The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults

Abstract

Background: Methylphenidate (MPH) influences catecholaminergic signaling. Extant work examined the effects of MPH on the neural circuits of attention and cognitive control, but few studies have investigated the effect of MPH on the brain's resting-state functional connectivity (rsFC).Methods: In this observational study, we compared rsFC of a group of 24 healthy adults who were administered an oral 45 mg dose of MPH with a group of 24 age and gender matched controls who did not receive MPH. We focused on three seed regions: basal nucleus of Meynert (BNM), locus coeruleus (LC), and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc), each providing cholinergic, noradrenergic and dopaminergic inputs to the cerebral cortex. Images were pre-processed and analyzed as in our recent work (Li et al., 2014; Zhang et al., 2015). We used one-sample t-test to characterize group-specific rsFC of each seed region and two-sample t-test to compare rsFC between groups.Results: MPH reversed negative connectivity between BNM and precentral gyri. MPH reduced positive connectivity between LC and cerebellum, and induced positive connectivity between LC and right hippocampus. MPH decreased positive VTA/SNc connectivity to the cerebellum and putamen, and reduced negative connectivity to left middle occipital gyrus.Conclusion: MPH had distinct effects on the rsFC of BNM, LC, and VTA/SNc in healthy adults. These new findings may further our understanding of the role of catecholaminergic signaling in Attention Deficit Hyperactivity Disorder (ADHD) and Parkinson's disease and provide insights into the therapeutic mechanisms of MPH in the treatment of clinical conditions that implicate catecholaminergic dysfunction.

Estimates of locus coeruleus function with functional magnetic resonance imaging are influenced by localization approaches and the use of multi-echo data

“…Previous functional studies on the LC have exclusively been done using 1E-fMRI and frequently use the Keren 2 SD atlas. Across those studies, regions that typically emerge in iFC analyses are the prefrontal cortex, cerebellum, right supplementary motor area, cingulate cortex, thalamus, visual cortex, lingual and fusiform gyrus, insula, amygdala, and the hippocampus (e.g., Bär et al, 2016;Köhler, Wagner, & Bär, 2016;Kline et al, 2016;Murphy et al, 2014;Sterpenich et al, 2006). Nearly all these regions were ranked highly across the 1E…”

In vivo anatomical mapping of human locus coeruleus functional connectivity at 3 T MRI

“…Recent human fMRI studies revealed the baseline functional connectivity of the LC (Murphy, O'Connell, O'Sullivan, Robertson, & Balsters, ; Jacobs, Müller‐Ehrenberg, Priovoulos, & Roebroeck, ; Wagner et al, ; Zhang, Hu, Chao, & Li, ). Furthermore, fc changes provoked by medication (Kline et al, ; Liebe et al, ; Song et al, ; Wagner, de la Cruz, Köhler, & Bär, ) and differences of the connectivity in Alzheimer's disease were found (Serra et al, ).…”

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

“…First, human PET studies have shown that at clinical doses (such as those used herein), MPH binds to the NET with a higher affinity than to the DAT [12,13]. Second, there is further evidence from studies in experimental animal showing that MPH can directly affect the discharge properties of the locus coeruleus (LC) [54], which is the main source of noradrenergic innervation in the brain; these findings are supported by a rs-fMRI study in humans showing that MPH exerts effects on the FC of the LC [55]. Third, there is a general consensus that the MPH procognitive effects in ADHD patients and HC involve modulation of the prefrontal cortex (PFC) [56].…”