Category: Neurology

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Bacteria Invade Brain after Implanting Medical Devices

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Deep brain stimulation illustration. Credit: NIH

Brain implants hold immense promise for restoring function in patients with paralysis, epilepsy and other neurological disorders. But a team of researchers at Case Western Reserve University has discovered that bacteria can invade the brain after a medical device is implanted, contributing to inflammation and reducing the device’s long-term effectiveness. 

The groundbreaking research, recently published in Nature Communications, could improve the long-term success of brain implants now that a target has been identified to address.

“Understanding the role of bacteria in implant performance and brain health could revolutionize how these devices are designed and maintained,” said Jeff Capadona, Case Western Reserve’s vice provost for innovation, the Donnell Institute Professor of Biomedical Engineering and senior research career scientist at the Louis Stokes Cleveland VA Medical Center.

Capadona’s lab led the study, which examined the presence of bacterial DNA in the brains of mouse models implanted with microelectrodes.

To their surprise, researchers found bacteria linked to the gut inside the brain. The discovery suggests that a breach in what is known as “the blood-brain barrier,” caused by implanting the device, could allow microbes to enter.

“This is a paradigm-shifting finding,” said George Hoeferlin, the study’s lead author, who was a biomedical engineering graduate student at Case Western Reserve in Capadona’s lab. “For decades, the field has focused on the body’s immune response to these implants, but our research now shows that bacteria—some originating from the gut—are also playing a role in the inflammation surrounding these devices.”

In the study, mouse models treated with antibiotics had reduced bacterial contamination and the performance of the implanted devices improved—although prolonged antibiotic use proved detrimental.

The discovery’s implications go beyond device failure. Some of the bacteria found in the brain have been linked to neurological diseases, including Alzheimer’s, Parkinson’s and stroke.

“If we’re not identifying or addressing this consequence of implantation, we could be causing more harm than we’re fixing,” Capadona said. “This finding highlights the urgent need to develop a permanent strategy for preventing bacterial invasion from implanted devices, rather than just managing inflammation after the fact. The more we understand about this process, the better we can design implants that work safely and effectively.”

Capadona said his lab is now expanding the research to examine bacteria in other types of brain implants, such as ventricular shunts used to treat hydrocephalus, an abnormal buildup of fluid in the brain.

The team also examined the faecal matter of a human subject implanted with a brain device and found similar results.

“This finding stresses the importance of understanding how bacterial invasion may not just be a laboratory phenomenon, but a clinically relevant issue,” said Bolu Ajiboye, professor in biomedical engineering at the Case School of Engineering and School of Medicine and scientist at the Cleveland VA Medical Center. “Through our strong translational pipeline between CWRU and the VA, we are now investigating how this discovery can directly contribute to safer, more effective neural implant strategies for patients.”

Source: Case Western Reserve University

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The Pupil as a Window into the Sleeping Brain

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The eye of the sleeping subject was kept open with a special fixation device to record the pupil movements for several hours.  (Image: Neural Control of Movement Lab / ETH Zurich)

For the first time, researchers have been able to observe how the pupils react during sleep over a period of several hours. A look under the eyelids showed them that more happens in the brain during sleep than was previously assumed.

While eyes are typically closed in sleep, there is a flurry of activity taking place beneath the eyelids: a team of researchers, led by principal investigators Caroline Lustenberger, Sarah Meissner and Nicole Wenderoth from the Neural Control of Movement Lab at ETH Zurich, have observed that the size of the pupil fluctuates constantly during sleep. As they report in Nature Communications, sometimes it increases in size, sometimes it decreases; sometimes these changes occur within seconds, other times over the course of several minutes.

“These dynamics reflect the state of arousal, or the level of brain activation in regions that are responsible for sleep-wake regulation,” says Lustenberger. “These observations contradict the previous assumption that, essentially, the level of arousal during sleep is low.”

Instead, these fluctuations in pupil size show that even during sleep, the brain is constantly switching between a higher and lower level of activation. These new findings also confirm for humans what other research groups have recently discovered in studies on rodents, who also exhibit slow fluctuations in the activation level (known in the field as arousal).

New method for an old mystery

The regions of the brain which control the activation level are situated deep within the brainstem, making it previously difficult to directly measure these processes in humans during sleep. Existing methods are technically demanding and have not yet been established in this context. The ETH researchers’ study therefore relies on pupil measurements. Pupils are known to indicate the activation level when a person is awake. They can therefore be used as markers for the activity in regions situated deeper within the brain.

