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Scientists Unveil Detailed Cell Maps of the Human Brain and the Nonhuman Primate Brain

Incredibly detailed cell maps help pave the way for new generation of treatments

October 12, 2023 • Press Release

A group of international scientists have mapped the genetic, cellular, and structural makeup of the human brain and the nonhuman primate brain. This understanding of brain structure, achieved by funding through the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies ® Initiative, or The BRAIN Initiative®  , allows for a deeper knowledge of the cellular basis of brain function and dysfunction, helping pave the way for a new generation of precision therapeutics for people with mental disorders and other disorders of the brain. The findings appear in a compendium of 24 papers across Science , Science Advances , and Science Translational Medicine .

“Mapping the brain’s cellular landscape is a critical step toward understanding how this vital organ works in health and disease,” said Joshua A. Gordon, M.D., Ph.D. , director of the National Institute of Mental Health. “These new detailed cell atlases of the human brain and the nonhuman primate brain offer a foundation for designing new therapies that can target the specific brain cells and circuits involved in brain disorders.”

The 24 papers in this latest BRAIN Initiative Cell Census Network (BICCN)  collection detail the exceptionally complex diversity of cells in the human brain and the nonhuman primate brain. The studies identify similarities and differences in how cells are organized and how genes are regulated in the human brain and the nonhuman primate brain. For example:

• Three papers in the collection present the first atlas of cells in the adult human brain, mapping the transcriptional  and epigenomic  landscape of the brain. The transcriptome is the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products. The epigenome refers to chemical modifications to a cell’s DNA and chromosomes that alter the way the cell’s genetic information is expressed.
• In another paper, a comparison of the cellular and molecular properties of the human brain and several nonhuman primate brains (chimpanzee, gorilla, macaque, and marmoset brains) revealed clear similarities in the types, proportions, and spatial organization of cells in the cerebral cortex of humans and nonhuman primates. Examination of the genetic expression of cortical cells across species suggests that relatively small changes in gene expression in the human lineage led to changes in neuronal wiring and synaptic function that likely allowed for greater brain plasticity in humans, supporting the human brain’s ability to adapt, learn, and change.
• A study exploring how cells vary in different brain regions in marmosets found a link between the properties of cells in the adult brain and the properties of those cells during development. The link suggests that developmental programming is embedded in cells when they are formed and maintained into adulthood and that some observable cellular properties in an adult may have their origins very early in life. This finding could lead to new insights into brain development and function across the lifespan.
• An exploration of the anatomy and physiology of neurons in the outermost layer of the neocortex—part of the brain involved in higher-order functions such as cognition, motor commands, and language—revealed differences in the human brain and the mouse brain that suggest this region may be an evolutionary hotspot, with changes in humans reflecting the higher demands of regulating humans’ more complex brain circuits.

The core aim of the BICCN, a groundbreaking effort to understand the brain’s cellular makeup, is to develop a comprehensive inventory of the cells in the brain—where they are, how they develop, how they work together, and how they regulate their activity—to better understand how brain disorders develop, progress, and are best treated.

“This suite of studies represents a landmark achievement in illuminating the complexity of the human brain at the cellular level,” said John Ngai, Ph.D.  , director of the NIH BRAIN Initiative. “The scientific collaborations forged through BICCN are propelling the field forward at an exponential pace; the progress—and possibilities—have been simply breathtaking.”

The census of brain cell types in the human brain and the nonhuman primate brain presented in this paper collection serves as a key step toward developing the brain treatments of the future. The findings also set the stage for the BRAIN Initiative Cell Atlas Network , a transformative project that, together with two other large-scale projects—the BRAIN Initiative Connectivity Across Scales  and the Armamentarium for Precision Brain Cell Access  —aim to revolutionize neuroscience research by illuminating foundational principles governing the circuit basis of behavior and informing new approaches to treating human brain disorders.

Maroso, M. (2023). A quest into the human brain. Science . http://www.science.org/doi/10.1126/science.adl0913  

Projects funded through the NIH BRAIN Initiative Cell Census Network 

About the National Institute of Mental Health (NIMH): The mission of the NIMH  is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website .

The NIH BRAIN Initiative   is managed by 10 Institutes and Centers whose missions and current research portfolios complement the goals of The BRAIN Initiative®: National Center for Complementary and Integrative Health, National Eye Institute, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute of Biomedical Imaging and Bioengineering, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute on Deafness and other Communication Disorders, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke.

About the National Institutes of Health (NIH) : NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH  and its programs, visit the NIH website  .

NIH…Turning Discovery Into Health ®

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Our Bigger Brains Came With a Downside: Faster Aging

A study comparing chimpanzee and human brains suggests that the regions that grew the most during human evolution are the most susceptible to aging.

By Carl Zimmer

The human brain, more than any other attribute, sets our species apart. Over the past seven million years or so, it has grown in size and complexity, enabling us to use language, make plans for the future and coordinate with one another at a scale never seen before in the history of life.

But our brains came with a downside, according to a study published on Wednesday. The regions that expanded the most in human evolution became exquisitely vulnerable to the ravages of old age.

“There’s no free lunch,” said Sam Vickery, a neuroscientist at the Jülich Research Center in Germany and an author of the study.

The 86 billion neurons in the human brain cluster into hundreds of distinct regions. For centuries, researchers could recognize a few regions, like the brainstem, by hallmarks such as the clustering of neurons. But these big regions turned out to be divided into smaller ones, many of which were revealed only with the help of powerful scanners .

As the structure of the human brain came into focus, evolutionary biologists became curious about how the regions evolved from our primate ancestors. (Chimpanzees are not our direct ancestors, but both species descended from a common ancestor about seven million years ago.)

The human brain is three times as large as that of chimpanzees. But that doesn’t mean all of our brain regions expanded at the same pace, like a map drawn on an inflating balloon. Some regions expanded only a little, while others grew a lot.

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October 12, 2023

"A new era in brain science”: Salk researchers unveil human brain cell atlas

The new research, part of the NIH BRAIN Initiative, paves the way toward treating, preventing, and curing brain disorders

Home - Salk News - “A new era in brain science”: Salk researchers unveil human brain cell atlas

“A new era in brain science”: Salk researchers unveil human brain cell atlas

LA JOLLA—Salk Institute researchers, as part of a larger collaboration with research teams around the world, analyzed more than half a million brain cells from three human brains to assemble an atlas of hundreds of cell types that make up a human brain in unprecedented detail.

