Stuttering: neural basis and genetics

Author: Giulia Dalla Dea
Date: 15/12/2013


Stuttering is a communication disorder in which the flow of speech is broken by repetitions, prolongations or abnormal stoppages of sounds and syllables.
In addition to theese exhibiting well-known speech symptoms, that primarily occur in initial sounds or syllables of words and sentences, children who stutter may also experience physical symptoms, such as eye squinting, neck and face tensing, and arm and leg movements that can be distracting to the listener.

As many as 5 percent of children between ages two and five stutter, usually beginning around the time they start forming simple sentences. Stuttering affects four times as many males as females.
Three-quarters of those will recover by late childhood, leaving about 1% with a long-term problem.

After many decades of attributing stuttering to causes ranging from childhood trauma to overly anxious personalities, scientists have the opportunity to use new techniques to discover something more about stuttering, which incidence is really high (more than 68 million people worldwide stutter, which is about 1% of the population. In the United States alone, are estimated 3 million people stutter).

A growing number of studies indicate there is a solid genetic connection and the advent of neuroimaging has permitted some recent advances in determining the neural bases of stuttering and discuss why early intervention may be important in the context of brain development.

Using Brain Imaging to Unravel the Mysteries of Stuttering:


The functional neuroanatomy of speech processing has been difficult to characterize. It has been outlined a dual-stream model of speech processing in which a ventral stream (connecting the middle temporal lobe and the ventrolateral prefrontal cortex via the extreme capsule) processes speech signals for comprehension, and a dorsal stream (connecting the superior temporal lobe and premotor cortices in the frontal lobe via the arcuate and superior longitudinal fascicle) maps acoustic speech signals to frontal lobe articulatory networks.

The model assumes that the ventral stream is largely bilaterally organized — although there are important computational differences between the left- and right-hemisphere systems — and that the dorsal stream is strongly left-hemisphere dominant.

The cortical organization of speech processing:

Ventral and dorsal pathways for language:


With the advent of neuroimaging, scientists now have the unprecedented ability to use sophisticated techniques to examine the anatomy and functions of living brains.
What we now know, based on neuroimaging research, is that people who stutter and people who speak fluently exhibit clear differences in brain-activity patterns during speech production.
In addition, people who stutter exhibit subtle structural deficits, primarily involving left-hemisphere brain regions that support fluent speech production.
In the future, researchers might develop therapies that maximize brain plasticity conducive to producing fluent speech.

Many people who stutter report that their stuttering goes away completely in certain situations, such as when they speak to their children or to a pet, sing, talk in chorus with others, or even adopt a novel manner of speaking (for example, speaking with an accent or speaking as an actor onstage).
Speaking under delayed auditory feedback, which delivers an “echo” of one’s voice while speaking or frequency-altered feedback, which delivers feedback of one’s voice with a pitch shift, can also induce fluency in many people who stutter.
This fact suggests that the auditory and motor centers of the brain interact differently in this group relative to fluent speakers and many of the fluency-inducing conditions, as described above, promote slowed rates of speech and provide externally delivered timing cues for speech movement .
These conditions may compensate for a speech system that is less able to sequence speech movements rapidly and perhaps unable to rely on internal timing of speech movements.

Data from recent neuroimaging studies on stuttering give us insights into the possible bases of these fluency-inducing conditions in stuttering speakers.
The main brain regions that work together to make fluent speech production possible include areas in the frontal cortex of the brain, which controls movement planning and execution, and auditory sensory regions located farther back, in the temporoparietal cortex.
Regions deeper within the brain, including the basal ganglia, thalamus, and cerebellum, also support speech movements by providing internal timing and sequencing cues.
It is in these brain regions and their connections that researchers have found brain function and anatomy differences between stuttering speakers and fluent speakers.

Fluid, effortless speech production is possible because of well-established connections among brain regions that support auditory processing, motor planning, and motor execution.
These connections become established when a child learns to speak by matching the sounds that he has heard in a model’s, such as a mother’s, speech with sounds generated by his own speech movements.
With practice, the child’s speech sounds begin to match the targeted speech sounds.
According to one speech model, the auditory cortex, which houses the auditory representation of speech sounds, is connected with speech planning and execution areas.

This connection is achieved through the dorsal stream that researchers posit to be much more highly developed in the left hemisphere, as described above.
Researchers claim that the dorsal stream anatomically corresponds to the superior longitudinal fasciculus, a major white-matter pathway that connects the brain structures located in the anterior (motor) and posterior (sensory) parts of the brain.
The white-matter tracts transmitts nerve impulses from one part of the brain to another.
If the integrity of these white-matter tracts is compromised, the rapid information exchange that needs to occur among the major areas that support speech may also be compromised.

