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Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia

Molecular Psychiatry volume 22, pages 857–864 (2017)Cite this article

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Abstract

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽−0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

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Acknowledgements

The RESIS trial was supported by the Deutsche Forschungsgemeinschaft Grant No. FA–210/1.

Trial Registration: http://clinicaltrials.gov/; NCT00783120.

Author information

Author notes

  1. A Hasan and T Wobrock: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany

    A Hasan, B Malchow, M F U Castro, D Dwyer, C Cabral, T Schneider-Axmann, P Falkai & N Koutsouleris

  2. Department of Psychiatry and Psychotherapy, Georg-August-University Göttingen, Göttingen, Germany

    T Wobrock & B Guse

  3. Department of Psychiatry and Psychotherapy, County Hospitals Darmstadt-Dieburg, Groß-Umstadt, Germany

    T Wobrock

  4. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

    B Langguth, M Landgrebe, P Eichhammer, E Frank, P M Kreuzer & T B Poeppl

  5. Department of Psychiatry, Psychosomatics and Psychotherapy, kbo-Lech-Mangfall-Klinik Agatharied, Agatharied, Germany

    M Landgrebe

  6. Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany

    J Cordes, W Wölwer, F Musso & W Gaebel

  7. Experimental and Clinical Research Centre, The Charité – Universitätsmedizin Berlin, Berlin, Germany

    G Winterer

  8. Department of Psychiatry, Psychosomatics and Psychotherapy, Sozialstiftung Bamberg, Bamberg, Germany

    G Hajak

  9. European Clinical Research Network, Düsseldorf, Germany

    C Ohmann

  10. Coordination Centre for Clinical Trials, Heinrich-Heine University, Düsseldorf, Germany

    P E Verde

  11. Department of Genetic Epidemiology in Psychiatry, Institute of Central Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    M Rietschel

  12. Institut für anwendungsorientierte Forschung und klinische Studien GmbH, Göttingen, Germany

    R Ahmed

  13. Department of Genetic Epidemiology in Psychiatry, Institute of Mental Health, The University of British Columbia, Vancouver, BC, Canada

    W G Honer

  14. Department of Cognitive Neurology, Georg-August-University Goettingen, Goettingen, Germany

    P Dechent

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Competing interests

AH has been invited to scientific meetings by Lundbeck, Janssen-Cilag and Pfizer, and he received a paid speakership from Desitin, Otsuka and Lundbeck. He was member of a advisory board of Roche. TW has received paid speakerships from Alpine Biomed, AstraZeneca, Bristol–Myers–Squibb, Eli Lilly, I3G, Janssen-Cilag, Novartis, Lundbeck, Roche, Sanofi-Aventis, Otsuka and Pfizer, and has accepted travel or hospitality not related to a speaking engagement from AstraZeneca, Bristol–Myers–Squibb, Eli Lilly, Janssen-Cilag and Sanofi-Synthelabo, and has received restricted research grants from AstraZeneca, Cerbomed, I3G and AOK (health insurance company). JC was a member of an advisory board of Roche, accepted travel or hospitality not related to a speaking engagement from Servier, support for symposia from Inomed, Localite, Magventure, Roche, Mag & More, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel and Diamedic. WW has received paid speakerships from Bristol–Myers–Squibb, Essex Pharma, Janssen-Cilag, Lilly Deutschland and Pfizer Neuroscience. He is a member of the Neuroscience Academy of Roche Pharma. WG has received symposia support from Janssen-Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg and Servier, Munich. He is a member of the Faculty of the Lundbeck International Neuroscience Foundation (LINF), Denmark. BL received honoraria and speakers’ fees from ANM, AstraZeneca, Autifony, Lundbeck, Merz, Magventure, Novartis, Pfizer and Servier, research funding from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium für Bildung und Forschung, the American Tinnitus Association, AstraZeneca and Cerbomed, funding for equipment from Magventure and Deymed and travel and accommodation payments from Lilly, Lundbeck, Servier and Pfizer. GH has received payments as speaker, consultant, author or for research funding during the last 5 years from Actelion, Affectis, AstraZeneca, Bayerische Motorenwerke, Bundesministerium für Bildung und Forschung, Bundesministerium für Strahlenschutz, Bristol-Meyers Squibb, Cephalon, Daimler Benz, Deutsche Forschungsgesellschaft, Elsevier, EuMeCom, Essex, Georg Thieme, Gerson Lerman Group Council of Healthcare Advisors, GlaxoSmithKline, Janssen-Cilag, Lilly, Lundbeck, Meda, Merck, Merz, Novartis, Pfizer, Proctor & Gamble, Sanofi-Aventis, Schering-Plough, Sepracor, Servier, Springer, Urban & Fischer and Volkswagen. WGH is an unpaid member of the Advisory Board of In Silico Biosciences, and a paid consultant to Otsuka/Lundbeck, Roche, Novartis, Eli Lilly, MDH Consulting and the Canadian Agency on Drugs and Technology in Health. PF was honorary speaker for Janssen-Cilag, AstraZeneca, Eli Lilly, Bristol–Myers–Squibb, Lundbeck, Pfizer, Bayer Vital, SmithKline Beecham, Wyeth and Essex. During the last 5 years, but not presently, he was a member of the advisory boards of Janssen-Cilag, AstraZeneca, Eli Lilly and Lundbeck. NK received paid speakership from Otsuka. The remaining authors declare no conflict of interest.

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Hasan, A., Wobrock, T., Guse, B. et al. Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia. Mol Psychiatry 22, 857–864 (2017). https://doi.org/10.1038/mp.2016.161

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