An elevated plus-maze in mixed reality for studying human anxiety-related behavior

Abstract

BackgroundA dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus-maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents.MethodsHere, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants’ anxiety on a behavioral, physiological, and subjective level.ResultsParticipants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants’ with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants’ acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2-adrenergic antagonism increased avoidance.ConclusionThese findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0463-6) contains supplementary material, which is available to authorized users.

The translational neural circuitry of anxiety

“…little is known about anxiety, especially its many human-specific cognitive-affective features. Indeed, many animal models of anxiety, such as the elevated-plus maze, have few analogues in humans 22 (although see Biederman et al 23 and Bach et al 24 ), and of course the impact of psychological therapies cannot be studied in animals. However, innovative approaches to study anxiety experimentally in humans have recently been developed.…”

Modeling anxiety in healthy humans: a key intermediate bridge between basic and clinical sciences

“…Behavioral avoidance tasks, where subjects anticipate a feared situation (e.g., anticipation of public speaking in social anxiety) is also a promising tool (188). For example, healthy controls and patients with social anxiety show distinct emotional responses and cognitive regulation to social threat compared to physical threat (185,189) and avoidance performance in a virtual elevated plus-maze is associated with symptom of acrophobia but not social anxiety or trait anxiety (190). This approach can also be extended to more specific symptoms such as emotional distraction by worries and intrusive thoughts (191).…”

Initial evidence for pharmacological modulation of observational threat learning by the GABAergic, but not the noradrenergic system in humans

“…In rodents, intra-amygdala injection of benzodiazepines, which enhance the action of GABA by allosteric modulation of the receptor subtype A, has been shown to produce anxiolytic-like effects in a number of animal models of anxiety, including the elevated plus maze (EPM) (Green and Vale, 1992;Nunes-de-Souza et al, 2000;Pesold and Treit, 1995). Similarly, we have recently shown that systemic administration of the benzodiazepine Lorazepam in humans reduces anxiety-like behavior on a virtual reality version of the EPM (Biedermann et al, 2017). These results fit to previous studies, reporting that benzodiazepines reduces several types of threat responses in general, such as eye-blink startle responses towards darkness (Baas et al, 2002) and towards unpleasant pictures (Patrick et al, 1996).…”

“…46 of the 61 subjects took part in a virtual reality version of an EPM (Biedermann et al, 2017) before participating in this experiment (groups: Placebo, Yohimbine, Lorazepam). 15 subjects participated solely in this experiment and received no medication (no treatment control).…”

“…Across species, threat learning by first-hand experiences is often examined within classical fear conditioning protocols (Haaker et al, 2019). These protocols include acquisition training, in which a cue (conditioned stimulus, CS+) is followed by an aversive event (unconditioned stimulus, US), for example an electric shock (Lonsdorf et al, 2017). Consequently, the CS is associatively learned as a predictor of the US and the presentation of the CS evokes a conditioned threat response.…”