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

Abstract

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 using 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. “Unseen” cue paradigm.

24 randomly-presented 33 msec targets in each of four categories (cocaine, sexual, aversive and neutral, interspersed with grey-screen nulls) were immediately followed by a 467 msec neutral “masking” stimulus”. Under these conditions, the 33 msec stimuli can escape conscious detection (see Methods for additional task details).

Figure 2. Limbic brain responses by 33 msec “unseen” cues in cocaine patients.

Both cocaine (A) and sexual (B) cues produced activation in amygdala and ventral striatum/ventral pallidum/substantia innominata, and insula, as well as the OFC (OFC not shown). Statistical parametric t maps were generated by SPM 2; thresholded for display (color bar: 2<t<5) on the single-subject MNI brain template (“Colin”) in MRICro. Coronal brain sections on the left in (a) and (b) are at y = −6 mm; images on the right in (A) and (B) are at y = 10 mm and y = 6 mm, respectively. The response to “unseen” cocaine cues in a large bilateral ventral pallidum/left amygdala cluster (C) strongly predicted (peak voxel, MNI x, y, z coordinates: −14, −6, −6; t = 7.11; p = 0.000 uncorrected; p = 0.015 cluster-corrected) future affective response to visible cocaine cues (D; r = 0.92). Brain response to 33 msec “unseen” aversive cues (not shown; see Figure S1 in Supporting Materials) varied across individuals, with increased activity in the insula predicting the later affective response to visible aversive cues. Abbreviations: R: right, L: left, v: ventral, amyg: amygdala, si: substantia innominata, tp: temporal pole. [NOTE: The ventral boundary of the BOLD acquisition plane for the current studies is z = −40; temporal pole activations may extend ventrally below the acquisition plane.].