In vivo mapping of functional connectivity in neurotransmitter systems using pharmacological MRI.
Pharmacological MRI (phMRI) methods map the hemodynamic response to drug challenge as a surrogate for changes in neuronal activity. However, the central effects of drugs can be complex and include activity at the primary site of action, downstream effects in other brain regions and direct effects on vasculature and neurovascular coupling. Univariate analysis, normally applied to phMRI data, does not discriminate between these effects, and can result in anatomically non-specific activation patterns. We analysed inter-subject correlations in the amplitude of the slow phMRI response to map functionally connected brain regions recruited in response to pharmacological challenge. Application of D-amphetamine and fluoxetine revealed well-defined functional structure underlying the widespread signal changes detected via standard methods. Correlated responses were found to delineate key neurotransmitter pathways selectively targeted by these drugs, corroborating a tight correspondence between the phMRI response and changes in neurotransmitter systems specific to the pharmacological action. In vivo mapping of correlated responses in this way greatly extends the range of information available from phMRI studies and provides a new window into the function of neurotransmitter systems in the active state. This approach may provide new important insights regarding the central systems underlying pharmacological action.
Schwarz
Adam J
AJ
Department of Neuroimaging, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline, Via Fleming 4, 37135 Verona, Italy. adam.j.schwarz@gsk.com
Gozzi
Alessandro
A
Reese
Torsten
T
Bifone
Angelo
A
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure; D001921:Brain / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods*; D003913:Dextroamphetamine / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D018377:Neurotransmitter Agents / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D009435:Synaptic Transmission / Q000502:physiology*
D018377:Neurotransmitter Agents; D003913:Dextroamphetamine