Clinical trial NCT04210557: Models of Auditory Hallucination
Official title: Models of Auditory Hallucination
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Schizophrenia
Schizo Affective Disorder
Auditory Hallucination
Keywords: TMS
Transcranial Magnetic Stimulation
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2019-12-24
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to address the shortcoming in clinical hallucination research by causally manipulating the neural loci of conditioned hallucination task behavior in-person in patients with psychosis using transcranial magnetic stimulation (TMS), tracking the impact of this manipulation on the number of times participants with hallucinations report hearing tones that were not presented. With such a causal intervention, the veracity of this explanation of hallucinations will be either validated or disconfirmed. If validated, the task can be further developed as a biomarker for predicting the hallucination onset, guiding, developing or tracking the effects of treatments for hallucinations.

Detailed description: Hallucinations are percepts without stimulus. 70% of patients with schizophrenia suffer distressing auditory hallucinations. Their mere presence increases the risk of suicide. Most reach remission with D2 dopamine receptor blocking drugs after 1 year of adherence. However, 30% of patients have intractable hallucinations, and 50% are non-adherent to their medications, commonly because of unfavorable side-effects - those intractable and non-adherent patients continue to suffer. There is a clear need for a mechanistic understanding of hallucinations as a prelude to rational treatment design.

This study provides the initial steps towards the development of an interventional biomarker for clinical hallucinations, grounded in computational neuroscience.

Computational psychiatry involves harnessing the power of computational neuroscience to address the clinical needs of those suffering from serious mental illnesses. There has been much discussion of the promise of the approach. There have been few studies thus far and they have largely involved correlative methods like functional neuroimaging. This study will address this shortcoming by causally manipulating the neural loci of computational model parameters in-person in patients with psychosis using transcranial magnetic stimulation (TMS), tracking the impact of this manipulation on behavioral task performance . With such a causal intervention, the veracity of the model's explanation of hallucinations will be either validated or disconfirmed. If validated, the model can be further developed as a biomarker for predicting the hallucination onset, guiding, developing or tracking the effects of treatments for hallucinations. If disconfirmed, the model ought to be discarded and other alternatives should be pursued.

Eligibility criteria: Inclusion Criteria:

* Aged 18 - 45 years
* Voice hearing patients
* Meet diagnostic criteria for DSM-V schizophrenia or schizophreniform disorder
* Report hearing voices at least once a day
* Score \> 3 on PANSS P3 (hallucinations item)

Exclusion Criteria:

* DSM-V substance use disorder within the past 6 months
* Previous head injury with neurological symptoms and/or unconsciousness
* Intellectual disability (IQ \< 70)
* Non-English speaker
* Contraindications for TMS, including:

  * History of seizures
  * Metallic implants
  * Pacemaker
  * Pregnancy
* Less than 6 weeks of a stable dose of psychotropic medication(s)
* Comorbid mood or anxiety diagnosis
* Clinically/behaviorally instability and unable to cooperate with TMS procedures
* Clinically significant medical condition(s)
* Unstable medical condition(s) based on EKG, medical history, physical examination, and routine lab work
* Personal history of stroke
* Family history of seizures

