Porky Pig may still draw laughs, but (take it from someone
who's been there) stuttering is no fun. The frustration, anxiety, and social stress
of speech marked by hesitation, repetition, and blocks can be a heavy burden
that, until fairly recently, was compounded by stigma born of misunderstanding.
"Because very little was known about this complex
disorder, there were wild theories." says Soo-Eun Chang,
director of the speech neurophysiology lab at University of Michigan. Bad
parenting, early trauma, and diverse psychiatric conditions were invoked.
"Just 40 years
ago, explanations didn't sound much different from the psychiatry of the
1800s," says Dennis Drayna, chief of the section on genetics of communication
disorders at the National Institute on Deafness and Other Communication
Nowadays, Chang says, "there's consensus among many
researchers that stuttering is a neurodevelopmental disorder, not a psychiatric
or emotional issue. With neuroimaging, we've just begun to find subtle
differences in brain structure and function in those who stutter." While
causes and mechanisms remain uncertain, this is an exciting time for
researchers, she says.
Beyond the practical need for answers to a vexing problem,
neuroscientists find stuttering "a profoundly interesting subject,"
says Drayna. "It's remarkable what's not wrong with the speech of
people who stutter; they have no problems with memory, syntax, grammar, word
finding, or articulation. They know exactly what to say, but just can't say it
at the rate they want to.
"There's nothing else wrong with them,
neurologically," he says. "There must be some extremely specific
population of neurons somewhere in the brain" that are affected. As the
picture of stuttering clears, "I think it will tell us something new and
remarkable about how the brain works."
Genes and a mouse that
Drayna's efforts at clarification center on genetics. Twin and
family studies estimate the heritability of stuttering is high (at .85), he
says. "There's also good evidence of gene-environment interactions; that
genetic predisposition is necessary, but not sufficient."
Linkage analyses suggest diverse gene locations. In studies of
families with many stutterers, however, Drayna and colleagues have identified
mutations in three genes on chromosome 12 that recur frequently.
They are involved in the lysosomal enzyme targeting pathway
(LETP), through which unwanted cellular fragments are disassembled and recycled
(disturbances in this system also are implicated in fatal diseases including
As reported in American Journal of Human Genetics,
Drayna and his group recently identified a fourth gene, AP4E1, in many
stutterers. Taken together, "these four appear to explain 12 to 20 percent
of stuttering cases," he says.
Although the mechanism linking these genes to stuttering phenomena
is unknown, all are involved in intracellular trafficking—the movement of
compounds within the cell—which is "emerging as a unifying concept across
many neurological disorders. Deficits in trafficking affect all cells, but have
unique impact on neurons," Drayna says. The trafficking motif "brings
stuttering into the mainstream of neurological disorders; it's probably a first
cousin to Alzheimer's, Parkinson's, and other common diseases."
Stuttering genetics took an important step forward with the
creation of an animal model. As reported in the April 25, 2016 Current Biology, Drayna and colleagues at NIH and
Washington University in St. Louis genetically modified a mouse to express one
of the LETP mutations associated with stuttering. Infant mice emit distinctive
sounds when separated from their mothers; in modified animals, these
vocalizations displayed patterns parallel to human stuttering.
"We made a mouse that stutters to take advantage of genetic
resources available to study the nervous system in this animal," Drayna
says. These include an assortment of promoters--genes that activate other
genes--that only operate in select populations of neurons.
By developing lines of mice that express the
mutation plus various promotors, he hopes to illuminate "the problem of
neuronal specificity" central to the mystery of stuttering: which small
subset of neurons are responsible. "Our results are not complete,” he says, “but it's clear that this approach will be productive."
Neuroscientists have explored brain differences between
stutterers and non-stutterers for two decades, but most work has involved
adults—the extended immobility MRI requires is more feasible for them—and the
problem here is distinguishing causes from effects of their speech difficulty.
Only recently have investigators reported findings in children
soon after stuttering begins. Using elaborate training to help young subjects
remain still in the scanner, and analytic methods to cancel the effects of
movement, Soo-Eun Chang and colleagues have collected data on more than 100
children age 3 to 12.
