Dr. Monica M. Bertagnolli (original) (raw)
NIH’s CARE for Health Primary Care Research Network: Connecting the Lab, the Clinic, and the Community
Posted on October 8th, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss
Since I became NIH Director last year, one key principle has guided my vision and approach: Our work is not finished when we deliver scientific discoveries; our work is finished when all people are living long and healthy lives.
But unfortunately, we’re seeing some alarming trends in the health of the U.S. population. It’s a bit of a puzzle. On one hand, significant advances in biomedical research over the last several decades have led to lifesaving interventions for a range of diseases and conditions. At the same time, the overall health of the people in this country appears to be stalled and even getting worse.
Looking at one measure of health, U.S. life expectancy is no longer steadily increasing—in fact, we’ve had a decline in life expectancy over the last decade. And though this included a dramatic drop because of the COVID-19 pandemic, the rate was declining before that. Life expectancy in the U.S. is also low compared to peer nations, even though we spend much more money on our health system. Disparities in mortality also persist among certain racial and ethnic groups and geographic regions. Our health is determined not only by the genes we inherit from our parents, but by our environment and social and economic factors. We know that in the U.S. today, your zip code can significantly impact your health.
I believe that biomedical research can play a key role in reversing these trends. In my first blog post, I explained how one of my goals as NIH Director is to ensure that the biomedical research enterprise is more inclusive to people from all walks of life, and I noted we can engage more communities as our research partners by meeting people where they are. Despite having the knowledge and technology to do so, our research and advances are not reaching everyone they should. Many people are not adequately represented in clinical research, and research data is especially lacking for people who are older, uninsured, belong to minority groups, or live in rural locations. Many people also face barriers to participating in clinical research, such as arranging and paying for transportation, getting time off from work and coordinating childcare, or lack of trust in medical institutions. To address these concerning trends in health, we need to do a better job of connecting the lab, the clinic, and the community.
In September, we moved closer to this goal by announcing awards as part of a new NIH primary care clinical research network that aims to improve access to and involve communities in the clinical research that informs medical care. The Communities Advancing Research Equity for Health™ or CARE for Health™ program will actively engage communities historically underrepresented in clinical research. This effort is very close to my heart, as I was born and raised in a rural community, and I’d like to tell you more about how it will work.
In this program, NIH will connect with primary care providers and their patients, giving them access to research and the opportunity to participate in clinical trials. By engaging people on the front lines of health care—in the primary care clinician’s office—we will build an infrastructure that leads to sustained relationships with primary care providers and patients and earns people’s trust. Many of the areas of the country where we want to focus do not have medical specialists, and primary care providers are often the only practitioners available for every health challenge. Through CARE for Health, we want to integrate clinical care with research to support knowledge generation that meets the needs of people in all communities.
The awards we’ve announced, totaling over 5millioninfundingforthefirstyear,willsupportthreeNetworkResearchHubstoestablishtheprogram’sinitialinfrastructure.ThefirstawardeeinstitutionsareOregonHealthandScienceUniversity,theUniversityofWisconsin−Madison,andWestVirginiaUniversity.TheseinstitutionswillparticipateinthreeongoingNIH−fundedclinicaltrialsthatcoverarangeoftopicsimportanttoprimaryhealthcare,includingpainmanagement,opioidandpolysubstanceuse,andgout,withmanymorestudiesonareasimportanttodiversecommunitiestocomeinthefuture.Overall,NIHis[investingapproximately5 million in funding for the first year, will support three Network Research Hubs to establish the program’s initial infrastructure. The first awardee institutions are Oregon Health and Science University, the University of Wisconsin-Madison, and West Virginia University. These institutions will participate in three ongoing NIH-funded clinical trials that cover a range of topics important to primary health care, including pain management, opioid and polysubstance use, and gout, with many more studies on areas important to diverse communities to come in the future. Overall, NIH is [investing approximately 5millioninfundingforthefirstyear,willsupportthreeNetworkResearchHubstoestablishtheprogram’sinitialinfrastructure.ThefirstawardeeinstitutionsareOregonHealthandScienceUniversity,theUniversityofWisconsin−Madison,andWestVirginiaUniversity.TheseinstitutionswillparticipateinthreeongoingNIH−fundedclinicaltrialsthatcoverarangeoftopicsimportanttoprimaryhealthcare,includingpainmanagement,opioidandpolysubstanceuse,andgout,withmanymorestudiesonareasimportanttodiversecommunitiestocomeinthefuture.Overall,NIHisinvestingapproximately30 million in total over fiscal years 2024 and 2025 to pilot the program, which is supported through the NIH Common Fund. After the first year, we will aim to broaden the program so communities throughout the country can participate.
