How do our brains tell us what went wrong?

New study identifies the neurons that have one job: to detect the unexpectedly erroneous

Peer-Reviewed Publication

NEW YORK UNIVERSITY

Whether improperly closing a door or shanking a kick in soccer, our brains tell us when we’ve made a mistake because these sounds differ from what we expect to hear. While it’s long been established that our neurons spot these errors, it has been unclear whether there are brain cells that have only one job—to signal when a sound is unexpected or “off.”

A team of New York University neuroscientists has now identified a class of neurons—what it calls “prediction-error neurons”—that are not responsive to sounds in general, but only respond when sounds violate expectations, thereby sending a message that a mistake has been made.

“Brains are remarkable at detecting what’s happening in the world, but they are even better at telling you whether what happened was expected or not,” explains David Schneider, an assistant professor in NYU’s Center for Neural Science and the senior author of the study, which appears in JNeurosci. “We found that there are specific neurons in the brain that don't tell you what happened, but instead tell you what went wrong.”

The paper’s authors add that the results could potentially help better illuminate the learning process, identify the causes behind certain afflictions, and spot sound-related aptitudes. 

“Neurons like these might be vital in learning how to speak or how to play a musical instrument,” observes Nicholas Audette, a postdoctoral fellow in NYU’s Center for Neural Science and the paper’s lead author. “Both of those behaviors involve lots of trial and error, lots of mistakes, and lots of learning from mistakes.”Schneider added, “Do expert musicians have better prediction error neurons than novices? And in diseases in which speech is underdeveloped, are prediction error neurons malfunctioning?”

Behaviors often have predictable sensory consequences. For example, when shutting a car door, we expect to hear an anticipated “thump” at a particular phase of our arm movement. And these behaviors are not limited to humans—monkeys, mice, and other animals can learn to predict what sound a movement will produce and when that sound will occur. 

Previous research has shown that in the brains of humans and other animals, neurons have significant responses when a sound violates the animal’s expectation and weaker responses when a sound matches expectation. But it had been unclear whether there were neurons that only had one job—to signal when a sound was unexpected.

To address this question, Schneider and Audette built upon their previous work, which uncovered how the brain makes distinctions between “right” and “wrong” sounds. In the new JNeurosci study, they studied responses in mice through a series of experiments and by isolating neuronal activity.

In the experiments, the mice heard a particular sound after pressing on a lever. This was done repeatedly, until they associated this sound when pressing. The researchers then altered the sounds the mice heard in making subsequent presses—a method designed to mimic unexpected sounds humans hear when making errors.

The scientists found that many of the mice’s neurons (“prediction-error neurons”) were silent—meaning that they did not produce signals that could be used by other parts of the brain—except for when the mice made a movement and heard something unexpected. 

More specifically, they found that individual prediction-error neurons in the mice’s auditory cortex not only signaled when something went wrong, but they also signaled what went wrong. 

For example, every time the sound was too quiet, one group of prediction-error neurons was activated. However, when the sound was the expected volume but came too late, a completely different group of prediction-error neurons was active.

“When a movement makes an unexpected sound, it can violate our expectations in a lot of different ways,” explains Schneider. “Different neurons are active when a movement makes too quiet a sound, and other neurons when the movement makes the wrong sound.”

This research was supported by a grant from the National Institutes of Health (R01-DC018802).

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JOURNAL

JNeurosci

DOI

10.1523/JNEUROSCI.0512-23.2023 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Stimulus-specific prediction error neurons in mouse auditory cortex

Consistent metabolism may prove costly for insects in saltier water

Peer-Reviewed Publication

NORTH CAROLINA STATE UNIVERSITY

Increased salinity usually spells trouble for freshwater insects like mayflies. A new study from North Carolina State University finds that the lack of metabolic responses to salinity may explain why some freshwater insects often struggle in higher salinity, while other freshwater invertebrates (like mollusks and crustaceans) thrive. Salinity in this case refers to the concentrations of all the salts in an aquatic environment, not just sodium.

“Freshwater habitats in general are getting saltier for a number of reasons, including road salt and agricultural runoff, extraction of coal and natural gas, drought, and sea level rise,” says David Buchwalter, professor of toxicology at NC State and corresponding author of the research. “Freshwater insects and other organisms that live in these systems are used as indicators of the ecosystem’s health. When these systems get saltier, we see that insect diversity decreases, but we aren’t sure why.”

