Altered neural activity in the 'when' pathway during temporal processing in fragile X premutation carriers

Abstract

Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Large expansions of the CGG repeat (>200 repeats) consequently result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 of CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA. Recent studies have shown that infants with FXS exhibit severely reduced resolution of temporal attention, whereas spatial resolution of attention is not impaired. Following from these findings in the full mutation, the current study used fMRI to examine whether premutation carriers would exhibit atypical temporal processing at behavioral and/or neural levels. Using spatial and temporal working memory (SWM and TWM) tasks, separately tagging spatial and temporal processing, we demonstrated that neurotypical adults showed greater activation in the 'when pathway' (i.e., the right temporoparietal junction: TPJ) during TWM retrieval than SWM retrieval. However, premutation carriers failed to show this increased involvement of the right TPJ during retrieval of temporal information. Further, multiple regression analyses on right TPJ activation and FMR1 gene expression (i.e., CGG repeat size and FMR1 mRNA) suggests that elevated FMR1 mRNA level is a powerful predictor accounting for reduced right TPJ activation associated with temporal processing in premutation carriers. In conclusion, the current study provides the first evidence on altered neural correlates of temporal processing in adults with the premutation, explained by their FMR1 gene expression.

Keywords: FMR1 gene; Fragile X premutation; Spatiotemporal processing; Temporoparietal junction; When pathway; Working memory.

Fig. 1

(A) Trial sequence in the spatial working memory (SWM) task. In the encoding phase, participants saw four red stars and eight white stars for 4 s. Participants were instructed to remember the four positions occupied with the red stars. After the stars disappeared, participants saw a central fixation cross for 10 s (the retention phase). During the retention period, participants were instructed to look at the fixation cross while covertly rehearse the four previously occupied location. After the retention phase, the twelve stars re-appeared with one star was colored yellow (a probe). Participants were asked to judge and respond whether the location of the probe was preoccupied with one of the red stars in the encoding phase. Participants had 4 s to respond, and then, they saw a central fixation cross for 12 s until the next trial begins. (B) Trial sequence in the temporal working memory (TWM) task. In the encoding phase, participants were presented with 12 stars in each trial, but in this task one of the stars was colored red and it changed its location every second during 4 s. Participants were asked to encode the order of the four positions of the red star in each trial. During the retention period, participants were asked to look at the central fixation cross while covertly rehearse the temporal order of the previous four positions with red stars. In the retrieval phase, 12 white stars reappeared and one of them was colored yellow with a number (one, two, three, or four) superimposed on top. Participants were asked to judge whether the number on the star matched to the correct serial position in which it had appeared. The timing of the each phase was identical to those in the SWM task. (For interpretation of the references to color in this legend, the reader is referred to the web version of the article.)

Fig. 2

(A) Right TPJ activation showed greater activation in the control group than the premutation group in the contrast of TWM retrieval > SWM retrieval (MNI coordinates (x,y,z): 52, −38, 22). (B) Beta coefficients in the right TPJ in neurotypical and premutation groups in the retrieval phase of each WM task. Only the neurotypical group showed significant enhancement of activation in the right TPJ during TWM retrieval than SWM retrieval, while such selective enhancement in the right TPJ for temporal processing was absent in the premutation group.