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The test leads people undergoing in vitro fertilization to discard thousands of embryos each year. The new research found implanting some “abnormal” embryos resulted in healthy live births.When they began their first two rounds of in vitro fertilization in 2015, Anna Dahlquist and her husband, Brian, took a common genetic test to determine the condition of the embryos they had created. The results were devastating: All 13 were “abnormal.”The embryos sat frozen at their fertility clinic in Seattle for six years as the couple underwent round after grueling round of unsuccessful I.V.F. After three years, they had a healthy daughter, using an embryo that they had decided not to test. Then, last year, they went to a new clinic — one that has questioned the reliability of the popular genetic test they took. The clinic implanted a round of the couple’s irregular embryos — two embryos with one chromosomal error and one with two errors. Last month, Ms. Dahlquist gave birth to a healthy baby boy.“I was 39 when I made his embryo,” Ms. Dahlquist said. “And I was 46 when I became pregnant with him. That’s a long time and a lot of valuable years in both my child’s upbringing and my life.”The genetic test, called preimplantation genetic testing for aneuploidy, or PGT-A, has, over the last two decades, become a standard add-on to already pricey I.V.F. procedures. But the test, which can cost anywhere from $4,000 to $10,000, has become controversial over the years as studies have cast doubt on whether it increases birthrates from I.V.F. at all. A growing number of scientists have questioned the widespread use of the test, which leads to tens of thousands of discarded embryos per year and causes many women to believe they may not be able to carry biological children.A new study published last week details 50 patients who underwent transfers of abnormal embryos at the Center for Human Reproduction in New York City. (The Dahlquists had their abnormal embryos transferred to this clinic, since their local clinic would not implant them.) The study reported eight births after 57 transfer cycles of embryos with abnormal genetic testing results since 2015. Seven of the babies were born healthy. The average age of the women in the study was 41 years old.The study is a follow-up to a 2015 study also led by the center that first showed that selected abnormal embryos could still be viable. Since then, other fertility clinics worldwide have also started to transfer such embryos.The research was funded by the clinic and by the Foundation for Reproductive Medicine, a nonprofit research organization also based in New York.The new study “supports concerns that I and others have had for several years now about the accuracy of these tests,” Josephine Johnston, a bioethicist and director of research at the Hastings Center who was not involved in the research, said by email. “The study strengthens the argument that PGT-A tests have been prematurely incorporated into fertility medicine and strongly suggests that these tests will have led patients to discard potentially viable embryos.”But the new study also shows the limitations of transferring such embryos. A vast majority of the 144 embryos transferred by the group had only one or two chromosomal abnormalities, but the transfers led to 11 miscarriages in addition to the eight live births.“There’s a lot of miscarriages in that ratio,” said Laura Hercher, director of student research at the Sarah Lawrence College genetic counseling program.The PGT-A test is used to screen for aneuploidy, which is when an improper number of chromosomes — either too few or too many — is detected in sampled cells. An abnormal number of chromosomes can, in serious cases, lead to genetic disabilities, like Down syndrome. More often, the wrong number of chromosomes can lead to failed pregnancies, either by preventing embryos from implanting or by causing miscarriages.But the problem with PGT-A, the authors of the study argue, is that it provides an incomplete picture that is often interpreted as a very definitive result. The test relies on sampling a handful of cells from the outer shell of the developing embryo and testing to see if each one has 23 pairs of chromosomes.“The point of PGT was to select embryos that would give somebody a better chance of achieving pregnancy,” said Dr. David Barad, an OB-GYN at the Center for Human Reproduction and a co-author of the study. “But doing genetic testing doesn’t make embryos better, it just kind of gives us some idea of who they are.”Though moving ahead with using these embryos with abnormalities may come with some risk, the authors of the new study, all of whom were connected to the clinic doing the transfers, argue that viable embryos are currently being disregarded, leaving many women to believe they have no other options to achieve a pregnancy.