The Mozart effect myth: Listening to music does not help against epilepsy

Over the past fifty years, there have been remarkable claims about the effects of Wolfgang Amadeus Mozart's music. Reports about alleged symptom-alleviating effects of listening to Mozart's Sonata KV448 in epilepsy attracted a lot of public attention. However, the empirical validity of the underlying scientific evidence has remained unclear. Now, University of Vienna psychologists Sandra Oberleiter and Jakob Pietschnig show in a new study published in the journal Nature Scientific Reports that there is no evidence for a positive effect of Mozart's melody on epilepsy.

In the past, Mozart's music has been associated with numerous ostensibly positive effects on humans, animals, and even microorganisms. For instance, listening to his sonata has been said to increase the intelligence of adults, children, or fetuses in the womb. Even cows were said to produce more milk, and bacteria in sewage treatment plants were said to work better when they heard Mozart's composition.

However, most of these alleged effects have no scientific basis. The origin of these ideas can be traced back to the long-disproven observation of a temporary increase in spatial reasoning test performance among students after listening to the first movement allegro con spirito of Mozart's sonata KV448 in D major.

More recently, the Mozart effect experienced a further variation: Some studies reported symptom relief in epilepsy patients after they had listened to KV448. However, a new comprehensive research synthesis by Sandra Oberleiter and Jakob Pietschnig from the University of Vienna, based on all available scientific literature on this topic, showed that there is no reliable evidence for such a beneficial effect of Mozart's music on epilepsy. They found that this alleged Mozart effect can be mainly attributed to selective reporting, small sample sizes, and inadequate research practices in this corpus of literature. "Mozart's music is beautiful, but unfortunately, we cannot expect relief from epilepsy symptoms from it" conclude the researchers.

From Science Daily

Scientists can control brain circuits, behavior, and emotion using light

Controlling signal transmission and reception within the brain circuits is necessary for neuroscientists to achieve a better understanding of the brain's functions. Communication among neuron and glial cells is mediated by various neurotransmitters being released from the vesicles through exocytosis. Thus, regulating vesicular exocytosis can be a possible strategy to control and understand brain circuits.

However, it has been difficult to freely control the activity of brain cells in a spatiotemporal manner using pre-existing techniques. One is an indirect approach that involves artificially controlling the membrane potential of cells, but it comes with problems of changing the acidity of the surrounding environment or causing unwanted misfiring of neurons. Moreover, it is not applicable for use in cells that do not respond to the membrane potential changes, such as glial cells.

To address this problem, South Korean researchers led by Director C. Justin LEE at the Center for Cognition and Sociality within the Institute for Basic Science (IBS) and professor HEO Won Do at Korea Advanced Institute of Science and Technology (KAIST) developed Opto-vTrap, a light-inducible and reversible inhibition system that can temporarily trap vesicles from being released from brain cells. Opto-vTrap directly targets transmitters containing vesicles, and it can be used in various types of brain cells, even the ones that do not respond to membrane potential changes.

In order to directly control the exocytotic vesicles, the research team applied a technology they previously developed in 2014, called light-activated reversible inhibition by assembled trap (LARIAT). This platform can inactivate various types of proteins when illuminated under blue light by instantly trapping the target proteins, like a lariat. Opto-vTrap was developed by applying this LARIAT platform to vesicle exocytosis. When the Opto-vTrap expressing cells or tissues are shined under blue light, the vesicles form clusters and become trapped within the cells, inhibiting the release of transmitters.

Most importantly, the inhibition triggered using this new technique is temporary, which is very important for neuroscience research. Other previous techniques that target vesicle fusion proteins damage them permanently and disable the target neuron for up to 24 hours, which is not appropriate for many behavioral experiments with short time constraints. By comparison, vesicles that were inactivated using Opto-vTrap decluster in about 15 minutes, and the neurons regain their full functions within an hour.