Aquatic animals (including insects and crustaceans) must constantly maintain the correct balance of water and salts within their body – a process called osmoregulation. Theoretically, the most favorable environment for aquatic animals would be one where external salinity levels are close to those inside the animal. That way the animal doesn’t have to work as hard to maintain osmoregulation.

However, the opposite seems to be true for freshwater insects – higher salinity is always associated with increased rates of ion uptake in insects, but it is also associated with developmental delays or death.

“We thought that freshwater insects might be shifting so much of their energy toward osmoregulation in saltier environments that they cannot grow or thrive,” Buchwalter says. “So we measured the metabolic rates of crustaceans and insects in dilute and saline environments to see if metabolic responses to salinity were similar.”

The team looked at three types of freshwater animals – two species of gammarid, or “scud,” which is a small freshwater crustacean; one freshwater snail; and three aquatic insect species.

In the first test, they measured the animals’ metabolism by placing them in waters with different concentrations of salt ions and looking at their rates of oxygen consumption. They observed that more dilute conditions made the crustaceans and snail breathe harder, increasing their metabolism, while insects’ metabolic rates were constant regardless of salinity.

Next, the team looked at whether an increase in breathing rates was linked to the transport of a particular ion. Radioactive isotopes of the salt ions calcium and sodium allowed the researchers to measure how much and how quickly the animals took up different ions.

The researchers found that calcium was the key driver of non-insects’ increased metabolism in lower salinity. In other words, the crustaceans and snail worked harder to transport the calcium ions they required in an environment where calcium was harder to find.

In contrast, the insects’ metabolic rates remained constant in both saline and dilute environments, even though they had a higher calcium ion transport rate in the saline environment. Insects seem to have very little demand for calcium; in fact, previous research has shown that excess calcium is potentially toxic to them.

The researchers think that the animals’ use of internal energy, or active transport, when moving the salts could be the explanation.

“When we see non-insects’ metabolisms increase in dilute environments, it could be due to the fact that they have to work harder to take in more calcium,” Buchwalter says. “And while it seems counterintuitive, the opposite is true for insects who are working harder in a more saline environment to maintain equilibrium, although their respiration rates don’t increase. Instead, they appear to utilize resources that would otherwise be dedicated to growth and development to ‘undo’ excessive ion uptake when things get saltier.

“Moving salt ions has an energy cost to the animal,” Buchwalter says. “So for freshwater insects, the idea that organisms should thrive in environments that are close to their internal salinity is wrong. Additionally, their low demand for calcium may help them thrive in very dilute environments where insects typically dominate the ecology. In contrast, low calcium appears to be stressful for the crustaceans and snail in this study. It is fascinating that species living in the same habitats can have such different physiologies.”

Future work will explore whether these physiological differences are based on the ancestry of the organisms tested, or the use of calcium in their exoskeletons/shells.

The work appears in the Journal of Experimental Biology and was supported by the National Science Foundation under grant IOS 1754884. First author and Ph.D. candidate Jamie Cochran was supported by a Goodnight Doctoral Fellowship. Catelyn Banks, formerly a student at the North Carolina School of Science and Mathematics, also contributed to the work.

-peake-

Note to editors: An abstract follows.

“Respirometry reveals major lineage-based differences in the energetics of osmoregulation in aquatic invertebrates”

DOI: 10.1242/jeb.246376

Authors: Jamie Cochran, David Buchwalter, North Carolina State University; Catelyn Banks, North Carolina School of Science and Mathematics
Published: Oct. 5, 2023 in the Journal of Experimental Biology

Abstract:
All freshwater organisms are challenged to control their internal balance of water and ions in strongly hypotonic environments. We compared the influence of external salinity on the M.O2 of three species of freshwater insects, one snail, and two crustaceans. Consistent with available literature, we find a clear decrease in M.O2 with increasing salinity in the snail Elimia sp. and crustaceans Hyalella azteca and Gammarus pulex (r(5)= -0.90, p=0.03). However, we show here that metabolic rates are generally unchanged by salinity in freshwater insects, whereas ion transport rates are positively correlated with higher salinities. In contrast, when we examined the ionic influx rates in freshwater snail and crustaceans, we found that Ca uptake rates were highest under the most dilute conditions, while Na uptake rates increased with salinity. In G. pulex exposed to a serially diluted ion matrix, calcium uptake rates were positively associated with oxygen consumption rates (r(5)=-0.93, p=0.02). This positive association between Ca uptake rate and oxygen consumption was also observed when conductivity was held constant, but Ca concentration was manipulated (1.7-17.3 mg Ca L-1) (r(5)=0.94, p=0.05). This finding potentially implicates the cost of calcium uptake as a driver of increased metabolic rate under dilute conditions in organisms with calcified exoskeletons and suggests major phyletic differences in osmoregulatory physiology. Freshwater insects may be energetically challenged by higher salinities, while lower salinities may be more challenging for other freshwater taxa.

