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Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats

Molecular Psychiatry volume 25, pages 896–905 (2020)Cite this article

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Abstract

Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.

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References

  1. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet (Lond, Engl). 2016;388:86–97.

    Article  Google Scholar 

  2. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry : Off J World Fed Soc Biol Psychiatry. 2012;13:318–78.

    Article  Google Scholar 

  3. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005;10:434–49.

    Article  CAS  Google Scholar 

  4. Heinssen RK, Insel TR. Preventing the onset of psychosis: not quite there yet. Schizophr Bull. 2015;41:28–9.

    Article  Google Scholar 

  5. Hadar R, Bikovski L, Soto-Montenegro ML, Schimke J, Maier P, Ewing S, et al. Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia. Mol Psychiatry. 2017;23:943–51.

  6. Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal, et al. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008;1:206–23.

    Article  Google Scholar 

  7. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron. 2010;66:198–204.

    Article  CAS  Google Scholar 

  8. Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001;57:1899–901.

    Article  CAS  Google Scholar 

  9. Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003;553(Pt 1):293–301.

    Article  CAS  Google Scholar 

  10. Hadar R, Soto-Montenegro ML, Gotz T, Wieske F, Sohr R, Desco M, et al. Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course. Schizophr Res. 2015;166:238–47.

    Article  Google Scholar 

  11. Zuckerman L, Weiner I. Post-pubertal emergence of disrupted latent inhibition following prenatal immune activation. Psychopharmacol (Berl). 2003;169:308–13.

    Article  CAS  Google Scholar 

  12. Gellner AK, Reis J, Fritsch B. Glia: A neglected player in non-invasive direct current brain stimulation. Front Cell Neurosci. 2016;10:188.

    Article  Google Scholar 

  13. Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of transcranial direct current stimulation: Evidence based update 2016. Brain Stimul. 2016;9:641–61.

    Article  Google Scholar 

  14. Song W, Truong DQ, Bikson M, Martin JH. Transspinal direct current stimulation immediately modifies motor cortex sensorimotor maps. J Neurophysiol. 2015;113:2801–11.

    Article  Google Scholar 

  15. Bikson M, Truong DQ, Mourdoukoutas AP, Aboseria M, Khadka N, Adair D, et al. Modeling sequence and quasi-uniform assumption in computational neurostimulation. Prog Brain Res. 2015;222:1–23.

    Article  Google Scholar 

  16. Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL. Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacol (Berl). 2008;199:331–88.

    Article  CAS  Google Scholar 

  17. Klein J, Hadar R, Gotz T, Manner A, Eberhardt C, Baldassarri J, et al. Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia. Brain Stimul. 2013;6:490–9.

    Article  Google Scholar 

  18. Mattei D, Djodari-Irani A, Hadar R, Pelz A, de Cossio LF, Goetz T, et al. Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun. 2014;38:175–84.

    Article  CAS  Google Scholar 

  19. Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res. 2005;39:311–23.

    Article  Google Scholar 

  20. Rea E, Rummel J, Schmidt TT, Hadar R, Heinz A, Mathe AA, et al. Anti-anhedonic effect of deep brain stimulation of the prefrontal cortex and the dopaminergic reward system in a genetic rat model of depression: an intracranial self-stimulation paradigm study. Brain Stimul. 2014;7:21–8.

    Article  Google Scholar 

  21. Edemann-Callesen H, Voget M, Empl L, Vogel M, Wieske F, Rummel J, et al. Medial forebrain bundle deep brain stimulation has symptom-specific anti-depressant effects in rats and as opposed to ventromedial prefrontal cortex stimulation interacts with the reward system. Brain Stimul. 2015;8:714–23.

    Article  Google Scholar 

  22. Schneider P, Bindila L, Schmahl C, Bohus M, Meyer-Lindenberg A, Lutz B, et al. Adverse social experiences in adolescent rats result in enduring effects on social competence, pain sensitivity and endocannabinoid signaling. Front Behav Neurosci. 2016;10:203.

