NS/ New microscopy tool captures data from 1 million neurons simultaneously
Neuroscience biweekly vol. 105, 28th February — 13th March
TL;DR
- Light-bead microscopy has enabled a 100-fold increase in the number of neurons that can be simultaneously recorded.
- A noninvasive treatment may help to counter ‘chemo brain’ impairment often seen in chemotherapy patients: Exposure to light and sound with a frequency of 40 hertz protected brain cells from chemotherapy-induced damage in mice, researchers found.
- Virtual reality exposure plus electric brain stimulation offers a promising treatment for PTSD. Combining two treatments could be a promising option for people, especially military veterans, whose lives are negatively affected by post-traumatic stress disorder, finds a new study. In a clinical trial conducted among U.S. military veterans, participants who received brain stimulation with a low electrical current during sessions of virtual reality exposure reported a significant reduction in PTSD symptom severity.
- Researchers discovered a brain circuit that drives vocalization and ensures that you talk only when you breathe out, and stop talking when you breathe in. This circuit is under control of a brainstem region called the pre-B tzinger complex.
- Scientists have found our visual perception dips as our feet hit the ground. Further understanding this could help develop early diagnostics for neuromuscular or psychiatric illness; understand changes in mobility as we age; or help with sports science and athletic training.
- Researchers have uncovered a strikingly similar suite of changes in gene activity in brain tissue from people with schizophrenia and from older adults. These changes suggest a common biological basis for the cognitive impairment often seen in people with schizophrenia and in the elderly.
- Effortless, enjoyable productivity is a state of consciousness prized and sought after by people in business, the arts, research, education and anyone else who wants to produce a stream of creative ideas and products. That’s the flow, or the sense of being “in the zone.” A new neuroimaging study from Drexel University’s Creativity Research Lab is the first to reveal how the brain gets to the creative flow state.
- A blood test that can accurately detect when someone has not slept for 24 hours has been developed at the University of Birmingham and Monash University. This level of sleep deprivation increases the risk of serious injury or fatality in safety critical situations. Published in Science Advances, the biomarker used a combination of markers found in the blood of healthy volunteers. Together, these markers accurately predicted when the study volunteers had been awake for more than 24 hours under controlled laboratory conditions.
- Brain organoids are important tools, but there are concerns about the possibility of these organoids developing consciousness.
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Simultaneous, cortex-wide dynamics of up to 1 million neurons reveal unbounded scaling of dimensionality with neuron number
by Jason Manley, Sihao Lu, Kevin Barber, Jeffrey Demas, Hyewon Kim, David Meyer, Francisca Martínez Traub, Alipasha Vaziri in Neuron
The mammalian brain is a web of densely interconnected neurons, yet one of the mysteries in neuroscience is how tools that capture relatively few components of brain activity have allowed scientists to predict behavior in mice. It is hard to believe that much of the brain’s complexity is irrelevant background noise. “We wondered why such a redundant and metabolically costly scheme would have evolved,” says Rockefeller’s Alipasha Vaziri.
Now, a new study in Neuron — which presents an unprecedented simultaneous recording of the activity of one million neurons in mice — offers a surprising answer to this fundamental question: technological limitations have misled us, and there’s far more to the brain than once thought.
“Previous assumptions about the true dimensionality of the brain dynamics might have been due the lack of ability to record from sufficiently large number of neurons,” Vaziri says.
Using a custom technique developed in the Vaziri lab, the researchers discovered that more than 90 percent of the dimensions they observed in neural activity (independent components that one needs in order to describe the observed neuronal dynamics that contain signals that are different from noise) were not connected to any spontaneous movements or sensory inputs in the mice studied. Thousands of these dimensions, containing more than half of the cumulative neural activity of the mice, were spread across the brain in space and time, without forming distinct clusters in any one region and ranging in time from minutes to less than seconds.
The mouse was using this thrum of pervasive, continuous activity for some purpose. But for what?
“We still don’t know, but it’s definitely a signal that is distinct from noise,” Vaziri says. “It could offer a window into to a variety of complex internal states or neurocomputation.”
Vaziri’s lab focuses on the development of optical technologies to advance neuroscience and allow observations of the simultaneous activity of many neurons distributed across the brain. In 2021 the lab developed light-beads microscopy, a two-photon imaging technique that uniquely enabled a 100-fold increase in the number of neurons that could be simultaneously recorded. Putting the technology to the test, the researchers recorded the activity of more than one million neurons across the entire cortex of the mouse brain for the first time while animals were observed by multiple cameras from different angles as they were engaged in spontaneous and uninstructed behaviors, such as running on a treadmill or grooming.
Having demonstrated the efficacy of the tool, the lab became interested in using it to address fundamental questions in neurobiology.
“We had a tool that could allow us to make discoveries that other technologies could not,” Vaziri says. “So we tried to ask questions that only such a tool could answer. To wit: how much more information are we extracting as we keep recording from more and more neurons, and what does that information represent?”
