©AdobeStock

Why do some of our choices appear to be driven by a desire to explore the unknown? An Inserm team from École Normale Supérieure led by 2017 ERC grant-winner Valentin Wyart has shown that most of these choices are not motivated by curiosity but by errors caused by the brain mechanisms implicated in evaluating our options. These findings have been published in Nature Neuroscience.

Where shall we eat tonight – at our usual restaurant or one we have not tried before? Where shall we spend our next vacation – in the old family cabin or a rental halfway around the world? When we have various options to choose from, our decisions do not always lead us towards the safest one based on our previous experiences. This variability which is characteristic of human decisions is most often described in terms of curiosity: our choices are thought to be the reflection of a compromise between exploiting options that are known and exploring others whose outcomes are more uncertain. Curiosity is even considered to be an attribute of human intelligence – a source of creativity and unexpected discoveries. This interpretation is based on a very strong (albeit rarely explicitly stated) hypothesis, according to which we weigh up our options without ever making any errors.

An Inserm research team from the Laboratory for Cognitive and Computational Neuroscience (LNC²) funded by the European Research Council (ERC) wanted to test this implicit hypothesis upon which many findings are based. The researchers suspected that our capacity to weigh up and review our options is largely overestimated, based on findings published in 2016 in Neuron:

“One of our researchers had previously shown that our capacity to make the right choice based on partial indicators is restricted by errors of reasoning when these indicators are combined, and not by hesitancy at the time of making the choice. So we asked ourselves whether these errors of reasoning could be responsible for some of the choices considered as being a matter of curiosity by current theories. “

To back up their suspicions, the researchers studied the behavior of around one hundred subjects using a slot machine-style game that consisted of choosing between two symbols associated with uncertain rewards. They analyzed the behavior of the participants using a new theoretical model developed by Charles Findling, postdoc in the team and co-lead author of the article, which takes into account evaluation errors of the symbols. 

As such, the authors discovered that over half of the choices usually considered as being a matter of curiosity were in reality due to errors of evaluation. “This finding is important, because it implies that many choices in favor of the unknown are made unbeknownst to us, without our being aware of it” explains team leader, Valentin Wyart.

In order to understand where these errors come from, the researchers recorded the brain activity of some of the participants using functional magnetic resonance imaging. They discovered that the activity of the anterior cingulate cortex, a region involved in decision-making, fluctuates with the evaluation errors made by the participants. The greater the activity of this region when evaluating the options, the greater the evaluation errors. For Vasilisa Skvortsova, postdoc and co-lead author of the article, “these errors of evaluation could be regulated via the anterior cingulate cortex by the noradrenaline neuromodulator system, controlling the precision of the mental operations performed by the brain”. In other words, our brain is thought to use its own errors to produce choices in favor of the unknown, without relying on our curiosity. “This is a radically different vision from the current theories that consider these errors as negligible”, insists Wyart.

Although these findings may appear surprising, are they really? Many major discoveries are the result of errors of reasoning: the discovery of America by Christopher Columbus, who believed he had reached the “East Indies” – a navigation error of 10,000 km, but also the discovery of radioactivity by Henri Becquerel, who initially thought that the radiation emitted by uranium was due to the re-emission of solar energy, or the discovery of the pacemaker by John Hopps when attempting to treat hypothermia with the help of radiofrequency. Going further, “the evolution of the species is also based on random variations of the genome, in other words genetic errors, some of which are retained by natural selection”, reiterates Wyart. So there is in fact nothing surprising about our brain taking advantage of its errors in order to think outside the box.

© Tim Mossholder on Unsplash

In a commentary published in the journal Nature Human Behavior, Inserm researcher Violetta Zujovic and her colleagues from the XX initiative committee at the Brain & Spine Institute (Inserm/CNRS/Sorbonne Université) at the AP-HP Pitié-Salpêtrière Hospital explain how a neuroscientific approach can be used to more effectively combat gender inequality. The actions taken by the researchers have increased the number of female speakers invited to take the floor at the research center from 25 to 44% in the space of a year and a half, and have increased the number of women in senior roles from 25 to 31%. Their neuroscience-based approach now constitutes an important mechanism for changing attitudes and behaviors. Among other things, their future work will focus on using “nudges”—a technique originating in neuroscience that tries to influence our behavior in our own interest—to improve gender equality. An example for others to follow.

Although internationally recognized as a country that supports women’s career progression through suitable infrastructure and specific legislation, France performs poorly when it comes to offering equal opportunities to men and women. This is the paradox highlighted by the XX initiative committee, made up of a dozen scientists, in a commentary published in Nature Human Behavior. If the entire community, including the scientific community, recognizes these inequalities, why do gender-related behaviors persist? The published commentary warns of the impact of cognitive biases, which are beyond our control but deeply rooted in our attitudes. Unconscious prejudices and stereotypes have a powerful influence over almost every decision we make.

