Gerald Maguire has stuttered since childhood, but you might not guess it from talking to him. For the past 25 years, he has been treating his disorder with antipsychotic medications not officially approved for the condition. Only with careful attention might you discern his occasional stumble on multisyllabic words like "statistically" and "pharmaceutical."

Maguire has plenty of company: More than 70 million people worldwide, including about 3 million Americans, stutter — they have difficulty with the starting and timing of speech, resulting in halting and repetition. That number includes approximately 5 percent of children (many of whom outgrow the condition) and 1 percent of adults. Their numbers include presidential candidate Joe Biden, deep-voiced actor James Earl Jones, and actress Emily Blunt. Though they and many others, including Maguire, have achieved career success, stuttering can contribute to social anxiety and draw ridicule or discrimination.

(MICHAEL STOKES; U.S. EMBASSY PHOTO BY S.J. MAYHEW; GAGE SKIDMORE/Courtesy Knowable Magazine)

Maguire, a psychiatrist at the University of California, Riverside, has been treating people who stutter, and researching potential treatments, for decades. He's now embarking on a clinical trial of a new medication, ecopipam, that streamlined speech and improved quality of life in a small pilot study in 2019.

Others, meanwhile, are delving into the root causes of stuttering. In past decades, therapists mistakenly attributed stuttering to defects of the tongue and voice box, to anxiety, trauma, or even poor parenting — and some still do. Yet others have long suspected that neurological problems might underlie stuttering, says J. Scott Yaruss, a speech-language pathologist at Michigan State University. The first data to back up that hunch came in 1991, when researchers reported altered blood flow in the brains of people who stuttered. Since then research has made it more apparent that stuttering is all in the brain.

"We are in the middle of an absolute explosion of knowledge being developed about stuttering," Yaruss says.

There's still a lot to figure out, though. Neuroscientists have observed subtle differences in the brains of people who stutter but can't be certain if those differences are the cause or a result of the stutter. Geneticists are identifying variations in certain genes that predispose a person to stutter, but only recently have their links to brain anatomy become apparent.

Maguire, meanwhile, is pursuing treatments based on dopamine, a chemical messenger in the brain that helps to regulate emotions and movement (precise muscle movements, of course, are needed for intelligible speech).

Slowed circuitry

Only when experts look closely at the brain's structure and activity do subtle differences between groups who do and don't stutter become apparent. It's all about connections between different brain parts, says speech-language pathologist and neuroscientist Soo-Eun Chang of the University of Michigan. For example, in the brain's left hemisphere, people who stutter often appear to have slightly weaker connections between the areas responsible for hearing and for the movements that generate speech. Chang has also observed structural differences in the corpus callosum, the big bundle of nerve fibers that links the brain's left and right hemispheres. These findings hint that stuttering might result from slight delays in communication between parts of the brain.

Chang has been trying to understand why about 80 percent of kids who stutter grow up to have normal speech patterns, while others continue to stutter. Stuttering typically begins around age 2. Chang studies children for up to four years, starting as early as possible, looking for changing patterns in brain scans.

In kids who lose their stutter, Chang's team has observed that the connections between areas involved in hearing and ones involved in speech movements get stronger over time. But that doesn't happen in children who continue to stutter.

In another study, Chang's group found a link between stuttering and a brain circuit called the default mode network, which has roles in ruminating over one's past or future activities. In children who stutter, the default mode network seems to insert itself — like a third person butting in on a romantic date — into the conversation between networks responsible for focusing attention and creating movements.

These changes to brain development or structure might be rooted in a person's genes, but understanding this part of the problem has taken time.

All in the family

In early 2001, geneticist Dennis Drayna received a surprising email: "I am from Cameroon, West Africa. My father was a chief. He had three wives and I have 21 full and half siblings. Almost all of us stutter," Drayna recalls it saying. "Do you suppose there could be something genetic in my family?"

Drayna, who worked at the National Institute on Deafness and Other Communication Disorders, had an uncle and elder brother who stuttered, and his twin sons did so as children. But he was reluctant to make a transatlantic journey based on an email. He mentioned the email to Francis Collins (director of the National Human Genome Research Institute at that time), who encouraged him to check it out, so he booked a ticket to Africa. He has also traveled to Pakistan, where intermarriage of cousins can reveal gene variants linked to genetic disorders in their children.

