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Cerebellar Theta Frequency Transcranial Pulsed Stimulation Increases Frontal Theta Oscillations in Patients with Schizophrenia

  • Arun Singh
  • Nicholas T. Trapp
  • Benjamin De Corte
  • Scarlett Cao
  • Johnathon Kingyon
  • Aaron D. Boes
  • Krystal L. ParkerEmail author
Original Paper

Abstract

Cognitive dysfunction is a pervasive and disabling aspect of schizophrenia without adequate treatments. A recognized correlate to cognitive dysfunction in schizophrenia is attenuated frontal theta oscillations. Neuromodulation to normalize these frontal rhythms represents a potential novel therapeutic strategy. Here, we evaluate whether noninvasive neuromodulation of the cerebellum in patients with schizophrenia can enhance frontal theta oscillations, with the future goal of targeting the cerebellum as a possible therapy for cognitive dysfunction in schizophrenia. We stimulated the midline cerebellum using transcranial pulsed current stimulation (tPCS), a noninvasive transcranial direct current that can be delivered in a frequency-specific manner. A single 20-min session of theta frequency stimulation was delivered in nine patients with schizophrenia (cathode on right shoulder). Delta frequency tPCS was also delivered as a control to evaluate for frequency-specific effects. EEG signals from midfrontal electrode Cz were analyzed before and after cerebellar tPCS while patients estimated the passage of 3- and 12-s intervals. Theta oscillations were significantly larger following theta frequency cerebellar tPCS in the midfrontal region, which was not seen with delta frequency stimulation. As previously reported, patients with schizophrenia showed a baseline reduction in accuracy estimating 3- and 12-s intervals relative to control subjects, which did not significantly improve following a single-session theta or delta frequency cerebellar tPCS. These preliminary results suggest that single-session theta frequency cerebellar tPCS may modulate task-related oscillatory activity in the frontal cortex in a frequency-specific manner. These preliminary findings warrant further investigation to evaluate whether multiple sessions delivered daily may have an impact on cognitive performance and have therapeutic implications for schizophrenia.

Keywords

Cerebellum Neuromodulation Noninvasive stimulation Cognitive task Schizophrenia 

Notes

Author Contributions

K.L.P. designed the research; K.L.P. and S.C acquired data; K.L.P., A.S., B.D., and J.K. analyzed data; K.L.P., N.T.T., A.D.B., B.D., and A.S. wrote the manuscript; and all authors provided feedback.

Funding Information

K.L.P has received generous funding to complete this research from the Brain & Behavior Foundation Young Investigator NARSAD Award, The Nellie Ball Research Trust, and NIMH K01 MH106824, the University of Iowa Department of Psychiatry, and the Iowa Neuroscience Institute.

Compliance with Ethical Standards

Written informed consent was obtained from every subject and all research protocols were approved by the University of Iowa Human Subjects Review Board.