The research, published in a special issue of the journal Science on October 13, 2023, is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.

“These papers represent the first tests of whether these approaches can work in human brain samples, and we were excited at just how well they translated,” says Professor  Joseph Ecker , director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. “This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease.”

The new work is part of the National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative , or The BRAIN Initiative , an effort launched in 2014 to describe the full plethora of cells—as characterized by many different techniques—in mammalian brains. Salk is one of three institutions awarded grants to act as central players in generating data for the NIH BRAIN Initiative Cell Census Network, BICCN .

Every cell in a human brain contains the same sequence of DNA, but in different cell types different genes are copied onto strands of RNA for use as protein blueprints. This ultimate variation in which proteins are found in which cells—and at what levels—allows the vast diversity in types of brain cells and the complexity of the brain. Knowing which cells rely on which DNA sequences to function is critical not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders and, relatedly, how to treat those disorders.

“Once we scale up our techniques to a large number of brains, we can start to tackle questions that we haven’t been able to in the past,” says Margarita Behrens , a research professor in Salk’s Computational Neurobiology Laboratory and a co-principal investigator of the new work.

In 2021, Ecker and Behrens led the Salk team that profiled 161 types of cells in the mouse brain , based on methyl chemical markers along DNA that specify when genes are turned on or off. This kind of DNA regulation, called methylation, is one level of cellular identity.

In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.

“It’s a big jump from mice to humans and also introduces some technical challenges that we had to overcome,” says Behrens. “But we were able to adapt things that we had figured out in mice and still get very high quality results with human brains.”

At the same time, the researchers also used a second technique, which analyzed the three-dimensional structure of DNA molecules in each cell to get additional information about what DNA sequences are being actively used. Areas of DNA that are exposed are more likely to be accessed by cells than stretches of DNA that are tightly folded up.

"This is the first time we’ve looked at these dynamic genome structures at a whole new level of cell type granularity in the brain, and how those structures may regulate which genes are active in which cell types,” says Jingtian Zhou, co-first author of the new paper and a postdoctoral researcher in Ecker’s lab.

Other research teams whose work is also published in the special issue of Science used cells from the same three human brains to test their own cell profiling techniques, including a group at UC San Diego led by Bing Ren—also a co-author in Ecker and Behrens’ study. Ren’s team revealed a link between specific brain cell types and neuropsychiatric disorders, including schizophrenia, bipolar disorder, Alzheimer’s disease, and major depression. Additionally, the team developed artificial intelligence deep learning models that predict risk for these disorders.

Other groups in the global collaboration focused on measuring levels of RNA to group cells together into subtypes. The groups found a high level of correspondence in each brain region between which genes were activated, based on the DNA studies by Ecker and Behrens’ team, and which genes were found to be transcribed into RNA.

Since the new Salk research was intended as a pilot study to test the efficacy of the techniques in human brains, the researchers say they can’t yet draw conclusions about how many cell types they might uncover in the human brain or how those types differ between mice and humans.

“The potential to find unique cell types in humans that we don’t see in mice is really exciting,” says Wei Tian, co-first author of the new paper and a staff scientist in Ecker’s lab. “We’ve made amazing progress but there are always more questions to ask.”

In 2022, the NIH Brain Initiative launched a new BRAIN Initiative Cell Atlas Network (BICAN), which will follow up the BICCN efforts. At Salk, a new Center for Multiomic Human Brain Cell Atlas funded through BICAN aims to study cells from over a dozen human brains and ask questions about how the brain changes during development, over people’s lifespans, and with disease. That more detailed work on a larger number of brains, Ecker says, will pave the way toward a better understanding of how certain brain cell types go awry in brain disorders and diseases.

“We want to have a full understanding of the brain across the lifespan so that we can pinpoint exactly when, how, and in which cell types things go wrong with disease—and potentially prevent or reverse those harmful changes,” says Ecker.

View the full BRAIN Initiative paper package here , including research from collaborators around the globe.

Other authors of the paper are Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Michelle Liem, Naomi Claffey and Caz O'Connor of Salk; Yang Li and Bing Ren of the Ludwig Institute for Cancer Research at UC San Diego; Kimberly Siletti and Sten Linnarsson of the Karolinska Institutet; Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca Hodge, Boaz P. Levi and Ed Lein of the Allen Institute for Brain Science; and C. Dirk Keene of the University of Washington.

The work was supported by grants from the National Institute of Mental Health (U01MH121282, UM1 MH130994, NIMH U01MH114812), the National Institutes of Health BRAIN Initiative (NCI CCSG: P30 014195),  the Nancy and Buster Alvord Endowment, and the Howard Hughes Medical Institute.

DOI: 10.1126/science.adf5357

PUBLICATION INFORMATION

Single-cell DNA methylation and 3D genome architecture in the human brain

Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Caz O’Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca Hodge, Boaz P. Levi, C. Dirk Keene, Sten Linnarsson, Ed Lein, Bing Ren, M. Margarita Behrens, Joseph R. Ecker

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Scientists built the largest-ever map of the human brain. Here's what they found

Jon Hamilton

Scientists have built an enormous atlas of the human brain that could help them chart a path toward preventing and treating many different neurological disorders. Andriy Onufriyenko/Getty Images hide caption

Scientists have built an enormous atlas of the human brain that could help them chart a path toward preventing and treating many different neurological disorders.

Scientists are one step closer to understanding the 170 billion brain cells that allow us to walk, talk, and think.

A newly published atlas offers the most detailed maps yet of the location, structure, and, in some cases, function of more than 3,000 types of brain cells.

"We really need this kind of information if we're going to understand what makes us unique as humans, or what makes us different as individuals, or how the brain develops," says Ed Lein , a senior investigator at the Allen Institute for Brain Science in Seattle and one of hundreds of researchers who worked on the maps.

The atlas also offers a new way to study neuropsychiatric conditions ranging from Alzheimer's to depression.

"You can use this map to understand what actually happens in disease and what kinds of cells might be vulnerable or affected," Lein says.

And the atlas is "critical for understanding how well different species can model human brain physiology, pathology and therapeutic response," write Alyssa Weninger and Paola Arlotta in a commentary accompanying the scientific papers.

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Weninger is a researcher at the University of North Carolina. Arlotta is a professor at Harvard and also holds a position at the Broad Institute in Cambridge, Mass.

