Stuttering, nerve defects in milliseconds

Lee Reeves, who suffers from stuttering, demonstrated 3 sounds that made him stutter, namely "L" (left), "W" (center), and "ST" (right). Reeves says that by staying relaxed when he speaks, he can go a long way toward reducing missteps in speech. (Global Science/Photo)

Lee Reeves has always wanted to be a veterinarian. When he was in high school in the suburbs of Washington, D.C., he applied for a job at an animal hospital near his home on a Saturday morning. At the time, the hospital was in a busy phase, and the reception staff told him that the veterinarian was too busy to receive him, but Reeves decided to wait for the veterinarian. After 3 and a half hours, the veterinarian, after seeing all the dogs and cats present, received him and asked Reeves what he could do.

Since the age of 3, Reeves has stuttered and has had difficulty answering questions. "I knew I wanted the job, but when he asked me my name," he said, "I couldn't say my name to save myself." "Finally, the veterinarian reached for a piece of paper and handed it to Reeves and asked him to write his name and phone number on it, but the veterinarian told him that there was no job suitable for him at the moment." I remember walking out of the clinic that morning, I felt like my life was actually over," Reeves said, "not only would I never be a veterinarian, I wouldn't even find the job of cleaning the cage." ”

More than fifty years have passed. Reeves, now 72, has become an influential advocate for stutterers, but the frustration and embarrassment of yesteryear are still fresh in their minds. These are all part of the complex experience that comes with stuttering. Stuttering refers to the forced interruption of relaxed, fluent spoken expression, and since stuttering is often accompanied by physical struggles and mood changes, this often leads to doctors misdiagnosing it as a tongue or throat defect, cognitive problem, emotional trauma or tension, and most unfortunately, stuttering is attributed to poor family upbringing. Freudian psychiatrists believe that stuttering represents a "verbal abuse conflict," while behaviorists believe that labeling children as stuttering exacerbates their stuttering symptoms. Doctors had told Reeves's parents not to focus on his stuttering, just be patient and wait, and the stuttering would naturally disappear.

Still, these mysteries and misconceptions about stuttering have been uncovered. In the 21st century, especially in the last 5 to 10 years, more and more studies have confirmed that stuttering is essentially a biological problem, specifically, it looks like a neurodevelopmental disorder. Of the more than 70 million stutterers worldwide, the majority of patients have stuttering symptoms that occur during the learning to speak phase. By looking at the brains of stutterers, scientists found that there are subtle structural and functional differences in their brains compared to normal people, which affect language fluency. Stutterers differ from normal people in the way neural connections, language and motor systems are integrated, and the activity of key neurotransmitters such as dopamine.

The emergence of stuttering is also inseparable from genetic factors: researchers have found 4 genes that greatly increase the likelihood of stuttering. Just like when a light bulb flashes, sometimes it's not the filament that's broken, it's the wiring in the room that's wrong. Together, these errors are what neuroscientists call the brain's "system-level" problem.

Neurobiological discoveries have spawned a number of new treatments. Currently, a drug against dopamine hyperactivity is in clinical trials, and other drugs to treat stuttering are also being developed. Recent studies have shown that brain stimulation may be effective in improving stuttering. Given the importance of neuroplasticity for young children, experts are currently recommending positive measures to treat stuttering rather than wait-and-see. J. Scott Jarus, a language pathologist at Michigan State University. Scott Yaruss said: "These studies on the brain confirm that we need to intervene in stuttering as early as possible. ”

Our understanding of stuttering is not yet comprehensive. Stuttering affects about 1 percent of adults and 5 percent of children, and up to 80 percent of these children are able to return to the point where they can communicate fluently. Scientists, parents, therapists, and stutterers themselves all want to understand what the difference is between those who stutter for a long time and those who can recover from it. While treatment can help, it doesn't seem to explain the situation. This may be explained by long-term studies of children who stutter, which are just beginning to yield results. Although researchers have identified some genes associated with stuttering, their function has not yet been confirmed.

As the understanding of stuttering deepens, researchers and therapists hope to gain a deeper understanding of the biological reasons for stuttering, thereby changing society's prejudice against stuttering. Many stutterers are unemployed and also suffer from social anxiety disorders and mood disorders. Psychiatrist and neuroscientist Gerald M. Thompson of the University of California, Riverside Gerald A. Maguire himself suffered from stuttering and was committed to understanding stuttering and developing drugs to treat it. Unfortunately, his brother committed suicide due to stuttering. Maguire said: "If we understand the biological mechanisms of stuttering, then there are various ways to treat stuttering. The stigma suffered by patients as a result of the disease is likely to decrease. ”

From pebbles to brain scans

Stuttering was noticed thousands of years ago, and this phenomenon exists in a variety of languages and cultures. From ancient times to the present, there are many stories of trying to overcome stuttering. For example, the ancient Greek orator Demosthenes would put small pebbles in his mouth to practice speech; the non-traditional language therapy received by King George VI of the United Kingdom was passed down by the 2010 film The King's Speech; and actor Samuel Lee was passed down by the 2010 film The King's Speech. Samuel L. Jackson improves his fluency by swearing.

