Anxiety disorders are the most common mental illnesses in the UK, with important consequences as reduced quality of life, functional impairment and increased costs. However, current treatment has a moderate effect with 50-60% response rates.
This symposium aimed to emphasize the need to understand the underlying biological mechanisms of anxiety disorders. All four speakers Oliver Robinson (University College London), Amy Milton (University of Cambridge), Angela Roberts (University of Cambridge) and Andrea Reinecke (University of Oxford) provided strong evidence of the role of translational research in understanding these mechanisms and developing new therapies.
Oliver Robinson introduced the role of anxiety as a response to fear in humans and animal models. Anxiety has a negative effect on control processes. However, anxiety induced by threat of shock in humans is associated with better attention control, probably because of an improved selectivity of attention in these circumstances. In a translational neuroimaging study Robinson et al found that anxiety increases the connectivity in dorsomedial prefrontal cortex (dmPFC)-amygdala circuit in humans and that this “aversive amplification circuit” is homologous to the prelimbic-amygdala circuit in rodents. In addition, the dmPFC-amygdala circuit can be modulated by induced serotonin depletion acute through tryptophan depletion diet and by serotonin augmentation through administration of antidepressants. Patients with anxiety disorder have impaired cognitive processing, such as difficulties to concentrate and take decisions, which increases the risk for avoidant behaviour. Oliver Robinson suggested that understanding the degree of the impaired cognitive processing is essential to identify targets for cognitive therapies for anxiety. He and his group use computation modelling to simulate and study behaviours such as maladaptive avoidance in anxiety disorders in humans and rodents. A possible therapeutic intervention in anxiety disorders is shifting the attention from anxiogenic stimuli towards more neutral or positive stimuli.
This talk was followed by Amy Milton on using rodent models of anxiety-like behaviour in post-traumatic stress disorder (PTSD). PTSD is regarded as a pavlovian fear conditioning; when a conditioned fear stimulus in association with an unconditioned stimulus generate the retrieval of memories of trauma which does not easily become extinct. A memory shifts from an “active” state to an “inactive” state through a process of reconsolidation and from an “inactive” state to an “active” state through a process of reactivation. In animal models as rats, exposure to a conditioned fear stimulus induces memory reconsolidation, while prolonged fear cue exposure results in memory extinction. Memory of fear persists through memory reconsolidation which can be targeted through a prolonged cue exposure or pharmacological. Amy Milton’s research suggests that in rats a prolonged cue exposure therapy has limited effects on maladaptive memories. An NMDA receptor agonist produces a pharmacological disruption of memory reconsolidation enhancing fear extinction, while an N-methyl-D-aspartate (NMDA) receptor antagonist prevents fear extinction. She describes that the transition from memory reconsolidation to extinction is done through a transitional state or “limbo” state when NMDA receptor agonists and antagonists are unable to influence the reconsolidation or extinction processes. Her further research focuses on determining the neurochemical mechanisms of fear memory reactivation/destabilisation. Amy Milton says that the “duration of the memory reactivation session is critical for successful treatment” and therefore we may need to develop markers of destabilisation. We may need to develop drugs which prevent memory destabilisation, but do not prevent the process of retrieval-extinction. She also emphasized the need to develop alternative ways to reduce the impact of trauma memories in those at risk.
The second half of the symposium began with a presentation by professor Angela Roberts on the role of distinct prefrontal and anterior cingulate cortex regions in modulating anxiety in primates. There are a lot of neuroanatomical similarities between humans and non-human primates’ prefrontal cortex. Cerebral cortex represents around 60% of the marmoset monkey brain. Moreover, using non-human primates facilitates the measurement of several behavioural and cardiovascular outputs such as arousal, avoidance, cardiac rate, blood pressure which are commonly seen in patients with anxiety disorders. Two tests are used: human intruder test of anxiety and exposure to a rubber snake (an imminent threat for marmosets). Marmosets with lesions in the ventrolateral prefrontal cortex (vlPFC) and anterior orbitofrontal cortex (antOFC) have higher scores on both tests suggesting that both brain regions can downregulate fear and anxiety. Both regions are equally important and can contribute independently to the regulation of fear. A lesion only on vlPFC is associated with a less adaptable, less affective flexibility and more autonomic fear responses, while a lesion only on antOFC is associated with a more rigid behaviour. Both regions have direct projections to the amygdala, (antOFC has more direct projections while vlPFC has less). Angela Roberts suggested that lesions in these areas are responsible for an impaired capacity in shifting attention and impaired capacity to predict punishment. Area 25 in the prefrontal cortex is another brain area involved in anxiety and fear response. Area 25 over-activation induces generalised cardiovascular and behavioural arousal and the recovery is delayed following termination of aversive stimuli. This area may also play a key role in anhedonia in patients with depression.
Answering a question on whether amygdala is a better target for future therapies in anxiety disorders, Angela Roberts said that amygdala can be one of the potential targets, but the circuits between the prefrontal cortex and amygdala may be a better target as a complete inhibition of amygdala probably will affect the normal response to fear.
The last speaker was Andrea Reinecke who introduced the concept of ultra brief treatments for anxiety disorders in humans. Previous reseach suggests that one single dose of antidepressants modulates emotional processing – increase capacity to recognise positive facial expressions and to remember these positive information – in patients with depression patients. Andrea Reinecke showed in her research that a single session of exposure-based cognitive behavioural therapy (CBT) modulates emotional processing. She recruited patients with agoraphobia who presented agoraphobic avoidance and panic-related safety behaviours (e.g. anxiolytic medication, water). After one session of exposure CBT the recovery rates were of 37% after 1 month. The antibiotic cycloserine is a NMDA receptor partial agonist and it has been found to enhance learning processes such as reward learning. A longitudinal study found that 1 single dose of cycloserine and one session of exposure CBT increases the recovery rates at 72% in moderate agoraphobia at 6 months. In future research Andrea Reinecke will try to explore the benefits of a single dose losartan in addition to a single session of exposure-based CBT. In animal models losartan has anxiolytic effects and enhance fear extinction.