Neurophysiological differences between patients clinically at high risk for schizophrenia and neurotypical controls – first steps in development of a biomarker

BMC Medicine

Joseph Gonzalez-Heydrich²  Alexander Rotenberg¹  Eugene D’Angelo²  Frank H. Duffy¹ 

[1] Department of Neurology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Boston 02115, Massachusetts, USA;Department of Psychiatry, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Boston 02115, Massachusetts, USA

关键词: Schizophrenia;    Prodrome;    Principal component analysis;    Frequency modulated auditory evoked response;    Electroencephalogram spectral coherence;    Discriminant function analysis;    Clinical high risk;    Biomarker;   

Others  :  1231046
DOI  :  10.1186/s12916-015-0516-z

 received in 2015-05-07, accepted in 2015-10-19,  发布年份 2015

【 摘 要 】

Background

Schizophrenia is a severe, disabling and prevalent mental disorder without cure and with a variable, incomplete pharmacotherapeutic response. Prior to onset in adolescence or young adulthood a prodromal period of abnormal symptoms lasting weeks to years has been identified and operationalized as clinically high risk (CHR) for schizophrenia. However, only a minority of subjects prospectively identified with CHR convert to schizophrenia, thereby limiting enthusiasm for early intervention(s). This study utilized objective resting electroencephalogram (EEG) quantification to determine whether CHR constitutes a cohesive entity and an evoked potential to assess CHR cortical auditory processing.

Methods

This study constitutes an EEG-based quantitative neurophysiological comparison between two unmedicated subject groups: 35 neurotypical controls (CON) and 22 CHR patients. After artifact management, principal component analysis (PCA) identified EEG spectral and spectral coherence factors described by associated loading patterns. Discriminant function analysis (DFA) determined factors’ discrimination success between subjects in the CON and CHR groups. Loading patterns on DFA-selected factors described CHR-specific spectral and coherence differences when compared to controls. The frequency modulated auditory evoked response (FMAER) explored functional CON–CHR differences within the superior temporal gyri.

Results

Variable reduction by PCA identified 40 coherence-based factors explaining 77.8 % of the total variance and 40 spectral factors explaining 95.9 % of the variance. DFA demonstrated significant CON–CHR group difference (P <0.00001) and successful jackknifed subject classification (CON, 85.7 %; CHR, 86.4 % correct). The population distribution plotted along the canonical discriminant variable was clearly bimodal. Coherence factors delineated loading patterns of altered connectivity primarily involving the bilateral posterior temporal electrodes. However, FMAER analysis showed no CON–CHR group differences.

Conclusions

CHR subjects form a cohesive group, significantly separable from CON subjects by EEG-derived indices. Symptoms of CHR may relate to altered connectivity with the posterior temporal regions but not to primary auditory processing abnormalities within these regions.

