Methylphenidate reduces spatial attentional bias by modulating fronto-striatal connectivity.

Spatial attention bias reflects tendency to direct attention to specific side in space. This bias reflects asymmetric dopamine (DA) signaling in the striatum. Administration of DA agonists reduces spatial bias, yet the underlying mechanism is not yet clear. To address this, the current study tested whether methylphenidate (MPH; an indirect DA agonist) reduces orienting bias by modulating fronto-striatal connectivity. 54 adults with consistent bias completed the greyscales task which detects subtle biases during fMRI scanning under MPH (20 mg) or placebo, in a double-blind design. As hypothesized, MPH reduced bias by increasing orienting towards non-preferred hemispace, regardless of whether the initial bias was left or right. MPH-induced increases were found in activation of the medial superior frontal gyrus (mSFG: F[1;53] = 4.632, cluster-defining threshold of P < 0.05, minimal cluster size = 0, p_FWE = 0.036, η2 = 0.08) and its functional connectivity with the caudate (left caudate: F[1;53] = 12.664, p_FWE = 0.001, η2 = 0.192; right caudate: F[1;53] = 11.069, p_FWE = 0.002, η2 = 0.172), when orienting towards the non-preferred hemispace. MPH also reduced mSFG activation and fronto-striatal connectivity for the preferred hemispace. Results suggest modulation of frontal excitability due to increased caudate-mSFG functional connectivity. This mechanism may underlie the positive effect of dopaminergic agonists on abnormal patterns of directing attention in space.

Graph analysis uncovers an opposing impact of methylphenidate on connectivity patterns within default mode network sub-divisions.

BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.