mental health disorders – NIH Director's Blog (original) (raw)
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
Insights into Molecular Basis of PTSD and Major Depression Could One Day Aid in Diagnosis and Treatment
Posted on June 13th, 2024 by Dr. Monica M. Bertagnolli
Credit: S. Thomas Carmichael/UCLA, Yuliia/Adobe Stock
We know stress can take a toll on our mental health. Yet, it’s unclear why some people develop stress-related mental health disorders and others don’t. The risk for developing a stress-related mental health disorder such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD) depends on a complex interplay between the genetic vulnerabilities we are born with and the impact of traumatic stress we experience over our lifetimes.
Given this complexity, it’s been difficult for researchers to pinpoint the underlying biological pathways in the body that ultimately produce changes associated with PTSD, major depression, or other mental health conditions. Now, a study reported in a special issue of Science on decoding the brain uses a comprehensive approach to examine multiple biological processes across brain regions, cell types, and blood to elucidate this complexity. It’s an unprecedented effort to understand in a more holistic way the essential biological networks involved in PTSD and MDD.
While earlier studies looked at stress hormones, the immune system, and other molecular signatures of stress in blood samples, what had been largely missing from the picture of PTSD and MDD were links between those changes in the body and changes in the brain. To get a more complete picture, a multisite research team led by Nikolaos P. Daskalakis and Kerry Ressler of McLean Hospital, Belmont, MA, developed a vast molecular dataset including DNA variants, RNA, proteins, and chemical modifications to DNA. This “multi-omic” dataset was generated by the NIH-supported PTSD Brainomics Project of the PsychENCODE Consortium, and included postmortem data from 231 individuals with PTSD and/or MDD, as well as from individuals who didn’t have known mental health conditions.
In the study, the researchers looked at three essential brain regions: the medial prefrontal cortex (mPFC), the hippocampal dentate gyrus, and the central nucleus of the amygdala. They conducted single-cell RNA sequencing analysis of 118 dorsolateral prefrontal cortex (dlPFC) samples to look at cell-type-specific patterns and evaluated protein changes in the blood of more than 50,000 UK Biobank samples to look for biomarkers of stress-related disorders. After identifying key brain-based genes whose expression was altered in PTSD and/or MDD, the researchers compared them to genes linked to increased risk for these conditions.
Among many findings, the study results show an important role for the mPFC in both stress-related conditions, which is interesting, as the mPFC is essential for integrating signals from other brain areas and is known to play a role in cognitive processes, emotional regulation, motivation, and sociability. The findings also highlight important roles for molecular pathways known to play a role in immune function, the regulation of neurons and neural connections, and stress hormones. The single-cell RNA sequencing in the dlPFC also uncovered dysregulated stress-related signals in neurons and other brain cell types.
Furthermore, the findings reveal shared changes in gene activity between PTSD and MDD, as well as notable differences in the patterns of methyl marks on the DNA, suggesting changes in the way genes are switched on or off, and at the level of cell-type-specific gene activity. The researchers also found that history of childhood trauma and suicide were drivers of molecular changes in both disorders.
The data point to a short list of proteins that may be important in regulating key genetic pathways underlying these disorders. They also reveal links to gene networks related to aging, inflammation, stress, and more. Similarities in disease signals in the brain and blood suggest that blood-based tests might one day offer an additional avenue for assessing these disorders. Interestingly, there was little overlap between PTSD and MDD risk genes and those involved in the underlying molecular-level changes in the brains of people with one or both conditions. This shows that there’s a need for more research into how genetic risk factors are related to molecular-level disease processes.
There’s clearly much more to discover in the years ahead. But these insights already point to important roles for known stress-related pathways in fundamental brain changes underlying PTSD and MDD, while also revealing more novel pathways as potentially promising new treatment targets. With further study, the researchers hope these findings can also begin to answer vexing questions, such as why some people develop PTSD or major depression after stressful events and others don’t.
Reference:
Daskalakis NP, et al. Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood. Science. DOI: 10.1126/science.adh3707 (2024).
This paper is part of a larger collection of studies from the PsychENCODE Consortium looking at the underlying mechanisms of neuropsychiatric diseases.
NIH Support: National Institute of Mental Health
Posted In: Health, News, Science
Tags: biomarkers, brain, depression, mental health, mental health disorders, molecular signature, multiomics, neuroscience, post-traumatic stress disorder, PTSD, stress
Brain Atlas Paves the Way for New Understanding of How the Brain Functions
Posted on October 24th, 2023 by Lawrence Tabak, D.D.S., Ph.D.
