NS/ Healthy human brains are hotter than previously thought, research finds
Neuroscience biweekly vol. 61, 28th June — 22nd June
TL;DR
- New research has shown that normal human brain temperature varies much more than we thought, and this could be a sign of healthy brain function. In healthy men and women, where the oral temperature is typically less than 37°C, the average brain temperature is 38.5°C, with deeper brain regions often exceeding 40°C, particularly in women during the daytime.
- The size of our primary visual cortex and the amount of brain tissue we have dedicated to processing visual information at certain locations of visual space can predict how well we can see, a team of neuroscientists has discovered. Its study, which appears in the journal Nature Communications, reveals a new link between brain structure and behavior.
- Humans tend to form groups, which often find themselves in conflict with rival groups. But why do people show such a ready tendency to harm people in opposing groups? A new study led by researchers at Virginia Commonwealth University used functional brain imaging technology to reveal a potential answer: It increases activity in the brain’s reward network.
- Researchers have discovered a small population of neurons near the base of the brain that can induce symptoms of sickness, including fever, appetite loss, and warm-seeking behavior.
- The cerebellum is essential for sensorimotor control but also contributes to higher cognitive functions including social behaviors. Researchers uncovered how dopamine in the cerebellum modulates social behaviors via its action on D2 receptors (D2R). These new findings pave the way to determine whether socially related psychiatric disorders are also associated with altered dopamine receptors expression in specific cerebellar cell types.
- Researchers have found that even the oldest adults can benefit from a game-like intervention that targets cognitive and physical function by combining body movement with tasks that stimulate frontal, temporal, and occipital brain activity to prevent age-associated declines.
- A new study demonstrates the possibility of changing the identity of synapses between neurons, both in vitro and in vivo, through enzymatic means. The results have implications for treating brain diseases caused by malfunctions in synaptic information processing and exchange.
- Researchers have developed a tiny, flexible neural probe that can be implanted for longer time periods to record and stimulate neural activity while minimizing injury to the surrounding tissue. The probe would be ideal for studying small and dynamic areas of the nervous system like peripheral nerves or the spinal cord.
- A research team has demonstrated in-vivo imaging of fine neuronal structures in the mouse cortex through the intact skull at an unprecedented depth of 750 µm below pia, making high-resolution microscopy in the cortex near non-invasive and measurably facilitating the study of the living brain.
- Researchers propose a new method to differentiate signals from the epileptic focus from those recorded in other parts of the brain without the presence of an epileptic seizure. This technique may help detect epilepsy-induced features from these signals much quicker than conventional analysis techniques.
- And more!
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Latest news and research
A daily temperature rhythm in the human brain predicts survival after brain injury
Nina M Rzechorzek, Michael J Thrippleton, Francesca M Chappell, Grant Mair, Ari Ercole, Manuel Cabeleira, Audny Anke, Ronny Beer, Bo-Michael Bellander, Erta Beqiri, Andras Buki, Manuel Cabeleira, Marco Carbonara, et all. by Brain
New research has shown that normal human brain temperature varies much more than we thought, and this could be a sign of healthy brain function. In healthy men and women, where the oral temperature is typically less than 37°C, the average brain temperature is 38.5°C, with deeper brain regions often exceeding 40°C, particularly in women during the daytime.
Previously, human brain temperature studies have relied upon data captured from brain-injured patients in intensive care, where direct brain monitoring is often needed. More recently, a brain scanning technique, called magnetic resonance spectroscopy (MRS), has enabled researchers to measure brain temperature non-invasively in healthy people. Until now, however, MRS had not been used to explore how brain temperature varies throughout the day, or to consider how an individual’s ‘body clock’ influences this.
The new study, led by researchers at the Medical Research Council (MRC) Laboratory for Molecular Biology, in Cambridge, UK, has produced the first 4D map of healthy human brain temperature. This map overturns several previous assumptions and shows the remarkable extent to which brain temperature varies by brain region, age, sex, and time of day. Importantly, these findings also challenge a widely held belief that the human brain and body temperature are the same.
The research, published in the journal Brain, also included an analysis of data from patients with traumatic brain injury, showing that the presence of daily brain temperature cycles strongly correlates with survival. These findings could be used to improve understanding, prognosis, and treatment of brain injury.
To study the healthy brain, the researchers recruited 40 volunteers, aged 20–40 years, to be scanned in the morning, afternoon, and late evening over one day, at the Edinburgh Imaging Facility, Royal Infirmary of Edinburgh.
Crucially, they also gave the participants a wrist-worn activity monitor, allowing genetic and lifestyle differences in the timing of each person’s body clock, or circadian rhythm, to be taken into account. For both ‘night owls’ or ‘morning larks’, knowing the biological time-of-day that each brain temperature measurement was taken at allowed differences between each volunteer’s body clock to be factored into the analysis.
