Certain about uncertainty: bridging cells and the clinic to uncover causal mechanisms of anxiety interventions

In an uncertain situation, people rely on clues from the environment – things known to be predictable from past experience – to determine what will happen next. If someone cannot predict what will happen next, anything could seem like a threat. Intolerance of uncertainty is increasingly recognised as a key risk factor in a range of mental health difficulties, most notably anxiety disorders. Research suggests that two neurotransmitters targeted by anti-anxiety medication, serotonin and noradrenaline, are crucially involved in how the brain represents uncertainty. Furthermore, psychological therapies incorporate various techniques (e.g., reinterpretation) targeting the belief that uncertainty is threatening. We propose that these two effective interventions act via a common core causal mechanism: altered uncertainty processing. To address this, we will use computational models that can capture an individual's ‘uncertainty fingerprint’ – a measure of how people process different kinds of uncertainty in different cognitive contexts. By working across scales and species, we will reveal how anxiety medications and psychological therapy improve symptoms via changes in how the brain encodes uncertainty, moving from cells and circuits to clinical treatment. This primes the field for the development of precision medicine approaches in anxiety, tailoring treatments according to each person's 'uncertainty fingerprint'.