Research Authors: Jun Yi Wang, Merna Danial, Cyrus Soleymanzadeh, Bella Kim, Yiming Xia, Kyoungmi Kim, Flora Tassone, Randi J. Hagerman & Susan M. Rivera


Jun Yi Wang and the study team out of the UC Davis MIND Institute are interested in learning more about the premutation carrier condition in relations to brain development and its impact on cognition.

As a reminder, cognition refers to the mental processes involved in learning and understanding. These mental processes impact the higher-level functions of the brain including language, learning new things, and making decisions. Little is known about the neurobiology of cognitive development and psychiatric conditions in children who are Fragile X premutation carriers.

Research in mouse models has suggested embryonic cortical development that may affect cortical folding or gyrification. Gyrification is a complex process that produces the folds of the brain; the folded shape of the brain allows the cerebral cortex, the thin outer layer of neurons and their connections, to attain a large surface area, which is thought to help with cognition. The development of gyri occurs mainly between four and 12 months and it has been suggested that disruptions in the development of gyri can impact cognition, language, and motor control. Certain disorders, like epilepsy, have been linked with altered development of the gyri. The study team was interested in learning more about the relationship between gyrification (cortical folding), premutation status, and cognition.

The study team enrolled 61 children ages 8 to 12 years old; 33 individuals who are Fragile X premutation carriers (19 boys, 14 girls) and 28 age-matched controls (15 boys, 13 girls). Each participant had one MRI; the MRIs produced an image of the individual’s brain.

Gyrification was measured using local gyrification index (LGI), which is the ratio of total surface area (both hidden within the sulci [brain folds] and exposed on the outer surface of the brain) and exposed surface area.

Participants also had a physical exam, participated in an IQ test, and those with the premutation had their blood drawn to confirm they were premutation carriers.

The study team found that the majority (78.8%) of the PMC in their sample showed aberrant (different than the usual) gyrification in comparison to the controls. The FMR1 gene is likely involved in cortical expansion and folding, which is important for development of cognition. It is true that both genes and environmental factors may contribute to the aberrant gyrification observed in the participants who were PMC, so more research needs to be done to understand the influence of carrier status and gyrification.

The link between gyrification and cognition was also studied, and the results suggest that there is a potential link between gyrification and IQ in cortical regions important for performing function.

The PMC sample and the findings of this study likely represent a subgroup of children who are PMC with co-occurring conditions such as ADHD and anxiety. More studies on unbiased sample selections from the PMC population are needed to establish a clear picture of clinical involvement and associated brain alterations. Even with the author’s cited limitations, this research supports some of the prior research on the premutation carrier condition, which has suggested challenges in executive functioning, motor-visual control, ADHD, and other co-occurring conditions. Learning more about brain development and its impact on our lives is complex and important. The need for additional research continues.

Why This Matters

This was the first neuroimaging study in children who carry the premutation. The way the study team measured gyrification could serve as a useful biomarker of fetal/infant neurodevelopment, which could help researchers, clinicians, and families better understand cognitive development and potential risk for conditions like ADHD experiences by some PMC. Early intervention is known to be helpful across conditions, so having a biomarker like this could help clinicians and families make a plan to support the child’s development.

Next Steps

Additional research to explore potential links between gyrification, cognition, and co-occurring conditions like ADHD. Understanding potential links can help families and professionals set each child up for success!

Acknowledgements: The study team shared their gratitude to the research participants and their families and to Patrick Adams and Yingratana McLennan for data collection.

Funding: This project was supported by NIH Roadmap Grant DE019583, NIH Grant HD036071 to R.J.H., the MIND Institute IDDRC Grant U54 HD079125, and private donors.

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