    Article  Google Scholar 

  23. Paxinos G, Watson C, The rat brain in stereotaxic coordinates: hard cover edition. Elsevier Science; 2013.

  24. Hadar R, Edemann-Callesen H, Reinel C, Wieske F, Voget M, Popova E, et al. Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders. Sci Rep. 2016;6:39145.

    Article  CAS  Google Scholar 

  25. van den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull. 2010;36:246–70.

    Article  Google Scholar 

  26. Jaaro-Peled H, Ayhan Y, Pletnikov MV, Sawa A. Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophr Bull. 2010;36:301–13.

    Article  Google Scholar 

  27. Barnes SA, Der-Avakian A, Markou A. Anhedonia, avolition, and anticipatory deficits: assessments in animals with relevance to the negative symptoms of schizophrenia. Eur Neuropsychopharmacol : J Eur Coll Neuropsychopharmacol. 2014;24:744–58.

    Article  CAS  Google Scholar 

  28. Piontkewitz Y, Bernstein HG, Dobrowolny H, Bogerts B, Weiner I, Keilhoff G. Effects of risperidone treatment in adolescence on hippocampal neurogenesis, parvalbumin expression, and vascularization following prenatal immune activation in rats. Brain Behav Immun. 2012;26:353–63.

    Article  CAS  Google Scholar 

  29. Meyer U. Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2014;75:307–15.

    Article  CAS  Google Scholar 

  30. Piontkewitz Y, Arad M, Weiner I. Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat. Biol Psychiatry. 2011;70:842–51.

    Article  Google Scholar 

  31. Piontkewitz Y, Arad M, Weiner I. Risperidone administered during asymptomatic period of adolescence prevents the emergence of brain structural pathology and behavioral abnormalities in an animal model of schizophrenia. Schizophr Bull. 2011;37:1257–69.

    Article  Google Scholar 

  32. Steullet P, Cabungcal JH, Coyle J, Didriksen M, Gill K, Grace AA, et al. Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry. 2017;22:936–43.

    Article  CAS  Google Scholar 

  33. Harvey PD, Koren D, Reichenberg A, Bowie CR. Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophr Bull. 2006;32:250–8.

    Article  Google Scholar 

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Acknowledgements

We thank Renate Winter and Doris Zschaber for excellent technical assistance and Susanne Müller for profound support on MRI studies.

Funding

This research was supported by the BMBF, Germany (01EE1403A+C (GCBS), 01EW1409 (EraNet Neuron, RD_aDBS). FW, BH, EBH were/are financed by the DFG, Germany (WI 2140/1-1/2; WI 2140/3-1).

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany

    Ravit Hadar, Henriette Edemann-Callesen, Franziska Wieske, Bettina Habelt, Elizabeth Barroeta-Hlusicka, Cristian Alexandru Tatarau & Christine Winter

  2. Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Ravit Hadar, Rebecca Winter, Henriette Edemann-Callesen, Bettina Habelt, Viktoria Felgel-Farnholz, Elizabeth Barroeta-Hlusicka, Nadine Bernhardt & Christine Winter

  3. International Graduate Program Medical Neurosciences, Charité Universitätsmedizin Berlin, Berlin, Germany

    Henriette Edemann-Callesen

  4. Department of Biomedical Engineering, The City College of New York, CUNY, New York, NY, 10031, USA

    Niranjan Khadka & Marom Bikson

  5. Department of Neurology, University Medical Center, Albert Ludwigs University Freiburg, Freiburg, Germany

    Janine Reis & Brita Fritsch

  6. Department of Neurophysiology, Medical School of the Ruhr-Universität Bochum, Bochum, Germany

    Klaus Funke

  7. Department Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany

    Michael A. Nitsche

  8. Department Neurology, University Hospital Bergmannsheil, Ruhr-Universität Bochum, Bochum, Germany

    Michael A. Nitsche

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  1. Ravit Hadar
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  2. Rebecca Winter
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Correspondence to Christine Winter.

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Hadar, R., Winter, R., Edemann-Callesen, H. et al. Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats. Mol Psychiatry 25, 896–905 (2020). https://doi.org/10.1038/s41380-019-0356-x

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