Stuttering is different from the occasional or habitual word mistakes that people make when they speak. When speaking, the stutter may pause, such as repeating a word or adding multiple "ah" or "um" to the sentence spoken. This means that a potential neurological difference between the stutterer and the other person affects the more basic language-generating process when it comes to language expression. Arus said: "Everyone is not fluent in speech, but only some people stutter. ”

Stutterers experience 3 situations: extending the pronunciation of a syllable (e.g., pronouncing "mmm-man" when saying "man"),repeating a syllable or pronunciation (I-I-I-I-myself); and blocking, i.e. being unable to make any sound. If a child still stutters after the age of 8, it is likely that stuttering will accompany him for the rest of his life.

Reeves described stuttering as an unexpected loss of control. "You know what you want to say and how to say words, phrases, sentence structures, changes in tone, but all of a sudden you're stuck," he explains, "you can't move forward, you can't go back, all the muscle activity seems to be stuck." "In 1928, the scientific community first realized that stuttering could be a neurological disorder. At the time, Dr. Samuel Orton and language pathologist Lee Travis proposed that stuttering was the result of two brain hemispheres competing with each other. But Maguire said: "Both cerebral hemispheres of stutterers are normal. "In the 1990s, with the advent of advanced brain imaging techniques, scientists began to be able to reveal neurological differences between stutterers and others. In 1995, Maguire and colleagues scanned the brains of four stutterers using positron emission tomography (PET) and published the first PET study on stuttering. They found that neural activity in the stutterer's linguistic area continued to decline. Other small, early studies have found that stuttering patients have elevated levels of dopamine in their striatum, a key part of the brain's reward circuit.

Based on these efforts, the researchers tested the therapeutic effects of antipsychotic drugs that block dopamine receptors on stutterers and found that these drugs improved the fluency of expression in some stutterers, but they may also have serious side effects, such as causing Parkinson's disease. Still, many skeptics believe that stuttering has nothing to do with the brain. Maguire recalls that when he proposed stuttering as a brain disease at a scientific conference in the late 1990s, "I kind of felt like I was booed down."

In the latest research, scientists have proven the findings of the earlier researchers correctly through high-tech scanners and sophisticated analytical techniques. For most people, language is primarily the responsibility of the left brain. Compared with adults who do not stutter, in the left brain of adults with stuttering, the activity level of the area supporting language production is lower, while the activity level of the right brain is higher. For example, Kate Watkins, a cognitive neuroscientist at the University of Oxford, found that ventral premotor cortex in the left hemisphere of the brain near the language region is not activated when a stutterer speaks. Watkins et al. found structural differences between stutterers and normal people in this neural region, which is located just above the bundle of white matter fibers that connect the auditory and motion control regions. White matter consists of the axons of neurons, elongated protrusions emitted by the cell bodies of neurons that transmit nerve impulses. Watkins said: "It provides the conditions for signaling between neurons. ”

Communication between neurons requires nerve impulses to arrive at a time that is very accurate. To achieve this, the axons are encased in a myelin sheath, a lipid that accelerates the transmission of nerve impulses. Axonal bundles with intact myelin sheaths usually transmit nerve impulses in the same direction, like the fibers in a celery stem. But the scientists scanned the stutterers' brains with diffusion-weighted imaging and found that the axons in their brains were likely staggered.

