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.