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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!

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

Anodal!n=12!

Cathodal!n=12!

Sham!n=12! Statistic! p!

Age! 45.8±11.2 ! 47.8±7.48! 41.6±10.3! F = 1.248! 0.300!

Education (yrs)! 12.2±2.48! 12.8±2.18! 13.3±1.78! F = 0.872! 0.428!

Parental Education (yrs)!

14.9±3.66! 13.5±2.98! 13.4±1.90! F = 0.628! 0.543!

Males, n (%)! 10 (83)! 6 (50)! 8 (67)! "2 = 3.00! 0.223!

Illness Years! 19.8±13.8! 24.8±10.9! 15.4±7.73! F = 1.784! 0.185!

BPRS! 47.3±13.9! 38.8±11.7! 37.6±11.4! F = 2.213! 0.125!

SANS! 49.8±12.3! 37.8±10.4! 39.3±17.5! F = 2.700! 0.082!

Anodal! Cathodal! Sham! Statistic for Main Effect

Condition!

Statistic for Interaction!

Baseline! Post-tDCS!

Baseline! Post-tDCS!

Baseline! Post-tDCS!

MMN (µV) ! -1.49 ± 0.66! -0.42 ± 1.04! -1.49 ± 1.35! -1.41 ± 0.62! -1.90 ± 1.07! -1.81 ± 1.06! F=3.70!

p=0.036!F = 2.364!p = 0.110!

P300 (µV)! 4.91 ± 3.68! 6.04 ± 3.04! 6.18 ± 4.31! 7.55 ± 5.12! 7.91 ± 2.95! 8.33 ± 5.53! F=2.10!

p=0.14!F = 0.195!p = 0.824!

Results!

Grand average MMN at electrode Fz at !baseline (black) and post-tDCS (red)!

Grand average P300 waveforms at electrode Pz at baseline (black) and post-tDCS (red)!

Sham!Anodal! Cathodal!

Mismatch Negativity!

milliseconds! milliseconds! milliseconds!

μV! μV! μV!

Sham!Anodal! Cathodal!

P300!

milliseconds! milliseconds!milliseconds!

μV!μV!μV!

Baseline!Post-tDCS!

Baseline!Post-tDCS!

Mean MMN amplitudes at baseline and !post-tDCS; changes in amplitude not sig (p>0.05)!

Mean MMN Amplitude!

Mean P300 amplitudes at baseline and !post-tDCS; changes in amplitude not sig (p>0.05)!

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Table 2: EEG Results!MMN and P300 amplitudes; shown are means + standard deviations at baseline and post-tDCS.!Statistics shown are main effect of condition (anodal, cathodal, sham) and the interaction effects of time (baseline, post-tDCS) by condition (anodal, cathodal, sham).!

Patients: 36 subjects DSM-IV criteria for schizophrenia;!12 pts assigned to one of 3 groups: anodal, cathodal, sham!

Design: Parallel, between group design !Each group participated in Session 1 and Session 2 (see Fig 2)!

!Anodal group: anodal tDCS at session 2!!Cathodal group: cathodal tDCS at session 2!!Sham group: sham tDCS at session 2!

tDCS Procedure!Montage: Two 5x7cm active electrodes placed over Fp2 and Fp1,!One 5x7cm reference electrode on upper right arm (see Fig 1)!

Current Density and Duration: 0.028 mA/cm2 at each active !electrode (corresponds to 1mA current through each active!electrode). 20 min stimulation followed by 1.5-2 hrs interval &!a second 20 min stimulation !

EEG Assessments:! Auditory Duration Deviant Mismatch Negativity:!-Standard: 1kHz, 90% probability, 50ms duration!-Deviant: 1kHz, 10% probability, 100ms duration !

P300 Auditory Oddball paradigm:!Subjects pay attention to a series of standard tones and signal when a deviant tone is heard!-Standard: 1kHz, 88% probability, 100ms duration!-Deviant: 1.5kHz, 12% probability, 100ms duration!

Materials and Methods!

Fig 1!Two 5x7 cm active electrodes !placed over Fp2 and Fp1 !targeting prefrontal cortex!

Demographic Data and Symptom Ratings!