To investigate, the researchers used LBM in combination with advanced data analysis, computational modeling, and machine learning techniques to study the neural activity of mice as they spontaneously moved and reacted to their environment.
Neural activity linked to animal movements was known to be streamlined into a low-dimensional subspace, allowing previous techniques, which could record fewer neurons, to identify these connections.
“However, it was only thanks to LBM’s capability that we could discover that more than 90 percent of the remaining dimensions contained reliable signals that were distinct from noise, not required for behavior and not explained by environmental stimuli.” Vaziri says.
Unexpectedly, these neurons were also firing everywhere.
“What are they doing? We don’t know,” Vaziri says. “They may underlie a brain-wide network of correlated neural fluctuations, perhaps related to some sort of internal state dynamics such as hunger or motivation.”
How this may apply to the human brain is still far from settled (“the human brain is an ocean compared to the pond of a mouse brain,” Vaziri says) but the findings strongly suggest that we are only beginning to understand the true complexity of the mammalian brain.
LBM is one of the key instruments that will find a home in the Rockefeller Brain Observatory, a new initiative spearheaded by Vaziri to make pioneering, commercially unavailable instruments accessible to neuroscientists “that can do things that are otherwise impossible,” Vaziri says.
The facility is akin to an astronomical observatory, where visiting scientists will be able to conduct research on powerful instruments.
“The idea is that people will be supported by staff as they conduct research using the microscopes in the center,” he says. “It’s something we want to open up to the community within Rockefeller but also to neuroscientists from around the world.”
Vaziri and his team are also helping researchers at several universities, including at Stanford University and UCL-London, replicate LBM technology in their own neuroscience labs. The data they’ve amassed from the current study is also available for analysis by other researchers.
They’re also hoping to increase the range of LBM’s applicability.
“For example, we’d like to welcome research groups that work with different model systems beyond mice — insects, nonhuman primates and so on — so we need to have versions of LBM that are more versatile, robust, and user friendly,” Vaziri says.
Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice
by TaeHyun Kim, Benjamin T. James, Martin C. Kahn, Cristina Blanco-Duque, Fatema Abdurrob, Md Rezaul Islam, Nicolas S. Lavoie, Manolis Kellis, Li-Huei Tsai in Science Translational Medicine
Patients undergoing chemotherapy often experience cognitive effects such as memory impairment and difficulty concentrating — a condition commonly known as “chemo brain.”
MIT researchers have now shown that a noninvasive treatment that stimulates gamma frequency brain waves may hold promise for treating chemo brain. In a study of mice, they found that daily exposure to light and sound with a frequency of 40 hertz protected brain cells from chemotherapy-induced damage. The treatment also helped to prevent memory loss and impairment of other cognitive functions.
This treatment, which was originally developed as a way to treat Alzheimer’s disease, appears to have widespread effects that could help with a variety of neurological disorders, the researchers say.
“The treatment can reduce DNA damage, reduce inflammation, and increase the number of oligodendrocytes, which are the cells that produce myelin surrounding the axons,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the Picower Professor in the MIT Department of Brain and Cognitive Sciences. “We also found that this treatment improved learning and memory, and enhanced executive function in the animals.”
Tsai is the senior author of the new study, which appears today in Science Translational Medicine. The paper’s lead author is TaeHyun Kim, an MIT postdoc.
Several years ago, Tsai and her colleagues began exploring the use of light flickering at 40 hertz (cycles per second) as a way to improve the cognitive symptoms of Alzheimer’s disease. Previous work had suggested that Alzheimer’s patients have impaired gamma oscillations — brain waves that range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory.
Tsai’s studies in mice have found that exposure to light flickering at 40 hertz or sounds with a pitch of 40 hertz can stimulate gamma waves in the brain, which has many protective effects, including preventing the formation of amyloid beta plaques. Using light and sound together provides even more significant protection. The treatment also appears promising in humans: Phase 1 clinical trials in people with early-stage Alzheimer’s disease have found the treatment is safe and does offer some neurological and behavioral benefits.
In the new study, the researchers set out to see whether this treatment could also counteract the cognitive effects of chemotherapy treatment. Research has shown that these drugs can induce inflammation in the brain, as well as other detrimental effects such as loss of white matter — the networks of nerve fibers that help different parts of the brain communicate with each other. Chemotherapy drugs also promote loss of myelin, the protective fatty coating that allows neurons to propagate electrical signals. Many of these effects are also seen in the brains of people with Alzheimer’s.
“Chemo brain caught our attention because it is extremely common, and there is quite a lot of research on what the brain is like following chemotherapy treatment,” Tsai says. “From our previous work, we know that this gamma sensory stimulation has anti-inflammatory effects, so we decided to use the chemo brain model to test whether sensory gamma stimulation can be beneficial.”
As an experimental model, the researchers used mice that were given cisplatin, a chemotherapy drug often used to treat testicular, ovarian, and other cancers. The mice were given cisplatin for five days, then taken off of it for five days, then on again for five days. One group received chemotherapy only, while another group was also given 40-hertz light and sound therapy every day.