CARE for Health is a new paradigm for biomedical research. NIH has never had a network for the primary care medical environment that works across all 27 Institutes and Centers of NIH. We are starting it with a pilot program because we know that for a program of this scale, we first need to learn from our research teams and from the primary care clinicians who are going to help us bring this kind of research to their communities. We will also ask community members what their health priorities are and allow them to select the research studies that are most meaningful to them. In the future, CARE for Health partners will have a long menu of studies to pick from based on local interests and needs.
Ultimately, we believe that this program will have a meaningful impact on health outcomes, especially among those who have been previously underrepresented and underserved in medical research.
Reference:
Bertagnolli MM. Connecting lab, clinic, and community. Science. DOI:10.1126/science.adq2140 (2024).
NIH Support: NIH Common Fund
AI Model Takes New Approach to Performing Diagnostic Tasks in Multiple Cancer Types
Posted on October 3rd, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH, Adobe Stock
In recent years, medical researchers have been looking for ways to use artificial intelligence (AI) technology for diagnosing cancer. So far, most AI models have been developed to perform specific tasks in cancer diagnosis, such as detecting cancer presence or predicting a tumor’s genetic profile in certain cancer types. But what if an AI system could be more flexible, like a large language model such as ChatGPT, performing a variety of diagnostic tasks across multiple cancer types?
As reported in the journal Nature, researchers have developed an AI system that can perform a wide range of cancer evaluation tasks and outperforms current AI methods in tasks like cancer cell detection and tumor origin identification. It was tested on 19 cancer types, leading the researchers to refer to it as “ChatGPT-like” in its flexibility. According to the research team, whose work is supported in part by NIH, this is also the first AI model based on analyzing slide images to not only accurately predict if a cancer is likely to respond to treatment, but also to validate these predictions across multiple patient groups around the world.
Today, when doctors order a biopsy to find out if cancer is present, those samples are sent to a pathologist, who examines the tissues or cells under a microscope to determine if they are cancerous. The team behind this AI model, led by Kun-Hsing Yu, Harvard Medical School, Boston, recognized that pathologists must analyze a wide variety of disease samples. To make accurate diagnoses in different cancer types, they must take many subtle factors into account.
Most earlier attempts to devise an AI model to analyze tissue samples have depended on training computers to recognize one cancer type at a time. In the new work, the researchers developed a more general-purpose pathology AI system that could analyze a broader range of tissues and sample types. To develop their Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model, the researchers used an AI approach known as self-supervised learning. In this method, a computer is given large volumes of data, in this case 15 million pathology images, to allow it to identify intrinsic patterns and structures. This process allows a computer to “learn” from experience to identify informative features in a vast data set.
The tool was then trained further on more than 60,500 whole-slide images in tissues collected from 19 different parts of the body—such as the lungs, breast, prostate, kidney, brain, and bladder—to bolster the model’s ability to capture similarities and differences among cancer types. This training data was in part comprised of data from The Cancer Genome Atlas (TCGA) program and the Genotype-Tissue Expression (GTEx) Project, both NIH-supported resources. The researchers directed the model to consider both the image as a whole and its finer details, enabling it to interpret the image in a broader context than one region. They then put CHIEF to the test, using another 19,491 whole-slide images from 32 independent slide sets collected from 24 hospitals around the world.
They found that CHIEF worked equally well no matter how the samples were collected (biopsy or surgical excision) and in different clinical settings. In addition to detecting cancers and predicting a cancer’s tissue of origin, CHIEF also predicted with 70% accuracy whether a tissue carried one among dozens of genetic mutations that are commonly seen in cancers. CHIEF showed an ability to predict whether a sample contained mutated copies of 18 genes that oncologists use to make treatment decisions. CHIEF could predict better than earlier models how long a patient was likely to survive following a cancer diagnosis and how aggressively a particular cancer would grow.