Primary outcomes:
measure: Conditioned Hallucinations Task Performance
timeFrame: approximately 13 months
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Connecticut Mental Health Center (CMHC)
state: Connecticut
Study officials:
affiliation: Yale University
name: Philip R Corlett, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pompili M, Amador XF, Girardi P, Harkavy-Friedman J, Harrow M, Kaplan K, Krausz M, Lester D, Meltzer HY, Modestin J, Montross LP, Mortensen PB, Munk-Jorgensen P, Nielsen J, Nordentoft M, Saarinen PI, Zisook S, Wilson ST, Tatarelli R. Suicide risk in schizophrenia: learning from the past to change the future. Ann Gen Psychiatry. 2007 Mar 16;6:10. doi: 10.1186/1744-859X-6-10.
citation: Kelleher I, Lynch F, Harley M, Molloy C, Roddy S, Fitzpatrick C, Cannon M. Psychotic symptoms in adolescence index risk for suicidal behavior: findings from 2 population-based case-control clinical interview studies. Arch Gen Psychiatry. 2012 Dec;69(12):1277-83. doi: 10.1001/archgenpsychiatry.2012.164.
citation: Harkavy-Friedman JM, Kimhy D, Nelson EA, Venarde DF, Malaspina D, Mann JJ. Suicide attempts in schizophrenia: the role of command auditory hallucinations for suicide. J Clin Psychiatry. 2003 Aug;64(8):871-4.
citation: Friston K. Hierarchical models in the brain. PLoS Comput Biol. 2008 Nov;4(11):e1000211. doi: 10.1371/journal.pcbi.1000211. Epub 2008 Nov 7.
citation: Friston K. The free-energy principle: a rough guide to the brain? Trends Cogn Sci. 2009 Jul;13(7):293-301. doi: 10.1016/j.tics.2009.04.005. Epub 2009 Jun 24.
citation: Powers AR, Mathys C, Corlett PR. Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science. 2017 Aug 11;357(6351):596-600. doi: 10.1126/science.aan3458.
citation: Powers AR III, Kelley M, Corlett PR. Hallucinations as top-down effects on perception. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016 Sep;1(5):393-400. doi: 10.1016/j.bpsc.2016.04.003.
citation: Helmholtz, H., & Southall, J. P. C. (1924). Helmholtz's treatise on physiological optics. Rochester, N.Y.: Optical Society of America.
citation: Friston K. A theory of cortical responses. Philos Trans R Soc Lond B Biol Sci. 2005 Apr 29;360(1456):815-36. doi: 10.1098/rstb.2005.1622.
citation: Rao RP, Ballard DH. Predictive coding in the visual cortex: a functional interpretation of some extra-classical receptive-field effects. Nat Neurosci. 1999 Jan;2(1):79-87. doi: 10.1038/4580.
citation: Bayes T. An essay towards solving a problem in the doctrine of chances. 1763. MD Comput. 1991 May-Jun;8(3):157-71. No abstract available.
citation: Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ. The computational anatomy of psychosis. Front Psychiatry. 2013 May 30;4:47. doi: 10.3389/fpsyt.2013.00047. eCollection 2013.
citation: Friston, K. (2005). Hallucinations and perceptual inference. Behavioral and Brain Sciences, 28(6), 764-766. doi:10.1017/S0140525X05290131
citation: G. Ellson, D. (1941). Hallucinations produced by sensory conditioning. Journal of Experimental Psychology. 28. 1-20. 10.1037/h0054167.
citation: Mathys C, Daunizeau J, Friston KJ, Stephan KE. A bayesian foundation for individual learning under uncertainty. Front Hum Neurosci. 2011 May 2;5:39. doi: 10.3389/fnhum.2011.00039. eCollection 2011.
citation: Watson AB, Pelli DG. QUEST: a Bayesian adaptive psychometric method. Percept Psychophys. 1983 Feb;33(2):113-20. doi: 10.3758/bf03202828. No abstract available.
citation: Verdoux H, van Os J. Psychotic symptoms in non-clinical populations and the continuum of psychosis. Schizophr Res. 2002 Mar 1;54(1-2):59-65. doi: 10.1016/s0920-9964(01)00352-8.
citation: Powers AR 3rd, Kelley MS, Corlett PR. Varieties of Voice-Hearing: Psychics and the Psychosis Continuum. Schizophr Bull. 2017 Jan;43(1):84-98. doi: 10.1093/schbul/sbw133. Epub 2016 Oct 7.
citation: Zmigrod L, Garrison JR, Carr J, Simons JS. The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies. Neurosci Biobehav Rev. 2016 Oct;69:113-23. doi: 10.1016/j.neubiorev.2016.05.037. Epub 2016 Jul 26.
citation: Mathys CD, Lomakina EI, Daunizeau J, Iglesias S, Brodersen KH, Friston KJ, Stephan KE. Uncertainty in perception and the Hierarchical Gaussian Filter. Front Hum Neurosci. 2014 Nov 19;8:825. doi: 10.3389/fnhum.2014.00825. eCollection 2014.