After three weeks, mice that received cisplatin but not gamma therapy showed many of the expected effects of chemotherapy: brain volume shrinkage, DNA damage, demyelination, and inflammation. These mice also had reduced populations of oligodendrocytes, the brain cells responsible for producing myelin.
However, mice that received gamma therapy along with cisplatin treatment showed significant reductions in all of those symptoms. The gamma therapy also had beneficial effects on behavior: Mice who received the therapy performed much better on tests designed to measure memory and executive function.
Using single-cell RNA sequencing, the researchers analyzed the gene expression changes that occurred in mice that received the gamma treatment. They found that in those mice, inflammation-linked genes and genes that trigger cell death were suppressed, especially in oligodendrocytes, the cells responsible for producing myelin.
In mice that received gamma treatment along with cisplatin, some of the beneficial effects could still be seen up to four months later. However, the gamma treatment was much less effective if it was started three months after the chemotherapy ended.
The researchers also showed that the gamma treatment improved the signs of chemo brain in mice that received a different chemotherapy drug, methotrexate, which is used to treat breast, lung, and other types of cancer.
“I think this is a very fundamental mechanism to improve myelination and to promote the integrity of oligodendrocytes. It seems that it’s not specific to the agent that induces demyelination, be it chemotherapy or another source of demyelination,” Tsai says.
Because of its widespread effects, Tsai’s lab is also testing gamma treatment in mouse models of other neurological diseases, including Parkinson’s disease and multiple sclerosis. Cognito Therapeutics, a company founded by Tsai and MIT Professor Edward Boyden, has finished a phase 2 trial of gamma therapy in Alzheimer’s patients, and plans to begin a phase 3 trial this year.
“My lab’s major focus now, in terms of clinical application, is Alzheimer’s; but hopefully we can test this approach for a few other indications, too,” Tsai says.
Virtual Reality and Transcranial Direct Current Stimulation for Posttraumatic Stress Disorder
by Mascha van ’t Wout-Frank, Amanda R. Arulpragasam, Christiana Faucher, Emily Aiken, M. Tracie Shea, Richard N. Jones, Benjamin D. Greenberg, Noah S. Philip in JAMA Psychiatry
Combining two treatments could be a promising option for people, especially military veterans, whose lives are negatively affected by post-traumatic stress disorder, a new study shows.
In a clinical trial conducted among U.S. military veterans at the Providence Veterans Affairs Medical Center, participants who received brain stimulation with a low electrical current during sessions of virtual reality exposure reported a significant reduction in PTSD symptom severity.
Study author Noah Philip, a professor of psychiatry and human behavior at Brown University’s Warren Alpert Medical School, said the findings are exciting considering existing challenges in treating patients with PTSD.
“This is a different and innovative way of approaching treatment where we’re combining the best aspects of psychotherapy, neuroscience and brain stimulation to help people get better,” said Philip, who leads mental health research at the Providence V.A. Center for Neurorestoration and Neurotechnology. “There’s a lot of promise here, and that offers hope.”
PTSD is a common psychiatric disorder characterized by intrusive thoughts and recollections, avoidance of trauma-related stimuli, hyperarousal and disturbed mood, the study noted. Initial PTSD treatments often include trauma-focused exposure therapy and medication.
Yet PTSD is particularly difficult to treat in military veterans, Philip said. Medications have significant adverse effects, and exposure therapy can be difficult to tolerate, since it involves describing highly traumatic experiences repeatedly. Up to 50% of patients drop out of traditional exposure therapy, and others decline to even start it.
For the study, Philip, whose background is in psychiatric research of brain simulation, teamed up with Mascha van ‘t Wout-Frank, an associate professor of psychiatry and human behavior (research) at the Warren Alpert Medical School who studies the effect of non-invasive brain stimulation on “fear extinction,” or learning that things that are regarded as harmful can actually be safe and can therefore become tolerable.
“Through exposure therapy, the brain is reprocessing the trauma, and learning that even though the traumatic experience was dangerous, the memories of the traumatic experience, as well as the thoughts and feelings that are conjured up by those memories, are not dangerous — they are safe,” said van ‘t Wout-Frank, an investigator at the V.A. Providence Center for Neurorestoration and Neurotechnology. “This results in a decline in conditioned fear response.” “
A leading theory of PTSD posits that the effectiveness of exposure as a therapy is impaired due to ineffective top-down control of the brain’s amygdala by the ventromedial prefrontal cortex and other brain regions. Affected individuals thus have impaired safety learning and memory, which in healthy people is supported by intact brain function, van ‘t Wout-Frank said.
Transcranial direct current stimulation, which involves administering a constant, low, pain-free electrical current to a part of the brain, is well-suited to potentially augment trauma-focused exposure therapy, van ‘t Wout-Frank said. The non-invasive current may boost neural activity, facilitating top-down control by the ventromedial prefrontal cortex to improve safety learning.