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76.  https://doi.org/10.1093/epirev/mxn001.CrossRefPubMedGoogle Scholar
  2. 2.
    Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24:203–18.CrossRefPubMedGoogle Scholar
  3. 3.
    Carroll CA, O’Donnell BF, Shekhar A, Hetrick WP. Timing dysfunctions in schizophrenia span from millisecond to several-second durations. Brain Cogn. 2009;70:181–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Green MF, Harvey PD. Cognition in schizophrenia: past, present, and future. Schizophr Res Cogn. 2014;1:e1–9.  https://doi.org/10.1016/j.scog.2014.02.001.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ho BC, Nopoulos P, Flaum M, Arndt S, Andreasen NC. Two-year outcome in first-episode schizophrenia: predictive value of symptoms for quality of life. Am J Psychiatry. 1998;155:1196–201.CrossRefPubMedGoogle Scholar
  6. 6.
    Ward RD, Kellendonk C, Kandel ER, Balsam PD. Timing as a window on cognition in schizophrenia. Neuropharmacology. 2011;62:1175–81.  https://doi.org/10.1016/j.neuropharm.2011.04.014.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, et al. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet. 1997;349:1730–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M, Cohen JD. Functional hypofrontality and working memory dysfunction in schizophrenia. 2014. Available at: http://ajp.psychiatryonline.org/doi/10.1176/ajp.155.9.1285 [Accessed March 27, 2015].
  9. 9.
    Parker KL, Kim Y, Kelley RM, Nessler AJ, Chen K-H, Muller-Ewald VA, et al. Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction. Mol Psychiatry. 2017;22:647–55.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia. Biol Psychiatry. 2008;64:81–8.  https://doi.org/10.1016/j.biopsych.2008.01.003.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Repovs G, Csernansky JG, Barch DM. Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry. 2011;69:967–73.  https://doi.org/10.1016/j.biopsych.2010.11.009.CrossRefPubMedGoogle Scholar
  12. 12.
    Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci. 2002;22:3708–19.CrossRefPubMedGoogle Scholar
  13. 13.
    Koziol LF, Budding D, Andreasen N, D’Arrigo S, Bulgheroni S, Imamizu H, et al. Consensus paper: the cerebellum’s role in movement and cognition. Cerebellum. 2013.  https://doi.org/10.1007/s12311-013-0511-x.
  14. 14.
    Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp. 1996;4:174–98.  https://doi.org/10.1002/(SICI)1097-0193(1996)4:3<174::AID-HBM3>3.0.CO;2-0.CrossRefPubMedGoogle Scholar
  15. 15.
    Schmahmann JD. Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci (Regul Ed). 1998;2:362–71.CrossRefGoogle Scholar
  16. 16.
    Schutter DJLG, van Honk J. An electrophysiological link between the cerebellum, cognition and emotion: frontal theta EEG activity to single-pulse cerebellar TMS. Neuroimage. 2006;33:1227–31.  https://doi.org/10.1016/j.neuroimage.2006.06.055.CrossRefPubMedGoogle Scholar
  17. 17.
    Stoodley CJ. The cerebellum and cognition: evidence from functional imaging studies. Cerebellum. 2011;11:352–65.  https://doi.org/10.1007/s12311-011-0260-7.CrossRefGoogle Scholar
  18. 18.
    Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.  https://doi.org/10.1146/annurev.neuro.31.060407.125606.CrossRefPubMedGoogle Scholar
  19. 19.
    Jurjus GJ, Weiss KM, Jaskiw GE. Schizophrenia-like psychosis and cerebellar degeneration. Schizophr Res. 1994;12:183–4.  https://doi.org/10.1016/0920-9964(94)90076-0.CrossRefPubMedGoogle Scholar
  20. 20.
    Nopoulos PC, Ceilley JW, Gailis EA, Andreasen NC. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry. 1999;46:703–11.CrossRefPubMedGoogle Scholar
  21. 21.
    Sandyk R. Psychotic behavior associated with cerebellar pathology. Int J Neurosci. 1993;71:1–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Tavano A, Grasso R, Gagliardi C, Triulzi F, Bresolin N, Fabbro F, et al. Disorders of cognitive and affective development in cerebellar malformations. Brain. 2007;130:2646–60.  https://doi.org/10.1093/brain/awm201.CrossRefPubMedGoogle Scholar
  23. 23.
