Fear is Fast in Phobics: The Time Course of Amygdala Activation in Response to Fear-relevant Stimuli

Evolutionary fitness dictates that threat must be detected quickly (1, 2). Efficient identification of sources of potential harm requires an ability to detect threat-related stimuli based on relatively simple stimulus features and at any position in the perceptual field, thus resulting in a system which functions in a relatively rapid, automatic fashion with minimal processing of incoming sensory information (1, 2). A growing corpus of data indicate that the amygdala is involved in fear processing and that moreover, it likely holds the key to rapid detection of potentially threatening stimuli (2, 3). An independent line of psychophysiological research has found that specific phobics respond rapidly to phobia relevant stimuli (4, 5). One possible mechanism underlying this accele rated response is exacerbation of the already rapid response of the amygdala to fear-relevant cues. To better understand the disjunction between normal and pathological fear, and the neural substrates of this distinction, we examined the chronometry of the amygdalar response in phobic fear, particularly the rapidity of its onset. Extensive data implicates the amygdala in negative affect, especially fear (3). Lesions of the amygdala block fear conditioning in numerous sensory modalities (6). In human neuroimaging studies increased amygdala activation has been found during viewing of negatively-valenced pictures (7, 8) and fear faces (9, 10) even when presented preattentively (11). Importantly, Breiter and colleagues (9) found that the amygdala response to fearful faces habituated rapidly. In addition, fMRI studies have shown that amygdala activation habituates over repeated conditioning trials or presentations of affective stimuli (12, 13, 14). Furthermore, Phelps and colleagues (15) found greater amygdala activation to a threat condition only when the first half of each of the trials was included in the analysis. Thus, not only does amygdala activation habituate across repeated trials, but attenuation of signal from the amygdala occurs within individual trials as well. These data suggest that the amygdala may play an immediate, but short-lived role in the unfolding reaction to a negative affective stimulus. In contrast to these data demonstrating amygdala involvement in fear-related processes, several O positron emission tomography (PET) studies of specific animal phobia have not found amygdala activation in response to phobia-relevant cues (16, 17). Given the mounting evidence indicating amygdalar habituation, it is likely that the temporal resolution of PET is not sufficient to capture these relatively fleeting patterns of activation. Independent research has suggested that phobic fear is characterized by an abnormally early onset of the fear response. Globisch and colleagues (4) found potentiation of the startle eyeblink response to phobic compared to neutral and pleasant stimuli among snake and spider phobics. Furthermore, this potentiation was evident as early as 300 ms following the onset of the picture, earlier than potentiation is typically found in response to non-phobic, aversive stimuli (18), suggesting that phobic fear is associated with a fast onset. In the current study we used an event-related fMRI paradigm to assess the magnitude and timing of the amygdalar response to fear-relevant compared to neutral and unpleasant nonphobic pictorial stimuli among female spider phobics (N = 13) and controls (N = 14). To enable fine-grained temporal sampling of activation in the amygdala, five coronal slices centered on the amygdala were collected at an effective time resolution of 300 ms. To extract magnitude and time to onset and peak of amygdala activation, a gamma variate function was fit to the resulting BOLD (blood-oxygen level dependent) responses. We demonstrate that in response to phobia -relevant stimuli phobics exhibit more rapid onset of amygdala activation than controls. We also show that among the phobics amygdala activation in response to spider pictures is more rapid than responses to negative or neutral pictures.