Category: Neurology

How Zebrafish Heal from Spinal Cord Injury could Help Humans

Photo by Cottonbro on Pexels

Zebrafish have a remarkable ability to heal their spinal cord after injury. Now, researchers at Karolinska Institutet have uncovered an important mechanism behind this phenomenon – a finding that could have implications for the treatment of spinal cord injury in humans.

In a new study published in Nature Communications, researchers show that the neurons of adult zebrafish immediately start to cooperate after a spinal cord injury, keeping the cells alive and stimulating the healing process.

“We have shown that the neurons form small channels called gap junctions, which create a direct connection between the neurons and enable the exchange of important biochemical molecules, allowing the cells to communicate and protect each other,” explains Konstantinos Ampatzis, a researcher in the Department of Neuroscience at Karolinska Institutet, who led the study.

The researchers will further investigate the exact mechanisms behind this protective strategy in zebrafish and hope this knowledge will lead to new ways of treating spinal cord injury in humans.

“Spinal cord injuries are a major burden for sufferers and their families,” says Konstantinos Ampatzis. “What if we could get human neurons to adopt the same survival strategy and behave like zebrafish neurons after an injury? This could be the key to developing new effective treatments.”

Source: Karolinka Institutet

Concussion is Associated with Iron Accumulation in Certain Brain Areas

Photo by Anna Shvets

People who suffer from headaches after experiencing concussions may also be more likely to have higher levels of iron in areas of the brain – a sign of injury to brain cells, according to a preliminary study presented at the American Academy of Neurology’s 76th Annual Meeting.

“These results suggest that iron accumulation in the brain can be used as a biomarker for concussion and post-traumatic headache, which could potentially help us understand the underlying processes that occur with these conditions,” said study author Simona Nikolova, PhD, of the Mayo Clinic in Phoenix, Arizona, and a member of the American Academy of Neurology.

The study involved 120 participants, 60 of whom who had post-traumatic headache (PTH) due to mild traumatic brain injury (mTBI), and 60 healthy controls. The injuries were due to a fall for 45% of the people, 30% were due to a motor vehicle accident and 12% were due to a fight. Other causes were the head hitting against or by an object and sports injuries. A total of 46% of the people had one mild traumatic brain injury in their lifetime, 17% had two, 16% had three, 5% had four and 16% had five or more mild traumatic brain injuries.

Participants underwent 3T brain magnetic resonance imaging (T2* maps). T2* differences were determined using age-matched paired t-tests. For the PTH group, scans were done an average of 25 days after injury. T2* correlations with headache frequency, number of lifetime mTBIs, time since most recent mTBI, and Sport Concussion Assessment Tool (SCAT) severity scale scores,

The researchers observed lower T2* values in PTH participants relative to HC in the right supramarginal area, left occipital, bilateral precuneus, right cuneus, right cerebellum, right temporal, bilateral caudate, genu of the corpus callosum, right anterior cingulate cortex and right rolandic operculum (p < 0.001).

Within PTH subjects, there were positive correlations with iron accumulation between lifetime mTBIs, the time since most recent mTBI and headache frequency in certain areas of the brain. For example, T2* levels in headache frequency with T2* in the posterior corona radiata, bilateral temporal, right frontal, bilateral supplemental motor area, left fusiform, right hippocampus, sagittal striatum, and left cerebellum were associated with headache frequency.

“Previous studies have shown that iron accumulation can affect how areas of the brain interact with each other,” Nikolova said. “This research may help us better understand how the brain responds and recovers from concussion.”

Nikolova said that using the indirect measure of iron burden also means that the change in that measure could be due to other factors such as haemorrhage or changes in tissue water rather than iron accumulation.

Source: American Academy of Neurology

Singing Repairs the Language Network of the Brain after Stroke

Photo by Sergio Capuzzimati on Unsplash

Cerebrovascular accidents, or strokes, are the most common cause of aphasia, a speech disorder of cerebral origin. People with aphasia have a reduced ability to understand or produce speech or written language. An estimated 40% of people who have had a stroke have aphasia. As many as half of them experience aphasia symptoms even a year after the original attack.

Researchers at the University of Helsinki previously found that sung music helps in the language recovery of patients affected by strokes. Now, the researchers have uncovered the reason for the rehabilitative effect of singing. The recently completed study was published in the eNeuro journal.

According to the findings, singing, as it were, repairs the structural language network of the brain. The language network processes language and speech in the brain, which has been damaged.

“For the first time, our findings demonstrate that the rehabilitation of patients with aphasia through singing is based on neuroplasticity changes, that is, the plasticity of the brain,” says University Researcher Aleksi Sihvonen from the University of Helsinki.

