Elsevier

NeuroImage

Volume 37, Issue 4, 1 October 2007, Pages 1427-1436
NeuroImage

Waiting for spiders: Brain activation during anticipatory anxiety in spider phobics

https://doi.org/10.1016/j.neuroimage.2007.06.023Get rights and content

Abstract

Anticipatory anxiety during expectation of phobogenic stimuli is an integral part of abnormal behaviour in phobics. The neural basis of anticipatory anxiety in specific phobia is unknown. Using functional magnetic resonance imaging (fMRI), we explored brain activation in subjects with spider phobia and in non-phobic subjects, while participants anticipated the presentation of either neutral or phobogenic visual stimuli. Subjective ratings indicated that anticipation of phobia-related stimuli was associated with increased anxiety in phobics but not in healthy subjects. FMRI results showed increased activation of the dorsal anterior cingulate cortex (ACC), insula, thalamus, and visual areas in phobics compared to controls during anticipation of phobia-relevant versus anticipation of neutral stimulation. Furthermore, for this contrast, we found also increased activation of the bed nucleus of the stria terminalis (BNST). This particular finding supports models, which propose, based on animal experiments, a critical involvement of the BNST in anticipatory anxiety. Finally, correlation analysis revealed that subjective anxiety of phobics correlated significantly with activation in rostral and dorsal ACC and the anterior medial prefrontal cortex. Thus, activation in different ACC regions and the medial prefrontal cortex seems to be specifically associated with the severity of experienced anticipatory anxiety in subjects with spider phobia.

Introduction

Specific phobia is characterized by rapid, exaggerated and persistent fear responses to phobia-related objects and situations (American Psychiatric Association, 1994). Besides fear responses to the perceived phobogenic threat, phobics also show pronounced anticipatory anxiety in situations, in which they expect the occurrence of phobia-related objects and events (e.g. Andrews et al., 1994, Dubrovsky et al., 1978). These anticipatory states include negative affect, autonomic arousal, and a hypervigilant monitoring of the environment (Andrews et al., 1994, Dubrovsky et al., 1978, Gray and McNaughton, 2000). Anticipatory anxiety contributes to avoidance behaviour, which reduces anxiety symptoms but also limits the chance for extinction of fear responses (Öst, 1996, Gray and McNaughton, 2000). Therefore, therapeutic interventions aim to reduce anticipatory anxiety as well as fear responses to real or symbolic threat stimuli (Öst, 1996, Straube et al., 2006a).

