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

The brain regions associated with language have increased during periods of technological boom, when the use of tools became more widespread. © Adobe stock

Our ability to understand the syntax of complex sentences is one of the most difficult language skills to acquire. In 2019, research had revealed a correlation between being particularly proficient in tool use and having good syntactic ability. A new study, by researchers from Inserm, CNRS, Université Claude Bernard Lyon 1 and Université Lumière Lyon 2 in collaboration with Karolinska Institutet in Sweden, has now shown that both skills rely on the same neurological resources, which are located in the same brain region. Furthermore, motor training using a tool improves our ability to understand the syntax of complex sentences and – vice-versa – syntactic training improves our proficiency in using tools. These findings could be applied clinically to support the rehabilitation of patients having lost some of their language skills. This study is published in November 2021 in the journal Science.

Language has long been considered a very complex skill, mobilizing specific brain networks. However, in recent years, scientists have revisited this idea.

Research suggests that brain areas, which control certain linguistic functions, such as the processing of word meanings, are also involved in controlling fine motor skills. However, brain imaging had not provided evidence of such links between language and the use of tools. Paleo-neurobiology^[1] has also shown that the brain regions associated with language had increased in our ancestors during periods of technological boom, when the use of tools became more widespread.

When considering this data, research teams couldn’t help wondering: what if the use of certain tools, which involves complex movements, relies on the same brain resources as those mobilized in complex linguistic functions such as syntax?

Syntax exercises and use of tongs

In 2019, Inserm researcher Claudio Brozzoli in collaboration with CNRS researcher Alice C. Roy and their team had shown that individuals who are particularly proficient in the use of tools were also generally better at handling the finer points of Swedish syntax.

In order to explore the subject in greater depth, the same team, in collaboration with CNRS researcher Véronique Boulenger[1], developed a series of experiments that relied on brain imaging techniques (functional magnetic resonance imaging or MRI) and behavioral measurements. The participants were asked to complete several tests consisting of motor training using 30 cm-long pliers and syntax exercises in French. This enabled the scientists to identify the brain networks specific to each task, but also common to both tasks.

They discovered for the first time that the handling of the tool and the syntax exercises produced brain activations in common areas, with the same spatial distribution, in a region called the “basal ganglia”.

The handling of the tongs and the syntax exercises proposed to the participants produced activations in a region called “basal ganglia”. © Claudio Brozzoli

Cognitive training

Given that these two skill types use the same brain resources, is it possible to train one in order to improve the other? Does motor training with the mechanical tongs improve the understanding of complex phrases? In the second part of their study, the scientists looked at these issues and showed that this is indeed the case.

This time, the participants were asked to perform a syntactic comprehension task before and after 30 minutes of motor training with the pliers (see box for details of the experiment). With this, the researchers demonstrated that motor training with the tool leads to improved performance in syntactic comprehension exercises.

In addition, the findings show that the reverse is also true: training of language faculties, with exercises to understand sentences with complex structure, improved motor performance with the tool.

The scientists are now thinking about how to best apply these findings in the clinical setting. “We are currently devising protocols that could be put in place to support the rehabilitation and recovery of language skills of patients with relatively preserved motor faculties, such as young people with developmental language disorders. Beyond these innovative applications, these findings also give us an insight into how language has evolved throughout history. When our ancestors began to develop and use tools, this proficiency profoundly changed the brain and imposed cognitive demands that may have led to the emergence of certain functions such as syntax,” concludes Brozzoli.

^[1] A field in which scientists study the evolution of our ancestors’ brain anatomy.

[2] Involved in these findings are the Lyon Neuroscience Research Center (Inserm/CNRS/Université Claude Bernard Lyon 1) and the Dynamics of Language laboratory (CNRS/Université Lumière Lyon 2).

3D motion capture ©Inserm/Guénet, François

With one week to go before astronaut Thomas Pesquet sets out on his space mission Alpha, knowledge about how we adapt to gravity here on Earth is progressing. Researchers from Inserm and Université de Bourgogne within the Cognition, Action and Sensorimotor Plasticity (CAPS) laboratory are interested in how the movements that depend on this omnipresent force are carried out.

For the past 30 years, it was thought that the brain – responsible for motor control – worked to continuously compensate for the effects of gravity. In an initial study in 2016, the researchers had suggested that our brains use gravity to minimize the effort our muscles have to make. Those results were recently confirmed by new experiments conducted in collaboration with New York University on non-human primate models and humans, the findings of which have been published in Science Advances.

