Adam M. Perkins

Threat avoidance is a prominent symptom of affective disorders, yet its biological basis remains poorly understood. Here, we used a validated task, the Joystick Operated Runway Task (JORT), combined with fMRI, to explore whether abnormal function in neural circuits responsible for avoidance underlies these symptoms. Eighteen individuals with major depressive disorder (MDD) and 17 unaffected controls underwent the task, which involved using physical effort to avoid threatening stimuli, paired with mild electric shocks on certain trials. Activity during anticipation and avoidance of threats was explored and compared between groups. Anticipation of aversive stimuli was associated with significant activation in the dorsal anterior cingulate cortex, superior frontal gyrus, and striatum, while active avoidance of aversive stimuli was associated with activity in dorsal anterior cingulate cortex, insula, and prefrontal cortex. There were no significant group differences in neural activity or behavioral performance on the JORT; however, participants with depression reported more dread while being chased on the task. The JORT effectively identified neural systems involved in avoidance and anticipation of aversive stimuli. However, the absence of significant differences in behavioral performance and activation between depressed and non-depressed groups suggests that MDD is not associated with abnormal function in these networks. Future research should investigate the basis of passive avoidance in major depression. Further, the JORT should be explored in patients with anxiety disorders, where threat avoidance may be a more prominent characteristic of the disorder.

Background: Anhedonia – a diminished interest or pleasure in activities – is a core self-reported symptom of depression which is poorly understood and often resistant to conventional antidepressants. This symptom may occur due to dysfunction in one or more sub-components of reward processing: motivation, consummatory experience, and/or learning. However, the precise impairments remain elusive. Dissociating these components (ideally, using cross-species measures) and relating them to the subjective experience of anhedonia is critical as it may benefit fundamental biology research and novel drug development. Methods: Using a battery of behavioural tasks based on rodent assays, we examined reward motivation (Joystick-Operated Runway Task, JORT; and Effort-Expenditure for Rewards Task, EEfRT) and reward sensitivity (Sweet Taste Test) in a non-clinical population who scored high ( N = 32) or low ( N = 34) on an anhedonia questionnaire (Snaith-Hamilton Pleasure Scale). Results: Compared to the low anhedonia group, the high anhedonia group displayed marginal impairments in effort-based decision-making (EEfRT) and reduced reward sensitivity (Sweet Taste Test). However, we found no evidence of a difference between groups in physical effort exerted for reward (JORT). Interestingly, whilst the EEfRT and Sweet Taste Test correlated with anhedonia measures, they did not correlate with each other. This poses the question of whether there are subgroups within anhedonia; however, further work is required to directly test this hypothesis. Conclusions: Our findings suggest that anhedonia is a heterogenous symptom associated with impairments in reward sensitivity and effort-based decision-making.

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.

Gray’s theory of personality postulates that fear and anxiety are distinct emotional systems with only the latter being sensitive to anxiolytic drugs. His work was mainly based on animal research, and translational studies validating his theory are scarce. Previous work in humans showed an influence of the benzodiazepine lorazepam on both systems, however, dependent on dosage (1 and 2 mg) and personality differences in negative emotionality. The present study aims to replicate these findings, and in addition tests the drug threshold effect by introducing a lower dosage of 0.5 mg lorazepam. Fifty healthy adults (23 males, age_mean 22.40, SD ± 3.68) participated in an experimental threat-avoidance paradigm designed to dissociate risk assessment intensity (RAI, reflecting anxiety) and flight intensity (FI, reflecting fear) and completed two self-report questionnaires assessing facets of negative emotionality (Spielberger State Trait Anxiety Inventory and Fear Survey Schedule). In a randomized placebo-controlled within-subjects design, 0.5 and 1 mg of lorazepam were applied per os. Saccadic peak velocity was assessed by means of eye-tracking in order to control for sedating drug effects. Results showed the expected and specific anxiolytic effect of lorazepam on RAI, however, only in the 0.5 mg condition. FI was not influenced by lorazepam, and previous findings of interaction effects of lorazepam with self-reported negative emotionality could not be corroborated. Overall, this study demonstrates anxiolytic effects of lorazepam in dosages ≤1 mg in the absence of a drug effect on fear using a translational behavioural task. However, a putative moderating role of personality on defensive behaviour has to be clarified in future research.

As demonstrated by neuroimaging data, the human brain contains systems that control responses to threat. The revised Reinforcement Sensitivity Theory of personality predicts that individual differences in the reactivity of these brain systems produce anxiety and fear-related personality traits. Here we discuss some of the challenges in testing this theory and, as an example, present a pilot study that aimed to dissociate brain activity during pursuit by threat and goal conflict. We did this by translating the Mouse Defense Test Battery for human fMRI use. In this version, dubbed the Joystick Operated Runway Task (JORT), we repeatedly exposed 24 participants to pursuit and goal conflict, with and without threat of electric shock. The runway design of JORT allowed the effect of threat distance on brain activation to be evaluated independently of context. Goal conflict plus threat of electric shock caused deactivation in a network of brain areas that included the fusiform and middle temporal gyri, as well as the default mode network core, including medial frontal regions, precuneus and posterior cingulate gyrus, and laterally the inferior parietal and angular gyri. Consistent with earlier research, we also found that imminent threat activated the midbrain and that this effect was significantly stronger during the simple pursuit condition than during goal conflict. Also consistent with earlier research, we found significantly greater hippocampal activation during goal conflict than pursuit by imminent threat. In conclusion, our results contribute knowledge to theories linking anxiety disorders to altered functioning in defensive brain systems and also highlight challenges in this research domain.