“The miscarriage rate is roughly what one expects at such advanced age,” Dr. Norbert Gleicher, director of the clinic and a co-author of the study, said by email. He added: “Ask women what they prefer. A risk of miscarriage or no chance of having a baby at all. The answer will be clear.”In one of the pregnancies in the study, the fetus was diagnosed with a heart defect in utero. The parents moved forward and had a live birth. After having surgery as a newborn, the baby is reportedly healthy. Dr. Gleicher said there was “no known connection whatsoever” between the birth defect and the chromosomal error.A bigger study of outcomes would make clearer whether there is a risk of birth defects, Ms. Hercher said. But this outcome also speaks to the complex level of uncertainty that fertility providers will have to face — and properly educate their patients about — when it comes to the potential risks involved with using these embryos.“We don’t really know what to tell them about the long term potential consequences to a child that’s born,” Ms. Hercher said. “Will there be an increased number of birth defects? Will we find that they have problems down the road? There’s a lot of ‘I don’t knows.’”Irregular numbers of chromosomes are surprisingly common, especially as women get older. For women over 35, there’s roughly a 50 percent incidence of aneuploidy in embryos produced during I.V.F. that increases with age. As the fertilized egg divides and multiplies into cells, errors that occur down the line can be replicated. But the normal cells might have a competitive advantage over the abnormal cells, leading the vast majority of the cells in the embryo to still have the correct number of chromosomes. Or some of those incorrect cells may eventually self-correct.Either way, the potential for this patchwork of cells means that any one picture of the embryo will be limited. A normal test result could miss irregular cells elsewhere, and one cell with the wrong number of chromosomes is enough to turn up abnormal results. By sampling just a small subset of cells at a very early stage in embryo development, PGT-A may cause some fertility clinics, wary of taking risks, to reject embryos that could lead to healthy pregnancies.False positives are also a problem for women who don’t undergo I.V.F. On Tuesday, the Food and Drug Administration warned that noninvasive prenatal tests, which look for signs of genetic abnormalities in the fetus, could lead patients to make decisions about their pregnancies based on incorrect information. Some researchers argue that PGT-A may still be useful for some people. For younger patients who produce more eggs, the test can help rank which embryos have the highest likelihood of succeeding, minimizing the number of procedures they have to undergo and pay for.But the Dahlquists, who were told that the “abnormal” embryos they produced in their first two cycles of I.V.F. could not be used, believe more nuance needs to be communicated to patients so they can be empowered to weigh the risks and make informed decisions.The fact that their fertility clinic would not allow potentially viable embryos to be used and forced them to wait six years to use them made her feel powerless, Ms. Dahlquist said. Few clinics will agree to transfer such embryos, and, at the time they took the test, the couple didn’t even know that was a possibility.“I just feel like it’s unfair,” she added. “They really are ruining a lot of people’s chances.”

21 million. That’s the number of genetic variations in the human genome that researchers are sifting to identify patterns predisposing people to Alzheimer’s disease.
It’s a huge haystack, and Alzheimer’s-related genetic variations, like needles, are miniscule in comparison. Sudha Seshadri, MD, and other faculty at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) readily attest to the deep gulf between what is known about Alzheimer’s genetics and what is yet to be discovered.
Dr. Seshadri, Habil Zare, PhD, and colleagues at the university’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases are investigators on a global project to answer the many Alzheimer’s riddles. Dr. Seshadri is a founding principal investigator of the International Genomics of Alzheimer’s Project, commonly called IGAP. Glenn Biggs Institute faculty contributed data for the newest research from IGAP, published April 4 in Nature Genetics, and helped craft the discussion on implications of the findings, Dr. Seshadri said.
Large sample
Genomic data of half a million people were used in this latest IGAP study, including 30,000 people with confirmed Alzheimer’s disease and 47,000 people categorized as proxies. Researchers could not be sure that proxy participants had Alzheimer’s clinically, but they were included based on conversations with their children.
“In Alzheimer’s disease research you need many samples, because some of these variants are very rare, and if you want to detect them, you need to study many, many people,” said Dr. Zare, assistant professor of cell systems and anatomy in the Joe R. and Teresa Lozano Long School of Medicine and an expert in computational biology and bioinformatics. “The only way to get there is through collaboration between centers and consortia, and IGAP was established for such kind of collaboration.”