The atlas arrived in the form of more than 20 research papers published simultaneously in three scientific journals: Science, Science Advances, and Science Translational Medicine.

Even so, the project still isn't finished. Researchers expect to find even more types of brain cells, and they don't fully understand some of the ones they've already found.

Take "splatter neurons," for example. The name describes what these highly complex cells look like when they're represented in two dimensions, instead of three. (Picture what a bug does when it hits a windshield.)

"When you do that with these types of neurons, it looks a bit like a Rorschach test," Lien says.

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In its current form, the atlas amounts to a first draft, Lien says, one that only begins to encompass the full complexity of the human brain.

"But it really has set the stage to show that this is a definable system," he says.

Mice, humans, and gorillas

Already, the atlas is offering a way to see how the human brain differs from animal brains.

Humans have specialized cells for processing visual information that aren't found in mice, says Dr. Trygve Bakken , an assistant investigator at the Allen Institute who worked on the atlas.

"We share kind of a basic plan with mice," he says, "but we see specializations in primates that we don't necessarily see in a mouse."

Those cells are present in chimps and gorillas, whose brains were also mapped as part of the atlas project. But in those species, scientists found subtle differences in the brain areas that humans use to process language.

"There really is a conserved set of cell types that we share with chimpanzees and gorillas," Bakken says. "But the gene expression has changed in those cells."

The changes in gene expression affect the connections between cells. That suggests humans' language abilities are the result of different wiring, not different cells. And that is a job for a whole different effort known as the Human Connectome Project , which is mapping the connections that allow individual brain cells to form vast networks.

Mapping new treatments

The atlas project is funded largely by the National Institutes of Health as part of its ongoing BRAIN Initiative, which was launched a decade ago by president Obama.

One goal of the initiative is to find new treatments for brain disorders. And the atlas could help make that a reality.

Why beautiful sadness — in music, in art — evokes a special pleasure

Alzheimer's, autism, depression and schizophrenia can all be driven by tiny variations in our DNA.

Scientists have found hundreds of these changes. But they have struggled to understand precisely how they affect individual brain cells.

So as part of the atlas project, a team of scientists created a sort of dictionary that allows scientists to link certain genetic changes to specific types of brain cells.

"For example, we found that late- onset Alzheimer's [is] particularly associated with a type of cell we call microglia," says Bing Ren , a professor of cellular and molecular medicine at the University of California, San Diego.

Microglia are immune cells that are known to become activated in Alzheimer's patients. Many researchers believe this process contributes to the loss of neurons involved in memory and thinking.

Ren's dictionary also connected one particular set of neurons to genes that raise the risk of major depressive disorder, and linked a different set of neurons to schizophrenia genes.

"I hope our work will allow scientists to develop new strategies for treating these disorders," Ren says.

Even when the cell atlas is complete, it will represent just one part of a much larger effort to understand the human brain. Other parts include mapping the connections between neurons, studying how brain circuits function in real time, and determining how huge networks of brain cells are able to form memories, solve problems, and produce consciousness.

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Michael Greenberg’s research has revealed how experiences and exposures modulate the activity of genes that regulate brain plasticity.

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Medical School neurobiologist wins prestigious Brain Prize

Catherine Caruso

HMS Communications

Michael Greenberg recognized for his pivotal insights into brain plasticity

Harvard Medical School neurobiologist  Michael Greenberg  has won  The Brain Prize 2023  for his lifelong research into brain plasticity: the ability of the organ to change, adapt, and learn over time.

Greenberg, who is the Nathan Marsh Pusey Professor of Neurobiology in the Blavatnik Institute at HMS, shares the award with Christine Holt, professor of developmental neuroscience at the University of Cambridge, and with Erin Schuman, director of the Max Planck Institute for Brain Research.

Collectively, the three scientists have made significant advances in unveiling the cellular and molecular mechanisms that enable the brain to restructure itself in response to external stimuli as it adapts, learns, and even recovers from injury.

The Brain Prize, considered the world’s most significant prize for brain research, includes approximately €1.3 million to be shared by the three recipients. The prize is awarded annually by the Danish Lundbeck Foundation to researchers who have made highly original and influential discoveries in brain research.

Greenberg’s research focuses on understanding how the brain responds to signals from the outside world to modulate the activity of genes that make proteins essential for brain plasticity. Throughout his career, Greenberg has delved into the details of this process, elucidating the identities, roles, and relationships of the various genes, proteins, and molecules involved.

“That our sensory experiences shape the structure and function of the brain is one of the profound discoveries in the field of neuroscience in the 20th century,” said  David Ginty , chair of neurobiology at HMS. “Mike’s work, which has extended into the 21st century, has explained how this fundamental feature of brain function is achieved at a molecular, cellular, and circuit level.”

Brain plasticity, or the brain’s ability to rewire itself in response to new information throughout life, is a hallmark of the brain; central to the organ’s ability to function over many decades and to recover or regain function after damage.

To achieve this feat, the brain must continuously create new neural circuits and modify existing ones as it encounters information from the environment. This highly complex and dynamic process requires the brain to carefully orchestrate a multitude of molecules that communicate in signaling pathways and form the cellular basis of learning and memory.

Throughout his career, Greenberg has explored the role of genes in this process — how they work together with life experiences and external signals to support brain development and to ensure that the brain remains adaptable, or plastic, over time.

“Mike’s elegant research highlights the power of basic discovery as the most essential fuel for scientific progress. His impressive accomplishments, which now include this wonderful accolade, show just how much is possible when researchers unwaveringly follow their curiosity and scientific passions,” said HMS Dean George Q. Daley.

A convergence of insights

Greenberg and co-recipients Holt and Schuman are each studying different aspects of protein production within the context of brain plasticity.

Holt’s research focuses on the vertebrate visual system — specifically, the neurons that extend from the eye to the brain — to understand how neural connections in the brain form and are maintained over time. She has shown that proteins must be made and degraded locally to guide the growth of cone cells needed for vision. A continuous supply of locally made proteins is also required to maintain axons — the long fibers that transmit information down neurons. Holt’s work sheds light on how neural connections are established and how axons are sustained throughout life.

Schuman is interested in the processes that control how proteins are made and degraded in neuron structures that are distant from the cell body, including axons and branching dendrites that extend into synapses. She has shown that neurons have localized cellular machinery — namely, ribosomes and proteasomes — in axons and dendrites. She has also established that proteins made in dendrites are needed for synaptic plasticity and revealed molecular details of the mRNA and ribosomes involved. Her lab has developed new tools to label, purify, identify, and visualize newly made proteins in neurons and other cells.

