aMedical School Berlin, Berlin, Germany
bDepartment of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
cCharité Research Organisation GmbH, Berlin, Germany
dSBGneuro Ltd., Oxford, UK
eTranslational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
fDepartment of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland
Log in to MyKarger to check if you already have access to this content.
Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more
CHF 38.00 *
EUR 35.00 *
USD 39.00 *
Buy a Karger Article Bundle (KAB) and profit from a discount!
If you would like to redeem your KAB credit, please log in.
Save over 20% compared to the individual article price. Rent via DeepDyve Unlimited fulltext viewing of this article Organize, annotate and mark up articles Printing and downloading restrictions apply Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more Select* The final prices may differ from the prices shown due to specifics of VAT rules.
Article / Publication DetailsFirst-Page Preview
Received: August 18, 2022
Accepted: October 17, 2022
Published online: February 02, 2023
Number of Print Pages: 13
Number of Figures: 4
Number of Tables: 0
ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)
For additional information: https://www.karger.com/NPS
AbstractIntroduction: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. Methods: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). Results: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine’s subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. Conclusion: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.
© 2023 S. Karger AG, Basel
References Dolan RJ. Emotion, cognition, and behavior. Science. 2002;298(5596):1191–4. LeDoux J. Fear and the brain: where have we been, and where are we going? Biol Psychiatry. 1998;44(12):1229–38. Pessoa L. On the relationship between emotion and cognition. Nat Rev Neurosci. 2008;9(2):148–58. Medford N, Critchley HD. Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response. Brain Struct Funct. 2010;214(5–6):535–49. Millan MJ, Agid Y, Brüne M, Bullmore ET, Carter CS, Clayton NS, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012;11(2):141–68. Baddeley A. Working memory: looking back and looking forward. Nat Rev Neurosci. 2003;4(10):829–39. Baddeley A. Working memory and emotion: ruminations on a theory of depression. Rev Gen Psychol. 2013;17(1):20–7. Pessoa L. How do emotion and motivation direct executive control? Trends Cogn Sci. 2009;13(4):160–6. Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp. 2005;25(1):46–59. Wang H, He W, Wu J, Zhang J, Jin Z, Li L. A coordinate-based meta-analysis of the n-back working memory paradigm using activation likelihood estimation. Brain Cogn. 2019;132:1–12. Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995;14(3):477–85. Jonides J, Smith EE, Koeppe RA, Awh E, Minoshima S, Mintun MA. Spatial working memory in humans as revealed by PET. Nature. 1993;363(6430):623–5. Petrides M. Frontal lobes and behaviour. Curr Opin Neurobiol. 1994;4(2):207–11. Rowe JB, Toni I, Josephs O, Frackowiak RSJ, Passingham RE. The prefrontal cortex: response selection or maintenance within working memory? Science. 2000;288(5471):1656–60. Bor D, Duncan J, Wiseman RJ, Owen AM. Encoding strategies dissociate prefrontal activity from working memory demand. Neuron. 2003;37(2):361–7. Bor D, Cumming N, Scott CEL, Owen AM. Prefrontal cortical involvement in verbal encoding strategies: modality independent PFC involvement in strategies. Eur J Neurosci. 2004;19(12):3365–70. Botvinick MM, Cohen JD, Carter CS. Conflict monitoring and anterior cingulate cortex: an update. Trends Cogn Sci. 2004;8(12):539–46. Duncan J, Owen AM. Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci. 2000;23(10):475–83. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007;27(9):2349–56. Craig ADB. How do you feel — now? The anterior insula and human awareness. Nat Rev Neurosci. 2009;10(1):59–70. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct. 2010;214(5–6):655–67. Döhnel K, Sommer M, Ibach B, Rothmayr C, Meinhardt J, Hajak G. Neural correlates of emotional working memory in patients with mild cognitive impairment. Neuropsychologia. 2008;46(1):37–48. Grimm S, Weigand A, Kazzer P, Jacobs AM, Bajbouj M. Neural mechanisms underlying the integration of emotion and working memory. NeuroImage. 2012;61(4):1188–94. Schweizer S, Satpute AB, Atzil S, Field AP, Hitchcock C, Black M, et al. The impact of affective information on working memory: a pair of meta-analytic reviews of behavioral and neuroimaging evidence. Psychol Bull. 2019;145(6):566–609. Meule A, Skirde AK, Freund R, Vögele C, Kübler A. High-calorie food-cues impair working memory performance in high and low food cravers. Appetite. 