Alcoholism and dementia risk


Excessive alcohol consumption is linked to a threefold increase in overall dementia risk and a twofold increase in that of developing Alzheimer’s disease, making it a major modifiable risk factor for these conditions. This is the conclusion of an Inserm study performed in collaboration with Canadian researchers via the QalyDays Study Group[1]. Using exhaustive data on hospitalizations in France between 2008 and 2013, the researchers studied the link between alcoholism and dementia. Their findings, published in The Lancet Public Health, confirm the importance of reinforcing measures to prevent the misuse of alcohol.

The list of alcohol-related conditions is getting longer. To cancer, liver and cardiovascular diseases can now be added dementia. Excessive alcohol consumption, corresponding to six or more glasses per day for men and four for women, is found to be linked to a threefold increase in dementia risk. This includes early-onset forms of dementia occurring before the age of 65 and directly attributed to alcohol, such as Korsakoff syndrome, vascular dementia caused for example by stroke, and neurodegenerative dementia such as Alzheimer’s disease.

Whereas some studies suggest a protective effect of low to moderate alcohol consumption on cognitive function, little data exists when studying high levels of consumption. It is indeed often the case that people with alcoholism refuse to participate in medical research cohorts. To get around this problem, the researchers used information from the French National Hospital Discharge database (Programme de Médicalisation des Systèmes d’Information, PMSI) which contains information on all causes of hospitalization. Using this database, they identified 31.6 million adults hospitalized between 2008 and 2013, of whom 1.3 million had dementia and 950,000 presented excessive alcohol consumption (as well as alcohol dependence in 85% of the cases). Following exclusion of the dementia cases which could be attributed to a clearly-identified pathology, the researchers found excessive alcohol consumption in 57% of the cases of early-onset dementia and 8% of those with onset after the age of 65. For all adults admitted to hospital, alcoholism rates were evaluated as being 6.2% in men and 1.5% in women.

According to analysis of this cohort, excessive alcohol consumption is linked to a threefold risk of dementia and a twofold risk of Alzheimer’s disease. After taking the other dementia risk factors into account, the researchers consider that not only is alcohol a risk factor for dementia, it can also be considered the biggest risk factor ahead of smoking and high blood pressure.

“We think that alcohol could precipitate the onset of these diseases and hasten their progression by increasing structural and functional damage in the brain, explain the paper’s authors Carole Dufouil, Inserm Research Director, and Michaël Schwarzinger (Translational Health Economics Network (THEN) and Inserm unit 1137 “Infection, antimicrobials, modeling, evolution” (IAME) affiliated researcher). However, many potential mechanisms remain to be elucidated. This study therefore once again raises the issue of the dangers of alcohol, suggesting that additional preventive measures could help reduce the risk of dementia and its financial and societal cost”, clarifies Carole Dufouil.

This research also confirms the interest of working with healthcare databases. “Using this type of data to reveal major health issues is looking very promising now that these databases have become accessible under the health system modernization law“, says Carole Dufouil. The researchers can now access the National Health Data System which pools several health databases[2] “The data used in our study are not perfect because they have not been collected specifically for our research. They do not, for example, enable the precise measurement of alcohol consumption, such as the threshold beyond which the dementia risk becomes high. But the number of cases is so high that the statistical power overcomes many of these imperfections. That is the major advantage of working with such databases”, conclude Michaël Schwarzinger and Carole Dufouil.

[1] The QalyDays group studies the determinants of life expectancy and dependence-free life expectancy. It brings together two Inserm teams from the Joint Research Units 1137 “Infection, antimicrobials, modeling, evolution (IAME)” (Inserm-Paris Diderot University) and 1219 “Bordeaux population health research center” (Inserm-University of Bordeaux).

[2] (French state health insurance SNIIRAM data, PMSI database on healthcare establishment activity, CepiDC database on causes of death or disability-related data, etc.).

Flunarizine: a New Drug Candidate in the Treatment of Spinal Muscular Atrophy


A team of researchers from Inserm (“Toxicology, pharmacology and cell signaling” JRU 1124) and the universities of Paris Descartes and Paris Diderot have recently discovered that flunarizine – a drug already used to treat migraine and epilepsy – enables the repair of a molecular defect related to spinal muscular atrophy, a severe and incurable disease. This discovery is the culmination of research efforts ongoing since 1995, when the Inserm team – comprising Suzie Lefebvre, leader of the current research projects – identified the gene responsible for infantile spinal muscular atrophy. The results of the initial animal tests, published in Scientific Reports, demonstrate a marked improvement in health. These extremely promising findings must now be confirmed in humans.