In healthy participants, the average brain temperature was 38.5°C, more than two degrees warmer than that measured under the tongue. The study also found that brain temperature varied depending on:
- time of day,
- brain region,
- sex and menstrual cycle,
- and age.
While the brain surface was generally cooler, deeper brain structures were frequently warmer than 40°C; with the highest observed brain temperature being 40.9°C. Across all individuals, brain temperature showed consistent time-of-day variation by nearly 1°C, with the highest brain temperatures observed in the afternoon, and the lowest at night.
On average, female brains were around 0.4°C warmer than male brains. This sex difference was most likely driven by the menstrual cycle since most females were scanned in the post-ovulation phase of their cycle, and their brain temperature was around 0.4°C warmer than that of females scanned in their pre-ovulation phase.
The results also showed that brain temperature increased with age over the 20-year range of the participants, most notably in deep brain regions, where the average increase was 0.6°C. The researchers propose that the brain’s capacity to cool down may deteriorate with age and further work is needed to investigate whether there is linked with the development of age-related brain disorders.
Dr John O’Neill, Group Leader at the MRC Laboratory for Molecular Biology, said:
“To me, the most surprising finding from our study is that the healthy human brain can reach temperatures that would be diagnosed as fever anywhere else in the body. Such high temperatures have been measured in people with brain injuries in the past, but had been assumed to result from the injury.”
“We found that brain temperature drops at night before you go to sleep and rises during the day. There is good reason to believe this daily variation is associated with long-term brain health — something we hope to investigate next.”
To explore the clinical implications of data obtained from healthy volunteers, the researchers analysed temperature data collected continuously from the brain in 114 patients who had suffered from moderate to severe traumatic brain injury (TBI). The patients’ average brain temperature was 38.5°C, but it varied even more widely, from 32.6 to 42.3°C.
Of 100 patients for whom there was enough data to test for daily rhythms, only a quarter had a daily rhythm in brain temperature. Focusing on predictors of survival in intensive care, the researchers found that absolute brain temperature measurements were of limited use, but daily brain temperature variation was strongly linked with survival — indeed, of TBI patients with a daily brain temperature rhythm only 4% died in intensive care, versus 27% who had no such rhythm.
The researchers caution that larger studies are needed to validate this association, and that the link between brain temperature and survival is correlative only, meaning that daily brain temperature rhythms cannot be assumed to directly increase survival. However, the observed link means that monitoring daily brain temperature cycles in TBI patients might be a promising tool to predict survival and would benefit from further research.
Together with the data from healthy people, the findings of this work raise important questions about the use of interventions to modify or control patient temperature in the clinic.
Dr Nina Rzechorzek, MRC Clinician Scientist Fellow from the MRC Laboratory for Molecular Biology who led the study, said:
“Using the most comprehensive exploration to date of normal human brain temperature, we’ve established ‘HEATWAVE’ — a 4D temperature map of the brain. This map provides an urgently-needed reference resource against which patient data can be compared, and could transform our understanding of how the brain works. That a daily brain temperature rhythm correlates so strongly with survival after TBI suggests that round-the-clock brain temperature measurement holds great clinical value.”
“Our work also opens a door for future research into whether disruption of daily brain temperature rhythms can be used as an early biomarker for several chronic brain disorders, including dementia.”
Linking individual differences in human primary visual cortex to contrast sensitivity around the visual field
by Marc M. Himmelberg, Jonathan Winawer, Marisa Carrasco in Nature Communications
The size of our primary visual cortex and the amount of brain tissue we have dedicated to processing visual information at certain locations of visual space can predict how well we can see, a team of neuroscientists has discovered. Its study, which appears in the journal Nature Communications, reveals a new link between brain structure and behavior.
“We have found that we can predict how well someone can see based on the unique structure of their primary visual cortex,” explains lead author Marc Himmelberg, a postdoctoral researcher in New York University’s Center for Neural Science and Department of Psychology. “By showing that individual variation in the structure of the human visual brain is linked to variation in visual functioning, we can better understand what underlies differences in how people perceive and interact with their visual environment.”
As with fingerprints, the bumps and grooves on each person’s brain surface are unique. However, the significance of these differences is not fully understood, especially when it comes to their impact on behavior, such as distinctions in our ability to see.
In the Nature Communications study, Himmelberg and his co-authors, Jonathan Winawer and Marisa Carrasco, professors in NYU’s Center for Neural Science and Department of Psychology, sought to illuminate the relevance of these brain traits to how we see.
The primary visual cortex (V1) is arranged into a map of the image projected from the eye. But like many kinds of maps, it is distorted, with some parts of the image enlarged compared to others.
“Think of a subway map of New York City which makes Staten Island look smaller than Manhattan,” explains Winawer. “The map maintains some degree of accuracy, but it enlarges regions likely to be of broader interest. Similarly, V1 enlarges the center of the image we see — that is, where our eyes are fixating — relative to the periphery.”