This is all good news, but there’s much more work ahead before an AI model like this could be used in the clinic. Next steps for the researchers include training the model on images of tissues from rare cancers, as well as from pre-cancerous and non-cancerous conditions. With continued development and validation, the researchers aim to enable the system to identify cancers most likely to benefit from targeted or experimental therapies in hopes of improving outcomes for more people with cancer in diverse clinical settings around the world.
Reference:
Wang X, et al. A pathology foundation model for cancer diagnosis and prognosis prediction. Nature. DOI: 10.1038/s41586-024-07894-z (2024).
NIH Support: National Institute of General Medical Sciences, National Cancer Institute
Posted In: Health, Science, technology
Tags: AI, artificial intelligence, cancer, cancer diagnosis, computer learning, genetic mutations, genetics, imaging, pathology, technology
‘Silent’ Mutations Could Have Unexpectedly Far-Reaching Effects that May Impact Health
Posted on September 26th, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
Genetic mutations affect nearly all human diseases. Some genetic disorders such as cystic fibrosis are caused by mutations in a single gene that a person inherits from their parents. Other diseases can be caused by changes in multiple genes or from a combination of gene mutations and environmental factors. We still have a lot to learn about the complex ways that variations in our genes affect health and disease.
Researchers investigating genetic disorders have primarily studied mutations that cause our cells to alter the makeup of proteins, like the most common mutations that cause cystic fibrosis. Less research has been done on alterations called synonymous mutations, which have been called “silent” because they don’t alter the makeup of proteins, leading scientists to long assume that these kinds of mutations don’t produce any noticeable differences in our biology or health. However, recent research has shown that synonymous mutations can lead to significant changes in a cell’s ability to survive and grow. A new NIH-supported study reported in Proceedings of the National Academy of Sciences sheds additional light on the impact of synonymous mutations and their effect on the way proteins are made.
The researchers behind this study, at the University of Notre Dame in Notre Dame, IN, wanted to understand how synonymous mutations may affect how much protein is made and whether proteins are folded correctly in cells. Misfolded proteins are known to play roles in numerous diseases, including cystic fibrosis, Alzheimer’s disease, and some cancers. The study team, led by Patricia L. Clark, who received an NIH Director’s Pioneer Award in 2021 for this work, has shown that synonymous mutations in a particular gene in Escherichia coli (E. coli) bacteria can alter how the encoded protein folds as it is being made, by altering the rate at which cells produce each copy of the protein. The new research goes a step further and shows that silent mutations in one gene can affect the amount of protein produced from a separate, neighboring gene.
Clark and colleagues, including first author Anabel Rodriguez, created nine synonymous versions of the E. coli chloramphenicol acetyltransferase (cat) gene. This gene encodes a protein enzyme that influences the bacterium’s sensitivity to a particular antibiotic. The researchers found that four of the nine synonymous cat gene sequences significantly affected the number of protein enzymes the E. coli produced from this gene. Unlike in prior work from Clark’s lab, the reason for those differences didn’t stem from changes in protein folding. The differences began one step earlier, in the synthesis of RNA copies, or transcripts, from the cat gene’s DNA. An RNA transcript carries the instructions cells use to produce proteins.
How did it happen? The researchers found that some of the synonymous mutations created new sites on the cat gene where the enzyme that synthesizes RNA could bind. As a result, E. coli cells started making RNA transcripts from part of the cat gene and the entire neighboring gene. These new RNA transcripts led those bacterial cells to make more of the protein encoded by the neighboring gene. In short, these findings unexpectedly showed that synonymous mutations in one gene can alter the production of the protein from other genes.
This discovery in E. coli may have important implications for understanding the bacteria’s biology and evolution. Clark’s team continues to study this system to learn more. Their findings may also prove to have broader implications for biology, including for some genetic disorders. It’s an area that warrants more study and attention, to better understand the roles that synonymous mutations may be playing in genes and their effects on human health.
Reference:
Rodriguez A, et al. Synonymous codon substitutions modulate transcription and translation of a divergent upstream gene by modulating antisense RNA production. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2405510121 (2024).
