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  • Can flashing lights stall Alzheimer’s? What the science shows

    Can flashing lights stall Alzheimer’s? What the science shows

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    Every day around mid-morning, Joan retreats into the bedroom of her central Massachusetts home. She lowers the window blinds, settles into her favourite armchair and puts on a special headset.

    For an hour, she surrenders to an immersive audiovisual experience of rhythmic clicking and flashing lights — tuned to repeat 40 times a second. Designed to synchronize particular electrical patterns called gamma waves in her brain, the sound-and-light show aims to combat the effects of dementia. “It’s relaxing, in a way,” says Joan, 78, who was diagnosed with early-stage Alzheimer’s disease two years ago. “I just kind of sit there.”

    After a year of this routine, scans taken in mid-June showed that Joan’s brain volume had remained stable. Memory tests found that her cognitive decline had stopped as well.

    Anecdotes such as Joan’s might seem hard to believe — and neuroscientist Li-Huei Tsai is no stranger to such scepticism. She and her colleagues at the Massachusetts Institute of Technology (MIT) in Cambridge first reported1 that flickering lights had beneficial effects on mice with Alzheimer’s-like conditions in 2016.

    Many researchers dismissed the results. “A lot of people just said, ‘This is too good to be true. This cannot be real,’” Tsai says. To prove her critics wrong, she realized she needed human data. So, Tsai — along with her MIT collaborator, synthetic neurobiologist Ed Boyden — co-founded a company called Cognito Therapeutics (also based in Cambridge). Within two years, they initiated clinical trials, and have since tested the technology on hundreds of individuals.

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    So far, the results have provided encouraging evidence of neuroprotection, with none of the serious side effects, such as brain swelling or bleeding, that often accompany the antibody drugs currently available or nearing regulatory approval for Alzheimer’s disease. “Everything is going in the right direction,” says Allan Levey, a neurologist at Emory University School of Medicine in Atlanta, Georgia, and an adviser to Cognito.

    Nevertheless, Levey has worked in the field for long enough to know that the vast majority of promising therapies for Alzheimer’s eventually end up in the dustbin of drug-development history, with more than 98% of all mid- to late-stage clinical trials ending in failure. And, although research from the MIT team and others continues to build a solid scientific foundation for this unconventional strategy, some groups have not managed to replicate their findings in mice.

    Now, all eyes are trained on a large, randomized trial involving more than 600 participants, including Joan. “I feel optimistic, but I also like to be cautious,” says Fiza Singh, a psychiatrist at the University of California, San Diego. “When you have a convergence of data like that, it says to me that there is some signal — something is going on.”

    Many, however, are not waiting for further validation. A cottage industry has already sprung up around devices marketed as ‘wellness’ products that put flashing lights and clicking sounds into desk lamps or smartphone apps, all claiming to improve brain health. This has sparked concern among some researchers that the rush to market might be getting ahead of the science, which could harm consumers.

    Yet, as the buzz surrounding this treatment grows, so does the pressure to separate hype from reality. The challenge for scientists is to confirm whether the approach offers more than just flickers of hope.

    Guided by gamma

    Alzheimer’s disease is characterized mainly by the accumulation of amyloid-β plaques and tau tangles in the brain. These protein structures are thought to interfere with neuronal communication and result in cell death. However, in the early 1990s, neuroscientist Rodolfo Llinás and his colleagues at New York University (NYU) Medical Center noticed another intriguing hallmark of the disease.

    While studying the magnetic fields produced by neuronal activity, they discovered a deficiency in some of the brain’s fastest-firing waves — specifically, those in the gamma frequency band, which oscillate at around 40 hertz. In individuals with Alzheimer’s disease, these gamma waves, which are crucial for processes such as attention and memory, were weaker than those of cognitively healthy individuals2.

    An experimental Cognito headset designed to combat Alzheimers disease.

    Cognito’s prototype device is in testing.Credit: David L. Ryan/The Boston Globe via Getty

    Over the years, other groups have made similar, corroborating observations. However, it was not until 2016, through the work of Tsai and Boyden, that a viable strategy emerged to address — and reverse — this gamma deficiency.

    The MIT researchers initially induced gamma waves in mouse brains using a complex technique that involved genetically modifying neurons and then implanting optical fibres through the skull1. They then developed less invasive methods, such as simple strip lights, mini sound systems or vibrating subwoofers near the animals’ cages.

    The rhythmic cues engage the brain through what Ralph Kern, Cognito’s chief medical officer, describes as “sensory on-ramps” — areas in the cortex responsible for processing sensory information. From there, the gamma signal spreads to deeper brain regions, such as the hypothalamus, that play key parts in memory and cognition.

    With repeated exposure comes brain ‘entrainment’: the firing patterns of neurons start to align with the rhythm of the stimulus. Synapses strengthen. Inflammation subsides. And, as the MIT team reported3 in February, 40-hertz stimulation also activates a neural-cleansing mechanism in mice, in which cerebrospinal fluid enters the brain, collects molecular debris and exits through specialized waste-removal channels. An independent team in China and Portugal has since replicated this finding4, and researchers at Boston University in Massachusetts have shown that the same process is activated by visual flickers in humans, as well5.

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    “There is a constellation of health-promoting effects,” Boyden says, and the results were consistent across several mouse models of Alzheimer’s. “That got me really excited about the translational possibilities,” he says.

    Among all the documented effects of the treatment, “it’s not entirely clear which ones are crucial for therapeutic efficacy”, says neurobiologist Annabelle Singer, a former postdoctoral fellow in Boyden’s lab who contributed to many of the early studies and continues to investigate the phenomenon at the Georgia Institute of Technology in Atlanta. But Singer, a Cognito adviser, is confident about the overall impact. “We have widespread modulation of human circuits, including in cognitive regions,” she says. “And these circuits kind of kick into high gear in response to 40-hertz stimulation.”

    On the same wavelength

    The potential benefits are not limited to Alzheimer’s disease. Researchers have found positive effects of sensory stimulation in mouse models of autism spectrum disorder, stroke, multiple sclerosis and chemotherapy-related cognitive impairment. In humans, there is early evidence of favourable outcomes for children with insomnia and adults with treatment-resistant epilepsy (see, for example, ref. 6), with trials now ongoing for people with depression, Parkinson’s disease and head trauma.

    Yet, despite the many mechanistic papers published by the MIT team and other scientists, not everyone is convinced that the therapy does what it says on the tin. Last year, two independent research groups — one led by neuroscientist György Buzsáki at NYU7, the other by neuroscientist Ted Weita Lai at China Medical University in Taichung, Taiwan8 — described their own investigations of flickering light therapy in mouse models of Alzheimer’s disease. Neither team found any reduction in amyloid-β levels.

    Methodological differences between these studies and the original MIT report might explain the conflicting results, proponents of the technique contend. And, although the most outspoken champions of 40-hertz therapy have financial stakes in the approach, they point to confirmatory studies published by independent groups without industry ties as validation of the science (see, for example, ref. 9). Nevertheless, both Buzsáki and Lai have urged the scientific community to exercise caution when it comes to interpreting mouse findings and extrapolating them to human therapeutic strategies.

    A woman uses a smartphone while sat next to an EVY Light.

    The EVY light from OptoCeutics hides it’s ‘flicker’ with pulses that alternate at different wavelengths.Credit: OptoCeutics

    More difficult to argue with might be the encouraging early clinical-trial data, says Sheng-Tau Hou, a neurobiologist at the Southern University of Science and Technology in Shenzhen, China. “Despite the fact that we don’t understand the molecular nitty-gritty of the mechanisms, the impact is quite obvious now,” he says.

    Academic studies10 by the teams at MIT and Emory, along with industry-sponsored trials by Cognito researchers, have collectively found that 1–6 months of 40-hertz stimulation with both light and sound, delivered at home for an hour a day, can boost cognition, preserve brain volume, improve sleep quality, enhance the ability to do everyday tasks and induce favourable changes in brain immunity.

    In one of the longest studies of its kind, Diane Chan, a neurologist at Massachusetts General Hospital in Boston and a postdoc in Tsai’s lab, is monitoring a handful of people with mild Alzheimer’s disease who have undergone daily 40-hertz treatment for 30 months and counting. Participants engage with the therapy through an easel-mounted light panel and soundbar system, with a tablet positioned in the centre so that users can entertain themselves with videos during each session.

    Typically, individuals with early-stage Alzheimer’s disease perform progressively worse on standard neuropsychological tests, losing a few points every year. But in Chan’s study, participants’ test scores have remained stable. Brain volumes have shown no signs of shrinking and levels of a disease-associated protein in the blood have even trended downwards. “These patients have conquered the test of time,” says Chan, who presented the findings at an international conference on neurodegenerative diseases in March.

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    At the same conference, Cognito reported similar benefits in both brain structure and cognitive function during 18 months of treatment with the company’s wearable technology — and some people have grown so attached to the daily routine of the sensory therapy that they have refused to return the device at the end of these studies, even though they are supposed to.

    “Far be it from me to take this away from them,” says trial investigator Paul Solomon, a neuropsychologist who directs the Boston Center for Memory in Newton, Massachusetts, where Joan receives her treatment.

    Roaring forty

    For now, Cognito’s platform is accessible solely through clinical trials. However, some competing developers have already started marketing similar devices as holistic health aids, arguing that the technology is safe and that individuals can experience its potential cognitive benefits without the need for formal regulatory approval.

    There are mobile-phone apps and websites that will make consumers’ devices flash and buzz at 40-hertz intervals. There are clicking-sound players, flickering light bulbs and stroboscopic desk lamps available for purchase online, ranging in price from US$50 to $274. And then there are more high-tech options, such as the ‘EVY Light’ from OptoCeutics, an academic spin-off firm with headquarters in Copenhagen and Berkeley, California. This shoebox-sized device delivers an ‘invisible spectral flicker’ — a white light created by two sets of light-emitting diodes, each emitting at different wavelengths and pulsing at 40 hertz but offset from one another.

    The company’s founders have published evidence suggesting that the brain synchronizes its activity accordingly, even though the light appears steady11. The firm is now sponsoring a 62-person trial designed to test whether the device can help individuals with mild-to-moderate Alzheimer’s disease. However, with trial results and regulatory approvals potentially years away, OptoCeutics has elected to offer its light box to the public ahead of regulatory clearance. For $1,999, anyone can now have an EVY Light in their home.

    “We want to be able to see how it can impact people now — today,” says co-founder and chief executive Mai Nguyen. “For us, the benefits outweigh the risks.”

    Other 40-hertz technologies in development include a $1,799 headset by Vielight in Toronto, Canada, that administers near-infrared light through a series of strategically placed light-emitting diodes on the scalp, plus one clipped to a nostril and pointed up the nose. Pilot trials that included individuals with dementia have shown early signs of clinical potential.

    Electrical-stimulation technologies can similarly provide targeted neuromodulation to specific brain areas with deficient gamma-wave activity. And in contrast to audiovisual approaches that administer 40-hertz stimuli — which remain inaccessible to people with hearing impairments, vision problems or other sensory-processing challenges — electrical stimulation should be broadly applicable, notes Barbara Borroni, a neurologist at the University of Brescia in Italy.

    Several research groups are even combining 40-hertz stimulation with music therapy. In Japan, for example, a music technology company called VIE is integrating 40-hertz frequencies into ethereal music compositions designed to make the auditory stimuli more pleasing on the ear.

    And at Northeastern University in Boston, music neuroscientist Psyche Loui and her colleagues are trialling a basketball-hoop-shaped device — developed by Oscillo Biosciences in Farmington, Connecticut, and nicknamed The Stargate — that synchronizes light with music, adding a rhythmic visual component tied to the beat of any song, while emitting a gentle flicker to promote brain activity in the gamma-frequency range.

    The music, Loui says, makes the medicine go down easier: “People love the music. They tolerate the lights.”

    A light touch

    The lack of regulation and quality control worries some researchers, including Chan, who has done internal tests on several commercial devices and found that they often fail to consistently deliver 40-hertz flickers. She also warns that side effects such as headaches occur in an appreciable fraction of users. Moreover, for those prone to seizures, the flashing lights could pose serious risks.

    “It’s really important to be a savvy consumer,” says Heather Snyder, head of medical and scientific operations at the Alzheimer’s Association, a non-profit research and advocacy organization in Chicago, Illinois.

    Another concern is the potential for false hope and financial exploitation, particularly if company websites make outsized promises with their marketing materials. “It is definitely a grey area,” says Timothy Daly, a bioethicist and dementia researcher at the Bordeaux Population Health Research Centre in France. “It’s a very slippery slope — especially with the vulnerability of people who are worried about having Alzheimer’s.”

    Conscious of those potential pitfalls, Cognito chief executive Christian Howell says the company has been “really purposeful about developing a very robust evidence base” for its device ahead of seeking marketing authorization, probably by early 2026. Alongside its year-long, randomized pivotal trial — which is on track to complete enrolment by the end of the year — Cognito is conducting an extension study, allowing participants such as Joan the opportunity to continue therapy for a further 12 months.

    Joan didn’t hesitate to opt in. She and Art, her husband of 51 years, credit the Cognito device with stabilizing her condition, which remains manageable and allows Joan to maintain a high degree of functional independence. “It’s a godsend,” says Art. “If this froze everything the way it is right now, we could go to our graves living like this.”

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  • Will the big neuroscience brainstorm pay off?

    Will the big neuroscience brainstorm pay off?

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    Unravelling how the billions of interacting neurons in the human brain conjure consciousness is one of the greatest challenges in twenty-first-century science. Over the past decade, large, well-funded initiatives, including in the United States, Europe and China, have been launched to unlock the mysteries of cognitive function — mental processes such as memory, language, perception and problem-solving — by coming at it from all angles.

    For the millions of people around the world who will develop an incurable or treatment-resistant brain disorder this year, the need to better understand cognitive function and dysfunction is pressing, says Christopher Rozell, a computational neuroengineer at Georgia Institute of Technology in Atlanta. Rozell co-leads a multidisciplinary team that is developing technology-based therapies for depression, the leading cause of ill health and disability worldwide. “Globally, more than 300 million people will have a major depressive episode this year — and that’s just one neurological disorder subtype,” he says.

    Nature Index 2024 Neuroscience

    Rozell is exploring a therapy for treatment-resistant depression based on deep-brain stimulation, in which implanted electrodes electrically stimulate specific brain areas to provide long-term symptom relief. The work is funded by the US National Institutes of Health’s (NIH) Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a major project launched in 2013, which to date has invested more than US$4 billion across neuroscience research. The BRAIN Initiative’s strategy is to develop tools, and then use these advances to gain a deeper understanding of brain function. According to Rozell, the decade-long investment is beginning to pay off.

    In depression treatment, for example, doctors have always had to make subjective clinical judgements and trial-and-error therapy adjustments when trying to manage the condition. But, in 2023, Rozell and his collaborators used new brain-implant and big-data processing technologies to identify changes in brain activity that can indicate a patient’s current clinical state, enabling doctors to adjust treatment in response1. At the end of the six-month trial, 90% of patients showed significant improvement and 70% were in remission or no longer depressed. BRAIN Initiative funding was key. “We work with clinicians and engineers in teams with a breadth of expertise that would have been very difficult to imagine under conventional funding programmes,” Rozell says. “Every week now, you see large, interdisciplinary teams making incredible advances that would not be happening if it were not for a programme like the BRAIN Initiative.”

    Likewise, proponents of the Human Brain Project (HBP), one of the largest research endeavours ever funded by the European Union (EU), which spent €600 million (US$668 million) over ten years before its completion in 2023, point to several advances. New brain-implant technologies that could restore partial vision in certain forms of blindness and brain-like ‘neuromorphic’ computer chips for more sophisticated artificial intelligence (AI) are important outcomes.

    But concerns remain that core questions in neuroscience have not been addressed by big projects. It’s not clear how cognitive function emerges from patterns of brain activity, for instance, let alone how these processes go awry caused by disease.

    And although big-neuroscience funding has increased in China over the past few years, it has been cut significantly in the EU and the United States, threatening the trajectory of brain science advancement.

    Uncharted territory

    If understanding human brain function is the ‘moonshot’ of neuroscience, we’ll never make it without the right maps, says Rozell. Creating brain atlases, each focused on different structural features, has been a key aim. In late 2023, the BRAIN Initiative’s Cell Census Network (BICCN), a multi-centre effort led by the Allen Institute for Brain Science in Seattle, Washington, produced the most detailed map yet of the cells that make up the human brain. Using single-cell genome sequencing — a technique that allows all or part of an individual cell’s genome to be sequenced — the team identified more than 3,000 different cell types in the human brain, many previously undescribed.

    BICCN researchers also produced the first complete cellular atlas of a mammalian brain, pinpointing the location and identity of each of the more than 32 million cells in a mouse brain2. When the team launched the project 10 years ago, it was unclear whether this was even feasible, says Allen Institute director, Hongkui Zeng, who led the work. But the rapid development and scaling-up of single-cell genomic technology has revolutionized the field.

    “Previously, the brain was just an unknown number of faceless cells,” says Zeng. “Now, we have the molecular identities for specific cells in specific brain regions, and we can start to label each cell type and see what they do.”

    Microglia intertwined with tiny blood vessels, called micro vessels, in the primary somatosensory cortex of a 4-day-old mouse. Genetic labelling techniques and 3D.

    Immune cells in a mouse brain, intertwined with tiny blood vessels, captured for a BRAIN-funded project.Credit: Josephine Liwang, Yongsoo Kim lab/Penn State College of Medicine, PA

    BICCN’s open-access brain-cell atlases are an indispensable resource, says Sebastian Seung, a computer scientist and neuroscientist at Princeton University in New Jersey. “To go from mapping the brain as a bunch of regions, to mapping cell types, is a huge jump in precision,” he says. Brain-cell atlases are foundational data supporting Seung’s own research, which focuses on the wiring between brain cells, known as the connectome. Together with cell mapping, new tools in connectomics — including those developed in Seung’s lab with BRAIN funding, which use AI to automate brain-scan image processing — allow scientists to study the brain in ways they’ve never done before.

    A different approach was used to build the Human Brain Atlas, the most detailed 3D anatomical map of a human brain yet assembled3. A team led by Katrin Amunts, a neuroscientist at the Jülich Research Centre, a large-scale national facility in the Helmholtz Association of German Research Centres, took a postmortem brain and analysed it, slice by slice, to build the atlas not from the cells up, but from a whole brain down. The Human Brain Atlas forms a core part of EBRAINS, an open-access digital platform that combines tools, services and data generated by the HBP, which has been used by more 10,000 people worldwide.

    The platform’s ‘virtual brain’ tool is being used to create personalized patient brain models to guide clinical decision-making in epilepsy, multiple sclerosis, depression and Parkinson’s, and its brain atlases and data are being accessed by researchers in neuroimaging, neurology, AI and basic science. In January, the EBRAINS project won a further €38 million from the European Commission to fund its continued development.

    There is an argument that although BRAIN and the HBP did not specifically focus on conceptual questions in neuroscience, the foundational resources that they have provided can help to fill major knowledge gaps that will benefit those working in both basic and applied neuroscience areas. Seung says this is why the BRAIN Initiative’s strategy of prioritizing neuroscience tool development was the right approach. “So much of the study of neuroscience has been limited by the scarcity of data,” he says. “The NIH would normally not necessarily fund technology development, but sometimes to get to important science, we need a technological revolution.”

    New model

    Still in its early phases, China’s big neuroscience project can benefit from lessons learned by its international counterparts. Conceived in 2013 — closely following the launch of BRAIN and the HBP — the China Brain Project (CBP) began in 2021 with ten-year funding of 12 billion yuan (US$1.66 billion) to advance brain-disease studies and basic neuroscience, as well as brain-inspired technologies and brain–computer interfaces. The project involves more than 500 laboratories across the country, and aims to build on China’s research strengths, including in connectomics and non-human primate animal models, a valuable, but contentious, aspect of neuroscience. “You cannot do invasive experiments in the human brain to understand what’s going on, so animal models are very important,” says Zeng.

    The protocols and standards for non-human primate research in China are based on those set by the NIH, but the work is easier to conduct because animal-rights groups don’t protest against animal use in research like they do in the United States, says Muming Poo, scientific director of the Institute of Neuroscience at the Chinese Academy of Sciences in Shanghai, who has led the CBP organizing committee since 2020. “There is a great need in the community for using non-human primate disease models because mouse models for brain disease, especially psychiatric disease, are just not working,” says Poo. He notes the slow global pace of drug development for brain disease, which is mostly based on rodent models, and says non-human primates, as our closest living relatives, should offer better models of the human brain.

    Poo’s group is developing a toolbox of genetic-engineering techniques to produce non-human primate models of disease that they hope can be used in drug testing. In late 2023, they reported the first live-born monkey chimaera4, created by taking stem cells from one macaque embryo and adding them to another. The work is a key step towards creating transgenic non-human primate models of human brain diseases, akin to way that transgenic rodent models of disease are currently made.

    Another strength that the CBP hopes to build on is China’s vast population, from which researchers can draw on extensive patient cohorts. According to Jialin Zheng, dean of the Tongji University School of Medicine in Shanghai, autism spectrum disorder in children, depression in adults and Alzheimer’s disease in ageing populations are the priority conditions addressed by CBP research.

    In parts of the CBP that are related to brain-inspired technology, such as AI and brain–computer interfaces, there is strong competition between institutions in China and abroad, says Poo. But in basic neuroscience and brain medicine, the CBP was specifically designed to complement work conducted by other countries. “We made a strong point of taking the directions that are deficient in the United States and Europe,” such as non-human primate models and large-cohort studies, says Poo. Some of the first internationally collaborative research conducted within the project are now close to publication, he adds. “I think it’s like the global-warming problem — brain disease is an urgent problem shared by all of society, and we should solve it together.”

    In many ways, the approaches and priorities of the big-brain projects in the United States, Europe and China complement each other to make the most of international resources and talent. In the United States, for instance, the BRAIN Initiative pooled resources to push technology development, whereas the HBP’s strategy focused on coordinating multidisciplinary research, such as bringing neuroscientists together with computer scientists to develop new treatments. China’s strategy is to use its unique strengths to fill important gaps and expand on them through international collaboration.

    There are challenges ahead if researchers want to build on the outputs of the three initiatives. For example, Zheng says it’s going to require coordination between governments to decide how genetic information and biological samples can safely be shared between countries. “Different countries have different regulation in terms of data. How can it be shared more openly? We are dealing with the same diseases, so, how can we work together to address these challenges?”

    In addition to restrictions on data sharing, coordination between different data centres is a major issue, says Poo. “It has been difficult to set up a generally agreed, smooth way of data-sharing among many big projects, because each big project has its own data centre,” he says. “We are in international discussions about the data problem, but there is no solution yet.”

    There are also concerns about whether long-standing questions around cognitive function can be answered by the kinds of projects being funded by big brain programmes. On the one hand, finding answers will require parallel studies of brain activity at the molecular, anatomical and physiological levels — something that large-scale initiatives are designed to facilitate, says Zeng.

    Bar chart showing country contributions to the bilateral collaboration score of the leading five collaborations in neuroscience in the Nature Index for 2019–23.

    Source: Nature Index

    But knowing how to piece this information together to explain cognitive function will require new ideas and hypotheses at a foundational level that none of the big neuroscience projects has yet produced, says Yves Frégnac, emeritus research director in cognitive science at the University of Paris-Saclay in France. “New concepts are not evolving at the same pace as technologies,” he says. “Reading out signs of cognitive activity is very different from understanding the brain.”

    For China, the CBP has brought a much-needed injection of cash to a field that has struggled to find funding in the past. Poo says the initiative, which so far seems to be on track to meet its decade-long funding promise, will not only advance neuroscience in highly applied areas, but also in fundamental research. “In other countries, there are avenues of support for basic research in brain science, through organizations such as the US NIH or National Science Foundation — but not in China,” he says.

    As the CBP builds momentum, researchers in Europe are trying to regain their footing, a year after the end of the HBP. Raising just over half of the expected €1 billion in funding from the EU and its member states, the HBP feels to many scientists like an opportunity not quite fulfilled, despite the progress made. “This money was needed in the field of brain sciences,” says Frégnac, who wrote an opinion piece on how the initiative could have been done better5. “People talk about €1 billion, US$4 billion, but if you compare it to initiatives in physics, this is peanuts.” NASA’s James Webb Space Telescope, for example, cost $10 billion, and the $1.5 billion annual budget of the European particle-physics laboratory, CERN, dwarfs the HBP’s entire ten-year funding. “If we want to be serious about the brain, we need to put more money in,” says Frégnac, who adds that the possibility of a well-funded follow-up to the HBP looks remote.

    The future of BRAIN Initiative-supported research is also unclear. In 2024, as the ten-year pot of funds set aside in 2016 entered its ramp-down phase, a budget cap across all federal spending constrained the US Congress from making up the shortfall. The result was a 40% cut to BRAIN Initiative funding, compared with 2023. Researchers such as Rozell, whose work on treating depression is directly threatened by the cuts, are worried. “We’ve made enormous progress, but this work is not finished — it is not an approved therapy,” says Rozell. With the global economic cost of mental disorders estimated at US$5 trillion, the need for investment is clear, he adds. “To have spent a decade of money, time and expertise to reach a place where we’re starting to see the returns, and then have the threat of these programmes being taken away, it’s enormously concerning.”

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  • United States sets the pace for implantable brain–computer interfaces

    United States sets the pace for implantable brain–computer interfaces

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    For seven years, British neuroscientist Luke Bashford trained as a postdoc in the United States, working on brain–computer interfaces (BCIs) — systems that directly link brain activity to external devices. By recording and decoding electrical signals from the brain to generate computer commands, BCIs allow people with limited movement to use their thoughts to control technologies such as smartphones, computers, wheelchairs and robotic arms. Unlike non-invasive BCIs — wearable devices such as caps or headbands that attach electrodes to the outside of the head — the implantable BCIs that Bashford works on require surgery to place the electrodes on or inside the brain to access more reliable and information-rich signals.

    A lot of academic research — and most commercial investment — is focused on implantable BCIs, because their potential to provide high-performance assistive interfaces is stronger than their non-invasive counterparts. But implanting electrodes directly in the brain comes with obvious risks, so implantable BCI trials are tightly controlled by regulators. The most advanced implantable BCIs in development remain in early-stage clinical trials, and no such system has been approved for clinical use anywhere in the world.

    Nature Index 2024 Neuroscience

    The United States took an early lead on regulating implantable BCI, which has made it an attractive place for researchers such as Bashford to work. Since the first volunteer received an implantable BCI in California in 2004, most of the roughly 60 long-term recipients have been based in the United States. All of the world’s most established implantable BCI companies are based there, too. The US Food and Drug Agency (FDA), which oversees all US implantable BCI trials, is now very familiar with the technology, says Bashford. “You make a query, and they come back with a very nice framework of ‘Here’s what’s got to be done and how and why’.”

    The dominance of the United States raises concerns about the potential for unequal access to implantable BCI technologies as they move from the laboratory to the clinic. When Bashford left his position at the University of California, Los Angeles, in 2023 to move to the University of Newcastle, in the United Kingdom, he realized how much work it would take to achieve his goal of running the country’s first clinical trials of implantable BCIs. When it comes to UK regulators, “there’s definitely an appetite for it”, he says. But the country’s inexperience with the technology makes getting approval for a clinical trial a lengthy process.

    Bashford co-founded a National Consortium for Neurotechnology Regulation (NCNR) in February with a group of UK-based researchers and companies to help address the problem. By forging greater connections between academics, clinicians, industry, regulators and policymakers, the NCNR aims to set guidelines for human neurotechnology trials, which it hopes will ultimately accelerate patient access to such devices on the UK’s National Health Service.

    Global private investment in BCIs and other neurotechnologies were worth an estimated US$7.3 billion in 2020 — a 22-fold increase from 2010. As research in this area becomes more widely distributed, national regulatory bodies are likely to play a key role in how trials progress and products develop, says Tim Denison, NCNR member and neurotechnology engineer at the University of Oxford, in the UK.

    Global competition

    Ruten, a company that makes implantable BCIs, has headquarters in both the United States and Japan. As a result, co-founder Kazutaka Takahashi has first-hand experience of the regulatory differences between the two countries. Japan, he says, lacks the expertise needed to evaluate new devices through the country’s Pharmaceuticals and Medical Devices Agency. “They’re still trying to come up with standards to be enforced in clinical trials,” he says. In the US, by contrast, the FDA has established protocols that it applies to initial feasibility trials of implantable BCIs. Ruten is working on implantable BCI-based therapies for paralysed people who have trouble swallowing. Almost certainly, any human trials of the device will be based in the United States, says Takahashi, following pathways set by the FDA.

