Connectivity of the Cognitive Control Network During Response Inhibition as a Predictive and Response Biomarker in Major Depression: Evidence From a Randomized Clinical Trial

Abstract

Background: In treating major depressive disorder, we lack tests anchored in neurobiology that predict antidepressant efficacy. Cognitive impairments are a particularly disabling feature of major depressive disorder. We tested whether functional connectivity during a response-inhibition task can predict response to antidepressants and whether its changes over time are correlated to symptom changes.

Methods: We analyzed data from outpatients with major depressive disorder (n = 124) randomized to receive escitalopram, sertraline, or venlafaxine (8 weeks) and healthy control subjects (n = 59; age 18-65 years). Before and after treatment, participants were interviewed and scanned using functional magnetic resonance imaging, and functional connectivity was measured using generalized psychophysiological interaction during response inhibition (Go-NoGo task). We investigated the interaction between treatment type and response (≥50% reduction on self-reported symptoms), coupling differences between responders and nonresponders at baseline, their correlation with symptom improvement, and their changes in time.

Results: During response inhibition, connectivity between the dorsolateral prefrontal cortex/supramarginal gyrus and supramarginal gyrus/middle temporal gyrus was associated with response to sertraline and venlafaxine, but not escitalopram. Sertraline responders had higher functional connectivity between these regions compared with nonresponders, whereas venlafaxine responders had lower functional connectivity. For sertraline, attenuation of connectivity in the precentral and superior temporal gyri correlated with posttreatment symptom improvement. For venlafaxine, enhancement of connectivity between the orbitofrontal cortex and subcortical regions correlated with symptom improvement.

Conclusions: Connectivity of the cognitive control circuit during response inhibition selectively and differentially predicts antidepressant treatment response and correlates with symptom improvement. These quantitative markers tied to the neurobiology of cognitive features of depression could be used translationally to predict and evaluate treatment response.

Trial registration: ClinicalTrials.gov NCT00693849.

Keywords: Biomarker; Cognitive control; Go-NoGo; Major depressive disorder; Treatment; fMRI.

Figure 1:. Functional connectivity of the DLPFC and supramarginal gyrus predicting differential treatment response to sertraline and venlafaxine.

A: Responders to sertraline showed higher FC between the right DLPFC and supramarginal gyrus (t=3.809, p<0.001) whereas, in the venlafaxine-XR group, the opposite was true (t=−2.391, p=0.020). Higher coupling at baseline was associated with greater QIDS-SR₁₆ decrease after treatment in the sertraline group (rho=−0.566, p<0.001) and the opposite was true for venlafaxine-XR (rho=0.441, p=0.005). B: The coupling between right supramarginal gyrus and middle temporal gyrus was higher in responders to sertraline compared to non-responders (t=3.591, p=0.001), whereas in venlafaxine-XR responders connectivity was lower compared to non-responders (t=−2.770, p=0.009). Higher coupling at baseline was associated with greater QIDS-SR₁₆ decrease after treatment in the sertraline group (rho=−0.560, p<0.001) and the opposite was true in the venlafaxine-XR group (rho=0.457, p=0.003). Numbers indicate slice coordinates in MNI space. Stars mark significant comparisons between groups (t-test p<0.05). For correlations, a linear fit line calculated based on the data is shown. ROI coordinates in MNI space: DLPFC=(34 58 0), SMG=(52 −44 46). FC is expressed as difference of the parameter estimates of the hemodynamic response function (beta values) for the NoGo and Go conditions. Abbreviations: DLPFC=dorsolateral prefrontal cortex (MFG1 in Table 2), Esc=escitalopram, FC=functional connectivity, HC=healthy controls, MNI=Montreal neurological institute MTG=middle temporal gyrus, NR=non-responders, QIDS=Quick Inventory of Depressive Symptomatology scale, R=responders, ROI=region of interest, Ser=sertraline, SMG=supramarginal gyrus, Ven=venlafaxine, XR=extended-release, Δ=difference between follow-up and baseline.

Figure 2:. Functional connectivity of the cerebellum and SMG predicting sertraline response.

A: Responders showed higher FC between the left external cerebellum and a cluster encompassing the left transverse temporal gyrus and insula during response inhibition compared to non-responders (t=5.33, p<0.001) and HC (t=2.48, p=0.01). Non-responders showed reduced FC compared to HC (t=−3.20, p=0.002). Higher FC at baseline was also associated with greater QIDS decrease after treatment (rho=−0.462, p<0.001). B: Responders showed higher FC between the right supramarginal gyrus and right middle temporal gyrus during response inhibition compared to non-responders (t=5.33, p<0.001) and HC t=2.64, p=0.01). Non-responders showed reduced FC compared to HC (t=−3.27, p=0.002). Higher FC at baseline was also associated with greater QIDS decrease after treatment (rho=−0.460, p<0.001). Numbers indicate slice coordinates in MNI space. Stars mark significant comparisons between groups (t-test p<0.05). For correlations, a linear fit line calculated based on the data is shown. ROI coordinates in MNI space: Cerebellum=(−40 −66 −30), SMG=(52 −44 46). FC is expressed as difference of the parameter estimates of the hemodynamic response function (beta values) for the NoGo and Go conditions. Abbreviations: Esc=escitalopram, FC=functional connectivity, HC=healthy controls, MNI=Montreal neurological institute, MTG=middle temporal gyrus, NR=non-responders, PCU=precuneus, QIDS= Quick Inventory of Depressive Symptomatology scale, R=responders, ROI=region of interest, Ser=sertraline, SMG=supramarginal gyrus, STG=superior temporal gyrus, Ven=venlafaxine, Δ=difference between follow-up and baseline.

Figure 3:. Functional connectivity correlates of antidepressant treatment response.

A: Participants responding to sertraline showed a decrease of FC between the left postcentral gyrus and left superior temporal gyrus (t=−3.476, p=0.002), whereas non-responders showed an increase (t=4.535, p<0.001). Also, changes in responders and non-responders were greater than the changes in HC (respectively t=−3.567, p=0.001 and t=3.066, p=0.004). Across all MDD participants, FC decrease was correlated with QIDS reduction after treatment (rho=0.588, p<0.001). B: MDD participants responding to venlafaxine-XR showed a decrease of FC between the left orbitofrontal cortex and the brainstem as well as caudate nucleus (t=3.853, p=0.001). Also, changes in responders were greater than the changes in HC (t=3.127, p=0.004). Across all MDD participants, FC decrease was correlated with QIDS reduction after treatment (rho=−0.658, p<0.001). Numbers indicate slice coordinates in MNI space. Stars mark significant comparisons (t-test p<0.05). For correlations, a linear fit line calculated based on the data is shown. ROI coordinates in MNI space: PCG=(−42 −30 46), OFC=(−40 54 −8). FC is expressed as difference of the parameter estimates of the hemodynamic response function (beta values) for the NoGo and Go conditions. Abbreviations: BL=baseline, CN=caudate nucleus, DC=diencephalon, Esc=escitalopram, FC=functional connectivity, FU=follow-up, HC=healthy controls, MNI=Montreal neurological institute NR=non-responders, OFC=orbitofrontal cortex, PCG=postcentral gyrus, QIDS=Quick Inventory of Depressive Symptomatology scale, R=responders, ROI=region of interest, Ser=sertraline, STG=superior temporal gyrus, Ven=venlafaxine, Δ=difference between follow-up and baseline.