Despite the norms of equality, and despite the evidence that teams are more successful when they include both men and women, social prejudices continue to silently pull the strings, for example by creating sexist or racist biases. The neuroscientific community is at the forefront of this issue, not only in raising awareness of such forms of unconscious bias, but also because it has the tools at its disposal to understand their cognitive origins and break societal stereotypes.

The XX initiative committee at the Brain & Spine Institute (ICM), which includes male and female neuroscientists from Inserm, the CNRS, and Sorbonne Université, have proposed a roadmap in several stages. Their recommendations highlight a crucial first stage: realization by each individual of their own implicit assumptions derived from existing prejudices, and the impact these have on their decision-making.

This first stage was put into practice by collecting comprehensive data on the male to female ratio by level of responsibility and job title. The internal ICM data gathered in April 2017 showed that just 26% of women held a management or joint management post within the institute, whose staff is 63% female.

Other figures showed that only 25% of invited speakers at the institute’s weekly scientific seminars were female.

The simple fact of presenting the findings of this investigation triggered a collective reassessment process that has resulted in the number of women heading up a research group increasing from 26 to 31%. The entire community has also been involved in efforts to showcase more female researchers, which has had the practical result of the number of female scientists taking the floor at the institute increasing from 25 to 44%.

“Thanks to the collective drive to combat gender inequality, we were also able to revise various institutional forms to remove all gender-specific information,”explains Violetta Zujovic, the Inserm researcher who led this work.

In this societal and economic context, in which we are trapped by unconscious prejudices and gender stereotypes, one of the key recommendations proposed by the researchers is to inform men and women and train them to overcome these forms of bias. The committee is holding a meeting on “Gender Bias: Science and Practice” on April 3, 2020, which is open to all, along with practical workshops providing individuals with the tools to combat their own prejudices and understand how to assess their own values and skills.

The impact of this committee, and the neuroscientific approach it instigated around eighteen months ago, highlights the importance of combining national policies with practical measures. To that end, the neuroscientists are already working on developing “nudges” that will cleverly encourage rather than impose male/female equality. Overall, these measures are designed to enable individuals to understand and recognize the unconscious gender-related prejudices that we perpetuate and pass on, and to individually strive for cultural change.

In May 2019, Inserm also set up a professional parity and equality mission that will shortly set out practical measures for advancing professional equality. These will be incorporated into a multi-year plan and integrated into the institution’s strategy.

©Braden Collum/Unsplash

Sport is good for health, we are always being told. However, in top athletes, excess physical activity can be harmful, as the cases of “overtraining syndrome” show. Responsible for major fatigue and reduced sporting performance, it is a phenomenon that intrigues scientists. A study performed by Mathias Pessiglione, Inserm Research Director at the Brain & Spine Institute (Inserm/CNRS/Sorbonne Université) in conjunction with the French Institute of Sport, Expertise and Performance (INSEP) and the French Anti-Doping Agency (AFLD) shows that intensive physical training can harm brain capacity, particularly cognitive control. The full results have been published in Current Biology.

Inserm researcher Mathias Pessiglione and his team were interested in identifying the causes of a common phenomenon in top athletes, known as “overtraining syndrome”. This is expressed by reduced sporting performance and intense fatigue. Athletes suffering from this syndrome may be tempted by products likely to restore their performance, hence the involvement of AFLD in the project.

The primary hypothesis of the researchers was clear: the fatigue caused by overtraining is similar to that caused by mental effort and is thought to be linked to the same brain mechanisms. Another recent study had already shown that mental fatigue affects cognitive control and leads to impulsive decisions.

To test their hypothesis, the team spent nine weeks working with 37 triathletes, who were split into two groups. The first underwent the “usual” high-level training whereas the second had additional training during the last three weeks of the experiment, with sessions lasting 40% longer, on average. The participants were all monitored at the Brain & Spine Institute, both behaviorally and via functional MRI.

Training sessions 40% longer, on average

From this, the researchers were able to identify similarities between overly intensive physical training and excessive mental work. This excessive physical activity leads to reduced activity of the lateral prefrontal cortex (a key region for cognitive control), similar to that observed during mental effort. A reduction in brain activity expressed by impulsive decisions, in which short-term gratification is prioritized over long-term goals. In the case of top athletes, such impulsiveness can, for example, lead to the decision to stop right in the middle of a sporting performance or abandon a race in order to end the pain felt during physical exertion.

Beyond these top athletes, the researchers consider that, clinically, fatigue and reduced cognitive control could constitute the first stage in the development of burnout syndrome, which affects many people across various professional domains.

Adobe Stock

An Inserm team has provided the first description of the behavior and language of the neurons responsible for memory consolidation during sleep. The researchers have shown that, far from being organized in a static and linear way as was previously thought, neurons vary in their role over time, and that information pathways are continually changing. Their research has been published in Science Advances.

Brain cells are continually exchanging information. During sleep, this plays a particularly important role in consolidating memory. But little is currently known about how these exchanges take place. Electroencephalograms, which measure overall electrical brain activity, show regular waves that vary in speed depending on the phase of sleep, but do not provide information about how information is processed at the neuronal level. This is what the team led by Christophe Bernard (Institute of Systems Neuroscience – Inserm U1106) have succeeded in revealing. To do so, the team used electrodes to record electrical activity from around a hundred neurons concentrated in a particular region. It is these electrical signals that carry information. Three areas known to be involved in memory were recorded in rats during sleep: the hippocampus, prefrontal cortex, and entorhinal cortex.