    Likewise, several of Europe’s top emerging neurotechnology companies are developing their implantable products in the United States, taking FDA pathways towards clinical approval and the market. Carolina Aguilar, chief executive of INBRAIN Neuroelectronics, says that for the company’s implantable epilepsy monitor, which requires similar implantation procedures to BCIs, going to the United States first is an obvious move. The device is designed to pinpoint where a patient’s epileptic activity originates and so needs to be implanted for only a month. In the United States, this qualifies it for non-implant status, which requires only animal testing to get FDA approval for clinical use, says Aguilar. In Europe, the device is classified as a chronic implant, which requires human testing for approval by the European Union’s Medical Device Regulation (MDR) agency.

    Utah Array with hand, and close-up of the Utah Array, a microelectrode array consisting of 100 electrodes between 0.5 and 1.5 mm in length.

    The Utah Array, an implantable BCI developed by Blackrock Neurotech in Utah, can stimulate individual neurons or groups of neurons.Credit: Blackrock Neurotech

    The relative ease with which researchers and companies can develop their products in the United States is a problem, says Takahashi, because early recipients of implantable BCIs should be more globally representative. He also worries about US health-care systems and insurers having an outsized influence on the industry, meaning only products that align with what they are willing to cover would make it to market. “If there’s only one country doing this, that’s bad,” says Takahashi.

    US dominance in the area has a lot to do with the large investments that have come from government and venture-capital firms over the past 25 years, says Matt Angle, chief executive of Paradromics, a BCI company based in Austin, Texas. Today, the combination of an established regulatory landscape and the world’s most valuable medical-device market — worth an estimated US$180 billion last year — appeals to start-ups from all over the world. “The regulatory pathway for these kinds of devices is better defined and the wheels are better greased in the US than in Europe,” Angle says.

    In addition to initiatives launched by the FDA in recent years, such as Early Feasibility Studies, which introduced exemptions for small exploratory studies in 2013, and its Breakthrough Devices Program, launched in 2016 to accelerate communication between developers and FDA officials, Angle also thinks a surge of new recruits at the agency has been a game-changer. “As recently as 2010, I would say the regulatory process was seen as an adversarial process, like a courtroom proceeding,” he says. “In 2024, it’s seen as a collaborative process. If you hadn’t had an influx of a new generation of people at the FDA, none of this would have worked.”

    Vikash Gilja, chief scientific officer at Paradromics, adds that many newer recruits at the FDA who deal with neurotechnology were once researchers with direct experience in the field. “They can act as really impactful translators between the medical device innovators and the FDA,” says Gilja. He points to the Implantable BCI Collaborative Community, established by the FDA this year to bring together government regulators, companies, academics and patient advocates, as an important step in advancing implantable BCI-related policies.

    Patient benefits

    Whether the United States will remain the favoured route for international companies is uncertain. INBRAIN is seeking approval to run human trials of its epilepsy monitor in both the United States and the United Kingdom, the latter through its Medicines and Healthcare products Regulatory Agency (MHRA). Although the MHRA required a “huge amount of work” as part of its application process, the organization has been “super-supportive”, says Aguilar. She is also optimistic about how the EU’s MDR is updating its regulatory pathways and says INBRAIN intends to trial a speech-decoding BCI — an implantable device that records speech-related neural activity in patients — in Europe. “We’re talking to many investigators who want to make it happen from the European perspective,” says Aguilar. “Europe is waking up, because they have to — because they have seen the advantages of the FDA.”

    Patient benefit is another major factor in how countries are choosing to regulate implantable BCIs. Denison says the globally accepted standards for keeping research participants safe means that no country’s approach is more dangerous than another’s. But regulators can differ in how they view the benefits of exploratory science to individual patients versus the potential clinical benefit for all future users. “Each country has a slightly different perspective on what they think is acceptable, in terms of the trade-offs,” he says.

    Having moved from the United States to the United Kingdom, Bashford is experiencing this tension. In addition to not having the kinds of exploratory study programmes that the FDA runs, the UK’s apparent reluctance to have volunteers participate in early-stage medical-device research speaks to cultural differences between British and US regulators, says Bashford. In the United States, there is a broader view of patient benefit, where participating in research “can just improve someone’s outlook and give them a sense of purpose, where they might otherwise just be left in palliative care”, he says. Denison adds that compared with the FDA, the MHRA asks much earlier in the process how a device will help future users and how that can be assessed from the outset. “I like the MHRA approach because it really keeps me very focused on the translation stuff,” he says.

    As one company draws closer to its goal of taking an implantable BCI to market, questions about patient benefit will need to be addressed. Synchron, a New York-based company founded on technology originally developed in Australia, has produced a device that allows recipients to control a smartphone using their thoughts. The company is in discussions with the FDA about what a large human trial must show in order to gain approval to go to market. “This is one of the biggest questions right now: how do we think about clinical endpoints in a pivotal study?” says Angle.

    For example, should an implantable BCI be assessed on how efficiently signals are transferred from a user’s brain to a computer interface, or by how much it subjectively improves the user’s wellbeing? Or, perhaps more likely, will it be measured by how well the computer or other external device is controlled? The bar must be set just right, says Angle, to ensure that implantable BCIs can leave the lab and impart meaningful benefits to patients.

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  • Neurotechnology race ramps up, but fundamental questions remain

    Neurotechnology race ramps up, but fundamental questions remain

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    Neuroscience has undergone remarkable progress. Researchers can now study specific areas of the brain with unprecedented detail thanks to cutting-edge imaging and genetic tools. Advanced modelling techniques, driven by artificial intelligence, have facilitated whole-brain mapping to track cognitive development over a lifetime. But fundamental questions about how the brain’s core functions emerge from cellular and molecular processes remain unanswered, limiting treatment options for neurological conditions.

    Nature Index 2024 Neuroscience

    Countries are pooling their resources and expertise to up the ante. Large-scale neuroscience projects are making use of unique strengths, including China’s vast population data and the United States’ med-tech industry. But researchers are calling for more funding, pointing out that budgets in other areas, such as the European particle-physics laboratory, CERN, and NASA’s James Webb Space Telescope, dwarf those of the biggest neuroscience initiatives.

