Patients with this unusual combination of conditions were referred to Mehul Dattani (UCL), and affected individuals were found to carry the same homozygous mutation in the PRDM13 gene, which encodes a chromatin modifying factor that contributes to regulating cell fate. Intriguingly, an unaffected heterozygous carrier of this mutation was identified by screening 42 unaffected individuals in the Maltese population, suggesting that this mutation is present at low levels in the population.
The researchers set out to model this condition and identify the underlying causes using a PRDM13-deficient mouse model. The researchers found evidence that both the cerebellar hypoplasia and reproductive phenotypes resulted from defects in the specification of specific populations of GABAergic neuronal progenitors in the developing cerebellum and hypothalamus, respectively.
The results indicate that this condition results from abnormal cell fate specification during development. Consequently, the hypoplastic cerebellum is deficient in molecular layer interneurons, which play critical roles in regulating cerebellar circuits. In the hypothalamus, fewer Kisspeptin neurons, which are important regulators of gonadotropin releasing hormone and puberty, were present in PRDM13 mutant mice.
Together, these findings identify PRDM13 as a critical regulator of neuronal cell fate in the cerebellum and hypothalamus, providing a mechanistic explanation for the co-occurrence of hypogonadism and cerebellar hypoplasia in this syndrome.
A healthy neuron. Credit: National Institutes of Health
Human Neurons Differ From Animal Ones in a Surprising WayIn a surprising new finding published in Nature, neuroscientists have shown that human neurons have a much smaller number of ion channels than expected, compared to the neurons of other mammals.
Ion channels are integral membrane proteins that contain pathways through which ions can flow. By shifting between closed and open conformational states (‘gating’ process), they control passive ion flow through the plasma membrane.
The researchers hypothesise that lower channel density may have helped the human brain evolve energy efficiency, letting it divert resources elsewhere.
“If the brain can save energy by reducing the density of ion channels, it can spend that energy on other neuronal or circuit processes,” said senior author Mark Harnett, an associate professor of brain and cognitive sciences.
Analysing neurons from 10 different mammals, the researchers identified a “building plan” that holds true for every examined species — save humans. They found that as the size of neurons increases, the density of channels found in the neurons also increases.
However, human neurons proved to be a striking exception to this rule.
“Previous comparative studies established that the human brain is built like other mammalian brains, so we were surprised to find strong evidence that human neurons are special,” said lead author and former MIT graduate student Lou Beaulieu-Laroche.
Neurons in the mammalian brain can receive electrical signals from thousands of other cells, and that input determines whether or not they will fire an electrical impulse called an action potential. In 2018, Prof Harnett and Beaulieu-Laroche discovered that human and rat neurons differ in some of their electrical properties, primarily in dendrites.
One of the findings from that study was that human neurons had a lower density of ion channels than neurons in the rat brain. The researchers were surprised by this observation, as ion channel density was generally assumed to be constant across species. In their new study, Harnett and Beaulieu-Laroche decided to compare neurons from several different mammalian species to see if they could find any patterns that governed the expression of ion channels. They studied two types of voltage-gated potassium channels and the HCN channel, which conducts both potassium and sodium, in layer 5 pyramidal neurons, a type of excitatory neurons found in the brain’s cortex.
They were able to obtain brain tissue from a range of 10 mammalian species, including human tissue removed from patients with epilepsy during brain surgery. This variety allowed the researchers to cover a range of cortical thicknesses and neuron sizes across the mammalian kingdom.
In nearly every mammalian species the researchers examined, the density of ion channels increased as the size of the neurons went up. Human neurons bucked this trend, having a much lower density of ion channels than expected.
The increase in channel density across species was a surprise, Prof Harnett explained, because the more channels there are, the more energy is required to pump ions in and out of the cell. However, it started to make sense once the researchers began thinking about the number of channels in the overall volume of the cortex, he said.
In the tiny brain of the Etruscan shrew, which is packed with very small neurons, there are more neurons in a given volume of tissue than in the same volume of tissue from the rabbit brain, which has much larger neurons. But because the rabbit neurons have a higher density of ion channels, the density of channels in a given volume of tissue is the same in both species, or any of the nonhuman species the researchers analysed.
“This building plan is consistent across nine different mammalian species,” Prof Harnett said. “What it looks like the cortex is trying to do is keep the numbers of ion channels per unit volume the same across all the species. This means that for a given volume of cortex, the energetic cost is the same, at least for ion channels.”
The human brain represents a striking deviation from this building plan, however. Instead of increased density of ion channels, the researchers found a dramatic decrease in the expected density of ion channels for a given volume of brain tissue.
