Functional connectivity correlates of reaction time variability in treatment-resistant major depression

Cognitive difficulties, including problems with attention and executive processing, are common in major depressive disorder (MDD), and strongly predict psychosocial and occupational functioning. Impairment in sustained attention contributes to increased intra-individual variability (IIV) in reaction times observed during cognitive tasks. Understanding brain network changes associated with IIV could guide novel neuromodulation strategies targeting cognitive difficulties.

We analyzed baseline resting-state fMRI data from 209 patients with moderate-to-severe treatment-resistant MDD who participated in the BRIGhTMIND neuromodulation trial. Following a preregistered analytic protocol, we examined associations between: functional connectivity across three core brain networks (executive control, ECN; default mode, DMN; and salience network, SN); components of IIV derived from a choice reaction time task (using a three-parameter ex-Gaussian model); and functioning.

Greater IIV was linked to increased ECN-DMN functional connectivity. The ECN supports top-down control and externally directed cognition, while the DMN supports internal mentation and rumination. ECN-DMN connectivity was modulated by the SN, which prioritizes salient internal and external stimuli. Higher SN-ECN connectivity was associated with lower ECN-DMN connectivity and with faster mean reaction times. Both IIV and mean reaction time predicted functioning, with poorer functioning related to a slowed and inflexible response pattern.

Distinct components of reaction time variability are associated with specific patterns of brain network connectivity, largely independent of mood severity. Connectivity between the salience and executive control networks may represent a promising target for neuromodulation interventions focused on cognitive deficits in MDD.