IGAP conducts genome-wide association studies. These studies reveal areas of the genome, the encyclopedia of human genes, that vary between people who have Alzheimer’s disease and people who don’t.

New evidence from a zebrafish model of epilepsy may help resolve a debate into how seizures originate, according to Weill Cornell Medicine and NewYork-Presbyterian investigators. The findings may also be useful in the discovery and development of future epilepsy drugs.
In the study, published Feb. 23 in Brain, the researchers were able to track the activities of neurons throughout the entire brains of larval zebrafish during seizures. They showed that the seizures originated from an excess of “excitatory” over “inhibitory” brain cell activity in relatively confined regions of the brain and spread only when they overcame strong inhibitory activity in surrounding regions.
Neurons in the brain come in two broad categories: excitatory neurons whose activity stimulates the activity of other neurons, and inhibitory neurons whose activity quiets other neurons. Some recent studies have indicated that surges in the activity of inhibitory neurons can paradoxically trigger seizures. The new findings suggest otherwise.
“What’s really nice about the zebrafish model is that we can image every brain region, and in this model, for the first time, we were able to distinguish and track the activity of both excitatory and inhibitory neurons,” said first author Dr. James Niemeyer, a postdoctoral associate in neurological surgery at Weill Cornell Medicine. “So, this is a good starting point for examining the nuanced roles of these cell types during seizures.”
Dr. Niemeyer is a member of the laboratory of co-senior author Dr. Theodore Schwartz, who is the David and Ursel Barnes Professor of Minimally Invasive Neurosurgery and vice chair for clinical research at the Weill Cornell Brain and Spine Center at Weill Cornell Medicine and a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center. The other co-senior authors of the study are Dr. Hongtao Ma, associate professor of neuroscience research in neurological surgery, and Dr. Emre Aksay, associate professor of physiology and biophysics, both at Weill Cornell Medicine.
Epilepsy is common, afflicting roughly fifty million people around the world at any one time. But how it originates has never been entirely clear. On the one hand, there is evidence that seizures arise from zones in the brain that favor excitatory neuron activity over the usual restraining influence of inhibitory neurons. On the other hand, several recent studies have suggested that excessive activity in inhibitory neurons may trigger seizures — some researchers have observed earlier seizure activity in these cells. This has left a gap in understanding of the different roles of excitation and inhibition in seizures.

Black women are disproportionately affected by poor sleep, which is associated with increased risk of adverse outcomes such as cardiovascular disease, depression and worse quality of life. The gold standard treatment for insomnia is cognitive behavioral therapy for insomnia (CBT-I), which specifically targets the individual’s problematic sleep behaviors and beliefs.
Internet-delivered CBT-I programs for insomnia have been developed to increase patient access to treatment. While these programs have been shown to be very effective, the vast majority of this research has been conducted among non-Hispanic White participants. This can be an issue for minority groups who understandably may not trust the healthcare system. In particular, Black women were less likely than White women to initiate internet-delivered CBT-I, or to stay engaged with treatment once they began. Now, a study led by researchers from the Slone Epidemiology Center (SEC) at Boston University and the Division of Sleep Medicine at Harvard Medical School shows that internet-delivered CBT-I is highly effective in Black women, and that a version of the program tailored specifically for Black women improves their engagement with treatment.
In a randomized trial, 333 women with insomnia from BU’s Black Women’s Health Study (BWHS) — (a large follow-up study of Black women in progress since 1995), were randomized to three internet-delivered treatments: Sleep Healthy Using the Internet (SHUTi); SHUTi-BWHS, a culturally-tailored version of SHUTi developed specifically for Black women, guided by a team of stakeholders including Black women; and patient education about sleep (PE).
