Rong Ye1,2, Ndabezinhle Mazibuko3, Jens Teichert4, Ralf Regenthal4, Angie A Kehagia3,5, Mitul A Mehta3. 1. Department of Clinical Neurosciences and Cambridge University Hospital NHS Trust, University of Cambridge, Herchel Smith Building, Robinson Way, Cambridge, CB2 0SZ, UK. ronye.uk@gmail.com. 2. Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. ronye.uk@gmail.com. 3. Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 4. Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig University, Leipzig, Germany. 5. University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK.
Abstract
RATIONALE: The effects of atomoxetine (ATO) on response inhibition have been typically examined using the stop signal task (SST) which is however confounded by attentional capture. The right inferior frontal cortex (rIFC) has been implicated in the modulation of ATO on inhibitory control, but a precise characterisation of its role is complicated by its functional inhomogeneity. OBJECTIVES: The current study aimed to directly investigate the effect of ATO in the SST using the imaging contrast unconfounded by attentional capture, to test the specific drug actions in functionally dissociable rIFC subregions, and to explore the role of locus coeruleus (LC), the main source of cortical noradrenaline, in mediating the drug effects. METHODS: This imaging study investigated the effect of ATO (40 mg) in 18 human participants during a modified SST that unconfounds attention from inhibition. Functional definitions for rIFC subdivisions were adopted in the analyses to isolate attention and inhibition during action cancellation. The LC integrity was measured in vivo using a neuromelanin-sensitive sequence. RESULTS: We identified one mechanism of ATO modulation specific to inhibitory control: ATO enhanced activity in pre-supplementary area (pre-SMA) for motor inhibition, and the recruitment of temporoparietal junction (TPJ) and inferior frontal junction (IFJ) for functional integration during response inhibition. Moreover, drug-related behavioural and neural responses correlated with variations in LC integrity. CONCLUSIONS: These findings provide a more nuanced and precise understanding of the effects of ATO on specific and domain general aspects of stopping.
RATIONALE: The effects of atomoxetine (ATO) on response inhibition have been typically examined using the stop signal task (SST) which is however confounded by attentional capture. The right inferior frontal cortex (rIFC) has been implicated in the modulation of ATO on inhibitory control, but a precise characterisation of its role is complicated by its functional inhomogeneity. OBJECTIVES: The current study aimed to directly investigate the effect of ATO in the SST using the imaging contrast unconfounded by attentional capture, to test the specific drug actions in functionally dissociable rIFC subregions, and to explore the role of locus coeruleus (LC), the main source of cortical noradrenaline, in mediating the drug effects. METHODS: This imaging study investigated the effect of ATO (40 mg) in 18 human participants during a modified SST that unconfounds attention from inhibition. Functional definitions for rIFC subdivisions were adopted in the analyses to isolate attention and inhibition during action cancellation. The LC integrity was measured in vivo using a neuromelanin-sensitive sequence. RESULTS: We identified one mechanism of ATO modulation specific to inhibitory control: ATO enhanced activity in pre-supplementary area (pre-SMA) for motor inhibition, and the recruitment of temporoparietal junction (TPJ) and inferior frontal junction (IFJ) for functional integration during response inhibition. Moreover, drug-related behavioural and neural responses correlated with variations in LC integrity. CONCLUSIONS: These findings provide a more nuanced and precise understanding of the effects of ATO on specific and domain general aspects of stopping.
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