Resting-state EEG oscillatory dynamics in fragile X syndrome: abnormal functional connectivity and brain network organization

Melle J W van der Molen, Cornelis J Stam, Maurits W van der Molen, Melle J W van der Molen, Cornelis J Stam, Maurits W van der Molen

Abstract

Disruptions in functional connectivity and dysfunctional brain networks are considered to be a neurological hallmark of neurodevelopmental disorders. Despite the vast literature on functional brain connectivity in typical brain development, surprisingly few attempts have been made to characterize brain network integrity in neurodevelopmental disorders. Here we used resting-state EEG to characterize functional brain connectivity and brain network organization in eight males with fragile X syndrome (FXS) and 12 healthy male controls. Functional connectivity was calculated based on the phase lag index (PLI), a non-linear synchronization index that is less sensitive to the effects of volume conduction. Brain network organization was assessed with graph theoretical analysis. A decrease in global functional connectivity was observed in FXS males for upper alpha and beta frequency bands. For theta oscillations, we found increased connectivity in long-range (fronto-posterior) and short-range (frontal-frontal and posterior-posterior) clusters. Graph theoretical analysis yielded evidence of increased path length in the theta band, suggesting that information transfer between brain regions is particularly impaired for theta oscillations in FXS. These findings are discussed in terms of aberrant maturation of neuronal oscillatory dynamics, resulting in an imbalance in excitatory and inhibitory neuronal circuit activity.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. An overview of the method…
Figure 1. An overview of the method used to calculate weighted graphs.
(A) EEG time-series from the 26 scalp electrodes were separately filtered for the delta, theta, alpha low, alpha high, beta, and gamma frequency bands. Higher alpha (10–13 Hz) is shown here as largest group differences were found for this frequency band. (B) Functional connectivity between all 26×26 electrode pairs was calculated based on the phase lag index, yielding connectivity values between 0 and 1 (higher values reflect more synchronization between electrodes). (C) When using graph theoretical analysis on EEG time series, electrodes represent “nodes” and the distance between these nodes represent the “edges” in the graph. PLI scores were used to calculate the path length (distance between the nodes) and the clustering coefficients (the degree in which nodes cluster together). In addition, a randomization procedure is employed to obtain measures independent of network size. From each original graph, random networks were derived by randomly shuffling the edge weights. Mean values of weighted graphs are then determined by dividing the original graph measures by these ‘surrogate’ measures.
Figure 2. Global functional connectivity as indexed…
Figure 2. Global functional connectivity as indexed by the Phase Lag Index (PLI).
(A) Functional connectivity matrices are presented for theta, alpha and beta bands, as group differences were largest for these spectral bands. (B) Group differences in PLI for the delta, theta, alpha, beta and gamma bands. As can be seen from these data, FXS males show significantly less functional connectivity in the upper alpha and beta frequency bands. Asterisks represent significant differences at p<.05. Error bars represent standard error of the mean.
Figure 3. Matrices of local and long-range…
Figure 3. Matrices of local and long-range functional connectivity in frontal and parietal/occipital clusters for the theta and upper alpha power bands.
In FXS males, significant increased local functional connectivity was found in the parietal-occipital cluster for theta oscillations, whereas a decrease in local functional connectivity was found in this cluster for alpha oscillations. A significant increase in long-range (frontal-parietal/occipital) theta functional connectivity was found in FXS males. Asterisks represent significant differences at p<.05. Error bars represent standard error of the mean.
Figure 4. Mean normalized clustering coefficients over…
Figure 4. Mean normalized clustering coefficients over all epochs for FXS and controls participants in the delta (0.05–4), theta (4–8 Hz), lower alpha (8–10 Hz), upper alpha (10–13 Hz), beta (13–30 Hz), and gamma (30–45 Hz) frequency range.
Error bars represent standard error of the mean.
Figure 5. Mean normalized path length over…
Figure 5. Mean normalized path length over all epochs for FXS and controls participants in the delta (0.05–4 Hz), theta (4–8 Hz), lower alpha (8–10 Hz), upper alpha (10–13 Hz), beta (13–30 Hz), and gamma (30–45 Hz) frequency range.
Path length in the theta band is significant longer in FXS males as compared to controls. Asterisks represent significant differences at p<.05. Error bars represent standard error of the mean.

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