Are there changes in brain function in carriers of Fragile X, who do not have clear FXTAS symptoms?

Functional MRI in carriers of the FMR1 premutation: Study results from University of Edinburgh and the Patrick Wild Centre

In 2013 to 2017 the Patrick Wild Centre at the University of Edinburgh carried out a brain imaging study in premutation carriers, funded by the Helen Maude Garfit fund and the RS MacDonald Charitable Trust. Our research group was generously helped with recruitment for the study by the Fragile X Society. We summarize our main findings in this short report.


We first set out to look at whether there were any changes in brain function in carriers who did not have clear symptoms of FXTAS, using a method called functional MRI. Participants in the study were asked to do a movement task inside the scanner, where they tapped their fingers in random order and then a predetermined order. Participants also had blood taken to investigate a molecule called FMR1 mRNA, which can become over-produced in premutation carriers and which might be one of the causes of FXTAS. In addition, tremor, co-ordination and balance were measured by a computerized system. Seventeen male premutation carriers took part in this study, along with seventeen males of similar ages who did not have the premutation.


Premutation carriers showed markedly lower brain activation than the comparison group during the movement task in brain regions known as the cerebellum and hippocampus. Additionally, as age increased in carriers, activation was reduced in certain brain areas (visual cortex, hippocampus, parietal and temporal lobes), whereas participants without the premutation showed increases in these areas as they age (Figure 1a).


Figure 1. a) The difference in brain activation between premutation carriers and the control group when carrying out a movement task in the scanner. b) Levels of FMR1 mRNA in premutation carriers and controls.

Small but definite changes in carrier movements were also identified by the computerized system. Even carriers without a diagnosis of FXTAS showed higher levels of hand tremor and were less co-ordinated than those without the premutation. Balance however was no different between the groups.


The measurements of FMR1 mRNA taken from blood showed that levels of mRNA were comparable between carriers and the control group, but when compared directly to an age-matched participant without the premutation, FMR1 mRNA levels can be increased up to 7-fold in carriers (Figure 1b). These measurements of blood flow in the brain, movement, and FMR1 mRNA did not show any direct associations, although this does not necessarily mean they are not linked.


Another part of the study investigated emotional changes in premutation carriers. Participants were asked to view emotional images in the scanner, and their brain activations were recorded. The images for this task were chosen based on how emotionally arousing they were and how pleasant they were. Outside of the scanner, participants filled out a questionnaire about their mental health and then carried out a computerized task where they were shown images of faces and were asked to identify what emotion the faces were portraying. All participants also filled out questionnaires about possible autistic traits and their empathy towards others.


The brain imaging revealed that in response to arousing images (which were both pleasant and unpleasant), certain areas were less activated in carriers than in the comparison group (Figure 2). In contrast to brain activations during movement, this difference showed no changes over age.


The questionnaire about mental health showed that overall, premutation carriers had notably worse symptoms of anxiety and obsessive-compulsiveness, as well as more autistic traits than the comparison groups. On the faces test, carriers performed worse at identifying some facial emotions but not others.



Figure 2. Differences in brain activation between carriers and controls when viewing emotional images in the scanner.

The first part of our study showed brain changes in carriers during movement that are detectable even in those who do not have FXTAS. In addition, these changes are age-sensitive and most marked in older carriers, suggesting they might be an early indicator of FXTAS vulnerability.


The second part of this study showed that premutation carriers have lower activity in the brain when regulating attention and emotional arousal response. This brain activity is not associated with age, suggesting that emotional changes in carriers are stable throughout their lifetime and are not early indicators of FXTAS. Additionally, carriers across all ages demonstrate increases in symptoms of anxiety, obsessive-compulsiveness and autistic traits.


We would like to sincerely thank all participants who took part in this study, without whom this research would not have been possible.


The results from this study are published in full in the following journal articles:

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