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JOURNAL

Journal of Experimental Biology

DOI

10.1242/jeb.246376 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

“Respirometry reveals major lineage-based differences in the energetics of osmoregulation in aquatic invertebrates”

 

The efficient perovskite cells with a structured anti-reflective layer – another step towards commercialization on a wider scale

Peer-Reviewed Publication

UNIVERSITY OF WARSAW, FACULTY OF PHYSICS

 

IMAGE: 

THE VISUALIZATION OF THE MANUFACTURED HONEYCOMB TEXTURE FOR THE PEROVSKITE SOLAR CELL (SOURCE: MACIEJ KRAJEWSKI, FACULTY OF PHYSICS AT THE UNIVERSITY OF WARSAW). THE RESEARCH OF THE TEAM OF SCIENTISTS WAS APPRECIATED BY BEING PRESENTED ON THE COVER OF THE JOURNAL "ADVANCED MATERIALS AND INTERFACES”

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CREDIT: MACIEJ KRAJEWSKI, FACULTY OF PHYSICS AT THE UNIVERSITY OF WARSAW

Perovskite-based solar cells, widely considered as successors to the currently dominant silicon cells, due to their simple and cost-effective production process combined with their excellent performance, are now the subject of in-depth research. A team of scientists from the Fraunhofer Institute for Solar Energy ISE and the Faculty of Physics at the University of Warsaw presented perovskite photovoltaic cells with significantly improved optoelectronic properties in the journal Advanced Materials and Interfaces. Reducing optical losses in the next-generation cells, as shown in the paper, is one of the key challenges for their broader implementation.

 

Photovoltaics has experienced a significant development over the past 20 years, considering both panel efficiency and the installed capacity, which has increased worldwide by a staggering 1000 times since year 2000. Silicon has been the most commonly used material for producing photovoltaic panels, yet currently cells based on this element are approaching their physical efficiency limits. Therefore, scientists are actively exploring innovative solutions targeted at enhancing cell efficiency and simultaneously enabling cheaper and more environmentally friendly production.

Perovskite-based cells meet both of these criteria, offering efficiency above 26%, ease and cost-effectiveness in production using well-established chemical methods. Currently, numerous research institutes worldwide are working on improving their efficiency and resistance to atmospheric conditions. One of the challenges they are facing is the integration of perovskite cells with silicon cells while simultaneously reducing losses from reflection and parasitic absorption. To minimize these losses, silicon cells are typically etched with highly corrosive chemical agents, a process that creates microscopic pyramid pattern on the surface, effectively reducing the reflection of the entire device, thereby increasing the current generated by the device. Unfortunately, perovskites are sensitive to many chemical substances, which is why less effective planar anti-reflective coatings applied through less invasive sputtering have been employed so far.

In research published in Advanced Materials and Interfaces, scientists used the nanoimprinting method to create an efficient anti-reflective structure with honeycomb-like symmetry atop the perovskite solar cell. This technique allows the production of nanometer-scale structures on very large surfaces, exceeding 100 cm². "This approach guarantees scalability in the production process of large-surface devices, which is crucial in the context of the urgent need for energy transformation toward renewable energy sources," says Msc Maciej Krajewski, a researcher from the Faculty of Physics at the University of Warsaw. Such modified samples demonstrate higher efficiency compared to cells using previously employed planar anti-reflective layers.

In addition to enhancing efficiency, another significant finding from the published work is that the application procedure for this layer does not damage the perovskite, opening the possibility of using other structures tailored to the specific cell architectures. Until now, scientists applied similar anti-reflective structures as separately prepared layers, which were transferred in another technological process that was inevitably small-scale and susceptible to damaging the active layer. By employing the direct nanoimprinting method, it becomes possible to manufacture the entire device on a large scale and in a single technological process, which is crucial for reducing the overall device costs.