The research team decided to combine transcranial direct current stimulation with virtual reality exposure, which provides a highly immersive sensory experience including visual, tactile and even olfactory stimuli to simulate real-world environments.
To test the combined treatment, the researchers expanded a previous pilot study to conduct a larger, more robust, double-blind study of 54 U.S. military veterans with chronic PTSD. Participants were randomly assigned to receive transcranial direct current stimulation or a sham experience that provided some sensation but not a significant amount or duration of electrical current. In the patients receiving transcranial direct current stimulation, a low (2 milliamp) amount of electricity was targeted to the ventromedial prefrontal cortex during six 25-minute sessions of standardized warzone virtual reality exposure, delivered over two to three weeks.
Participants in the active transcranial direct current stimulation group reported a superior reduction in self-reported PTSD symptom severity at one month. While all participants had meaningful reductions in PTSD symptoms (attributed to the VR procedure), active transcranial direct current stimulation significantly accelerated psychological and physiological adjustment to the virtual reality events between sessions compared with the sham treatment patients.
In the experiment, the virtual reality was generalized to include trauma-inducing elements, but didn’t replicate any one participant’s personal experience.
“It can be difficult for patients to talk about their personal trauma over and over, and that’s one common reason that participants drop out of psychotherapy,” Philip said. “This VR exposure tends to be much easier for people to handle.”
In just two weeks, the combination of electric stimulation plus VR treatment accelerated a process that happens normally during prolonged exposure therapy, but usually takes around 12 weeks to show effects.
What’s more, Philip added, the effects continued to build over time.
“What we found was that people continued to get better after they were done with the treatment, and we started seeing the biggest effects one month later,” Philip said.
Brainstem control of vocalization and its coordination with respiration
by Jaehong Park, Seonmi Choi, Jun Takatoh, Shengli Zhao, Andrew Harrahill, Bao-Xia Han, Fan Wang in Science
MIT researchers have discovered a brain circuit that drives vocalization and ensures that you talk only when you breathe out, and stop talking when you breathe in.
The newly discovered circuit controls two actions that are required for vocalization: narrowing of the larynx and exhaling air from the lungs. The researchers also found that this vocalization circuit is under the command of a brainstem region that regulates the breathing rhythm, which ensures that breathing remains dominant over speech.
“When you need to breathe in, you have to stop vocalization. We found that the neurons that control vocalization receive direct inhibitory input from the breathing rhythm generator,” says Fan Wang, an MIT professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.
Jaehong Park, a Duke University graduate student who is currently a visiting student at MIT, is the lead author of the study, which appears today in Science. Other authors of the paper include MIT technical associates Seonmi Choi and Andrew Harrahill, former MIT research scientist Jun Takatoh, and Duke University researchers Shengli Zhao and Bao-Xia Han.
Located in the larynx, the vocal cords are two muscular bands that can open and close. When they are mostly closed, or adducted, air exhaled from the lungs generates sound as it passes through the cords.
The MIT team set out to study how the brain controls this vocalization process, using a mouse model. Mice communicate with each other using sounds known as ultrasonic vocalizations (USVs), which they produce using the unique whistling mechanism of exhaling air through a small hole between nearly closed vocal cords.
“We wanted to understand what are the neurons that control the vocal cord adduction, and then how do those neurons interact with the breathing circuit?” Wang says.
To figure that out, the researchers used a technique that allows them to map the synaptic connections between neurons. They knew that vocal cord adduction is controlled by laryngeal motor neurons, so they began by tracing backward to find the neurons that innervate those motor neurons.
This revealed that one major source of input is a group of premotor neurons found in the hindbrain region called the retroambiguus nucleus (RAm). Previous studies have shown that this area is involved in vocalization, but it wasn’t known exactly which part of the RAm was required or how it enabled sound production.
The researchers found that these synaptic tracing-labeled RAm neurons were strongly activated during USVs. This observation prompted the team to use an activity-dependent method to target these vocalization-specific RAm neurons, termed as RAmVOC. They used chemogenetics and optogenetics to explore what would happen if they silenced or stimulated their activity. When the researchers blocked the RAmVOC neurons, the mice were no longer able to produce USVs or any other kind of vocalization. Their vocal cords did not close, and their abdominal muscles did not contract, as they normally do during exhalation for vocalization.
Conversely, when the RAmVOC neurons were activated, the vocal cords closed, the mice exhaled, and USVs were produced. However, if the stimulation lasted two seconds or longer, these USVs would be interrupted by inhalations, suggesting that the process is under control of the same part of the brain that regulates breathing.
“Breathing is a survival need,” Wang says. “Even though these neurons are sufficient to elicit vocalization, they are under the control of breathing, which can override our optogenetic stimulation.”
Additional synaptic mapping revealed that neurons in a part of the brainstem called the pre-Bötzinger complex, which acts as a rhythm generator for inhalation, provide direct inhibitory input to the RAmVOC neurons.