This is because V1 has more tissue dedicated to the center of our field of view. Likewise, V1 also enlarges locations to the left and right of where our eyes are fixating relative to locations above or below, again because of differences in the arrangement of cortical tissue.
Using functional magnetic resonance imaging (fMRI), the scientists mapped the primary visual cortex (or “V1”) size of more than two dozen humans. The researchers also measured the quantity of V1 tissue these individuals have dedicated to processing visual information from different locations in their field of view — locations to the left, right, above, and below fixation.
These participants also undertook a task designed to assess the quality of their vision at the same locations in their field of view as the V1 measurements. The participants discriminated among the orientation of patterns shown on a computer screen, which were used to gauge “contrast sensitivity,” or the ability to make distinctions among images.
Their results showed that differences in V1 surface area could predict measurements of people’s contrast sensitivity. First, people with a large V1 had better overall contrast sensitivity than did those with a small V1 (the largest surface area being 1,776 square millimeters [mm2] and the smallest being 832 mm2). Second, people whose V1 had more cortical tissue processing visual information from a specific region in their field of view had higher contrast sensitivity at that region relative to those with less cortical tissue dedicated to the same region. Third, across participants, higher contrast sensitivity at a specific location (e.g., left) than at another location equidistant from fixation (e.g., above) corresponded to regions with more or less cortical tissue, respectively.
“In sum, the more local V1 surface area dedicated to encoding a specific location, the better the vision at that location,” concludes Carrasco. “Our findings show differences in visual perception are inextricably linked to differences in the structure of the primary visual cortex in the brain.”
Neural Mechanisms of Intergroup Exclusion and Retaliatory Aggression
by Emily Lasko, Abigale C Dagher, Samuel James West, David Chester in Social Neuroscience
Humans tend to form groups, which often find themselves in conflict with rival groups. But why do people show such a ready tendency to harm people in opposing groups?
A new study led by researchers at Virginia Commonwealth University used functional brain imaging technology to reveal a potential answer: It increases activity in the brain’s reward network.
“At a time of deepening political divisions and global conflict, it is crucial for us to understand why people divide each other up into ‘us’ and ‘them’ and then show a profound willingness to harm ‘them,’” said corresponding author David Chester, Ph.D., an associate professor in the Department of Psychology in the College of Humanities and Sciences. “Our findings advance this understanding by suggesting that harming outgroup members is a relatively rewarding experience.”
The researchers had 35 male college students complete a competitive, aggressive task against either a student from their university or from what they were told was a rival university. In reality, participants unknowingly played against a computer program, and no real people were harmed.
They found that participants who were more aggressive against outgroup members (students from a rival university) versus ingroup members (students from their own university) exhibited greater activity in core regions of the brain’s reward circuit — the nucleus accumbens and ventromedial prefrontal cortex — while they decided how aggressive to be.
Both before and after outgroup exclusion, aggression toward outgroup members was positively associated with activity in the ventral striatum during decisions about how aggressive to be toward their outgroup opponent. Aggression toward outgroup members was also linked to greater post-exclusion activity in the rostral and dorsal medial prefrontal cortex during provocation from their outgroup opponent. These altered patterns of brain activity suggest that frontostriatal mechanisms may play a significant role in motivating aggression toward outgroup members.
The findings suggest that harming outgroup members is especially rewarding and associated with the experience of positive emotions. Such psychological reinforcement mechanisms may help explain why humans seem so prone to intergroup conflict, Chester said.
“This finding helps to balance the narrative about the psychological processes that underlie aggression against outgroup members, which typically emphasizes negative emotional states such as anger and fear,” Chester said. “This study showed that positive emotions may play a role in motivating intergroup aggression, which suggests many new directions for future research on this topic and informs potential interventions that seek to reduce group conflict.”
The findings raise the possibility that one day treatments that disrupt the reward of intergroup aggression might help to reduce the costly and persistent human phenomenon of violence toward other groups, Chester said.
Chester is director of the Social Psychology and Neuroscience Lab at VCU, which seeks to understand why people try to harm one another. In the past, the lab has focused on conflicts between two individuals, and sought to remove any element of group membership, identity or partisanship in carefully controlled experiments. This new study, however, is the lab’s first foray into exploring the neural correlates of intergroup aggression.
“These new findings fit nicely with our previous research, which has repeatedly implicated the brain’s reward circuitry (i.e., the nucleus accumbens and ventromedial prefrontal cortex) in promoting aggressive acts,” he said. “We have advanced this line of investigation by showing that such reward activity during aggression exerts even more of an effect in an intergroup context than in a nongroup context.”
While the researchers weren’t surprised by the new findings, they were surprised to find such results even when experimenting with a weak group rivalry.