Furthermore, the applied method is compatible with a tandem configuration, i.e., combining silicon and perovskite cells, opening up an entirely new possibilities for its application. Consequently, there is the potential for directly transferring the procedure to emerging photovoltaic architectures, which could lead to further improvements in efficiency. The published results pave the way for new photovoltaic devices with outstanding optoelectronic properties, utilizing nanoimprinting techniques in their production.

The experiment and modeling were conducted at Fraunhofer ISE in Freiburg, with a participation of researcher Msc. Maciej Krajewski from the University of Warsaw. Funding for the research was provided by: Fraunhofer Gesellschaft (project MEEt within the ICON program), the Institute of Experimental Physics at the Faculty of Physics UW, University of Warsaw, Faculty of Physics UW, University of Warsaw Foundation, as well as from the Erasmus+ program and the Deutsche Bundesstiftung Umwelt.

 

Faculty of Physics of the University of Warsaw

Physics and astronomy at the University of Warsaw appeared in 1816 as part of the then Faculty of Philosophy. In 1825, the Astronomical Observatory was established. Currently, the Faculty of Physics at the University of Warsaw consists of the following institutes: Experimental Physics, Theoretical Physics, Geophysics, the Department of Mathematical Methods and the Astronomical Observatory. The research covers almost all areas of modern physics, on scales from quantum to cosmological. The Faculty's research and teaching staff consists of over 250 academic teachers. About 1,100 students and over 170 doctoral students study at the Faculty of Physics UW. The University of Warsaw is among the 75 best universities in the world educating in the field of physics according to the Shanghai’s Global Ranking of Academic Subjects.

SCIENTIFIC PUBLICATION:

M. Krajewski, A. Callies, M. Heydarian, M. Heydarian, M. Hanser, P. S. C. Schulze, B. Bläsi, O. Höhn, Roller Nanoimprinted Honeycomb Texture as an Efficient Antireflective Coating for Perovskite Solar Cells, Adv. Mater. Interfaces 26/2023
https://onlinelibrary.wiley.com/doi/10.1002/admi.202370076

CONTACT:

Maciej Krajewski
Faculty of Physics, University of Warsaw
email: maciej.krajewski@fuw.edu.pl
phone: +48 22 55 32 769

RELATED WEBSITES WWW:

https://www.fuw.edu.pl/faculty-of-physics-home.html
Website of the Faculty of Physics at the University of Warsaw

https://www.fuw.edu.pl/press-releases.html
Press service of the Faculty of Physics at the University of Warsaw

https://www.ise.fraunhofer.de/en.html
Website of Fraunhofer Institute for Solar Energy ISE

 

GRAPHIC MATERIALS:

FUW231006b_fot02
https://www.fuw.edu.pl/tl_files/press/images/2023/FUW231006b_fot02.png
The visualization of the manufactured honeycomb texture for the perovskite solar cell (source: Maciej Krajewski, Faculty of Physics at the University of Warsaw). The research of the team of scientists was appreciated by being presented on the cover of the journal "Advanced Materials and Interfaces”

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JOURNAL

Advanced Materials Interfaces

DOI

10.1002/admi.202370076 

ARTICLE TITLE

Roller Nanoimprinted Honeycomb Texture as an Efficient Antireflective Coating for Perovskite Solar Cells

 

Integrated health services in Africa can improve patient care and save money

Integrated health care for chronic high-burden conditions in sub-Saharan Africa is feasible and health services could deliver high-quality services for less cost than with the current approach of separate vertical care for each condition, a new study led

Peer-Reviewed Publication

UNIVERSITY COLLEGE LONDON

Integrated health care for chronic high-burden conditions in sub-Saharan Africa is feasible and health services could deliver high-quality services for less cost than with the current approach of separate vertical care for each condition, a new study led by UCL researchers shows.

Presently, health care services for non-communicable conditions such as diabetes and hypertension are fragmented and the quality of care is inequitable when compared with services for HIV. Much less than half of the people who start treatment for diabetes or hypertension on the continent remain in care one year later and about 2 million premature deaths are attributed annually to the effects of these two conditions. In contrast, the vast majority of people living with HIV are in regular care and virally suppressed. Mortality rates of people with HIV have fallen over 5-fold since their peak in the early 2000s.