“The pre-Bötzinger complex generates inhalation rhythms automatically and continuously, and the inhibitory neurons in that region project to these vocalization premotor neurons and essentially can shut them down,” Wang says.
This ensures that breathing remains dominant over speech production, and that we have to pause to breathe while speaking.
The researchers believe that although human speech production is more complex than mouse vocalization, the circuit they identified in mice plays the conserved role in speech production and breathing in humans.
“Even though the exact mechanism and complexity of vocalization in mice and humans is really different, the fundamental vocalization process, called phonation, which requires vocal cord closure and the exhalation of air, is shared in both the human and the mouse,” Park says.
The researchers now hope to study how other functions such as coughing and swallowing food may be affected by the brain circuits that control breathing and vocalization.
Walking modulates visual detection performance according to stride cycle phase
by Matthew J. Davidson, Frans A. J. Verstraten, David Alais in Nature Communications
For the first time, neuroscientists have established a link between shifts in our visual perception and the cadence of our steps while walking.
The research, published in Nature Communications, shows that the brain processes vision in a rhythmic manner, rising and falling in sensitivity in a cycle that corresponds to the rhythm of our steps. When swinging from one step to the next, human perception is good and reactions fast. During footfall, however, our vision is not as sharp and reactions are slowed.
Lead author Dr Matthew Davidson from the School of Psychology at the University of Sydney said: “This work reveals a previously unknown relationship between perception and movement. It bridges a gap between experimental psychology and our natural, everyday behaviour.”
The study also confirms our understanding of the visual brain sensing the environment in a strobe-like way; our perception takes regular samples of the world before stitching them together to create our seamless experience.
However, the new finding that reveals shifts in our visual perception has important implications for understanding human behaviour, how we interact with our environment and make decisions.
The work was conducted by Dr Matthew Davidson with colleagues Professor David Alais and Professor Frans Verstraten in the School of Psychology, University of Sydney.
Dr Davidson said: “We are consciously aware of a seamless stream of vision but this is deceptive. I use the analogy of a duck swimming on a pond. Beneath the smooth motion on the surface there is a lot cycling activity beneath.”
This study extends earlier work from the same lab showing that perception of vision and sound is cyclic, with our brain taking around eight samples per second.
Professor Alais said: “The critical new finding in this study is that these oscillations in the brain’s sampling of the world slow down when walking to match the step cycle.
“Humans take about two steps per second when walking and generally keep to a consistent rhythm. The reported oscillations in visual sensitivity also occur at about two cycles per second and are locked to the step cycle. In some participants these rhythmic oscillations occur at four cycles per second but these were also locked to the step cycle.”
This work is the first time that visual perception has been finely and continuously sampled during walking. Without virtual reality headsets and motion tracking, it would not be possible.
Dr Davidson said: “Thanks to VR technology we have discovered that our vision moves through a good and a bad phase on every step.”
It is unclear why our brain’s perceptual processes are so closely linked to walking.
Professor Alais said: “One possible explanation is that vision becomes secondary to motor control while your foot is grounded and the next step is planned. Once you are in the swing phase between footfalls, the brain switches back to prioritising perceptual sampling of the world, creating an ongoing perceptual rhythm that harmonises with your step rate.”
The findings open questions that the research team will pursue in further studies. For example, does perception of sound and touch also modulate as we walk? And what about neural activity?
The research team plans to follow up on these questions to further understand the implications.
Dr Davidson said: “An obvious question is whether these oscillations in perception are more pronounced in the elderly given difficulties with balance and coordination as we age.
“It also raises the exciting possibility that we could develop cheap and easy diagnostic tests using VR headsets, or use this information to develop tests for early onset of neuro-muscular disorders or some psychiatric illnesses, which can manifest in abnormal gaits.”
He said it could also be applied to further research in sports science to see if the findings could be applied to optimize decision-making and reaction times in athletes.
Underlying all this research remains a persistent mystery. If the world is sampled by our brains rhythmic pulses, why is our conscious perception so seamlessly smooth?
Professor Verstraten said: “This was once a question for philosophers, but with access to technology neuroscientists have been able to shed light on how the gaps get filled in. The current view is that the brain is a predictive machine that actively constructs perception and predicts what ought to be there and fills in the blanks. But clearly, we need more research to deepen our understanding.”
Researchers tracked the walking of 45 subjects walking back and forth along a 10-metre path in a virtual environment. During each walk (lasting about 9 seconds), subjects were required to respond to between zero and eight random visual stimuli. The same stimuli were also presented in stationary trials. Eye and head movement was tracked along with gait and walking information.
Of the 45 subjects, insufficient data was collected for seven subjects. In the datasets for 38 subjects, reduced perception at footfall was recorded 83 percent of the time.
