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TMS in Schizophrenia: Potential Mechanistic Insights via Resting-State Network Analyses

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Abstract

Purpose of review

This review uses a dysconnectivity-based lens for understanding schizophrenia pathophysiology. From this vantage recent studies on the clinical utility of transcranial magnetic stimulation in schizophrenia are consolidated, with particular attention to studies reporting resting-state network functional connectivity (FC) changes after treatment.

Recent findings

In schizophrenia, functional connectivity is predominantly decreased across brain regions and functional networks. Specific networks implicated in symptomatology include the default mode network and central executive network. TMS modalities which increase functional connectivity, particularly when targeting the dorsolateral PFC, have shown relative efficacy in treating negative symptoms of schizophrenia. However, post-treatment changes in specific network connectivity vary by study design and by degree of concordance with symptom improvement.

Summary

Generally, increased functional connectivity between brain networks seems to confer some benefit of TMS in schizophrenia, particularly for negative symptoms. Among studies conducted thus far, there has been substantial variation in both target selection and observed post-treatment connectivity changes. While there is convincing evidence for pathological DMN-CEN connectivity in the disease process of schizophrenia, as well as evidence that dlPFC-targeted TMS modulates the DMN-CEN in depression, restoration of this particular network aberrancy by TMS in schizophrenia has not been observed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-an overview. JAMA Psychiatry. 2020;77(2):201–10.

    Article  PubMed  Google Scholar 

  2. Kendler KS, Schaffner KF. The dopamine hypothesis of schizophrenia: an historical and philosophical analysis. Philos Psychiatry Psychol. 2011;18(1):41–63.

    Article  Google Scholar 

  3. Sato M, Chen CC, Akiyama K, Otsuki S. Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatry. 1983;18(4):429–40.

    CAS  PubMed  Google Scholar 

  4. Serper MR, Chou JC, Allen MH, Czobor P, Cancro R. Symptomatic overlap of cocaine intoxication and acute schizophrenia at emergency presentation. Schizophr Bull. 1999;25(2):387–94.

    Article  CAS  PubMed  Google Scholar 

  5. Kalkman HO. Antischizophrenic activity independent of dopamine D2 blockade. Expert Opin Ther Targets. 2002;6(5):571–82.

    Article  CAS  PubMed  Google Scholar 

  6. Mackowick KM, Barr MS, Wing VC, Rabin RA, Ouellet-Plamondon C, George TP. Neurocognitive endophenotypes in schizophrenia: modulation by nicotinic receptor systems. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;52:79–85.

    Article  CAS  Google Scholar 

  7. Li P, Snyder GL, Vanover KE. Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem. 2016;16(29):3385–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. de Araujo AN, de Sena EP, de Oliveira IR, Juruena MF. Antipsychotic agents: efficacy and safety in schizophrenia. Drug Healthc Patient Saf. 2012;4:173–80.

    PubMed  PubMed Central  Google Scholar 

  9. Weston-Green K. Antipsychotic drug development: from historical evidence to fresh perspectives. Front Psych. 2022;13:903156.

    Article  Google Scholar 

  10. Kraepelin E, Barclay RM, Robertson GM. Dementia præcox and paraphrenia. Edinburgh: E. & S. Livingstone; 1919. p. 331.

    Google Scholar 

  11. Silverstein ML, Harrow M. Schneiderian first-rank symptoms in schizophrenia. Arch Gen Psychiatry. 1981;38(3):288–93.

    Article  CAS  PubMed  Google Scholar 

  12. Sass LA, Parnas J. Schizophrenia, consciousness, and the self. Schizophr Bull. 2003;29(3):427–44.

    Article  PubMed  Google Scholar 

  13. Weinberger DR, Wagner RL, Wyatt RJ. Neuropathological studies of schizophrenia: a selective review. Schizophr Bull. 1983;9(2):193–212.

    Article  CAS  PubMed  Google Scholar 

  14. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122(Pt 4):593–624.

    Article  PubMed  Google Scholar 

  15. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc. Natl. Acad. Sci. U. S. A. 2003;100(1):253–8.

    Article  CAS  PubMed  Google Scholar 

  16. Andrews-Hanna JR, Smallwood J, Spreng RN. The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann. N. Y Acad Sci. 2014;1316(1):29–52.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mohr HM, Goebel R, Linden DE. Content- and task-specific dissociations of frontal activity during maintenance and manipulation in visual working memory. J. Neurosci. 2006;26(17):4465–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Collette F, Van der Linden M. Brain imaging of the central executive component of working memory. Neurosci Biobehav Rev. 2002;26(2):105–25.

    Article  PubMed  Google Scholar 

  19. Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci U. S A. 2008;105(34):12569–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Whitfield-Gabrieli S, et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U. S. A. 2009;106(4):1279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chai XJ, et al. Abnormal medial prefrontal cortex resting-state connectivity in bipolar disorder and schizophrenia. Neuropsychopharmacology. 2011;36(10):2009–17.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Whitfield-Gabrieli S, et al. Understanding marijuana’s effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: a pilot investigation. Schizophr Res. 2018;194:70–7.

    Article  PubMed  Google Scholar 

  23. Hermiller MS, VanHaerents S, Raij T, Voss JL. Frequency-specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity. Hippocampus. 2019;29(7):595–609.

    PubMed  Google Scholar 

  24. Eshel N, et al. Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation. Neuropsychopharmacology. 2020;45(6):1018–25.