NIH Support: National Institute of General Medical Sciences
Welcoming Senator Reed and Congressional Staff to the NIH Campus
Posted on September 24th, 2024 by Dr. Monica M. Bertagnolli
Senator Jack Reed (right) visited the NIH Clinical Center, which included a tour of the National Cancer Institute’s pediatric oncology lab. Credit (all photos): Chia-Chi Charlie Chang, NIH
On September 13, I was delighted to welcome Senator Jack Reed to the NIH campus. His tour included a visit to the NIH Clinical Center, where he heard about recent findings in RNA sequencing from experts from the National Institute of Environmental Health Sciences and the National Human Genome Research Institute. We then joined several senior leaders and scientists from the National Cancer Institute to discuss advances in childhood cancer research, and to visit a pediatric oncology lab and meet with a patient who received treatment there. He also met with leaders of NIH’s Fogarty International Center. Later in the day, I welcomed a group of new Congressional Staff from the House Democratic Caucus. They, too, got a chance to visit NIH labs and talk to researchers. We then had a roundtable discussion where I introduced myself and my background, talked about current trends in health, and answered questions about the work we do here and my vision and priorities for NIH. I’d like to thank Sen. Reed and Congressional Staff for coming to NIH and joining in such informative conversations.
NIH Director Monica Bertagnolli (left) on a tour of the NIH Clinical Center, talking with Sen. Reed (center) and Dr. Brigitte Widemann (right), Chief of the National Cancer Institute’s Pediatric Oncology Branch.
Dr. Bertagnolli speaking at a roundtable with Congressional Staff.
Taking Inspiration from Art Created by a Patient’s Granddaughter
Posted on September 20th, 2024 by Dr. Monica M. Bertagnolli
NIH Director Dr. Monica Bertagnolli in her office with Suzi Grossman’s artwork. Credit: Chia-Chi Charlie Chang, NIH
I have a specific ritual when moving into a new office, as I did when I became NIH Director in 2023: I hang a very special framed screen print on the wall. This piece of art has followed me through several different offices, representing different positions I have held as a cancer surgeon, researcher, and educator. It’s always the first thing I want to see as I settle into a new workplace. It serves as an inspiration for my work, for what so many of us involved in health care strive to do. I’d like to take this opportunity to tell you the story behind it.
Many years ago, in my role as an oncologist and surgeon, I had a very memorable patient, an older woman who had advanced cancer. From the time that I met her, she had incurable disease, so our goal was to make every effort, through multiple surgeries and chemotherapy, to help her continue living a life that she enjoyed for as long as possible. She was very courageous and spirited in her attitude toward her disease; although realistic about her situation, she was determined not to let anything get in her way. She was in my care and remained undaunted for about a decade until she passed away as a result of her disease.
Sometime after that, an unexpected package arrived at my office. It was a screen print created and sent to me by my patient’s granddaughter, an emerging artist in the Boston area. She titled it, “We Are Not What You Have Taken: A Response to Cancer.” It is a very powerful piece of art.
“We Are Not What You Have Taken: A Response to Cancer,” by Suzi Grossman
As you can see in the piece, my patient’s granddaughter created an artistic equation. First, she shows us a widely used symbol of a woman. Then, she uses images to represent the many surgeries her grandmother underwent, including a double mastectomy and operations to remove a kidney and a tumor that I remember describing to her as “the size of a football.” She also underwent bowel resection and thyroid surgeries, and another image represents the loss of her hair with chemotherapy. But the product of the equation is the original symbol of a woman, telling us that after all that was taken from her, she was still the same person, with the same indomitable spirit and sense of self she had at the start.
Seeing this artwork every time I come into my office is a humbling experience for me. To me, this image recognizes the trauma that a surgeon inflicts to counteract the harm that cancer creates. People with cancer face incredible challenges and must make many difficult decisions concerning their treatment. As a feature of these decisions, I don’t believe there is anything more profound than the trust a patient puts in their surgeon, allowing the surgeon to perform potentially life-altering operations. This work of art reminds me of the amazing courage of the woman it represents, who trusted in me and was determined not to let the trauma of cancer treatment diminish or define her.
Receiving such a meaningful work of art from a family member is very special for me. It is so challenging for family members to see a loved one going through all it takes to persevere in the face of this kind of disease, but my patient must have conveyed a message of strength and optimism to her granddaughter that led her to create this beautiful artwork.
I am so grateful to my patient’s granddaughter for creating and sharing this gift with me. I know her grandmother would be very proud of her for conveying its inspirational message in such a wonderful, moving way.