The trial participants were unaware of the program to which they had been assigned. The PE group was provided with sleep education materials, such as sleep hygiene recommendations, while the women assigned to SHUTi and SHUTi-BWHS worked their way through the interactive program that contained six “modules” addressing various aspects of sleep. The modules delivered CBT-I using psychoeducational content, customized recommendations based on the participant’s reported sleep, videos highlighting common challenges that insomnia patients experience when implementing CBT-I, and advice from experts. The SHUTi-BWHS program addressed key issues that may be more likely to affect a Black woman’s sleep, with all of the program’s visual content revamped to include only Black patients and sleep physicians.
Participants in both SHUTi and SHUTi-BWHS had greater improvements in their insomnia symptoms compared with the PE group, with these gains sustained at 6 months after program completion. Significantly more women receiving SHUTi-BWHS completed the program than those receiving SHUTi. This is important as women who completed either SHUTi or SHUTi-BWHS were more likely to see their sleep improve.
“While Internet-delivered interventions offer better access to evidence-based care, patient adherence with automated programs that are designed to change health behaviors can be an issue. The development of a culturally tailored intervention may be the key to better engaging minority patients with proven insomnia treatment,” explains senior author Lynn Rosenberg, ScD, epidemiologist at the SEC and a principal investigator of the BWHS.
The leaders of the study were encouraged that efforts to address sleep problems facing Black women was successful. “Profound health inequities affect the lives of so many racial/ethnic minority patients. We are proud to have conducted research designed specifically to address sleep health disparities in Black women, and are hopeful that this work spurs further interest and investment into research in this critical domain,” said corresponding author Eric Zhou, PhD, clinical psychologist, Dana-Farber Cancer Institute.
The study was funded by the Patient-Centered Outcomes Research Institute. The SHUTi program is located at the University of Virginia where it is directed by Dr. Lee. M. Ritterband.
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Residential exposure to ambient air pollutants is linked to an elevated risk of SARS-CoV-2 infection, an observational study of young adults in Stockholm, Sweden shows. The study was conducted by researchers from Karolinska Institutet and is published in JAMA Network Open.
Since pollutants in outdoor air can increase the risk of respiratory infections such as influenza and SARS, the COVID-19 pandemic aroused fears that they could also contribute to the risk of SARS-CoV-2 infection. Studies have also shown that areas of poor air quality have more cases of COVID-19.
Researchers at Karolinska Institutet have now studied this more closely by examining the link between estimated exposure to air pollutants at home addresses and positive PCR tests for SARS-CoV-2 in young adults in Stockholm, Sweden.
The results show that exposure to certain traffic-related air pollutants is associated with a greater likelihood of testing positive.
“Our results add to the growing body of evidence that air pollution has a part to play in COVID-19 and support the potential benefit of improving air quality,” says Olena Gruzieva, associate professor at the Institute of Environmental Medicine at Karolinska Institutet and one of the study’s last authors.
The study draws on the population-based BAMSE project, which has regularly followed over 4,000 participants in Stockholm from birth. By linking these data to the national communicable disease registry (SmiNet), the researchers identified 425 individuals who had tested positive for SARS-CoV-2 (PCR test) between May 2020 and the end of March 2021. The average age of the participants was 26, and 54 per cent were women.

Inside brain cells, errors in DNA can accumulate as we age. But in patients with Alzheimer’s disease, these errors — known as somatic mutations — may build up at a faster rate. A new study by investigators from Brigham and Women’s Hospital and Boston Children’s Hospital found that patients with Alzheimer’s disease (AD) have a greater number of somatic mutations in their brain cells and that these mutations differed from people without Alzheimer’s disease. The team’s results are published in Nature.
“As we age, neurons are known to accumulate somatic mutations. In AD neurons, however, we see more mutations and DNA alterations,” said lead author Michael B. Miller, MD, PhD, of the Department of Pathology at the Brigham. “Our results suggest that AD neurons experience genomic damage that causes immense stress on cells and creates dysfunction among them. These findings may explain why many brain cells die during AD.”