 Spinal muscular atrophy is a rare genetic disease, affecting between 1 and 9 out of every 100,000 people. It is caused by degeneration of the motor neurons in the spinal cord, resulting in progressive muscle loss. In the majority of cases, symptoms appear either following birth – with the infant unable to hold up his or her head, or a little later in early childhood – with the inability to walk. More rarely, symptoms can begin in adolescence, in which case the muscular disorders are substantial but compatible with a more-or-less normal life.

The disease is caused by a mutation of the SMN1 gene, leading to a deficiency in the SMN protein. The SMN2 gene, which is virtually identical, then takes over. However, the SMN protein that it produces is for the most part truncated and not highly functional.


An SMN protein targeting problem

In healthy individuals, the SMN protein is drawn into cell nucleus structures known as Cajal bodies. There, small non-coding RNA is formed, which is implicated in a maturation step of the messenger RNA (known as splicing), a precursor of the proteins. In spinal muscular atrophy, the truncated SMN proteins are unable to reach the Cajal bodies. The Cajal bodies then function poorly and the production of the small non-coding RNA is altered. As such, many messenger RNA present maturation problems and result in abnormal or deficient proteins – a phenomenon occurring in all tissues.

In an attempt to restore this mechanism, the researchers tested therapeutic molecules in vitro, on cells taken from patients with a severe form of the disease. The objective was to find one or more cells able to retransport the SMN proteins to the Cajal bodies so that they regain their function.


Flunarizine effective on cells from a variety of patients

Just one molecule has demonstrated an effect on a large number of cells from various patients: flunarizine, which is already used in the treatment of migraine and epilepsy. In a second step, it was used to treat mice with spinal muscular atrophy, at a rate of one spinal cord injection per day from birth. Their life expectancy increased by 40% on average, from 11 to 16 days and even up to 36 days in one case. Analysis of the motor neurons and muscles show that they are preserved for longer in the treated animals. “The molecule presents a major neuroprotective effect even if we currently don’t know why that is,” declares Lefebvre, research leader and a member of the team having discovered the gene responsible for infantile spinal muscular atrophy in 1995. In addition, her team observed that flunarizine makes it possible to restore the functioning of the small non-coding RNA produced in the Cajal bodies for the maturation of the messenger RNA.


Findings to be confirmed in humans

Flunarizine remains to be tested in humans, a stage which will face the challenge of enrolling patients in the context of a rare disease. In addition, most of these patients are already enrolled in a clinical trial to evaluate a new-generation drug that was granted marketing authorization in 2016, meaning that they cannot be mobilized to participate in a second trial. Ultimately, the two therapeutic approaches – each of which targeting a different mechanism – could very well complement each other to promote patient survival and quality of life.

Rare Disease Day 2018: Show Your Rare. Show You Care.

February 28, 2018, marks the eleventh annual world Rare Disease Day, which carries the slogan “Show your rare. Show you care.” and the #ShowYourRare hashtag. World Rare Disease Day was created in 2008 by EURORDIS and the Council of National Alliances. Ninety countries will be participating in 2018.

Orphanet: a Portal for Rare Diseases and Orphan Drugs

Orphanet, which is coordinated by Inserm and is a member of the Rare Disease Platform, is the portal of reference for rare diseases and orphan drugs. It offers an array of freely accessible services to allow patients to understand their disease and its consequences, and to orient them in their care pathways by identifying diagnosis laboratories and reference centers.

Access Orphanet

Contact Orphanet

SOLVE-RD: Major European Funding for Rare Disease Research

A large consortium headed by the University of Tübingen (Germany), the Radboud University Medical Center in Nijmegen (Netherlands), and the University of Leicester (UK), as well as Inserm in France through Orphanet, two major research institutions (the Myology Center for Research and the Brain and Spine institute in Paris), Eurordis, and the Dijon University Hospital, received a €15 million grant for the SOLVE-RD research program.

