Mismatch Negativity and P300: Biomarkers of Target Engagement for ! Transcranial Direct Current Stimulation in Schizophrenia!

Walter Dunna,b, Yuri Rassovskyb,c, Jonathan Wynna,b, Allan D. Wud, Marco Iacobonib,e, Gerhard Hellemannb, Michael F. Greena,b!

!! ! ! a Department of Veteran Affairs VISN-22 Mental Illness Research Education Clinical Center, Los Angeles, CA, USA; b Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA ! cDepartment of Psychology and Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel; d Department of Neurology, University of California, Los Angeles, USA; e Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, USA!

Introduction! Results! Summary/Conclusions! Mismatch Negativity! Schizophrenia is an illness characterized by deficits in neurocognitive and social cognitive domains. Dysfunction of auditory processing contributes to these higher domain deficits Mean MMN Amplitude! Anodal! Cathodal! Sham! • A statistically significant main effect of condition which are closely correlated with functional impairment. Deficits in auditory processing (p=0.036) was observed for the mismatch negativity are a potential target for novel interventions given that correcting these defects may (MMN) ERP amplitude. ! cascade into improvement of higher-level social cognition and ultimately functioning. MMN amplitude by tDCS condition! Within the auditory pathway are early and late stage events that compose the process. ! μV! μV! μV! Anodalmemory or auditory processing). ! baseline (black) and post-tDCS (red)! Post-tDCS! biomarker of target engagement for tDCS treatment of Mean MMN amplitudes at baseline and ! auditory processing deficits in schizophrenia as MMN EEG based event-related potentials (ERP) such as mismatch negativity (MMN) and P300 post-tDCS; changes in amplitude not sig (p>0.05)! P300! are electrophysiological measures of auditory processing components. MMN reflects an reflects an early stage process (pre-attentional) in the Mean P300 Amplitude! pathway of auditory processing.! early stage event which is pre-attentional and represents automatic detection of novel Anodal! Cathodal! Sham! stimuli. P300 is related to cognitive resources devoted to the process of context updating.! We hypothesized that tDCS stimulation of the prefrontal cortex could modulate • This finding is notable given that MMN is highly auditory processing with MMN and P300 serving as biomarkers indicating tDCS correlated with patient functioning. Modulation of engagement of the auditory processing circuits.! MMN suggests the targeted pathophysiological process μV! μV! μV! Materials and Methods! of auditory processing in schizophrenia is being engaged "V! and may eventually lead to improved patient outcomes Patients: 36 subjects DSM-IV criteria for schizophrenia;! 12 pts assigned to one of 3 groups: anodal, cathodal, sham! [1].!

