Selective modulation of brain network dynamics by seizure therapy in treatment-resistant depression

Abstract

Background: Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression, yet its mechanism of action is still unclear. Understanding the mechanism of action of ECT can advance the optimization of magnetic seizure therapy (MST) towards higher efficacy and less cognitive impairment. Given the neuroimaging evidence for disrupted resting-state network dynamics in depression, we investigated whether seizure therapy (ECT and MST) selectively modifies brain network dynamics for therapeutic efficacy.

Methods: EEG microstate analysis was used to evaluate resting-state network dynamics in patients at baseline and following seizure therapy, and in healthy controls. Microstate analysis defined four classes of brain states (labelled A, B, C, D). Source localization identified the brain regions associated with these states.

Results: An increase in duration and decrease in frequency of microstates was specific to responders of seizure therapy. Significant changes in the dynamics of States A, C and D were observed and predicted seizure therapy outcome (specifically ECT). Relative change in the duration of States C and D was shown to be a strong predictor of ECT response. Source localization partly associated C and D to the salience and frontoparietal networks, argued to be impaired in depression. An increase in duration and decrease in frequency of microstates was also observed following MST, however it was not specific to responders.

Conclusion: This study presents the first evidence for the modulation of global brain network dynamics by seizure therapy. Successful seizure therapy was shown to selectively modulate network dynamics for therapeutic efficacy.

Keywords: Electroconvulsive therapy; Electroencephalography; Magnetic seizure therapy; Microstate analysis; Network dynamics; Treatment-resistant depression.

Fig. 1

Effect of seizure therapy (ECT and MST) on the average duration of all four microstates. In each subplot, the raw data is plotted on top of a boxplot showing the mean (red line), 95% confidence interval (red area) and 1 standard deviation (blue area). Significant comparisons are marked with a green (*). (A) Left panel: Following seizure therapy (ECT and MST), there was a significant increase in the duration of State A (y-axis) (p < 0.0001). Middle and right panels: This increase was specific to responders of seizure therapy (p < 0.0001). (B) No significant changes were observed in the duration of State B. (C) No significant changes were observed in the duration of State C. (D) No significant changes were observed in the duration of State D.

Fig. 2

Effect of seizure therapy (ECT and MST) on the frequency of all four microstates. In each subplot, the raw data is plotted on top of a boxplot showing the mean (red line), 95% confidence interval (red area) and 1 standard deviation (blue area). Significant comparisons are marked with a green (*). (A) No significant changes were observed in the frequency of State A. (B) Left panel: A decrease in the frequency of State B (y-axis) was observed following seizure therapy (p = 0.03). Middle and right panels: This decrease in frequency of State B was specific to responders of seizure therapy (p = 0.01). (C) Left panel: A decrease in the frequency of State C (y-axis) was observed following seizure therapy (p = 0.004). Middle and right panels: This decrease in frequency of State C was specific to responders of seizure therapy (p = 0.0004). (D) Left panel: A decrease in the frequency of State D (y-axis) was observed following seizure therapy (p = 0.0008). Middle and right panels: This decrease in frequency of State D was specific to responders of seizure therapy (p = 0.04).

Fig. 3

Effect of electroconvulsive therapy (ECT) on the average duration of all four microstates. In each subplot, the raw data is plotted on top of a boxplot showing the mean (red line), 95% confidence interval (red area) and 1 standard deviation (blue area). Significant comparisons are marked with a green (*). (A) Left panel: Following ECT, there was a significant increase in the duration of State A (y-axis) (p < 0.0001). Middle panel and right: This increase was specific to responders of ECT (p < 0.0001). (B) No significant changes were observed in the duration of State B. (C) No significant changes were observed in the duration of State C. (D) No significant changes were observed in the duration of State D.

Fig. 4

Effect of electroconvulsive therapy (ECT) on the frequency of all four microstates. In each subplot, the raw data is plotted on top of a boxplot showing the mean (red line), 95% confidence interval (red area) and 1 standard deviation (blue area). Significant comparisons are marked with a green (*). (A) No significant changes were observed in the frequency of State A. (B) Left panel: A decrease in the frequency of State B (y-axis) was observed following ECT (p = 0.03). Middle and right panels: This decrease in frequency of State B was specific to responders of ECT (p = 0.03). (C) Left panel: A decrease in the frequency of State C (y-axis) was observed following ECT (p = 0.002). Middle and right panels: This decrease in frequency of State C was specific to responders of ECT (p = 0.008). (D) Left panel: A decrease in the frequency of State D (y-axis) was observed following ECT (p = 0.0003). Middle and right panels: This decrease in frequency of State D was specific to responders of ECT (p = 0.04).

Fig. 5

Change in the duration of State A following seizure therapy (ECT + MST) correlated with improvement in depressive symptoms (HRSD). For the receiver operating characteristic (ROC) curve (right panels), the x-axes represents the false positive rate (1-specificity) and the y-axes represents the true positive rate (sensitivity). The red circle depicts the optimum operating point of the ROC curve. The area under the curve (AUC) at this optimum point is specified on the graph. (A) An increase in the duration of State A significantly correlated with improvement in depressive symptoms (x-axis), Hamilton Rating Scale for Depression (HRSD) (r = 0.33, p = 0.02). X-axis represents change in HRSD (pre-post)/(pre*100). Y-axis represents change in coverage of State D (post-pre)/(pre*100). (B) Change in State A duration was also a fair predictor of response to seizure therapy (AUC = 0.71, p = 0.003).