“Together, the Brain Prize 2023 winners have made groundbreaking discoveries by showing how the synthesis of new proteins is triggered in different neuronal compartments, thereby guiding brain development and plasticity in ways that impact our behavior for a lifetime,” said Richard Morris, a professor of neuroscience at the University of Edinburgh and chair of the selection committee.

Of proteins and plasticity

As a postdoctoral researcher in the lab of Edward Ziff, a professor of biochemistry and neural science at New York University School of Medicine, Greenberg began studying the genetic changes that occur inside a mammalian cell when it is stimulated from the outside. He discovered that within minutes of stimulation, the cell begins to express a  gene called  c-fos , which, in turn, boosts the production of the associated Fos protein.

This turned out to be a milestone discovery.

“The idea that gene expression changes could be induced on such a rapid timescale was a paradigm shift that ushered in a new era for neuroscience,” wrote Emily Osterweil, a professor of molecular neuroscience at the University of Edinburgh, in a commentary about the work of the three winners.

Greenberg continued this line of research as an assistant professor at HMS. Notably, he established a  connection between neurotransmitters  — chemical messengers that flow from one neuron to the next — and changes in the activity of genes. He described a signaling cascade that starts with the release of neurotransmitters and leads to a spike in calcium in the neuron receiving the message. This influx of calcium induces the neuron to activate  c-fos  and other genes that make proteins, which, in turn, initiate downstream signaling.

Greenberg went on to more fully define the signaling pathways that neurotransmitters use to activate genes and identify the specific proteins involved. The work of other labs suggests that one of these proteins, CREB, is an important mediator of long-term memory. Building on Greenberg’s work, scientists have also identified hundreds of stimuli that induce Fos production in the brain during different behaviors, thus demonstrating the protein’s ubiquity and importance for brain function.

Greenberg is now working to further characterize the products of genes controlled by neural activity, including how these gene products interact. For example, he learned that Fos works with another protein, NPAS4, to regulate the expression of certain genes by modulating the on-off signals in neurons in response to stimuli. His findings offer a new possible mechanism for long-lasting brain plasticity that may underlie associative learning and spatial navigation. He also established that Fos plays a role in remodeling genetic material inside cells in conjunction with a protein complex called BAF, which has been implicated in neurodevelopmental disorders such as autism.

Greenberg’s efforts have provided insight into the mechanisms by which activity-related genes control the maturation, pruning, and stability of synapses — the small gaps where neurons connect and communicate. Greenberg has linked the gene transcription programs he is studying to key aspects of experience-dependent brain maturation and plasticity, including the formation of context-dependent memories and the plasticity of the visual system during development. His work sheds light on the origins of disorders in which mechanisms of neural plasticity are disrupted.

Greenberg’s research has also yielded important technical advances. His discovery of Fos induction provided researchers with a tool that is now widely used to identify the neurons and neural circuits that mediate behavior. His discoveries have also led to innovative ways of trapping these neurons to assess their function in neural circuits, and new strategies for making detailed observations about the molecules and mechanisms that mediate learning, memory, and behavior.

“For me, this is the culmination of a 40-year odyssey aimed at understanding how our sensory experiences impinge on the neuronal genome to orchestrate brain maturation and the plasticity that underlies long-term memory and how these processes go awry in disorders of the nervous system,” Greenberg said.

Greenberg earned a bachelor’s degree in chemistry from Wesleyan University and completed his PhD at Rockefeller University. Following his postdoctoral research at NYU, he became an assistant professor in the Department of Microbiology and Molecular Genetics at HMS, and later, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. In 2008, he became the chair of neurobiology at HMS, a position he held for 14 years.

Greenberg is a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the National Academy of Medicine. He has received numerous other awards, including a McKnight award for technological advances in neuroscience, the 2015 Gruber Prize in Neuroscience, the 2019 Ralph W. Gerard Prize in Neuroscience, and the 2022 Edward M. Scolnick Prize in Neuroscience.

The Lundbeck Foundation has awarded The Brain Prize annually since 2011. Winners are selected by a committee of nine leading neuroscientists from around the world who have expertise in diverse neuroscience disciplines.

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Scientists just drafted an incredibly detailed map of the human brain

A massive suite of papers offers a high-res view of the human and non-human primate brain.

• Cassandra Willyard archive page

This article first appeared in The Checkup, MIT Technology Review's weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first,  sign up here .

When scientists first looked at brain tissue under a microscope, they saw an impenetrable and jumbled mess. Santiago Ramon y Cajal, the father of modern neuroscience, likened the experience to walking into a forest with a hundred billion trees, “looking each day at blurry pieces of a few of those trees entangled with one another, and, after a few years of this, trying to write an illustrated field guide to the forest,” according to the authors of The Beautiful Brain , a book about Cajal’s work.

Today, scientists have a first draft of that guide. In a set of 21 new papers published across three journals, the teams report that they've developed large-scale whole-brain cell atlases for humans and non-human primates. This work, part of the National Institutes of Health  BRAIN Initiative , is the culmination of five years of research. “It's not just an atlas,” says Ed Lein, a neuroscientist at the  Allen Institute for Brain Science and one of the lead authors. “It's really opening up a whole new field, where you can now look with extremely high cellular resolution in brains of species where this typically hasn't been possible in the past.”

Welcome back to The Checkup. Let’s talk brains.

What is a brain atlas, and what makes this one different?

A brain atlas is a 3-D map of the brain. Some brain atlases already exist, but this new suite of papers provides unprecedented resolution of the whole brain for humans and non-human primates. The human brain atlas includes the location and function of more than 3,000 cell types in adult and developing individuals. “This is far and away the most complete description of the human brain at this kind of level, and the first description in many brain regions,”  Lein says. But it’s still a first draft. 

The work is part of the BRAIN Initiative Cell Census Network , which kicked off in 2017 with the aim of generating a comprehensive 3-D reference brain cell atlas for mice (that project is still in the works). The results reported on October 12 were part of a set of pilot studies to validate whether the methods used in mice would work for bigger brains. Spoiler: those methods did work. Really well, in fact.

What did these initial studies find?