The ETH researchers developed a new method for examining the changes in people’s pupils while asleep: using a special adhesive technique and a transparent plaster, they were able to keep the eyes of the test subjects open for several hours.

“Our main concern was that the test subjects would be unable to sleep with their eyes open. But in a dark room, most people forget that their eyes are still open and they are able to sleep,” explains the study’s lead author, Manuel Carro Domínguez, who developed the technique.

Analysis of the data showed that pupil dynamics is related not just to the different stages of sleep, but also to specific patterns of brain activity, such as sleep spindles and pronounced deep sleep waves – brain waves that are important for memory consolidation and sleep stability. The researchers also discovered that the brain reacts to sounds with varying degrees of intensity, depending on the level of activation, which is reflected in the size of the pupil.

A central regulator of the activation level is a small region in the brainstem, known as the locus coeruleus. In animals, scientists have been able to show that this is important for the regulation of sleep stages and waking. The ETH researchers were unable to prove in this study whether the locus coeruleus is indeed directly responsible for pupil changes. “We are simply observing pupil changes that are related to the level of brain activation and heart activity,” Lustenberger explains.

In a follow-up study, the researchers will attempt to influence the activity of the locus coeruleus using medication, so that they can investigate how this affects pupil dynamics. They hope to discover whether this region of the brain is in fact responsible for controlling the pupils during sleep, and how changes in the level of activation affect sleep and its functions.

Using pupillary dynamics to diagnose illnesses

Understanding pupil dynamics during sleep could also provide important insights for the diagnosis and treatment of sleep disorders and other illnesses. The researchers therefore want to investigate whether pupil changes during sleep can provide indications of dysfunctions of the arousal system. These include disorders such as insomnia, post-traumatic stress disorder and possibly Alzheimer’s. “These are just hypotheses that we want to investigate in the future,” says Lustenberger.

Another goal is to make the technology usable outside of sleep laboratories, such as in hospitals where it could help to monitor waking in coma patients or to diagnose sleep disorders more accurately. The pupil as a window onto the brain could thus pave the way for new opportunities in sleep medicine and neuroscience.

Source: ETH Zurich

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New Intervention Boosts Diagnosis and Care of Brain Infection

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University of Liverpool researchers have worked with global partners to identify and successfully implement an intervention package that has significantly improved the diagnosis and management of brain infections in hospitals across Brazil, India, and Malawi.

The study, published in The Lancet, was coordinated by researchers at the University of Liverpool in collaboration with international partners and implemented across 13 hospitals.

The intervention included:

• A clinical algorithm which offered a flowchart of guidance for clinicians on how to manage the first crucial hours and days of suspected brain infections, including which tests (blood tests, lumbar puncture, brain scans) and treatments to administer.
• A lumbar puncture pack, providing clinicians with sample containers, equipment, and guidance to ensure proper cerebrospinal fluid collection and testing, addressing challenges like knowing how much fluid to take and which tests to request.
• A panel of laboratory tests to enable correct and timely testing for a wide range of pathogens, addressing gaps in availability and sequencing of tests, with the main goal of identifying the cause of infection.
• Training for clinicians and lab staff to enhance their knowledge and skills in diagnosing and managing brain infections, including proper use of the new intervention tools.

These measures led to significant improvements in diagnosing patients with suspected acute brain infections, such as encephalitis and meningitis. Both conditions cause significant mortality and morbidity, especially in low- and middle-income countries (LMICs), where diagnosis and management are hindered by delayed lumbar punctures, limited testing, and resource constraints. Improved diagnosis and optimal management are a focus for the World Health Organization (WHO) in tackling meningitis and reducing the burden of encephalitis.

As a result of the intervention package, the proportion of patients receiving a syndromic diagnosis (confirming they had a brain infection) increased from 77% to 86%, while the microbiological diagnosis rate (identifying the exact pathogen) rose from 22% to 30%. In addition to improving diagnosis, the intervention enhanced the performance of lumbar punctures, optimised initial treatment, and improved patients’ functional recovery after illness.

Lead author Dr Bhagteshwar Singh, Clinical Research Fellow, Clinical Infection, Microbiology & Immunology said: “Following patients and their cerebrospinal fluid (CSF) samples through the hospital system, we tailored our intervention to address key gaps in care. The results speak for themselves: better diagnosis, better management, and ultimately, better outcomes for patients. Unlike most studies, we embedded improvements into routine care, so the impact continues well beyond the study.”