In search for the biological basis of specific phobia, brain circuits have been identified that might be involved in the pathophysiology of specific phobia. By means of functional brain imaging, increased amygdala activation to phobia-related pictures has been shown in animal phobics (e.g. Dilger et al., 2003, Sabatinelli et al., 2005, Schienle et al., 2005, Larson et al., 2006), even when subjects were distracted from or unaware of these stimuli (Straube et al., 2006b, Carlsson et al., 2004). The latter findings support influential models suggesting a role of the amygdala in the rapid, automatic and initial processing of phobia-related stimuli (LeDoux, 1998, Öhman and Mineka, 2001). Remarkably, during sustained periods of symptom provocation, an absence of amygdala activation was reported by several studies (e.g. Mountz et al., 1989, Fredrikson et al., 1993; Rauch et al., 1995, Reiman, 1997, Paquette et al., 2003, Straube et al., 2006a). These results suggest that sustained processing of phobogenic stimuli and corresponding affective reactions might be based on activation of other regions than the amygdala. During intense symptom provocation, activation of areas such as dorsomedial prefrontal cortex (DMPFC), anterior cingulate cortex (ACC), and anterior insula has been described (Reiman, 1997, Rauch et al., 1995, Straube et al., 2006a, Straube et al., 2006b). Furthermore, while amygdala activation to phobia-related stimuli was found to be widely independent of attentional resources or stimulus awareness, this is not the case for activation of ACC, DMPFC, and insula (Carlsson et al., 2004, Straube et al., 2006b). Activation of these areas was suggested to reflect the interplay of arousal, attentional processes, coping behaviour, and the conscious emotional experience of fear and anxiety (e.g. Reiman, 1997, Rauch et al., 1997, Straube et al., 2006a, Straube et al., 2006b). In particular, activation of the DMPFC seems to correlate with the magnitude of self-referential and higher evaluation processes (Phan et al., 2002, Amodio and Frith, 2006, Kalisch et al., 2006). The dorsal ACC is implicated in monitoring functions, attentional control, and response selection (Bush et al., 2000, Paus, 2001) but also in elicitation and representation of sympathetic autonomic arousal (Critchley et al., 2003). Especially rostral parts of the ACC have been shown to correlate with emotional awareness and emotional experiences, respectively (Rainville et al., 1997, Lane et al., 1998, Phan et al., 2002). Activation of the ACC during fear/anxiety and emotional arousal often covaries with responses of the insula (Reiman, 1997, Rauch et al., 1997, Critchley, 2004, Critchley et al., 2003, Straube et al., 2006a, Straube et al., 2006b), a brain region strongly involved in interoception and representation of bodily states (Craig, 2002, Critchley, 2004, Critchley et al., 2003). It has been suggested that the insula might support subjective aversive feelings by the interaction of perceived threat signals and bodily states of arousal (Critchley, 2004, Critchley et al., 2003). Recently, we showed that successful psychotherapy normalizes activation in the ACC and the insula to phobogenic stimulation in spider phobics (Straube et al., 2006b).

In contrast to the growing body of research on brain activation during the presence of fear-related stimuli, there is only one functional imaging study yet on the neural correlates of anticipatory anxiety in specific phobia. In a PET-study of Wik et al. (1996), animal phobics were exposed to neutral videos while expecting feared animals to occur in the films. The authors detected only reduced activation in visual cortex, suggesting strong avoidance behaviour. The reported absence of anxiety-related brain activation is in contrast to findings on neural correlates of anticipatory anxiety in healthy subjects (e.g. Chua et al., 1999, Ploghaus et al., 1999, Simpson et al., 2001, Jensen et al., 2003, Kalisch et al., 2006) and patients with panic disorder (e.g. Boshuisen et al., 2002). Anticipatory anxiety paradigms were found to activate medial prefrontal areas/ACC (Chua et al., 1999, Ploghaus et al., 1999, Simpson et al., 2001, Jensen et al., 2003, Kalisch et al., 2006) and the insula (Chua et al., 1999; Ploghaus et al., 1999; but see Boshuisen et al., 2002), regions being also activated during the presence of aversive stimuli. Simmons et al., 2004, Simmons et al., 2006 showed increased insula responses during expectation of spider pictures in healthy subjects, especially in subjects with increased trait anxiety (Simmons et al., 2006). However, these studies did not induce significant anxiety and the relevance of these findings for phobic experiences and behaviour remains unclear.

In social phobics, anticipation of public speech has been shown to activate the medial–temporal lobe including the amygdala (Tillfors et al., 2002, Lorberbaum et al., 2004), the insula (Lorberbaum et al., 2004), and to deactivate the ACC (Lorberbaum et al., 2004). These findings are only partially comparable to some of the results reviewed above. Besides methodological factors (e.g. no inclusion of a healthy control group or of a non-phobic control condition), discrepancies might indicate specificity of activation during anticipatory anxiety in phobics or during performance anticipation in social phobic subjects.