The researchers believe this lower density may have evolved as a way to expend less energy on pumping ions, which allows the brain to use that energy for something else, like creating more complicated synaptic connections between neurons or firing action potentials at a higher rate.
“We think that humans have evolved out of this building plan that was previously restricting the size of cortex, and they figured out a way to become more energetically efficient, so you spend less ATP per volume compared to other species,” Prof Harnett said.
He now hopes to study where that extra energy might be going, and whether there are specific gene mutations that help neurons of the human cortex achieve this high efficiency. The researchers are also interested in exploring whether primate species that are more closely related to humans show similar decreases in ion channel density.
A pioneering new study from Taiwan showed that focused ultrasound, which can be used to non-invasively target circuits in the brain, may benefit some patients with epilepsy who experience seizures which remain unresponsive to standard anti-seizure medications.
The results showed that of six patients with drug-resistant seizures, two patients had fewer seizures within three days of receiving focused ultrasound; however, one patient showed signs of more frequent subclinical seizures (which are not felt by the individual). The findings from the study were published in the journal Epilepsia.
Imaging tests performed after the treatment show that there were no negative effects on the brain. One patient reported a sensation of heat on the scalp during the treatment, and another patient experienced temporary memory impairment that resolved within three weeks.
“Neuromodulation is an alternative treatment for drug-resistant epilepsy. Compared with the present modalities used in neuromodulation for epilepsy, focused ultrasound can access deeper brain regions and focus on the main target of the epileptic network in a relatively less invasive approach,” explained senior author Hsiang-Yu Yu, MD, of Taipei Veterans General Hospital, in Taiwan. “It gives new hope and sheds new light for patients with drug-resistant epilepsy.”
University of Utah scientists have discovered a new type of neuron in the retina, which will help fill in our understanding of how sensory information is relayed.
In the central nervous system a complex network of neurons communicate with each other to relay sensory and motor information. In this chain of communication, a type of neuron called interneurons serve as intermediaries . A research team led by Ning Tian, PhD, identified a previously unknown type of interneuron in the mammalian retina. Their findings were published in the journal PNAS.
This discovery is a major step forward for the field as scientists strive to build a better understanding of the central nervous system by identifying all classes of neurons and their connections.
“Based on its morphology, physiology, and genetic properties, this cell doesn’t fit into the five classes of retinal neurons first identified more than 100 years ago,” said Dr Tian. “We propose they might belong to a new retinal neuron class by themselves.”
The research team called their discovery the Campana cell after its shape, which resembles a hand bell. Campana cells relay visual signals from both types of light-sensing rod and cone photoreceptors in the retina, however their exact purpose is the subject of ongoing research. Experiments revealed that Campana cells remain activated for an unusually long time – as long as 30 seconds – in response to a 10 millisecond light flash stimulation.
“In the brain, persistent firing cells are believed to be involved in memory and learning,” said Dr Tian. “Since Campana cells have a similar behaviour, we theorise they could play a role in prompting a temporal ‘memory’ of a recent stimulation.”
Oxygen-deprived newborns who undergo hypothermia therapy have a higher risk of seizures and brain damage during the rewarming period, according to a new study. The finding, published online in JAMA Neurology, could lead to better ways to protect these vulnerable patients during an often overlooked yet critical period of hypothermia therapy.
“A wealth of evidence has shown that cooling babies who don’t receive enough oxygen during birth can improve their neurodevelopmental outcomes, but few studies have looked at events that occur as they are rewarmed to a normal body temperature,” said study leader Lina Chalak, MD, MSCS, Professor at UT Southwestern. “We’re showing that there’s a significantly elevated risk of seizures during the rewarming period, which typically go unnoticed and can cause long-term harm.”
Millions of newborns around the world are affected by neonatal hypoxic-ischaemic encephalopathy (HIE), brain damage initially caused by hypoxia during birth. Although the World Health Organization estimates that birth asphyxia is responsible for nearly a quarter of all neonatal deaths, those babies that survive oxygen deprivation are often left with neurological injuries, Dr Chalak explained.
To help improve outcomes, babies diagnosed with HIE are treated with hypothermia, using a cooling blanket that brings the body temperature down to as low as 33.5°C, said Dr. Chalak.
Studies initially showed that during cooling, babies with HIE commonly have symptomless seizures, which are neurological events that can further damage the brain, prompting the addition of electroencephalographic (EEG) monitoring to the hypothermia protocol. However, Dr Chalak explained, babies typically haven’t been monitored during the rewarming period, in which the temperature of the blanket is increased by 0.5°C every hour.