    Andreasen NC, O’Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, et al. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci U S A. 1996;93:9985–90.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rüsch N, Spoletini I, Wilke M, Bria P, Di Paola M, Di Iulio F, et al. Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007;93:79–89.  https://doi.org/10.1016/j.schres.2007.01.029.CrossRefPubMedGoogle Scholar
  25. 25.
    Middleton FA, Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Rev. 2000;31:236–50.  https://doi.org/10.1016/S0165-0173(99)00040-5.CrossRefPubMedGoogle Scholar
  26. 26.
    Ferrucci R, Cortese F, Bianchi M, Pittera D, Turrone R, Bocci T, et al. Cerebellar and motor cortical transcranial stimulation decrease levodopa-induced dyskinesias in Parkinson’s disease. Cerebellum. 2016;15:43–7.  https://doi.org/10.1007/s12311-015-0737-x.CrossRefPubMedGoogle Scholar
  27. 27.
    Grimaldi G, Argyropoulos GP, Boehringer A, Celnik P, Edwards MJ, Ferrucci R, et al. Non-invasive cerebellar stimulation-a consensus paper. Cerebellum. 2014;13:121–38.  https://doi.org/10.1007/s12311-013-0514-7.CrossRefPubMedGoogle Scholar
  28. 28.
    Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A, Feredoes E, et al. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res. 2005;166:23–30.  https://doi.org/10.1007/s00221-005-2334-6.CrossRefPubMedGoogle Scholar
  29. 29.
    Jo JM, Kim Y-H, Ko M-H, Ohn SH, Joen B, Lee KH. Enhancing the working memory of stroke patients using tDCS. Am J Phys Med Rehabil. 2009;88:404–9.  https://doi.org/10.1097/PHM.0b013e3181a0e4cb.CrossRefPubMedGoogle Scholar
  30. 30.
    Ferrucci R, Marceglia S, Vergari M, Cogiamanian F, Mrakic-Sposta S, Mameli F, et al. Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory. J Cogn Neurosci. 2008;20:1687–97.  https://doi.org/10.1162/jocn.2008.20112.CrossRefPubMedGoogle Scholar
  31. 31.
    Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, et al. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010;124:91–100.  https://doi.org/10.1016/j.schres.2010.08.015.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Garg S, Sinha VK, Tikka SK, Mishra P, Goyal N. The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: a randomized rater blind-sham controlled study. Psychiatry Res. 2016;243:413–20.  https://doi.org/10.1016/j.psychres.2016.07.023.CrossRefPubMedGoogle Scholar
  33. 33.
    Vasquez A, Malavera A, Doruk D, Morales-Quezada L, Carvalho S, Leite J, et al. Duration dependent effects of transcranial pulsed current stimulation (tPCS) indexed by electroencephalography. Neuromodulation. 2016;19:679–88.  https://doi.org/10.1111/ner.12457.CrossRefPubMedGoogle Scholar
  34. 34.
    Ivry RB, Spencer RM. The neural representation of time. Curr Opin Neurobiol. 2004;14:225–32.  https://doi.org/10.1016/j.conb.2004.03.013.CrossRefPubMedGoogle Scholar
  35. 35.
    Parker KL, Chen K-H, Kingyon JR, Cavanagh JF, Naryanan NS. Medial frontal ~4 Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion. J Neurophysiol. 2015.  https://doi.org/10.1152/jn.00412.2015.
  36. 36.
    Rakitin BC, Gibbon J, Penney TB, Malapani C, Hinton SC, Meck WH. Scalar expectancy theory and peak-interval timing in humans. J Exp Psychol Anim Behav Process. 1998;24:15–33.CrossRefPubMedGoogle Scholar
  37. 37.
    Gibbon J, Church RM, Meck WH. Scalar timing in memory. Ann N Y Acad Sci. 1984;423:52–77.CrossRefPubMedGoogle Scholar
  38. 38.
    Buhusi CV, Meck WH. What makes us tick? Functional and neural mechanisms of interval timing. Nat Rev Neurosci. 2005;6:755–65.  https://doi.org/10.1038/nrn1764.CrossRefPubMedGoogle Scholar
  39. 39.
    Parker KL, Chen K-H, Kingyon JR, Cavanagh JF, Narayanan NS. D1-dependent 4 Hz oscillations and ramping activity in rodent medial frontal cortex during interval timing. J Neurosci. 2014;34:16774–83.  https://doi.org/10.1523/JNEUROSCI.2772-14.2014.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gülekon IN, Turgut HB. The external occipital protuberance: can it be used as a criterion in the determination of sex? J Forensic Sci. 2003;48:513–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Bocci T, Santarcangelo E, Vannini B, Torzini A, Carli G, Ferrucci R, et al. Cerebellar direct current stimulation modulates pain perception in humans. Restor Neurol Neurosci. 2015;33:597–609.  https://doi.org/10.3233/RNN-140453.PubMedGoogle Scholar