This large-scale research program is operating under the European Commission’s Horizon 2020 program. Its aim is to use a single infrastructure to coordinate and analyze all data generated across Europe on rare diseases in order to better identify and diagnose people suffering from the same rare disease.

Today, no less than twenty-four European Reference Networks (ERN) have been set up to improve and harmonize diagnosis and treatment for people with rare diseases. To date, four of them have joined SOLVE-RD by adding and sharing their patient data: RND for rare neurological diseases, EURO-NMD for neuromuscular diseases, ITHACA for congenital malformations and intellectual disability, and GENTURIS for genetic tumor risk syndromes. Other ERNs will join the project in the months to come.

The SOLVE-RD project website

Download the press release

The SOLVE-RD Member Inserm Teams

Inserm Unit US14 Information and service platform for rare diseases and orphan drugs (Orphanet)

Contribution: description of profiles of patients suffering from unnamed rare diseases

Inserm Unit 1127 Brain and Spine Institute (ICM)

Contribution: ERN-RND

Inserm Unit 974 Myology Center for Research (CRM)

Contribution: ERN-EURO-NMD

View Inserm’s latest press releases on rare diseases:

A new gene implicated in hypertension

A team of researchers led by Maria-Christina Zennaro, Inserm research Director at the Paris Cardiovascular Research Center (Inserm/ Paris-Descartes University), in collaboration with German colleagues[1], has identified a new gene implicated in hypertension. This study has been published in Nature Genetics.

These new findings highlight the role of genetic predisposition in the onset of common diseases and the importance of the French Plan for Genomic Medicine 2025. A plan in which one objective is to enable access to genetic screening, even for common diseases, in order to provide personalized medical care.

Hypertension is a major cardiovascular risk factor which affects up to 25% of the population. In around 10% of cases, it is due to dysfunction of the adrenal gland, which produces too much aldosterone – a hormone that regulates blood pressure. This is known as primary aldosteronism. Patients with this condition have hypertension that is often severe and resistant to standard treatments. They are also at greater risk of experiencing cardiovascular events, notably myocardial infarction or stroke.

To elucidate the causes of this disease, Maria-Christina Zennaro and Fabio Fernandes-Rosa, Inserm researchers in Paris, analyzed the exomes (the part of the genome that codes for proteins) of patients affected by primary aldosteronism before the age of 20. By doing so, they identified a mutation in a previously unknown gene – CLCN2 – which codes for a chloride channel, whose presence and effects in the adrenal gland were at that point unknown. 


Autonomous aldosterone production

Thanks to their partnership with a German team, the researchers studied the mechanisms by which this mutation could induce autonomous aldosterone production and trigger hypertension. They discovered that the mutation led to a permanent opening in the chloride channel.

In an animal model, the researchers showed that this channel was indeed expressed in the area of the adrenal glands that produces aldosterone.

Through electrophysiology and cellular biology experiments, they showed that the influx of chloride through the mutated channel led to increased chloride flow and depolarization of the cell membrane. The cells of the adrenal cortex then produced more aldosterone in the presence of the mutated channel and expressed to a greater degree the enzymes implicated in its biosynthesis.

This study reveals a previously unknown role of a chloride channel in the production of aldosterone. It opens up entirely new prospects for the pathogenesis and management of hypertension.


[1] From the Leibniz Institute for Molecular Pharmacology (FMP) and the Max Delbrück Center for Molecular Medicine (MDC) in Berlin.

Type 1 diabetes: the role of the thymus is not what we thought!

©nerthuz – adobestock 

A small revolution has taken place in the world of type 1 diabetes research. A study conducted by an Inserm team led by Roberto Mallone at the Cochin Institute (Inserm, CNRS, Paris Descartes University) is calling into question the role long attributed to the thymus in selecting and eliminating white blood cells associated with type 1 diabetes and reveals that we are all auto-immune. Discoveries which change our understanding of the mechanisms of type 1 diabetes and point to new therapeutic strategies in fighting this disease. 

This research has been published in Science Immunology. 

