Resting-state quantitative electroencephalography reveals increased neurophysiologic connectivity in depression

Abstract

Symptoms of Major Depressive Disorder (MDD) are hypothesized to arise from dysfunction in brain networks linking the limbic system and cortical regions. Alterations in brain functional cortical connectivity in resting-state networks have been detected with functional imaging techniques, but neurophysiologic connectivity measures have not been systematically examined. We used weighted network analysis to examine resting state functional connectivity as measured by quantitative electroencephalographic (qEEG) coherence in 121 unmedicated subjects with MDD and 37 healthy controls. Subjects with MDD had significantly higher overall coherence as compared to controls in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-20 Hz) frequency bands. The frontopolar region contained the greatest number of "hub nodes" (surface recording locations) with high connectivity. MDD subjects expressed higher theta and alpha coherence primarily in longer distance connections between frontopolar and temporal or parietooccipital regions, and higher beta coherence primarily in connections within and between electrodes overlying the dorsolateral prefrontal cortical (DLPFC) or temporal regions. Nearest centroid analysis indicated that MDD subjects were best characterized by six alpha band connections primarily involving the prefrontal region. The present findings indicate a loss of selectivity in resting functional connectivity in MDD. The overall greater coherence observed in depressed subjects establishes a new context for the interpretation of previous studies showing differences in frontal alpha power and synchrony between subjects with MDD and normal controls. These results can inform the development of qEEG state and trait biomarkers for MDD.

Figure 1. Topographic locations for the electrode montage used in EEG recordings and coherence calculations.

Electrode locations were based upon an enhanced version of the International 10–20 System of electrode placement, with additional electrodes placed over the frontal and parietal regions (1A). Locations were projected through Cartesian coordinates onto a two-dimensional representation of the brain, using a central electrode (Cz) as the origin, with locations labeled and indicated by red dots. Recordings were performed referenced to the Pz electrode, and data were recalculated by subtraction offline for a bipolar montage consisting of 66 nearest-neighbor electrode pairs (signified by the lines connecting individual electrodes). Bipolar pairs were considered as nodes of a brain network, with the nodes located at the midpoint between the electrode pairs shown (indicated by the blue dots and the oval labels in 1B). Coherence was calculated between all pairs of nodes as described in the methods.

Figure 2. Boxplots of median coherence for MDD and healthy control groups (by frequency band).

The short horizontal line within each box shows the median values, and the notches represent 95% confidence intervals for the median values. Statistical significance listed for each frequency band is based upon the Kruskal Wallis test.

Figure 3. Map of connection strengths

showing significant differences between groups (by frequency band). Red lines represent connections (edges) whose strength remained significantly different between MDD and control subjects after Bonferroni correction (p≤2.33×10⁻⁵). All red edges represent coherence values that were greater in the MDD group with line thickness proportional to the magnitude of the difference. The nodes most commonly involved in significant edges across frequency bands were located in the prefrontal region.

Figure 4. Boxplots of edge lengths

of connections that showed significant difference between groups (by frequency band). Edge length was determined from the relative physical distance between nodes on a two-dimensional plane as shown in Figure 1B. Edges with significantly different connection strength differed significantly in length across frequency bands (p = 0.00001). Significance level represents the p value for the Kruskal Wallis test examining the equality of the median edge length values between groups. Short horizontal lines within boxes show the median edge length, with notches indicating 95% confidence intervals of the medians. Median edge length was significantly greater for alpha than any other band. The width of the bars is proportional to the number of edges that were significantly different between groups in the frequency band: in the delta band, there were 17 significant edges; in theta, 42; in alpha, 141; and in beta, 121.

Figure 5. Maps showing the median connectivity CE (coherence) between hub node Fp1-Fpz and all other nodes in all frequency bands, separately for MDD and healthy control subjects.

This node demonstrates broadly higher median connectivity in the MDD subjects (A, C, E, and G) compared to the control subjects (B, D, F, and H). Coherence values are indicated by the color bar on the left of the maps. Coherence values decrease with distance from the hub node in both MDD and control subjects, but show greater decrease with distance in control subjects.

Figure 6. Nearest centroid classification of MDD and healthy control subjects.

Six edges (listed on the right) selected using nearest centroid analysis classified subjects into MDD and control groups, with classification indicated by the dendrogram at the top of the figure. Individual subjects are represented by the terminal branches of the dendrogram, with MDD subjects clustering toward the right (indicated by black bars in the top row) and control subjects clustering toward the left (indicated by red bars) in the supervised cluster analysis. Data values for each subject are indicated by a color column in the heatmap corresponding to a terminal branch. MDD subjects tended to have higher coherence values than controls on edges involving frontopolar electrodes, while controls tended to have higher coherence on the edge involving parietooccipital electrodes (indicated by green-to-yellow colors in the heatmap). As part of the clustering algorithm, the coherence values were scaled to have zero mean and unit variance across the subjects (as shown in colorbar).