The truth about stuttering

Leviathan: There is no doubt that stuttering, as a speech disorder, has a great impact on the patient's life. Contrary to popular belief, stuttering has no direct correlation with intelligence. Most stuttering patients are quite healthy in all aspects except speech disorders. Moreover, psychological factors such as anxiety, lack of self-confidence and tension are usually not the cause of stuttering, but more the result of the disease. In the past few decades, thanks to the progress of neuroscience and brain science, the academic community has begun to turn its attention to an important tissue in the human body: the brain.

Gerald Maguire has stuttered since he was a child. But you wouldn't know it if you were talking to him, unless you listened carefully and noticed his occasional stumbles over polysyllabic words like "statistically" and "pharmaceutical." For the past 25 years, Maguire, a neuroscientist at the University of California, Riverside, has taken antipsychotic drugs to treat his stuttering. However, these drugs are not officially approved for the treatment of stuttering.

There are many people like Maguire who stutter. There are about 70 million people who stutter worldwide, 3 million in the United States alone. People who stutter have difficulty learning to speak and increasing their speaking speed, resulting in pauses and repetitions in their speech. These 3 million people include about 5% of American children and 1% of adults, and many of these children no longer have the symptoms when they grow up. Among them are presidential candidate Joe Biden, actor James Earl Jones with a deep voice, and actress Emily Blunt. Although they and many others, including Maguire, have achieved success in their careers, stuttering still causes social anxiety and leads to ridicule or discrimination from others.

Maguire has been treating people who stutter and researching potential treatments for decades. Every day he receives emails from people seeking medication, to join his clinical trials, or even to donate their brains for research after death. He is currently conducting a clinical trial on a new drug called ecopipam, which improved patients' stuttering symptoms and quality of life in a small 2019 study.

(www.sciencedaily.com/releases/2019/08/190828140048.htm)

Meanwhile, other researchers are exploring the underlying causes of stuttering, which could also lead to new treatments.

For decades, therapists have mistakenly attributed stuttering to defects in the tongue and larynx, anxiety, trauma, or even a flawed upbringing—and some still believe that today. J. Scott Yaruss, a speech-language pathologist at Michigan State University, says that people have long suspected that stuttering might be caused by a neurological problem. Data supporting this idea first appeared in 1991, when researchers reported changes in blood flow to the brains of people who stutter. Over the past three decades, studies have continued to show that the roots of stuttering lie squarely in the brain.

(jamanetwork.com/journals/jamaneurology/article-abstract/590851)

Yaros says we're in the midst of an explosion of research on stuttering.

Still, many questions remain to be answered. Neuroscientists have observed subtle differences in the brains of people who stutter, but they can't be sure whether these are causes or effects of stuttering. Geneticists have found that variations in certain genes make people more likely to stutter, but the genes themselves were puzzling; only recently have the links between genes and brain anatomy become clear.

Maguire, meanwhile, is pursuing treatments based on dopamine, a chemical messenger in the brain that helps regulate mood and movement. (Precise muscle movement is, of course, necessary for speech comprehension.) Scientists are just beginning to connect these disparate threads, and they are now working on early tests of treatments based on those findings.

If a radiologist simply looked at a standard brain scan of a person who stutters, he or she might not notice anything unusual. It was only when experts used specialized techniques to observe the deep structures and activity in the brain while people spoke that subtle differences between stutterers and non-stutterers were discovered.

The problem isn't limited to one part of the brain; instead, it's all about the connections between different brain regions, says Soo-Eun Chang, a speech pathologist and neurologist at the University of Michigan.

For example, in the left hemisphere of the brain, the connection between the area responsible for hearing and the motor area responsible for producing speech seemed to be weaker in people who stutter. Zhang also observed structural differences in the corpus callosum, a large bundle of nerve fibers that connects the left and right hemispheres of the brain.

The findings suggest that stuttering may be caused by slight delays in communication between parts of the brain. Zhang believes that language skills are particularly susceptible to such delays because speech must be coordinated at lightning speed.

Professor Zhang has been studying why 80% of children who stutter have normal language skills when they grow up, while the other 20% continue to stutter as adults. Stuttering begins when children first string words together into simple sentences around the age of 2. Zhang has been studying children for four years, hoping to start looking for patterns of changes in brain scans as early as possible.