To better understand seizure risk during rewarming, Dr. Chalak and colleagues studied 120 babies who were enrolled in another study that compared two different cooling protocols, one longer and colder than the other. The babies in the study were also monitored with EEG to check for seizures both during the cooling and the rewarming phases of hypothermia.
When the researchers compared data from the last 12 hours of cooling and the first 12 hours of rewarming, they found that rewarming roughly tripled the odds of seizures. Additionally, babies who had seizures during rewarming, there was twice the risk of mortality or neurological disability by age 2, compared with those who didn’t have seizures during this period. This finding held true even after adjusting for differences in medical centers and the newborns’ HIE severity.
While it is not known how to prevent seizures from occurring in babies with HIE, treating seizures when they do occur can help prevent further brain damage, Dr Chalak said. Thus, monitoring during both cooling and rewarming can help protect the babies’ brains from further insults while they heal.
“This study is telling us that there’s an untapped opportunity to improve care for these babies during rewarming by making monitoring a standard part of the protocol,” said Dr Chalak.
A study of five Russian cosmonauts who had stayed on the International Space Station (ISS) reveals that extended time in space causes signs of brain injury. The study is published in the scientific journal JAMA Neurology.
Scientists followed five male Russian cosmonauts working on the permanently manned International Space Station (ISS), in an orbit 400km above the surface of the Earth.
Early on in spaceflight history, extended time in zero gravity was found to result in muscle atrophy and bone loss. More recently, changes in vision were discovered during long flights, a potentially serious hazard. The vision changes were ascribed to increased cerebral pressurecaused by the lack of gravity no longer pulling fluid into the lower extremities. On Earth this is similar to lying with a head-down tilt, causing fluids to pool in the upper body and head.
Blood samples were taken from the cosmonauts, whose mean age was 49, 20 days before their departure to the ISS, where they had an average stay of 169 days.
After landing on Earth, follow-up blood samples were taken one day, one week, and about three weeks after landing. Concentrations of three of the biomarkers analysed – NFL, GFAP and the amyloid beta protein Aβ40 – were increased after their stay in space. The peak readings did not occur simultaneously after the men’s return to Earth, but their biomarker trends nonetheless broadly tallied over time.
“This is the first time that concrete proof of brain-cell damage has been documented in blood tests following space flights. This must be explored further and prevented if space travel is to become more common in the future,” said Henrik Zetterberg, professor of neuroscience and one of the study’s two senior coauthors.
”To get there, we must help one another to find out why the damage arises. Is it being weightless, changes in brain fluid, or stressors associated with launch and landing, or is it caused by something else? Here, loads of exciting experimental studies on humans can be done on Earth,” he continued.
Changes also seen in magnetic resonance imaging (MRI) of the brain after space travel add evidence to the notion of spaceflight causing brain injurt. Clinical tests of the men’s brain function that show deviations linked to their assignments in space further support this, but the present study was too small to investigate these associations in detail.
Prof Zetterberg and his coauthors are currently discussing follow-up studies.
“If we can sort out what causes the damage, the biomarkers we’ve developed may help us find out how best to remedy the problem,” Prof Zetterberg said.
New research from the University of Connecticut has brought the drug-free technology of electrical anaesthesia for all chronic pain sufferers a step closer.
Pain stimuli, or ‘nociceptive stimuli’ is picked up by nociceptors which send signals to the spinal cord, which passes it on to the brain where the perception of pain is manifested.
Bin Feng, associate professor in the Biomedical Engineering Department, led research which discovered how electrical stimulation of the dorsal root ganglia (DRG), sensory neural cell body clusters, can block nociceptive signal transmission to the spinal cord and prevent the brain from perceiving chronic pain signals. The findings are reported in PAIN.
Electrical devices to treat pain typically deliver electrical signals to the peripheral nervous system and spinal cord to block nociceptive signals from reaching the brain.
A major obstacle with these devices is that while some patients find them beneficial in relieving their chronic pain, others have little or no pain reduction. Despite incremental developments of neurostimulator technologies, there has not been much improvement in getting the devices to work for these patients.
“The trouble with this technology is that it can benefit a portion of patients very well, but for a larger portion of patients it has little benefit,” Prof Feng said.
One of the reasons is that such devices lag behind research into neural stimulation.
“We’re sitting on a huge pile of clinical data,” Prof Feng says. “But the science of neuromodulation remains understudied.”
Neurostimulators relieve pain according to a ‘gate control’ theory. Our bodies can detect both innocuous stimuli, like something brushing against the skin, and painful stimuli, through low- and high-threshold sensory neurons, respectively.