In the large family of white blood cells, lymphocytes are in charge of immune response during infection. Among them, the T-cells are responsible for the recognition and specific destruction of pathogens. The “T” in T-cells is derived from the thymus, an organ to which the T-cells migrate from their place of birth, the bone marrow, prior to entering the blood circulation. Up until now, it was thought that the thymus was a place for the maturation and selection of T-cells, particularly that of CD8+ T-cells – a rare subset implicated in type 1 diabetes (T1D). So rare in fact that 10 mL of blood contains only 5 to 10 of these cells! These auto-immune lymphocytes become active when they encounter certain characteristic proteins for the first time, such as those of the β cells of the pancreas, subsequently leading them to consider them as undesirable and destroy them.

Up until now, it was accepted that the thymus “presented” to the CD8+ T-cells protein fragments characteristic of pancreatic β cells in order to pre-activate, detect and eliminate them. In T1D, it was thought that the selection by the thymus was altered – that if a healthy thymus filtered virtually all CD8+ T-cells, then that of a person with diabetes allowed many more to pass into the blood circulation. However, by comparing blood samples from healthy subjects and those with T1D, the Inserm researchers observed that not only did the blood of the healthy subjects present CD8+ T-cells but also that it contained as many as that of the diabetic subjects. These unexpected results call into question the role of the thymus in the selection of T-cells: since its presentation of β fragments to the CD8+ T-cells does not lead to their elimination, its selection turns out to be incomplete and inefficient.

The astonishing part of this discovery is that we are all auto-immune. This is the price we pay for being well-protected against the threat of infection, because the CD8+ T-cells spared by the thymus are also capable of recognizing microbial protein fragments that are similar to those of the β cells (a phenomenon known as “cross-recognition”).

But if we are all auto-immune, why then are we not all diabetic? According to Roberto Mallone, Inserm researcher at the Cochin Institute who led this study: “The next challenge is to better understand the ingredients that transform the “benign” auto-immunity of Mr. Average into T1D. Identifying these ingredients will allow us to diagnose T1D earlier and develop therapies to revert the auto-immunity to its benign state.”

 Two principal hypotheses are under investigation: the first one is that non-diabetic individuals may be capable of keeping their CD8+ T-cells under control, either due to a “policing” role played by other regulatory T cells or thanks to low CD8+ T-cell activation. The second is based on potential β cell vulnerability in T1D individuals, leading either to their abnormal recognition by the CD8+ T-cells or to their self-destruction.

Diabetes is a common disease in which complex genetic factors are involved. That is why it is the focus of the French Plan for Genomic Medicine 2025, supported by Aviesan and Inserm. As of 2019, a pilot experiment on diabetes as a common-disease model will be conducted in France to determine how the access to genetic sequencing could lead to earlier and more refined diagnosis than at present and the implementation of suitable treatments. New programs to screen the relatives of T1D patients are also being set up with the studies TRAKR and INNODIA, in order to achieve early diagnosis and the subsequent launch of clinical prevention trials.

Consumption of ultra-processed food and risk of cancer

© AdobeStock

A new study bringing together researchers from Inserm, Inra and University of Paris 13 (Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, EREN team) suggests a link between the consumption of ultra-processed food and the additional risk of developing cancer. In total, 104,980 participants from the French NutriNet-Santé cohort were included.  During the follow-up period (8 years), 2,228 cases of cancer were diagnosed and validated.  A 10% increase in the proportion of ultra-processed foods in the diet was associated with a greater than 10% increase in the risk of overall cancer and, more specifically, breast cancer. Out of the various hypotheses which could explain these findings, the generally poorer nutritional quality of ultra-processed food may not be the only contributing factor, thereby pointing to mechanisms involving other compounds (additives, substances formed during industrial processes, materials in contact with food, etc.).  These findings, which must therefore be considered as an initial avenue of investigation in this area, need to be confirmed in other study populations.  The causal relationship in particular remains to be proven.  This study was published on February 15, 2018 in the British Medical Journal.


In recent decades, dietary habits have shifted towards an increased consumption of ultra-processed foods, which currently account for over half of the total daily energy intake in many western countries.  Such foods are often characterized by lower nutritional quality, in addition to the presence of additives, neoformed compounds and substances from packaging and other contact materials. 


Recent studies have shown links between the consumption of ultra-processed foods and an increased risk of dyslipidemia, overweight, obesity, and hypertension.  However, none of the studies looked at the risk of cancer, even though animal experiments suggest potential carcinogenic effects of a number of components usually present in ultra-processed food. 