Singing improves language network pathways

The language network encompasses the cortical regions of the brain involved in the processing of language and speech, as well as the white matter tracts that convey information between the different end points of the cortex.

According to the study results, singing increased the volume of grey matter in the language regions of the left frontal lobe and improved tract connectivity especially in the language network of the left hemisphere, but also in the right hemisphere.

“These positive changes were associated with patients’ improved speech production,” Sihvonen says.

A total of 54 aphasia patients participated in the study, of whom 28 underwent MRI scans at the beginning and end of the study. The researchers investigated the rehabilitative effect of singing with the help of choir singing, music therapy and singing exercises at home.

Singing is a cost-effective treatment

Aphasia has a wide-ranging effect on the functional capacity and quality of life of affected individuals and easily leads to social isolation.

According to Sihvonen, singing can be seen as a cost-effective addition to conventional forms of rehabilitation, or as rehabilitation for mild speech disorders in cases where access to other types of rehabilitation is limited.

“Patients can also sing with their family members, and singing can be organised in healthcare units as a group-based, cost-efficient rehabilitation,” Sihvonen says.

Source: University of Helsinki

Difference in Brain Structures may Explain Concussion Outcomes for Males and Females

Coup and contrecoup brain injury. Credit: Scientific Animations CC4.0

Important brain structures that are key for signalling in the brain are narrower and less dense in females, and more likely to be damaged by brain injuries, such as concussion. Long-term cognitive deficits occur when the signals between brain structures weaken due to the injury. These structural differences in male and female brains might explain why females are more prone to concussions and experience longer recovery from the injury than their male counterparts, according to a University of Pennsylvania-led preclinical study published in Acta Neuropathologica.

Each year, approximately 50 million individuals worldwide suffer a concussion, also referred to as mild traumatic brain injury (TBI). For more than 15% of individuals who suffer persisting cognitive dysfunction, which includes difficulty concentrating, learning and remembering new information, and making decisions.

Although males make up the majority of emergency department visits for concussion, this has been primarily attributed to their greater exposure to activities with a risk of head impacts compared to females. In contrast, it has recently been observed that female athletes have a higher rate of concussion and appear to have worse outcomes than their male counterparts participating in the same sport.

“Clinicians have observed for a long time that females suffer from concussion at higher rates than males in the same sports, and that they take longer to recover cognitive function, but couldn’t explain the underlying mechanisms of this phenomenon,” said senior author Douglas Smith, MD, a professor of Neurosurgery and director of Penn’s Center for Brain Injury and Repair. “The variances in brain structures of females and males not only illuminate why this disparity exists, but also exposes biomarkers, such as axon protein fragments, that can be measured in the blood to determine injury severity, monitor recovery, and eventually help identify and develop treatments that help patients repair these damaged structures and restore cognitive function.”

Axons connect neurons, allowing communication across the brain. These axons form bundles that make up white matter in the brain and play a large role in learning and communication between different brain regions. Axons are delicate structures and are vulnerable to damage from concussion.

Communication between axons in the brain is powered by sodium channels that serve as the brain’s electric grid. When axons are damaged, these sodium channels are also impaired, which causes loss of signaling in the brain. The loss of signaling causes the cognitive impairment experienced by individuals after concussion.

In this study, researchers used large animal models of concussion to identify differences in brains of males and females after a concussion. They found that females had a higher population of smaller axons, which researchers demonstrated are more vulnerable to injury. They also reported that in these models, females had greater loss of sodium channels after concussion.

“The differences in brain structure not only tell us a lot about how brain injury affects males and females differently but could offer insights in other brain conditions that impact axons, like Alzheimer’s and Parkinson’s disease,” said Smith. “If female brains are more vulnerable to damage from concussion, they might also be more vulnerable to neurodegeneration, and it’s worth further research to understand how sex influences the structure and functions of the brain.”

Source: University of Pennsylvania School of Medicine

Study Finds Some TBI Patients Could have Recovered if Life Support was Kept on

Photo by Rodnae Productions on Pexels

Severe traumatic brain injury (TBI) is a major cause of hospitalisations and deaths around the world, affecting more than five million people each year. Predicting outcomes following a brain injury can be challenging, yet families are asked to make decisions about continuing or withdrawing life-sustaining treatment within days of injury.

In a new study published in the Journal of Neurotrauma, Mass General Brigham investigators analysed potential clinical outcomes for TBI patients enrolled in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study for whom life support was withdrawn. The investigators found that some patients for whom life support was withdrawn may have survived and recovered some level of independence a few months after injury. These findings suggest that delaying decisions on withdrawing life support might be beneficial for some patients.