A concerted neuron–astrocyte program declines in ageing and schizophrenia
by Emi Ling, James Nemesh, Melissa Goldman, Nolan Kamitaki, Nora Reed, Robert E. Handsaker, Giulio Genovese, Jonathan S. Vogelgsang, Sherif Gerges, Seva Kashin, Sulagna Ghosh, John M. Esposito, Kiely Morris, Daniel Meyer, Alyssa Lutservitz, Christopher D. Mullally, Alec Wysoker, Liv Spina, Anna Neumann, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll in Nature
Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have uncovered a strikingly similar suite of changes in gene activity in brain tissue from people with schizophrenia and from older adults. These changes suggest a common biological basis for the cognitive impairment often seen in people with schizophrenia and in the elderly.
In a study published in Nature, the team describes how they analyzed gene expression in more than a million individual cells from postmortem brain tissue from 191 people. They found that in individuals with schizophrenia and in older adults without schizophrenia, two brain cell types called astrocytes and neurons reduced their expression of genes that support the junctions between neurons called synapses, compared to healthy or younger people. They also discovered tightly synchronized gene expression changes in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed expression of a distinct set of genes that support synapses.
The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program (SNAP). Even in healthy, young people, the expression of the SNAP genes always increased or decreased in a coordinated way in their neurons and astrocytes.
“Science often focuses on what genes each cell type expresses on its own,” said Steve McCarroll, a co-senior author on the study and an institute member at the Broad Institute. “But brain tissue from many people, and machine-learning analyses of those data, helped us recognize a larger system. These cell types are not acting as independent entities, but have really close coordination. The strength of those relationships took our breath away.”
Schizophrenia is well-known for causing hallucinations and delusion, which can be at least partly treated with medications. But it also causes debilitating cognitive decline, which has no effective treatments and is common in aging as well. The new findings suggest that the cognitive changes in both conditions might involve similar cellular and molecular alterations in the brain.
“To detect coordination between astrocytes and neurons in schizophrenia and aging, we needed to study tissue samples from a very large number of individuals,” said Sabina Berretta, a co-senior author of the study, an associate professor at Harvard Medical School, and a researcher in the field of psychiatric disorders. “Our gratitude goes to all donors who chose to donate their brain to research to help others suffering from brain disorders and to whom we’d like to dedicate this work.”
McCarroll is also the director of genomic neurobiology for the Broad’s Stanley Center for Psychiatric Research and a professor at Harvard Medical School. Berretta also directs the Harvard Brain Tissue Resource Center (HBTRC), which provided tissue for the study. Emi Ling, a postdoctoral researcher in McCarroll’s lab, was the study’s first author.
The brain works in large part because neurons connect with other neurons at synapses, where they pass signals to one another. The brain constantly forms new synapses and prunes old ones. Scientists think new synapses help our brains stay flexible, and studies — including previous efforts by scientists in McCarroll’s lab and international consortia — have shown that many genetic factors linked to schizophrenia involve genes that contribute to the function of synapses.
In the new study, McCarroll, Berretta, and colleagues used single-nucleus RNA sequencing, which measures gene expression in individual cells, to better understand how the brain naturally varies across individuals. They analyzed 1.2 million cells from94 people with schizophrenia and 97 without.
They found that when neurons boosted the expression of genes that encode parts of synapses, astrocytes increased the expression of a distinct set of genes involved in synaptic function. These genes, which make up the SNAP program, include many previously identified risk factors for schizophrenia. The team’s analyses indicated that both neurons and astrocytes shape genetic vulnerability for the condition.
“Science has long known that neurons and synapses are important in risk for schizophrenia, but by framing the question a different way — asking what genes each cell type regulates dynamically — we found that astrocytes too are likely involved,” said Ling.
To their surprise, the researchers also found that SNAP varied greatly even among people without schizophrenia, suggesting that SNAP could be involved in cognitive differences in healthy humans. Much of this variation was explained by age; SNAP declined substantially in many — but not all — older individuals, including both people with and without schizophrenia.
With better understanding of SNAP, McCarroll says he hopes it might be possible to identify life factors that positively influence SNAP, and develop medicines that help stimulate SNAP, as a way to treat the cognitive impairments of schizophrenia or help people maintain their cognitive flexibility as they age.
In the meantime, McCarroll, Berretta, and their team are working to understand if these changes are present in other conditions such as bipolar disorder and depression. They also aim to uncover the extent to which SNAP appears in other brain areas, and how SNAP affects learning and cognitive flexibility.
Creative flow as optimized processing: Evidence from brain oscillations during jazz improvisations by expert and non-expert musicians
by David Rosen, Yongtaek Oh, Christine Chesebrough, Fengqing (Zoe) Zhang, John Kounios in Neuropsychologia
Effortless, enjoyable productivity is a state of consciousness prized and sought after by people in business, the arts, research, education and anyone else who wants to produce a stream of creative ideas and products. That’s the flow, or the sense of being “in the zone.” A new neuroimaging study from Drexel University’s Creativity Research Lab is the first to reveal how the brain gets to the creative flow state.
The study isolated flow-related brain activity during a creative task: jazz improvisation. The findings reveal the creative flow state involves two key factors: extensive experience, which leads to a network of brain areas specialized for generating the desired type of ideas, plus the release of control — “letting go” — to allow this network to work with little or no conscious supervision.