The team conducted its study using single-cell whole genome sequencing of 319 hippocampal and prefrontal cortex neurons of patients with or without AD to determine the link between the number and type of somatic mutations and AD. To better understand the genomic changes that occur in AD neurons, researchers sequenced tissue DNA and discovered a greater number of mutations termed somatic single-nucleotide variants (sSNVs) in patients with AD. Theorizing that the large number of mutations is the result of increased DNA oxidation, researchers then measured 8-Oxoguanine, an indicator of oxidative stress and DNA damage, and found that AD neurons were in fact more oxidized.
Ultimately, the discovery of accumulating DNA alterations in AD neurons provides researchers with a window into molecular and cellular events in AD pathogenesis. “Our findings suggest that the sheer number of oxidative lesions and somatic mutations we observed in AD neurons may contribute to its pathology,” said Miller.
The authors acknowledge two main study limitations. First, two groups were primarily studied: patients with no neurologic disease and those with advanced AD based on the Braak staging system. In the future, researchers are eager to study the neurons of individuals with intermediate-stage AD. Second, while single-cell, whole-genome sequencing was feasible for the preliminary studies, the authors note that there are advanced methods that allow for an in-depth analysis of each strand of DNA that should be explored in the future.
“In the future, we are eager to elucidate how the observed mutations in AD neurons cause neuronal cell death and are dedicated to aiding in the discovery of novel treatments that target these pathways,” Miller said.
Disclosures: Christopher A. Walsh is a paid consultant (cash, no equity) to Third Rock Ventures and Flagship Pioneering (cash, no equity) and is on the Clinical Advisory Board (cash and equity) of Maze Therapeutics. No research support is received. These companies did not fund and had no role in the conception or performance of this research project.
Funding: This work was supported by the National Institutes of Health (K08 AG065502,T32 HL007627, T32 GM007753, T15 LM007098, R00 AG054748, K01 AG051791, R01 NS032457-20S1, R01 AG070921, DP2 AG072437), the Brigham and Women’s Hospital Program for Interdisciplinary Neuroscience through a gift from Lawrence and Tiina Rand, the donors of the Alzheimer’s Disease Research program of the BrightFocus Foundation (A20201292F), the Doris Duke Charitable Foundation Clinical Scientist Development Award (2021183), Suh Kyungbae Foundation, the F616 Prime Foundation, and the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation.
Paper cited: Miller MB et al. “Somatic genomic changes in single Alzheimer’s disease neurons” Nature 2022 DOI: 10.1038/s41586-022-04640-1
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In experiments on mice, researchers at ETH Zurich show that non-​essential amino acids act as appetite suppressants and promote the urge to move. Their research provides insight into the neural mechanism that controls this behaviour.
Proteins can suppress appetite, so a protein-​rich diet can help people lose weight. That’s just one of the reasons why this kind of diet has become increasingly popular in recent years. Working with mice, researchers at ETH Zurich have now demonstrated a new mechanism by which the building blocks of proteins — the amino acids — curb appetite. Specifically, it involves what are known as non-​essential amino acids.
Of the 21 amino acids our bodies require, there are 9 they are unable to produce on their own. They are called essential amino acids. Because we must obtain these through our diet, they have far been the focus of nutrition research. The other 12 amino acids are considered non-​essential. The body can produce them itself by altering other molecules.
Shown in mice
It has been known that both essential and non-​essential amino acids can suppress appetite. For the non-​essential amino acids, the mode of action had not yet been demonstrated in living organisms, however. Now, a group of researchers led by Denis Burdakov, Professor of Neuroscience at ETH Zurich, have shown for the first time in a living organism that the non-​essential amino acids influence the brain in a way that curbs appetite and promotes exercise.
The researchers first fed mice either a mixture of various non-​essential amino acids or a sugar solution with the same amount of calories (control group). Both groups of mice were then allowed to drink a milkshake, which they normally love. While the control group drank copious amounts of it, the mice that had been fed non-​essential amino acids avoided theirs. Instead, they went around their enclosure in search of alternative sustenance.