“Many groups have ancient histories of deep hatred of one another and our use of rival universities didn’t even come close to capturing what many truly problematic intergroup conflicts look like around the world,” Chester said. “We chose such a mild intergroup rivalry for several reasons, a major one being that invoking a deeply rooted intergroup conflict might cause our participants undue distress. But it was still surprising to see such clear results despite our use of a relatively minor intergroup rivalry. I surmise that our observed effect would be even stronger in the context of intergroup conflict between two groups that deeply hate each other.”
The area of the brain implicated in the study is not only associated with reward, it is also involved in other psychological processes such as learning, motivation and identity. While Chester said it is possible that the brain activity was not reflecting the subjective experience of pleasure, decades of brain research suggests that area’s core functions are reliably reward-linked to the point where the researchers felt comfortable making the inference, Chester said. More research would be needed to definitely say that reward is the “culprit underlying intergroup conflict,” he said.
A preoptic neuronal population controls fever and appetite during sickness
by Jessica A. Osterhout, Vikrant Kapoor, Stephen W. Eichhorn, Eric Vaughn, Jeffrey D. Moore, Ding Liu, Dean Lee, Laura A. DeNardo, Liqun Luo, Xiaowei Zhuang, Catherine Dulac in Nature
When someone gets an infection, most people think it’s the immune system kicking into gear when they feel some of the body’s natural defenses like a fever, chills, or fatigue. What most people don’t know is that it’s actually the brain behind all of this.
Here’s what happens: The nervous system talks to the immune system to figure out that the body has an infection and then orchestrates a series of behavioral and physiological alterations that manifest as the unpleasant symptoms of sickness. For neuroscientists, long-standing questions have been: How and where does this happens in the brain? Harvard researchers from the labs of Catherine Dulac and Xiaowei Zhuang sought the answer in the brains of mice.
In a new study published in Nature, the researchers and their collaborators describe finding a small population of neurons near the base of the brain that can induce symptoms of sickness, including fever, appetite loss, and warm seeking behavior.
The neurons, which have not been previously described, are found in an area of the hypothalamus, a part of the brain known for controlling key homeostatic functions that keep the body in a balanced, healthy state. The researchers found these neurons have receptors that are capable of directly detecting molecular signals coming from the immune system, an ability most neurons don’t have.
“It was important for us to establish this general principle that the brain can even sense these immune states,” said Jessica Osterhout, a postdoctoral researcher in the Dulac Lab and the study’s lead author. “This was poorly understood before.”
The researchers found that the key area of the hypothalamus is located right next to a permeable section of the brain called the blood-brain barrier, which helps circulates blood to the brain.
“What’s happening is that the cells of the blood-brain barrier that are in contact with the blood and with the peripheral immune system get activated and these non-neuronal cells secrete cytokines and chemokines that, in turn, activate the population of neurons that we found,” said Dulac, Lee and Ezpeleta Professor of Arts and Sciences and Higgins Professor of Molecular and Cellular Biology.
The hope is that scientists can one day use the knowledge from how this mechanism works to target the process in humans to reverse it when it becomes aversive to someone’s health.
A fever, for instance, is typically a healthy reaction that helps eliminate a pathogen. But when it gets too high, it can also become dangerous. The same can be said for loss of appetite or a lowered thirst, which can, at first, be beneficial. But a sustained lack of nutrients or hydration then start to impede recovery.
“If we know how it works, perhaps we can help patients who have difficulty with these kinds of symptoms, like chemo patients or cancer patients, for example, who have a very low appetite but there’s really nothing we can do for them,” Osterhout said.
The work originally started as an effort to look at what is known as the fever effect in autism patients. It’s a phenomenon where autistic patients have a reduction in autistic symptoms when the patient have symptoms of an infection like a fever. The goal was to find the neurons that generate fever and link them to the neurons that are involved with social behavior.
Instead, Osterhout found many populations of neurons that are activated when an animal is sick. She zeroed in on about 1,000 neurons in ventral medial preoptic area of the hypothalamus because of their location next to the blood-brain barrier.
To find the different areas of neurons that become activated, Osterhout injected mice with pro-inflammatory agents, lipopolysaccharide or polycytidylic acid, which mimic bacterial or viral infection. She analyzed the areas of the brain that lit up in the brain scans.
Osterhout and colleagues then used a powerful and precise set of methods called chemo- and optogenetics to control and investigate the connectivity between the different neuronal populations. Using these tools, they were able to activate or silence these neurons on command in the brains of mice and pin down their function by seeing what happened.
The researchers found that using these tools they could increase body temperature in the mice, increase warmth seeking behavior, and decrease appetite. The report says the neurons they describe project to 12 brain areas, some of which are known to control thirst, pain sensation, and social interactions. This suggests that other sickness behaviors may also be affected by the neuron activity here.
During the experiments, the scientists also noticed increased activity and activation in this population of neurons when molecules from the immune system gave off increased signals. That suggests that the brain and the immune system were communicating with each other through paracrine signaling at the location they focused on — the ventral medial preoptic area and the blood-brain barrier right next to it. Paracrine signaling is when cells produce a signal to trigger changes in nearby cells.