    Raising more money is not the only challenge. Over the past decade, tens of billions have been spent on finding effective treatments for Alzheimer’s disease, with limited patient benefit. A greater understanding of how brain conditions relate to other organs and biological systems, and vice versa, is needed. Studies investigating long COVID, for instance, could have major implications for autoimmune diseases.

    In the coming years, technological advances such as implantable brain–computer interfaces (BCIs) are expected to fundamentally change how neuroscience is researched, and how neurological disorders are treated and diagnosed. The United States, the leading country in Nature Index neuroscience output by some margin, is setting the pace for BCI regulation, and other nations will need to find their footing fast.

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  • CRISPR helps brain stem cells regain youth in mice

    CRISPR helps brain stem cells regain youth in mice

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    Fluorescent light micrograph of groups of neural stem cells shown in pink and yellow colours on a black background

    Brain stem cells (artificially coloured) give rise to neurons in young individuals, but that ability fades with advancing age.Credit: Riccardo Cassiani-Ingoni/Science Photo Library

    Clues to keeping the brain’s regenerative cells youthful and energetic into old age have emerged by applying CRISPR gene editing to mice1.

    Age impedes the ability of the brain’s stem cells to churn out new cells, but the study’s authors found that reducing the activity of a particular gene rejuvenated these stem cells, allowing them to proliferate and provide the brain with a supply of fresh neurons.

    That gene regulates stem cells’ consumption of glucose, a sugar that is key to cellular metabolism. The results in mice fit well with an emerging picture from studies of postmortem human brains. These efforts, too, have found that age affects metabolism in the brain, says Maura Boldrini, a neuroscientist and psychiatrist at Columbia University Irving Medical Center in New York City who was not involved in the latest research. “Probably their metabolism is less efficient than it used to be,” she says, adding that both the human results and the mouse study, published today in Nature, “open new avenues for potential therapeutics.”

    A youthful brain

    The role of neural stem cells in the adult human brain has been controversial. Boldrini and others have published evidence that new neurons are made in the hippocampus, a region of the brain that is important for learning and memory, at least until the age of 792. Her team is now looking to see whether production of new neurons is altered in people with Alzheimer’s disease or psychiatric illnesses. But some researchers have reported that they could not find evidence that adults make new neurons in the hippocampus. “This controversy is still continuing,” Boldrini says.

    Human brain cells implanted in rats prompt excitement — and concern

    In mice, the picture is clearer. Neural stem cells in a region of the brain called the subventricular zone can give rise to neurons and other types of cells. These young cells then migrate to the olfactory bulb, which controls the sense of smell. A steady supply of fresh neurons to the olfactory bulb makes sense in mice, because they rely heavily on smell to perceive changes in their environment, says Anne Brunet, a geneticist who studies ageing at Stanford University in California and who is an author of the new study.

    As mice age, however, those stem cells become less active. Brunet and her colleagues decided to find out why. The team used CRISPR-Cas9 genome editing to systematically disrupt 23,000 genes, and then tested the effect of each disrupted gene on neural stem cells that had been taken from young and old mice and grown in the laboratory.

    Neuronal boost

    The screen yielded 300 genes that might play a part in neural stem-cell ageing. The researchers further narrowed the pool by using CRISPR-Cas9 to disrupt some of these genes in cells in the subventricular zone of living young and old mice. The authors then checked the animals’ olfactory bulbs and identified a select group of key genes. Disruption of these genes boosted stem cells’ production of neurons in the old animals — but did not affect stem cells in young animals.

    Five ways the brain can age: 50,000 scans reveal possible patterns of damage

    One such gene, called Slc2a4, codes for a protein that imports glucose into cells. Disrupting it reduced cells’ glucose intake and increased their power to proliferate.

    That result meshes with previous studies that have found a link between sugar metabolism and ageing, says Saul Villeda, a neuroscientist at the University of California, San Francisco. For example, researchers recently reported that a diabetes drug can stave off age-related cognitive decline in monkeys. But the latest finding is particularly important, he says, because it points to a specific protein that has a key role and could be targeted in future studies.

    Even if the role of neural stem cells in adult humans is in question, the results provide crucial information for the design of cell therapies that might one day treat neurodegenerative conditions, Villeda says.

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  • Largest brain map ever reveals fruit fly’s neurons in exquisite detail

    Largest brain map ever reveals fruit fly’s neurons in exquisite detail

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    A fruit fly might not be the smartest organism, but scientists can still learn a lot from its brain. Researchers are hoping to do that now that they have a new map — the most complete for any organism so far — of the brain of a single fruit fly (Drosophila melanogaster). The wiring diagram, or ‘connectome’, includes nearly 140,000 neurons and captures more than 54.5 million synapses, which are the connections between nerve cells.

    “This is a huge deal,” says Clay Reid, a neurobiologist at the Allen Institute for Brain Science in Seattle, Washington, who was not involved in the project but has worked with one of the team members who was. “It’s something that the world has been anxiously waiting for, for a long time.”

    The map1 is described in a package of nine papers about the data published in Nature today. Its creators are part of a consortium known as FlyWire, co-led by neuroscientists Mala Murthy and Sebastian Seung at Princeton University in New Jersey.

    A long road

    Seung and Murthy say that they’ve been developing the FlyWire map for more than four years, using electron microscopy images of slices of the fly’s brain. The researchers and their colleagues stitched the data together to form a full map of the brain with the help of artificial-intelligence (AI) tools.

    But these tools aren’t perfect, and the wiring diagram needed to be checked for errors. The scientists spent a great deal of time manually proofreading the data — so much time that they invited volunteers to help. In all, the consortium members and the volunteers made more than 3 million manual edits, according to co-author Gregory Jefferis, a neuroscientist at the University of Cambridge, UK. (He notes that much of this work took place in 2020, when fly researchers were at loose ends and working from home during the COVID-19 pandemic.)