2012;59(2):264–9. Rebetez MML, Rochat L, Billieux J, Gay P, Van der Linden M. Do emotional stimuli interfere with two distinct components of inhibition? Cogn Emot. 2015;29(3):559–67. González-Garrido AA, López-Franco AL, Gómez-Velázquez FR, Ramos-Loyo J, Sequeira H. Emotional content of stimuli improves visuospatial working memory. Neurosci Lett. 2015;585:43–7. Luo Y, Qin S, Fernández G, Zhang Y, Klumpers F, Li H. Emotion perception and executive control interact in the salience network during emotionally charged working memory processing: examination of neural mechanisms on processing of emotional WM. Hum Brain Mapp. 2014;35(11):5606–16. Fellous J-M, Rudolph M, Destexhe A, Sejnowski TJ. Synaptic background noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity. Neuroscience. 2003;122(3):811–29. Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008;31(5):234–42. Roberts BM, Seymour PA, Schmidt CJ, Williams GV, Castner SA. Amelioration of ketamine-induced working memory deficits by dopamine D1 receptor agonists. Psychopharmacology. 2010;210(3):407–18. Honey RAE, Turner DC, Honey GD, Sharar SR, Kumaran D, Pomarol-Clotet E, et al. Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology. 2003;28(11):2037–44. Honey RAE, Honey GD, O’Loughlin C, Sharar SR, Kumaran D, Bullmore ET, et al. Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an fMRI study. Neuropsychopharmacology. 2004;29(6):1203–14. Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, et al. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012;109(41):16720–5. Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D’Souza DC, et al. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology. 2013;38(13):2613–22. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101(5):774–8. Shinohara R, Aghajanian GK, Abdallah CG. Neurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities. Biol Psychiatry. 2021;90(2):85–95. Elliott R, Zahn R, Deakin JFW, Anderson IM. Affective cognition and its disruption in mood disorders. Neuropsychopharmacology. 2011;36(1):153–82. McClintock SM, Husain MM, Greer TL, Cullum CM. Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychopharmacology. 2010;36:153–82. Gärtner M, Aust S, Bajbouj M, Fan Y, Wingenfeld K, Otte C, et al. Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine. Eur Neuropsychopharmacol. 2019;29(4):501–8. Gotlib IH, Joormann J. Cognition and depression: current status and future directions. Annu Rev Clin Psychol. 2010;6:285–312. Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH. Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of baseline activation and neural response data. Am J Psychiatry. 2012;169(7):693–703. Araújo-de-Freitas L, Santos-Lima C, Mendonça-Filho E, Vieira F, França RJAF, Magnavita G, et al. Neurocognitive aspects of ketamine and esketamine on subjects with treatment-resistant depression: a comparative, randomized and double-blind study. Psychiatry Res. 2021;303:114058. Basso L, Bönke L, Aust S, Gärtner M, Heuser-Collier I, Otte C, et al. Corrigendum to “Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients” [J. Psychiatr. Res. 123 (2020) 1-8]. J Psychiatr Res. 2020;124:143–8. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49. Scheidegger M, Henning A, Walter M, Boeker H, Weigand A, Seifritz E, et al. Effects of ketamine on cognition–emotion interaction in the brain. NeuroImage. 2016;124(Pt A):8–15. Becker B, Steffens M, Zhao Z, Kendrick KM, Neumann C, Weber B, et al. General and emotion-specific neural effects of ketamine during emotional memory formation. NeuroImage. 2017;150:308–17. Large CH, Webster EL, Goff DC. The potential role of lamotrigine in schizophrenia. Psychopharmacology. 2005;181(3):415–36. Veraart JKE, Smith-Apeldoorn SY, Bakker IM, Visser BAE, Kamphuis J, Schoevers RA, et al. Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review. Int J Neuropsychopharmacol. 2021;24(10):808–31. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13(1):71–82. Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GMI, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018;43(10):2154–60. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57(3):270–6. Deakin JFW, Lees J, McKie S, Hallak JEC, Williams SR, Dursun SM. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco–magnetic resonance imaging study. Arch Gen Psychiatry. 2008;65(2):154–64. Doyle OM, De Simoni S, Schwarz AJ, Brittain C, O’Daly OG, Williams SCR, et al. Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents. J Pharmacol Exp Ther. 2013;345(1):151–60. Joules R, Doyle OM, Schwarz AJ, O’Daly OG, Brammer M, Williams SC, et al. Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile. Psychopharmacology. 2015;232(21–22):4205–18. Shcherbinin S, Doyle O, Zelaya FO, de Simoni S, Mehta MA, Schwarz AJ. Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects. Psychopharmacology. 2015;232(21–22):4191–204. Walter M, Li S, Demenescu LR. Multistage drug effects of ketamine in the treatment of major depression. Eur Arch Psychiatry Clin Neurosci. 2014;264(Suppl 1):55–65. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–64. Stiglmayr C, SchmahlBremner CJD, Bohus M, Ebner-Priemer U, Ebner-Priemer, Ulrich . Development and psychometric characteristics of the DSS-4 as a short instrument to assess dissociative experience during neuropsychological experiments. Psychopathology. 