Her data and those of other groups show changes in a left
hemisphere frontal region overlapping with Broca’s area, which is associated
with speech production. "Auditory and motor regions also seem less
well-connected, critical regions that allow us to put sounds together in
sequence for fluid speech production. And there's increasing evidence of
connection deficits between these cortical areas and subcortical
regions—particularly the basal ganglia, which allows us to initiate and
sequence movement”, she says.
These differences, initially identified by functional
connectivity analysis, were recently confirmed in children by DTI studies
showing poorer white matter coherence in tracts linking the areas in question.
Among controls, white matter integrity was greater in older children—an
expected consequence of maturity. Among stutterers, this wasn't seen. These
findings mirror differences between adults who stutter and those who don’t, she says.
Chang and her group followed their young subjects for four
years, repeating MRIs and cognitive, motor, and speech tests. "We want to
track the developmental trajectory of each child," she says. While about 5
percent of children age 2 to 5 stutter, 80 percent of them spontaneously
recover; one goal of the study is to determine if initial data can predict each
outcome. "We're working on these papers now," she says.
Although Chang's group studied brain function and structure in
much younger stutterers than prior
work, it still might not have been early enough to distinguish causes from
effects, she grants—"even if a child has just been stuttering for six
months, he may have developed compensatory issues."
Mark Onslow, director
of the Australian Stuttering Research Centre at University of Sydney, hopes to eliminate
this uncertainty by comparing newborns (to the age of 12 weeks), with a family
history (two first degree relatives who stutter) to controls, for white matter
differences that precede speech.
want to sort out whether there’s any
brain structural problem responsible for the development of stuttering,” Onslow
says. “The only way to tease it out is by scanning at-risk babies before its onset.”
By following the group for six years at least, he hopes to
determine, further, whether certain characteristics predict who in the high-risk
group will stutter.
"I'd be very curious about what he finds," Chang
Missing a beat
J. Devin McAuley of
Michigan State University has a different perspective. Head of MSU’s Timing,
Attention, and Perception laboratory, he notes that the cortical-subcortical
brain networks engaged by rhythm are also involved in certain developmental
language disorders, including stuttering.
In a study reported in Brain & Language in 2015, researchers including
McAuley and Chang found that stutterers tested worse than controls in rhythm
perception, especially for complex rhythms— when the beat is implied rather
than clearly marked.
“Stutterers apparently have particular difficulty generating
an internal beat,” says McAuley. This could account for the observation that “fluency
is improved [for stutterers] in choral or group speech, or when you provide a
Subsequent neuroimaging work showed that functional
connectivity within the “rhythm network” correlated with rhythm perception
acuity only for non-stutterers; in stutterers, it was sharply diminished
overall. “There are multiple timing networks in the brain, and they might be
relying on others,” he says.
While it’s too early to know whether his research might have
treatment applications, McAuley says, it could lead to more precisely targeted
rhythmic training for some patients.
But rhythm impairment may not be significant for all. Stuttering
“is fairly heterogeneous,” he says. “There’s probably no single cause, and
what’s needed is a personalized approach.”
For Chang, improved therapy is always in the picture. “I’m a
clinician myself, and my long-term goal is to have my research contribute to
developing better treatments for those with the disorder. But I’m cautious
about implications of current findings. We still have much more research to do.
“That said, we do have several regions we might target in
working with the brain’s neuroplasticity, perhaps using behavioral treatments
to enhance connectivity between those we find weaker in stutterers,” she says.
Noninvasive brain stimulation techniques may help treatment
effects last by promoting connectivity, she adds. Transcranial direct current
stimulation (tDCS), which has shown promise in motor rehabilitation and
aphasia, “can potentially augment behavioral treatment.”
Drayna suggests that genetic
advances could improve stuttering treatment through more accurate subtyping. “A
broad array of therapies have similar rates of success, but none are as good as
we might hope. Maybe we need to match particular treatments with particular
Drugs for stuttering that target mechanisms uncovered by
genetics are “an exciting but unknowable prospect,” he says. “The genome is
full of genes that encode products unsuitable for pharmacological
Generally, says Drayna, the field needs collaboration
and communication beyond neuroscience.
“There’s a great gulf between researchers like me and those who really
understand stuttering—the clinical people. We have very different training and
background; we hardly speak the same language. A lot could benefit from
bridging those two worlds.”