“Because of the regularity of waves seen on the encephalogram, we thought that neurons worked in a very precise and repetitive way to transmit or store information (rather like a fine-tuned machine). But the recordings show that this is not at all the case,” notes Christophe Bernard.

Free-flowing circulation

The other major discovery is that, during a given substate, the information does not always follow the same pathway. “This came as a surprise, as the dominant theory was that information transfer followed a set pathway. But we found that this is not the case. In the brain, the partners with which a neuron exchanges information fluctuate from one moment to the next. It works a bit like the internet,” illustrates the researcher.

“An email sent from Paris to Sydney passes through servers located in various countries during its journey, and these servers vary over the course of the day depending on traffic. It’s the same in the brain: even if the information is the same, it does not follow a set pathway, and the partners are never the same.”

Finally, this research has made it possible to decode the type of language spoken by the neurons. If a substate corresponds to a “word,” then the sequence of substates constitutes a sentence. But while the meaning of the words and sentences still evades the researchers, they have been able to establish that the neurons speak a complex language, which makes it possible to optimize information processing. A simple language contains very few words; it is easy to understand but struggles to convey complex concepts. A chaotic system of language contains a word for every possible situation, and is impossible to learn. The language of neurons is complex, like human languages, and its complexity is notably greater in paradoxical sleep (during dreams) than in deep sleep.

The researchers will now look at what happens during the waking state, when performing specific tasks, or in disease. This will include studying the possible link between memory loss in subjects with epilepsy and the complexity of neuronal language.

Cellules de Purkinje dans une coupe horizontale du cervelet de souris exprimant une protéine fluorescente (GFP) sous le contrôle du promoteur des récepteurs dopaminergiques D2. Ces cellules dégénèrent chez les patients atteints d’ataxie spinocérébelleuse SCA3. ©Inserm/Valjent, Emmanuel

Spinocerebellar ataxias are neurodegenerative genetic diseases of the cerebellum and brain stem that lead to numerous motor disorders. The most well-known of these ataxias is SCA3, which is also called Machado-Joseph disease. In her research published on June 14 in Acta Neuropathologica, Nathalie Cartier-Lacave, Inserm researcher at the Brain and Spine Institute, discovered with her team the crucial role of an enzyme that can improve symptoms of this disease in mice.

Certain neurodegenerative diseases are caused by a mutation that leads to the production of malformed proteins in possession of excess amino acids (polyglutamine expansion). This occurs with Huntington’s disease and some forms of spinocerebellar ataxia.

In this study, a team from the Brain and Spine Institute (Inserm/Sorbonne Université/APHP) led by Nathalie Cartier-Lacave looked at another group of diseases that presents this polyglutamine-expanded protein production – spinocerebellar ataxias – and more specifically SCA3. In this disease which affects 1-2 in every 100,000 people, the ataxin 3 protein mutates and aggregates in neurons, leading to their death and the subsequent onset of motor disorders. The researchers were able to show that supplying a key enzyme of brain cholesterol metabolism, CYP46A1, to the regions affected by the disease improves symptoms. A strategy that could also be effective in the other ataxias linked to polyglutamine expansion.

The researchers began by studying the cholesterol metabolism in mice with SCA3, revealing an imbalance in this metabolism and decreased levels of the enzyme CYP46A1.
These initial findings led the researchers to test whether or not restoring the expression of this enzyme in SCA3 mice could be beneficial. They performed a single injection of a gene therapy vector carrying gene CYP46A1 into the cerebellum of SCA3 mice, revealing reduced degeneration of the Purkinje neurons of the cerebellum, an improvement in the motor disorders, and decreased ataxin 3 aggregates when compared with untreated mice with the disease.

“These findings show that CYP46A1 is an important therapeutic target for restoring this metabolism, decreasing
toxic mutated protein aggregates and thereby improving the symptoms of the disease”, explains Inserm Research Director Cartier-Lacave.

To further elucidate the phenomenon, the researchers revealed that the pathway used to evacuate the malformed or mutated proteins – the autophagy pathway – is disrupted in SCA3 mice. This led them to conclude that ataxin 3 proteins aggregate as a result of dysfunction of this pathway. However, if normal CYP46A1 levels are reinstated, autophagy is restored, and the disease symptoms attenuated.

Interestingly, the researchers also observed improved evacuation of the ataxin 2 aggregates during overexpression of the enzyme, leading to hopes for treatment, with one product having the potential to be effective in multiple severe and rare diseases.

A European program (Erare) coordinated by Inserm at the Brain and Spine Institute (N. Cartier, A. Durr) is in progress to confirm these results on other models of ataxia and to evaluate the feasibility and tolerance of a potential therapeutic application in patients with these severe genetic diseases.