Opto-vTrap directly controls the signal transmitters' release, enabling the researchers to freely control brain activity. The research team verified the usability of Opto-vTrap in cultured cells and brain tissue slices. Furthermore, they tested the technique in live mice, which enabled them to temporarily remove fear memory from fear-conditioned animals.

In the future, Opto-vTrap will be used to uncover complex interactions between multiple parts of the brain. It will be a highly useful tool for studying how certain brain cell types affect brain function in different circumstances.

Professor Heo stated, "Since Opto-vTrap can be used in various cell types, it is expected to be helpful in various fields of brain science research," He explained, "We plan to conduct a study to figure out the spatiotemporal brain functions in various brain cell types in a specific environment using Opto-vTrap technology."

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Preventing the long-term effects of traumatic brain injury

You've been in a car accident and sustained a head injury. You recovered, but years later you begin having difficulty sleeping. You also become very sensitive to noise and bright lights, and find it hard to carry out your daily activities, or perform well at your job.

This is a common situation after a traumatic brain injury -- many people experience bad side effects months or years later. These long-term effects can last a few days or the rest of a person's life.

"No therapies currently exist to prevent the disabilities that can develop after a brain trauma," says Jeanne Paz, PhD, associate investigator at Gladstone Institutes. "So, understanding how the traumatic brain injury affects the brain, especially in the long term, is a really important gap in research that could help develop new and better treatment options."

In a new study published in the journal Science, Paz and her team helped close that gap. They identified a specific molecule in a part of the brain called the thalamus that plays a key role in secondary effects of brain injury, such as sleep disruption, epileptic activity, and inflammation. In collaboration with scientists at Annexon Biosciences, a clinical-stage biopharmaceutical company, they also showed that an antibody treatment could prevent the development of these negative outcomes.

A Vulnerable Brain Region

Traumatic brain injuries, which range from a mild concussion to a severe injury, can be the result of a fall, sports injury, gunshot injury, blow to the head, explosion, or domestic violence. Often, soldiers returning from war also suffer head injuries, which commonly lead to the development of epilepsy. Traumatic brain injury affects 69 million people around the world annually, and is the leading cause of death in children and a major source of disability in adults.

"These injuries are frequent and can happen to anyone," says Paz, who is also an associate professor of neurology at UC San Francisco (UCSF) and a member of the Kavli Institute for Fundamental Neuroscience. "The goal of our study was to understand how the brain changes after traumatic brain injuries and how those changes can lead to chronic problems, such as the development of epilepsy, sleep disruption, and difficulty with sensory processing."

To do so, Paz and her team recorded the activity of different cells and circuits in the brain of mice after brain injury. The researchers monitored the mice continually and wirelessly, meaning the mice could go about their normal activities without being disrupted.

"We collected so much data, from the time of injury and over the next several months, that it actually crashed our computers," says Paz. "But it was important to capture all the different stages of sleep and wakefulness to get the whole picture."

During a trauma to the head, the region of the brain called the cerebral cortex is often the primary site of injury, because it sits directly beneath the skull.

But at later time points, the researchers discovered that another region -- the thalamus -- was even more disrupted than the cortex. In particular, they found that a molecule called C1q was present at abnormally high levels in the thalamus for months after the initial injury, and these high levels were associated with inflammation, dysfunctional brain circuits, and the death of neurons.

"The thalamus seems particularly vulnerable, even after a mild traumatic brain injury," says Stephanie Holden, PhD, first author of the study and former graduate student in Paz's lab at Gladstone. "This doesn't mean the cortex isn't affected, but simply that it might have the necessary tools to recover over time. Our findings suggest that the higher levels of C1q in the thalamus could contribute to several long-term effects of brain injury."