EEG Results!

Effect Sizes!

• A statistically significant main effect of condition (p=0.036) was observed for the mismatch negativity (MMN) ERP amplitude. ! MMN amplitude by tDCS condition! Anodal<Cathodal< Sham!

• A suggestion of a condition by time interaction (p=0.110) for anodal tDCS that decreased MMN amplitude (large effect size, Cohen’s d= 0.95) after stimulation.!

• If replicated, this suggests that MMN could serve as a biomarker of target engagement for tDCS treatment of auditory processing deficits in schizophrenia as MMN reflects an early stage process (pre-attentional) in the pathway of auditory processing.!

• This finding is notable given that MMN is highly correlated with patient functioning. Modulation of MMN suggests the targeted pathophysiological process of auditory processing in schizophrenia is being engaged and may eventually lead to improved patient outcomes [1].!

Auditory Processing Social Cognition Patient Functioning! [MMN]!(early stage auditory processing component) !

Novel features of study:! • Application of tDCS targeting the auditory processing ! network in a schizophrenia population! • Use of quantitative electrophysiological measures in tDCS ! of schizophrenia to validate engagement of the targeted ! pathophysiological process!

Future Directions:! • tDCS stimulation of alternative sites involved in auditory ! processing (e.g., primary auditory cortex) with the aim of ! treating auditory processing dysfunction in schizophrenia! • Use of within-subject design to increase power and reduce ! error variance!

Table 1: Effect Sizes!Cohen’s d effect sizes of MMN and P300 amplitude change, baseline vs post-tDCS stimulation. Changes in amplitude were not statistically significant (p>0.05).!

Table 3: Demographics and Symptoms!

Fig 2!

tDCS!20 min!

Cognitive !Testing: 1.5-2hrs!

EEG !MMNP300 (60 min)!

tDCS!20 min!

Session 2!

Baseline!Cognitive Testing!

Baseline!EEG: MMNP300!

Session 1!

Screening!Informed Consent!

Introduction!

NARSAD Independent Investigator Award to Yuri Rassovsky!

Funding provided by VA VISN 22 MIRECC !

Thank you to our coordinators and testers: Mark McGee, Ana Cecilia Mel, Cory Tripp, Gabrielle Pascual, Aaron McNair, Aaron Waters!

Contact Info: wdunn@mednet.ucla.edu!

Summary/Conclusions!

References!1.  Jahshan, C., J.K. Wynn, and M.F. Green, Relationship between auditory processing

and affective prosody in schizophrenia. Schizophr Res, 2013. 143(2-3): p. 348-53. !

Acknowledgements!

BPRS: Brief Psychiatric Rating Scale; SANS: Scale for the Assessment of Negative Symptoms; shown are mean ± standard deviation or number (%) of cases !

MMN! P300!Anodal! d= 0.95! d= 0.24!Cathodal! d= 0.06! d= 0.23!Sham! d= 0.08! d= 0.15!

Mean P300 Amplitude!

Baseline! Post-tDCS!

Baseline! Post-tDCS!

3D head-turbosquid.com!

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Schizophrenia is an illness characterized by deficits in neurocognitive and social cognitive domains. Dysfunction of auditory processing contributes to these higher domain deficits which are closely correlated with functional impairment. Deficits in auditory processing are a potential target for novel interventions given that correcting these defects may cascade into improvement of higher-level social cognition and ultimately functioning. Within the auditory pathway are early and late stage events that compose the process.  !

 Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that uses electrical current to enhance or decrease cortical activity.!

Methodological Question Being Addressed !A present challenge with tDCS is the lack of a target engagement biomarker indicating that electrical stimulation is reaching the intended target site and engaging the process of interest (e.g. working memory or auditory processing). !

EEG based event-related potentials (ERP) such as mismatch negativity (MMN) and P300 are electrophysiological measures of auditory processing components. MMN reflects an early stage event which is pre-attentional and represents automatic detection of novel 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 auditory processing with MMN and P300 serving as biomarkers indicating tDCS engagement of the auditory processing circuits.!

[Early Stage]!Auditory Processing Social Cognition Patient Functioning !

[Late Stage]!