Eventually, Drayna's team identified mutations in four genes — GNPTAB, GNPTG, and NAGPA from the Pakistan studies, and AP4E1 from the clan in Cameroonthat may underlie as many as one in five cases of stuttering.

It took some work before Drayna's team linked the genes to brain activity. They started by engineering mice to have one of the mutations observed in people, in the mouse version of GNPTAB, to see if it affected the mice's vocalizations. Recording the ultrasonic calls of pups, the team observed patterns similar to human stuttering. "They have all these gaps and pauses in their train of vocalizations," says Drayna, who cowrote an overview of genetics research on speech and language disorders for the Annual Review of Genomics and Human Genetics.

Still, the team struggled to spot any clear brain defect until one determined researcher found fewer cells called astrocytes in the corpus callosum. Astrocytes do big jobs that are essential for nerve activity: providing the nerves with fuel, for example. Perhaps, Drayna muses, the limited astrocyte population slows down communication between the brain hemispheres by a tiny bit.

Drayna's research has received mixed reviews. "It's really been the pioneering work in the field," says Angela Morgan, a speech-language pathologist at the University of Melbourne and Murdoch Children's Research Institute in Australia. But Maguire doubts that mutations in such important genes could cause defects only in the corpus callosum, and only in speech. He also finds it difficult to compare mouse squeaks to human speech. "That's a bit of a stretch," he says.

Scientists are sure there are more stuttering genes to find. Drayna has retired, but Morgan and collaborators are initiating a large-scale study of genetic contributors in more than 10,000 people.

The dopamine connection

Maguire has been investigating the role of dopamine. Dopamine can ramp neuron activity up or down, depending on the brain location and the nerve receptors it sticks to. There are five different dopamine receptors (named D1, D2, and so on).

During the 1990s, Maguire and colleagues were among the first to use a certain kind of brain scan, positron emission tomography, on people who stutter. They found too much dopamine activity, apparently stifling the activity of some of the brain regions that Chang and others have linked to stuttering.

Backing up the dopamine connection, other researchers reported in 2009 that people with a certain version of the D2 receptor gene, one that indirectly enhances dopamine activity, are more likely to stutter.

So Maguire wondered: Could blocking dopamine be the answer? Conveniently, antipsychotic drugs do just that. Over the years, Maguire has conducted small, successful clinical studies with these medications, including risperidone, olanzapine, and lurasidone. The result: "Your stuttering won't completely go away, but we can treat it," he says.

None of those medications are approved for stuttering by the U.S. Food and Drug Administration, and they can cause unpleasant side effects. In part, that's because they act on the D2 receptor. Maguire's new medication, ecopipam, works on the D1 version, which he expects will diminish some side effects.

In a small study of 10 volunteers, Maguire, Yaruss and colleagues found that people who took ecopipam stuttered less than they did pre-treatment.

Connecting the dots

Chang notes that one of the brain's circuits involved in stuttering includes two areas that make and use dopamine, which might help explain why dopamine is important in the disorder.

She and collaborators compared the problem areas identified by her brain scans with maps of where various genes are active in the brain. Two of Drayna's genes, GNPTG and NAGPA, were active at high levels in the speech and hearing network in the brains of non-stutterers.

The team also observed that genes involved in energy processing were active in the speech and hearing areas. There's a big rise in brain activity during the preschool years, when stuttering tends to start. Perhaps, Chang theorizes, those speech-processing regions don't get all the energy they need. So she plans to look for mutations in those energy-control genes in children who stutter. "There are obviously a lot of dots that need to be connected," she says.

Get help today

If you're worried about your child's language development, schedule an appointment with a speech-language pathologist sooner rather than later, advises Michigan State University speech-language pathologist Scott Yaruss.

Therapy is most effective if it's started early and nears completion around age 6 or 7, a time when the young brain is still malleable. But therapy can certainly help older people handle their stutter, too. For more information:

For the complete version of this article, visit Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.