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Mapping the effects of atomoxetine during response inhibition across cortical territories and the locus coeruleus

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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.

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References

  • Aron AR, Cai W, Badre D, Robbins TW (2015) Evidence supports specific braking function for inferior PFC. Trends Cogn Sci 19:711–712

    Article  PubMed  Google Scholar 

  • Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113

    Article  PubMed  Google Scholar 

  • Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450

    Article  CAS  PubMed  Google Scholar 

  • Bari A, Aston-Jones G (2013) Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons. Neuropharmacology 64:53–64

    Article  CAS  PubMed  Google Scholar 

  • Bari A, Eagle DM, Mar AC, Robinson ESJ, Robbins TW (2009) Dissociable effects of noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in rats. Psychopharmacology 205:273–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Betts MJ, Kirilina E, Otaduy MCG, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lusebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maass A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HIL, Duzel E, Hammerer D (2019) Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain 142:2558–2571

    Article  PubMed  PubMed Central  Google Scholar 

  • Borchert RJ, Rittman T, Passamonti L, Ye Z, Sami S, Jones SP, Nombela C, Rodriguez PV, Vatansever D, Rae CL, Hughes LE, Robbins TW, Rowe JB (2016) Atomoxetine enhances connectivity of prefrontal networks in Parkinson’s disease (vol 41, pg 2171, 2016). Neuropsychopharmacology 41:2188–2188

    Article  PubMed  PubMed Central  Google Scholar 

  • Brass M, Derrfuss J, Forstmann B, von Cramon DY (2005) The role of the inferior frontal junction area in cognitive control. Trends Cogn Sci 9:314–316

    Article  PubMed  Google Scholar 

  • Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 27:699–711

    Article  CAS  Google Scholar 

  • Cai WD, Ryali S, Chen TW, Li CSR, Menon V (2014) Dissociable roles of right inferior frontal cortex and anterior insula in inhibitory control: evidence from intrinsic and task-related functional parcellation, connectivity, and response profile analyses across multiple datasets. J Neurosci 34:14652–14667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chamberlain SR, Del Campo N, Dowson J, Muller U, Clark L, Robbins TW, Sahakian BJ (2007) Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry 62:977–984

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain SR, Hampshire A, Muller U, Rubia K, Del Campo N, Craig K, Regenthal R, Suckling J, Roiser JP, Grant JE, Bullmore ET, Robbins TW, Sahakian BJ (2009) Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study. Biol Psychiat 65:550–555

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006) Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311:861–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Scangos KW, Stuphorn V (2010) Supplementary motor area exerts proactive and reactive control of arm movements. J Neurosci 30:14657–14675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clewett DV, Lee TH, Greening S, Ponzio A, Margalit E, Mather M (2016) Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiol Aging 37:117–126

    Article  CAS  PubMed  Google Scholar 

  • Corbetta M, Patel G, Shulman GL (2008) The reorienting system of the human brain: from environment to theory of mind. Neuron 58:306–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coxon JP, Goble DJ, Leunissen I, Van Impe A, Wenderoth N, Swinnen SP (2016) Functional brain activation associated with inhibitory control deficits in older adults. Cereb Cortex 26:12–22

    Article  PubMed  Google Scholar 

  • Dalley JW, Robbins TW (2017) Fractionating impulsivity: neuropsychiatric implications. Nat Rev Neurosci 18:158–171

    Article  CAS  PubMed  Google Scholar 

  • Dayan P, Yu AJ (2006) Phasic norepinephrine: a neural interrupt signal for unexpected events. Network 17:335–350

    Article  PubMed  Google Scholar 

  • Derrfuss J, Brass M, Neumann J, von Cramon DY (2005) Involvement of the inferior frontal junction in cognitive control: meta-analyses of switching and Stroop studies. Hum Brain Mapp 25:22–34

    Article  PubMed  PubMed Central  Google Scholar 

  • Erika-Florence M, Leech R, Hampshire A (2014) A functional network perspective on response inhibition and attentional control. Nat Commun 5:4073