    Article  PubMed  PubMed Central  Google Scholar 

  25. • Tseng PT, et al. Assessment of noninvasive brain stimulation interventions for negative symptoms of schizophrenia: a systematic review and network meta-analysis. JAMA Psychiat. 79(8):770–9. This is a rigorous meta-analysis of neuromodulation trials for schizophrenia, reflecting the current state of the field. Evidence of efficacy to date is strongest for reduction in negative symptoms, with particular successes when interventions target the left dlPFC with excitatory stimulation.

  26. Chopra S, et al. Functional connectivity in antipsychotic-treated and antipsychotic-naive patients with first-episode psychosis and low risk of self-harm or aggression: a secondary analysis of a randomized clinical trial. JAMA Psychiat. 2021;78(9):994–1004.

    Article  Google Scholar 

  27. Chen C, et al. Aberrant functional connectivity of the orbitofrontal cortex is associated with excited symptoms in first-episode drug-naive patients with schizophrenia. Front Psych. 2022;13:922272.

    Article  Google Scholar 

  28. Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry. 2007;164(3):450–7.

    Article  PubMed  Google Scholar 

  29. Mannell MV, Franco AR, Calhoun VD, Canive JM, Thoma RJ, Mayer AR. Resting state and task-induced deactivation: a methodological comparison in patients with schizophrenia and healthy controls. Hum Brain Mapp. 2010;31(3):424–37.

    PubMed  Google Scholar 

  30. Salgado-Pineda P, Fakra E, Delaveau P, McKenna PJ, Pomarol-Clotet E, Blin O. Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients. Schizophr Res. 2011;125(2-3):101–9.

    Article  CAS  PubMed  Google Scholar 

  31. Haatveit B, et al. Reduced load-dependent default mode network deactivation across executive tasks in schizophrenia spectrum disorders. Neuroimage Clin. 2016;12:389–96.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bolton TAW, et al. Triple network model dynamically revisited: lower salience network state switching in pre-psychosis. Front Physiol. 2020;11:66.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Carhart-Harris RL, et al. Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr Bull. 2013;39(6):1343–51.

    Article  PubMed  Google Scholar 

  34. McNabb CB, et al. Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia. Schizophr Res. 2018;195:160–7.

    Article  PubMed  Google Scholar 

  35. Nawaz U, Lee I, Beermann A, Eack S, Keshavan M, Brady R. Individual variation in functional brain network topography is linked to schizophrenia symptomatology. Schizophr Bull. 2021;47(1):180–8.

    Article  PubMed  Google Scholar 

  36. Abualait T, et al. Assessment of cortical plasticity in schizophrenia by transcranial magnetic stimulation. Neural Plast. 2021;2021:5585951.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Baliga SP, Mehta UM. A review of studies leveraging multimodal TMS-fMRI applications in the pathophysiology and treatment of schizophrenia. Front Hum Neurosci. 2021;15:662976.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Jannati A, Oberman LM, Rotenberg A, Pascual-Leone A. Assessing the mechanisms of brain plasticity by transcranial magnetic stimulation. Neuropsychopharmacology. 2023;48(1):191–208.

    Article  PubMed  Google Scholar 

  39. Liston C, et al. Default mode network mechanisms of transcranial magnetic stimulation in depression. Biol Psychiat. 2014;76(7):517–26.

    Article  PubMed  Google Scholar 

  40. Brady RO Jr, et al. Cerebellar-prefrontal network connectivity and negative symptoms in schizophrenia. Am J Psychiat. 2019;176(7):512–20.

    Article  PubMed  Google Scholar 

  41. Bation R, Magnin C, Poulet E, Mondino M, Brunelin J. Intermittent theta burst stimulation for negative symptoms of schizophrenia-A double-blind, sham-controlled pilot study. NPJ Schizophr. 2021;7(1):10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Basavaraju R, et al. Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: a randomized controlled trial. Schizophr Res. 2021;238:108–20.

    Article  PubMed  PubMed Central  Google Scholar 

  43. • Xie Y, et al. Impact of low-frequency repetitive transcranial magnetic stimulation on functional network connectivity in schizophrenia patients with auditory verbal hallucinations. Psychiatry Res. :320, 114974. This study revealed changes in brain network functional connectivity after TMS treatment in schizophrenia, including a specific increase between the Central Executive Network and Auditory network which corresponded to decreased severity of auditory hallucinations.

  44. Lorentzen R, Nguyen TD, McGirr A, Hieronymus F, Ostergaard SD. The efficacy of transcranial magnetic stimulation (TMS) for negative symptoms in schizophrenia: a systematic review and meta-analysis. Schizophrenia (Heidelb). 2022;8(1):35.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Marzouk T, Winkelbeiner S, Azizi H, Malhotra AK, Homan P. Transcranial magnetic stimulation for positive symptoms in schizophrenia: a systematic review. Neuropsychobiology. 2020;79(6):384–96.

    Article  PubMed  Google Scholar 

  46. Cash RFH, Cocchi L, Lv J, Wu Y, Fitzgerald PB, Zalesky A. Personalized connectivity-guided DLPFC-TMS for depression: advancing computational feasibility, precision and reproducibility. Hum Brain Mapp. 2021;42(13):4155–72.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

Funding support was provided by the University of Maryland/Sheppard Pratt Residency Physician Scientist Training Program (PSTP).

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Correspondence to Andrew van der Vaart.

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van der Vaart, A. TMS in Schizophrenia: Potential Mechanistic Insights via Resting-State Network Analyses. Curr Behav Neurosci Rep 10, 58–63 (2023). https://doi.org/10.1007/s40473-023-00260-9

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