The Paz Lab collaborated with Eleonora Aronica, MD, PhD, a neuropathologist at the University of Amsterdam, to validate their findings in human brain tissues obtained from autopsies, in which they found high levels of the C1q molecule in the thalamus 8 days after people had sustained a traumatic brain injury. In addition, by working with fellow Gladstone Assistant Investigator Ryan Corces, PhD, they determined that C1q in the thalamus likely came from microglia, the immune cells in the brain.

"Our study answered some very big questions in the field about where and how changes are happening in the brain after a trauma, and which ones are actually important for causing deficits," says Paz.

The Right Window to Treat Chronic Effects After Traumatic Brain Injury

The C1q molecule, which is part of an immune pathway, has well-documented roles in brain development and normal brain functions. For instance, it protects the central nervous system from infection and helps the brain forget memories -- a process needed to store new memories. The accumulation of C1q in the brain has also been studied in various neurological and psychiatric disorders and is associated, for example, with Alzheimer's disease and schizophrenia.

"C1q can be both good and bad," says Paz. "We wanted to find a way to prevent this molecule's detrimental effect, but without impacting its beneficial role. This is an example of what makes neuroscience a really hard field these days, but it's also what makes it exciting."

She and her group decided to leverage the "latent phase" after a traumatic brain injury, during which changes are occurring in the brain but before long-term symptoms appear.

"My cousin, for example, was hit in the head when he was 10 years old, and the impact broke his skull and damaged his brain," says Paz. "But it wasn't until he was 20 that he developed epilepsy. This latent phase presents a window of opportunity for us to intervene in hopes of modifying the disease and preventing any complications."

Paz reached out to her collaborators at Annexon Biosciences, who produce a clinical antibody that can block the activity of the C1q molecule. Then, her team treated the mice who sustained brain injury with this antibody to see if it might have beneficial effects.

When the researchers studied mice genetically engineered to lack C1q at the time of the trauma, the brain injury appeared much worse. However, when they selectively blocked C1q with the antibody during the latent phase, they prevented chronic inflammation and the loss of neurons in the thalamus.

"This indicates that the C1q molecule shouldn't be blocked at the time of injury, because it's likely very important at this stage for protecting the brain and helping prevent cell death," says Holden. "But at later time points, blocking C1q can actually reduce harmful inflammatory responses. It's a way of telling the brain, 'It's okay, you've done the protective part and you can now turn off the inflammation.'"

"There is a paucity of treatments for patients who have suffered from an acute brain injury," says Ted Yednock, PhD, executive vice president and chief scientific officer at Annexon Biosciences, and an author of the study. "This result is exciting because it suggests that we could treat patients in the hours to days after an acute injury like traumatic brain injury to protect against secondary neuronal damage and provide significant functional benefit."

Path to a Potential Treatment

In addition to chronic inflammation, Paz and her team also uncovered abnormal brain activity in the mice with traumatic brain injury.

First, the researchers noticed disruptions in sleep spindles, which are normal brain rhythms that occur during sleep. These are important for memory consolidation, among other things. The scientists also found epileptic spikes, or abnormal fluctuations in brain activity. These spikes can be disruptive to cognition and normal behavior, and are also indicative of a greater susceptibility to seizures.

The scientists observed that the anti-C1q antibody treatment not only helped restore the sleep spindles, but also prevented the development of epileptic activities.

"Overall, our study indicates that targeting the C1q molecule after injury could avoid some of the most devastating, long-term consequences of traumatic brain injury," says Holden. "We hope this could eventually lead to the development of treatments for traumatic brain injury."

Annexon's anti-C1q inhibitors are designed to treat multiple autoimmune and neurological disorders, and are already being examined in clinical trials, including for an autoimmune disorder known as Guillain-Barré syndrome, where the drug has been shown to be safe in humans.

"The fact that the drug is already in clinical trials may speed the pace at which a treatment could eventually be made available to patients," says Yednock. "We already understand doses of drug that are safe and effective in patients for blocking C1q in the brain, and could move directly into studies that ameliorate the chronic effects after traumatic brain injury."