Corresponding author Professor Tom Solomon, Chair of Neurological Science at the University of Liverpool and Director of The Pandemic Institute, added: “We increased microbiological diagnoses by one-third across very diverse countries, which has profound implications for treatment and public health globally. As we scale this up in more hospitals and feed it into national and international policy, including WHO’s work on defeating meningitis and controlling encephalitis, the potential impact is enormous.”

The intervention was co-designed by clinicians, lab specialists, hospital administrators, researchers, and policymakers in each country, ensuring it was feasible and sustainable. Professor Priscilla Rupali, lead researcher from Christian Medical College, Vellore, India, also commented: “The co-design process ensured that the intervention would work within local healthcare settings and could be sustained beyond the study. We are already incorporating the findings into India’s national Brain Infection Guidelines, ensuring long-term benefits for patient care.”

The intervention package is freely available as a toolkit for adaptation in different settings: https://braininfectionsglobal.tghn.org/resources/brain-infections-global-tools/.

Source: University of Liverpool

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Innovative In Vivo Imaging Offers New Treatment and Hope for Chronic TMJ Pain

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Photo by engin akyurt on Unsplash

Facial pain and discomfort related to the temporomandibular joint (TMJ) is the second-leading musculoskeletal disorder, after chronic back pain, affecting 8% to 12% of Americans. Current treatments for TMJ disorders are not always sufficient, leading researchers to further explore the vast nerve and vessel network connected to this joint – the second largest in the human body.

In a study published in December 2024 in the journal Pain, a research team led by Yu Shin Kim, PhD, associate professor at the The University of Health Science Center at San Antonio (UT Health San Antonio), observed for the first time the simultaneous activity of more than 3000 trigeminal ganglion (TG) neurons, which are cells clustered at the base of the brain that transmit information about sensations to the face, mouth and head.

“With our novel imaging technique and tools, we can see each individual neuron’s activity, pattern and dynamics as well as 3000 neuronal populational ensemble, network pattern and activities in real time while we are giving different stimuli,” said Kim.

When the TMJ is injured or misaligned, it sends out signals to increase inflammation to protect the joint. However, this signaling can lead to long-term inflammation of the joint and other parts of the highly connected nerve network, leading to chronic pain and discomfort. About 80% to 90% of TMJ disorders occur in women, and most cases develop between the ages of 15–50.

Activation at the cellular level

Previous animal studies observed behavioural changes related to pain, but this study was the first to record reactions at the cellular level and their activities. To see which portions of the nerve pathway respond to various types of pain, Kim’s team created different models of pain and observed the neuronal activity with high-resolution confocal imaging, which uses a high-resolution camera and scanning system to observe neurons in action.

The team discovered that during TMJ activation, more than 100 neurons spontaneously fire at the same time. Activation was observed in localised areas of the TMJ innervated to TG neurons. The localisation of this activation highlights the specific neural pathways involved in TMJ pain, offering deeper insight into how pain develops and spreads to nearby areas. The study is also the first to quantify the degree of TG neuronal sensitivity and network activities.

Potential link to migraine, headaches

Chronic TMJ pain in humans is often linked to other pain comorbidity such as migraines and other headaches. Kim’s team observed this crossover in the in vivo model as inflammation of TG neurons spread to the nearby orofacial areas. Kim’s previous research demonstrated how stress-related migraine pain originates from a certain molecule, begins in the dura and innervates throughout the dura and TG neurons. This current study and novel imaging technique further reveals potential connections between the TMJ, migraines and other headaches.

Potential of CGRP treatment

Calcitonin gene-related peptides (CGRP), molecules involved in transmitting pain signals and regulating inflammation, are often found in higher amounts in synovial fluid of TMJ disorder patients. Synovial fluid surrounds joints in the body, helping to reduce friction between bones and cartilage. Higher amounts of CGRP are often associated with increased pain and inflammation. Kim hypothesised in this study that a reduction in CGRP may reduce TMJ disorder symptoms. He found that CGRP antagonist added to the synovial fluid relieved both TMJ pain and hypersensitivity of TG neurons.

Currently, there are no Federal Drug Administration-approved medications for TMJ disorders other than non-steroidal anti-inflammatory drugs (NSAIDS). While some CGRP antagonist medications are FDA-approved for treating migraines, this study suggests these drugs may also provide relief for TMJ disorders. Confirmation of the positive effect of the drug on TMJ pain is a major leap forward in understanding how CGRP affect TMJ pain, said Kim.