Led by John Kounios, PhD, professor in the College of Arts and Sciences and Creativity Research Lab director, and David Rosen, PhD, a recent graduate from the College and Johns Hopkins University postdoc — the team determined their results suggest that creative flow can be achieved by training people to release control when they have built up enough expertise in a particular domain.
“Flow was first identified and studied by the pioneering psychological scientist Mihaly Csikszentmihalyi,” said Kounios. “He defined it as ‘a state in which people are so involved in an activity that nothing else seems to matter; the experience is so enjoyable that people will continue to do it even at great cost, for the sheer sake of doing it.’”
Kounios noted that although flow has long been a topic of public fascination as well as the focus of hundreds of behavioral research studies, there has been no consensus about what flow is. Their new study decided between different theories of how flow is involved when people produce creative ideas.
One view is that flow might be a state of highly focused concentration or hyperfocus that shuts out extraneous thoughts and other distractions to enable superior performance on a task. A related theory based on recent research on the neuroscience of creativity is that flow occurs when the brain’s “default-mode network,” a collection of brain areas that work together when a person daydreams or introspects, generates ideas under the supervision of the “executive control network” in the brain’s frontal lobes, which directs the kinds of ideas the default-mode network produces. Kounios likened it to the analogy of a person “supervising” a TV by picking the movie it streams.
An alternative theory of creative flow is that through years of intense practice, the brain develops a specialized network or circuit to automatically produce a specific type of ideas, in this case musical ones, with little conscious effort. In this view, the executive control network relaxes its supervision so that the musician can “let go” and allow this specialized circuit to go on “autopilot” without interference. The research team said the key to this notion is the idea that people who do not have extensive experience at a task or who have difficulty releasing control will be less likely to experience deep creative flow.
The study’s results support the “expertise-plus-release” view of creative flow.
The researchers tested these competing theories of creative flow by recording high-density electroencephalograms (EEGs) from 32 jazz guitar players, some highly experienced and others less experienced. Each musician improvised to six jazz lead sheets (songs) with programmed drums, bass and piano accompaniment and rated the intensity of their flow experience for each improvisation. The resulting 192 recorded jazz improvisations, or “takes,” were subsequently played for four jazz experts individually so they could rate each for creativity and other qualities. The researchers then analyzed the EEGs to discover which brain areas were associated with high-flow takes (compared to low-flow takes).
The high-experience musicians experienced flow more often and more intensely than the low-experience musicians. This shows that expertise enables flow. However, expertise is not the only factor contributing to creative flow.
The EEGs showed that a high-flow state was associated with increased activity in left-hemisphere auditory and touch areas that are involved in hearing and playing music. Importantly, high flow was also associated with decreased activity in the brain’s superior frontal gyri, an executive control region. This is consistent with the idea that creative flow is associated with reduced conscious control, that is, letting go. This previously hypothesized phenomenon has been called “transient hypofrontality.”
For the high-experience musicians, flow was associated with greater activity in auditory and vision areas. However, they also showed reduced activity in parts of the default-mode network, suggesting that the default-mode network was not contributing much to flow-related idea generation in these musicians.
In contrast, the low-experience musicians showed little flow-related brain activity.
“A practical implication of these results is that productive flow states can be attained by practice to build up expertise in a particular creative outlet coupled with training to withdraw conscious control when enough expertise has been achieved,” said Kounios. “This can be the basis for new techniques for instructing people to produce creative ideas.”
Kounios added, “If you want to be able to stream ideas fluently, then keep working on those musical scales, physics problems or whatever else you want to do creatively — computer coding, fiction writing — you name it. But then, try letting go. As jazz great Charlie Parker said, ‘You’ve got to learn your instrument. Then, you practice, practice, practice. And then, when you finally get up there on the bandstand, forget all that and just wail.’”
Accurate detection of acute sleep deprivation using a metabolomic biomarker — A machine learning approach
by Jeppe K, Ftouni S, Nijagal B, et al. in Science Advances
A blood test that can accurately detect when someone has not slept for 24 hours has been developed at the University of Birmingham and Monash University. This level of sleep deprivation increases the risk of serious injury or fatality in safety-critical situations. Published in Science Advances, the biomarker used a combination of markers found in the blood of healthy volunteers. Together, these markers accurately predicted when the study volunteers had been awake for more than 24 hours under controlled laboratory conditions.
The biomarker detected whether individuals had been awake for 24 hours with a 99.2 percent probability of being correct, when compared to their own well-rested sample. When a single sample was considered without the well-rested comparison (similar to a diagnostic blood test), it dropped to 89.1 per cent, which was still very high.
With about 20 per cent of road accidents worldwide caused by sleep deprivation, researchers hope the discovery may inform future tests to quickly and simply identify sleep deprived drivers. The biomarker could also be developed for other situations where sleep deprivation may lead to catastrophic consequences, such as in safety-critical workplaces.
