and Lionel Naccache (Sorbonne Université, AP-HP) at the Brain Institute, shows that the boundary between wakefulness and sleep is much more porous than it would appear.

The scientists have shown that sleepers with no particular disorders are able to capture verbal information transmitted by a human voice and respond to it by contracting facial muscles. What is more, this astonishing ability manifests itself intermittently during almost all stages of sleep — as if windows to the outside world were temporarily opened.

These new data on sleep behavior suggest that it may eventually be possible to develop standardized protocols for communication with sleepers in order to better understand how mental activity changes during sleep.

On the horizon: a new access route to the cognitive processes that underpin normal and pathological sleep.


A Thousand and One Variations in Consciousness

Even if it seems familiar to us because we do it every night, sleep is a very complex phenomenon. Our research has taught us that wakefulness and sleep are not stable states: both resemble a kaleidoscope of conscious moments… and moments that do not appear to be so,” explains Prof. Lionel Naccache, neurologist at Pitié-Salpêtrière Hospital AP-HP and neuroscience researcher.

It is essential to improve our understanding of the brain mechanisms that underlie these intermediate states between wakefulness and sleep.

When out of sync, they can be associated with disorders such as sleepwalking, sleep paralysis, hallucinations, the feeling of not sleeping at night or, on the contrary, sleeping with the eyes open“, explains Prof. Isabelle Arnulf, head of the Sleep Disorders Department at Pitié-Salpêtrière Hospital AP-HP.

However, in order to distinguish between wakefulness and the different stages of sleep, we have so far used simple and inaccurate physiological indicators, such as specific brain waves made visible through electroencephalography. Such indicators do not capture in detail what is going on inside the heads of sleepers, especially as they are sometimes in contradiction with what the sleepers tell us themselves.

We need more refined physiological measurements that are aligned with the sleeper’s feelings and ability to respond to the outside world; this is to better define their level of vigilance“, adds Delphine Oudiette, Inserm researcher in cognitive neuroscience.


A Game Between Unconsciousness and Lucidity

The research team[1] therefore explored this avenue and recruited 22 people without sleep disorders and 27 narcoleptic patients — i.e. victims of irrepressible sleep episodes.

People with narcolepsy have the particularity of having many lucid dreams, namely in which they are aware of being asleep and can sometimes shape the scenario. In addition, they easily and quickly reach REM sleep (the stage where the lucid dream emerges) during the day, making them good candidates for studying consciousness during sleep under experimental conditions.

One of our previous studies had shown that two-way communication, between the scientist and the dreamer and vice versa, is possible during lucid REM sleep, explains Oudiette. For our latest study, we wanted to know if these findings could be extrapolated to other sleep stages and to individuals who do not have lucid dreams. “

The study participants were asked to take a nap. The researchers had them do a “lexical decision” test in which a human voice uttered a series of words, both real and made up. The participants had to respond by smiling or frowning, in order to place the words in one of the two categories. Throughout the experiment, the participants were monitored using polysomnography—a comprehensive examination to record their brain and heart activity, eye movements, and muscle tone. Finally, upon waking, they had to report whether or not they had a lucid dream during their nap, and whether they remembered interacting with someone.

Most of the participants, whether narcoleptic or not, managed to respond correctly to the verbal stimuli while sleeping. These events were admittedly more frequent during episodes of lucid dreams, characterized by a high level of consciousness; however, we observed them occasionally in both groups, during all sleep phases”, specifies Arnulf.

By combining these physiological and behavioral data with the subjective reports of the participants, the researchers also show that it is possible to predict the opening of these windows of connection with the environment, i.e. the times when the sleepers were able to respond to stimuli. These were heralded by an acceleration of brain activity, and by physiological indicators usually associated with rich cognitive activity.

In people who had a lucid dream during their nap, the ability to dialog with the investigator and talk about this experience on waking was also characterized by a specific electrophysiological signature, adds Naccache. Our data suggest that lucid dreamers have privileged access to their inner world, and that this increased awareness also extends to the outside world.

