Nitric oxide-haemoglobin interaction: a new biochemical hypothesis for signal changes in fMRI

A new hypothesis on the origin of activation-induced signal changes in functional magnetic resonance imaging (fMRI) is presented, involving transient formation of paramagnetic species, i.e. methaemoglobin (Hb+) and nitrosylhaemoglobin (Hb-NO), by reaction of nitric oxide (NO) with oxy-(Hb-O2) and deoxyhaemoglobin (Hb). Hb+ and Hb-NO, generated in erythrocytes, were found to produce marked concentration-dependent signal intensity changes when examined by T1-, T2- and T2*-weighted MRI. Intravenous administration of ascorbic acid (3 g) to healthy volunteers, to specifically reduce any Hb+ formed during brain activation, markedly decreased fMRI signal changes during standard tasks, suggesting a blood flow-independent effect produced by the reductant. These results open a new perspective on the fMRI evaluation of physiological processes associated with task-specific activation of brain structures.