For Holden, who previously worked with individuals who experienced brain injury and heard many of their personal stories, the impact of this study is particularly meaningful.

"Brain injury is a hidden disability for many of the people I met," she says. "The side effects they experience can be difficult to diagnose and their physicians often can't provide any medical treatment. Being able to contribute to finding ways to treat the detrimental consequences of the injury after it happens is really inspiring."

Paz and her lab are continuing to expand their understanding of what happens in the brain after injury. Next, they will focus on studying whether they can help prevent convulsive seizures, which are often reported by people with severe traumatic brain injuries.

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Struggling to learn a new language? Blame it on your stable brain

A study in patients with epilepsy is helping researchers understand how the brain manages the task of learning a new language while retaining our mother tongue. The study, by neuroscientists at UC San Francisco, sheds light on the age-old question of why it's so difficult to learn a second language as an adult.

The somewhat surprising results gave the team a window into how the brain navigates the tradeoff between neuroplasticity -- the ability to grow new connections between neurons when learning new things -- and stability, which allows us to maintain the integrated networks of things we've already learned. The findings appear in the Aug. 30, 2021, issue of Proceedings of the National Academy of Sciences.

"When learning a new language, our brains are somehow accommodating both of these forces as they're competing against each other," said Matt Leonard, PhD, assistant professor of neurological surgery and a member of the UCSF Weill Institute for Neurosciences.

By using electrodes on the surface of the brain to follow high-resolution neural signals, the team found that clusters of neurons scattered throughout the speech cortex appear to fine-tune themselves as a listener gains familiarity with foreign sounds.

"These are our first insights into what's changing in the brain between first hearing the sounds of a foreign language and being able to recognize them," said Leonard, who is a principal investigator on the study.

"That in-between stage is a crucial step in language learning but has been difficult to tackle, because the process is dynamic and unique to the individual," he said. "With this study, we were able to see what's actually happening in the brain regions involved in differentiating sounds during this initial phase of learning."

Brain Activity Shifts as Foreign Sounds Become Familiar

Learning the sounds of a new language is the first step in learning to use that language, said Leonard. So for this study, Leonard and lead author and postdoctoral scholar Han Yi, PhD, investigated how the activity in the dispersed brain regions associated with language shifted as the listener became more familiar with the foreign sounds.

The team worked with 10 patient volunteers, aged 19 to 59, whose native language is English, and asked them to recognize speech sounds in Mandarin. Mandarin is a tonal language in which the meaning of the word relies not only on the vowel and consonant sounds but also on subtle changes in the pitch of the voice, known as tones. Speakers of non-tonal languages like English often find it very challenging to discern these unfamiliar sounds.

Each of the volunteers had previously had brain surgery, during which electrodes were implanted in their brains to locate the source of their seizures. The study included seven patients at the UCSF Epilepsy Center, and three in the Epilepsy Center at the University of Iowa Hospitals and Clinics. The volunteers agreed to allow Leonard and his team to gather data from high-density, 256-channel electrodes placed on the surface of the brain regions that process speech sounds.

Over the course of the next few days, Leonard and Yi worked with the volunteers individually, playing recordings of several native Mandarin speakers of different ages, both male and female, pronouncing syllables like "ma" and "di" using each of the four tones. After each sound, the patient indicated whether they thought the tone was going up, down, up and then down, or staying flat, and received feedback on whether they were correct. Patients repeated this task about 200 times, over several 5- to 10-minute sessions.

After that brief amount of time, Leonard said, people had gotten through the initial learning phase and had become somewhat adept at categorizing the sounds.

"We also saw a lot of variability," he added. "Some people will get a bunch of trials right and then they'll start getting them wrong and then they'll get it right again in this kind of up-and-down that seems to be part of the learning process."

Learning New Sounds Involves Fine-Tuning Neural "Knobs"

When Leonard and Yi looked at the neural signals generated by the language learners, they saw a pattern that both surprised them and explained the performance curve they'd observed.

