Methylphenidate (MPH) is a first line treatment for ADHD and is also misused as a purported cognitive enhancer, yet its effects on brain function are still poorly understood. Recent functional magnetic resonance imaging (fMRI) studies showed that MPH altered cortico-striatal resting functional connectivity (RFC). Here we investigated the effects of MPH in thalamic connectivity since the thalamus modulates striato-cortical signaling. We hypothesized that MPH would increase thalamic connectivity and metabolism, and that this response would be blunted in cannabis abusers. For this purpose, we measured RFC in seven thalamic nuclei using fMRI and brain glucose metabolism using positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) in sixteen healthy controls and thirteen participants with cannabis use disorder (CUD) twice after placebo and after MPH (0.5 mg/kg, iv). MPH significantly increased thalamo-cerebellar connectivity and cerebellar metabolism to the same extent in both groups. Group comparisons revealed that in CUD compared to controls, metabolism in nucleus accumbens was lower for the placebo and MPH measures, that MPH-induced increases in thalamic metabolism were blunted, and that enhanced negative connectivity between thalamus and accumbens in CUD was normalized by MPH (reducing negative connectivity). Our findings identify the thalamus as a target of MPH, which increased its metabolism and connectivity. The reduced metabolism in nucleus accumbens and the disrupted thalamo-accumbens connectivity (enhanced negative connectivity) in CUD is consistent with impaired reactivity of the brain reward’s circuit. MPH’s normalization of thalamo-accumbens connectivity (reduced negative connectivity) brings forth its potential therapeutic value in CUD, which merits investigation.
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We would like to thank Karen Torres for her administrative assistance, and Chris Wong for his contribution in data collection. We also thank Joanna Fowler and Anna Konova for their valuable input for the discussions. We would like to thank David Schlyer and Michael Schueller for cyclotron operations; Donald Warner, David Alexoff, and Paul Vaska for PET operations; Colleen Shea, Youwen Xu, Lisa Muench, and Payton King for radiotracer preparation and analysis, Millard Jayne for subject recruitment and Barbara Hubbard and Pauline Carter for patient care.
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Demiral, Ş.B., Tomasi, D., Wiers, C.E. et al. Methylphenidate’s effects on thalamic metabolism and functional connectivity in cannabis abusers and healthy controls. Neuropsychopharmacol. 44, 1389–1397 (2019) doi:10.1038/s41386-018-0287-2