In total, 104,980 participants from the French NutriNet-Santé cohort (followed up between 2009 and 2017) were included.  Dietary intakes were collected with the help of repeated 24h dietary records, designed to evaluate participants’ usual consumption for 3300 different food items. These were grouped according to their degree of processing by the NOVA classification (see text box below).


During the follow-up period, 2,228 cases of cancer were diagnosed and validated.  A 10% increase in the proportion of ultra-processed foods in the diet was associated with a greater than 10% increase in the risk of overall cancer and, more specifically, breast cancer. These results were significant after a large number of sociodemographic and lifestyle characteristics were taken into account, as well as also the nutritional quality of the diet. This suggests that the lower overall nutritional quality of ultra-processed foods may not be the only factor involved.


These findings must be considered as an initial avenue of investigation in this area and require confirmation in other study populations. The causal relationship in particular remains to be proven. Likewise, further studies are needed to better understand the relative impact of the various dimensions of food processing (nutritional composition, additives, contact materials and neoformed contaminants) on these associations.


To continue this work, the research team is currently launching a new program on food additives, the principal objective of which will be to evaluate the usual dietary exposures to these substances and study their potential effects on health and chronic disease development.  This will be made possible thanks to the accurate and repeated evaluation of dietary exposures in the NutriNet-Santé cohort (together with nutrition supplements and medicines), including the brands and trade names of the processed foods consumed.  This last point is fundamental in accurately determining exposure to additives at the individual level given the wide variability of composition between the brands.  The recruitment of new volunteers to participate in the NutriNet-Santé study continues. Simply register online ( and complete the questionnaires. These will enable the researchers to deepen their knowledge on the links between nutrition and health and thereby improve the prevention of chronic diseases through our diet.


Definition and examples of ultra-processed foods


Food and drinks are assigned to one of the four groups in the NOVA classification, based on their degree of industrial processing (unprocessed or minimally processed foods, processed culinary ingredients, processed foods, ultra-processed foods). This study primarily focused on the “ultra-processed foods” group, which includes, for example, mass produced breads and buns, candy bars, savory snacks, sodas and sweetened drinks, poultry and fish nuggets, instant soups, frozen or shelf-stable ready meals, and any processed products with the addition of preservatives other than salt (for example, nitrites), as well as food products made mostly or entirely from sugar, oils and fats and other substances not used in culinary preparations, such as hydrogenated oils and modified starches.  Industrial processes notably include hydrogenation, hydrolysis, extruding, and pre-processing by frying.  Colors, emulsifiers, texturizing agents, non-sugar sweeteners and other additives are often added to these products.


– Fruit compotes with only sugar added are considered “processed foods”, whereas flavored fruit desserts with the addition of not just sugar but also texturizing agents and colors are considered “ultra-processed” foods.

-Salted red or white meats are considered “processed foods”, whereas smoked meats and/or with added nitrites and preservatives, such as sausages and ham, are considered “ultra-processed foods”.

-Likewise, canned vegetables with only salt added are considered “processed foods”, whereas industrially cooked or fried vegetables, marinated in sauces and/or with added flavors or texturizing agents (such as industrially-produced vegetable stir-fry preparations) are considered “ultra-processed foods”.


Source: Monteiro CA, Cannon G, Moubarac JC, Levy RB, Louzada MLC, Jaime PC. The UN Decade of Nutrition, the NOVA food classification and the trouble with ultra-processing. Public Health Nutr 2018;21:5-17.

A novel high-performance and non-invasive hybrid medical imaging technique

The rapidly-developing medical imaging field could well have found a novel technique in which multiple facets of a living being can be observed in real time and non-invasively. Teams from the Langevin Institute (ESPCI Paris – PSL University / CNRS), the biomedical ultrasound Technology Research Accelerator (Inserm A.R.T.) and the Paris-Cardiovascular Research Center (Inserm / Paris Descartes University) have developed a new medical imaging instrument which combines positron emission tomography – Pet-scan* – with ultrafast ultrasound imaging. Named PETRUS, the acronym of Positron Emission Tomography Registered Ultrafast Sonography, it has obtained 3D images in which organ anatomy, metabolism, function and even elasticity are perfectly superimposed. This research made the cover of the February 6 issue of Nature Biomedical Engineering.