Osterhout said the process expanded her understanding of how neurons work.
“As a neuroscientist, we often think of neurons activating other neurons and not that these other paracrine type or secretion type methods are really critical,” she said. “It changed how I thought about the problem.”
Cognitive and physical benefits of a game‐like dual‐task exercise among the oldest nursing home residents in Japan
by Jieun Yoon, Hiroko Isoda, Tetsuya Ueda, Tomohiro Okura in Alzheimer’s & Dementia: Translational Research & Clinical Interventions
As human lifespans increase, new societal challenges arise. In a “superaging society,” in which young people are few and older people are many, caring for the older adult population adequately with limited resources is a difficult balancing act to perform. However, the hope is that by implementing new knowledge of how to keep aging adults healthy, caring responsibilities may be lightened.
In an article that was recently published in Alzheimer’s & Dementia, a research team from the University of Tsukuba puts their findings that a game-like intervention called Synapsology helps to improve cognitive function and physical capabilities in older adults and its implications into perspective.
In areas of research such as pathological changes to the brain during aging (for example, mild cognitive impairment and dementia), a lot remains unknown. Although drug therapies to treat dementia are available and more are continually being developed, prevention is arguably the most important area of focus in working toward humankind’s goal of healthy long life. Convincing evidence exists that dual-task exercises, which are performed by the brain and body simultaneously, have the potential to be beneficial for the physical and mental health of older adults. However, as highlighted by the World Health Organization, the weak link in this area of research was the lack of translation of dual-task exercises into practice to yield concrete evidence on efficacy.
“We conducted a study to assess the effects of 60-minute sessions of Synapsology twice per week,” says Professor Jieun Yoon. “The exercises combined body movement with tasks that stimulate frontal, temporal, and occipital brain activity. We found that, in comparison with older adults aged 85 to 97 who did not take part, those who did maintained or improved their cognitive and physical abilities over a period of 24 weeks.”
Synapsology is also a cost-effective intervention, because it doesn’t require special tools or facilities. This means that the findings of the study were likely to be useful because Synapsology can be scaled and adapted.
“Furthermore, we used well-known measures to quantify the changes to cognitive and physical function,” adds Professor Yoon, “which means that both the intervention and the assessment can be extended to different populations of older adults to yield sufficient evidence to support the use of this dual-task intervention at a scale that can have a societal impact.”
Some questions remain — such as can an intervention help prevent or delay the onset of Alzheimer disease? The team has already begun research that will address this question by simultaneously monitoring biological changes in the brain from the disease and those that may represent cognitive and physical improvements from Synapsology.
Cerebellar dopamine D2 receptors regulate social behaviors
by Laura Cutando, Emma Puighermanal, Laia Castell, Pauline Tarot, Morgane Belle, Federica Bertaso, Margarita Arango-Lievano, Fabrice Ango, Marcelo Rubinstein, Albert Quintana, Alain Chédotal, Manuel Mameli, Emmanuel Valjent in Nature Neuroscience
The cerebellum is essential for sensorimotor control but also contributes to higher cognitive functions including social behaviors. In a recent study, an international research consortium including scientists from Inserm — University of Montpellier (France), the Institut de Neurociències Universitat Autònoma de Barcelona (INc-UAB) (Spain), and the University of Lausanne (Switzerland) uncovered how dopamine in the cerebellum modulates social behaviors via its action on D2 receptors (D2R). By using different mouse models and genetic tools, the researchers’ work shows that changes in D2R levels in a specific cerebellar cell type, the Purkinje cells, alter sociability and preference for social novelty without affecting motor functions. These new findings pave the way to determine whether socially related psychiatric disorders, such as autism spectrum disorders (ASD), bipolar mood disorder, or schizophrenia, are also associated with altered dopamine receptors expression in specific cerebellar cell types.
Dopamine (DA) neurons are a major component of the brain reward system. By encoding motivational value and salience, they tightly regulate motivation, emotional states, and social interactions. Although the regulation of these processes has been largely ascribed to neural circuits embedded in limbic regions, recent evidence indicates that the cerebellum, a region primarily involved in motor control, may also contribute to higher cognitive functions including social behaviors. However, whether cerebellar dopamine signaling could participate in the modulation of these functions remained unexplored. Researchers from Inserm — Montpellier University (France), the Institut de Neurociències UAB (Spain), and the University of Lausanne (Switzerland) uncovered a new role for dopamine as a modulator of social behaviors in the mouse cerebellum.
By combining cell-type-specific transcriptomics, immunofluorescence analyses and 3D imaging, researchers first demonstrated the presence of dopamine D2 receptors (D2R) in Purkinje cells (PCs), the output neurons of the cerebellar cortex. Using patch-clamp recordings, they were able show D2R modulated synaptic excitation onto PCs.