Families are often asked to make decisions to withdraw life support measures, such as mechanical breathing, within 72 hours of a brain injury. Information relayed by physicians suggesting a poor neurologic prognosis is the most common reason families opt for withdrawing life support measures. However, there are currently no medical guidelines or precise algorithms that determine which patients with severe TBI are likely to recover.

Using data collected over a 7.5-year period on 1392 TBI patients in intensive care units at 18 US trauma centres, the researchers created a mathematical model to calculate the likelihood of withdrawal of life-sustaining treatment, based on properties like demographics, socioeconomic factors and injury characteristics. Then, they paired individuals for whom life-sustaining treatment was not withdrawn (WLST-) to individuals with similar model scores, but for whom life-sustaining treatment was withdrawn (WLST+).

Based on follow-up of their WLST- paired counterparts, the estimated six-month outcomes for a substantial proportion of the WLST+ group was either death or recovery of at least some independence in daily activities. Of survivors, more than 40%of the WLST- group recovered at least some independence. In addition, the research team found that remaining in a vegetative state was an unlikely outcome by six-months after injury. Importantly, none of the patients who died in this study were pronounced brain dead, and thus the results are not applicable to brain death.

According to the authors, the findings suggest there is a cyclical, self-fulfilling prophecy taking place: Clinicians assume patients will do poorly based on outcomes data. This assumption results in withdrawal of life support, which in turn increases poor outcomes rates and leads to even more decisions to withdraw life support.

The authors suggest that further studies involving larger sample sizes that allow for more precise matching of WLST+ and WLST- cohorts are needed to understand variable recovery trajectories for patients who sustain traumatic brain injuries.

“Our findings support a more cautious approach to making early decisions on withdrawal of life support,” said corresponding author Yelena Bodien, PhD, of the Department of Neurology’s Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital and of the Spaulding-Harvard Traumatic Brain Injury Model Systems. “Traumatic brain injury is a chronic condition that requires long term follow-ups to understand patient outcomes. Delaying decisions regarding life support may be warranted to better identify patients whose condition may improve.”

Read more in the study, published May 13, in the Journal of Neurotrauma.

Nutrient’s Pathway into the Brain could be Used to Treat Neurological Disorders

Source: CC0

A University of Queensland researcher has found molecular doorways that could be used to help deliver drugs into the brain to treat neurological disorders. Dr Rosemary Cater from UQ’s Institute for Molecular Bioscience led a team which discovered that an essential nutrient called choline is transported into the brain by a protein called FLVCR2.

“Choline is a vitamin-like nutrient that is essential for many important functions in the body, particularly for brain development,” Dr Cater said.

“We need to consume 400-500mg of choline per day to support cell regeneration, gene expression regulation, and for sending signals between neurons.”

Dr Cater said that until now, little was known about how dietary choline travels past the layer of specialised cells that separates the blood from the brain.

“This blood-brain barrier prevents molecules in the blood that are toxic to the brain from entering,” she explained. “The brain still needs to absorb nutrients from the blood, so the barrier contains specialised cellular machines – called transporters – that allow specific nutrients such as glucose, omega-3 fatty acids and choline to enter. While this barrier is an important line of defence, it presents a challenge for designing drugs to treat neurological disorders.”

Dr Cater was able to show that choline sits in a cavity of FLVCR2 as it travels across the blood-brain barrier and is kept in place by a cage of protein residues.

“We used high-powered cryo-electron microscopes to see exactly how choline binds to FLVCR2,” she said. “This is critical information for understanding how to design drugs that mimic choline so that they can be transported by FLVCR2 to reach their site of action within the brain. These findings will inform the future design of drugs for diseases such as Alzheimer’s and stroke.”

The research also highlights the importance of eating choline-rich foods – such as eggs, vegetables, meat, nuts and beans.

The research is published in Nature and funded by the National Institutes of Health.

Source: University of Queensland

Neuron Cluster may Create a Little-understood Form of Chronic Pain

Source: Pixabay CC0

Stimulating a small cluster of neurons in the brain appears to create a response in mice that mimics nociplastic pain, a type of unexplained chronic pain, researchers at the University of Washington School of Medicine in Seattle have found. 