The human brain is really, really complex. I know, shocker! Thus far, the teams have identified more than 3,300 cell types. And as the resolution gets even higher (that’s what they’re working on now), they’re likely to uncover many more. Efforts to develop an atlas of the mouse brain, which are further along, have identified 5,000 cell types. (For more, check out these preprints: 1 and 2 )

But underneath that complexity are some commonalities. Many regions, for example, share cell types, but they have them in different proportions. 

And the location of that complexity is surprising. Neuroscience has focused much of its research on the outer shell of the brain, which is responsible for memory, learning, language, and more. But the majority of cellular diversity is actually in older evolutionary structures deep inside the brain,  Lein says. 

How did they make these atlases?

The classic neuroscience approach to classifying cell types relies on either cell shape–think of star-shaped astrocytes –or the cells’ type of activity–such as fast-spiking interneurons. “These cell atlases capitalize on a new suite of technologies that come from genomics,”  Lein says, primarily a technique known as single-cell sequencing.

First, the researchers start with a small piece of frozen brain tissue from a biobank. “You take a tissue, you grind it up, you profile lots of cells to try to make sense of it,”  Lein says. They make sense of it by sequencing the cells’ nuclei to look at the genes that are being expressed. “Each cell type has a coherent set of genes that they typically use. And you can measure all these genes and then cluster all the types of cells on the basis of their overall gene expression pattern,” Lein says. Then, using imaging data from the donor brain, they can put this functional information where it belongs spatially.

How can scientists use these brain cell atlases?

So many ways. But one crucial use is to help understand the basis of brain diseases.  A reference human brain atlas that describes a normal or neurotypical brain could help researchers understand depression or schizophrenia or many other kinds of diseases, Lein says. Take Alzheimer’s as an example. You could apply these same methods to characterize the brains of people with differing levels of severity of Alzheimer’s, and then compare those brain maps with the reference atlas. “And now you can start to ask questions like, ‘Are certain kinds of cells vulnerable in disease, or are certain kinds of cells causal,” Lein says. (He’s part of a team that’s already working on this .) Rather than investigating plaques and tangles, researchers can ask questions about “very specific kinds of neurons that are the real circuit elements that are likely to be perturbed and have functional consequences,” he says. 

What’s the next step?

Better resolution. “The next phase is really moving into very comprehensive coverage of the human and non-human primate brain in adults and development.” In fact, that work has already begun with the BRAIN Initiative Cell Atlas Network , a five-year, $500 million project.  The aim is to generate a complete reference atlas of cell types in the human brain across the lifespan, and also to map cell interactions that underlie a wide range of brain disorders.

It’s a level of detail that Ramon y Cajal couldn’t have imagined. 

Another thing

Gene editing helped chickens resist bird flu. “It could take decades to work through the necessary technical and regulatory steps, but researchers say CRISPR gene editing could eventually save countless chickens’ lives—and transform animal farming,” writes Abdullahi Tsanni .  

Read more from Tech Review’s archive

Brain atlases have been around for a minute. In 2013, Courtney Humphries reported on the development of BigBrain , a human brain atlas based on MRI images of more than 7,000 brain slices. 

And in 2017, we flagged the Human Cell Atlas project, which aims to categorize all the cells of the human body, as a breakthrough technology . That project is still underway . 

Cell atlases could help provide the data needed for AI to build a virtual cell, argue Priscilla Chan and Mark Zuckerberg in an op-ed published last month . 

From around the web

An experimental RSV vaccine launched in the 1960s worsened symptoms of the illness rather than providing protection. A months-long investigation into the history of RSV research reveals that the families who participated in these trials knew little about the risks. This is a long one, but worth it. ( Undark )

A fascinating commentary on the new class of weight-loss drugs and the problems it can’t solve. Ozempic mania is “an example of how the American penchant for solving structural issues by fixing individual bodies is excellent at creating demand without solving social problems,” writes Tressie McMillan Cottom. ( New York Times )

The FDA is launching an advisory committee on digital health technologies. ( FDA )

One of the terrifying things we always hear about the 1918 flu is how hard it hit the young and healthy. But genetic research suggests that people with chronic diseases or nutritional deficiencies were twice as likely to die than healthy people. ( New York Times)

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New MRI probe can reveal more of the brain’s inner workings

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Using a novel probe for functional magnetic resonance imaging (fMRI), MIT biological engineers have devised a way to monitor individual populations of neurons and reveal how they interact with each other.

Similar to how the gears of a clock interact in specific ways to turn the clock’s hands, different parts of the brain interact to perform a variety of tasks, such as generating behavior or interpreting the world around us. The new MRI probe could potentially allow scientists to map those networks of interactions.

“With regular fMRI, we see the action of all the gears at once. But with our new technique, we can pick up individual gears that are defined by their relationship to the other gears, and that's critical for building up a picture of the mechanism of the brain,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.

Using this technique, which involves genetically targeting the MRI probe to specific populations of cells in animal models, the researchers were able to identify neural populations involved in a circuit that responds to rewarding stimuli. The new MRI probe could also enable studies of many other brain circuits, the researchers say.

Jasanoff is the senior author of the study , which appears today in Nature Neuroscience . The lead authors of the paper are recent MIT PhD recipient Souparno Ghosh and former MIT research scientist Nan Li.

Tracing connections

Traditional fMRI imaging measures changes to blood flow in the brain, as a proxy for neural activity. When neurons receive signals from other neurons, it triggers an influx of calcium, which causes a diffusible gas called nitric oxide to be released. Nitric oxide acts in part as a vasodilator that increases blood flow to the area.

Imaging calcium directly can offer a more precise picture of brain activity, but that type of imaging usually requires fluorescent chemicals and invasive procedures. The MIT team wanted to develop a method that could work across the brain without that type of invasiveness.

“If we want to figure out how brain-wide networks of cells and brain-wide mechanisms function, we need something that can be detected deep in tissue and preferably across the entire brain at once,” Jasanoff says. “The way that we chose to do that in this study was to essentially hijack the molecular basis of fMRI itself.”

The researchers created a genetic probe, delivered by viruses, that codes for a protein that sends out a signal whenever the neuron is active. This protein, which the researchers called NOSTIC (nitric oxide synthase for targeting image contrast), is an engineered form of an enzyme called nitric oxide synthase. The NOSTIC protein can detect elevated calcium levels that arise during neural activity; it then generates nitric oxide, leading to an artificial fMRI signal that arises only from cells that contain NOSTIC.