The spinal cord ‘gate’ can be shut by activating low-threshold sensory neurons, preventing painful nociceptive signals from high-threshold sensory neurons from crossing the spinal cord to the brain.
Neurostimulators reduce pain in patients by activating low-threshold sensory neurons with electrical pulses. This usually causes a non-painful tingling sensation in certain areas of the skin, or paresthaesia, masking the perception of pain.
Many patients receiving DRG stimulation treatment reported pain relief without the expected paraesthesia.
Seeking to understand this, Prof Feng’s lab discovered that electrical stimulation to the DRG can block transmission to the spinal cord at frequencies as low as 20 hertz. This is in contrast to previous research indicating that blocking requires kilohertz electrical stimulation.
“The cell bodies of sensory neurons form a T-junction with the peripheral and central axons in the DRG,” Feng says. “This T-junction appears to be the region that causes transmission block when DRG is stimulated.”
More remarkably, sensory nerve fibres with different characteristics are blocked by different electrical stimulation frequency ranges at the DRG, allowing the development of new neural stimulation protocols to enhance selective transmission blocking with different sensory fibre types.
“A-fibre nociceptors with large axon diameters are generally responsible for causing acute and sharp pain,” Prof Feng explained. “It is the long-lasting and dull-type pain that bothers the chronic pain patients mostIn a chronic pain condition, C-fibre nociceptors with small axon diameter and no myelin sheath play central role in the persistence of pain. Selectively blocking C-fibres while leaving A-fibres intact can be a promising strategy to target the cause of chronic pain.”
This provides evidence to place more electrodes for devices that target the DRG and surrounding neuronal tissues, letting doctors provide more precise neuromodulation.
“The next-generation neurostimulators will be more selective with fewer off-target effects,” Prof Feng said. “They should also be more intelligent by incorporating chemical and electrical sensory capabilities and ability to communicate bidirectionally to a cloud-based server.”
Prof Feng hopes that more people will be eventually able to achieve chronic pain relief with this technology. He is now working toward conducting clinical studies with his collaborators at UConn Health to test the efficacy of this method in humans.
Researchers have discovered that there are brain waves and regions sensitive to team flow (ie, being ‘in the zone’ together) compared to non-engaging teamwork or a solo flow.
Flow experiences are considered to be some of the most enjoyable, rewarding, and engaging experiences of all, and typically involve automatic and effortless action coupled with intense focus. The benefits of having flow experiences are still being catalogued, but include improved overall quality of life, increased self-efficacy, and a stronger sense of self.
This is the first study to objectively measure this psychological state. These neural correlates not only can be used to understand and predict the team flow experience, but could be used to monitor and predict team performance. This is an area the authors are currently investigating/ Team flow is experienced when team players get ‘in the zone’ to accomplish a task together. Successful teams experience this psychological phenomenon, ranging from sports to bands and even in the office. When teamwork reaches the team flow level, one can observe the team perform in harmony, breaking their performance limits.
In order to investigate neural processing of this team flow state, something which has been a challenge for decades, it has to be reproduced in the lab and measured.
Researchers at at Toyohashi University of Technology and California Institute of Technology found solutions to these challenges and provided the first neuroscience evidence of team flow. Using 10 teams of two playing a music video game together, the researchers measured the team members’ brain activity using EEG. In some trials, a partition separated the teammates so they couldn’t see each other while they played, allowing a solo flow state but preventing team flow.
The research team scrambled the music in other trials, thereby preventing a flow state but still enabling teamwork. Participants also answered questions after each game to assess their level of flow. The researchers also developed an objective neural method to evaluate the depth of the team flow experience. Team flow was marked by a unique signature: increased beta and gamma brain waves in the middle temporal cortex, a type of brain activity linked to information processing. In comparison to the regular teamwork state, teammates also had more synchronised brain activity during the team flow state.
Neural models from this study can inform more effective team-building strategies in areas where human performance and pleasure matters, such as sports, business and music. This will also enable improved team performance.
Enhancing performance while maintaining enjoyment will improve quality of life, which could result in reduced mental health problems.
By using hot and cold massage stones, scientists have found that the brain’s prefrontal cortex conjures up sensations based on other sensory information, such as feeling warmth when viewing a beach.
Publishing their findings in The Journal of Neuroscience, the researchers investigated patterns of neural activity in the prefrontal cortex as well as the other regions of the brain known to be responsible for processing stimulation from all the senses and discovered significant similarities.