  42. 42.
    Bocci T, Ferrucci R, Barloscio D, Parenti L, Cortese F, Priori A, et al. Cerebellar direct current stimulation modulates hand blink reflex: implications for defensive behavior in humans. Phys Rep. 2018;6.  https://doi.org/10.14814/phy2.13471.
  43. 43.
    Ferrucci R, Giannicola G, Rosa M, Fumagalli M, Boggio PS, Hallett M, et al. Cerebellum and processing of negative facial emotions: cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness. Cognit Emot. 2012;26:786–99.  https://doi.org/10.1080/02699931.2011.619520.CrossRefGoogle Scholar
  44. 44.
    Ferrucci R, Brunoni AR, Parazzini M, Vergari M, Rossi E, Fumagalli M, et al. Modulating human procedural learning by cerebellar transcranial direct current stimulation. Cerebellum. 2013;12:485–92.  https://doi.org/10.1007/s12311-012-0436-9.CrossRefPubMedGoogle Scholar
  45. 45.
    van Driel J, Sligte IG, Linders J, Elport D, Cohen MX. Frequency band-specific electrical brain stimulation modulates cognitive control processes. PLoS One. 2015;10:e0138984.  https://doi.org/10.1371/journal.pone.0138984.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cohen MX. Analyzing neural time series data: theory and practice (issues in clinical and cognitive neuropsychology). The MIT Press; 2014.Google Scholar
  47. 47.
    Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9–21.  https://doi.org/10.1016/j.jneumeth.2003.10.009.CrossRefPubMedGoogle Scholar
  48. 48.
    Cavanagh JF, Frank MJ. Frontal theta as a mechanism for cognitive control. Trends Cogn Sci. 2014;18(8):414-2.Google Scholar
  49. 49.
    Singh A, Richardson SP, Narayanan N, Cavanagh JF Mid-frontal theta activity is diminished during cognitive control in Parkinson's disease. Neuropsychologia. 2018;117:113-122.Google Scholar
  50. 50.
    Malapani C, Deweer B, Gibbon J. Separating storage from retrieval dysfunction of temporal memory in Parkinson’s disease. J Cogn Neurosci. 2002;14:311–22.  https://doi.org/10.1162/089892902317236920.CrossRefPubMedGoogle Scholar
  51. 51.
    Ozen S, Sirota A, Belluscio MA, Anastassiou CA, Stark E, Koch C, et al. Transcranial electric stimulation entrains cortical neuronal populations in rats. J Neurosci. 2010;30:11476–85.  https://doi.org/10.1523/JNEUROSCI.5252-09.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Parazzini M, Rossi E, Ferrucci R, Liorni I, Priori A, Ravazzani P. Modelling the electric field and the current density generated by cerebellar transcranial DC stimulation in humans. Clin Neurophysiol. 2014;125:577–84.  https://doi.org/10.1016/j.clinph.2013.09.039.CrossRefPubMedGoogle Scholar
  53. 53.
    Vöröslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernández-Ruiz A, et al. Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun. 2018;9:483.  https://doi.org/10.1038/s41467-018-02928-3.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Underwood E. How the body learns to hurt. Science. 2016;354:694.  https://doi.org/10.1126/science.354.6313.694.CrossRefPubMedGoogle Scholar
  55. 55.
    Halko MA, Farzan F, Eldaief MC, Schmahmann JD, Pascual-Leone A. Intermittent Theta-burst stimulation of the lateral cerebellum increases functional connectivity of the default network. J Neurosci. 2014;34:12049–56.  https://doi.org/10.1523/JNEUROSCI.1776-14.2014.CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of NeurologyUniversity of IowaIowa CityUSA
  2. 2.Department of PsychiatryUniversity of IowaIowa CityUSA
  3. 3.Neuroscience Graduate ProgramUniversity of IowaIowa CityUSA
  4. 4.University of Iowa Carver College of MedicineIowa CityUSA
  5. 5.Department of Pediatrics, Neurology and PsychiatryUniversity of IowaIowa CityUSA
  6. 6.Iowa Neuroscience ProgramUniversity of IowaIowa CityUSA

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