“This imaging technique and tool allows us to see pain at its source – down to the activity of individual neurons – offering unprecedented insights into how pain develops and spreads. Our hope is that this approach will not only advance treatments for TMJ disorders but also pave the way for understanding and managing various chronic pain conditions more effectively,” said Kim.

Source: University of Texas Health Science Center at San Antonio

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Dopamine has an Unexpected Role in Memory Devaluation

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New research out of Michigan State University expands on current understanding of the brain chemical dopamine, finding that it plays a role in reducing the value of memories associated with rewards. The study, published in Communications Biology, opens new avenues for understanding dopamine’s role in the brain.

The research team discovered that dopamine is involved in reshaping memories of past rewarding events – an unexpected function that challenges established theories of dopamine function.

“We discovered that dopamine plays a role in modifying how a reward-related memory is perceived over time,” said Alexander Johnson, associate professor in MSU’s Department of Psychology and lead researcher of the study.

In the study, mice were presented with an auditory cue that had previously been associated with a sweet-tasting food. This led to a retrieval of the memory associated with consuming the food. At this time, mice were made to feel temporarily unwell, similar to how you feel if you’ve eaten something that has upset your stomach.

When the mice had fully recovered, they displayed behaviour as if the sweet-tasting food had made them unwell. This occurred despite the fact that when mice were made to feel unwell, they had only retrieved the memory of the food, not the food itself. This initial finding suggests that devaluing the memory of food is sufficient to disrupt future eating of that food.

The research team next turned their attention to the brain mechanisms that could be controlling this phenomenon. Using an approach by which they could label and reactivate brain cells that were engaged when the food memory was retrieved, the researchers identified that cells producing the chemical dopamine appeared to play a particularly important role. This was confirmed through actions that manipulated and recorded dopamine neuron activity during the exercise.

“Our findings were surprising based on our prior understanding of dopamine’s function. We typically don’t tend to think of dopamine being involved in the level of detailed informational and memory processing that our study showed,” Johnson explained. “It’s a violation of what we expected, revealing that dopamine’s role is more complex than previously thought.”

The team also used computational modelling and were able to capture how dopamine signals would go about playing this role in reshaping reward memories.

“Understanding dopamine’s broader functions in the brain could provide new insights into how we approach conditions like addiction, depression and other neuropsychiatric disorders,” said Johnson. “Since dopamine is implicated in so many aspects of brain function, these insights have wide-ranging implications. In the future, we may be able to use these approaches to reduce the value of problematic memories and, as such, diminish their capacity to control unwanted behaviours.”

Source: Michigan State University

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What Drives Mood Swings in Bipolar Disorder? Study Points to a Second Brain Clock

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A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research.

The McGill University-led study published in Science Advances marks a breakthrough in understanding what drives shifts between the two states, something that, according to lead author Kai-Florian Storch, is considered the “holy grail” of bipolar-disorder research.

“Our model offers the first universal mechanism for mood switching or cycling, which operates analogously to the sun and the moon driving spring tides at specific, recurring times,” said Storch, an Associate Professor in McGill’s Department of Psychiatry and a researcher at the Douglas Research Centre.

The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two “clocks”: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time.

Notably, the authors say this second dopamine-based clock probably stays dormant in healthy people.

To carry out their study, the scientists activated the second clock in mice to create behavioral rhythms similar to the mood swinging in bipolar disorder. When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder.

Hope for new treatments: Silencing the clock

Current treatments for bipolar disorder focus on stabilizing moods but often don’t address the root causes of mood swings, the researchers said.

“Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes,” said Storch.

What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans. The research team’s next step will be to focus on these molecular “gears” and investigate these potential triggers.

Source: McGill University

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New AI Tool for TBI Investigations in Forensics and Law Enforcement

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A study led by University of Oxford researchers has developed an advanced physics-based AI-driven tool to aid traumatic brain injury (TBI) investigations in forensics and law enforcement. The findings have been published in Communications Engineering.

TBI is a critical public health issue, with severe and long-term neurological consequences. In forensic investigations, determining whether an impact could have caused a reported injury is crucial for legal proceedings, yet there is currently no standardised, quantifiable approach to do this. The new study demonstrates how machine learning tools informed by mechanistic simulations could provide evidence-based injury predictions. This would help police and forensic teams accurately predict TBI outcomes based on documented assault scenarios.

