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The fractional signal intensity change (⌬S/S) observed during activation in T 2 -weighted fMRI of the spinal cord has previously been shown to depend linearly on the echo time (TE) but to have a positive value of roughly 2.5% extrapolated to zero TE. In this study we investigated the origin of this finding by measuring the ⌬S/S in spinal fMRI with very short TEs. Our results demonstrate that the ⌬S/S does not approach zero, but has a value as high as 3.3% at TE ‫؍‬ 11 ms. At TEs > 33 ms we observed the linear relationship between ⌬S/S and TE as in previous studies. These data demonstrate that there is a non-BOLD contribution to signal changes observed in spinal fMRI. We hypothesize that this contribution is a local proton density increase due to increased water exudation from capillaries with increased blood flow during neuronal activation, and term this effect "signal enhancement by extravascular protons" (SEEP The currently accepted theory of blood oxygen-level dependent (BOLD) contrast predicts that the fractional signal intensity change (⌬S/S) that occurs with neuronal stimulation is a linear function of the echo time (TE) according to the expression (1):This is a first-order approximation, but generally holds true over the range of TEs typically used for fMRI studies. The slope of the plot of ⌬S/S as a function of TE is therefore -⌬(1/T 2 ), the negative of the change in relaxation rate which occurs upon neuronal stimulation. The same expression applies for T * 2 -weighted data, with T 2 simply replaced by T * 2 . It has also been shown that ⌬(1/T * 2 ) is greater than ⌬(1/T 2 ) by at least a factor of 3.5 (2). Hence, the fractional signal changes detected with T * 2 -weighted imaging are much larger than those detected with T 2 -weighted imaging. However, fMRI data obtained in the spinal cord demonstrate very similar fractional signal changes in T 2 -and T * 2 -weighted images (3,4). The data collected over a range of TEs show a linear relationship between ⌬S/S and TE, but have a zero intercept value (⌬S/S extrapolated to TE ϭ 0) of roughly 2.5% (5). To investigate this finding we repeated studies with visual stimulation in healthy human volunteers at both 1.5 T and 3T (6). Both of these data sets demonstrated zero intercepts that are significantly greater than zero at 0.7-1.0% with T 2 -weighted data, but are not significantly greater than zero with T * 2 -weighted data. The values of ⌬(1/T 2 ) and ⌬(1/T * 2 ) determined at these two field strengths are in excellent agreement with published values (6). Hence, the data we obtained agree with the BOLD theory in every way except that the zero intercept with T 2 -weighted data is greater than zero. We therefore hypothesize that there is a second effect, other than the BOLD effect, that is contributing to the fractional signal changes observed in T 2 -weighted fMRI data.Previous work also supports our observations in the brain and spinal cord, and has suggested the existence of non-BOLD contrast mechanisms in fMRI (7-10). Hennig et al. (7) identified an "ampli...