Targeting Dyslexia

About 10 percent of US children have persistent, unexplained difficulties in reading — developmental dyslexia, the most common learning disability. Decades of neuroimaging studies have shown that the process of reading engages a complex network of brain regions involved in diverse sensory and cognitive functions. Researchers have linked dyslexia to functional and structural changes within these regions and in the white matter tracts that connect them.

But since most of these studies have involved older children and adults, such findings don’t answer the question of causation: Do these brain differences from fluent readers cause dyslexia, or are they the consequence of poor reading? Research in the past few years has come closer to answering such questions.

“I think the field has evolved to become part of the whole new area of developmental cognitive neuroscience,” says Nadine Gaab, principal investigator at the Laboratories of Cognitive Neuroscience at the Children’s Hospital, Boston. “Where it used to be static, it now asks more dynamic questions about trajectories over time.”

Improvements in neuroimaging technology and a growing acceptance among researchers and the public have made it possible to use MRI with very young children who have not yet learned to read, comparing those who are at risk of the disorder (by virtue of behavioral signs or family history), with controls who are not.

Inside baby brains

Subjects in such studies have typically been kindergarten age, but they are getting younger. Gaab was senior author of a study, reported in Cerebral Cortex in 2015, that involved 14 infants between 6 and 18 months of age who had a family history of dyslexia (which carries a 34–77 percent risk of the disorder), and 18 who did not.

The researchers focused on the arcuate fasciculus (AF), a white matter tract that connects language processing areas in the front and rear of the brain. Earlier studies have consistently found that fibers in this tract are less organized and efficient in poor readers and those with dyslexia.

Diffusion-weighted imaging showed that the left AF was similarly less developed in the infants with a positive family history of dyslexia than in others. The difference, apparently, not only predates reading instruction, but most experience with language.

“We’re currently seeing these children again,” says Gaab. The plan is to reassess them just before and after kindergarten, and after the second grade, when they have presumably learned to read. “We can then nicely look at how predictive [of dyslexia] early white matter alterations are.”

Such studies may also shed light on “protective” or “compensatory” factors in children with a family history of dyslexia who do become fluent readers. A leading possibility is that     these children may have shifted some language processing from  the left hemisphere, which usually predominates, to the right side of the brain. One recent study in her lab has found more developed white matter tracts in the right hemisphere and corpus callosum, (which connects the hemispheres), in such individuals.

Form before function

In another study, published in 2016 in Nature Neuroscience, researchers focused on a small region of the visual cortex essential for reading: the visual word form area (VWFA), which responds, in readers only, more to the shapes of letters than to faces or drawings of objects,

“It has remarkably high selectivity for orthographic stimuli,” says Zeynep Saygin of the McGovern Institute for Brain Research at Massachusetts Institute of Technology, first author of the paper. How does the VWFA get that way? Are areas prewired to serve specific functions, or do connectivity patterns form as a result of brain activity?

Saygin and her colleagues took advantage of the fact that although the VWFA emerges in roughly the same spot in everyone, its precise location differs among individuals. With functional and structural MRI, they scanned 14 children at age 5, before they learned to read, and then again at 8, after they had learned to read. At age 8, but not 5, a small area selectively responded to letters— the VWFA.

Using diffusion-weighted imaging, the researchers then examined white matter patterns and found, at age 8, a “connectivity fingerprint” running from the VWFA to other brain regions. The same “fingerprint,” in the pre-reading 5-year-olds, could predict exactly where the VWFA would be three years later.

“There seems to be a set of connections that helps this become a reading area,” Saygin says. “As the individual learns to read, it becomes more and more selective for letters.”

This study only considered the predictive power of the pre-wired “connectivity fingerprint,” not the details of its connections. “There is a broad network responsible for reading, but we haven’t looked across regions in these kids,” Saygin says. “Future studies should investigate if these are the same tracts linked to reading difficulty by other researchers.”

For such reasons, the finding that part of the brain is apparently pre-wired for reading does not provide direct evidence that pre-existing structural differences cause dyslexia. But it is consistent with that hypothesis, she says.

“This study is both elegant and exciting,” says April Benasich, professor of developmental neuroscience at Rutgers University. “It highlights the importance of looking early on at how the brain organizes connectivity networks.

“These effects have been shown in sensory systems in animal models; this work is particularly interesting because it looks at the underpinnings of a higher cognitive function, reading. I think it’s a big step forward.”

At the same time, Benasich says, the research does not address how connectivity arises. “My thinking is that [researchers] need to take a few steps back and look at how these areas are coming together; it may be cytoarchitecture (cellular composition of the tissue), it may be genetic influence,” she says.

“They also haven’t looked at the effects of experience, such as how many words the child hears, which is important for reading development. But you can’t do everything in one paper.”

Hopes for the tomorrow

Future research, investigators say, will similarly look beyond emerging findings for a more detailed picture.  “If we see differences in very young infants, something is most likely happening prenatally,” says Gaab.  Fetal imaging “is a really interesting prospect: It’s the next logical step.”

In particular, she thinks, “spectroscopy will be an important tool of the future, to look at prenatal differences in glutamine, choline, and other neurotransmitters.” Not just for dyslexia, but a broader swath of neurodevelopmental disorders: “This goes to fundamental levels of brain development: Think about how choline is involved in the building and myelination of white matter tracts,” she says.

Fumiko Hoeft, director of BrainLENS (Laboratory for Educational Neuroscience) at University of California in San Francisco, wants to dissect the powerful influence of family. “We’re considering the whole family structure. With intergenerational neuroimaging, we can now look at parents and offspring, and see similarities in brain networks.”

She is also probing sex-specific transmission patterns—older fathers appear more likely to have dyslexic offspring, and the children of mothers with a history of reading difficulties have reduced cortical surface in some language-processing areas.

Further research, she says, may be able to tease out genetic from epigenetic processes involved in parental transmission, and pre-natal from post-natal influences.

Clarifying risk factors and biomarkers, researchers hope, will facilitate timely intervention. “We’re trying to identify mechanisms in the brain and behavioral indications that could give us the clue who will go on to develop reading disabilities.” says Gaab.

Earlier seems indeed better. Hoeft noted that an effectiveness gap of 50 percent can already be seen between the response rate to some interventions initiated for at-risk children in kindergarten and first grade,

For example, with better understanding of dyslexia risk “we can start parent education earlier,” she says. “It has been shown that training parents can change the outcome for kids with other neurodevelopmental disorders, like ADHD, so why not for dyslexia also?”.

Clarifying protective factors like right brain compensation may help circumvent the development of dyslexia in high-risk children, Gaab says. “People ask how you teach to the right hemisphere. One hint: home literacy–the number of books at home, how much parents read to kids–seems to have more effect on the right hemisphere of those at genetic risk,” as well as brain activation linked to reading-associated skills.

A deeper understanding of mechanisms underlying dyslexia could also help clinicians tailor treatment to the individual. “It may not happen in the next couple of years,” says Hoeft. “But the potential power is very exciting.”