“This first set of results was already determinant for us, as they unveiled that D2R were present in the cerebellum and that, despite their low expression level, they were functional,” highlights Dr Emmanuel Valjent, research director at Inserm (France), and coordinator of the study.
The researchers then went on to study their functions. By using genetic approaches to invalidate or overexpress D2R selectively in PCs, they analyzed the impact of these alterations on motor and non-motor cerebellar functions.
“We have uncovered an unexpected causal link between PCs D2R expression levels right in the center of the cerebellum, the Crus I/II lobules, and the modulation of social behaviors. Reducing the expression of this specific dopamine receptor impaired the sociability of mice as well as their preference for social novelty, while their coordination and motor functions remained unaffected” explains Dr. Laura Cutando, Marie-Curie researcher at the Mitochondrial Neuropathology research group at INc-UAB, and first author of the article.
This study constitutes a first step towards a better understanding of the role of dopamine in the cerebellum and the mechanisms underlying psychiatric disorders such as schizophrenia, ADHD and anxiety disorders, which have all in common aberrant DA signaing and altered social behaviors.
Phase irregularity: A conceptually simple and efficient approach to characterize electroencephalographic recordings from epilepsy patients
by Anaïs Espinoso, Ralph G. Andrzejak in Physical Review E
Researchers from the UPF Department of Information and Communication Technologies (DTIC) propose a new method to differentiate signals from the epileptic focus from those recorded in other parts of the brain without the presence of an epileptic seizure. This technique may help detect epilepsy-induced features from these signals much quicker than conventional analysis techniques. The results have been published in the journal Physical Review E.
Around 1% of the world’s population suffers from epilepsy, a neurological disorder that causes epileptic seizures. In these seizures, a group of neurons displays abnormal excessive neuronal activity in the brain.
But 9% of all epileptic patients suffer from what is known as pharmacoresistant focal-onset epilepsy. In these patients, epileptic seizures cannot be controlled by medication. For them, one potential therapy is the neurosurgical resection of the brain area where seizures start.
Nevertheless, various diagnostic techniques must be performed to try to locate this focus. The brain’s electrical activity is measured by means of electroencephalography, a technique that uses electrodes to collect the electroencephalographic signals (EEG signals). In this work, signals were used recorded using intracranial electrodes (see photo), directly connected to the surface of the brain, to record the patient’s electrical activity and thus locate the focus.
But, does this study seek to pinpoint exactly where in the brain the epileptic seizure begins? Anaïs Espinoso, a PhD researcher with the “Nonlinear Time Series Analysis” (NTSA) research group at UPF and first author of the publication, explains that “this is not the goal of the work, the signals of the epileptic focus have a different dynamic from those that do not come directly from the focus. We study these dynamics and we want to achieve the technique that can best accentuate the differences between the two types of signals.”
For this reason, they studied the signals produced by five patients suffering from pharmacoresistant focal-onset epilepsy. They applied EEG signal analysis techniques to see various aspects such as phase synchronization and irregularity, a conceptually simple and effective approach to characterize electroencephalographic recordings of patients with epilepsy.
Espinoso explains that “many studies of electroencephalographic signals apply complex techniques that encourage the analysis of a large number of patients. These studies, moreover, analyse the signal directly, but this can be altered by physiological artefacts or during the signal acquisition process.”
“It is a simple and effective method that allows analysing various signals very quickly, and you also don’t have to wait for the person to suffer an epileptic fit to get results. Suffering a fit can lead to a number of problems for the patient, such as seizures, involuntary muscle movements, loss of consciousness, etc. Thus, signals without epileptic fits gain in importance when it comes to supplementing the diagnosis”
For this reason, in this study, the authors obtain the instantaneous phase of the signals.
“Obtaining the phase is nothing more than considering that the dynamic of the signal oscillates in a circle every certain amount of time and indicating its position in this circle at every point of time,” explains Ralph Gregor Andrzejak, director of the NTSA group and co-author of the publication. “Hence, signal analysis techniques to try to differentiate the signals of the epileptic focus (focal signals) from others recorded in different parts of the brain (non-focal signals) directly analyse this phase.”
The results showed that focal signals are more synchronized than non-focal signals.
As for phase irregularity, this technique also enables differentiating both types of signals, “focal signals have fewer irregularities than the non-focal ones, the absence of these irregularities is induced by the epileptic process itself,” Espinoso continues. “In highly simplified terms, the brain signals involved in the seizure tend to synchronize more easily and be more regular.”
The technique in question, the authors point out, is to quantify the irregularity of the phase obtained from the signal. Espinoso explains that
“irregularity can be due to several reasons: the noise, non-linearity, stochasticity and non-stationarity of the signal phase.”
Andrzejak comments that they had previously studied these signals with other analysis techniques and had not achieved such a high level of difference as in this article.
This technique has several advantages.