The study’s AI framework, trained on real, anonymised police reports and forensic data, achieved remarkable prediction accuracy for TBI-related injuries:

  • 94% accuracy for skull fractures
  • 79% accuracy for loss of consciousness
  • 79% accuracy for intracranial haemorrhage

In each case, the model showed high specificity and high sensitivity (a low rate of false positive and false negative results).

This research represents a significant step forward in forensic biomechanics. By leveraging AI and physics-based simulations, we can provide law enforcement with an unprecedented tool to assess TBIs objectively.

The framework uses a general computational mechanistic model of the head and neck, designed to simulate how different types of impacts—such as punches, slaps, or strikes against a flat surface—affect various regions. This provides a basic prediction of whether an impact is likely to cause tissue deformation or stress. However, it does not predict on its own any risk of injury. This is done by an upper AI layer which incorporates this information with any additional relevant metadata, such as the victim’s age and height, before providing a prediction for a given injury.

Lead researcher Antoine Jérusalem, Professor of Mechanical Engineering in the Department of Engineering Science, University of Oxford

The researchers trained the overall framework on 53 anonymised real police reports of assault cases. Each report included information about a range of factors which could affect the blow’s severity (e.g., age, sex, body build of the victim/offender). This resulted in a model capable of integrating mechanical biophysical data with forensic details to predict the likelihood of different injuries occurring.

When the researchers assessed which factors had the most influence on the predictive value for each type of injury, the results were remarkably consistent with medical findings. For instance, when predicting the likelihood of skull fracture, the most important factor was the highest amount of stress experienced by the scalp and skull during an impact. Similarly, the strongest predictor of loss of consciousness was the stress metrics for the brainstem.

Understanding brain injuries using innovative technology to support a police investigation, previously reliant on limited information, will greatly enhance the interpretation required from a medical perspective to support prosecutions.

Ms Sonya Baylis, Senior Manager at the National Crime Agency

The research team insists that the model is not intended to replace the involvement of human forensic and clinical experts in investigating assault cases. Rather, the intention is to provide an objective estimate of the probability that a documented assault was the true cause of a reported injury. The model could also be used as a tool to identify high-risk situations, improve risk assessments, and develop preventive strategies to reduce the occurrence and severity of head injuries.

Lead researcher Antoine Jérusalem, Professor of Mechanical Engineering in the Department of Engineering Science at the University of Oxford said: ‘Our framework will never be able to identify without doubt the culprit who caused an injury. All it can do is tell you whether the information provided to it is correlated with a certain outcome. Since the quality of the output depends on the quality of the information fed into the model, having detailed witness statements is still crucial.’

Dr Michael Jones, Researcher at Cardiff University, and Forensics Consultant, said: ‘An “Achilles heel” of forensic medicine is the assessment of whether a witnessed or inferred mechanism of injury, often the force, matches the observed injuries. With the application of machine learning, each additional case contributes to the overall understanding of the association between the mechanism of cause, primary injury, pathophysiology and outcome.’

The study ‘A mechanics-informed machine learning framework for traumatic brain injury prediction in police and forensic investigations’ has been published in Communications Engineering. It was conducted by an interdisciplinary team of engineers, forensic specialists, and medical professionals from the University of Oxford, Thames Valley Police, the National Crime Agency, Cardiff University, Lurtis Ltd., the John Radcliffe Hospital and other partner institutions.

Source: University of Oxford

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High Temperatures Could Impact the Brain Function of Young Children

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Exposure to high ambient temperatures is associated with lower connectivity in three brain networks in preadolescents, suggesting that heat may impact brain function. This is the conclusion of a study led by the Barcelona Institute for Global Health (ISGlobal). The results have been published in the Journal of the American Academy of Child & Adolescent Psychiatry. 

The study involved 2229 children aged 9 to 12 from the “Generation R” cohort in Rotterdam, Netherlands. Functional connectivity data from brain networks, i.e., how different regions of the brain communicate and collaborate, were assessed using resting-state magnetic resonance imaging, when the children were not performing any active tasks. Daily mean temperature estimates were obtained from the UrbClim urban climate model, developed by the Flemish Institute for Technological Research. Temperature values were calculated for the period from 2013 to 2015, assigning daily averages to each participant based on their home address.