Energy-Producing Enzyme Fuels the Brain with Promise for Treating Parkinson’s Disease
Posted on September 12th, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
In Parkinson’s disease, neurons in parts of the brain gradually weaken and die, leading people to experience worsening problems with movement and other symptoms. While the causes of this disease aren’t fully known, studies have suggested the Parkinson’s brain lacks fuel to power dopamine-producing neurons that are essential for movement. When too many of those neurons are lost, Parkinson’s disease symptoms appear. But what if there was a way to boost energy levels in the brain and stop the neurodegenerative process in its tracks?
While the findings are preliminary, an NIH-supported study reported in Science Advances takes an encouraging step toward this goal. The key element, according to the new work, is an energy-producing enzyme known as phosphoglycerate kinase (PGK1). In fact, these latest preclinical findings in models of the disease suggest that boosting this enzyme in the brain even slightly may be enough to restore energy and afford some protection against Parkinson’s disease.
The team, led by Timothy Ryan and Alexandros Kokotos, Weill Cornell Medicine, New York City, was inspired by recent discoveries suggesting an unexpectedly important role for PGK1 in protecting the normal function of neurons. They knew PGK1 plays an essential role in the pathway through which cells use glucose to generate and store energy in the form of adenosine 5′-triphosphate (ATP) molecules. The surprise came when studies showed the drug terazosin, which is used to treat high blood pressure and enlarged prostate, has an unexpected side effect: it enhances PGK1 activity, although perhaps weakly.
Could the boost in PGK1 activity be enough to fuel and protect dopamine-producing neurons? Studies in Parkinson’s models including mice, rats, flies, and human cells treated with terazosin suggested that it could. A retrospective study in people taking terazosin for an enlarged prostate also showed that those taking the drug were less likely to develop Parkinson’s.
As promising as that sounded, it was hard to imagine that such a seemingly small increase in PGK1 activity was enough to explain the findings. To investigate further in the new study, the researchers ran more sensitive studies to see just how much of a difference PGK1 can make when it comes to energy production in neurons. Their new studies show that even a small increase in PGK1 activity keeps neurons firing, even when glucose levels are low.
The researchers report that the increases in PGK1 they saw were enough to protect neurons carrying mutations in genes with known links to familial forms of Parkinson’s disease. They found that effects of a PGK1 boost also depend on another protein, called DJ-1, which has also been implicated in Parkinson’s disease. When the researchers experimentally increased PGK1 levels in mouse models of the disease, it strongly protected their dopamine neurons.
For the approximately one million Americans with Parkinson’s disease today, current treatments help to relieve symptoms but don’t stop the disease from progressing. These new findings raise the possibility that terazosin or drugs that enhance PGK1 activity even more may fuel the brain, helping to protect essential dopamine-producing neurons to treat or even prevent Parkinson’s disease, as well as other neurodegenerative conditions where PGK1 may play a role.
Reference:
Kokotos AC, et al. Phosphoglycerate kinase is a central leverage point in Parkinson’s Disease driven neuronal metabolic deficits. Science Advances. DOI: 10.1126/sciadv.adn6016 (2024).
NIH Support: National Institute of Neurological Disorders and Stroke, National Institute of General Medical Sciences
New Clues for Healing Spinal Cord Injuries Found in Single-Cell Studies in Zebrafish
Posted on September 5th, 2024 by Dr. Monica M. Bertagnolli
Credit: Bigemrg/Adobe Stock, Mokalled Lab/WashU
Each year in the U.S. there are about 18,000 new spinal cord injuries, which damage the bundle of nerves and nerve fibers that send signals from the brain to other parts of the body and can affect feeling, movement, strength, and function below the injured site. A severe spinal cord injury can lead to immediate and permanent paralysis, as our spinal cords lack the capacity to regenerate the damaged tissues and heal.
So far, even the most groundbreaking regenerative therapies have yielded only modest improvements after spinal cord injuries. Now, an NIH-supported study reported in Nature Communications offers some new clues that may one day lead to ways to encourage healing of spinal cord injuries in people. The researchers uncovered these clues through detailed single-cell analysis in what might seem an unlikely place: the zebrafish spinal cord.
Why zebrafish? Unlike mammals, zebrafish have a natural ability to spontaneously heal and recover after spinal cord injuries, even when the injuries are severe. Remarkably, after a complete spinal cord injury, a zebrafish can reverse the paralysis and start swimming again within six to eight weeks. Earlier studies in zebrafish after spinal cord injury found that this regenerative response involves many types of cells, including immune cells, progenitor cells, neurons, and supportive glial cells, all of which work together to successfully repair damage.