The researchers were able to test their method using commercially-available instruments which were assembled without any major modifications. They imaged cancerous tumors in mice and cardiac activity in rats to test the synchronization of the two methods and the complementarity of the parameters observed.  With its ability to visualize several fundamental biological parameters simultaneously in the form of quantitative parametric maps, this new imaging reflects the complex topology of living beings with even greater finesse.

This totally non-invasive technique for observing living beings in real time offers many possibilities, such as to explore the link between the metabolism and the vasculature of organs like the heart, kidney or liver, or to track with greater precision the effect of new cancer treatments, characterize the aftermath of an infarction, etc. Developed in a preclinical setting, PETRUS represents a high-performance and clinically translatable technology for biomedical research.

Figure 1: a: PETRUS combines positron emission tomography (PET), computed tomography and ultrafast ultrasound imaging. The three image volumes are correlated using a motorized micropositioner.b: on the left, glucose metabolism kinetics obtained by PET following fluorodeoxyglucose administration; on the right, Doppler 3D ultrafast imaging (500 images per second) showing tumor vasculature.c: imaging of a mouse showing the topography of the metabolic and vascular signals superimposed; on the left, oblique projection; at the center and on the right, enlarged 3D view and slice of a tumor.  The color scales shown on the left are the same for the three images. (Provost J et al., Nature Biomedical Engineering)

Figure 2: Closed-thorax PETRUS imaging of a beating rat heart in a short-axis view showing the cardiac anatomy by ultrafast ultrasound (in black and white) and the metabolic activity of the myocardium at end-diastole (left), end-systole (middle) and mid-diastole (right). Note the perfect overlay of the metabolic signal with the myocardial wall. Each image corresponds to the mean signal during one-tenth of a heart cycle.  Scale: 1 mm. (Provost J et al., Nature Biomedical Engineering)

*Positron Emission Tomography (Pet-Scan): 3D medical imaging used to visualize the metabolic or molecular activity of an organ, using the principle of scintigraphy.

The Biological Clock Sets a Different Rhythm for Each Organ

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A team of Inserm researchers led by Howard Cooper (Inserm Unit 1208 “Stem Cell and Brain Institute”) in collaboration with their colleagues in the U.S. have for the first time established a reference map of gene expression, by organ and time of day. A mammoth task that began a decade ago and has required two years of analysis. These results, published in Science, show just how important it is to consider the biological clock in order to administer medication at the right time for optimized efficacy and minimal side effects. The researchers are now preparing an atlas which will be available for use by the entire scientific community.

 Roughly two thirds of protein-coding genes are expressed in a cyclical manner over the 24-hour period with peaks occurring in the morning and late afternoon. However, this expression varies greatly from one tissue to another, confirming that, in addition to the internal central clock, each organ expresses its own clock. An Inserm team has been the first to prove it in a diurnal species, providing a spatiotemporal map of the genetic circadian expression for the various organs. This work marks a major step forward in the field of chronobiology.

Prior to that, studies exploring the circadian rhythm in various organs were generally conducted in animal models such as the fruit fly (research which received last year’s Nobel Prize) and nocturnal species, particularly mice. Since the body clock is primarily synchronized by the light-dark cycle, it would have been tempting to reverse the cycle to obtain data in diurnal animals. However, rodents are not just phase-shifted in relation to humans, their way of life is also very different. Their sleep is fragmented across the whole 24-hour period, unlike diurnal species, which get most of their sleep at night. They also feed continuously over the nocturnal waking phase, whereas humans take their meals at regular times. All of these factors also help to synchronize the biological clock. The time had come therefore to work with species closer to our own in order to deepen knowledge of ourselves.

This involved the researchers analyzing the RNA of over 25,000 genes from 64 organs and tissues, every two hours for 24 hours, in non-human primates. The major organs underwent detailed analysis as well as the various regions of the brain. All in all, the researchers analyzed 768 samples. A mammoth task that began a decade ago and which has required two years of analysis! For each sample, they looked for, quantified and identified the RNA present in the cells. This RNA then either goes on to become proteins or it remains as RNA with regulatory properties on other molecules. This is what we call the transcriptome.