Rooted in evolutionary history
With additional experiments, the researchers were able to decode the underlying mechanism, in which specialised nerve cells in the brain — orexin neurons — play the main role. Proteins that the mice take in through food are broken down in the gut into their amino acids, which then enter the bloodstream. From there, the blood transports them to the brain. The orexin neurons in the hypothalamus have receptors that specifically recognise the non-​essential amino acids. In response, they initiate a neural circuit that produces the described behavioural changes.
This mechanism is likely rooted in evolutionary history. “Today, we have sufficient access to all nutrients, and we have plenty of time for eating. In prehistoric times, when this mechanism developed, that was likely not the case,” says Paulius Viskaitis, a postdoc in Burdakov’s group and lead author of the study. “Back then, it was advantageous for individuals to spend only a short amount of time at a food source that consisted primarily of non-​essential amino acids.” If eating non-​essential amino acids promotes the urge to move, the animal will go in search of other sources of food — which potentially contain more essential nutrients and are more important for the individual.
Viskaitis stresses that the results are transferable to humans and other animals, as this mechanism affects a region of the brain that is very old in terms of evolutionary history and occurs equally in all mammals and many other vertebrates. Still, for people who want to lose weight, a diet that includes especially many non-​essential amino acids cannot be recommended across the board, Viskaitis says. Nutritional recommendations should be made on an individual basis, and they should also take health aspects into account.
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New study demonstrates that in utero exposure to mother’s antiepileptic or antidepressant medication may affect development of the newborn brain networks. In the study, novel mathematical methods were developed to allow future research on how commonly used drugs or other environmental conditions affect the newborn brain.
Pregnant mothers may need treatment for their medical conditions, such as mood disorder or epilepsy. The effects of such drug treatment on newborn brain network functions was examined in a study conducted at the BABA Center, a research unit in University of Helsinki and New Children’s Hospital of HUS Helsinki University Hospital. The study used electroencephalography (EEG) to measure electrical brain activity during sleep, and cortical network properties were calculated using advanced mathematical techniques.
“In prior studies, we have shown that changes in cortical activity across sleep states may provide important information on infants’ neurological condition,” Senior Researcher Anton Tokariev says.
The study demonstrated that exposure to antiepileptics and antidepressants during the fetal period leads to widespread changes in the cortical networks, and these effects may be specific to the type of drug exposure. In the case of antidepressants, the effect was more pronounced in local cortical networks. In contrast, exposure to antiepileptics had drug-specific effects on brain wide networks. Both drug types affected brain networks that are reactive to changes in sleep stages.
“What was clinically significant in the findings was that, some EEG findings linked to children’s subsequent neuropsychological development. Stronger changes in neural networks predicted a greater deviation in development at two years of age,” says Mari Videman, specialist in paediatric neurology at HUS Helsinki University Hospital.
Shedding new light on early brain development
The studies offer an entirely new way of assessing the effects of pharmaceutical agents on the development of child’s brain function.
“The EEG measurement technique developed at the BABA Center and its associated state-of-the-art mathematical assessment of the brain’s neural networks constitute breakthroughs in clinical research on early neurodevelopment,” Professor Sampsa Vanhatalo says.
Vanhatalo considers it particularly important that these EEG -based measures open a window into mechanisms that operate between neuronal cell. This leads to an opportunitity to compare results observed in human children with research conducted using laboratory-animal models. Such translational work is needed to understand the mechanistic underpinnings of the drug effects. For instance, identical animal work is required to study how the amount or timing of maternal drug treatment would affect brain function of the offspring.
“Our novel methods provide a general analytical framework to support extensive future research on the questions how fetal brain development is affected by changes in intrauterine environment. Such studies may go far beyond maternal drug treatment, including also mother’s nutrition and overall physical condition, as well as myriad of further environmental factors,” Vanhatalo summarises.
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Scientists have known for years that amyloid fibrils — fibrous, ropelike structures formed by closely linked protein molecules — are present in the brains of patients with Alzheimer’s and Parkinson’s diseases and likely play a role in the progression of these disorders.
Now, UCLA biochemists have discovered such fibrils in the brains of people with a form of frontotemporal lobar degeneration, or FTLD, the most common neurodegenerative disorder after Alzheimer’s and Parkinson’s. But surprisingly, the type of protein they expected to find in these potentially harmful fibrils wasn’t there at all; instead, a little-known protein called TMEM106B was identified as the culprit.