citation: Guediche S, Holt LL, Laurent P, Lim SJ, Fiez JA. Evidence for Cerebellar Contributions to Adaptive Plasticity in Speech Perception. Cereb Cortex. 2015 Jul;25(7):1867-77. doi: 10.1093/cercor/bht428. Epub 2014 Jan 22.
citation: Shergill SS, White TP, Joyce DW, Bays PM, Wolpert DM, Frith CD. Functional magnetic resonance imaging of impaired sensory prediction in schizophrenia. JAMA Psychiatry. 2014 Jan;71(1):28-35. doi: 10.1001/jamapsychiatry.2013.2974.
citation: George MS. Stimulating the brain. Sci Am. 2003 Sep;289(3):66-73. doi: 10.1038/scientificamerican0903-66. No abstract available.
citation: Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger A, Krystal JH, Charney DS. Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices". Biol Psychiatry. 1999 Jul 1;46(1):130-2. doi: 10.1016/s0006-3223(98)00358-8.
citation: Kring AM, Gur RE, Blanchard JJ, Horan WP, Reise SP. The Clinical Assessment Interview for Negative Symptoms (CAINS): final development and validation. Am J Psychiatry. 2013 Feb;170(2):165-72. doi: 10.1176/appi.ajp.2012.12010109.
citation: Borckardt JJ, Nahas Z, Koola J, George MS. Estimating resting motor thresholds in transcranial magnetic stimulation research and practice: a computer simulation evaluation of best methods. J ECT. 2006 Sep;22(3):169-75. doi: 10.1097/01.yct.0000235923.52741.72.
citation: Arana AB, Borckardt JJ, Ricci R, Anderson B, Li X, Linder KJ, Long J, Sackeim HA, George MS. Focal electrical stimulation as a sham control for repetitive transcranial magnetic stimulation: Does it truly mimic the cutaneous sensation and pain of active prefrontal repetitive transcranial magnetic stimulation? Brain Stimul. 2008 Jan;1(1):44-51. doi: 10.1016/j.brs.2007.08.006.
citation: Stromer R, McIlvane W.J, Serna R.W. Complex stimulus control and equivalence. The Psychological Record. 1993;43:585-598.
citation: Gekas N, Chalk M, Seitz AR, Series P. Complexity and specificity of experimentally-induced expectations in motion perception. J Vis. 2013 Mar 13;13(4):8. doi: 10.1167/13.4.8.
citation: Jones PD, Holding DH. Extremely long-term persistence of the McCollough effect. J Exp Psychol Hum Percept Perform. 1975 Nov;1(4):323-7. doi: 10.1037//0096-1523.1.4.323.
citation: Shams L, Seitz AR. Benefits of multisensory learning. Trends Cogn Sci. 2008 Nov;12(11):411-7. doi: 10.1016/j.tics.2008.07.006.
citation: Downar J, Blumberger DM, Daskalakis ZJ. The Neural Crossroads of Psychiatric Illness: An Emerging Target for Brain Stimulation. Trends Cogn Sci. 2016 Feb;20(2):107-120. doi: 10.1016/j.tics.2015.10.007. Epub 2015 Dec 3.
citation: Dinur-Klein L, Dannon P, Hadar A, Rosenberg O, Roth Y, Kotler M, Zangen A. Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial. Biol Psychiatry. 2014 Nov 1;76(9):742-9. doi: 10.1016/j.biopsych.2014.05.020. Epub 2014 Jun 5.
citation: Hardwick RM, Lesage E, Miall RC. Cerebellar transcranial magnetic stimulation: the role of coil geometry and tissue depth. Brain Stimul. 2014 Sep-Oct;7(5):643-9. doi: 10.1016/j.brs.2014.04.009. Epub 2014 May 6.
citation: Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, Seidman LJ, Schmahmann JD, Pascual-Leone A. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010 Dec;124(1-3):91-100. doi: 10.1016/j.schres.2010.08.015.
citation: Oberman L, Edwards D, Eldaief M, Pascual-Leone A. Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol. 2011 Feb;28(1):67-74. doi: 10.1097/WNP.0b013e318205135f.
citation: Rosner, B. Fundamentals of biostatistics. 1995. Duxbury Press: New York.
citation: Gulli G, Tarperi C, Cevese A, Acler M, Bongiovanni G, Manganotti P. Effects of prefrontal repetitive transcranial magnetic stimulation on the autonomic regulation of cardiovascular function. Exp Brain Res. 2013 Apr;226(2):265-71. doi: 10.1007/s00221-013-3431-6. Epub 2013 Mar 2.
citation: Kimhy D, Wall MM, Hansen MC, Vakhrusheva J, Choi CJ, Delespaul P, Tarrier N, Sloan RP, Malaspina D. Autonomic Regulation and Auditory Hallucinations in Individuals With Schizophrenia: An Experience Sampling Study. Schizophr Bull. 2017 Jul 1;43(4):754-763. doi: 10.1093/schbul/sbw219.
citation: Flashman LA, Flaum M, Gupta S, Andreasen NC. Soft signs and neuropsychological performance in schizophrenia. Am J Psychiatry. 1996 Apr;153(4):526-32. doi: 10.1176/ajp.153.4.526.
citation: Miall RC, Christensen LO. The effect of rTMS over the cerebellum in normal human volunteers on peg-board movement performance. Neurosci Lett. 2004 Nov 23;371(2-3):185-9. doi: 10.1016/j.neulet.2004.08.067.