Some neuroimaging data support the idea that people who stutter may have aberrant connections primarily in the left hemisphere that involves a major white-matter tract (figure above).
In this white-matter pathway, the superior longitudinal fasciculus connects the brain regions involved in speech planning in the inferior frontal region with the auditory regions involved in the sensory feedback of speech sounds, via the motor cortex, which is responsible for speech-motor execution.
Studies have reported subtle decreases in white-matter integrity in the left superior longitudinal fasciculus in both children and adults who stutter.

The image below presents a simplified model of the left hemisphere showing the inferior frontal region (speech planning), motor cortex (speech execution), and superior longitudinal fasciculus (auditory processing), which is interconnected via the superior longitudinal fasciculus.

The left-lateralized activations of the auditory system are thought to support the self-monitoring of speech and selectively deactivated a frontal-temporal system implicated in speech production.

When the connection of auditory cortex and motor cortex is aberrant, there's no control on speech production with overactivity in most motor areas.

According to some studies, stuttering speakers have greater volume (grey matter) and activity in the right side of the brain compared to the left side, perhaps as a reaction to the left-sided connectivity deficits.
Nonstuttering adults, in contrast, have greater left- than right-side auditory cortex volume.
Moreover, stuttering adults with the greatest rightward asymmetry (right greater than left) brain volume in an auditory association region exhibited more severe stuttering and experienced the greatest benefit from delayed auditory feedback during speech production.
Researchers who examined brain-activity patterns in adults who stutter during various speech-production tasks found underactivity in the auditory cortex and overactivity in the motor regions.
Relative to the nonstuttering control group, stuttering speakers exhibited heightened activity in the right hemisphere in motor regions 8-10 as well as in the cerebellum 11 and lowered activity in the auditory areas.
In conjunction with abnormal anatomy in these regions, and particularly in the left hemisphere, this right-sided overactivity might be explained as a compensatory reaction to the left-sided deficit in the auditory areas.

In order to understand which of theese characters appear primitively a lot of studies have been undertaken in children.
In a published study on the neuroanatomical bases of childhood stuttering, have been compared children with persistent stuttering, children who recovered naturally from stuttering, and age-matched fluent controls on several different brain structure measures.
All children who participated were 8- to 12-year-old, right-handed boys.
It was found evidence of decreased white-matter integrity in the superior longitudinal fasciculus underlying the sensorimotor cortex in stuttering children relative to age-matched controls.
A decrease in white-matter integrity in this area may mean that signals among the movement planning, execution, and sensory brain areas may not be transmitted in a sufficiently rapid manner to allow for fluent speech production.
This decrease was common for both those who were persistent stutterers and those who had recovered from stuttering. Interestingly, the recovered group showed an intermediate level of white-matter integrity, between that of the persistent stuttering and control groups.
Additionally, the recovered children showed trends of increased white-matter integrity in the right-hemisphere homologue region, the equivalent region in the right hemisphere that mirrored the left hemisphere region found to have less integrity in stuttering children.
These findings warrant confirmation with larger groups to determine whether brain areas showing distinct growth in recovered children (as found in this study) underlie natural recovery.

At present, behavioral therapy by a skilled speech-language pathologist is the most viable option for treating stuttering.
The brain regions found to be different in stuttering children are primarily those that undergo active growth and are plastic during childhood, and are thus more likely to respond to treatment that stimulates brain development toward more normal growth patterns.
It is probable that there is greater chance of lasting recovery if therapy is delivered during early childhood rather than after adolescence.
If a child continues to stutter into adolescence and beyond, the window of dynamic growth in the speech regions supporting fluent speech may close; an adult is likely to be much more resistant to change.
Reflecting these ideas, the goal for most adult therapeutic interventions is not normal fluency, but rather a state in which stuttering occurs with less tension or a speech pattern that is volitional and consciously controlled due to relearning the components of fluent speech, including respiration, phonation, and articulation .

Using Brain Imaging to Unravel the Mysteries of Stuttering:


Although the underlying causes of stuttering are unknown, results of twin studies (adoption studies and family studies) support a role for genetic contributions in the etiology of this disorder.
Genetic-linkage studies have provided suggestive or significant evidence of linkage with numerous loci across the genome.
On the basis of a study involving a group of consanguineous families in Pakistan, the strongest linkage is with a locus on the long arm of chromosome 12.
This locus have been analyzed in a group of affected Pakistani families and in a series of affected but unrelated subjects from Pakistan, North America, and Britain, as well as in unaffected, unrelated control subjects from both Pakistan and North America.

Even studies on fraternal twins have been conducted to understand what can be the role of genetic in stuttering.
In one of the latest study the heritability of stuttering is 80%, which is extremely high.
But it's still not 100%, so something else is likely going on.
The environment can be only one other possible factor.


The variant showing the highest degree of cosegregation with stuttering in families analysed was the mutation G3598A that predicts the substitution of a lysine residue for a glutamic acid residue at position 1200 (Glu1200Lys) in GlcNAc-phosphotransferase (encoded by GNPTAB).
With three exceptions, the affected persons in the families carried one or two copies of this variant.
The fact that the highest linkage scores were obtained for the GNPTAB G3598A variant, combined with the lack of other plausible genetic variants within the linkage interval, suggested that this variant increases the risk of stuttering when present in either one or two copies.
There are also other three potential mutation on GTPTAB.

GNPTG gene, which encodes the recognition subunit of GlcNAc-phosphotransferase, has been sequenced and reseacrches had identified three mutations in some affected (none of these variants were present in the control group).
The missense mutation observed at amino acid position 74 encodes a negatively charged glutamic acid in place of the small, nonpolar amino acids (alanine and glycine) at this position.
The mutation at position 688 encodes a valine in place of leucine that occurs at this position and the third mutation was a 9-bp duplication, encoding an in-frame duplication of amino acids 5, 6, and 7.

The GlcNAc-phosphotransferase enzyme encoded by GNPTAB/G acts in the pathway that generates the mannose-6-phosphate targeting signal that directs enzymes to the lysosome (as suggested by the image below).

The subsequent step in this pathway is catalyzed by N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (NAGPA).
Even in this case sequencing 10 exons have been revealed three mutation in some unrelated affected persons (some heterozygotes and one homozygote).
The mutation at amino-acid position 328 encodes a cysteine in place of an arginine, while the mutation at amino-acid position 84 encodes a glutamine in place of the normal histidine.
The third mutation was a 16-bp deletion that changes the penultimate amino acid from lysine to asparagine and removes the last amino acid and the stop codon, resulting in an extended open reading frame that predicts the addition of 112 amino acids to the carboxyl terminus of this protein.

Mutations in GNPTAB and GNPTG have been associated with the rare inherited lysosomal storage disorders mucolipidosis types II and III respectively, which are characterized by disorders of the joints, skeletal system, heart, liver, spleen, and motor systems and by developmental delay.
Mutations in NAGPA have not been reported.

Three findings support a pathogenic role of these mutations in stuttering:

- none of these GNPTAB, GNPTG, and NAGPA mutations was observed in the unaffected control subjects;

- all the mutations occurred at positions at which amino acid identity is conserved to a large extent across species;

- all the mutations occurred within a single, well-defined metabolic pathway.

Further supporting a causative role of these mutations in stuttering is the observation that although persons with mucolipidosis types II and III predominantly have skeletal, cardiac, and ocular disorders, they often have deficits in speech, particularly in expressive speech.

These three genes are widely expressed in many tissues in the body throughout life, and lifelong expression of these genes is consistent with the persistent nature of stuttering in our subjects.

The observed mutations in the genes encoding the alpha and beta subunit (GNPTAB) and the gamma subunit (GNPTAG) of GlcNAc-1-phophotransferase and the likely evidence of lysosomal dysfunction in patients with persistent developmental stuttering now provide a possible neurochemical basis for white-matter abnormalities, because lysosomes participate in protein trafficking, which is crucial for the biogenesis and maintenance of myelin sheaths.

The findings open new research avenues into possible treatments for stuttering.
For example, current treatment methods for some metabolic disorders involve injecting a manufactured enzyme into a person's bloodstream to replace the missing enzyme.
The researchers wonder if enzyme replacement therapy might be a possible method for treating some types of stuttering in the future.
It's believed that mutations in these genes account for perhaps 10% of people who stutter that have a family history of the disorder.
While this information has provided a start for understanding exactly how stuttering can be caused, it's important to find the cause of the disorder in the other 90% of individuals who stutter.
Fortunately, it appears that genetic approaches are on track to find additional genes that cause stuttering , for example a recent study identified a location on chromosome 3q that contains another autosomal recessive stuttering locus.

Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering

In Search of Stuttering's Genetic Code

Genetic Susceptibility to Persistent Stuttering

Parkinsonian speech disfluencies: effects of L-dopa-related fluctuations.

The excess dopamine theory of stuttering (Wu et al., 1997) contends that stuttering may be related to excess levels of the neurotransmitter dopamine in the brain.


The results of this study do not strongly support the excess dopamine theory of stuttering.

Rather, the disfluency changes exhibited by individual participants support a hypothesis that speech disfluencies may be related to increases or decreases in dopamine levels in the brain.

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