    Article  CAS  PubMed  Google Scholar 

  • Geng JJ, Vossel S (2013) Re-evaluating the role of TPJ in attentional control: contextual updating? Neurosci Biobehav Rev 37:2608–2620

    Article  PubMed  PubMed Central  Google Scholar 

  • Gilmour G, Arguello A, Bari A, Brown VJ, Carter C, Floresco SB, Jentsch DJ, Tait DS, Young JW, Robbins TW (2013) Measuring the construct of executive control in schizophrenia: Defining and validating translational animal paradigms for discovery research. Neurosci Biobehav Rev 37:2125–2140

    Article  PubMed  Google Scholar 

  • Grinband J, Wager TD, Lindquist M, Ferrera VP, Hirsch J (2008) Detection of time-varying signals in event-related fMRI designs. Neuroimage 43:509–520

    Article  PubMed  Google Scholar 

  • Hampshire A (2015) Putting the brakes on inhibitory models of frontal lobe function. Neuroimage 113:340–355

    Article  PubMed  Google Scholar 

  • Hampshire A, Sharp D (2015) Inferior PFC subregions have broad cognitive roles. Trends Cogn Sci 19:712–713

    Article  PubMed  Google Scholar 

  • Kahnt T, Tobler PN (2013) Salience signals in the right temporoparietal junction facilitate value-based decisions. J Neurosci 33:863–869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kehagia AA, Housden CR, Regenthal R, Barker RA, Muller U, Rowe J, Sahakian BJ, Robbins TW (2014) Targeting impulsivity in Parkinson’s disease using atomoxetine. Brain : a journal of neurology 137: 1986-97.

  • Keren NI, Lozar CT, Harris KC, Morgan PS, Eckert MA (2009) In vivo mapping of the human locus coeruleus. Neuroimage 47:1261–1267

    Article  PubMed  Google Scholar 

  • Keren NI, Taheri S, Vazey EM, Morgan PS, Granholm AC, Aston-Jones GS, Eckert MA (2015) Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. Neuroimage.

  • Levy BJ, Wagner AD (2011) Cognitive control and right ventrolateral prefrontal cortex: reflexive reorienting, motor inhibition, and action updating. Ann N Y Acad Sci 1224:40–62

    Article  PubMed  PubMed Central  Google Scholar 

  • Lindenbach D, Bishop C (2013) Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson’s disease. Neurosci Biobehav Rev 37:2737–2750

    Article  PubMed  Google Scholar 

  • Lipszyc J, Schachar R (2010) Inhibitory control and psychopathology: a meta-analysis of studies using the stop signal task. J Int Neuropsychol Soc 16:1064–1076

    Article  PubMed  Google Scholar 

  • Mather M, Harley CW (2016) The locus coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn Sci 20:214–226

    Article  PubMed  PubMed Central  Google Scholar 

  • Murphy K, Garavan H (2004) An empirical investigation into the number of subjects required for an event-related fMRI study. Neuroimage 22:879–885

    Article  PubMed  Google Scholar 

  • O'Callaghan C, Hezemans FH, Ye R, Rua C, Jones PS, Murley AG, Holland N, Regenthal R, Tsvetanov K, Wolpe N, Barker R, Williams-Gray C, Robbins T, Passamonti L, Rowe J (2020) Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease. 2020.09.03.20176800.

  • O'Callaghan C, Hezemans FH, Ye R, Rua C, Jones PS, Murley AG, Holland N, Regenthal R, Tsvetanov KA, Wolpe N, Barker RA, Williams-Gray CH, Robbins TW, Passamonti L, Rowe JB (2021) Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease. Brain.

