J Korean Neuropsychiatr Assoc JKNA Journal of Korean Neuropsychiatric Association 1015-4817 2289-0963 Korean Neuropsychiatric Association 10.4306/jknpa.2019.58.2.105 Special Article The Clinical Use of Electroencephalography in Psychiatry Electroencephalography and Schizophrenia Lee Seung-Hwan MD PhD 1 2 Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, Korea. Department of Psychiatry, Inje University Ilsan-Paik Hospital, Goyang, Korea. Address for correspondence: Seung-Hwan Lee, MD, PhD. Department of Psychiatry, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea. Tel +82-31-910-7776, Fax +82-31-919-9776, lshpss@hanmail.net 05 2019 31 05 2019 58 2 105 114 23 04 2019 30 04 2019 13 05 2019 Copyright © 2019 Korean Neuropsychiatric Association 2019 Korean Neuropsychiatric Association

Electroencephalography (EEG) and event-related potentials (ERPs) are useful measures of information processing that are believed to reflect the cognitive processing of the brain. Recently, these electrophysiological markers have been studied repeatedly to examine patients with schizophrenia. Among the ERPs components, P50, P300, mismatch negativity, loudness dependence of auditory evoked potentials, and 40 Hz auditory steady state response are meaningful neurophysiological markers of schizophrenia. The employment of novel ERP paradigms designed to carefully characterize the early spectrum of perceptual and cognitive information processing allows investigators to identify the neurophysiological basis of cognitive dysfunction in schizophrenia and examine the associated clinical and functional impairments. Lately, functional neural networks using resting state EEG have been studied extensively in patients with schizophrenia. In this article, qEEG, several ERP components, and functional neural networks that were considered useful neurophysiological markers of schizophrenia are reviewed and their clinical implications are discussed.

 Schizophrenia EEG P50 evoked potentials Event-related potentials Functional neural network Korea Science and Engineering Foundation https://doi.org/10.13039/501100004084 National Research Foundation of Korea https://doi.org/10.13039/501100003725 NRF-2018R1A2A2A05018505 Inje University https://doi.org/10.13039/501100002636 Acknowledgments

This work was supported by a grant from the Korea Science and Engineering Foundation (KOSEF), funded by the Korean government (NRF-2018R1A2A2A05018505), and by the 2017 creative research program of Inje university.

The author has no financial conflicts of interest.

 Hughes JR John ER Conventional and quantitative electroencephalography in psychiatry J Neuropsychiatry Clin Neurosci 1999 11 190 208 Yeum TS Kang UG Reduction in alpha peak frequency and coherence on quantitative electroencephalography in patients with schizophrenia J Korean Med Sci 2018 33 e179 Leiser SC Dunlop J Bowlby MR Devilbiss DM Review: aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research Biochem Pharmacol 2011 81 1408 1421 Boutros NN Arfken C Galderisi S Warrick J Pratt G The status of spectral EEG abnormality as a diagnostic test for schizophrenia Schizophr Res 2008 99 225 237 Gambini O Colombo C Macciardi F Locatelli M Calabrese G Sacchetti E EEG power spectrum profile and structural CNS characteristics in schizophrenia Biol Psychiatry 1990 27 1331 1334 Sponheim SR Clementz BA Iacono WG Beiser M Resting EEG in first-episode and chronic schizophrenia Psychophysiology 1994 31 37 43 Omori M Koshino Y Murata T Murata I Nishio M Sakamoto K Quantitative EEG in never-treated schizophrenic patients Biol Psychiatry 1995 38 305 309 Jetha MK Schmidt LA Goldberg JO Resting frontal EEG asymmetry and shyness and sociability in schizophrenia: a pilot study of community-based outpatients Int J Neurosci 2009 119 847 856 Begić D Hotujac L Jokić-Begić N Quantitative EEG in ‘positive’ and ‘negative’ schizophrenia Acta Psychiatr Scand 2000 101 307 311 Lee SH Wynn JK Green MF Kim H Lee KJ Nam M Quantitative EEG and low resolution electromagnetic tomography (LORETA) imaging of patients with persistent auditory hallucinations Schizophr Res 2006 83 111 119 Adler LE Pachtman E Franks RD Pecevich M Waldo MC Freedman R Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia Biol Psychiatry 1982 17 639 654 