80% of the genes regulated by the biological clock ensure essential cell functions

The authors observed that 80% of the cyclically expressed genes code for proteins that ensure functions essential to cell life, such as waste elimination, DNA replication and repair, metabolism, etc. However, there is a very broad diversity of transcriptomes, i.e. all RNA present in the cells of the various samples over the 24 hours.

The cyclically expressed genes vary in terms of number (with roughly 3,000 in the thyroid or prefrontal cortex versus only 200 in the bone marrow) and type (less than 1% of the “rhythmic” genes in one tissue are also present in the other tissues). Even the 13 known genes of the biological clock, which the authors expected to encounter cyclically in all of the samples, were not all present, neither in the same quantities nor at the same time. What these 64 tissues do have in common are the well-defined peaks of gene expression in the late morning and late afternoon. The first – and biggest – occurs between 6 and 8 hours after waking with more than 11,000 genes expressed at that point in the body. And the second less intense peak sees approximately 5,000 genes in action in the tissues. The cells are then virtually at rest during the night, particularly the first part of the night.

The authors were surprised by the degree of rhythmicity of the organs of the non-human primate and the potential applications. “Two thirds of coding genes are highly rhythmic, that’s a lot more than we were expecting,” clarifies Howard Cooper, Inserm Research Director from the “Chronobiology & Affective Disorders” team of Inserm Unit 1208. “But above all, 82% of these code for proteins that are targeted by medication or which are therapeutic targets for future treatments. This proves just how important it is to consider the biological clock in order to administer medication at the right time for optimized efficacy and minimal side effects. Some experts are working on these questions, particularly in the field of cancer, but in my opinion we need to go much further. That’s why we’re preparing a veritable atlas, in the form of a searchable database, to provide scientists worldwide with the expression profile of each gene in the various organs over the 24-hour period,” explains the researcher.

Migraine: Regions of the Brain We Thought Felt No Pain

©Carson Arias – Unsplash

Could we have been wrong over the past 70 years in thinking that certain regions of the brain are insensitive to pain? This is what the findings of a team of researchers from Inserm, Nice University Hospital, Université Côte d’Azur and St Anne Hospital in Paris would suggest. By collecting observations of brief painful events occurring during brain surgery in awake patients, they found that certain structures – hitherto considered not to feel pain – were at the origin of pain sensations when stimulated mechanically. These findings, to be published shortly in Brain, open up new avenues for research into the treatment of headache and, in particular, migraine.

For more than 70 years it has been commonly accepted that intracranial pain sensitivity is limited to the dura mater – the outermost meningeal layer which lines the vault and base of the cranium – and its nutrient vessels. The pia mater – the delicate innermost layer, which adheres closely to the surface of the brain – and its nutrient vessels are considered insensitive to pain. This assumption enables neurosurgeons to perform painless intracranial surgery (craniotomies) on awake patients. Until now, this principle also influenced research into the treatment of headaches, particularly migraine.

For a deeper understanding of the origin of headaches, researchers from Inserm, Nice University Hospital and Université Côte d’Azur studied this supposed insensitivity of the pia mater and its nutrient vessels. Between 2010 and 2017, 3 neurosurgeons and 53 of their patients with brain tumors requiring removal by awake craniotomy participated. During the surgery, the patients subjected to the mechanical stimulations which form an integral part of the procedure had to indicate when and where they felt pain. The surgeon noted the cranial structures whose stimulation had triggered pain.

On average, almost two pain sensations were reported per patient, which were always on the same side as the stimulus. The pain, which was brief and intense, ceased immediately following stimulation. The researchers observed that stimulation of the pia mater and its nutrient vessels led to pain, localized mainly in the sensitive V1 territory. A territory which innervates the forehead, eye sockets, cornea, superior and anterior temporal regions, nasal bridge and nasal mucosa.


©Denys Fontaine – Correspondence between (on the right) the areas of the pia mater stimulated during surgery and (on the left) the areas where the patients indicated pain.


These observations contradict the existing accepted theory and argue in favor of the pia mater and its nutrient vessels being sensitive to pain. They would also suggest that these structures could be involved in headache, in the same way as the other sensitive cranial structures.

For ethical and practical reasons, it was not possible during this study to systematically explore the cranial structures that appeared sensitive. However, the identification of the receptors implicated in the detection of pain messages could constitute a novel research avenue for the treatment of headache and, in particular, migraine.

French Estates General 2018 on Bioethics