There has been growing interest to establish one stop integrated service delivery clinics using the platforms developed for and the learning acquired by HIV programmes to improve outcomes for people with non-communicable conditions. However, high quality evidence on the feasibility of such clinics, their potential effect on HIV outcomes and their costs, was lacking.

The paper, which has been published by The Lancet, addresses this evidence gap. It reports a large study led by the National Institute for Medical Research in Tanzania, MRC/UVRI/LSHTM Uganda Research Unit and initially by LSTM, and later by the UCL Institute for Global Health.

The study involved multiple institutions from Tanzania, Uganda and Europe. It showed that integrated care was associated with high levels of retention in care for people with diabetes or hypertension, that it did not adversely affect the rate of viral suppression among people with HIV, and that it was cost-saving for health care providers.  

The World Health Organisation recommended integration of diabetes and hypertension care with HIV services in 2021, but at the time there was limited data on outcomes.This study supports the WHO’s recommendation, which also called for more data on health outcomes, cost, and preferences.

Dr Meg Doherty, Director of the World Health Organisation Department of Global HIV, Hepatitis and STI Programmes, said: “This was a large, ambitious and well-conducted study with the potential to change policy and practice. It is the first study to test successfully the concept of a fully integrated one-stop clinic for people with HIV or non-communicable conditions, with excellent HIV and NCD outcomes. It is exciting to see that by including hypertension and diabetes screening into the HIV clinic in these two countries, there was no change in HIV viral load suppression outcomes.” 

Dr Gerald Mutungi, Assistant Commissioner for Non-Communicable Diseases in Uganda, said: “This study is the culmination of more than six years of research, conducted in partnership with the Ministries of Health. It demonstrates that integrated management is effective and cost-saving. The findings will inform future control of non-communicable diseases on the continent.”

Professor Tumaini Nagu, Chief Medical Officer of Tanzania, said: “Our study provides clear evidence for policymakers to consider scale up of integrated care for HIV, diabetes and hypertension. With the high burden of non-communicable conditions now in Africa, and more and more people living with multiple chronic conditions, integrated management will be an essential and cost-effective approach for the continent.”

Stephen Watiti, a patient representative based in Uganda and an author on the study, said: “Patients are interested in their overall health and do not look at diseases individually. Integrated management will be a big welcome going forward, thanks to the findings of this study”.

Katie Dain, CEO of the NCD Alliance, said: “We need the same powerful and coordinated global response to tackle NCDs that we’ve seen for HIV. We know how to do this, and this time, we can build on existing infrastructure. Integrated care is a win-win opportunity to make NCD care more accessible for people living with HIV and cost-effectively strengthen our health systems.”

Professor Shabbar Jaffar (UCL Institute for Global Health), the corresponding author, said: "I am very proud of all of the investigators. We worked as equal partners and because of this were able to pull off this most challenging of research studies."

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JOURNAL

The Lancet

DOI

10.1016/S0140-6736(23)01573-8 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial

ARTICLE PUBLICATION DATE

6-Oct-2023

KILLER KULTURE

States vary in firearm ownership – as well as the storage and carrying habits of owners

Rutgers researchers find firearm owning communities in five states are diverse, with risky behaviors more common in some than others

Peer-Reviewed Publication

RUTGERS UNIVERSITY

A new study by the New Jersey Gun Violence Research Center at Rutgers assesses the degree to which firearm owners in each state differ from one another with respect to firearm ownership, exposure and use.

Keeping a firearm in the home sharply increases the risk for injury and death. Previous research aimed at characterizing firearm ownership, storage and carrying has focused on national samples, which limits the collective understanding of if and how firearm owning communities throughout the United States differ from one another.

“Americans have a Constitutional right to own firearms, but individuals in different states exercise that right and use their firearms very differently from one another depending on the community they are in,” said Michael Anestis, executive director of the New Jersey Gun Violence Research Center and the lead author of the study appearing in the journal Injury Prevention. “Because of this, the risk for firearm injury and death varies widely from state to state.”

Anestis said most earlier studies on this topic have collected samples that aren’t representative of the population and those that have used optimal samples pre-dated the recent unprecedented surge in firearm sales, which raises questions about their relevance to the current moment.