Higher ambient temperatures during the week preceding the MRI assessment were associated with lower functional connectivity within the medial parietal, salience, and hippocampal networks, which are essential for proper brain functioning. This implies that brain areas may work less synchronously, affecting processes such as attention, memory, and decision-making. The medial parietal network is related to introspection and self-perception; the salience network detects environmental stimuli and prioritises what deserves our attention; and the hippocampal network is critical for memory and learning.

The research shows that the association between high temperatures and lower functional connectivity was strongest on the day before the brain scan and progressively decreased on subsequent days. In contrast, low average daily temperatures were not associated with functional connectivity.

“We hypothesise that dehydration could explain our findings, as children are particularly vulnerable to fluid loss when exposed to heat, which can affect the functional connectivity of brain networks,” says study lead author Laura Granés, researcher at IDIBELL and ISGlobal.

“In the current climate emergency, public health policies aimed at protecting children and adolescents from high temperatures could help mitigate potential effects on brain function,” says Mònica Guxens, ICREA researcher at ISGlobal and senior author of the study.

Implications for mental health

Although brain function alterations have been suggested as a possible mechanism linking temperature and mental health, no study to date has examined the effects of ambient temperature on functional brain networks. In another recent study, the same research team found that exposure to cold and heat can affect psychiatric symptoms such as anxiety, depression and attention problems. In addition, other studies have linked lower connectivity within the brain’s salience network to suicidal ideation and self-harming behaviours in adolescents with depression, as well as to anxiety disorders.

“Given the role of the salience network in suicidal ideation, our findings raise a new hypothesis: high temperatures could decrease the functional connectivity of this network, indirectly contributing to a higher risk of suicide in individuals with pre-existing mental health conditions,” explains Carles Soriano-Mas, researcher at IDIBELL and the University of Barcelona and one of the study’s authors. “While we do not propose that these connectivity changes, triggered by heat exposure, directly induce suicidal behaviours, they could act as a trigger in vulnerable individuals,” adds the researcher. 

Source: Barcelona Institute for Global Health (ISGlobal)

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Memory is Impaired in Aged Rats After 3 Days of High-fat Diet

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Some fast food offerings, such as cheeseburgers, contain more than 60% of calories from fat. Photo by Jonathan Borba

Just a few days of eating a diet high in saturated fat could be enough to cause memory problems and related brain inflammation in older adults, a new study in rats suggests. 

In the study, published in Immunity & Aging, researchers fed separate groups of young and old rats the high-fat diet for three days or for three months to compare how quickly changes happen in the brain versus the rest of the body when eating an unhealthy diet. 

As expected based on previous diabetes and obesity research, eating fatty foods for three months led to metabolic problems, gut inflammation and dramatic shifts in gut bacteria in all rats compared to those that ate normal chow, while just three days of high fat caused no major metabolic or gut changes.

When it came to changes in the brain, however, researchers found that only older rats – whether they were on the high-fat diet for three months or only three days – performed poorly on memory tests and showed negative inflammatory changes in the brain. 

The results dispel the idea that diet-related inflammation in the aging brain is driven by obesity, said senior study author Ruth Barrientos, an investigator in the Institute for Behavioral Medicine Research at The Ohio State University. Most research on the effects of fatty and processed foods on the brain has focused on obesity, yet the impact of unhealthy eating, independent of obesity, remains largely unexplored. 

“Unhealthy diets and obesity are linked, but they are not inseparable. We’re really looking for the effects of the diet directly on the brain. And we showed that within three days, long before obesity sets in, tremendous neuroinflammatory shifts are occurring,” said Barrientos, also an associate professor of psychiatry and behavioural health and neuroscience in Ohio State’s College of Medicine.  

“Changes in the body in all animals are happening more slowly and aren’t actually necessary to cause the memory impairments and changes in the brain. We never would have known that brain inflammation is the primary cause of high-fat diet-induced memory impairments without comparing the two timelines.” 

Years of research in Barrientos’ lab has suggested that aging brings on long-term “priming” of the brain’s inflammatory profile coupled with a loss of brain-cell reserve to bounce back, and that an unhealthy diet can make matters worse for the brain in older adults. 

Fat constitutes 60% of calories in the high-fat diet used in the study, which could equate to a range of common fast-food options: For example, nutrition data shows that fat makes up about 60% of calories in a McDonald’s double smoky BLT quarter pounder with cheese or a Burger King double whopper with cheese. 