  • Obeso I, Robles N, Marron EM, Redolar-Ripoll D (2013) Dissociating the role of the pre-SMA in response inhibition and switching: a combined online and offline TMS approach. Front Hum Neurosci 7:150

    Article  PubMed  PubMed Central  Google Scholar 

  • Obeso I, Wilkinson L, Jahanshahi M (2011) Levodopa medication does not influence motor inhibition or conflict resolution in a conditional stop-signal task in Parkinson’s disease. Exp Brain Res 213:435–445

    Article  CAS  PubMed  Google Scholar 

  • Pauls AM, O’Daly OG, Rubia K, Riedel WJ, Williams SC, Mehta MA (2012) Methylphenidate effects on prefrontal functioning during attentional-capture and response inhibition. Biol Psychiat 72:142–149

    Article  CAS  PubMed  Google Scholar 

  • Priovoulos N, Jacobs HIL, Ivanov D, Uludag K, Verhey FRJ, Poser BA (2018) High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage 168:427–436

    Article  PubMed  Google Scholar 

  • Rae CL, Nombela C, Rodriguez PV, Ye Z, Hughes LE, Jones PS, Ham T, Rittman T, Coyle-Gilchrist I, Regenthal R, Sahakian BJ, Barker RA, Robbins TW, Rowe JB (2016) Atomoxetine restores the response inhibition network in Parkinson’s disease. Brain : a Journal of Neurology 139:2235–2248

    Article  PubMed  PubMed Central  Google Scholar 

  • Rey-Mermet A, Gade M (2018) Inhibition in aging: what is preserved? What declines? A meta-analysis. Psychon B Rev 25:1695–1716

    Article  Google Scholar 

  • Robbins TW, Kehagia AA (2017) The neurochemistry of prefrontal control processes. In: Eigner T (ed) The Wiley Handbook of Cognitive Control. John Wiley and Sons, Chichester, UK

  • Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, Dalley JW, Robbins TW (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33:1028–1037

    Article  CAS  PubMed  Google Scholar 

  • Sauer JM, Ring BJ, Witcher JW (2005) Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet 44:571–590

    Article  CAS  PubMed  Google Scholar 

  • Sebastian A, Baldermann C, Feige B, Katzev M, Scheller E, Hellwig B, Lieb K, Weiller C, Tuscher O, Kloppel S (2013) Differential effects of age on subcomponents of response inhibition. Neurobiol Aging 34:2183–2193

    Article  CAS  PubMed  Google Scholar 

  • Sebastian A, Jung P, Neuhoff J, Wibral M, Fox PT, Lieb K, Fries P, Eickhoff SB, Tuscher O, Mobascher A (2016) Dissociable attentional and inhibitory networks of dorsal and ventral areas of the right inferior frontal cortex: a combined task-specific and coordinate-based meta-analytic fMRI study. Brain Struct Funct 221:1635–1651

    Article  PubMed  Google Scholar 

  • Sharp DJ, Bonnelle V, De Boissezon X, Beckmann CF, James SG, Patel MC, Mehta MA (2010) Distinct frontal systems for response inhibition, attentional capture, and error processing. Proc Natl Acad Sci U S A 107:6106–6111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shulman GL, McAvoy MP, Cowan MC, Astafiev SV, Tansy AP, d’Avossa G, Corbetta M (2003) Quantitative analysis of attention and detection signals during visual search. J Neurophysiol 90:3384–3397

    Article  PubMed  Google Scholar 

  • Swick D, Ashley V, Turken U (2011) Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks. Neuroimage 56:1655–1665

    Article  PubMed  Google Scholar 

  • Tsvetanov KA, Ye Z, Hughes L, Samu D, Treder MS, Wolpe N, Tyler LK, Rowe JB, Neuroscience CCA (2018) Activity and Connectivity Differences Underlying Inhibitory Control Across the Adult Life Span. J Neurosci 38:7887–7900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verbruggen F, Aron AR, Band GPH, Beste C, Bissett PG, Brockett AT, Brown JW, Chamberlain SR, Chambers CD, Colonius H, Colzato LS, Corneil BD, Coxon JP, Dupuis A, Eagle DM, Garavan H, Greenhouse I, Heathcote A, Huster RJ, Jahfari S, Kenemans JL, Leunissen I, Li CSR, Logan GD, Matzke D, Morein-Zamir S, Murthy A, Pare M, Poldrack RA, Ridderinkhof KR, Robbins TW, Roesch MR, Rubia K, Schachar RJ, Schall JD, Stock AK, Swann NC, Thakkar KN, van der Molen MW, Vermeylen L, Vink M, Wessel JR, Whelan R, Zandbelt BB, Boehler CN (2019) A consensus guide to capturing the ability to inhibit actions and impulsive behaviors in the stop-signal task. Elife 8.