2009;42(6):370–4. Dittrich A. The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry. 1998;31(Suppl 2):80–4. Hartling C, Metz S, Pehrs C, Scheidegger M, Gruzman R, Keicher C, et al. Comparison of four fMRI paradigms probing emotion processing. Brain Sci. 2021;11(5):525–13. Võ MLH, Conrad M, Kuchinke L, Urton K, Hofmann MJ, Jacobs AM. The Berlin affective word list reloaded (BAWL-R). Behav Res Methods. 2009;41(2):534–8. Paret C, Niedtfeld I, Lotter T, Wunder A, Grimm S, Mennes M, et al. Single-dose effects of citalopram on neural responses to affective stimuli in borderline personality disorder: a randomized clinical trial. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6(8):837–45. Horacek J, Brunovsky M, Novak T, Tislerova B, Palenicek T, Bubenikova-Valesova V, et al. Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect. Psychol Med. 2010;40(9):1443–51. Hegoburu C, Parrot S, Ferreira G, Mouly A-M. Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory. Learn Mem. 2014;21(12):651–5. Vieira PA, Corches A, Lovelace JW, Westbrook KB, Mendoza M, Korzus E. Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction. Neurobiol Learn Mem. 2015;119:52–62. Lindström BR, Bohlin G. Emotion processing facilitates working memory performance. Cogn Emot. 2011;25(7):1196–204. Vuilleumier P. How brains beware: neural mechanisms of emotional attention. Trends Cogn Sci. 2005;9(12):585–94. Okon-Singer H, Hendler T, Pessoa L, Shackman AJ. The neurobiology of emotional cognition interactions: fundamental questions and strategies for future research. Front Hum Neurosci. 2015;9:1–14. Gärtner M, Ghisu ME, Scheidegger M, Bönke L, Fan Y, Stippl A, et al. Aberrant working memory processing in major depression: evidence from multivoxel pattern classification. Neuropsychopharmacology. 2018;43(9):1972–9. Duncan GE, Leipzig JN, Mailman RB, Lieberman JA. Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. Brain Res. 1998;812(1–2):65–75. Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA. Sequential regional cerebral blood flow brain scans using PET with H215O demonstrate ketamine actions in CNS dynamically. Neuropsychopharmacology. 2001;25(2):165–72. Långsjö JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology. 2003;99(3):614–23. Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, et al. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol. 1997;7(1):9–24. De Simoni S, Schwarz AJ, O’Daly OG, Marquand AF, Brittain C, Gonzales C, et al. Test–retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers. NeuroImage. 2013;64:75–90. Höflich A, Hahn A, Küblböck M, Kranz GS, Vanicek T, Ganger S, et al. Ketamine-dependent neuronal activation in healthy volunteers. Brain Struct Funct. 2017;222(3):1533–42. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17(8):2921–7. Simmons A, Strigo I, Matthews SC, Paulus MP, Stein MB. Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol Psychiatry. 2006;60(4):402–9. Lee Y, Syeda K, Maruschak NA, Cha DS, Mansur RB, Wium-Andersen IK, et al. A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect. J Clin Psychopharmacol. 2016;36(1):50–6. Fan J, Hof PR, Guise KG, Fossella JA, Posner MI. The functional integration of the anterior cingulate cortex during conflict processing. Cereb Cortex. 2008;18(4):796–805. Nelson SM, Dosenbach NUF, Cohen AL, Wheeler ME, Schlaggar BL, Petersen SE. Role of the anterior insula in task-level control and focal attention. Brain Struct Funct. 2010;214(5–6):669–80. D’Esposito M, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J. Functional MRI studies of spatial and nonspatial working memory. Brain Res Cogn Brain Res. 1998;7:1–13. Xie W, Li H, Ying X, Zhu S, Fu R, Zou Y, et al. Affective bias in visual working memory is associated with capacity. Cogn Emot. 2017;31(7):1345–60. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11(9):642–51. Davidson RJ, Irwin W. The functional neuroanatomy of emotion and affective style. Trends Cogn Sci. 1999;3(1):11–21. Grimm S, Beck J, Schuepbach D, Hell D, Boesiger P, Bermpohl F, et al. Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biol Psychiatry. 2008;63(4):369–76. Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, et al. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry. 2004;55(6):578–87. Neta M, Whalen PJ. Individual differences in neural activity during a facial expression vs. identity working memory task. NeuroImage. 2011;56(3):1685–92. Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, et al. Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex. 1999;9(1):20–6. Article / Publication DetailsFirst-Page Preview
Received: August 18, 2022
Accepted: October 17, 2022
Published online: February 02, 2023
Number of Print Pages: 13
Number of Figures: 4
Number of Tables: 0
ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)
For additional information: https://www.karger.com/NPS
Copyright / Drug Dosage / Disclaimer Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Comments (0)