Catecholaminergic manipulation alters dynamic network topology across cognitive states

Abstract

The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.

Keywords: Atomoxetine; Flexibility; Integration; Network; Noradrenaline; fMRI.

Figure 1.. (A) Effect of atomoxetine versus placebo on the cartographic profile, which demonstrates a shift toward segregation: red/yellow, increased frequency postatomoxetine; and blue, decreased frequency postatomoxetine (FDR q ≤ 0.05). (B) Parcels with decreases in their between-module connectivity (i.e., participation coefficient) following atomoxetine (vs. placebo); see Supporting Information Table S1 (Shine et al., 2018) for parcel MNI coordinates (FDR q ≤ 0.05). (C) Effect of atomoxetine versus placebo on the relationship between the cartographic profile and pupil diameter, which demonstrates a shift toward integration: red/yellow, increased frequency postatomoxetine; and blue, decreased frequency postatomoxetine (FDR q ≤ 0.05). (D) Parcels with increased time-varying connectivity between between-module connectivity (i.e., participation coefficient) and pupil diameter following atomoxetine (vs. placebo); see Table S1 for parcel MNI coordinates (FDR q ≤ 0.05). Key: ATX, atomoxetine; B_T, between-module connectivity; W_T, within-module connectivity; see Table S1 for parcel coordinates.

Figure 2.. (A) Mean cartographic profile across all four blocks of load comparing post-ATX to postplacebo; similar patterns were observed in each block (FDR q ≤ 0.05). (B) Mean parcelwise B for each N-back load in both the placebo (PLC, blue) and atomoxetine (ATX, red) conditions (error bars represent standard error across subjects). (C) Parcels with higher B_T post-ATX as a function of task performance (FDR q ≤ 0.05); main effect (red) and load effect (yellow). (D) Correlation between the regions that showed highest B_T during task performance (ATX > Placebo) and regions that were shifted toward segregation in the rest study (ATX_(Post>Pre) > Placebo_(Post>Pre)); see Supporting Information Table S1 (Shine et al., 2018) for parcel MNI coordinates (FDR q ≤ 0.05). Key: ATX, atomoxetine; B_T, between-module connectivity; W_T, within-module connectivity.

Figure 3.. (A) Effect of atomoxetine (vs. placebo) on regional flexibility in the resting state (left, blue) and during the N-back task (right, red); regions depicted with increased flexibility (FDR q ≤ 0.05). (B) Correlation between effect of atomoxetine (vs. placebo) on B_T and regional flexibility during rest (left, blue; r = 0.02) and during the N-back task (right, red; r = 0.61); the difference between the two correlations was also significant (ZI* = 2.08; p = 0.037).