Our brain uses the effects of gravity to minimize the physical exertion required.

In order to perform our many activities, the movements of our limbs need to be precise. For a movement to be successful, the brain must generate muscle contractions by anticipating the environmental factors liable to affect that movement. One of the most important of these factors is gravity. The brain develops an internal representation of gravity that it can use to anticipate its effects on our body.

What is the purpose of this anticipation?

Initially, the researchers thought that the brain continuously compensated for the effects of gravity to achieve movements undisturbed by them. Recent studies by researchers from Université de Bourgogne and Inserm at the CAPS laboratory in collaboration with a team from New York University (Dora E. Angelaki, Professor of Neuroscience at the Tandon School of Engineering – New York) challenge this idea. The researchers hypothesized that anticipating the effects of gravity allows us to plan movements that use those effects on our bodies to minimize our muscular exertion.

To confirm this theory, the research team recorded the activations that the brain sends to the muscles. These recordings were made in non-human primates and humans performing horizontal and vertical arm movements.

The information obtained show that the brain sends electrical commands that activate and deactivate the muscles in a very precise way – phenomena that last just a few milliseconds – in order to harness the effects of gravity to accelerate our downward movements and decelerate our upward movements. These findings were observed in both the non-human primates and humans.

This observation supports the hypothesis of profound nervous system adaptation to its environment. 

In the long term, this new knowledge could be put to use in various fields such as movement assistance for people with disabilities or the programming of humanoid robot movements.

Huntington’s disease is a rare and hereditary neurodegenerative disorder. A striatal neuron expresses the causative mutant huntingtin protein (red), which accumulates in the nucleus (blue) to form an aggregate of huntingtin and other proteins, including ubiquitin (yellow). © Frédéric Saudou

Huntington’s disease is a hereditary disorder that causes degeneration of the neurons involved in cognitive, motor and psychiatric functions. While existing treatments address the symptoms and relieve certain aspects of the disease, they cannot alter its course. Researchers from Inserm, Université Grenoble Alpes and Grenoble Alpes University Hospital at the Grenoble Institute of Neuroscience are hoping to remedy this. They are studying a new therapeutic approach in the hope of offering patients the first neuroprotective treatment – one that protects neurons – in the years to come. The therapeutic molecule in question has shown promising results in mice and is currently undergoing preclinical evaluation. Their research has been published in Science Advances.

Huntington’s disease is a rare and hereditary neurodegenerative disorder. It usually begins between the ages of 30 and 50 and manifests with cognitive disorders, psychiatric disorders and uncontrolled movements that worsen over time until death some 20 years later. In France, this condition affects around 18,000 people: 6,000 already have symptoms, whereas around 12,000 carry the mutated gene and will develop symptoms later. The team of Frédéric Saudou, Director of the Grenoble Institute of Neuroscience (Inserm/Université Grenoble Alpes/Grenoble Alpes University Hospital), is working on a new therapeutic approach in an attempt to provide solutions for these patients.

The disease is caused by an abnormality on the gene coding for the protein huntingtin, which interacts with and regulates the activity of at least 400 other proteins involved in various cell functions, including the transport of molecules. This abnormality leads to a reduction in the transport of a key molecule, BDNF, in the brain between the cortex and the striatum. The role of this molecule is to promote the survival of neurons and ensure the connections between them. This reduced transport therefore causes the death of neurons in these brain regions.

“Long before symptoms develop, a reduction in BDNF transport is observed. This molecule is essential for the survival of neurons and for neural connections between the cortex and striatum – two regions involved, among other things, in mood and movement control,” explains Saudou, a professor at Université Grenoble Alpes and Grenoble Alpes University Hospital.

The researcher and his colleagues therefore thought that restoring its circulation would at least afford the brain partial protection from neuron death.

A molecule to restore BDNF transport

In collaboration with Inserm Research Director Sandrine Humbert, Saudou and his team had previously shown that BDNF is transported within vesicles made up of numerous proteins, including huntingtin. In this new study, the researchers identified an enzyme that regulates the transport of these BDNF vesicles by controlling a cell mechanism known as “palmitoylation.” By increasing palmitoylation with the help of a molecule called ML348, they were able to restore the transport of BDNF vesicles.

Several in vitro experiments on human neurons and in vivo experiments on mice have shown that ML384 crosses the blood-brain barrier and restores BDNF traffic from the cortex to the striatum. When administered in a mouse model of the disease, it reversed the symptoms.