Rutgers researchers surveyed a representative sample of English-speaking adults from five states: New Jersey, Minnesota, Mississippi, Colorado, and Texas. These states were chosen because they vary widely from one another geographically, politically and culturally and have broadly different firearm policies and rates of gun violence.

The researchers found the states vary sharply with respect to firearm ownership, with Mississippi reporting the highest percentage (45.6 percent) and New Jersey the lowest (13.2 percent). New Jersey residents were less likely to grow up in homes with firearms (18 percent), with the other states exceeding 40 percent and Mississippi at 53.2 percent.

With respect to firearm use, Mississippi and Texas firearm owners stood out as exhibiting more dangerous behavior. For instance, firearm owners in Mississippi and Texas store firearms loaded and carry firearms outside the home more frequently than other firearm owners. Also, Mississippi firearm owners are more likely than others to store their firearms unhidden in vehicles.

Notably, firearm regulations in these states are particularly lenient. In contrast, in New Jersey, where firearm regulations are particularly stringent, firearm owners use gun safes more frequently. Notably, Minnesota firearm owners stood out in that they were less likely to own handguns and more likely to own rifles and shotguns. Minnesota firearm owners were the only group to report that hunting was the most common primary reason for firearm ownership, with all other states listing safety at home as the primary reason.

Given that previous research has shown unsecure firearm storage increases the risk for firearm injury and death and that recent loosening of restrictions on concealed carry resulted in subsequent increases in fatal and nonfatal violent crime, these findings highlight that the policies in place in any given state may have profound effects on the behaviors of the residents and the safety of the communities in those states, Anestis said.

“The decision to bring a firearm into the home is a personal one and different families are comfortable with different levels and types of risk,” he said. “What is troubling to me, however, is that some states seem to be fostering situations in which their firearm owning residents feel compelled to use their firearms unsafely – storing them unsecured in their homes or vehicles and carrying them frequently outside their homes – and are perhaps unaware of the risks associated with those behaviors.

Anestis added: “In a nation with overwhelming rates of firearm injury and death, it is beholden upon our policy makers and leaders to ensure that firearm owners are empowered with accurate information about risk and that communities are protected by policies that foster safety. Alienating firearm owners is not the solution, but allowing politics to justify endangering families is not the solution either.”

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JOURNAL

Injury Prevention

DOI

10.1136/ip-2023-044878 

METHOD OF RESEARCH

Survey

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Regional differences in firearm ownership, storage and use: results from a representative survey of five US states

ARTICLE PUBLICATION DATE

5-Oct-2023

 

Patterns in physician burnout

JAMA Network Open

Peer-Reviewed Publication

JAMA NETWORK

About The Study: The findings of this survey study involving 1,373 physicians and three survey periods suggest that the physician burnout rate in the U.S. is increasing. This pattern represents a potential threat to the ability of the health care system to care for patients and needs urgent solutions. 

Authors: Marcus V. Ortega, M.D., of Massachusetts General Hospital in Boston, is the corresponding author. 

 To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2023.36745)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Embed this link to provide your readers free access to the full-text article 

http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2023.36745?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=100623

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JOURNAL

JAMA Network Open

OF MICE AND MEN

Human brain seems impossible to map. What if we started with mice?

Project seeks to create first comprehensive diagram of every neural connection

Grant and Award Announcement

HARVARD UNIVERSITY

 

IMAGE: 

SCANNING ELECTRON MICROSCOPY SHOWS INDIVIDUAL NEURONS IN A PIECE OF CEREBRAL CORTEX. DATA IS ON THE SCALE OF WHAT HARVARD AND GOOGLE RESEARCHERS WILL PRODUCE WITH THE NEW CONNECTOME PROJECT. CELLS ARE COLOR-CODED BY SIZE: RED ARE LARGEST NEURONS, BLUE SMALLEST.

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CREDIT: BERGER, SHAPSON-COE, JANUSZEWSKI ET AL., HARVARD AND GOOGLE

The human brain is a tangled highway of wires emanating from nearly 100 billion neurons, all of which communicate across trillions of junctions called synapses. “Depressingly complex,” Harvard neuroscientist Jeff Lichtman calls it. The only way to understand this highway, says Lichtman, is to create a map.

Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology, has spent several decades generating such maps, and in doing so has pioneered a field known as “connectomics.” His ultimate goal is a whole-mammalian brain map accounting for every neural connection, a so-called “connectome.”