    An animation of the CT1 neuron in the fruit-fly brain. There are two of them; each one spans an entire eye and has more than 148,000 synapses. Credit: Amy Sterling, Murthy and Seung laboratories, Princeton University (ref. 1)

    But the work wasn’t finished: the map still had to be annotated, a process in which the researchers and volunteers labelled each neuron as a particular cell type. Jefferis compares the task to assessing satellite images: AI software might be trained to recognize lakes or roads in such images, but humans would have to check the results and name the specific lakes or roads themselves. All told, the researchers identified 8,453 types of neuron — much more than anyone had expected. Of these, 4,581 were newly discovered, which will create new research directions, Seung says. “Every one of those cell types is a question,” he adds.

    The team was surprised by some of the ways in which the various cells connect to one another, too. For instance, neurons that were thought to be involved in just one sensory wiring circuit, such as a visual pathway, tended to receive cues from multiple senses, including hearing and touch1. “It’s astounding how interconnected the brain is,” Murthy says.

    Exploring the map

    The FlyWire map data have been available for the past few years for researchers to explore. This has enabled scientists to learn more about the brain and about fruit flies — findings that are captured in some of the papers published in Nature today.

    Cubic millimetre of brain mapped in spectacular detail

    In one paper2, for example, researchers used the connectome to create a computer model of the entire fruit-fly brain, including all the connections between neurons. They tested it by activating neurons that they knew either sense sweet or bitter tastes. These neurons then launched a cascade of signals through the virtual fly’s brain, ultimately triggering motor neurons tied to the fly’s proboscis — the equivalent of the mammalian tongue. When the sweet circuit was activated, a signal for extending the proboscis was transmitted, as if the insect was preparing to feed; when the bitter circuit was activated, this signal was inhibited. To validate these findings, the team activated the same neurons in a real fruit fly. The researchers learnt that the simulation was more than 90% accurate at predicting which neurons would respond and therefore how the fly would behave.

    In another study3, researchers describe two wiring circuits that signal a fly to stop walking. One of these contains two neurons that are responsible for halting ‘walk’ signals sent from the brain when the fly wants to stop and feed. The other circuit includes neurons in the nerve cord, which receives and processes signals from the brain. These cells create resistance in the fly’s leg joints, allowing the insect to stop while it grooms itself.

    One limitation of the new connectome is that it was created from a single female fruit fly. Although fruit-fly brains are similar to each other, they are not identical. Until now, the most complete connectome for a fruit-fly brain was a map of a ‘hemibrain’ — a portion of a fly’s brain containing around 25,000 neurons. In one of the Nature papers out today4, Jefferis, Davi Bock, a neurobiologist at the University of Vermont in Burlington, and their colleagues compared the FlyWire brain with the hemibrain.

    Some of the differences were striking. The FlyWire fly had almost twice as many neurons in a brain structure called the mushroom body, which is involved in smell, compared with the fly used in the hemibrain-mapping project. Bock thinks the discrepancy could be because the hemibrain fly might have starved while it was still growing, which harmed its brain development.

    The FlyWire researchers say that much work remains to be done to fully understand the fruit-fly brain. For instance, the latest connectome shows only how neurons connect through chemical synapses, across which molecules called neurotransmitters send information. It doesn’t offer any information about electrical connectivity between neurons or about how neurons chemically communicate outside synapses. And Murthy hopes to eventually have a male fly connectome, too, which would allow researchers to study male-specific behaviours such as singing. “We’re not done, but it’s a big step,” Bock says.

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  • High-performers and specialists in neuroscience research

    High-performers and specialists in neuroscience research

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    Strong focus

    Among the top 25 countries for neuroscience output in the Nature Index, these ten have the highest proportion of neuroscience Share relative to their overall Share (neuroscience %). The United States, Germany, United Kingdom and Canada all rank within the top 10 overall for neuroscience; Norway and Portugal have the lowest overall ranks, at 22 and 23, respectively.

    On the up

    The Share of the fastest rising institutions in neuroscience for 2022–23 is shown over a five-year period. The University of Queensland in Australia is the only institution from outside China in the top five. The top-ranked institution in neuroscience overall, Harvard University in Cambridge, Massachusetts, was the sixth fastest riser, increasing its Share by 4.5% to reach 229.20 in 2023.

    Institution outputs

    Institutions with a special focus on neuroscience research are highlighted in this chart, which plots their neuroscience Share against their neuroscience %. Just over 10% of the top 200 institutions in neuroscience have more than 200 Share in the topic for the period 2019–23, and only 8.5% have more than 30% of their overall Share related to neuroscience.

    The Chinese Academy of Sciences in Beijing has a relatively low proportion of its Nature Index output focused on neuroscience research, but it has the 6th highest Share in the topic, at 378.76. Harvard University’s Share in neuroscience (996.17) dwarfs that of all other institutions. With 19.6% of its total Share in the Index related to neuroscience, this is a clear priority area. Neuroscience-related outputs represented 89.7% of the total Share of the Allen Institute in Seattle, Washington, for 2019–23. The institution is ranked 144th in the topic overall, with a Share of 53.15.

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  • A blood-borne biomarker for Alzheimer’s disease

    A blood-borne biomarker for Alzheimer’s disease

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  • 2021: Anti-amyloid antibodies take a bumpy road to the clinic

    2021: Anti-amyloid antibodies take a bumpy road to the clinic

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    Nature, Published online: 26 September 2024; doi:10.1038/d41586-024-02952-y

    The arrival of the first disease-modifying therapy for Alzheimer’s was significant, but it was not met with the joy that might have been expected.

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  • 1985: Disentangling tau pathology

    1985: Disentangling tau pathology

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    Nature, Published online: 26 September 2024; doi:10.1038/d41586-024-02883-8

    The protein tau is identified as the core component of neurofibrillary tangles — nearly 80 years after the structures were spotted in the brains of people with Alzheimer’s disease.

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