“Injecting ML348 reduced the motor and psychiatric behavioral disorders, allowing the mice to regain activity close to that of their healthy counterparts,” explains Saudou. What is more, this molecule improves BDNF transport in human neurons derived from induced pluripotent stem cells (iPS cells) from Huntington’s patients, demonstrating that this molecule is potentially capable of having an effect in humans.

Following this proof of concept, the researcher and his team will move on to the preclinical testing phase to evaluate, using cell and animal models, the behavior of the molecule in the body, its safety, and identify effective doses. The ultimate goal is to develop a drug for patients. If these results are confirmed, this molecule could become the first “neuroprotective” treatment for Huntington’s disease, sparing certain neurons from degeneration and perhaps slowing its progression.

Photo by Thanos Pal on Unsplash

When it comes to recognizing a melody or understanding a spoken sentence, the human brain does not mobilize its hemispheres in an equivalent way. Although the concept is recognized by scientists, there had been no physiological or neural explanation for the phenomenon until now. A team co-led by Inserm researcher Benjamin Morillon at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) in collaboration with researchers at Montreal Neurological Institute and Hospital of McGill University has been able to show that, due to different receptivities to the components of sound, the left auditory cortex neurons participate in the recognition of speech, whereas the right auditory cortex neurons participate in that of music. These findings, to be published in the journal Science, suggest that the respective specializations of the brain hemispheres for music and speech enable the nervous system to optimize the processing of sound signals for communication purposes.

Sound is produced from a complex set of air vibrations, which, when reaching the cochlea of the inner ear, are distinguished according to their speed. At any given moment, slow vibrations are being translated into deep sounds and rapid vibrations into high-pitched ones. As a result, sound can be represented according to two dimensions: spectral (frequency) and temporal (time).

These two auditory dimensions are fundamental because it is their simultaneous combination that stimulates the neurons of the auditory cortex. The latter are thought to discriminate sounds that are relevant for individuals, such as those used for communication enabling people to talk to and understand each other.

In humans, speech and music constitute the main uses of sound and the most complex on the cognitive level. The left hemisphere is primarily implicated in the recognition of speech, whereas the right hemisphere is primarily implicated in that of music. However, until now little was known about the physiological and neural reasons for this asymmetry.

A team co-led by Inserm researcher Benjamin Morillon at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) in collaboration with researchers at Montreal Neurological Institute and Hospital of McGill University used an innovative approach to understand how speech and music are decoded within each of the human brain hemispheres.

The researchers recorded 10 sentences sung by a soprano to 10 new melodies composed especially for the experiment. These 100 recordings, in which melody and speech are dissociated, were then distorted by decreasing the amount of information present in each dimension of the sound. Forty-nine participants were asked to listen to pairs of these distorted recordings, and to determine whether they were identical in terms of speech content and melody. The experiment was conducted in French and English speakers to see whether the results were reproducible in different languages.

A demonstration of the audio test proposed to the participants is available here:

https://www.zlab.mcgill.ca/spectro temporal modulations/

The research team found that for both languages, when the temporal information was distorted, participants had trouble distinguishing the speech content, but not the melody. Conversely, when the spectral information was distorted, they had trouble distinguishing the melody, but not the speech.

Functional magnetic resonance imaging (fMRI) of the participants’ neural activity showed that in the left auditory cortex the activity varied according to the sentence presented but remained relatively stable from one melody to another, whereas in the right auditory cortex the activity varied according to the melody presented but remained relatively stable from one sentence to another.

What is more, they found that degradation of the temporal information affected only the neural activity in the left auditory cortex, whereas degradation of the spectral information only affected neural activity in the right auditory cortex. Finally, the participants’ performance in the recognition task could be predicted simply by observing the neural activity of these two areas.

Original a capella extract (bottom left) and its spectrogram (above, in blue) broken down according to the amount of spectral and temporal information (center). The right and left cerebral auditory cortexes (right) decode melody and speech respectively.

“These findings indicate that in each brain hemisphere, neural activity depends on the type of sound information, specifies Morillon. While temporal information is secondary for recognizing a melody, it is essential for the correct recognition of speech. Conversely, while spectral information is secondary for recognizing speech, it is essential for recognizing a melody. “

The neurons in the left auditory cortex are therefore considered to be primarily receptive to speech thanks to their superior temporal information processing capacity, whereas those in the right auditory cortex are considered to be receptive to music thanks to their superior spectral information processing capacity. “Hemispheric specialization could be the nervous system’s way of optimizing the respective processing of the two communication sound signals that are speech and music,” concludes Morillon.