In the new work, a team at Washington University School of Medicine in St. Louis led by Mayssa Mokalled took advantage of tools that make it possible to study the gene activity underlying this spinal healing response by sequencing RNA transcripts within individual neurons. The goal was to learn in much more detail about the zebrafish’s response to spinal cord injury in major neural cell types. The researchers also wanted to compare what they found in zebrafish to other single-cell studies in mice, which lack this regenerative capacity.
To do it, the researchers sequenced RNA from spinal cells at the time of injury and then again one, three, and six weeks later. Their analyses show that zebrafish neurons demonstrate a dramatic response indicated by changes in gene activity, followed by the growth of new neurons to restore essential connections. Importantly, the researchers also found that some of the existing injured neurons get reprogrammed, showing a regenerative pattern of gene activity after a week that encourages their survival and increased flexibility to allow healing. When those injury-responsive neurons, which the researchers call iNeurons, were disabled, the zebrafish didn’t regain the ability to swim, even when regenerative stem cells remained active.
In people or mice, by comparison, a spinal cord injury sets off a toxic chain of events that kills the existing neurons and prevents repair. Interestingly, the new study suggests that, in the zebrafish, the regeneration is not only due to stem cells sprouting new neurons as long suspected, and may be more related to the processes that protect and save the injured neurons and lend them more flexibility to heal. It’s possible that this kind of protective and regenerative capacity is present in mammalian neurons, even if the regenerative process doesn’t automatically switch on in the way seen in zebrafish, according to the researchers. Indeed, many of the genes that play important roles in the zebrafish healing process are also present in the human genome.
In future work, the researchers plan to conduct similar studies in the many other cell types known to play some role in spinal cord healing in zebrafish, including supportive glia and immune cells. They’re also continuing to explore how the activities they see in the zebrafish spinal cord compare to what happens in mice and humans. With much more study, these kinds of findings in zebrafish may lead to promising new ideas and even treatments that encourage neural protection, flexibility, and recovery in the human nervous system after spinal cord injuries.
Reference:
Muraleedharan Saraswathy V, et al. Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair. Nature Communications. DOI: 10.1038/s41467-024-50628-y (2024).
NIH Support: National Institute of Neurological Disorders and Stroke
Study Identifies Previously Unknown Pain Control Pathway Underlying Placebo Effect
Posted on August 29th, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
When someone receives an inactive sugar pill for their pain, the expectation of benefit often leads them to experience some level of pain relief. Researchers have long known that this placebo effect is a very real phenomenon. However, the brain mechanisms underlying the placebo effect for pain have been difficult for researchers to understand.
Now, findings from an intriguing NIH-supported study in mice published in Nature offer insight into how this powerful demonstration of the mind-body connection works in the brain. Furthermore, the researchers identified a previously unknown neural pathway for pain control and suggest that specifically activating this pathway in the brain by other means could one day offer a promising alternative for treating pain more safely and effectively than with current methods, including opioids.
The findings come from a team led by Grégory Scherrer, University of North Carolina School of Medicine, Chapel Hill; with colleagues from Stanford University, Stanford, CA; the Howard Hughes Medical Institute, Ashburn, VA; and the Allen Institute for Brain Science, Seattle. The researchers knew from earlier human brain imaging studies that the placebo effect activates certain brain areas, including the anterior cingulate cortex, which is involved in emotion, attention, and mood. By conducting a series of more detailed studies in mice, the team sought to learn more about the specific brain activities involved.
To do this, the researchers set up an experiment in which mice were put in an apparatus with two distinct chambers, each with comfortably warm floors (about 86 degrees Fahrenheit). After a period of acclimatization, the floor of one of the chambers was made unpleasantly hot (about 118 degrees Fahrenheit—similar to hot pavement in the summertime). The mice learned that they could avoid their discomfort by spending time in the chamber with the comfortably warm floor. The researchers then equalized the floor temperature in both chambers to 118 degrees. Despite identical hot conditions in both chambers, the mice still exhibited fewer behaviors associated with discomfort, such as paw licking, in the chamber that was previously comfortable, indicating that the animals showed signs of a classic placebo effect.