In addition to this, neurotransmitters should pass through the white matter bundle like water flowing along parallel fibers through celery. In brain scan maps, this transmission of neural signals can be quantified by a parameter— fractional anisotropy (FA). When the FA value is higher, the white matter tissue is more compact. In stutterers, the FA value of this white matter bundle is consistently low. Watkins suspects that areas of the brain that instinctively get nerve signals provided by the white matter bundle sometimes don't receive information and are therefore not activated. (In stutterers, some other tracts of white matter, such as the callosum that connects the cerebral hemispheres, have similar defects.) ）

Functionally, one of the stutterer's neural pathways— the cortico-basal ganglia-thalamocortical loop — appears to be flawed, and it is the brain's infrastructure for integrating auditory, verbal, and motor nerve signals. As the name suggests, this pathway connects structures deep in the brain, including the thalamus and basal ganglion striatum, to various areas in the cortex on the surface of the brain. SooEun Chang, a neuroscientist at the University of Michigan in the United States, said: "Speaking is one of the most complex motor behaviors that humans perform. It relies on millisecond coordination between neural circuits and muscles. In addition, this neural circuit enables multiple movement modes to be activated smoothly and in a timely manner. ”

It's unclear exactly why this circuit was broken, but even a few minor mistakes can cause speech to become unsmooth. "Everything is pointing to the basal ganglia, which is the key to this process," Maguire said, "and if any of the processes in this neural pathway are interfered with, it can lead to symptoms of stuttering." ”

Brain differences such as these may be the root cause of stuttering, or perhaps compensatory changes in the brain in an attempt to adapt to stuttering. To discern the above causal relationship, Zhang Xiuen followed more than 250 stuttering children: starting at the age of 3 and continuing to follow for at least 4 years. Some of these children recover from stuttering, but some do not.

In 2017, Zhang xiuen and colleagues reported that there was a defect in the integrity of the left brain white matter connecting the auditory and motor areas of children who stuttered compared with children who did not stutter. But in children who recover, white matter gradually returns to integrity over time. Zhang Xiuen said: "In the recovered children, the white matter in this area will gradually become complete and normal; in children who have stuttered for a long time, the situation has not improved, and even becomes worse." ”

She found that both adults and children who stuttered had defects in their left brain. Until now, this phenomenon has been prevalent among adult stutterers. She also found that their right brain was overactive, an adaptive change that would only occur later. Zhang Xiuen believes that the most important question is whether there is a detectable difference in the beginning that can be used to distinguish between children who can return to normal later and children who stutter for a long time. "It's crucial to get this objective test standard early on," she said. "Because this will indicate which children are at higher risk of developing stuttering in the long term."

Effects of genes

To a large extent, the risk of stuttering is inherited through familial DNA. Some studies of twins and adopted children have shown that 42 to 85 percent of stuttering risk is genetically linked. One study showed that if one of the twins had stuttering, the proportion of identical twins who also stuttered was 63 percent; in heterosexual same-sex twins, the percentage was only 19 percent. Other risks include environmental factors (this non-genetic factor is reflected in the fact that only one of the partial identical twins suffers from stuttering). Although some environmental factors can be combined with genetic predisposition, at the moment, we do not know exactly what these environmental factors are.

Thanks to research begun about 20 years ago by Dennis Drayna, a geneticist at the National Institute on Deafness and Other Communication Disorders, some genes associated with stuttering have been identified. Drena has been to Pakistan, where it is common for close relatives to marry, a practice that enhances the effects of certain genes (especially harmful genes) throughout the family. Drena said: "I could easily find a large family with a lot of stutterers. ”

In 2010, Dreyner and colleagues reported three stuttering genes. One of them is a mutant of the gene GNPTAB, which has been found in a serious genetic disorder that is completely unrelated to stuttering; the other two are mutants of the genes GNPTG and NAGPA, respectively. Subsequently, Drena received a question from a man from Cameroon who asked online. He wondered why the incidence of stuttering was so high in his extended family: 33 out of 71 family members suffered from stuttering. Through their study, Drena found the fourth stuttering gene, AP4E1. (A report on the fifth stuttering gene has not yet been published.) Drena said these genes only cause illness in 20 to 25 percent of people who stutter. The higher familial prevalence of stuttering also suggests that there are more genes to be discovered, and in search of these genes, a consortium of 22 research groups led by Australian scientists is conducting a new genome-wide association analysis (GWAS) of stuttering populations.

All of the genes found so far are associated with the transport of substances or molecules within cells. In a 2019 study, Dreyner and colleagues found that mice mutated with the gene GNPTAB (the protein it expresses is involved in synthesizing some new enzymes that are transferred to lysosomes) had an unusually long pause during vocalization, similar to stuttering. They found defects in the mice's astrocytes, which are widely present in the white matter bundles that connect the two brain hemispheres. Mutations in genes that are associated with lysosomal function and help to clear waste products have the potential to link the genetic and neuroscience basis for the emergence of stuttering.

