Evaluating global brain connectivity as an imaging marker for depression: influence of preprocessing strategies and placebo-controlled ketamine treatment

Abstract

Major depressive disorder (MDD) is associated with altered global brain connectivity (GBC), as assessed via resting-state functional magnetic resonance imaging (rsfMRI). Previous studies found that antidepressant treatment with ketamine normalized aberrant GBC changes in the prefrontal and cingulate cortices, warranting further investigations of GBC as a putative imaging marker. These results were obtained via global signal regression (GSR). This study is an independent replication of that analysis using a separate dataset. GBC was analyzed in 28 individuals with MDD and 22 healthy controls (HCs) at baseline, post-placebo, and post-ketamine. To investigate the effects of preprocessing, three distinct pipelines were used: (1) regression of white matter (WM)/cerebrospinal fluid (CSF) signals only (BASE); (2) WM/CSF + GSR (GSR); and (3) WM/CSF + physiological parameter regression (PHYSIO). Reduced GBC was observed in individuals with MDD only at baseline in the anterior and medial cingulate cortices, as well as in the prefrontal cortex only after regressing the global signal. Ketamine had no effect compared to baseline or placebo in either group in any pipeline. PHYSIO did not resemble GBC preprocessed with GSR. These results concur with several studies that used GSR to study GBC. Further investigations are warranted into disease-specific components of global fMRI signals that may drive these results and of GBCr as a potential imaging marker in MDD.

Trial registration: ClinicalTrials.gov NCT00088699.

Figures

Fig. 1. Total gray matter (GM) global connectivity with global signal regression (GSR).

Reductions in total GM global brain connectivity (GBC) observed with white matter (WM)/ cerebrospinal fluid (CSF) + GSR (GBCr) in individuals with major depressive disorder (MDD). No significant results were observed with the other preprocessing pipelines (all p > 0.05, FWE corrected). a Average baseline connectivity in both groups (p < 0.05, uncorrected). Blue circles indicate areas demonstrating significant reductions in individuals with MDD compared to healthy controls (HCs). b Top: main effect of group across all baseline, post-ketamine, and post-placebo scans. Bottom: reduced connectivity in individuals with MDD compared to HCs in the baseline scan in the medial cingulate cortex (MCC) and anterior cingulate cortex (ACC), as well as in the medial frontal cortex (t tests, p < 0.001 and p < 0.01, FWE corrected at p < 0.05). c Reduced GBCr values in individuals with MDD at baseline (top) were also observed across scans, leading to the significant main effect of group across scans depicted in b. Reduced GBC values in the MCC were not observed with the other preprocessing strategies (bottom). No main effect of drug or post hoc GBCr differences between ketamine, placebo, or each vs. baseline were found within the HC or MDD groups (all p > 0.05, FWE corrected). For statistical results see Supplementary Table S3.

Fig. 2. Reductions of intra-prefrontal cortex (PFC) global brain connectivity (GBC) with global signal regression (GSR; GBCr) in individuals with MDD.

a Average baseline GBCr in the PFC in both groups. Blue circles correspond to c and indicate reduced baseline GBCr in individuals with MDD. b Baseline whole-brain GBCr Fisher-transformed Z-scores (Fz-scores) in the total PFC mask plotted for both groups indicating no difference, in contrast to previous studies (see Fig. 3b in the study by Abdallah and colleagues [12], who reported a strong reduction with d = 0.95). c Reduced GBCr as indicated in a (p < 0.05, FWE corrected, initial p = 0.001). As with total gray matter (GM) GBCr, no significant effect was seen vs. baseline for ketamine, placebo, or treatment (all p > 0.05, FWE corrected). sFC superior frontal cortex, mFC medial frontal cortex.

Fig. 3. Comparison of the three preprocessing strategies on measures of global brain connectivity (GBC) in 22 healthy controls (HCs) at baseline.

a Unthresholded GBC maps (group average) with white matter (WM)/cerebrospinal fluid (CSF) regression (BASE) resembled those with WM/CSF regression + physiological parameter regression (PHYSIO). GBC maps after WM/CSF + global signal regression (GSR) yielded peaks around the basal ganglia, insulae, and cingulate cortices. Negative Fisher-transformed Z-scores (Fz-scores) were introduced in terminal fields along the anterior–posterior axis. b Absolute Fz-score distributions corresponding to a. Fz-scores centered around zero after GSR; color-coding represents tail probabilities around the median (dark line). c Comparison between BASE regression and GSR GBC maps yielded strong brain-wide reductions in Fz-scores with an emphasis on posterior-basal regions. Histograms depict total gray matter (GM) Fz-scores in 22 HCs at baseline; lines represent means.