McGhie A Disorders of attention and perception in early schizophrenia Br J Med Psychol 1961 34 103 116 Sánchez-Morla EM García-Jiménez MA Barabash A Martínez-Vizcaíno V Mena J Cabranes-Díaz JA P50 sensory gating deficit is a common marker of vulnerability to bipolar disorder and schizophrenia Acta Psychiatr Scand 2008 117 313 318 Vlcek P Bob P Raboch J Sensory disturbances, inhibitory deficits, and the P50 wave in schizophrenia Neuropsychiatr Dis Treat 2014 10 1309 1315 Freedman R Adler LE Waldo MC Pachtman E Franks RD Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients Biol Psychiatry 1983 18 537 551 Freedman R Adler LE Gerhardt GA Waldo M Baker N Rose GM Neurobiological studies of sensory gating in schizophrenia Schizophr Bull 1987 13 669 678 Nagamoto HT Adler LE Waldo MC Freedman R Sensory gating in schizophrenics and normal controls: effects of changing stimulation interval Biol Psychiatry 1989 25 549 561 Braff DL Grillon C Geyer MA Gating and habituation of the startle reflex in schizophrenic patients Arch Gen Psychiatry 1992 49 206 215 Brockhaus-Dumke A Schultze-Lutter F Mueller R Tendolkar I Bechdolf A Pukrop R Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients Biol Psychiatry 2008 64 376 384 Yee CM Williams TJ White PM Nuechterlein KH Ames D Subotnik KL Attentional modulation of the P50 suppression deficit in recent-onset and chronic schizophrenia J Abnorm Psychol 2010 119 31 39 Smucny J Stevens KE Olincy A Tregellas JR Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation Transl Psychiatry 2015 5 e587 Friedman D Squires-Wheeler E Event-related potentials (ERPs) as indicators of risk for schizophrenia Schizophr Bull 1994 20 63 74 Ford JM Mathalon DH Marsh L Faustman WO Harris D Hoff AL P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia Biol Psychiatry 1999 46 94 101 Bramon E Rabe-Hesketh S Sham P Murray RM Frangou S Meta-analysis of the P300 and P50 waveforms in schizophrenia Schizophr Res 2004 70 315 329 Verleger R On the utility of P3 latency as an index of mental chronometry Psychophysiology 1997 34 131 156 Goodin DS Squires KC Henderson BH Starr A Age-related variations in evoked potentials to auditory stimuli in normal human subjects Electroencephalogr Clin Neurophysiol 1978 44 447 458 Polich J Meta-analysis of P300 normative aging studies Psychophysiology 1996 33 334 353 O'Donnell BF McCarley RW Potts GF Salisbury DF Nestor PG Hirayasu Y Identification of neural circuits underlying P300 abnormalities in schizophrenia Psychophysiology 1999 36 388 398 Wang J Hirayasu Y Hiramatsu K Hokama H Miyazato H Ogura C Increased rate of P300 latency prolongation with age in drug-naive and first episode schizophrenia Clin Neurophysiol 2003 114 2029 2035 Lim Y Lee S Hong S Application of N100, P300 and QEEG as a biological marker in patients with schizophrenia Korean Journal of Psychopharmacology 2010 21 78 86 Kim DW Shim M Kim JI Im CH Lee SH Source activation of P300 correlates with negative symptom severity in patients with schizophrenia Brain Topogr 2014 27 307 317 Mathalon DH Ford JM Pfefferbaum A Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study Biol Psychiatry 2000 47 434 449 Bramon E Shaikh M Broome M Lappin J Bergé D Day F Abnormal P300 in people with high risk of developing psychosis Neuroimage 2008 41 553 560 Ozgürdal S Gudlowski Y Witthaus H Kawohl W Uhl I Hauser M Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia Schizophr Res 2008 105 272 278 Näätänen R Selective attention and evoked potentials in humans--a critical review Biol Psychol 1975 2 237 307 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 Näätänen R Jacobsen T Winkler I Memory-based or afferent processes in mismatch negativity (MMN): a review of the evidence Psychophysiology 2005 42 25 32 Duncan CC Barry RJ Connolly JF Fischer C Michie PT Näätänen R Event-related potentials in clinical research: guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400 Clin Neurophysiol 2009 120 1883 1908 Winkler I Interpreting the mismatch negativity J Psychophysiol 2007 21 147 163 Ruusuvirta T Huotilainen M Fellman V Näätänen R Numerical discrimination in newborn infants as revealed by event-related potentials to tone sequences Eur J Neurosci 2009 30 1620 1624 Ilvonen T Kujala T Kozou H Kiesiläinen A Salonen O