(www.aafp.org/afp/2008/0501/p1271.html)

It’s not easy to convince such young children to stay still in a giant, humming brain-imaging machine. Zhang’s team modified the scanner to hide all the scary parts. (“It looks like an ocean adventure,” Zhang says.) Her team found that for children who had outgrown their stuttering, the connections between areas of the brain associated with hearing and those associated with speech strengthened with age. But that didn’t happen in children who had been stuttering for a long time.

(onlinelibrary.wiley.com/doi/10.1002/hbm.23590)

In another study, Zhang's team looked at how different parts of the brain work together or not at the same time, using blood flow as an indicator of activity. They found a link between stuttering and a brain circuit called the default mode network, which plays a role in how a person thinks about the past, the future, and daydreams. For children who stutter, the default mode network seems to insert itself into the interactions of networks responsible for focusing attention and producing movements, like a third party intruding on a romantic date. This can also slow down speech production, she said.

(www.sciencedirect.com/science/article/abs/pii/S0094730X16300754)

Changes in brain development or structure may stem from a person's genes, but understanding of this will also take time to mature.

In early 2001, geneticist Dennis Drayna received a surprising e-mail. He recalls the message: "I am from Cameroon, West Africa. My father is a chief. He has three wives, and I have 21 brothers and sisters. Almost all of them stutter. Do you think there might be some genetic cause in our family?"

Drena, who works at the National Institute on Deafness and Other Communication Disorders, had a long-standing interest in the genetics of stuttering. His uncle and brother stuttered, and his twin sons also stuttered as children. But he was reluctant to cross the Atlantic to Cameroon for the email, and he was also concerned that his clinical skills were not adequate to analyze the family's stuttering.

He mentioned the email to Francis Collins, then director of the National Human Genome Research Institute and now director of the National Institutes of Health. Collins encouraged him to check it out, so Drayna booked a ticket to Africa. He then went to Pakistan to do research, where the offspring of first cousin marriages could reveal whether gene variants are linked to inherited diseases.

Even as these families were studied, finding the genes involved was slow: stuttering is not inherited in a simple pattern like blood type or freckles. But eventually, Drayna’s team found mutations in four genes—GNNPTAB, GNPTG, NAGPA from a Pakistani study, and AP4E1 from a tribe in Cameroon—that he believes may be responsible for stuttering in as many as one-fifth of patients.

(www.nejm.org/doi/pdf/10.1056/NEJMoa0902630)

(www.sciencedirect.com/science/article/pii/S0002929715004097)

Oddly, none of the genes Drayna found had a significant association with language ability. Instead, they were all involved in transporting materials from the cell to the lysosome, a cell's garbage collection station. Drayna's team did more work before they could link the genes to brain activity.

They first inserted a mutation they observed in humans into the GNPTAB gene of mice to see if the mutation would affect the mice's ability to produce sounds. Mice are talkative, but most of their conversations take place in the ultrasonic band, which is inaudible to humans. By recording the ultrasonic sounds emitted by mouse pups, the team observed speech patterns similar to stuttering in humans.

“They have gaps and pauses in their vocalization sequences,” said Drena, who co-authored a review of genetic research on language disorders in the Annals of Genomics and Human Genetics.

(www.annualreviews.org/doi/10.1146/annurev-genom-090810-183119)

Even so, the team struggled to find any obvious flaws in the animals’ brains—until a determined researcher noticed that the corpus callosum was becoming increasingly devoid of astrocytes. Astrocytes play an important role in neural activity: They provide energy to nerves and recycle metabolites. Perhaps, Drayna mused, the limited number of astrocytes slowed communication between the left and right hemispheres of the brain, but that this would only be noticeable during speech.

Drayna's research has received mixed reviews. "This is really groundbreaking work in the field," says Angela Morgan, a speech pathologist at the University of Melbourne and the Murdoch Children's Research Institute in Australia. Maguire, on the other hand, has long suspected that mutations in these key genes, which are expressed in almost all cells, would only lead to defects in the corpus callosum and, in turn, to language disorders. He also thinks it's difficult to draw analogies between mouse calls and human speech. "It's a bit over the top," he says.

Scientists are certain that there are more genes involved in stuttering that have yet to be discovered. Drayna has since retired, but Morgan and his colleagues are launching a large-scale study that hopes to find more genes involved in stuttering in more than 10,000 people.