After the animals were on high-fat diets for three days or three months, researchers ran tests assessing two types of memory problems common in older people with dementia that are based in separate regions of the brain: contextual memory mediated by the hippocampus (the primary memory center of the brain), and cued-fear memory that originates in the amygdala (the fear and danger center of the brain). 

Compared to control animals eating chow and young rats on the high-fat diet, aged rats showed behaviors indicating both types of memory were impaired after only three days of fatty food – and the behaviors persisted as they continued on the high-fat diet for three months. 

Researchers also saw changes in levels of a range of proteins called cytokines in the brains of aged rats after three days of fatty food, which signaled a dysregulated inflammatory response. Three months after being on the high-fat diet, some of the cytokine levels had shifted but remained dysregulated, and the cognitive problems persisted in behavior tests. 

“A departure from baseline inflammatory markers is a negative response and has been shown to impair learning and memory functions,” Barrientos said. 

Compared to rats eating normal chow, young and old animals gained more weight and showed signs of metabolic dysfunction – poor insulin and blood sugar control, inflammatory proteins in fat (adipose) tissue, and gut microbiome alterations – after three months on the high-fat diet. Young rats’ memory and behavior and brain tissue remained unaffected by the fatty food. 

“These diets lead to obesity-related changes in both young and old animals, yet young animals appear more resilient to the high-fat diet’s effects on memory. We think it is likely due to their ability to activate compensatory anti-inflammatory responses, which the aged animals lack,” Barrientos said. 

“Also, with glucose, insulin and adipose inflammation all increased in both young and old animals, there’s no way to distinguish what is causing memory impairment in only old animals if you look only at what’s happening in the body. It’s what is happening in the brain that’s important for the memory response.” 

Source: Ohio State University

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Leakiness of First Blood–brain Barrier Layer Results in Cognitive Deficits

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a, Diagram of the BBB and brain endothelial glycocalyx layer. b, TEM of cortical capillaries with lanthanum nitrate staining from young (3-month-old) and aged (21-month-old) mice. Scale bars, 1 µm. Source: Shi et al., Nature, 2025.

A study published in Nature reveals how a key component of the blood–brain barrier (BBB), the endothelial glycocalyx layer, becomes dysregulated in ageing, causing the BBB to become compromised. The researchers also investigated the possibility of to restore this layer’s integrity, reducing neuroinflammation and restoring cognitive function.

The BBB is a highly specialised safeguard keeping the brain separate from harmful factors, such as toxins and also albumin, IgG and fibrinogen (and, unfortunately, many medications which could otherwise treat brain disease). The leakage of such blood-derived molecules into the brain has been shown to trigger neuroinflammatory changes and create a neurotoxic brain environment. The part of the BBB directly in contact with the blood is the endothelial glycocalyx layer, a carbohydrate-rich meshwork mostly composed of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen. Yet the endothelial glycocalyx’s composition and role is poorly understood despite it being the first layer of interface between the blood and brain.

The researchers found that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. Two mucin-type O-glycan biosynthetic enzymes, C1GALT1 and B3GNT3 were also found to be downregulated mouse models of ageing and in the brains of Alzheimer’s and Huntington’s disease patients. To test these, the researchers used adeno-associated viruses (AAV) in young mice to turn down the expression of C1GALT1 and B3GNT3. These mice showed signs of BBB leakage and in severe cases, brain haemorrhaging occurred in mice.

In samples from the brains of Alzheimer’s patients, the researchers also observed reduced C1GALT1 in microvessels.

To test if it was possible to restore the BBB’s ability to protect the brain against harmful blood-borne molecules, they administered AAVs in aged mice to restore levels of B3GNT3 and C1GALT1.

Assessing cognitive function, they found that aged mice treated with B3GNT3 via an AAV displayed improvements in spatial working memory in a maze test and hippocampal-dependent learning and memory in a fear conditioning test. Aged mice treated with C1GALT1 did not improve in the maze test, and no significant difference was observed in cued freezing in the fear conditioning among the three aged groups.

Although the study shows that increasing C1GALT1 and B3GNT3 reduces BBB permeability and improves brain health, the precise mechanisms that underlie these beneficial effects remain unclear. The researchers believe that by limiting the nonspecific uptake of blood-derived molecules, the brain can be protected. But C1GALT1 and B3GNT3 are also likely to influence a wide range of proteins and glycan structures and in order to further understand brain ageing and rejuvenation it is therefore crucial to understand the molecular pathways affected by them.

The authors concluded: “Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.”