Models and mechanisms of anxiety: evidence from startle studies

Abstract

Rationale: Preclinical data indicates that threat stimuli elicit two classes of defensive behaviors, those that are associated with imminent danger and are characterized by flight or fight (fear), and those that are associated with temporally uncertain danger and are characterized by sustained apprehension and hypervigilance (anxiety).

Objective: The objectives of the study are to (1) review evidence for a distinction between fear and anxiety in animal and human experimental models using the startle reflex as an operational measure of aversive states, (2) describe experimental models of anxiety, as opposed to fear, in humans, (3) examine the relevance of these models to clinical anxiety.

Results: The distinction between phasic fear to imminent threat and sustained anxiety to temporally uncertain danger is suggested by psychopharmacological and behavioral evidence from ethological studies and can be traced back to distinct neuroanatomical systems, the amygdala and the bed nucleus of the stria terminalis. Experimental models of anxiety, not fear, are relevant to non-phobic anxiety disorders.

Conclusions: Progress in our understanding of normal and abnormal anxiety is critically dependent on our ability to model sustained aversive states to temporally uncertain threat.

Fig. 1

Context conditioning following paired CS-shock (predictable shocks), unpaired CS-shock (unpredictable shocks), and non aversive conditionings (control) in a between-group design. During non-aversive conditioning, the US was a signal for button-press. Subjects underwent conditioning in two experiment sessions separated by 4–5 days. Context conditioning was assessed by delivering startle stimuli at the beginning of sessions 1 and 2, before conditioning occurred. The figure shows that when subjects received unpaired CS-US, startle magnitude was significantly larger when they return for testing (session 2) compared to before initial conditioning (session 1). In contrast, during the non-aversive condition, startle decreased (due to long-term habituation) between sessions 1 and 2. Startle magnitude in the paired CS-US condition was intermediated between these two conditions, suggesting weak context conditioning. * indicates a significant difference in startle magnitude between sessions 1 and 2 (Adapted from Grillon & Davis 1997)

Fig. 2

Context conditioning using virtual reality. Subjects were presented with three virtual environments in which they underwent different types of aversive conditioning counterbalanced across contexts in a within-subject design. The three contexts were a casino, a bank, and a restaurant. Subjects were safe in the no-shock (N) context. They received paired CS-shock in the predictable (P) context and unpaired CS-shock in the unpredictable (U) context. An 8-sec duration cue, a light, was presented in each context (not shown). The cue signaled the shock in the P context, but had no signal value in the N and U contexts. (From Grillon et al 2006).

Fig. 3

Magnitude of startle in each virtual context in the presence and in the absence of the CS (during inter-trial interval or ITI). As expected, startle was significantly larger during the CS compared to ITI (fear-potentiated startle) only in the predictable condition, when the cue signaled the shock (two middle bars). Startle during ITI (black bars) is a measure of context conditioning, reflecting the degree of contextual anxiety associated with each context. Startle increased linearly from the control, to the predictable, to the unpredictable contexts confirming that 1) context conditioning develops to environments associated with an aversive event and that 2) that context conditioning is affected by the predictability of the aversive event, unpredictable environments resulting in greater context conditioning compared to predictable environments. * indicates a significant increased in startle magnitude during the cue compared to ITI. (Adapted from Grillon et al 2006).

Fig. 4

Verbal instructions experiment. Subjects were verbally instructed that they would be safe in the no shock (N) condition, and that they would receive aversive stimuli signaled by a threat cue in the predictable (P) condition and unsignaled aversive stimuli in the unpredictable (U) condition. An 8-sec duration cue was presented in each context. The cue signaled the aversive stimulus in the P context, but had no signal value in the N and U contexts. Two types of aversive stimuli were used in a between-group design, a shock, and a blast of air directed to the throat at the level of the larynx. The results of the shock group are very similar to results in the context conditioning shown in Fig. 3. In the predictable condition, startle was larger during the CS compared to ITI (fear-potentiated startle). In addition, startle during ITI (black bars) increased linearly from the control, to the P, to the U condition. However, such a pattern of response was not seen in the airblast group. * indicates a significant increased in startle magnitude during the cue compared to ITI. (Adapted from Grillon et al 2004).

Fig. 5

Effect of the benzodiazepine alprazolam on verbally-mediated cued fear and contextual anxiety. The paradigm was the same as presented in Fig. 4. Subjects were informed that there would be three conditions, 1) no shock (N), 2) predictable (P) shocks, and unpredictable (U) shocks. Each subject received placebo, 0.5 mg of alprazolam, 1 mg of alprazolam, or 50 mg of diphenhydramine (Benadryl). Diphenhydramine was used as an active control to match the sedative properties of alprazolam on startle. Top; startle magnitude during the cue and ITI in the P condition in the P conditions only. The difference scores between cue and ITI is a measure of fear-potentiated startle. Alprazolam did not affect fear-potentiated startle. Bottom; Startle during ITI (contextual anxiety) in the N, P, and U condition. As in Figure 3 and Figure 4, startle increased linearly from the N to the P to the U condition with placebo. This effect was replicated with the low dose of alprazolam and with diphenhydramine. However, there was a significant reduction of startle with the high dose of alprazolam, indicating substantial reduction in contextual anxiety. This effect was not caused by sedation because diphenhydramine, which reduced baseline startle to the same extent as 1 mg alprazolam, did not affect contextual anxiety. * indicates a significant increased in startle magnitude during the cue compared to ITI. # indicates a significant Condition × Drug linear trend between conditions. (Adapted from Grillon et al 2006).

Fig. 6

Context conditioning in Vietnam veterans with PTSD. Subject underwent differential aversive conditioning in which one cue was paired with a shock (CS+) and the other was not (CS−) over two experimental sessions separated by a week. Context conditioning was assessed by delivering startle stimuli at the beginning of each session, before conditioning occurred. The figure shows significant context conditioning in the PTSD (startle magnitude increased from session 1 to session 2) but not in the control group (startle magnitude habituated between session 1 and 2). This pattern of startle modulation resulted in a significant Group × Session interaction. (Adapted from Grillon & Davis 1999)