(www.geneticsofstutteringstudy.org.au/)

Maguire has been looking at the causes of stuttering from a completely different angle: studying the role of dopamine, a key signaling molecule in the brain. Dopamine can either turn up or down the activity of neurons, depending on where it is in the brain and which receptors it binds to. There are five different subtypes of dopamine receptors (named D1, D2, and so on) that pick up dopamine signals and respond.

In the 1990s, Maguire and his colleagues were the first to use a type of positron emission tomography brain scan on people who stuttered. They found that these people had a surge in dopamine activity in their brains. This excess dopamine seemed to suppress activity in some of the same brain regions that Zhang and others had linked to stuttering.

(journals.lww.com/neuroreport/Abstract/1997/02100/Increased_dopamine_activity_associated_with.37.aspx)

Other researchers reported in 2009 that people with a certain type of D2 receptor gene are more likely to stutter, which can indirectly enhance the activity of dopamine, supporting the view that there is a link between dopamine and stuttering.

(www.nature.com/articles/jhg200960/)

So Maguire wondered: Could stuttering be treated by blocking dopamine? It was easy, because antipsychotics do that. Over the years, Maguire has run small clinical trials with drugs like risperidone, olanzapine, and lurasidone, with success (he personally prefers the latter because lurasidone doesn’t cause weight gain like the first two). The result: “Stuttering won’t go away completely,” Maguire says, “but we can treat it.”

These drugs are not approved by the Food and Drug Administration to treat stuttering. And they can have nasty side effects: not only weight gain, but also muscle stiffness and movement problems. That’s partly because they act on dopamine D2 receptors. Maguire’s new drug, ecolopam, acts on dopamine D1 receptors, which he hopes will reduce some of the side effects—although he still needs to watch out for others, such as weight loss and depression.

In a small study of 10 volunteers, Maguire, Yarus and colleagues found that people who took ecolepam had improved stuttering. Some participants also had improved quality-of-life scores related to feelings of helplessness and acceptance of stuttering.

(escholarship.org/uc/item/8ct0028k)

Ecolpipan isn’t the only treatment under consideration. Back at Michigan, Zhang hoped to improve speech fluency by stimulating specific parts of the brain while communicating. Her team placed electrodes on the subjects’ scalps to gently stimulate parts of the auditory brain region, strengthening that region’s connection to the language-management brain region (Zhang says the stimulation only caused a mild itchy sensation). The researchers stimulated the subjects’ brains while they were doing traditional speech therapy. The team had to pause the trial for nearly half of the 50 subjects because of the coronavirus pandemic. The team is now analyzing the data.

(clinicaltrials.gov/ct2/show/NCT03437512)

Dopamine, cellular metabolic waste, and neural connections - how are these keywords connected? Professor Zhang noticed that a neural pathway related to stuttering contains two areas that produce and use dopamine, which may help explain why dopamine is related to stuttering.

She hoped that neuroimaging could link these disparate regions together. First, she and her collaborators matched the problem areas in brain scans with areas of the brain with high rates of mutated genes. She found that two of Drayna's genes, GNPTG and NAGPA, were highly active in the speech and hearing networks in the brains of non-stutterers. This showed that these regions indeed needed the genes, supporting Drayna's hypothesis that genetic defects interfere with language ability.

The team also made some new discoveries: genes involved in energy metabolism are also very active in language and hearing areas. Professor Zhang said that brain activity increases greatly in early childhood when stuttering begins. She speculated that perhaps these language processing areas do not get all the energy they need when they really need to operate at maximum power. With this in mind, she plans to look for mutations in energy control genes in children who stutter. "There are obviously a lot of dots that need to be connected," she said.

Maguire is also connecting the dots: He says he's working on a theory that would tie his work to Drayna's genetic findings. Meanwhile, despite his speech impediment, Maguire has slogged through medical school interviews and even considered talk therapy as a career option. Now he's hopeful about ecolpiram: Along with colleagues, they've started a new study that will test 34 people taking ecolpiram against 34 people taking a placebo. If the therapy becomes a standard stuttering treatment, he says, he'll have achieved a lifelong dream.

(clinicaltrials.gov/ct2/show/NCT04492956?term=ecopipam&draw=2&rank=11)

By Amber Dance

Translated by Pharmacist

Proofreading/Yord

Original article/www.theatlantic.com/science/archive/2020/09/why-people-stutter/616111/

This article is based on the Creative Commons Agreement (BY-NC) and is published by Pharmacist on Leviathan

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