Altered frontal connectivity as a mechanism for executive function deficits in fragile X syndrome

Abstract

Background: Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and autism spectrum disorder. Executive function (EF), necessary for adaptive goal-oriented behavior and dependent on frontal lobe function, is impaired in individuals with FXS. Yet, little is known how alterations in frontal lobe neural activity is related to EF deficits in FXS.

Methods: Sixty-one participants with FXS (54% males) and 71 age- and sex-matched typically-developing controls (TDC; 58% males) completed a five-minute resting state electroencephalography (EEG) protocol and a computerized battery of tests of EF, the Test of Attentional Performance for Children (KiTAP). Following source localization (minimum-norm estimate), we computed debiased weighted phase lag index (dWPLI), a phase connectivity value, for pairings between 18 nodes in frontal regions for gamma (30-55 Hz) and alpha (10.5-12.5 Hz) bands. Linear models were generated with fixed factors of group, sex, frequency, and connection. Relationships between frontal connectivity and EF variables also were examined.

Results: Individuals with FXS demonstrated increased gamma band and reduced alpha band connectivity across all frontal regions and across hemispheres compared to TDC. After controlling for nonverbal IQ, increased error rates on EF tasks were associated with increased gamma band and reduced alpha band connectivity.

Limitations: Frontal connectivity findings are limited to intrinsic brain activity during rest and may not generalize to frontal connectivity during EF tasks or everyday function.

Conclusions: We report gamma hyper-connectivity and alpha hypo-connectivity within source-localized frontal brain regions in FXS compared to TDC during resting-state EEG. For the first time in FXS, we report significant associations between EF and altered frontal connectivity, with increased error rate relating to increased gamma band connectivity and reduced alpha band connectivity. These findings suggest increased phase connectivity within gamma band may impair EF performance, whereas greater alpha band connectivity may provide compensatory support for EF. Together, these findings provide important insight into neurophysiological mechanisms of EF deficits in FXS and provide novel targets for treatment development.

Keywords: Connectivity; EEG; Electroencephalography; Executive function; FXS; Fragile X syndrome.

Fig. 1

Visualization of frontal connectivity measured by dWPLI across FXS and TDC participants. Each data point represents the average of dWPLI values specific to a region and a frequency band within an individual subject. Boxplots show the 25, 50, and 75 percentiles (lower hinge, median, and upper hinge) per subgroup, separated by group and sex. Any data points beyond the whiskers, which are 1.5 times of IQR from the hinge, are regarded as outliers. Triangle markers denote a typically developing control (TDC), and circle markers denote a participant with Fragile X syndrome (FXS)

Fig. 2

Circular chart of connections highlighting significant group differences in connectivity. Statistically significant group differences (multiple comparisons were FDR corrected per model) for band-specific connectivity depicted in regions a left frontal, b left prefrontal, c cross-hemisphere, d right frontal, and e right prefrontal. Male and females are shown separately when an interaction with sex was significant. Green ribbon denotes significant FXS > TDC connections, and red ribbon denotes significant FXS < TDC connections. Darker colors represent higher T-values. Atlas abbreviations: cMFG caudal middle frontal, FP frontal pole, LOF lateral orbitofrontal, MOF medial orbitofrontal, pOPER pars opercularis, pORB pars orbitalis, pTRI pars triangularis, rMFG rostral middle frontal, sFG superior frontal

Fig. 3

Circular chart of connections highlighting significant group differences in connectivity after accounting for nonverbal IQ. Statistically significant group differences (multiple comparisons were FDR corrected per model) for band-specific connectivity depicted in regions a left frontal, b left prefrontal, c cross-hemisphere, d right frontal, and e right prefrontal. Male and females are shown separately when an interaction with sex was significant. Green ribbon denotes significant FXS > TDC connections, and red ribbon denotes significant FXS < TDC connections. Darker colors represent higher T values. Atlas abbreviations: cMFG caudal middle frontal, FP frontal pole, LOF lateral orbitofrontal, MOF medial orbitofrontal, pOPER pars opercularis, pORB pars orbitalis, pTRI pars triangularis, rMFG rostral middle frontal, sFG superior frontal

Fig. 4

Correlations between frontal connectivity and executive function measures across FXS. Spearman’s correlations showing positive correlation in the gamma band (A) and negative correlation in alpha band (B) between connectivity strength and number of errors

Fig. 5

Correlations between frontal connectivity and executive function measures by sex. Sex-specific significant Spearman’s correlations are shown separately for males (A, B) and females (C) for both gamma and alpha bands