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Neural correlates of instrumental responding in the context of alcohol-related cues index disorder severity and relapse risk

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Abstract

The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = − 3.86, p < .001), but not in healthy controls (t = − 0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t(30) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.

Clinical trial: LeAD study, http://www.lead-studie.de, NCT01679145.

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Acknowledgements

This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, FOR 1617: Grants HE 2597/13-1 and 13-2, HE 2597/14-1 and 14-2, HE 2597/15-1 and 15-2, RA 1047/2-1 and 2-2, SCHA 1971/1-2, SCHL 1969/2-1 and 2-2, SM 80/7-1 and 7-2, WI 709/10-1 and 10-2, and ZI 1119/3-1 and 3-2). Eva Friedel is a participant in the BIH Charité Clinician Scientist Program funded by the Charité-Universitätsmedizin and the Berlin Institute of Health. Moreover, we thank the LeAD study teams in Berlin and Dresden for all the work and help regarding data collection! We would also like to gratefully thank Carolin Wackerhagen for producing the alcohol- and water-related background stimuli! Finally, we are grateful to Lee Hogarth for discussing the nature of our PIT effects, and for interference account predictions. MR-imaging for this study was performed at the Berlin Center for Advanced Neuroimaging (BCAN) and Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden.

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Author notes

  1. Daniel J. Schad, Maria Garbusow, Florian Schlagenhauf, Quentin J. M. Huys, Andreas Heinz and Michael A. Rapp contributed equally.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Charité Mitte, Berlin, Germany

    Daniel J. Schad, Maria Garbusow, Eva Friedel, Miriam Sebold, Claudia Hägele, Shuyan Liu, Anne Beck, Henrik Walter, Philipp Sterzer, Florian Schlagenhauf & Andreas Heinz

  2. Social and Preventive Medicine, Humanwissenschaftliche Fakultät, Area of Excellence Cognitive Sciences, University of Potsdam, Am Neuen Palais 10, 14469, Potsdam, Germany

    Daniel J. Schad & Michael A. Rapp

  3. Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany

    Maria Garbusow & Miriam Sebold

  4. Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Christian Sommer & Ulrich S. Zimmermann

  5. Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany

    Nadine Bernhardt, Stephan Nebe & Michael N. Smolka

  6. Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    Sören Kuitunen-Paul & Hans-Ulrich Wittchen

  7. Department of Psychiatry and Psychotherapy, Vivantes Wenckebach-Klinikum, Berlin, Germany

    Uta Eichmann

  8. Max Planck Fellow Group ‘Cognitive and Affective Control of Behavioral Adaptation’, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

    Florian Schlagenhauf

  9. Translational Neuromodeling Unit, Department of Biomedical Engineering, ETH Zürich and University of Zürich, Zurich, Switzerland

    Quentin J. M. Huys

  10. Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland

    Quentin J. M. Huys

  11. Berlin Institute of Health (BIH), Berlin, Germany

    Eva Friedel

  12. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nußbaumstraße 7, 80336, München, Germany

    Hans-Ulrich Wittchen

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  1. Daniel J. Schad
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Contributions

AB, AH, MAR, MNS, QJMH, USZ were responsible for the study concept and design. CS, DJS, HW, MG, MS, NB, PS and QJMH implemented and piloted the PIT (behavioral and fMRI) paradigm. AH, CH, CS, EF, MG, MS, UE, and USZ recruited alcohol-dependent patients and assessed the follow-up data. HUW and SKP were responsible for the assessment of questionnaires. SN set up a preprocessing pipeline for the imaging data. DJS, EF, FS and MG performed the first- and second-level analyses on fMRI data. DJS and MG performed further statistical analyses with support of AH, MAR and QJMH. AH, DJS, EF, FS, MG and MS drafted the manuscript. CS, HUW, HW, MAR, MNS, NB, PS, QJMH, SKP, SL, SN and USZ provided critical revision of the manuscript for important intellectual content. All the authors critically reviewed content and approved the final version for publication.

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Correspondence to Michael A. Rapp.

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Schad, D.J., Garbusow, M., Friedel, E. et al. Neural correlates of instrumental responding in the context of alcohol-related cues index disorder severity and relapse risk. Eur Arch Psychiatry Clin Neurosci 269, 295–308 (2019). https://doi.org/10.1007/s00406-017-0860-4

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