Stop stigmatization

The presence of stuttering is genetic, which does not mean that it cannot be treated. The latest research already offers the possibility of treating stuttering. Some pharmacological methods are gradually being perfected. Maguire and colleagues believe that treating stuttering with drugs that reduce dopamine activity in specific neural circuits, such as antipsychotics, is by far the most promising approach. Maguire has successfully tested risperidone, olanzapine, and rulasidone, all of which reduce the severity of stuttering. However, none of them are currently approved by the U.S. Food and Drug Administration (FDA). Unfortunately, these medications can have big side effects, such as causing weight gain and movement disorders. Still, many people, including Maguire, use such unapproved drugs.

Maguire is currently leading a larger randomized clinical trial testing a drug called Ecopipam. Several studies have tested the drug's effectiveness in treating Tourette's Syndrome. Unlike previous drugs, ecopipan targets a different set of dopamine receptors. A small pilot study showed that the drug improved language fluency and quality of life in stutterers without significant side effects. But even drugs approved by the FDA for the treatment of stuttering are not effective for every stutterer. "Our next step is to personalize therapy and figure out exactly what each stutter went through," Maguire said. We now know that stuttering is not just one symptom. ”

Stimulating the brain with a gentle electrical current is also a promising therapy. At Oxford, Watkins combined noninvasive transcranial stimulation with known methods of improving language fluency, such as having a group of people read aloud together or having people speak to the rhythm of a metronome. These techniques have been shown to temporarily improve the verbal fluency of the stutterer, possibly because external cues prompt the stutterer to start speaking. Watkins' team found that among patients receiving combination therapy, the proportion of repeating, prolonged syllables, or other stuttering features dropped from 12 percent to 8 percent. However, in the control group that did not receive brain stimulation, this proportion did not change. Although the study was small and lasted only 5 days, these treatments may be able to achieve better results from the current effect.

Adding brain stimulation to stuttering therapy can enhance the effectiveness of the treatment. "We cement this pathway through electrical stimulation to make it work more efficiently," Watkins said. "Now, many stutterers can only be corrected by traditional language barriers. These techniques typically include practicing speech and learning how to communicate effectively with stutterers. Language disorder correction can be very effective, but the effects are not necessarily long-lasting. Most stutterers will return to their previous state at some point.

As a result of the growing recognition of the truth about stuttering, coupled with a change in cultural awareness, in recent years the goal of treating stuttering has shifted from trying to eradicate stuttering to making stuttering more acceptable and controllable. Jarus said: "A big part of the work is related to adaptation. He likened it to learning to skate. When you put on your skates for the first time and step on the ice, you'll stumble and feel like you're about to slip at any moment. But when you learn to endure this feeling of slipping at any moment, you can cope with it more skillfully. "You could say that when symptoms of stuttering come on, I know what to do so you can cope with stuttering more skillfully," he says. ”

This shift in the focus of treatment was welcomed. Catherine Moroney, 54, is an atmospheric physicist and software engineer at NASA's Jet Propulsion Laboratory. When she was a child, she said, "I couldn't get people to understand me." Language barrier correction has greatly improved her language fluency, but this is only temporary. When she finished her treatment, she was taking a difficult physics bit course. Stress and anxiety don't cause stuttering, but it makes her stuttering symptoms worse.

Compared to the past, Moroni's stuttering symptoms are much lessened now. She is studying clouds and their role in the climate system, and fortunately, her leaders are only concerned with the quality of her work. Now, she is also taking the antipsychotic drug olanzapine. "It's just to make my daily life a little easier." But what really changed Moroni's life was that she joined what she called "my stuttering family." "It may be counterintuitive, but the noisiest place in the world is a meeting where only stutters are involved," she laughs, "and no one shuts up." Being the majority is so free. ”

Reeves was a former president of the American Stuttering Association and an early advocate of the Stutterer Self-Help Movement. The correction of the language disorder did improve his speech fluency, but more importantly, his therapist was a clinical psychologist who helped Reeves improve the mental stress that came with stuttering, which was crucial to Reeves' treatment. Reeves said: "I learned a way to stutter that I could accept. ”

His stuttering didn't stop him from becoming a veterinarian. Three weeks after Reeves went to that animal hospital as a teenager, Peter Malnati, the hospital's veterinarian, called him and offered him a job. Reeves worked at the clinic in high school and college, and then he spent 50 years as a veterinarian, treating small animals, most of that time in Plano, Texas. For him now, the days of frustration and embarrassment are long gone. "I also have symptoms of stuttering. I stuttered yesterday and today," Reeves said, "and I hope I'll stutter tomorrow because it means I'm still alive." ”

(Authorized publication by Scientific American Chinese Edition of Global Science, translated by Yu Wenjing, reviewed by Li Weijun and Yue Siqi)

Lydia Denworth