“It is a simple and effective method that allows analysing various signals very quickly, and you also don’t have to wait for the person to suffer an epileptic fit to get results. Suffering a fit can lead to a number of problems for the patient, such as seizures, involuntary muscle movements, loss of consciousness, etc. Thus, signals without epileptic seizures gain importance when it comes to supplementing the diagnosis,” they conclude.
The concept of open science is the idea that scientific research should be accessible to everyone, free of charge. For this reason, the authors of this article have published in public repositories the results and codes obtained in the study. Thus, Espinoso clarifies, “it will be possible to advance in the study of epilepsy more quickly with the help of other researchers.” An unformatted version of the article can be found in the UPF e-Repository. This research is part of Espinoso’s doctoral thesis and was carried out with the support of the Spanish Ministry of Science and Innovation and the State Research Agency.
Induction of synapse formation by de novo neurotransmitter synthesis
Scott R. Burlingham, Nicole F. Wong, Lindsay Peterkin, Lily Lubow, Carolina Dos Santos Passos, Orion Benner, Michael Ghebrial, Thomas P. Cast, Matthew A. Xu-Friedman, Thomas C. Südhof, Soham Chanda in Nature Communications
As you’re reading this sentence, the cells in your brain, called neurons, are sending rapid-fire electrical signals between each other, transmitting information. They’re doing so via tiny, specialized junctions between them called synapses.
There are many different types of synapses that form between neurons, including “excitatory” or “inhibitory,” and the exact mechanisms by which these structures are generated remain unclear to scientists. A Colorado State University biochemistry lab has uncovered a major insight into this question by showing that the types of chemicals released from synapses ultimately guide which kinds of synapses form between neurons.
Soham Chanda, assistant professor in the Department of Biochemistry and Molecular Biology, led the study published in Nature Communications that demonstrates the possibility of changing the identity of synapses between neurons, both in vitro and in vivo, through enzymatic means. The other senior scientists who contributed to the project were Thomas Südhof of Stanford University and Matthew Xu-Friedman of the University at Buffalo.
In the lab, Chanda and colleagues were able to make synapses changes between excitatory and inhibitory types, using only enzymes, by making the neurons express just a few genes that induced a cascade of changes in the synapses’ machinery. Such a breakthrough could have major implications for treating brain diseases that are caused by malfunctions in synaptic information processing and exchange.
“We know very little about how the human brain functions, and at the center of it, we need to understand how neurons communicate with each other,” Chanda said. “Understanding the fundamental mechanisms of synapse formation and maintenance has tremendous implications in understanding brain disorders.”
Their results show that the cell-adhesion proteins expressed in the synaptic junction area are not the only purveyors of the synapses’ function, as some have thought; rather, chemicals called neurotransmitters that are released from the presynaptic site (where the information is coming from) also seem to play a major role in controlling which types of synapses form, and where.
The CSU team used stem cell-derived human neurons to demonstrate their ability to produce certain types of synaptic connections by controlled release of specific neurotransmitters. Collaborators at the University at Buffalo showed the same phenomenon in live mouse brains.
“Synapses need lots of other machinery; the neurons took care of all that and turned excitatory synapses into inhibitory ones — a fundamental change in their identity,” Xu-Friedman said.
Chanda is fascinated by neurons, “because no other cell type in the human body has the same level of functional complexity that is tied so closely to their shape and structure.”
Deep tissue multi-photon imaging using adaptive optics with direct focus sensing and shaping
by Zhongya Qin, Zhentao She, Congping Chen, Wanjie Wu, Jackie K. Y. Lau, Nancy Y. Ip, Jianan Y. Qu in Nature Biotechnology
A research team from the Hong Kong University of Science and Technology (HKUST) has demonstrated for the first time in-vivo imaging of fine neuronal structures in mouse cortex through the intact skull at an unprecedented depth of 750 µm below pia, making high-resolution microscopy in cortex near non-invasive and measurably facilitating the study of the living brain.
The direct and non-invasive visualization of neurons, glia, and microvasculature in the brain in vivo is critical for enhancing our understanding of how the brain functions. Over recent decades, great effort has been focused on developing novel techniques for in vivo imaging of the intact brain. However, none of the prevalent technologies, including ultrasound imaging (sonography), positron emission tomography (PET), and magnetic resonance imaging (MRI), provides sufficient spatial resolution to visualize biological structures at the subcellular level.
While optical microscopy such as three-photon microscopy (3PM) can provide structural and functional information in living specimens at high spatiotemporal resolution, optical aberration and scattering occur as light travels through and interacts with inhomogeneous biological tissues, fundamentally limiting the performance of optical microscopy in both resolution and depth.
Although adaptive optics (AO) is a possible solution to correct for the aberration and restore the rsolution of in vivo optical microscopy, it is not without shortcomings: the guide star signal for the conventional wavefront sensing fades away quickly when imaging depth increases.
Now, co-led by Prof. QU Jianan, professor in Department of Electronic and Computer Engineering, and Prof. Nancy IP, chair professor in Division of Life Science, an HKUST research team developed a microscope that combines 3PM with two forms of AO, demonstrating fast measurements and the correction of both low-order and high-order aberrations in tissue at great depth.
The technology makes use of two AO techniques: direct focus sensing with phase-sensitive detection and conjugate adaptive optics (CAO) with remote focusing. The guide star signal is coded and then decoded in the aberration measurement to achieve AO correction of aberrations. These enable the accurate measurement of the aberrant electric-field point-spread function of a laser in tissue and the fast correction of the aberration over a large imaging volume in the brain.
The team validated the imaging performance of the AO-3PM system using a wavelength of 1300 nm, imaging through intact skull both in vivo and on in vitro preparations. The results showed that AO-3PM achieved high spatial resolution with a drastically improved fluorescence signal over a large depth, and high-resolution in vivo structural and functional imaging of mouse cortices through the intact skull up to 750 µm below the pia mater.
Further, by using a pupil AO-3PM, the team achieved high-resolution imaging of subcortical structures up to 1.1 mm below the pia mater within the intact brain. Taking advantage of the tight focus provided by their unique AO technique, the team went on to demonstrate the capability of AO-3PM to guide precise laser microsurgery and investigate post-operative microglial dynamics in the cortex through the intact skull.
“It is absolutely fun to exploit the marriage of electronics and optics to bring a new tool for experimental biology,” Prof. Qu said. “Overall, our results demonstrate that AO-3PM technology holds great potential to advance in vivo imaging techniques and facilitate study of living brain.”
“It is truly remarkable what this state-of-the-art AO-3PM system can achieve,” Prof. Ip explained, “the high performance and unparalleled accuracy of this advanced deep-brain imaging technology will substantially widen our understanding of living brain with optimal physiological representation.”
Electro-optical mechanically flexible coaxial microprobes for minimally invasive interfacing with intrinsic neural circuits
by Spencer Ward, Conor Riley, Erin M. Carey, Jenny Nguyen, Sadik Esener, Axel Nimmerjahn, Donald J. Sirbuly in Nature Communications
Researchers at the University of California San Diego and the Salk Institute for Biological Studies have developed a tiny neural probe that can be implanted for longer time periods to record and stimulate neural activity, while minimizing injury to the surrounding tissue.
The new neural probe, detailed in a paper published in Nature Communications, is extremely thin — about one-fifth the width of a human hair — and flexible. The team says that this type of neural probe would be ideal for studying small and dynamic areas of the nervous system like peripheral nerves or the spinal cord.
“This is where you’d need a really small, flexible probe that can fit in between vertebrae to interface with neurons and can bend as the spinal cord moves,” said Axel Nimmerjahn, associate professor at the Salk Institute and co-senior author of the study.
These features also make it more compatible with biological tissue and less prone to triggering an immune response, which in turn make it suitable for long-term use.
“For chronic neural interfacing, you want a probe that’s stealthy, something that the body doesn’t even know is there but can still communicate with neurons,” said study co-senior author Donald Sirbuly, professor of nanoengineering at the UC San Diego Jacobs School of Engineering.
While there are other ultra-thin, flexible probes out there, what sets this small probe apart is that it can both record the electrical activity of neurons and stimulate specific sets of neurons using light.
“Having this dual modality — electrical recording and optical stimulation — in such a small footprint is a unique combination,” said Sirbuly.
The probe consists of an electrical channel and an optical channel. The electrical channel contains an ultra-thin polymer electrode. The optical channel contains an optical fiber that is also ultra-thin. Putting these two channels together required some clever engineering. The researchers needed to figure out how to insulate the channels to keep them from interfering with each other and have them both fit into a tiny probe measuring just 8 to 14 micrometers in diameter, all while making sure that the device was mechanically flexible, robust, biocompatible and able to perform on par with state-of-the-art neural probes. This involved finding the right combination of materials to build the probe and optimizing the fabrication of the electrical channel.
The team implanted the probes in the brains of live mice for up to one month. The probes caused hardly any inflammation in the brain tissue after prolonged implantation. As the mice moved about in a controlled environment, the probes were able to record electrical activity from neurons with high sensitivity. The probes were also used to target specific neuron types to produce certain physical responses. Using the probes’ optical channels, the researchers stimulated neurons in the cortex of the mice to move their whiskers.
These tests in brain tissue were done as a proof of concept. The team hopes to perform future studies in the spinal cord using their probe.
“Currently, we know relatively little about how the spinal cord works, how it processes information, and how its neural activity might be disrupted or impaired in certain disease conditions,” said Nimmerjahn. “It has been a technical challenge to record from this dynamic and tiny structure, and we think that our probes and future probe arrays have the unique potential to help us study the spinal cord — not just understand it on a fundamental level, but also have the ability to modulate its activity.”
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