Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia

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Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through “bottom-up” tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment.

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  1. 1.

    Hochberger WC, Hill SK, Nelson CLM, Reilly JL, Keefe RSE, Pearlson GD, et al. Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives. Schizophr Res. 2016;170:156–61.

  2. 2.

    Bowie CR, Leung WW, Reichenberg A, McClure MM, Patterson TL, Heaton RK. et al. Predicting schizophrenia patients’ real world behavior with specific neuropsychological and functional capacity measure. Biol Psychiatry. 2008;63:505–511.

  3. 3.

    Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: Implications for MATRICS. Schizophr Res. 2004;72:41–51.

  4. 4.

    Hill SK, Schuepbach D, Herbener ES, Keshavan MS, Sweeney JA. Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia. Schizophr Res. 2004;68:49–63.

  5. 5.

    Kishi T, Matsuda Y, Iwata N. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis. Psychopharmacology. 2017;234:2113–2125.

  6. 6.

    Fisher M, Herman A, Stephens DB, Vinogradov S. Neuroscience-informed computer-assisted cognitive training in schizophrenia. Ann N Y Acad Sci. 2016;1366:90–114.

  7. 7.

    Loewy R, Fisher M, Schlosser DA, Biagianti B, Stuart B, Mathalon DH, et al. Intensive auditory cognitive training improves verbal memory in adolescents and young adults at clinical high risk for psychosis. Schizophr Bull. 2016;42:S118–S126.

  8. 8.

    Tarasenko M, Perez VB, Pianka ST, Vinogradov S, Braff DL, Swerdlow NR, et al. Measuring the capacity for auditory system plasticity: an examination of performance gains during initial exposure to auditory-targeted cognitive training in schizophrenia. Schizophr Res. 2016;172:123–130.

  9. 9.

    Dale CL, Brown EG, Fisher M, Herman AB, Dowling AF, Hinkley LB, et al. Auditory cortical plasticity drives training-induced cognitive changes in schizophrenia. Schizophr Bull. 2016;42:220–228.

  10. 10.

    Javitt DC. When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu Rev Clin Psychol. 2009;5:249–275.

  11. 11.

    Lee SH, Sung K, Lee KS, Moon E, Kim CG. Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 2014

  12. 12.

    Rissling AJ, Miyakoshi M, Sugar CA, Braff DL, Makeig S, Light GA. Cortical substrates and functional correlates of auditory deviance processing deficits in schizophrenia. Neuroimage Clin. 2014;6:424–437.

  13. 13.

    Suga M, Nishimura Y, Kawakubo Y, Yumoto M, Kasai K. Magnetoencephalographic recording of auditory mismatch negativity in response to duration and frequency deviants in a single session in patients with schizophrenia. Psychiatry Clin Neurosci. 2016;70:295–302.

  14. 14.

    Thomas ML, Green MF, Hellemann G, Sugar CA, Tarasenko M, Calkins ME, et al. Modeling deficits from early auditory information processing to psychosocial functioning in schizophrenia. JAMA Psychiatry. 2017;74:37.

  15. 15.

    Thomas ML, Bismark AW, Joshi YB, Tarasenko M, Triechler EBH, Hochberger WC, et al. Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care. Schizophr Res. in press.

  16. 16.

    Thomas ML, Treichler EBH, Bismark A, Shiluk AL, Tarasenko M, Zhang W, et al. Computerized cognitive training is associated with improved psychosocial treatment engagement in schizophrenia. Schizophr Res. in press.

  17. 17.

    Fisher M, Holland C, Merzenich MM, Vinogradov S. Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009;166:805–811.

  18. 18.

    Fisher DJ, Labelle A, Knott VJ. Auditory hallucinations and the P3a: Attention-switching to speech in schizophrenia. Biol Psychol 2010.

  19. 19.

    Fisher M, Holland C, Subramaniam K, Vinogradov S. Neuroplasticity-based cognitive training in schizophrenia: an interim report on the effects 6 months later. Schizophr Bull. 2010;36:869–879.

  20. 20.

    Biagianti B, Fisher M, Neilands TB, Loewy R, Vinogradov S. Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia. Neuropsychology. 2016;30:998–1008.

  21. 21.

    Murthy NV, Mahncke H, Wexler BE, Maruff P, Inamdar A, Zucchetto M, et al. Computerized cognitive remediation training for schizophrenia: an open label, multi-site, multinational methodology study. Schizophr Res. 2012;139:87–91.

  22. 22.

    Mcgurk S, Twamley E, Sitzer D, Mchugo G, Mueser K. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry. 2007;164:1791–1802.

  23. 23.

    Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P, Craufurd D, et al. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011;168:472–485.

  24. 24.

    Light GA, Näätänen R. Mismatch negativity is a breakthrough biomarker for understanding and treating psychotic disorders. Proc Natl Acad Sci. 2013;110:15175–15176.

  25. 25.

    Light GA, Swerdlow NR. Neurophysiological biomarkers informing the clinical neuroscience of schizophrenia: mismatch negativity and prepulse inhibition of startle. Curr Top Behav Neurosci 2014

  26. 26.

    Perez VB, Swerdlow NR, Braff DL, Näätänen R, Light GA. Using biomarkers to inform diagnosis, guide treatments and track response to interventions in psychotic illnesses. Biomark Med. 2014;8:9–14.

  27. 27.

    Garrido MI, Kilner JM, Stephan KE, Friston KJ. The mismatch negativity: a review of underlying mechanisms. Clin Neurophysiol. 2009;120:453–463.

  28. 28.

    Light GA, Swerdlow NR, Rissling AJ, Radant A, Sugar CA, Sprock J, et al. Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia. PLoS ONE. 2012;7:e39434.