Now, Lichtman and colleagues are embarking on a critical new step of that journey by seeking to capture synapse-level connectome data from a mouse brain at unprecedented clarity and resolution.

Lichtman and partners including Princeton University, MIT, Cambridge University and Johns Hopkins have received $30 million from the National Institutes of Health and an additional $3 million from Harvard and Princeton toward the goal of reconstructing, for the first time, all the neural wiring inside a mouse brain. They’ll prove the feat possible by first imaging a 10 cubic-millimeter region in the mouse hippocampal formation, the portion of the brain responsible for memory consolidation, spatial navigation, and other complex tasks.

Like the Human Genome Project cataloged every human gene and its unique DNA sequence, Lichtman’s connectome, which he has worked on since arriving at Harvard in 2004, would be a comprehensive diagram of every neural connection in the brain.

Creating a connectome of the human brain could lead to new approaches in diagnosing and treating disorders of the brain, from autism to schizophrenia. Scientists suspect these diseases are “connectopathies” — subtle miswirings that no currently available brain scans can detect.

“Connectomics is the only pathway,” said Lichtman, an affiliate of Harvard’s Center for Brain Science. “If we get to a point where doing a whole mouse brain becomes routine, you could think about doing it in say, animal models of autism. There is this level of understanding about brains that presently doesn’t exist. We know about the outward manifestations of behavior. We know about some of the molecules that are perturbed. But in between, the wiring diagrams, until now, there was no way to see them. Now, there is a way.”

The National Institutes of Health awarded new recipients of the Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or BRAIN Initiative, funding in early September. The Harvard team is being funded through the BRAIN Initiative Connectivity Across Scales network, aimed at developing research capacity and technical capabilities for creating wiring diagrams of whole brains.

“Current techniques lack either the resolution or the ability to scale across and map out large regions of the entire brain, information that is essential for unraveling the mysteries of this incredible organ,” said John Ngai, director of the BRAIN Initiative. “Following years of careful planning and input from the scientific community, BRAIN CONNECTS — which represents our third, large-scale transformative project — aims to develop the tools needed to obtain brain-wide connectivity maps at unprecedented levels of detail and scale.”

The mouse brain is, of course, much smaller than a human’s, but when looking at individual neurons, synaptic vesicles and glial cells, “you can’t tell the difference,” Lichtman said. “At the level of cells and synapses, all mammalian brains are basically the same.”

Given recent advances in computing and data processing, and prior work by Lichtman and others — including Professor Florian Engert in molecular and cell biology —­ on the brains of zebrafish and fruit flies, achieving a mouse brain map has become more feasible and would serve as an early proving ground for imaging the human brain. Lichtman and colleagues urged collective efforts toward the lofty goal of a mouse brain connectome in a 2020 opinion piece titled “The Mind of a Mouse.”

The researchers will apply biological imaging techniques Lichtman and colleagues have invented over the course of several decades to achieve their goals. For the NIH project, they will employ a two-tiered system. First, two 91-beam scanning electron microscopes, one at Harvard and one at Princeton, will capture images of thin sections of the mouse hippocampal formation. The surface of each section will then be etched away with an ion beam just a few nanometers at a time, and the imaging process will be repeated until the entire volume is viewed. A team at Google Research will computationally extract the resulting wiring diagram with machine learning.

The team expects to generate about 10,000 terabytes of data for their 10-square-millimeter mouse brain section; 50 times that amount of data would be generated for a whole mouse brain. Over the first half of their five-year project, the team expects to generate up to 50 terabytes of data per day.

Lichtman’s team has worked with Google over the last several years on image processing techniques that allow them to make sense of large amounts of data quickly. Engineers led by grant co-investigator Viren Jain will apply artificial intelligence algorithms to these brain images to categorize and color-code nerve cells and synapses. Google will also help publicly share this enormous brain map.

“We plan on using our experience with computational reconstruction and analysis of large-scale electron microscopy data, along with Google’s highly scalable data processing infrastructure, in order to enable mouse connectomics at an unprecedented scale,” said Google’s Jain. “We have worked closely with Jeff’s lab over five years, and this collaboration has been highly successful in pushing the frontiers of data-intensive neuroscience.”

