Multilayer MEG functional connectivity as a potential marker for suicidal thoughts in major depressive disorder

Abstract

Major depressive disorder (MDD) is highly heterogeneous in its clinical presentation. The present exploratory study used magnetoencephalography (MEG) to investigate electrophysiological intrinsic connectivity differences between healthy volunteers and unmedicated participants with treatment-resistant MDD. The study examined canonical frequency bands from delta through gamma. In addition to group comparisons, correlational studies were conducted to determine whether connectivity was related to five symptom factors: depressed mood, tension, negative cognition, suicidal thoughts, and amotivation. The MDD and healthy volunteer groups did not differ significantly at baseline when corrected across all frequencies and clusters, although evidence of generalized slowing in MDD was observed. Notably, however, electrophysiological connectivity was strongly related to suicidal thoughts, particularly as coupling of low frequency power fluctuations (delta and theta) with alpha and beta power. This analysis revealed hub areas underlying this symptom cluster, including left hippocampus, left anterior insula, and bilateral dorsolateral prefrontal cortex. No other symptom cluster demonstrated a relationship with neurophysiological connectivity, suggesting a specificity to these results as markers of suicidal ideation.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Connectivity; Frequency; Magnetoencephalography; Major depressive disorder; Oscillation; Suicide.

Fig. 1

Super-adjacency matrices illustrating mean connectivity in A) healthy controls (HCs) and B) participants with major depressive disorder (MDD). The raw correlation matrices were converted using the Fisher r-to-z transform before averaging. C) Mean connectivity, with standard error, for each tile in both groups. D) Z-value for the difference between HC and MDD participants.

Fig. 2

A) As an aid to visualization, the total connectivity for each node was calculated as a summation of adjacency matrix along one axis for the healthy control (HC) and major depressive disorder (MDD) groups separately, and then subtracted. The size of each thus represents the difference in total connectivity of that node between groups for within-frequency theta connectivity (top) and within-frequency alpha connectivity (bottom). B) The Z-score for the difference in total theta connectivity between groups for each node pair is plotted versus the difference in total alpha connectivity, indicating that nodes showing the greatest increase in theta-mediated connectivity tended to show the greatest decrease in alpha-mediated connectivity in participants with MDD compared to HCs.

Fig. 3

Super-adjacency matrix showing Z-values for the association between connectivity and the magnitude of suicidal thoughts. Supra-threshold (Z = 4.45, q < 0.00005) connections are shown in color, and all other connections are shown in greyscale. Tiles across the diagonal represent within-band connections, while off-diagonal tiles represent connections between frequency bands.

Fig. 4

Expanded delta band connectivity tile from Fig. 1 at the same statistical threshold (Z = 4.45, q < 0.00005), illustrating delta band connections significantly associated with the suicidal thoughts (ST) factor. Also shown is a glass brain perspective of the connections (middle right), as well as maps of the nodes with size scaled by the total Z value summed over all connections (far right). Left anterior insula (LAI) and left hippocampus emerged as hubs, with a large number of connections significantly associated with ST factor. Greyscale colorbar is the same as in Fig. 3, omitted here for space.

Fig. 5

Expanded theta band connectivity tile from Fig. 1 at the same statistical threshold (Z = 4.45, q < 0.00005), illustrating theta band connections significantly associated with the suicidal thoughts (ST) factor. Also shown is a glass brain perspective of the connections (middle right), as well as maps of the nodes with size scaled by the total Z value summed over all connections (far right). While anterior insula (AI) and left hippocampus still showed a large number of connections associated with the ST factor, there was greater involvement of frontal connections, particularly the left and right dorsolateral prefrontal cortex (DLPFC) and orbitofrontal regions of interest (ROIs). Greyscale colorbar is the same as in Fig. 3, omitted here for space.

Fig. 6

Graph illustrating within- and across-frequency connections correlating with the suicidal thoughts (ST) factor, where region nodes are collapsed according to their network membership. All connections show a positive relationship with the ST factor, as in Fig. 3. The graph is thresholded to show only the 50 most significant edges for clarity (Z = 4.9, q = 3.6e-6). Abbreviations: DMN: default mode network; CEN: central executive network; SAL: salience network; SubCort: subcortical regions; Dep: depression-associated regions; Vis: visual regions; Mot: motor regions.

Fig. 7

A) Map of nodes with size scaled according to total Z-value for the difference between healthy controls (HCs) and individuals with major depressive disorder (MDD) with high suicidal thoughts (ST) factor scores (MDD_S). B) Within- and across-frequency connections where MDD_S participants showed greater connectivity than HCs. Regions of interest (ROIs) have been collapsed according to their network membership. The graph is thresholded to show only the 50 most significant edges for clarity (Z = 3.45, q = 0.0034). C) For all 14,365 connections in the super-adjacency matrix, the Z-score difference in connectivity between MDD_S and HC participants was plotted versus the Z-score for the association of connectivity with the magnitude of ST factor score.