Prelude to passion: Limbic activation by "unseen" drug and sexual cues

Background. The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are "unseen", i.e., presented in a way that prevents their conscious recognition? Can the brain response to "unseen" reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness? Methodology/Principal Findings. We exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to "unseen" (backward-masked) cocaine sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined usinq an affective bias (priming) task. We demonstrate for the first time, limbic brain activation by "unseen" drug and sexual cues of only 33 msec duration. Importantly, increased activity in an large interconnected ventral pallidum/amygdala cluster to the "unseen" cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness. Conclusions/Significance. These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to "unseen" reward signals and may represent the brain's primordial signature for desire, The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature.