RESUMEN
It is generally thought that the effect of acute stress on higher-order functions such as working memory is, for an important part, mediated by central catecholamine activity. However, little is known about the association between neuroendocrine stress responses and catecholamine-dependent working memory-related brain function in the absence of stress. Here, we investigate for the first time in healthy humans (n = 18) how neuroendocrine responses to stress (cortisol and alpha-amylase) relate to fronto-parietal working memory activity changes in response to atomoxetine, a noradrenaline transporter inhibitor that selectively increases extracellular cortical dopamine and noradrenaline. We observed positive correlations between stress-induced cortisol (Pearson's r = 0.75, P < 0.001) and alpha amylase (r = 0.69, P = 0.02) increases and catecholamine-dependent working memory-related activity in dorsolateral prefrontal cortex. Stress-induced cortisol increases furthermore correlated with supramarginal gyrus working memory-related activity (r = 0.79, P < 0.001). Comparing high vs low stress responders revealed that these correlations were driven by decreased working memory activity on placebo and greater working memory activity increases following atomoxetine in high stress responders. These results further corroborate the notion that neuroendocrine responses to stress are an informative proxy of catecholamine function relevant to higher order functions and provide novel hints on the complex relationship between acute stress, catecholamine function and working memory.
Asunto(s)
Nivel de Alerta/fisiología , Lóbulo Frontal/fisiología , Memoria a Corto Plazo/fisiología , Sistemas Neurosecretores/fisiología , Lóbulo Parietal/fisiología , Corteza Prefrontal/fisiología , alfa-Amilasas Salivales/metabolismo , Adolescente , Adulto , Nivel de Alerta/efectos de los fármacos , Clorhidrato de Atomoxetina/farmacología , Mapeo Encefálico , Dopamina/fisiología , Lóbulo Frontal/efectos de los fármacos , Humanos , Hidrocortisona/metabolismo , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Sistemas Neurosecretores/efectos de los fármacos , Norepinefrina/metabolismo , Lóbulo Parietal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Estadística como Asunto , Adulto JovenRESUMEN
Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response.