Further research will be needed to determine whether the increase in these windows is correlated with sleep quality, and whether they could be used to improve certain sleep disorders or promote learning.

More advanced neuroimaging techniques, such as magnetoencephalography and intracranial recording of brain activity, will help us to better understand the brain mechanisms that orchestrate sleep behaviors“, concludes Oudiette.

Finally, these new data could help to revise the definition of sleep, a state that is ultimately very active, perhaps more conscious than we thought, and open to the world and others.

This study was funded by the French National Research Agency and the French Society for Sleep Research and Medicine (SFRMS).

[1] Including PhD students Başak Türker, Esteban Munoz Musat and Emma Chabani, whose participation was essential to the conduct of this study. 

Infection of Certain Neurons With SARS-CoV-2 Could Cause Persistent Symptoms


Illustration of SARS-CoV-2 infection (immunoreactivity for the S-protein in white) in the olfactory neurons expressing the olfactory marker protein (OMP, in red) in the human nasal epithelium. © Vincent Prévot/Inserm

The brain impacts of infection with SARS-CoV-2, responsible for COVID-19, are increasingly well documented in the scientific literature. Researchers from Inserm, Lille University Hospital and Université de Lille, at the Lille Neuroscience & Cognition unit, in collaboration with their colleagues at Imperial College London, focused more specifically on the impacts of this infection on a population of neurons known for regulating sexual reproduction via the hypothalamus (the neurons that express the GnRH hormone). Their findings suggest that SARS-CoV-2 infection can lead to the death of these neurons and cause certain symptoms that persist over time. The findings of this study have been published in eBioMedicine.

Numerous scientific studies have documented the brain impacts of SARS-CoV-2 infection. One such effect is that a significant proportion of men have low testosterone levels that persist over time. Persistence beyond a period of four weeks is referred to as “long COVID”.

For many years, a research team from Inserm, Lille University Hospital and Université de Lille has been studying the role of certain neurons that express gonadotropin-releasing hormone (GnRH). From the hypothalamus, these neurons control all the processes associated with reproductive function: puberty, acquisition of secondary sexual characteristics, and fertility in adulthood.

These are the same scientists who had, for example, previously revealed that GnRH neuron dysfunction in an animal model of Down syndrome could affect the cognitive function impairment associated with this condition.

In this latest study, the scientists wanted to test the hypothesis that SARS-CoV-2 infection may have harmful consequences on this population of neurons that regulate reproduction.


The Virus Penetrates GnRH Neurons and Alters Their Functions

Following hormone measurements (testosterone and luteinizing hormone) performed three months and then one year after infection in a small group of 47 men[1], the scientists observed that contact with the virus could alter the functions of GnRH neurons, leading to a fall in testosterone levels in certain patients some time after the infectious episode.

The scientists then wanted to verify whether the infection of the GnRH neurons and the subsequently observed hormone abnormalities could be associated with cognitive deficits. To do this, they listed the cognitive symptoms reported by the cohort patients, who underwent extensive testing three months and then one year after the infection.

The outcome was that the proportion of patients reporting memory or attention disorders, regardless of frequency or severity, and also concentration difficulties, tended to be slightly higher in the patients with abnormal hormone measurements, characterized by a decrease in testosterone levels.

“Although these were measurements made on a small sample of only male patients, these findings are very interesting and warrant further exploration in other larger-scale studies,” explains Waljit Dhillo, professor at Imperial College London and co-last author of this study.

To supplement their analyses, the researchers went on to study the cortexes of patients who died as a result of COVID-19. They identified the presence of the virus in the hypothalamus and the death of part of the GnRH neuron population.

“These findings may be worrying on several levels in terms of the role of these neurons in reproduction and their involvement in certain cognitive functions. They point to the necessity to optimize and generalize the medical follow-up of people with persistent symptoms following COVID-19 infection,” concludes Vincent Prévot, Inserm research director and co-last author of this study.