Data from other published studies suggested that activity across the speech cortex might increase as a person becomes more familiar with the language. What the researchers discovered instead was a spectrum of changes distributed throughout that speech cortex; with activity increasing in some areas but decreasing in others, maintaining a careful balance.

Those changes might be related to a brain area becoming tuned in to a particular tone, said Yi.

"We could see some groups of cells would respond more to the falling tone, and just keep ramping up their response, while right next to it another group of cells would increasingly engage when the person heard the dipping tone," Yi said. "It's as if these small clumps of neurons took on different roles."

In addition, which brain regions were more activated by which tone varied across individuals.

"It's more like each person's brain has a unique set of knobs that are getting fine-tuned while they're becoming familiar with these sounds," Leonard said.

Leonard and Yi think this may explain why some people pick up the sounds much more easily than others, as each unique brain strikes its own balance between maintaining the stability of the native language while calling on the plasticity required to learn a new one.

"The volunteers were able to learn the tones in Mandarin without affecting their ability to perceive pitch in English or in music," said Leonard. "These little neural knobs were all communicating with each other to reach the point where they can do the task correctly by working together."

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Brain-repair discovery could lead to new epilepsy treatments

University of Virginia School of Medicine researchers have discovered a previously unknown repair process in the brain that they hope could be harnessed and enhanced to treat seizure-related brain injuries.

Common seizure-preventing drugs do not work for approximately a third of epilepsy patients, so new and better treatments for such brain injuries are much needed. UVA's discovery identifies a potential avenue, one inspired by the brain's natural immune response.

Using high-powered imaging, the researchers were able to see, for the first time, that immune cells called microglia were not just removing damaged material after experimental seizures but actually appeared to be healing damaged neurons.

"There has been mounting generic support for the idea that microglia could be used to ameliorate seizures, but direct, visualized evidence for how they could do this has been lacking," said researcher Ukpong B. Eyo, PhD, of UVA's Department of Neuroscience, the UVA Brain Institute and UVA's Center for Brain Immunology and Glia (BIG). "Our results indicate that microglia may not be simply clearing debris but providing structural support for neuronal integrity that may have implications even beyond the scope of seizures and epilepsy."

A Surprising Response to Seizures

The new findings come from a collaboration of scientists at UVA, Mayo Clinic and Rutgers University. They used an advanced imaging technique called two-photon microscopy to examine what happened in the brains of lab mice after severe seizures. What they saw was strange and unexpected.

Rather than simply cleaning up debris, the microglia began forming pouches. These pouches didn't swallow up damaged material, as many immune cells do. Instead, they began tending to swollen dendrites -- the branches of nerve cells that transmit nerve impulses. They weren't removing, the scientists realized; they appeared to be healing.

These odd little pouches -- the scientists named them "microglial process pouches" -- stuck around for hours. They often shrank, but they were clearly doing something beneficial because the dendrites they targeted ended up looking better and healthier than those they didn't.

"We did not find microglia to be 'eating' the neuronal elements in this context," Eyo said. "Rather, we saw a strong correlation between these interactions and a structural resolution of injured neurons suggestive of a 'healing' process."

The new insights into the brain's immune response points scientists in promising new directions. "Although these findings are exciting, there is yet a lot to follow-up on them. For example, the precise mechanisms that regulate the interactions remain to be identified. Moreover, at present, the 'healing' feature is suggested from correlational results and more definitive studies are required to certify the nature of the 'healing,'" Eyo said. "If these questions can be answered, they will provide a rationale for developing approaches to enhance this process ... in seizure contexts."

Eyo has already received two grants totaling almost $5 million from the National Institutes of Health to continue his study of microglia. The funding will allow him to study how the immune cells help regulate vascular function, which could be important in diseases such as Alzheimer's, and their role in brain-hyperactivity disorders such as febrile seizures that can trigger epilepsy.

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