The research is supported by the NIH BRAIN Initiative under award number 1UM1NS132250-01. Lichtman is involved with another BRAIN CONNECTS grant awarded by the NIH, which is led by Professor of Physics Aravinthan D.T. Samuel and is aimed at developing a rapid-imaging strategy for connectomics. More information on other awardees.

 

Rise in overdose deaths increasingly affects those with lower educational attainment, RAND study finds

Longstanding trend has surged during the pandemic

Peer-Reviewed Publication

RAND CORPORATION

Drug overdose deaths increased sharply among Americans without a college education and nearly doubled over a three-year period among those who don’t have a high school diploma, according to a new RAND Corporation study. The findings further highlight a potential association between the rise in drug overdose deaths and barriers to education access, a social determinant of health.  

 

Lower educational attainment has been one of the socioeconomic factors historically associated with drug use and overdose deaths, but the emergence of fentanyl in street drugs and the rise of the COVID-19 pandemic may have caused this longstanding health disparity to surge, according to the study.

 

The findings are published by the journal JAMA Health Forum.

 

“The analysis shows that the opioid crisis increasingly has become a crisis involving Americans without any college education,” said David Powell, the study’s author and a senior economist at RAND, a nonprofit research organization. “The study suggests large and growing education disparities within all racial and ethnic groups – disparities that have accelerated since the beginning of the COVID-19 pandemic.”

 

Drug overdose deaths continue to surge in the U.S., contributing to declining life expectancy.   Much recent attention has focused on the demographics of the opioid crisis, documenting overdose death rates by sex, race and ethnicity and age. Less attention has focused on educational attainment – especially during the COVID-19 pandemic – despite its central importance in broader discussions of “deaths of despair.”

 

The RAND study examines how drug overdose deaths have disproportionately affected populations who are affected by lower educational attainment using more recent data than previous examinations of the issue.

 

Examining information from the National Vital Statistics System Mortality Multiple Cause-of-Death Data, Powell investigated the association between educational attainment with the rise in overdose deaths from 2000 to 2021. During that period, the analysis identified 912,057 overdose deaths with education information for those ages 25 and higher. Nearly 70% had no college experience, while the remainder had at least some college.

 

Overdose death rates increased from 2000 to 2021 for both education categories, but the no-college group experienced faster growth nearly every year.

 

For people with no college education, the overdose death rate increased from 12 deaths per 100,000 individuals in 2000 to 82 deaths per 100,000 in 2021. Among people with at least some college, the 2000 rate was 4.6 deaths per 100,000 individuals, growing to 18.6 deaths per 100,000 in 2021. 

 

The study also highlights overdose deaths from 2018-2021 among people without a high school diploma. During this short time overdose deaths among this group increased by 35 deaths per 100,000 people, or 83%. This compared to increases of 32 deaths per 100,000 for people with high school diplomas, 10 deaths per 100,000 for those with some college, and 2 deaths per 100,000 for those with a bachelor’s degree. 

 

The American Indian and Alaskan Native population showed substantially larger overdose rates than the rest of the population for every educational group, implying that race and ethnicity were independently associated with overdose death rate growth. 

 

Relative to White individuals, Black individuals experienced higher overdose death rates among people with high school diplomas. For those without a high school diploma, White individuals showed higher overdose death rates, though Black individuals experienced faster growth since 2018. 

 

The study highlights another crucial factor among populations disproportionately affected by overdose deaths, which could help inform development of effective and socially inclusive prevention and intervention strategies. It suggests the importance of providing additional resources, such as expanded treatment access and subsidized naloxone, to economically disadvantaged individuals and communities. It also highlights the potential gains of broader social and economic policies in addressing the opioid crisis.

 

“Understanding who is most affected by overdose deaths provides critical information about how resources, such as access to treatment and preventive medicine like naloxone, should be more effectively allocated,” Powell said.   

 

Support for the study was provided by the National Institute on Drug Abuse of the National Institutes of Health under award number 2P50DA046351-06A1 and the federal Centers for Disease Control and Prevention. The content in this news release is solely the responsibility of the authors and does not necessarily represent the official views of these federal agencies.

 

RAND Health Care promotes healthier societies by improving health care systems in the United States and other countries.

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JOURNAL

JAMA Health Forum

DOI

10.1001/jamahealthforum.2023.3274 

METHOD OF RESEARCH

Data/statistical analysis

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Educational Attainment and US Drug Overdose Deaths

ARTICLE PUBLICATION DATE

6-Oct-2023