The study also encourages further research into the neurological impacts of long COVID.


[1]These data were collected as part of a larger study evaluating adrenal and thyroid function following Sars-CoV-2 infection:

Restoring Vision Through a New Brain-Machine Interface: Sonogenetic Therapy

 thérapie sonogénétique

Sonogenetic therapy consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. © Alexandre Dizeux/Physics for Medicine Paris

Restore vision using a combination of ultrasound and genetics? This is the goal of an international team led by Inserm research directors Mickael Tanter and Serge Picaud from Paris’ Physics for Medicine unit (ESPCI Paris/PSL Université/Inserm/CNRS) and Vision Institute (Sorbonne Université/Inserm/CNRS), respectively, in partnership with the Institute of Molecular and Clinical Ophthalmology in Basel. In a new study, they provide proof of concept of this so-called “sonogenetic” therapy in animals. This consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. The results show that when used on rodent neurons sonogenetics can induce a behavioral response associated with light perception. This discovery makes it possible to envisage, in the longer term, an application in blind people with optic nerve atrophy. The study has been published in Nature Nanotechnology.

Sonogenetic therapy consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. This technology had previously been tested in culture and the first in vivo tests did not enable the researchers to become aware of its therapeutic potential linked to its very high spatiotemporal resolution. The genetic modification in question consists of introducing the genetic code of a mechanosensitive ion channel into the cells. The neurons that express this channel can then be remotely activated by low-intensity ultrasound applied to the surface of the brain without the need for contact (see diagram below).

Ultrasound waves can access tissue deep down, such as in the visual cortex – even from the surface of the dura mater[1] that surrounds the brain – and target very specific areas. It is these waves that form the basis for high-resolution brain imaging or ultrasound technologies. In this case, they enable highly selective activation, because only those neurons carrying the mechanosensitive channel and targeted by the ultrasound beam are stimulated.

In a recent study, a team of researchers led by Inserm research directors Mickael Tanter and Serge Picaud tested the efficacy of this sonogenetic therapy in animals. The aim of this research is to provide a solution to restore vision to patients having lost the connection between their eyes and brain due to conditions such as glaucoma, diabetic retinopathy, or hereditary or dietary optic neuropathies.

Their findings show that sonogenetic stimulation of the visual cortex induces a behavioral response associated with light perception. The animal learns an associative behavior in which it seeks to drink as soon as it perceives light. Ultrasound stimulation of its visual cortex induces the same reflex, but only if the neurons in the cortex express the mechanosensitive channel. The animal’s behavior suggests that sonogenetic stimulation of its cortex induced the light perception at the origin of the behavioral reflex.

The study showed that therapy works on different types of neurons, whether in the retina or visual cortex of the rodents, thereby demonstrating the universal nature of this approach.

By converting the images of our environment into the form of a coded ultrasound wave to directly stimulate the visual cortex – at rates of several tens of images per second – sonogenetic therapy appears to offer genuine hope for restoring vision to patients who have lost optic nerve function.

More generally, this sonogenetic stimulation approach offers innovative technology for interrogating brain function. Unlike current neuron stimulators or prostheses, its “non-contact” and selective cell type functioning represents a major innovation in relation to electrode devices.

“This sonogenetic therapy to ultimately restore the vision of blind people illustrates the power of a multidisciplinary project and a beautiful human adventure between a retinal biologist like Serge Picaud, and myself, a wave physicist for medicine,” declares Tanter, Inserm research director at the Physics for Medicine unit in Paris (ESPCI Paris/PSL Université/Inserm/CNRS).

“The development of a clinical trial of sonogenetic therapy still has many steps to go through to validate its efficacy and safety. If the results are confirmed, this therapy could succeed in restoring patients’ vision in a stable and safe manner,” concludes Picaud, Inserm research director and director of the Vision Institute (Sorbonne Université/Inserm/CNRS).

[1] Outermost layer of the meninges that protect the brain