Measurements of plasma norepinephrine concentrations and norepinephrine spillover into plasma were used to gauge sympathetic nervous system activation during cognitive challenge (forced mental arithmetic) in 12 human subjects. Norepinephrine levels were influenced by the sampling site, with the fractional increase being greatest for norepinephrine spillover from the heart (where norepinephrine release almost trebled), intermediate for the arterial plasma norepinephrine concentration and total body norepinephrine spillover (50-70% increase), and inconsequential for antecubital venous plasma norepinephrine levels (less than 20% increase). These findings are explained by patterning of the sympathetic response, which only minimally involves the sympathetic outflow to the skeletal muscle of the forearm but preferentially involves the heart. Antecubital venous plasma norepinephrine levels are not sufficiently sensitive to allow satisfactory monitoring of the sympathetic neural outflow to organs, such as the heart, which are selectively activated in the response to mental challenge.