The researchers used a variety of sophisticated imaging techniques to visualize the activity of individual neurons in mice to better understand their behaviors. They found the placebo effect links the anterior cingulate cortex in the front of the brain through the pontine nucleus, a part of the brain with clusters of cells in the brainstem that has not previously been associated with pain or pain relief, to the cerebellum in the back of the brain. This research indicates that the pontine nucleus could be a promising target for novel pain-relieving therapies.
The experiments also revealed an unexpected abundance of opioid receptors in the pontine nucleus, lending further support for the role of this brain area in responding to the body’s natural opioids that modulate pain.
While the experience of pain is exceedingly complex, and this research is in mice, the researchers expect that these findings will have relevance to people. The next step is to explore the role of activity in this newly discovered pain pathway in humans’ experience of the placebo effect. The hope is that with continued study it may one day be possible to target this brain area using small molecules or neural stimulation as a potentially more effective and safer means to ease pain compared to current methods.
Reference:
Chen C, et al. Neural circuit basis of placebo pain relief. Nature. DOI: 10.1038/s41586-024-07816-z (2024).
NIH Support: National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse
Mapping Psilocybin’s Brain Effects to Explore Potential for Treating Mental Health Disorders
Posted on August 15th, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
Psilocybin is a natural ingredient found in “magic mushrooms.” A single dose of this psychedelic can distort a person’s perception of time and space, as well as their sense of self, for hours. It can also trigger strong emotions, ranging from euphoria to fear. While psilocybin comes with health risks and isn’t recommended for recreational use, there’s growing evidence that—under the right conditions—its effects on the brain might be harnessed in the future to help treat substance use disorders or mental illnesses.
To explore this potential, it will be important to understand how psilocybin exerts its effects on the human brain. Now, a study in Nature supported in part by NIH has taken a step in this direction, using functional brain mapping in healthy adults before, during, and after taking psilocybin to visualize its impact. While earlier studies in animals suggested that psilocybin makes key brain areas more adaptable or “plastic,” this new research aims to clarify changes in the function of larger brain networks and their connection to the experiences people have with this psychedelic drug.
In the study, the team led by Joshua Siegel, Nico Dosenbach and Ginger Nicol, Washington University School of Medicine in St. Louis, recruited seven healthy adults to take, in separate sessions, a high dose of psilocybin and the stimulant methylphenidate, the generic form of Ritalin, under controlled conditions. Because taking psilocybin comes with a risk for having disturbing or negative experiences, a pair of trained experts stayed with each participant throughout the sessions to provide guidance and support. They also helped participants prepare for and process the experience afterwards.
To visually capture the impact of psilocybin on the brain, the researchers had each participant undergo an average of 18 functional MRI brain scan visits. Four of the study’s participants also returned six to 12 months later to take an additional psilocybin dose. Comparisons of the brain images revealed profound and widespread, but temporary, changes to the brain’s functional networks. While an individual’s functional brain network is typically as distinctive as a fingerprint, psilocybin made the participants’ brain networks look so similar in the scans that the researchers couldn’t tell them apart. In addition, by following the brain scans with specialized questionnaires given to elicit details about participants’ subjective experiences with psilocybin, the researchers were able to generate precise data on each person’s unique impressions and associated changes in their brain networks.
For all the participants, psilocybin desynchronized the brain’s default mode network, an interconnected set of brain areas that are most active when people are daydreaming or otherwise not engaged in any focused, goal-directed mental activity. By comparison, the default mode network remained stable after study participants took methylphenidate. Once the effects of psilocybin wore off, brain function returned almost to its original state. However, the researchers did note small but potentially important differences in each participant’s brain scans after taking psilocybin that remained for weeks.
The researchers suggest that the short-term changes in the default mode network likely explain psilocybin’s psychedelic effects, including the way it changes the way a person thinks about themselves in relation to other people and the world. They also suggest that the more subtle, longer-term effects they observed might indicate that the brain is more flexible in the weeks following a dose of psilocybin in ways that could allow for a healthier state. This may help explain preliminary research showing that psilocybin may have benefits for treating substance use disorders, as well as depression, anxiety, and other mental health conditions.
