Modafinil-Induced Changes in Functional Connectivity in the Cortex and Cerebellum of Healthy Elderly Subjects

Abstract

In the past few years, cognitive enhancing drugs (CEDs) have gained growing interest and the focus of investigations aimed at exploring their use to potentiate the cognitive performances of healthy individuals. Most of this exploratory CED-related research has been performed on young adults. However, CEDs may also help to maintain optimal brain functioning or compensate for subtle and or subclinical deficits associated with brain aging or early-stage dementia. In this study, we assessed effects on resting state brain activity in a group of healthy elderly subjects undergoing acute administration of modafinil, a wakefulness-promoting agent. To that aim, participants (n = 24) were investigated with resting state functional Magnetic Resonance Imaging (rs-fMRI) before and after the administration of a single dose (100 mg) of modafinil. Effects were compared to age and size-matched placebo group. Rs-fMRI effects were assessed, employing a graph-based approach and Eigenvector Centrality (EC) analysis, by taking in account topological changes occurring in functional brain networks. The main finding of the study is that modafinil promotes enhanced centrality, a measure of the importance of nodes within functional networks, of the bilateral primary visual (V1) cortex. EC analysis also revealed that modafinil-treated subjects show increased functional connectivity between the V1 and specific cerebellar (Crus I, Crus II, VIIIa lobule) and frontal (right inferior frontal sulcus and left middle frontal gyrus) regions. Present findings provide functional data supporting the hypothesis that modafinil can modulate the cortico-cerebellar connectivity of the aging brain.

Keywords: aging; cognitive enhancing drugs; connectivity; dopamine; eigenvector centrality; graph theory; resting state fMRI.

FIGURE 1

Eigenvector centrality (EC) changes induced by acute administration of modafinil or placebo. The image depicts maps of a paired t-tests obtained from the contrast (drug effect > drug baseline) > (placebo effect > placebo baseline) and considering the gender as a variable of not interest. A significant EC increase was observed in the primary visual cortex bilaterally (BA17) in the modafinil study group. Depicted clusters survived correction for multiple comparisons across space with FWE correction at P values < 0.05. Coordinates refer to MNI space.

FIGURE 2

Seed based r² connectivity analysis of the BA17 region in the modafinil and placebo groups. The image depicts maps of a paired t-tests calculated for the contrast (drug effect > drug baseline) > (placebo effect > placebo baseline) and considering the gender as a variable of not interest. Significant increases of r² were observed in the left and right cerebellar Crus I, the left and right cerebellar Crus II, the left and right cerebellar VIIIa, the right IFS and the left MFG. Depicted clusters survived correction for multiple comparisons across space with FWE correction at P values < 0.05. Coordinates refer to MNI space.