Design: Parallel, between group design ! Each group participated in Session 1 and Session 2 (see Fig 2)! Auditory Processing  Social Cognition  Patient Functioning! !Anodal group: anodal tDCS at session 2! Baseline! Post-tDCS! milliseconds! milliseconds! milliseconds! [MMN]! !Cathodal group: cathodal tDCS at session 2! Mean P300 amplitudes at baseline and ! Grand average P300 waveforms at electrode Pz Baseline! (early stage auditory processing component) ! !Sham group: sham tDCS at session 2! post-tDCS; changes in amplitude not sig (p>0.05)! at baseline (black) and post-tDCS (red)! Post-tDCS! tDCS Procedure! Novel features of study:! Montage: Two 5x7cm active electrodes placed over Fp2 and Fp1,! • Application of tDCS targeting the auditory processing ! One 5x7cm reference electrode on upper right arm (see Fig 1)! Effect Sizes! network in a schizophrenia population! Demographic Data and Symptom Ratings! • Use of quantitative electrophysiological measures in tDCS ! 2 Current Density and Duration: 0.028 mA/cm at each active ! Table 1: Effect Sizes! of schizophrenia to validate engagement of the targeted ! electrode (corresponds to 1mA current through each active! MMN! P300! Cohen’s d effect sizes of MMN and P300 amplitude Anodal! Cathodal! Sham! pathophysiological process! electrode). 20 min stimulation followed by 1.5-2 hrs interval &! Anodal! d= 0.95! d= 0.24! Statistic! p! a second 20 min stimulation ! change, baseline vs post-tDCS stimulation. Changes n=12! n=12! n=12! Cathodal! d= 0.06! d= 0.23! in amplitude were not statistically significant Age! Future Directions:! 45.8±11.2 ! 47.8±7.48! 41.6±10.3! F = 1.248! 0.300! EEG Assessments:! 3D head-turbosquid.com! (p>0.05).! Fig 1! Sham! d= 0.08! d= 0.15! • tDCS stimulation of alternative sites involved in auditory ! Auditory Duration Deviant Mismatch Negativity:! processing (e.g., primary auditory cortex) with the aim of ! -Standard: 1kHz, 90% probability, 50ms duration! Two 5x7 cm active electrodes ! Education placed over Fp2 and Fp1 ! EEG Results! 12.2±2.48! 12.8±2.18! 13.3±1.78! F = 0.872! 0.428! treating auditory processing dysfunction in schizophrenia! -Deviant: 1kHz, 10% probability, 100ms duration ! (yrs)! targeting prefrontal cortex! • Use of within-subject design to increase power and reduce ! Parental P300 Auditory Oddball paradigm:! Anodal! Cathodal! Sham! Statistic for error variance! Education Subjects pay attention to a series of standard tones and signal when a deviant tone is heard! Baseline! Post- Baseline! Post- Baseline! Post- Main Statistic for 14.9±3.66! 13.5±2.98! 13.4±1.90! F = 0.628! 0.543! (yrs)! -Standard: 1kHz, 88% probability, 100ms duration! tDCS! tDCS! tDCS! Effect Interaction! -Deviant: 1.5kHz, 12% probability, 100ms duration! Fig 2! Condition! Males, n 10 (83)! 6 (50)! 8 (67)! "2 = 3.00! 0.223! Acknowledgements! Session 1! (%)! MMN F=3.70! F = 2.364! NARSAD Independent Investigator Award to Yuri Rassovsky! -1.49 ± 0.66! -0.42 ± 1.04! -1.49 ± 1.35! -1.41 ± 0.62! -1.90 ± 1.07! -1.81 ± 1.06! (µV) ! p=0.036! p = 0.110! Illness . Years! 19.8±13.8! 24.8±10.9! 15.4±7.73! F = 1.784! 0.185! Funding provided by VA VISN 22 MIRECC ! Screening! Baseline! Baseline! P300 F=2.10! F = 0.195! Informed Consent! Cognitive Testing! EEG: MMNP300! 4.91 ± 3.68! 6.04 ± 3.04! 6.18 ± 4.31! 7.55 ± 5.12! 7.91 ± 2.95! 8.33 ± 5.53! BPRS! 47.3±13.9! 38.8±11.7! 37.6±11.4! F = 2.213! 0.125! Thank you to our coordinators and testers: Mark McGee, Ana (µV)! p=0.14! p = 0.824! Cecilia Mel, Cory Tripp, Gabrielle Pascual, Aaron McNair, Session 2! SANS! 49.8±12.3! 37.8±10.4! 39.3±17.5! F = 2.700! 0.082! Aaron Waters! Table 3: Demographics and Symptoms! Table 2: EEG Results! Contact Info: [email protected]! MMN and P300 amplitudes; shown are means + standard deviations at baseline and post-tDCS.! BPRS: Brief Psychiatric Rating Scale; SANS: Scale for the Assessment References! Statistics shown are main effect of condition (anodal, cathodal, sham) and the interaction effects of of Negative Symptoms; shown are mean ± standard deviation or Cognitive ! tDCS! EEG ! tDCS! time (baseline, post-tDCS) by condition (anodal, cathodal, sham).! number (%) of cases ! 1. Jahshan, C., J.K. Wynn, and M.F. Green, Relationship between auditory processing 20 min! Testing: 1.5-2hrs! 20 min! MMNP300 (60 min)! and affective prosody in schizophrenia. Schizophr Res, 2013. 143(2-3): p. 348-53. !