Alku P The processing of speech and non-speech sounds in aphasic patients as reflected by the mismatch negativity (MMN) Neurosci Lett 2004 366 235 240 Ilvonen TM Kujala T Tervaniemi M Salonen O Näätänen R Pekkonen E The processing of sound duration after left hemisphere stroke: event-related potential and behavioral evidence Psychophysiology 2001 38 622 628 Kane NM Butler SR Simpson T Coma outcome prediction using event-related potentials: P(3) and mismatch negativity Audiol Neurootol 2000 5 186 191 Kane NM Curry SH Butler SR Cummins BH Electrophysiological indicator of awakening from coma Lancet 1993 341 688 Fischer C Morlet D Bouchet P Luaute J Jourdan C Salord F Mismatch negativity and late auditory evoked potentials in comatose patients Clin Neurophysiol 1999 110 1601 1610 Fischer C Luauté J Evoked potentials for the prediction of vegetative state in the acute stage of coma Neuropsychol Rehabil 2005 15 372 380 Wijnen VJ Van Boxtel GJ Eilander HJ De Gelder B Mismatch negativity predicts recovery from the vegetative state Clin Neurophysiol 2007 118 597 605 Pekkonen E Huotilainen M Virtanen J Sinkkonen J Rinne T Ilmoniemi RJ Age-related functional differences between auditory cortices: a whole-head MEG study Neuroreport 1995 6 1803 1806 Pekkonen E Huotilainen M Virtanen J Näätänen R Ilmoniemi RJ Erkinjuntti T Alzheimer's disease affects parallel processing between the auditory cortices Neuroreport 1996 7 1365 1368 Escera C Grau C Short-term replicability of the mismatch negativity Electroencephalogr Clin Neurophysiol 1996 100 549 554 Escera C Yago E Polo MD Grau C The individual replicability of mismatch negativity at short and long inter-stimulus intervals Clin Neurophysiol 2000 111 546 551 Tervaniemi M Kujala A Alho K Virtanen J Ilmoniemi RJ Näätänen R Functional specialization of the human auditory cortex in processing phonetic and musical sounds: a magnetoencephalographic (MEG) study Neuroimage 1999 9 330 336 Kim S Jeon H Jang KI Kim YW Im CH Lee SH Mismatch negativity and cortical thickness in patients with schizophrenia and bipolar disorder Schizophr Bull 2019 45 425 435 Kiang M Braff DL Sprock J Light GA The relationship between preattentive sensory processing deficits and age in schizophrenia patients Clin Neurophysiol 2009 120 1949 1957 Light GA Braff DL Mismatch negativity deficits are associated with poor functioning in schizophrenia patients Arch Gen Psychiatry 2005 62 127 136 Wynn JK Sugar C Horan WP Kern R Green MF Mismatch negativity, social cognition, and functioning in schizophrenia patients Biol Psychiatry 2010 67 940 947 Shaikh M Valmaggia L Broome MR Dutt A Lappin J Day F Reduced mismatch negativity predates the onset of psychosis Schizophr Res 2012 134 42 48 Higuchi Y Seo T Miyanishi T Kawasaki Y Suzuki M Sumiyoshi T Mismatch negativity and p3a/reorienting complex in subjects with schizophrenia or at-risk mental state Front Behav Neurosci 2014 8 172 Bodatsch M Ruhrmann S Wagner M Müller R Schultze-Lutter F Frommann I Prediction of psychosis by mismatch negativity Biol Psychiatry 2011 69 959 966 Laton J Van Schependom J Gielen J Decoster J Moons T De Keyser J Single-subject classification of schizophrenia patients based on a combination of oddball and mismatch evoked potential paradigms J Neurol Sci 2014 347 262 267 Hegerl U Juckel G Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis Biol Psychiatry 1993 33 173 187 Min JA Lee SH Lee SY Chae JH Lee CU Park YM Clinical characteristics associated with different strengths of loudness dependence of auditory evoked potentials (LDAEP) in major depressive disorder Psychiatry Res 2012 200 374 381 Hensch T Wargelius HL Herold U Lesch KP Oreland L Brocke B Further evidence for an association of 5-HTTLPR with intensity dependence of auditory-evoked potentials Neuropsychopharmacology 2006 31 2047 2054 Linka T Müller BW Bender S Sartory G The intensity dependence of the auditory evoked N1 component as a predictor of response to Citalopram treatment in patients with major depression Neurosci Lett 2004 367 375 378 Linka T Müller BW Bender S Sartory G Gastpar M The intensity dependence of auditory evoked ERP components predicts responsiveness to reboxetine treatment in major depression Pharmacopsychiatry 2005 38 139 143 Park YM Lee SH Kim S Bae SM