  29. 29.

    Näätänen R, Paavilainen P, Rinne T, Alho K. The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clin Neurophysiol. 2007;118:2544–2590.

  30. 30.

    Light GA, Swerdlow NR, Thomas ML, Calkins ME, Green MF, Greenwood TA, et al. Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2. Schizophr Res. 2015;163:63–72.

  31. 31.

    Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res 2005

  32. 32.

    Baldeweg T, Klugman A, Gruzelier J, Hirsch SR. Mismatch negativity potentials and cognitive impairment in schizophrenia. Schizophr Res. 2004;69:203–217.

  33. 33.

    Light GA, Swerdlow NR, Braff DL. Preattentive sensory processing as Indexed by the MMN and P3a brain responses is associated with cognitive and psychosocial functioning in healthy adults. J Cogn Neurosci. 2007;19:1624–1632.

  34. 34.

    Salisbury DF, McCathern AG. Abnormal complex auditory pattern analysis in schizophrenia reflected in an absent missing stimulus mismatch negativity. Brain Topogr. 2016

  35. 35.

    Biagianti B, Roach BJ, Fisher M, Loewy R, Ford JM, Vinogradov S, et al. (2017). Trait aspects of auditory mismatch negativity predict response to auditory training in individuals with early illness schizophrenia. Neuropsychiatr Electrophysiol. 2017;3:1

  36. 36.

    Potter D, Summerfelt A, Gold J, Buchanan RW. Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schizophr Bull. 2006

  37. 37.

    Perez VB, Tarasenko M, Miyakoshi M, Pianka ST, Makeig SD, Braff DL, et al. Mismatch negativity is a sensitive and predictive biomarker of perceptual learning during auditory cognitive training in schizophrenia. Neuropsychopharmacology. 2017;42:2206–2213.

  38. 38.

    First MB, Spitzer RL, Gibbon M, Williams JB (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders. New York State Psychiatric Institute at

  39. 39.

    Kern RS, Gold JM, Dickinson D, Green MF, Nuechterlein KH, Baade LE, et al. The MCCB impairment profile for schizophrenia outpatients: results from the MATRICS psychometric and standardization study. Schizophr Res. 2011;126:124–131.

  40. 40.

    Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203–213.

  41. 41.

    Andreasen, N.C., 1984a. Modified Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa City.

  42. 42.

    Andreasen, N.C., 1984b. Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City.

  43. 43.

    Hox, J.J., 2010. Multilevel analysis: Techniques and applications. Routledge/Taylor & Francis Group, New York.

  44. 44.

    Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015

  45. 45.

    Tabachnick B, Fidell L. Using multivariate statistics, vol. 28. Boston: Pearson Educ Inc.; 2007.

  46. 46.

    Tukey JW. Exploratory data analysis. Analysis. 1977.

  47. 47.

    Swerdlow NR, Bhakta S, Light GA. Room to move: plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge. Schizophr Res. 2018.

  48. 48.

    Gunduz-Bruce H, Reinhart RMG, Roach BJ, Gueorguieva R, Oliver S, D’Souza DC, et al. Glutamatergic modulation of auditory information processing in the human brain. Biol Psychiatry. 2012.

  49. 49.

    Javitt DC. Glycine transport inhibitors and the treatment of schizophrenia. Biol Psychiatry. 2008.

  50. 50.

    Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC. Role of cortical N-methyl-d-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci USA. 1996.

  51. 51.

    Näätänen R. Mismatch negativity (MMN) as an index of central auditory system plasticity. Int J Audiol. 2008;47:S16–20.

  52. 52.

    Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry. 2000.

  53. 53.

    Menning H, Roberts LE, Pantev C. Plastic changes in the auditory cortex induced by intensive frequency discrimination training. Neuroreport. 2000;11:817–822.

  54. 54.

    Lovio R, Halttunen A, Lyytinen H, Näätänen R, Kujala T. Reading skill and neural processing accuracy improvement after a 3-hour intervention in preschoolers with difficulties in reading-related skills. Brain Res. 2012;1448:42–55.

  55. 55.

    Lindenmayer J-P, Ozog VA, Khan A, Ljuri I, Fregenti S, McGurk SR. Predictors of response to cognitive remediation in service recipients with severe mental illness. Psychiatr Rehabil J. 2017;40:61–69.

  56. 56.

    Tarasenko MA, Swerdlow NR, Makeig S, Braff DL, Light GA. The auditory brain-stem response to complex sounds: a potential biomarker for guiding treatment of psychosis. Front Psychiatry. 2014.

  57. 57.

    Javitt DC, Lee M, Kantrowitz JT, Martinez A. Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia. Schizophr Res. 2016.

  58. 58.

    Lee M, Balla A, Sershen H, Sehatpour P, Lakatos P, Javitt DC. Rodent mismatch negativity (MMN)/theta neuro-oscillatory response as a translational Neurophysiological biomarker for N-methyl-d-aspartate receptor-based new treatment development in schizophrenia. Neuropsychopharmacology 2017;1–12

  59. 59.

    Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, et al. Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol Psychiatry 2017;1–9

  60. 60.

    Light GA, Zhang W, Joshi YB, Bhakta S, Talledo JA, Swerdlow NR. Single-dose memantine improves cortical oscillatory response dynamics in patients with schizophrenia. Neuropsychopharmacology. 2017.

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The authors also wish to thank George B. Handran and the Sidney R. Baer, Jr. Foundation for their generous support of this research. We also wish to thank all of the participants and non-author support staff that made this study possible, including the following key personnel: Sean Pianka, Marlena Pela, Sonia Rackelmann, and Alexandra L. Shiluk.

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Correspondence to Gregory A. Light.

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