The probe is delivered by a virus that is injected into a particular site, after which it travels along axons of neurons that connect to that site. That way, the researchers can label every neural population that feeds into a particular location.

“When we use this virus to deliver our probe in this way, it causes the probe to be expressed in the cells that provide input to the location where we put the virus,” Jasanoff says. “Then, by performing functional imaging of those cells, we can start to measure what makes input to that region take place, or what types of input arrive at that region.”

Turning the gears

In the new study, the researchers used their probe to label populations of neurons that project to the striatum, a region that is involved in planning movement and responding to reward. In rats, they were able to determine which neural populations send input to the striatum during or immediately following a rewarding stimulus — in this case, deep brain stimulation of the lateral hypothalamus, a brain center that is involved in appetite and motivation, among other functions.

One question that researchers have had about deep brain stimulation of the lateral hypothalamus is how wide-ranging the effects are. In this study, the MIT team showed that several neural populations, located in regions including the motor cortex and the entorhinal cortex, which is involved in memory, send input into the striatum following deep brain stimulation.

“It's not simply input from the site of the deep brain stimulation or from the cells that carry dopamine. There are these other components, both distally and locally, that shape the response, and we can put our finger on them because of the use of this probe,” Jasanoff says.

During these experiments, neurons also generate regular fMRI signals, so in order to distinguish the signals that are coming specifically from the genetically altered neurons, the researchers perform each experiment twice: once with the probe on, and once following treatment with a drug that inhibits the probe. By measuring the difference in fMRI activity between these two conditions, they can determine how much activity is present in probe-containing cells specifically.

The researchers now hope to use this approach, which they call hemogenetics, to study other networks in the brain, beginning with an effort to identify some of the regions that receive input from the striatum following deep brain stimulation.

“One of the things that's exciting about the approach that we're introducing is that you can imagine applying the same tool at many sites in the brain and piecing together a network of interlocking gears, which consist of these input and output relationships,” Jasanoff says. “This can lead to a broad perspective on how the brain works as an integrated whole, at the level of neural populations.”

The research was funded by the National Institutes of Health and the MIT Simons Center for the Social Brain.

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Mind Mapping: A Human Brain Cell Atlas Ushering In “A New Era in Brain Science”

The new research, part of the NIH BRAIN Initiative, paves the way toward treating, preventing, and curing brain disorders.

Salk Institute researchers, as part of a larger collaboration with research teams around the world, analyzed more than half a million brain cells from three human brains to assemble an atlas of hundreds of cell types that make up a human brain in unprecedented detail.

The research, published in a special issue of the journal Science on October 13, 2023, is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.

“These papers represent the first tests of whether these approaches can work in human brain samples, and we were excited at just how well they translated,” says Professor Joseph Ecker, director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. “This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease.”

The BRAIN Initiative and Brain Cell Diversity

The new work is part of the National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative , or The BRAIN Initiative , an effort launched in 2014 to describe the full plethora of cells—as characterized by many different techniques—in mammalian brains. Salk is one of three institutions awarded grants to act as central players in generating data for the NIH BRAIN Initiative Cell Census Network, BICCN .

Every cell in a human brain contains the same sequence of DNA , but in different cell types different genes are copied onto strands of RNA for use as protein blueprints. This ultimate variation in which proteins are found in which cells—and at what levels—allows the vast diversity in types of brain cells and the complexity of the brain. Knowing which cells rely on which DNA sequences to function is critical not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders and, relatedly, how to treat those disorders.

“Once we scale up our techniques to a large number of brains, we can start to tackle questions that we haven’t been able to in the past,” says Margarita Behrens, a research professor in Salk’s Computational Neurobiology Laboratory and a co-principal investigator of the new work.

From Mice to Men: Adapting Research Techniques

In 2020, Ecker and Behrens led the Salk team that profiled 161 types of cells in the mouse brain , based on methyl chemical markers along DNA that specify when genes are turned on or off. This kind of DNA regulation, called methylation, is one level of cellular identity.

In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.

“It’s a big jump from mice to humans and also introduces some technical challenges that we had to overcome,” says Behrens. “But we were able to adapt things that we had figured out in mice and still get very high quality results with human brains.”

Innovative Techniques and Collaborative Efforts

At the same time, the researchers also used a second technique, which analyzed the three-dimensional structure of DNA molecules in each cell to get additional information about what DNA sequences are being actively used. Areas of DNA that are exposed are more likely to be accessed by cells than stretches of DNA that are tightly folded up.

“This is the first time we’ve looked at these dynamic genome structures at a whole new level of cell type granularity in the brain, and how those structures may regulate which genes are active in which cell types,” says Jingtian Zhou, co-first author of the new paper and a postdoctoral researcher in Ecker’s lab.

Other research teams whose work is also published in the special issue of Science used cells from the same three human brains to test their own cell profiling techniques, including a group at UC San Diego led by Bing Ren—also a co-author in Ecker and Behrens’ study. Ren’s team revealed a link between specific brain cell types and neuropsychiatric disorders, including schizophrenia, bipolar disorder, Alzheimer’s disease, and major depression. Additionally, the team developed artificial intelligence deep learning models that predict risk for these disorders.

Other groups in the global collaboration focused on measuring levels of RNA to group cells together into subtypes. The groups found a high level of correspondence in each brain region between which genes were activated, based on the DNA studies by Ecker and Behrens’ team, and which genes were found to be transcribed into RNA.

The Road Ahead: More Discoveries Await

Since the new Salk research was intended as a pilot study to test the efficacy of the techniques in human brains, the researchers say they can’t yet draw conclusions about how many cell types they might uncover in the human brain or how those types differ between mice and humans.

“The potential to find unique cell types in humans that we don’t see in mice is really exciting,” says Wei Tian, co-first author of the new paper and a staff scientist in Ecker’s lab. “We’ve made amazing progress but there are always more questions to ask.”

In 2022, the NIH Brain Initiative launched a new BRAIN Initiative Cell Atlas Network (BICAN), which will follow up the BICCN efforts. At Salk, a new Center for Multiomic Human Brain Cell Atlas funded through BICAN aims to study cells from over a dozen human brains and ask questions about how the brain changes during development, over people’s lifespans, and with disease. That more detailed work on a larger number of brains, Ecker says, will pave the way toward a better understanding of how certain brain cell types go awry in brain disorders and diseases.