citation: Davies P, Davies GL, Bennett S. An effective paradigm for conditioning visual perception in human subjects. Perception. 1982;11(6):663-9. doi: 10.1068/p110663.
citation: Dobek CE, Blumberger DM, Downar J, Daskalakis ZJ, Vila-Rodriguez F. Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupropion. Neuropsychiatr Dis Treat. 2015 Nov 30;11:2975-87. doi: 10.2147/NDT.S91126. eCollection 2015.
citation: Maizey L, Allen CP, Dervinis M, Verbruggen F, Varnava A, Kozlov M, Adams RC, Stokes M, Klemen J, Bungert A, Hounsell CA, Chambers CD. Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Clin Neurophysiol. 2013 Mar;124(3):536-44. doi: 10.1016/j.clinph.2012.07.024. Epub 2012 Sep 15.
citation: Anderson BS, Kavanagh K, Borckardt JJ, Nahas ZH, Kose S, Lisanby SH, McDonald WM, Avery D, Sackeim HA, George MS. Decreasing procedural pain over time of left prefrontal rTMS for depression: initial results from the open-label phase of a multi-site trial (OPT-TMS). Brain Stimul. 2009 Apr;2(2):88-92. doi: 10.1016/j.brs.2008.09.001.
citation: Pascual-Leone A, Houser CM, Reese K, Shotland LI, Grafman J, Sato S, Valls-Sole J, Brasil-Neto JP, Wassermann EM, Cohen LG, et al. Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroencephalogr Clin Neurophysiol. 1993 Apr;89(2):120-30. doi: 10.1016/0168-5597(93)90094-6.
citation: Horwitz NH. Historical perspective. David Ferrier (1843-1928). Neurosurgery. 1994 Oct;35(4):793-5. doi: 10.1227/00006123-199410000-00042. No abstract available.
citation: Morabito C. David Ferrier and Luigi Luciani on the localization of brain functions. Physis Riv Int Stor Sci. 1999;36(2):387-405.
citation: Bohning, D. E. (2000). Introduction and overview of TMS physics. Transcranial magnetic stimulation in neuropsychiatry, 13-44.
citation: George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology. 2010 Jan;35(1):301-16. doi: 10.1038/npp.2009.87.
citation: George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, Sackeim HA. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010 May;67(5):507-16. doi: 10.1001/archgenpsychiatry.2010.46.
citation: Johnson KA, Baig M, Ramsey D, Lisanby SH, Avery D, McDonald WM, Li X, Bernhardt ER, Haynor DR, Holtzheimer PE 3rd, Sackeim HA, George MS, Nahas Z. Prefrontal rTMS for treating depression: location and intensity results from the OPT-TMS multi-site clinical trial. Brain Stimul. 2013 Mar;6(2):108-17. doi: 10.1016/j.brs.2012.02.003. Epub 2012 Mar 14.
citation: Janicak PG, Nahas Z, Lisanby SH, Solvason HB, Sampson SM, McDonald WM, Marangell LB, Rosenquist P, McCall WV, Kimball J, O'Reardon JP, Loo C, Husain MH, Krystal A, Gilmer W, Dowd SM, Demitrack MA, Schatzberg AF. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study. Brain Stimul. 2010 Oct;3(4):187-99. doi: 10.1016/j.brs.2010.07.003. Epub 2010 Aug 11.
citation: Mantovani A, Pavlicova M, Avery D, Nahas Z, McDonald WM, Wajdik CD, Holtzheimer PE 3rd, George MS, Sackeim HA, Lisanby SH. Long-term efficacy of repeated daily prefrontal transcranial magnetic stimulation (TMS) in treatment-resistant depression. Depress Anxiety. 2012 Oct;29(10):883-90. doi: 10.1002/da.21967. Epub 2012 Jun 11.
citation: Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969. Epub 2012 Jun 11.
citation: Hoffman RE, Wu K, Pittman B, Cahill JD, Hawkins KA, Fernandez T, Hannestad J. Transcranial magnetic stimulation of Wernicke's and Right homologous sites to curtail "voices": a randomized trial. Biol Psychiatry. 2013 May 15;73(10):1008-14. doi: 10.1016/j.biopsych.2013.01.016. Epub 2013 Feb 26.
citation: Chen R, Gerloff C, Classen J, Wassermann EM, Hallett M, Cohen LG. Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalogr Clin Neurophysiol. 1997 Dec;105(6):415-21. doi: 10.1016/s0924-980x(97)00036-2.
citation: Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.
citation: Anderson B, Mishory A, Nahas Z, Borckardt JJ, Yamanaka K, Rastogi K, George MS. Tolerability and safety of high daily doses of repetitive transcranial magnetic stimulation in healthy young men. J ECT. 2006 Mar;22(1):49-53. doi: 10.1097/00124509-200603000-00011.
citation: Rachid F. Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review. Psychiatry Res. 2018 Apr;262:363-372. doi: 10.1016/j.psychres.2017.09.009. Epub 2017 Sep 19.