The findings, published in the journal Nature, are likely to lead to a new focus on TMEM106B in FTLD and similar brain diseases, the researchers said.
FTLD, which involves damage to the brain’s frontal and temporal lobes, strikes people earlier in life than Alzheimer’s and Parkinson’s, causing dementia in 80 out of 100,000 people between the ages of 45 and 64. Symptoms can include acute changes in behavior and a decline in language skills. The form of the disease studied by the researchers is characterized molecularly by dense, spherical aggregates in brain cells, which are made up of the protein TDP-43.
The UCLA team presumed that if there were amyloid fibrils in the brains of people with FTLD, these fibrils would be composed of TDP-43.
The study’s lead authors, UCLA molecular biology graduate student Yi Xiao (Sean) Jiang and UCLA postdoctoral fellow Qin Cao, both working in laboratory of UCLA professor David Eisenberg, were indeed able to extract amyloid fibrils from frozen brain tissues provided by the Mayo Clinic from four deceased patients who had been diagnosed with FTLD-TDP.

The brain is able to detect and regulate localized or systemic inflammation by using two communication pathways. The first, humoral, makes use of specific brain structures that enable circulating inflammatory mediators to enter the brain. The second, neural, involves nerves whose sensory afferents transmit the inflammatory signal detected at local level.
The vagus nerve therefore uses identified receptors to detect a digestive or lung inflammation. Specific brain structures and networks perceive and integrate these humoral and neural messages and orchestrate a regulatory response involving neuroendocrine, neurovegetative and behavioral elements. These corrective interventions are controlled respectively by the hypothalamus and the hypophysis — the autonomic nervous system and the limbic system. Neuroendocrine activation is characterized by the release of cortisol, the main stress hormone. The autonomic response involves the combined activation of the sympathetic and vagal systems, with the latter believed to induce a local anti-inflammatory response. Behavioral changes affect mood, attention, sleep and appetite. The aim of the overall response is to control inflammation so as to preserve bodily integrity, or homeostasis. But in some circumstances, it can be ill adapted and can lead to immunological and/or psychological disorders.
A severe infection known as sepsis is the most common condition capable of inducing this defense strategy against inflammatory stress. Sepsis is the leading cause of death worldwide and represents a major public health challenge. What makes the situation worse is that sepsis is also associated with chronic psychological disorders such as anxiety, depression and post-traumatic stress disorder. These conditions significantly increase suicide risk and have a lasting impact on the personal, social and professional lives of patients. “No preventive treatments have so far been demonstrated to be effective, probably because of a lack of understanding of the pathophysiology of these disorders, especially the neural networks implicated in their onset,” explains Professor Tarek Sharshar, Head of the Sainte-Anne Neurology Department.
In an experimental study published in the journal Brain, a team of scientists from the Institut Pasteur (Perception and Memory laboratory) and clinicians from the Paris Psychiatry and Neurosciences University Hospital Group (GHU) (Neurological Resuscitation Department) used pharmacogenetic techniques to identify a dedicated neural circuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis. The activation of this circuit in the first few hours of sepsis induces anxious behavior two weeks after the infection has cleared. This behavior observed in mice mimics the post-traumatic stress disorder observed in patients recovering from sepsis.
“This discovery paves the way for new therapeutic strategies for sepsis: we observed that administering an agent capable of preventing the hyperactivation of this circuit reduces the risks of developing anxiety disorders,” explains Professor Pierre-Marie Lledo, Institut Pasteur and CNRS. This effect is thought to be partly linked with reduced activation of the vagal afferent integration center.
This study is of particular interest because it identifies both a dedicated circuit for post-sepsis anxiety and a potential pharmacological treatment. The latter will soon be tested in a multicenter randomized therapeutic trial. By revealing the link between neuroinflammation and psychiatric disorders, this research resonates with the current context of the COVID-19 pandemic and long COVID.
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