Abstract Body (Do not enter title and authors here):
Background: Takotsubo syndrome is a life-threatening neuro-cardiac emergency typically triggered by stress and subtended by systemic inflammation. We assessed if behavioural modifications are associated with changes in brain structure and function after acute takotsubo.

Methods: In a multi-centre randomised controlled trial, 56 patients with acute takotsubo cardiomyopathy were randomised 1:1:1 to standard care or behavioural modification through either physical exercise training or cognitive behavioural therapy. All participants underwent structural and functional brain magnetic resonance imaging, echocardiography, post-awakening salivary cortisol and venous blood sampling, and completed patient reported outcomes at baseline and following intervention.

Results: Participants were 66±9 years and predominantly women (91%). The primary outcome (hippocampal volume) was unaffected by either behavioural modification. Both physical exercise and cognitive behavioural therapy decreased total cortical volume (p=0.03 and 0.01, respectively) and right insular volume (p=0.046 and 0.004, respectively). In addition, cognitive behavioural therapy increased cerebral white matter, decreased grey matter (p=0.009 and 0.014 respectively), improved perceived stress score (p=0.04) and decreased systemic inflammation. Behavioural modification groups maintained functional connectivity whilst insular and amygdala functional connectivity declined in standard care group (p<0.05). Both behavioural modification interventions decreased post-awakening salivary cortisol stress responses (p<0.004). There was comparable cardiac function recovery across groups.

Conclusions: After acute takotsubo syndrome, behavioural modifications improve brain volumes and functional connectivity in both the interoceptive insular cortex and emotion-mediating amygdala and are associated with improvements in humoral stress and inflammation.