McDonald JS, Mannion DJ, Clifford CWG. Gain control in the response of human visual cortex to plaids. J Neurophysiol 107: 2570-2580, 2012. First published February 29, 2012 doi:10.1152/jn.00616.2011.-A recent intrinsic signal optical imaging study in tree shrew showed, surprisingly, that the population response of V1 to plaid patterns comprising grating components of equal contrast is predicted by the average of the responses to the individual components (MacEvoy SP, Tucker TR, Fitzpatrick D. Nat Neurosci 12: 637-645, 2009). This prompted us to compare responses to plaids and gratings in human visual cortex as a function of contrast and orientation. We found that the functional MRI (fMRI) blood oxygenation level-dependent (BOLD) responses of areas V1-V3 to a plaid comprising superposed grating components of equal contrast are significantly higher than the responses to a single component. Furthermore, the orientation response profile of a plaid is poorly predicted from a linear combination of the responses to its components. Together, these results indicate that the model of MacEvoy et al. (2009) cannot, without modification, account for the fMRI BOLD response to plaids in human visual cortex.contrast; spatial; functional magnetic resonance imaging; vision THE DYNAMIC RESPONSE RANGE of neurons is limited compared with the range of natural contrasts. Gain control allows neural sensitivity to be dynamically adjusted to suit the prevailing ambient contrasts (Crowder et al. 2008;Durant et al. 2007). This adjustment could be achieved through temporal sampling, i.e., adaptation (Gardner et al. 2005;Ohzawa et al. 1982), or spatial sampling in the area of the classic receptive field (Morrone et al. 1982) and extra classic receptive field (Levitt and Lund 1997) of a neuron. For two decades, divisive normalization has been the dominant model of contrast gain control (Brouwer and Heeger 2011;Heeger 1992). Principally intended to explain neuronal response saturation and crossorientation suppression-suppression of response to optimally oriented stimuli by an overlaid stimulus of a different orientation-the original divisive normalization model proposed that neuronal response is inhibited by a large pool of neurons tuned to different orientations and spatial frequencies. Although subsequent research has challenged the notion that inhibitory neural circuitry is responsible for the divisive gain behavior Freeman et al. 2002;Li et al. 2006;Priebe and Ferster 2006), the model retains considerable descriptive power and attractive theoretical properties.Two recent studies boast population, rather than isolated single-unit, measures of cross-orientation suppression (Busse et al. 2009;MacEvoy et al. 2009). Busse et al. (2009) found magnitudes of suppression in cat and human V1 consistent with traditional divisive normalization. However, MacEvoy et al. (2009) demonstrated that the response of tree shrew V1 to plaids is reliably predicted by the contrast-weighted average of the responses to the two components. In the case of two grati...