Neurons. Credit: Leterrier, NeuroCyto Lab, INP, Marseille, France
When NIH launched The BRAIN Initiative® a decade ago, one of many ambitious goals was to develop innovative technologies for profiling single cells to create an open-access reference atlas cataloguing the human brain’s many parts. The ultimate goal wasn’t to produce a single, static reference map, but rather to capture a dynamic view of how the brain’s many cells of varied types are wired to work together in the healthy brain and how this picture may shift in those with neurological and mental health disorders.
So I’m now thrilled to report the publication of an impressive collection of work from hundreds of scientists in the BRAIN Initiative Cell Census Network (BICCN), detailed in more than 20 papers in Science, Science Advances, and _Science Translational Medicine._1 Among many revelations, this unprecedented, international effort has characterized more than 3,000 human brain cell types. To put this into some perspective, consider that the human lung contains 61 cell types.2 The work has also begun to uncover normal variation in the brains of individual people, some of the features that distinguish various disease states, and distinctions among key parts of the human brain and those of our closely related primate cousins.
Of course, it’s not possible to do justice to this remarkable body of work or its many implications in the space of a single blog post. But to give you an idea of what’s been accomplished, some of these studies detail the primary effort to produce a comprehensive brain atlas, including defining the brain’s many cell types along with their underlying gene activity and the chemical modifications that turn gene activity up or down.3,4,5
Other studies in this collection take a deep dive into more specific brain areas. For instance, to capture normal variations among people, a team including Nelson Johansen, University of California, Davis, profiled cells in the neocortex—the outermost portion of the brain that’s responsible for many complex human behaviors.6 Overall, the work revealed a highly consistent cellular makeup from one person to the next. But it also highlighted considerable variation in gene activity, some of which could be explained by differences in age, sex and health. However, much of the observed variation remains unexplained, opening the door to more investigations to understand the meaning behind such brain differences and their role in making each of us who we are.
Yang Li, now at Washington University in St. Louis, and his colleagues analyzed 1.1 million cells from 42 distinct brain areas in samples from three adults.4 They explored various cell types with potentially important roles in neuropsychiatric disorders and were able to pinpoint specific cell types, genes and genetic switches that may contribute to the development of certain traits and disorders, including bipolar disorder, depression and schizophrenia.
Yet another report by Nikolas Jorstad, Allen Institute, Seattle, and colleagues delves into essential questions about what makes us human as compared to other primates like chimpanzees.7 Their comparisons of gene activity at the single-cell level in a specific area of the brain show that humans and other primates have largely the same brain cell types, but genes are activated differently in specific cell types in humans as compared to other primates. Those differentially expressed genes in humans often were found in portions of the genome that show evidence of rapid change over evolutionary time, suggesting that they play important roles in human brain function in ways that have yet to be fully explained.
All the data represented in this work has been made publicly accessible online for further study. Meanwhile, the effort to build a more finely detailed picture of even more brain cell types and, with it, a more complete understanding of human brain circuitry and how it can go awry continues in the BRAIN Initiative Cell Atlas Network (BICAN). As impressive as this latest installment is—in our quest to understand the human brain, brain disorders, and their treatment—we have much to look forward to in the years ahead.
References:
A list of all the papers part of the brain atlas research is available here: https://www.science.org/collections/brain-cell-census.
[1] M Maroso. A quest into the human brain. Science DOI: 10.1126/science.adl0913 (2023).
[2] L Sikkema, et al. An integrated cell atlas of the lung in health and disease. Nature Medicine DOI: 10.1038/s41591-023-02327-2 (2023).
[3] K Siletti, et al. Transcriptomic diversity of cell types across the adult human brain. Science DOI: 10.1126/science.add7046 (2023).
[4] Y Li, et al. A comparative atlas of single-cell chromatin accessibility in the human brain. Science DOI: 10.1126/science.adf7044 (2023).
[5] W Tian, et al. Single-cell DNA methylation and 3D genome architecture in the human brain. Science DOI: 10.1126/science.adf5357 (2023).
[6] N Johansen, et al. Interindividual variation in human cortical cell type abundance and expression. Science DOI: 10.1126/science.adf2359 (2023).
[7] NL Jorstad, et al. Comparative transcriptomics reveals human-specific cortical features. Science DOI: 10.1126/science.ade9516 (2023).
NIH Support: Projects funded through the NIH BRAIN Initiative Cell Consensus Network
Tags: bipolar disorder, brain, brain atlas, BRAIN Initiative, chromatin, depression, epigenomics, mental health disorders, neurological disorders, neuron, schizophrenia, single cell, transcriptomics