Though these findings are encouraging, they should not be seen as a reason to try psilocybin without clinician supervision or use it to self-medicate. The drug is not proven or approved as a treatment for any condition, and its unsupervised use comes with serious risks. The researchers hope that with much more clinical study of how and why this drug affects individuals in the powerful ways that it does, this kind of research may one day lead to a greater understanding of the human brain and promising new interventions that improve mental health.
Reference:
Siegel JS, et al. Psilocybin desynchronizes the human brain. Nature. DOI: 10.1038/s41586-024-07624-5 (2024).
NIH Support: National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke
Tags: anxiety, brain, default mode network, depression, imaging, mental health disorders, neuroscience, psilocybin, psychedelic, substance use disorders
Maternal Brain Hormone Key to Strengthening Bones Could Help Treat Osteoporosis, Bone Fractures
Posted on August 1st, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
More than 200 million people around the world have osteoporosis, a condition that weakens bones to the point that they break easily. Women are at especially high risk after menopause due to declining levels of the hormone estrogen, which helps keep bones strong. While osteoporosis rarely has noticeable symptoms, it can lead to serious injuries when otherwise minor slips and falls cause broken bones that in turn can lead to further fracture risk and fracture-related mortality. So, I’m pleased to share NIH-supported research suggesting a surprising candidate for strengthening bones: a maternal hormone produced in the brain.
The study in mice reported in Nature shows that this newly discovered hormone maintains and rebuilds bone strength in lactating females, even as estrogen levels dip and calcium is lost to the demands of milk production. 1 The findings suggest this hormone—or a drug that acts similarly—could be key to treating osteoporosis and preventing and healing broken bones.
The findings come from a team led by Holly Ingraham, University of California, San Francisco. The researchers knew from studies in mice and humans that a protein related to parathyroid hormone, which is made in the mammary glands, is the main driver for stripping calcium from maternal bones for milk production. As a result of this process, nursing mothers tend to lose a lot of bone. In humans, this bone loss is 10% on average, compared to nearly 30% in mice. Fortunately, these losses are reversed after lactation ends, suggesting to the researchers there must be some other bone-strengthening factor in play.
Previous work in Ingraham’s lab, also supported by NIH, offered other clues. The researchers found that in female mice, blocking a certain estrogen receptor in select neurons in a small area of the brain led to the development of bones that were exceptionally dense and strong. 2 This was an early hint that an unidentified hormone might have a role. The team’s search in this latest study led them to brain-derived communication network factor 3 (CCN3).
The new findings showed that, in lactating female mice, CCN3 is produced in the same brain area identified in the previous study. When the researchers prevented the brain from making CCN3, lactating female mice rapidly lost bone. The researchers also found that male and female young adult and older mice gained a considerable amount of bone mass and strength when their levels of circulating CCN3 were boosted over a two-week period. In fact, in some female mice that were very old or completely lacked estrogen, the hormone more than doubled their bone mass. Tests showed that the animals’ bones weren’t just denser, but also stronger.
Further studies conducted by co-author Thomas Ambrosi, University of California, Davis, revealed that bone stem cells were responsible for receiving signals and generating the new bone. When those cells were exposed to CCN3, they ramped up bone production even more. When the researchers applied a hydrogel patch containing CCN3 to the sites of bone breaks, this spurred the formation of new bone. As a result, the researchers saw rapid bone healing in older mice comparable to what would be expected in much younger mice.
In future studies, the researchers want to gain insight into the underlying mechanisms of CCN3. They also plan to explore the hormone’s potential for treating bone loss in people at increased risk, including postmenopausal women, breast cancer survivors taking estrogen blockers, and those with other conditions leading to unhealthy bone mass, such as genetic bone disorders, chronic kidney disease, or premature ovarian failure. They suggest that more immediate local uses for CCN3 include fracture repair, cartilage regeneration, and bone improvements for anchoring dental implants. It’s a great example of how finding an answer to a scientific puzzle—like how maternal bones stay strong during breastfeeding—can potentially lead to advances that help many more people.
References:
[1] Babey ME, et al. A maternal brain hormone that builds bone. Nature. DOI: 10.1038/s41586-024-07634-3 (2024).
[2] Herber CB, et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nature Communications. DOI: 10.1038/s41467-018-08046-4 (2019).
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Posted In: Health, Science, Uncategorized
Tags: aging, basic research, Bone, bone fracture, breastfeeding, calcium, estrogen, hormone, maternal health, menopause, osteoporosis