“When we stimulate these neurons, the mouse behaves as though gentle touch is very painful, which is one of the characteristics of nociplastic pain,” said Richard Palmiter, a professor of biochemistry and investigator of the Howard Hughes Medical Institute. Dr Logan Condon, who spearheaded this research as a PhD student at UW, was lead author on the paper, which was published in Cell Reports

Chronic pain can arise from ongoing injury or persistent damage to the nervous system. Pain caused by injury is called nociceptive from the Latin nocere “to harm.” Pain due to nerve damage is called neuropathic. But these categories do not explain a common form of chronic pain the persists even after an injury has fully healed and there is no evidence of neurological damage. This led the International Association for the Study of Pain to define a new category called nociplastic pain, meaning “able to be moulded.” 

Although the cause of nociplastic pain is unknown, scientists think it involves changes in pain circuits in the spinal cord and brain. These changes result in the perception of pain even when no nerve injury exists. 

In the new study, researchers demonstrated that stimulating a cluster of cells in the brain’s parabrachial nucleus can generate chronic pain behaviour typical of nociplastic pain. They also showed that inhibiting these cells can prevent pain from nerve injury. 

The parabrachial nucleus is in an area of the brain known as the pons. It acts as a hub that relays aversive sensory information from the body to different parts of the brain. The parabrachial neurons found to create nociplastic pain are called Calca neurons, named for a defining gene for these cells. 

“You can think of these Calca neurons as a warning system for the brain,” said Palmiter. “They respond to any aversive event you can think of – a pinch, a visual threat, a bad odour, a loud noise – and they tell your brain that something bad is happening in the environment and you’d better do something about it.”

It is possible to manipulate genetically defined neurons using viral techniques to express molecules that activate, or inhibit, those neurons. 

The researchers also found that the nociplastic pain behaviour continues even after the Calca-neuron activation has stopped. This suggests signals from the stimulated Calca neurons cause persistent effects – a sign of plasticity – in the nerve circuits leading to the spinal cord. 

They also showed that it was possible to create nociplastic behaviours in the mice by exposing them to unpleasant, aversive experiences like nausea, chemotherapy drugs or migraine-like conditions. 

Palmiter’s team is currently focusing on the neural circuits and plasticity that arises when parabrachial Calca neurons are activated.

“The brain is somehow sending signals to the spinal cord,” he said. “We want to figure out the pathway for those signals.”

Source: University of Washington

The First Half of a Night’s Sleep Resets Brain Connections

…but not the second half

Source: CC0

During a night’s sleep, the brain weakens the new connections between neurons that had been forged while awake – but only during the first half, according to a new study in fish by UCL scientists.

The researchers say that their findings, published in Nature, provide insight into the role of sleep, but still leave an open question around what function the latter half of a night’s sleep serves.

The researchers say the study supports the Synaptic Homeostasis Hypothesis, a key theory on the purpose of sleep which proposes that sleeping acts as a reset for the brain.

Lead author Professor Jason Rihel (UCL Cell & Developmental Biology) said: “When we are awake, the connections between brain cells get stronger and more complex. If this activity were to continue unabated, it would be energetically unsustainable. Too many active connections between brain cells could prevent new connections from being made the following day.

“While the function of sleep remains mysterious, it may be serving as an ‘off-line’ period when those connections can be weakened across the brain, in preparation for us to learn new things the following day.”

For the study, the scientists used optically translucent zebrafish, with genes enabling synapses to be easily imaged. The research team monitored the fish over several sleep-wake cycles.

The researchers found that brain cells gain more connections during waking hours, and then lose them during sleep. They found that this was dependent on how much sleep pressure (need for sleep) the animal had built up before being allowed to rest; if the scientists deprived the fish from sleeping for a few extra hours, the connections continued to increase until the animal was able to sleep.

Professor Rihel added: “If the patterns we observed hold true in humans, our findings suggest that this remodelling of synapses might be less effective during a mid-day nap, when sleep pressure is still low, rather than at night, when we really need the sleep.”

The researchers also found that these rearrangements of connections between neurons mostly happened in the first half of the animal’s nightly sleep. This mirrors the pattern of slow-wave activity, which is part of the sleep cycle that is strongest at the beginning of the night.

First author Dr Anya Suppermpool (UCL Cell & Developmental Biology and UCL Ear Institute) said: “Our findings add weight to the theory that sleep serves to dampen connections within the brain, preparing for more learning and new connections again the next day. But our study doesn’t tell us anything about what happens in the second half of the night. There are other theories around sleep being a time for clearance of waste in the brain, or repair for damaged cells – perhaps other functions kick in for the second half of the night.”

Source: University College London

X-chromosome Inactivation may Reduce Females’ Autism Risk

X-chromosome inactivation varies across different areas of brains. Here, fluorescent imaging data from a mouse reveal where the father’s X chromosome is most active (white) and least active (blue). Credit: Eric Szelenyi

A study using mice published in the journal Cell Reports suggests how chromosome inactivation may protect women from autism disorder inherited from their father’s X chromosome.

Because cells do not need two copies of the X chromosome, the cells inactivate one copy early in embryonic development, a well-studied process known as X chromosome inactivation. As a result of this inactivation, every female is made up of a mix of cells, some have an active X chromosome from her father and others from her mother, a phenomenon known as mosaicism. 

For many years, it has been thought that this was random and would result, on average, in a roughly 50/50 mix of cells, with 50% having an active paternal X chromosome and 50% an active maternal X chromosome.

Now a new study finds that, in the mouse brain at least, this is not the case. Instead, there appears to be a bias in the process that results in the paternal X chromosome being inactivated in 60% of the cells rather than the expected 50%.

When the X-linked mutation that is the most common cause of autism spectrum disorder is inherited from the father, the pattern of X-chromosome inactivation in the brain circuitry of females can prevent the effects of that mutation, the study found.

“This bias may be a way to reduce the risk of harmful mutations, which occur more frequently in male chromosomes,” said corresponding author Eric Szelenyi, acting assistant professor of biological structure at the University of Washington School of Medicine in Seattle.

The X-chromosome is of particular interest because it carries more genes involved in brain development than any other chromosome. Mutations in the chromosome are linked to more than 130 neurodevelopmental disorders, including fragile X syndrome and autism.

In the study, the researchers first determined the ratio of X chromosome inactivation in healthy mice by analyzing roughly 40 million brain cells per mouse. The scientists did this by using high-throughput volumetric imaging and automated counting. This analysis revealed a systematic 60:40 ratio across all possible anatomical regions.

They then examined what would happen if they genetically added a mouse model for fragile X syndrome. This syndrome is the most common form of inherited intellectual and developmental disability in humans.

They first tested the mice for behaviors thought to be analogous to those impaired in people with fragile X syndrome. These tests evaluate such things as their sensorimotor function, spatial memory and tendencies towards anxiety and sociability.

They found that the mice who inherited the mutation on their mother’s X chromosome, which are less likely to be inactivated in the 60:40 ratio, were more likely to exhibit behaviour analogous to fragile X syndrome. They exhibited more signs of anxiety, less sociability, poor performance in spatial learning, and deficits in sensorimotor function. 

But mice that inherited the mutation from one their father’s X chromosomes, which were more likely to be inactivated, did not appear impaired. 

“What was most interesting is that using each animal’s behavioural performance was most accurately predicted by X chromosome inactivation in brain circuits, rather than just looking at the brain as a whole, or single brain regions,” said Szelenyi. “This suggests that having more mutant X-active cells due to maternal inheritance increases overall disease risk, but specific mosaic pattern within brain circuitry ultimately decides which behaviors are impacted the most.”

“This suggests that the 20% difference in mutant X-active cells created by the bias can be protective against X mutations from the father, which occur more commonly,” he said.

The findings may also explain why symptoms of X-linked syndromes, like X-linked autism spectrum disorder, vary more in females than males.

Source: University of Washington

Study Reveals ‘Profound’ Link between Dietary Choices and Brain Health

Photo by Fakurian Design on Unsplash

New research published in Nature has shown that a healthy, balanced diet was linked to superior brain health, cognitive function and mental wellbeing. The study, involving researchers at the University of Warwick, sheds light on how food preferences influence more than just physical health, and also significantly impact brain health.

With the help of machine learning, the researchers analysed a large sample of 181 990 participants from the UK Biobank, comparing their dietary choices against a range of physical evaluations, including cognitive function, blood metabolic biomarkers, brain imaging, and genetics.

The food preferences of each participant were collected via an online questionnaire, which the team categorised into 10 groups (eg, alcohol, fruits and meats).

A balanced diet was associated with better mental health, superior cognitive functions and even higher amounts of grey matter in the brain – linked to intelligence – compared with those with a less varied diet.

The study also highlighted the need for gradual dietary modifications, particularly for individuals accustomed to highly palatable but nutritionally deficient foods. By slowly reducing sugar and fat intake over time, individuals may find themselves naturally gravitating towards healthier food choices.

Genetic factors may also contribute to the association between diet and brain health, the scientists believe, showing how a combination of genetic predispositions and lifestyle choices shape wellbeing.

Lead Author Professor Jianfeng Feng, University of Warwick, emphasised the importance of establishing healthy food preferences early in life. He said: “Developing a healthy balanced diet from an early age is crucial for healthy growth. To foster the development of a healthy balanced diet, both families and schools should offer a diverse range of nutritious meals and cultivate an environment that supports their physical and mental health.”

Source: University of Warwick