While some studies with social phobics (Tillfors et al., 2002, Lorberbaum et al., 2004) or healthy subjects (e.g. Phelps et al., 2001) found activation of the amygdala during anticipatory anxiety paradigms, several studies failed to show an amygdala involvement (e.g. Reiman et al., 1989, Chua et al., 1999, Ploghaus et al., 1999, Boshuisen et al., 2002). Based on animal models, a dissociation between the role of the amygdala and a part of the so-called extended amygdala, the bed nucleus of the stria terminalis (BNST), has been proposed (e.g. Walker et al., 2003). While the amygdala is thought to mediate rapid fear responses especially to fear-conditioned stimuli, the BNST was suggested to play a critical role in anxiety states during sustained and unpredictable situations (e.g. Walker et al., 2003, Kalin et al., 2005). The BNST receives input from medial prefrontal cortex and the central nucleus of the amygdala and projects to several other limbic areas as well as to various brain stem nuclei (e.g. Walker et al., 2003, Kalin et al., 2005). Inhibition or lesion of the BNST attenuates behavioural signs of anxiety in anxiety provoking paradigms (e.g. Fendt et al., 2003, Waddell et al., 2006). Furthermore, anxiety was shown to increase activation in the BNST (Kalin et al., 2005) and stimulation of the BNST evokes physiological and behavioural indices of anxiety (Casada and Dafny, 1991, Dunn, 1987, Walker et al., 2003). Although these animal studies indicate a critical role of the BNST in anxiety, it is an unsolved question whether the BNST is also involved in the mediation of anxiety states in humans.

Taken together, while there are some consisting findings in healthy subjects, knowledge on neural correlates of anticipatory anxiety in clinical populations is limited or, as in the case of phobias, inconclusive. In the present study, we used fMRI to investigate brain activation in regions such as the DMPFC, ACC, BNST, insula, and amygdala during anticipation of phobia-related vs. neutral visual stimuli in subjects with spider phobia and in non-phobic control subjects. The experimental design ensured that the onset of the presentation of phobogenic stimuli was unpredictable by the subjects during the sustained anticipation periods. Specifically, we tested the prediction that activation in the ACC/medial prefrontal cortex, the anterior insula, and the BNST is related to anticipatory anxiety in spider phobics. Analysis included exploration of effects of condition (phobogenic vs. neutral) and group (healthy control subjects vs. phobics) as well as a correlation approach. The latter analysis aimed to elucidate the relation between individual differences in experienced anxiety and brain activation.

Section snippets

Subjects

Sixteen right-handed female spider phobic subjects (age: 21.8 ± 0.6 years) and 15 right-handed healthy female control subjects (age: 22.7 ± 0.9 years) participated in the study. All participants were university students. The participants were recruited by public advertisement and received 6 Euro per hour for participation. Spider phobics were diagnosed by means of a structured clinical interview (Wittchen et al., 1997) according to the criteria for spider phobia of the Diagnostic and Statistic

Behavioural data

Anxiety ratings for each group and condition are displayed in Fig. 1. The ANOVA of these data showed main effects of condition [F(1,29) = 61.02, P < 0.0001] and group [F(1,29) = 82.15, P < 0.0001] and an interaction of condition by group [F(1,29) = 56.89, P < 0.0001]. Post-hoc analysis revealed that phobics, in contrast to controls, showed significantly increased anxiety during anticipation of spider pictures compared to anticipation of mushroom pictures (phobics: t = 8.0, P < 0.0001; controls: t = 1.0, P > 0.05).

Discussion

The present study provides evidence for increased activation in specific brain regions during anticipatory anxiety in subjects with specific phobia. We found enhanced activation of the ACC, insula, thalamus, BNST, and extrastriate visual cortical areas in phobics compared to controls during the anticipation of phobia-relevant relative to the anticipation of neutral stimulation. Furthermore, correlation analysis revealed that subjective anticipatory anxiety of phobics correlated with activation

Acknowledgments

The study was supported by grants of the Deutsche Forschungsgemeinschaft awarded to TS and WHRM (STR 987/2-1; MI 265/6-1,2) and by a grant of the Federal State of Thuringia and the University of Jena awarded to TS. We are thankful to Madlen Glauer for her help during acquisition and analysis of the data.

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