Senior author Professor Clare Anderson led the research while she was with the Monash University School of Psychological Sciences and Turner Institute for Brain and Mental Health. She is now Professor of Sleep and Circadian Science at the University of Birmingham in the UK.
“This is a really exciting discovery for sleep scientists, and could be transformative to the future management of health and safety relating to insufficient sleep,” Professor Anderson said. “While more work is required, this is a promising first step.
“There is strong evidence that less than five hours’ sleep is associated with unsafe driving, but driving after 24 hours awake, which is what we detected here, would be at least comparable to more than double the Australian legal limit of alcohol performance wise.”
The test may be also ideal for future forensic use but further validation is required.
First author Dr Katy Jeppe, from the Monash Proteomics and Metabolomics Platform, previously from the School of Psychological Sciences, said it was difficult to say how soon the test could be developed for post-accident use.
“Next steps would be to test it in a less controlled environment and maybe under forensic conditions, particularly if it was to be used as evidence for crashes involving drivers falling asleep,” Dr Jeppe said.
“Given it’s blood, the test is more limited in a roadside context, but future work could examine whether our metabolites, and therefore the biomarker, are evident in saliva or breath.”
This sleep deprivation biomarker is based on 24 hours or more awake, but can detect down to 18 hours awake. A biomarker for limited sleep over the previous night could be developed but more research is required to combine the time since sleep with the amount of sleep in the predictions.
“Much further work would be needed if laws were to change and a sleep deprivation test introduced on the road or in workplaces,” Dr Jeppe said. “This would include further validation of biomarkers, as well as establishing safe levels of sleep to prevent and recover from impairment, not to mention the extensive legal process.”
“A biomarker for limited sleep over the previous night could be developed, and others have made progress in this respect (Depner et al.).”
Sleep deprivation can have fatal consequences for other safety-critical occupations. Major catastrophes including the Chernobyl nuclear reactor meltdown and the Challenger space shuttle Disaster* are thought to be caused, in part, by human error associated with fatigue.
“Objective tests that identify individuals who present as a risk to themselves or others are urgently needed in situations where the cost of a mistake is fatal,” Professor Anderson said.
“Alcohol testing was a game changer for reducing road crashes and associated serious injuries and fatalities, and it is possible that we can achieve the same with fatigue. But much work is still required to meet this goal.”
The donation of human biological material for brain organoid research: The problems of consciousness and consent
by Kataoka M, Gyngell C, Savulescu J, Sawai T. by Sci Eng Ethics
With advances in neuroscience and the development of new technologies, new ethical considerations have emerged.
This is particularly true for human brain organoids, which are three-dimensional tissues grown from stem cells that partially replicate the characteristics of the human brain. Brain organoids have emerged as important tools for studying brain development and disease, but there are concerns about the possibility of these organoids developing consciousness. This has important implications for research ethics and the need to obtain informed consent from cell donors.
To address these questions, an international team of researchers has sought to shed light on the intricate ethical landscape of brain organoid research, offering insights that will be important for researchers, ethicists, and policymakers alike.
Through a comprehensive literature review and ethical analysis, they examined how the potential for consciousness in brain organoids complicates the process of obtaining informed consent from cell donors. Their study revealed uncertainties in two key aspects: the scientific understanding of consciousness in brain organoids and the moral implications of brain organoid consciousness. These uncertainties pose significant challenges for respecting donor autonomy and determining the scope of consent in human brain organoid research.
To clear these uncertainties, the researchers proposed three tentative methods for obtaining consent from donors. First, to address donor concerns and uncertainties, they advocated for project-specific consent procedures by explicitly informing cell donors that their cells will be used in brain organoid research.
Second, they emphasized the importance of incorporating the abovementioned uncertainties into consent procedures by providing donors with comprehensive information about the potential for brain organoid consciousness and measures implemented to address this.
Finally, they proposed the development of a risk framework for brain organoid research to guide ethical considerations and minimize potential harm. The researchers note that some scientists may believe that such concerns are unwarranted, at least at the current stage. However, they argue that if the goal of human brain organoid research is to contribute to the advancement of science and medicine, and ultimately society as a whole, it is important to conduct research that earns public trust.
Says Dr. Sawai “Ignoring these aspects may lead to short-term success, but it’s unlikely to be sustainable in the long term. Our findings can be considered foundational research that solidifies the ethical groundwork essential for the progression of scientific and medical research.”
The findings of this study have far-reaching implications for the fields of neuroscience and research ethics, especially in terms of how future studies obtain informed consent from cell donors.
As brain organoid research progresses, it is imperative to navigate these ethical complexities, particularly those regarding potential consciousness, with diligence and foresight. By tailoring informed consent procedures and prioritizing ethical oversight, scientists can uphold the principles of autonomy while advancing our understanding of the brain.
This study serves as a call to action for researchers, ethicists, and policymakers to engage in thoughtful discourse and decision-making regarding brain organoid research. By confronting these ethical challenges head-on, scientists can ensure that the quest to understand the brain is guided by ethical principles.
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