“We want to have a full understanding of the brain across the lifespan so that we can pinpoint exactly when, how, and in which cell types things go wrong with disease—and potentially prevent or reverse those harmful changes,” says Ecker.

Reference: “Single-cell DNA methylation and 3D genome architecture in the human brain” by Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang E. Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Carolyn O’Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Song-Lin Ding, Rebecca Hodge, Boaz P. Levi, C. Dirk Keene, Sten Linnarsson, Ed Lein, Bing Ren, M. Margarita Behrens and Joseph R. Ecker, 13 October 2023,  Science . DOI: 10.1126/science.adf5357

Other authors of the paper are Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Michelle Liem, Naomi Claffey and Caz O’Connor of Salk; Yang Li and Bing Ren of the Ludwig Institute for Cancer Research at UC San Diego; Kimberly Siletti and Sten Linnarsson of the Karolinska Institutet; Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca Hodge, Boaz P. Levi and Ed Lein of the Allen Institute for Brain Science; and C. Dirk Keene of the University of Washington .

The work was supported by grants from the National Institute of Mental Health (U01MH121282, UM1 MH130994, NIMH U01MH114812), the National Institutes of Health BRAIN Initiative (NCI CCSG: P30 014195),  the Nancy and Buster Alvord Endowment, and the Howard Hughes Medical Institute.

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I hope this research may lead to answers as to why some with intellectual disability are unable to speak and unable to understand receptive language, something we take so for granted. MRI and EEG scans rarely recognise such severe cognitive disabilities, even genetic testing rarely gives answers, few scientific studies, if any, have focused on this debilitating lifelong condition often linked with autism.

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Scientists Just Uncovered A Whole New Layer of Brain Anatomy

The human brain is a ridiculously complex organ that doesn't give up its secrets easily. Thanks to advances in imaging technology, hidden forms and functions of neurological anatomy continue to emerge, from novel kinds of nerve cells to entirely new nubs of tissue .

Now researchers from the University of Copenhagen and University of Rochester have identified a layer of tissue that helps protect our gray and white matter, one that hasn't been distinguished before.

Only a few cells thick, this membrane seems to play a role in mediating the exchange of small, dissolved substances between compartments in the brain. It also appears to be the home base of brain-specific immune cells, not to mention assisting in the brain's waste-removal ( glymphatic ) system.

University of Copenhagen molecular biologist Kjeld Møllgård and colleagues have called their discovery the Subarachnoid LYmphatic-like Membrane (SLYM). While much of their research on this structure is so far from mice, using two-photon microscopy and dissections, they have confirmed the SLYM's presence in an adult human brain too.

The SLYM lies between two other membranes protecting the brain. It divides our brain fluid space in two, bringing the total number of known membranes encasing our brain up to four. It appears to act as a barrier for molecules in our brain fluid that are larger than around 3 kilodaltons ; comparable to an extremely small protein .

Unlike the rest of our body, our central nervous system does not have lymphatic (immune) vessels and is considered immune privileged – a term that refers to sites in our bodies where immune responses are highly controlled, such as our eyes and testes .

So the team suspects cerebrospinal fluid may pick up some of the immune system's role in the brain. The presence of the SLYM could explain how this works.

"The discovery of a new anatomic structure that segregates and helps control the flow of cerebrospinal fluid (CSF) in and around the brain now provides us much greater appreciation of the sophisticated role that CSF plays not only in transporting and removing waste from the brain, but also in supporting its immune defenses," says University of Rochester neuroscientist Maiken Nedergaard.

Møllgård and team found several types of immune cells – including myeloid cells and macrophages – camping out in the SLYM, keeping surveillance over the brain. In mice, the types of cells changed in response to swelling and natural aging, suggesting this site may play an important part in disease pathologies.

The SLYM shares molecular markers with the mesothelial membrane that lines the rest of our organs, encasing their blood vessels and storing immune cells. So the researchers propose that the SLYM is the brain's mesothelium, lining the blood vessels in the cavity between the brain and skull.

Mesothelium also plays a role of lubricant between organs that slide against each other.

"Physiological pulsations induced by the cardiovascular system, respiration, and positional changes of the head are constantly shifting the brain within the cranial cavity," the researchers explain in their paper . "SLYM may, like other mesothelial membranes, reduce friction between the brain and skull during such movements."

Tears in the SLYM may explain some of the long term symptoms of traumatic brain injury, Møllgård and team speculate. Disruption of this barrier would allow immune cells from the skull direct access into the brain, cells that are not calibrated for brain conditions. This could explain ongoing inflammation.

The flow of waste out of the brain can also continue to be suppressed for a long period after brain injury, and altered flow patterns of the cerebrospinal fluid because of the membrane's rupture may explain this.

As this extra layer of brain armor has only just been discovered, there's still a lot to work out. The researchers question if this tissue may also be involved in a more general immunity of the central nervous system and therefore play a role in associated diseases like multiple sclerosis.

"We conclude that SLYM fulfills the characteristics of a mesothelium by acting as an immune barrier that prevents exchange of small solutes between the outer and inner subarachnoid space compartments and by covering blood vessels in the subarachnoid space," write Møllgård and colleagues.

This research was published in Science .

December 16, 2022

This Year’s Most Thought-Provoking Brain Discoveries

Neural circuits that label experiences as “good” or “bad” and the emotional meaninglessness of facial expressions are some standouts among 2022’s mind and brain breakthroughs

By Gary Stix

Jonathan Kitchen/Getty Images

Can the human brain ever really understand itself? The problem of gaining a deep knowledge of the subjective depths of the conscious mind is such a hard problem that it has in fact been named the hard problem.

The human brain is impressively powerful . Its 100 billion neurons are connected by 100 trillion wirelike fibers, all squeezed into three pounds of squishy flesh lodged below a helmet of skull. Yet we still don’t know whether this organ will ever be able to muster the requisite smarts to hack the physical processes that underlie the ineffable “quality of deep blue” or “the sensation of middle C,” as philosopher David Chalmers put it when giving examples of the “hard problem” of consciousness, a term he invented, in a 1995 paper.

This past year did not uncover a solution to the hard problem, and one may not be forthcoming for decades, if ever. But 2022 did witness plenty of surprises and solutions to understanding the brain that do not require a complete explanation of consciousness. Such incrementalism could be seen in mid-November, when a crowd of more than 24,000 attendees of the annual Society for Neuroscience meeting gathered in San Diego, Calif. The event was a tribute of sorts to reductionism—the breaking down of hard problems into simpler knowable entities. At the event, there were reports of an animal study of a brain circuit that encodes social trauma and a brain-computer interface that lets a severely paralyzed person mentally spell out letters to form words.