The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls Prog Neuropsychopharmacol Biol Psychiatry 2010 34 313 316 Yang E Lee SH Oh S Kim S N100 amplitude slopes in major depressive disorder, bipolar disorder, schizophrenia and normal controls Korean J Biol Psychiatry 2009 16 181 189 Gudlowski Y Ozgürdal S Witthaus H Gallinat J Hauser M Winter C Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity Schizophr Res 2009 109 141 147 Park YM Jung E Kim HS Hahn SW Lee SH Differences in central serotoninergic transmission among patients with recent onset, sub-chronic, and chronic schizophrenia as assessed by the loudness dependence of auditory evoked potentials Schizophr Res 2015 168 180 184 Juckel G Serotonin: from sensory processing to schizophrenia using an electrophysiological method Behav Brain Res 2015 277 121 124 Woolley DW Shaw E A biochemical and pharmacological suggestion about certain mental disorders Proc Natl Acad Sci U S A 1954 40 228 231 Van Veelen NM Kahn RS Dopamine, serotonin, and schizophrenia Adv Neurol 1999 80 425 429 Ngan ET Yatham LN Ruth TJ Liddle PF Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: a PET study using [(18)F]setoperone Am J Psychiatry 2000 157 1016 1018 Eastwood SL Burnet PW Gittins R Baker K Harrison PJ Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia Synapse 2001 42 104 114 Kidmose P Looney D Ungstrup M Rank ML Mandic DP A study of evoked potentials from ear-EEG IEEE Trans Biomed Eng 2013 60 2824 2830 Rass O Krishnan G Brenner CA Hetrick WP Merrill CC Shekhar A Auditory steady state response in bipolar disorder: relation to clinical state, cognitive performance, medication status, and substance disorders Bipolar Disord 2010 12 793 803 Thuné H Recasens M Uhlhaas PJ The 40-Hz auditory steady-state response in patients with schizophrenia: a meta-analysis JAMA Psychiatry 2016 73 1145 1153 Maran M Grent T Uhlhaas PJ Electrophysiological insights into connectivity anomalies in schizophrenia: a systematic review Neuropsychiatric Electrophysiology 2016 2 6 Javitt DC Sweet RA Auditory dysfunction in schizophrenia: integrating clinical and basic features Nat Rev Neurosci 2015 16 535 550 Leicht G Andreou C Polomac N Lanig C Schöttle D Lambert M Reduced auditory evoked gamma band response and cognitive processing deficits in first episode schizophrenia World J Biol Psychiatry 2015 16 387 397 Puvvada KC Summerfelt A Du X Krishna N Kochunov P Rowland LM Delta vs gamma auditory steady state synchrony in schizophrenia Schizophr Bull 2018 44 378 387 Kim S Jang SK Kim DW Shim M Kim YW Im CH Cortical volume and 40-Hz auditory-steady-state responses in patients with schizophrenia and healthy controls Neuroimage Clin 2019 22 101732 Hong LE Summerfelt A McMahon R Adami H Francis G Elliott A Evoked gamma band synchronization and the liability for schizophrenia Schizophr Res 2004 70 293 302 Hall MH Taylor G Sham P Schulze K Rijsdijk F Picchioni M The early auditory gamma-band response is heritable and a putative endophenotype of schizophrenia Schizophr Bull 2011 37 778 787 Rass O Forsyth JK Krishnan GP Hetrick WP Klaunig MJ Breier A Auditory steady state response in the schizophrenia, firstdegree relatives, and schizotypal personality disorder Schizophr Res 2012 136 143 149 McNally JM McCarley RW Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities Curr Opin Psychiatry 2016 29 202 210 Kim T Thankachan S McKenna JT McNally JM Yang C Choi JH Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations Proc Natl Acad Sci U S A 2015 112 3535 3540 Steullet P Cabungcal JH Monin A Dwir D O'Donnell P Cuenod M Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology? Schizophr Res 2016 176 41 51 Cohen SM Tsien RW Goff DC Halassa MM The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia Schizophr Res 2015 167 98 107 Hall MH Chen CY Cohen BM Spencer KM Levy DL Öngür D Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report Am J Med Genet B Neuropsychiatr Genet 2015 168B 151 161 Sivarao DV Chen P Senapati A Yang Y Fernandes A Benitex Y 40 Hz auditory steady-state response is a pharmacodynamic biomarker for cortical NMDA receptors Neuropsychopharmacology 2016 41 2232 2240 O'Donnell BF Vohs JL Krishnan GP Rass O Hetrick WP Morzorati SL The auditory steady-state response (ASSR): a translational biomarker for schizophrenia Suppl Clin Neurophysiol 2013 62 101 112 Bolaños M Bernat EM He B Aviyente S A weighted small world network measure for assessing functional connectivity J Neurosci Methods 2013 212 133 142 Fraschini M Hillebrand A Demuru M Didaci L Marcialis GL An EEG-based biometric system using eigenvector centrality in resting state brain networks IEEE Signal Process Lett 2015 22 666 670 Liu Q Ganzetti M Wenderoth N Mantini D Detecting large-scale brain networks using EEG: impact of electrode density, head modeling and source localization Front Neuroinform 2018 12 4 Micheloyannis S Graph-based network analysis in schizophrenia World J Psychiatry 2012 2 1 12 Yin Z Li J Zhang Y Ren A Von Meneen KM Huang L Functional brain network analysis of schizophrenic patients with positive and negative syndrome based on mutual information of EEG time series Biomed Signal Process Control 2017 31 331 338 Shim M Kim DW Lee SH Im CH Disruptions in small-world cortical functional connectivity network during an auditory oddball paradigm task in patients with schizophrenia Schizophr Res 2014 156 197 203 Strelets VB Novototsky-Vlasov VY Golikova JV Cortical connectivity in high frequency beta-rhythm in schizophrenics with positive and negative symptoms Int J Psychophysiol 2002 44 101 115 Zhou Y Liang M Tian L Wang K Hao Y Liu H Functional disintegration in paranoid schizophrenia using resting-state fMRI Schizophr Res 2007 97 194 205 The figure on the left shows topography of the beta wave activity of schizophrenia patients with AH, and schizophrenia patients with N-AH (A). The right figure shows activated regions of the brain in AH compared to N-AH by calculating the signal source activity of quantified brainwaves in the LORETA program; increased areas in the beta 1 band (B) and increased areas in the beta 2 band (C). Adapted from Lee et al. Schizophr Res 2006;83:111-119.<xref ref-type="bibr" rid="B10">10)</xref> AH : Auditory hallucinations, N-AH : Non-auditory hallucinations, LORETA : Low resolution electromagnetic tomography. While the P50 paradigm waveform of the healthy controls shows a significant decrease in the width of S2 compared to S1, there is no significant difference between S1 and S2 in schizophrenia (A). This is the result of reflecting abnormalities in the auditory gating of patients with schizophrenia. Treatment of schizophrenia can normalize these P50s, with treatments that increase the amplitude of S1 and treatments that reduce the amplitude of S2 (B). Adapted from Smucny et al. Transl Psychiatry 2015;5:e587.<xref ref-type="bibr" rid="B21">21)</xref> S1 : First stimulus, S2 : Second stimulus, Sz : Schizophrenia. Mean event-related potentials waveform for patients with schizophrenia and healthy controls (arrow indicates P300). Adapted from Kim et al. Brain Topogr 2014;27:307-317.<xref ref-type="bibr" rid="B31">31)</xref> Topographic maps of MMN of patients with schizophrenia and bipolar disorder patients and healthy controls (A); Comparison of Three Group MMN amplitude at FCz (B). Adapted from Kim et al. Schizophr Bull 2019;45:425-435.<xref ref-type="bibr" rid="B53">53)</xref> MMN : Mismatch negativity. Comparison of event-related potentials waveforms by sound loudness between patients with recent-onset, sub-chronic and chronic schizophrenia and healthy controls (A). LDAEP comparison between patients with recent-onset, sub-chronic and chronic schizophrenia and healthy controls (B). LDAEP comparison between all schizophrenia patients and healthy controls (C). Adapted from Park et al. Schizophr Res 2015;168:180-184.<xref ref-type="bibr" rid="B69">69)</xref> LDAEP : Loudness dependence of auditory evoked potential. ASSR comparison between patients with SZ and HCs. If the inter-train interval (3050-3500 ms) between each sound stimulation is given longer than the existing study paradigm, patients with SZ report greater ASSR activity than HCs. Adapted from Kim et al. Neuroimage Clin 2019;22:101732.<xref ref-type="bibr" rid="B82">82)</xref> SZ : Schizophrenia, HC : Healthy control. The node points where the clustering coefficient is reduced in patients with schizophrenia compared to healthy controls are shown. Adapted from Shim et al. Schizophr Res 2014;156:197-203.<xref ref-type="bibr" rid="B98">98)</xref>