  • Verbruggen F, Aron AR, Stevens MA, Chambers CD (2010) Theta burst stimulation dissociates attention and action updating in human inferior frontal cortex. Proc Natl Acad Sci USA 107:13966–13971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verbruggen F, Logan GD (2008) Response inhibition in the stop-signal paradigm. Trends Cogn Sci 12:418–424

    Article  PubMed  PubMed Central  Google Scholar 

  • Verbruggen F, Logan GD (2009) Models of response inhibition in the stop-signal and stop-change paradigms. Neurosci Biobehav Rev 33:647–661

    Article  PubMed  Google Scholar 

  • Waller DA, Hazeltine E, Wessel JR (2019) Common neural processes during action-stopping and infrequent stimulus detection: the frontocentral P3 as an index of generic motor inhibition. Int J Psychophysiol.

  • Warren CM, Wilson RC, van der Wee NJ, Giltay EJ, van Noorden MS, Cohen JD, Nieuwenhuis S (2017) The effect of atomoxetine on random and directed exploration in humans. PloS one 12:e0176034

    Article  PubMed  PubMed Central  Google Scholar 

  • Wessel JR, Aron AR (2017) On the globality of motor suppression: unexpected events and their influence on behavior and cognition. Neuron 93:259–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA (2013) Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology 80:1202–1208

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu KZ, Anderson BA, Emeric EE, Sali AW, Stuphorn V, Yantis S, Courtney SM (2017) Neural basis of cognitive control over movement inhibition: human fMRI and primate electrophysiology evidence. Neuron 96: 1447-+.

  • Ye R, Rua C, O’Callaghan C, Jones PS, Hezemans FH, Kaalund SS, Tsvetanov KA, Rodgers CT, Williams G, Passamonti L, Rowe JB (2021) An in vivo probabilistic atlas of the human locus coeruleus at ultra-high field. Neuroimage 225:117487

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the study participants for their time and commitment. We gratefully acknowledge S. Stephensen, V. Kotoula and P. Selvaggi for assistance with data collection; D. Lythgoe for the neuromelanin-sensitive sequence development.

Funding

This study was funded from departmental sources.

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Authors and Affiliations

  1. Department of Clinical Neurosciences and Cambridge University Hospital NHS Trust, University of Cambridge, Herchel Smith Building, Robinson Way, Cambridge, CB2 0SZ, UK

    Rong Ye

  2. Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Rong Ye, Ndabezinhle Mazibuko, Angie A. Kehagia & Mitul A. Mehta

  3. Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig University, Leipzig, Germany

    Jens Teichert & Ralf Regenthal

  4. University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK

    Angie A. Kehagia

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  1. Rong Ye
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  2. Ndabezinhle Mazibuko
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  3. Jens Teichert
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  4. Ralf Regenthal
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  5. Angie A. Kehagia
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  6. Mitul A. Mehta
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Correspondence to Rong Ye.

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Conflict of interest

The authors declare no competing financial interests. R. Y. is grateful for support from the China Scholarship Council (CSC). A. A. K. was supported by the King’s College London and a Fellowship from the Foulkes Foundation during her training in medicine. M. A. M was partly supported by the National Institute for Health Research Biomedical Research Centre at South London and the Maudsley NHS Foundation Trust and King’s College London.

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Ye, R., Mazibuko, N., Teichert, J. et al. Mapping the effects of atomoxetine during response inhibition across cortical territories and the locus coeruleus. Psychopharmacology 239, 365–376 (2022). https://doi.org/10.1007/s00213-021-05998-2

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  • DOI: https://doi.org/10.1007/s00213-021-05998-2

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