Preferential amygdala reactivity to the negative assessment of neutral faces.

BACKGROUND: Prior studies suggest that the amygdala shapes complex behavioral responses to socially ambiguous cues. We explored human amygdala function during explicit behavioral decision making about discrete emotional facial expressions that can represent socially unambiguous and ambiguous cues. METHODS: During functional magnetic resonance imaging, 43 healthy adults were required to make complex social decisions (i.e., approach or avoid) about either relatively unambiguous (i.e., angry, fearful, happy) or ambiguous (i.e., neutral) facial expressions. Amygdala activation during this task was compared with that elicited by simple, perceptual decisions (sex discrimination) about the identical facial stimuli. RESULTS: Angry and fearful expressions were more frequently judged as avoidable and happy expressions most often as approachable. Neutral expressions were equally judged as avoidable and approachable. Reaction times to neutral expressions were longer than those to angry, fearful, and happy expressions during social judgment only. Imaging data on stimuli judged to be avoided revealed a significant task by emotion interaction in the amygdala. Here, only neutral facial expressions elicited greater activity during social judgment than during sex discrimination. Furthermore, during social judgment only, neutral faces judged to be avoided were associated with greater amygdala activity relative to neutral faces that were judged as approachable. Moreover, functional coupling between the amygdala and both dorsolateral prefrontal (social judgment > sex discrimination) and cingulate (sex discrimination > social judgment) cortices was differentially modulated by task during processing of neutral faces. CONCLUSIONS: Our results suggest that increased amygdala reactivity and differential functional coupling with prefrontal circuitries may shape complex decisions and behavioral responses to socially ambiguous cues.

Differentiating allocation of resources and conflict detection within attentional control processing.

Increasing demands for conflict detection and for allocation of attentional resources increase the need for attentional control. While prior evidence suggests that different cortical regions are preferentially engaged by these two attentional processes, the effect of increasing demand for conflict detection and/or allocation of attentional resources has been relatively unexplored. We designed a novel task (the 'variable attentional control'--VAC--task) that varies the demand for attentional control by increasing conflict detection and allocation of attentional resources within the same stimuli. We studied 34 subjects who underwent event-related functional magnetic resonance imaging while performing the VAC task. Increasing demand for attentional control, as reflected by longer reaction time and reduced accuracy, was associated with greater activation in the dorsolateral prefrontal cortex, parietal cortex and dorsal cingulate. Furthermore, an increase in conflict detection was associated with greater dorsal cingulate activity, whereas an increase in demand for allocation of attentional resources implied greater activation in the dorsolateral prefrontal and parietal cortices. In essence, in addition to allowing the exploration of the overall effects of increasing demand for attentional control, our novel task also allowed parsing of the neural components of attentional control into those related to allocation of attentional resources and those related to conflict detection.

Tolcapone improves cognition and cortical information processing in normal human subjects.

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.