“Whether an individual was directly exposed to warmth, for example, or simply looking at a picture of a sunny scene, we saw the same pattern of neural activity in the prefrontal cortex,” said Dirk Bernhardt-Walther, an associate professor in the department of psychology in the Faculty of Arts & Science, and coauthor of a study published last week in the Journal of Neuroscience describing the findings. “The results suggest that the prefrontal cortex generalizes perceptual experiences that originate from different senses.”
To understand how the human brain processes the torrent of information from the environment, researchers often study the senses in isolation, with much prior work focused on the visual system. Bernhardt-Walther says that while such work is illuminating and important, it is equally important to find out how the brain integrates information from the different senses, and how it uses the information in a task-directed manner. “Understanding the basics of these capabilities provides the foundation for research of disorders of perception,” he said.
Capturing brain activity with functional magnetic resonance imaging (fMRI), the researchers conducted two experiments with the same participants, based on knowing how regions of the brain respond differently depending on the intensity of stimulation.
In the first, the participants viewed images of various scenes, such as beaches, city streets, forests and train stations, and were asked to judge if the scenes were warm or cold and noisy or quiet.
For the second experiment, participants were first handed a series of massage stones that were either heated to 45C or cooled to 9C, and later exposed to a variety of sounds such as birds, people and waves at a beach.
“When we compared the patterns of activity in the prefrontal cortex, we could determine temperature both from the stone experiment and from the experiment with pictures as the neural activity patterns for temperature were so consistent between the two experiments,” said lead author of the study Yaelan Jung, who recently completed her PhD at U of T working with Bernhardt-Walther and is now a postdoctoral researcher at Emory University.
“We could successfully determine whether a participant was holding a warm or a cold stone from patterns of brain activity in the somatosensory cortex, which is the part of the brain that receives and processes sensory information from the entire body – while brain activity in the visual cortex told us if they were looking at an image of a warm or cold scene.”
“Overall, the neural activity patterns in the prefrontal cortex produced by participants viewing the images were the same as those triggered by actual experience of temperature and noise level,” said Dr Jung.
This opens up insights into how the brain processes and represents complex real-world attributes that span multiple senses, even without directly experiencing them.
“In understanding how the human brain integrates information from different senses into higher-level concepts, we may be able to pinpoint the causes of specific inabilities to recognise particular kinds of objects or concepts,” said Bernhardt-Walther.
“Our results might help people with limitations in one sensory modality to compensate with another and reach the same or very similar conceptual representations in their prefrontal cortex, which is essential for making decisions about their environment.”
Researchers in Japan have discovered that capillary blood flow in the brain is increased in mice during the dream-active REM phase of sleep, possibly preventing a buildup of waste products.
Scientists have long wondered why almost all animals sleep, despite the disadvantages to survival of being unconscious. Now, researchers led by a team from the University of Tsukuba have found new evidence of brain refreshing that takes place during a specific phase of sleep: rapid eye movement (REM) sleep, where dreaming occurs.
Previous studies have seen conflicting results when measuring differences in blood flow in the brain between REM sleep, non-REM sleep, and wakefulness using various methods. For this study, the investigators used a technique to directly visualise red blood cell movement in the brain capillaries of mice during awake and asleep states.
“We used a dye to make the brain blood vessels visible under fluorescent light, using a technique known as two-photon microscopy,” explained the senior study author, Professor Yu Hayashi. “In this way, we could directly observe the red blood cells in capillaries of the neocortex in non-anaesthetised mice.”
The researchers also measured electrical activity in the brain to identify REM sleep, non-REM sleep, and wakefulness, and looked for differences in blood flow between these phases.
“We were surprised by the results,” said Professor Hayashi. “There was a massive flow of red blood cells through the brain capillaries during REM sleep, but no difference between non-REM sleep and the awake state, showing that REM sleep is a unique state”
The research team then disrupted the mice’s sleep, resulting in ‘rebound’ REM sleep, which is a stronger form of REM sleep to compensate for the earlier disruption. During rebound REM sleep, blood flow was increased even further, suggesting an association between blood flow and REM sleep strength. However, when the researchers repeated the same experiments in mice without adenosine A2a receptors (blocking these receptors makes you feel more awake after a coffee), there was less of an increase in blood flow during REM sleep, even during rebound REM sleep.
“These results suggest that adenosine A2a receptors may be responsible for at least some of the changes in blood flow in the brain during REM sleep,” said Professor Hayashi.
Given that reduced blood flow in the brain and decreased REM sleep are correlated with the development of Alzheimer’s disease, in which waste products are seen to build up in the brain, this increased blood flow in the brain capillaries during REM sleep could be important for waste removal from the brain. This study highlights the role of adenosine A2a receptors in this process, perhaps leading to the development of new treatments for Alzheimer’s disease and other conditions.