Fig. 6

Changes in microstate characteristics following electroconvulsive therapy (ECT) correlated with improvement in self-rated depressive symptoms. For the receiver operating characteristic (ROC) curves (all right panels), the x-axes represents the false positive rate (1-specificity) and the y-axes represents the true positive rate (sensitivity). The red circle depicts the optimum operating point of the ROC curve. The area under the curve (AUC) at this optimum point is specified on the graph. (A) Left panel: An increase in the coverage of State A significantly correlated with improvement in self-rated depressive symptoms (x-axis), Beck's Depression Inventory scale (BDI) (r = 0.57, p = 0.02). X-axis represents change in BDI (pre-post)/(pre*100). Y-axis represents change in coverage of State D (post-pre)/(pre*100). Right panel: Change in State A coverage was also a strong predictor of response to ECT (BDI) (AUC = 0.79, p = 0.005). (B) Left panel: A decrease in the duration of State D was significantly correlated with improvement in BDI (r =−0.55, p = 0.02). X-axis represents change in BDI (pre-post)/(pre*100). Y-axis represents change in duration of State D (post-pre)/(pre*100). Right panel: Change in State D duration was also a strong predictor of response to ECT (BDI) (AUC = 0.83, p = 0.0007). (C) Left panel: The correlation between State D duration and BDI remained significant when the change in duration of State D was presented relative to the change in duration of State C (r = −0.66, p = 0.003). X-axis represents change in BDI (pre-post)/(pre*100). Y-axis represents the log of the absolute ratio between change in duration of State D (post-pre)/(pre*100) over the change in duration of State C (post-pre)/(pre*100). Right panel: Ratio of change in State D duration over the change in State C duration was an excellent predictor of self-rated response to ECT (BDI) (AUC = 0.97, p < 0.0001).

Fig. 7

Effect of magnetic seizure therapy (MST) on microstate characteristics. (A) Left panel: Following MST, patients showed a significant improvement in scale for suicidal ideation (SSI). Middle and right panels: Reduction in SSI was significantly associated with baseline resting-state microstate characteristics of all microstate classes. X-axes represents change in SSI score (Post-Pre) and y-axes represents baseline characteristics of each microstate A, B, C and D. (B) Left panel: Following MST, patients showed a significant improvement in cognition scores (Montreal Cognitive Assessment (MOCA)). Middle panel: A decrease in the frequency of State B following MST correlated with improvement in cognition scores. X-axis represents change in MOCA (Post-Pre) and y-axis represent change in State B frequency (post-pre)/(pre*100). Right panel: This decrease in frequency was also a strong predictor of cognitive score outcome. The x-axis represents the false positive rate (1-specificity) and the y-axis represents the true positive rate (sensitivity). The red circle depicts the optimum operating point of the receiver operating characteristic curve. The area under curve (AUC) at this optimum point is specified on the graph (AUC = 0.80, p = 0.002).

Fig. 8

Microstate characteristics of treatment-resistant depression (TRD) compared to healthy (HLT) subjects before and after seizure therapy. In each subplot, the raw data is plotted on top of a boxplot showing the mean (red line), 95% confidence interval (red area) and 1 standard deviation (blue area). All comparisons shown in (A) to (D) were significant. (A) & (B) Patients showed a longer duration (p = 0.03) and lower frequency (p = 0.03) of microstate dynamics compared to healthy subjects. (C) & (D) Following seizure therapy, patients showed a much longer duration (p < 0.0001) and lower frequency (p = 0.0001) of microstates compared to healthy subjects. In all plots of (A–D, x-axes represents the subject group. In (A–B), y-axis represents the duration of all microstates in milliseconds (main effect of group in ANCOVA). In (C–D), y-axis represents the frequency of all microstates per second (main effect of group in ANCOVA). (E) Seizure therapy (ECT and MST) was shown to normalize the high coverage of State D in patients compared to healthy subjects (p = 0.01). X-axis represents each microstate class. Y-axis represents the percent coverage of all microstates, and each line in the graph represents a subject group (interaction effect of Microstate Class × Group in ANCOVA).

Fig. 9

Global microstate classes clustered over all groups and all subjects with their source (eLORETA) images. All microstates show activation in the posterior cingulate gyrus. (A) Microstate A was shown to be associated with the left superior and middle temporal gyrus. (B) Microstate B was associated with the cuneus and precuneus of the occipital lobe. (C) Microstate C was associated with the anterior cingulate, insula and cuneus and precuneus of the occipital lobe. (D) Microstate D was associated with the paracentral lobe of the frontal lobe, the precuneus of the parietal lobe, the parahippocampal gyrus, and the lingual gyrus of the occipital lobe.