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Brain discoveries abounded in 2022—and will certainly continue in 2023. Here’s a look at a few prime pickings from what we published at Scientific American this year.

Your Brain Has a Thumbs-Up–Thumbs-Down Switch

When neuroscientist Kay Tye was pursuing her Ph.D., she was told a chapter on emotion was inappropriate for her thesis. Emotion just wasn’t accepted as an integral, intrinsic part of behavioral neuroscience, her field of study. That didn’t make any sense to Tye. She decided to go her own way to become a leading researcher on feelings. This year Tye co-authored a Nature paper that reported on a kind of molecular switch in rodents that flags an experience as either good or bad. If human brains operate the same way as the brains of the mice in her lab, a malfunctioning thumbs-up–thumbs-down switch might explain some cases of depression, anxiety and addiction.

Facial Expressions Do Not Convey What You’ve Been Taught about Someone’s Emotional Demeanor

Charles Darwin proposed that facial expressions are universal: a smile conveys happiness; a frown indicates sadness. He was wrong, suggests research published in recent years. Investigators found that innate expressions grounded in biology do not exist—and instead are highly variable. Neuroscientist Lisa Feldman Barrett warned in an essay that a recognition of Darwin’s fallacy has implications for AI facial recognition systems intended to detect emotions.

Your Kid May Be a Dandelion and an Orchid—And even a Tulip

Pigeonholing a child as either sensitive or resilient is probably a mistake. That child is not necessarily just an “orchid”—overly sensitive to adverse experiences—or a “dandelion”—relatively immune to such events. Newly arrived in the mix are “tulips,” children who experience modest effects from what’s happening around them. But even this floral triad might not suffice. Many kids are psychological mixes, mosaics, studies showed this past year . They display sensitivity to some but not all influences around them, depending on a particular situation.

If You See Something, It May Help You to Say Something

In a marriage of neuroscience and pedagogy, researchers tried to assess what a curriculum that emphasized the learning of spatial skills would do for kids. One example: an assignment that involved creating a map to track bears in the Blue Ridge Mountains. Kids at five Virginia high schools took courses, and their performance was matched against another group that received lessons without the spatial-learning component. The results of the research , published in August, showed that students in the spatial learning group improved not only spatial skills but also verbal abilities—figuring out a problem using words.

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UVA Research Cracks the Autism Code, Making the Neurodivergent Brain Visible

Model Grounded in Biology Reveals the Tissue Structures Linked to the Disorder

A multi-university research team co-led by University of Virginia engineering professor Gustavo K. Rohde has developed a system that can spot genetic markers of autism in brain images with 89 to 95% accuracy. 

Their findings suggest doctors may one day see, classify and treat autism and related neurological conditions with this method, without having to rely on, or wait for, behavioral cues. And that means this truly personalized medicine could result in earlier interventions.

“Autism is traditionally diagnosed behaviorally but has a strong genetic basis. A genetics-first approach could transform understanding and treatment of autism,” the researchers wrote in a paper published June 12 in the journal Science Advances.

Rohde, a professor of biomedical and electrical and computer engineering, collaborated with researchers from the University of California San Franscisco and the Johns Hopkins University School of Medicine, including Shinjini Kundu, Rohde’s former Ph.D. student and first author of the paper.

While working in Rohde’s lab, Kundu — now a physician at the Johns Hopkins Hospital — helped develop a generative computer modeling technique called transport-based morphometry, or TBM, which is at the heart of the team’s approach.

Using a novel mathematical modeling technique, their system reveals brain structure patterns that predict variations in certain regions of the individual’s genetic code — a phenomenon called “copy number variations,” in which segments of the code are deleted or duplicated. These variations are linked to autism.

TBM allows the researchers to distinguish normal biological variations in brain structure from those associated with the deletions or duplications.

“Some copy number variations are known to be associated with autism, but their link to brain morphology — in other words, how different types of brain tissues such as gray or white matter, are arranged in our brain — is not well known,” Rohde said. “Finding out how CNV relates to brain tissue morphology is an important first step in understanding autism’s biological basis.”

How TBM Cracks the Code

Transport-based morphometry is different from other machine learning image analysis models because the mathematical models are based on mass transport — the movement of molecules such as proteins, nutrients and gases in and out of cells and tissues. “Morphometry” refers to measuring and quantifying the biological forms created by these processes.

Most machine learning methods, Rohde said, have little or no relation to the biophysical processes that generated the data. They rely instead on recognizing patterns to identify anomalies.

But Rohde’s approach uses mathematical equations to extract the mass transport information from medical images, creating new images for visualization and further analysis.

Then, using a different set of mathematical methods, the system parses information associated with autism-linked CNV variations from other “normal” genetic variations that do not lead to disease or neurological disorders — what the researchers call “confounding sources of variability.” 

 Major discoveries from such vast amounts of data may lie ahead if we utilize more appropriate mathematical models to extract such information.

These sources previously prevented researchers from understanding the “gene-brain-behavior” relationship, effectively limiting care providers to behavior-based diagnoses and treatments.

According to Forbes magazine , 90% of medical data is in the form of imaging, which we don’t have the means to unlock. Rohde believes TBM is the skeleton key.

“As such, major discoveries from such vast amounts of data may lie ahead if we utilize more appropriate mathematical models to extract such information.”

The researchers used data from participants in the Simons Variation in Individuals Project, a group of subjects with the autism-linked genetic variation.

Control-set subjects were recruited from other clinical settings and matched for age, sex, handedness and non-verbal IQ while excluding those with related neurological disorders or family histories.

“We hope that the findings, the ability to identify localized changes in brain morphology linked to copy number variations, could point to brain regions and eventually mechanisms that can be leveraged for therapies,” Rohde said.

Publication

Discovering the gene-brain-behavior link in autism via generative machine learning was published online June 12, 2024, in Science Advances for the June 14 edition. 

Additional co-authors are Haris Sair of the Johns Hopkins School of Medicine and Elliott H. Sherr and Pratik Mukherjee of the University of California San Francisco’s Department of Radiology.

The research received funding from the National Science Foundation, National Institutes of Health, Radiological Society of North America and the Simons Variation in Individuals Foundation.

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