【 授权许可】

   
2015 Duffy et al.

【 图 表 】

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【 参考文献 】

• [1]Saha S, Whiteford H, McGrath J. Modelling the incidence and mortality of psychotic disorders: data from the second Australian national survey of psychosis. Aust N Z J Psychiatry. 2014; 48(4):352-9.
• [2]Hogerzeil SJ, van Hemert AM, Rosendaal FR, Susser E, Hoek HW. Direct comparison of first-contact versus longitudinal register-based case finding in the same population: early evidence that the incidence of schizophrenia may be three times higher than commonly reported. Psychol Med. 2014; 44(16):3481-90.
• [3]Larson MK, Walker EF, Compton MT. Early signs, diagnosis and therapeutics of the prodromal phase of schizophrenia and related psychotic disorders. Expert Rev Neurother. 2010; 10(8):1347-59.
• [4]Bera RB. Patient outcomes within schizophrenia treatment: a look at the role of long-acting injectable antipsychotics. J Clin Psychiatry. 2014; 75 Suppl 2:30-3.
• [5]Quarantelli M, Palladino O, Prinster A. Patients with poor response to antipsychotics have a more severe pattern of frontal atrophy: a voxel-based morphometry study of treatment resistance in schizophrenia. Biomed Res Int. 2014; 2014:325052.
• [6]Lysaker PH, Roe D, Buck KD. Recovery and wellness amidst schizophrenia: definitions, evidence, and the implications for clinical practice. J Am Psychiatr Nurses Assoc. 2010; 16:36-42.
• [7]Silverstein SM, Bellack AS. A scientific agenda for the concept of recovery as it applies to schizophrenia. Clin Psychol Rev. 2008; 28(7):1108-24.
• [8]Harrow M, Jobe TH. How frequent is chronic multiyear delusional activity and recovery in schizophrenia: a 20-year multi-follow-up. Schizophr Bull. 2010; 36(1):192-204.
• [9]Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br Med J. 1987; 295:538-55.
• [10]Walker E, Lewis N, Loewy R, Palyo S. Motor dysfunction and risk for schizophrenia. Dev Psychopathol. 1999; 11(3):509-23.
• [11]Walker EF. Developmentally moderated expressions of the neuropathology underlying schizophrenia. Schizophr Bull. 1994; 20(3):453-80.
• [12]Schenkel LS, Silverstein SM. Dimensions of premorbid functioning in schizophrenia: a review of neuromotor, cognitive, social, and behavioral domains. Genet Soc Gen Psychol Monogr. 2004; 130(3):241-70.
• [13]Munro JC, Russell AJ, Murray RM, Kerwin RW, Jones PB. IQ in childhood psychiatric attendees predicts outcome of later schizophrenia at 21 year follow-up. Acta Psychiatr Scand. 2002; 106(2):139-42.
• [14]Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry. 1999; 156(9):1328-35.
• [15]Zipursky RB, Christensen BK, Mikulis DJ. Stable deficits in gray matter volumes following a first episode of schizophrenia. Schizophr Res. 2004; 71(2–3):515-6.
• [16]Olsen KA, Rosenbaum B. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatr Scand. 2006; 113(4):247-72.
• [17]Cadenhead KS. Vulnerability markers in the schizophrenia spectrum: implications for phenomenology, genetics, and the identification of the schizophrenia prodrome. Psychiatr Clin North Am. 2002; 25(4):837-53.
• [18]Mason O, Startup M, Halpin S, Schall U, Conrad A, Carr V. Risk factors for transition to first episode psychosis among individuals with ‘at-risk mental states’. Schizophr Res. 2004; 71(2–3):227-37.
• [19]McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller TJ, Woods SW et al.. The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design. Schizophr Res. 2003; 61(1):7-18.
• [20]Miller TJ, McGlashan TH, Rosen JL, Cadenhead K, Cannon T, Ventura J et al.. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003; 29(4):703-15.
• [21]Morrison AP, French P, Walford L, Lewis SW, Kilcommons A, Green J et al.. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004; 185:291-7.
• [22]Nieman DH, Rike WH, Becker HE, Dingemans PM, van Amelsvoort TA, de Haan L et al.. Prescription of antipsychotic medication to patients at ultra high risk of developing psychosis. Int Clin Psychopharmacol. 2009; 24(4):223-8.
• [23]Manninen M, Lindgren M, Therman S, Huttunen M, Ebeling H, Moilanen I et al.. Clinical high-risk state does not predict later psychosis in a delinquent adolescent population. Early Interv Psychiatry. 2014; 8(1):87-90.
• [24]Benton MK, Schroeder HE. Social skills training with schizophrenics: a meta-analytic evaluation. J Consult Clin Psychol. 1990; 58(6):741-7.
• [25]McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW et al.. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006; 163(5):790-9.
• [26]Ruhrmann S, Bechdolf A, Kuhn KU, Wagner M, Schultze-Lutter F, Janssen B et al.. Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis. Br J Psychiatry Suppl. 2007; 51:s88-95.
• [27]Woods SW, Tully EM, Walsh BC, Hawkins KA, Callahan JL, Cohen SJ et al.. Aripiprazole in the treatment of the psychosis prodrome: an open-label pilot study. Br J Psychiatry Suppl. 2007; 51:s96-101.
• [28]Combs DR, Adams SD, Penn DL, Roberts D, Tiegreen J, Stem P. Social cognition and interaction training (SCIT) for inpatients with schizophrenia spectrum disorders: preliminary findings. Schizophr Res. 2007; 91(1–3):112-6.
• [29]McGorry PD, Nelson B, Phillips LJ, Yuen HP, Francey SM, Thampi A et al.. Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome. J Clin Psychiatry. 2013; 74(4):349-56.
• [30]Amminger GP, Schafer MR, Schlogelhofer M, Klier CM, McGorry PD. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat Commun. 2015; 6:7934.
• [31]Lappin JM, Dazzan P, Morgan K, Morgan C, Chitnis X, Suckling J et al.. Duration of prodromal phase and severity of volumetric abnormalities in first-episode psychosis. Br J Psychiatry Suppl. 2007; 51:s123-127.
• [32]Ho BC. MRI brain volume abnormalities in young, nonpsychotic relatives of schizophrenia probands are associated with subsequent prodromal symptoms. Schizophr Res. 2007; 96(1–3):1-13.
• [33]Tognin S, Riecher-Rossler A, Meisenzahl EM, Wood SJ, Hutton C, Borgwardt SJ et al.. Reduced parahippocampal cortical thickness in subjects at ultra-high risk for psychosis. Psychol Med. 2014; 44(3):489-98.
• [34]Owens SF, Picchioni MM, Ettinger U, McDonald C, Walshe M, Schmechtig A et al.. Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia. Brain. 2012; 135(Pt 7):2231-44.
• [35]Duffy FH, Als H. A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls – a large case control study. BMC Med. 2012; 10(1):64.
• [36]Hughes JR, John ER. Conventional and quantitative electroencephalography in psychiatry. J Neuropsychiatry Clin Neurosci. 1999; 11(2):190-208.
• [37]van Drongelen W. Signal processing for neuroscientists: an introduction to the analysis of physiological signals. Elsevier, Oxford; 2011.
• [38]Press WH, Teukolsky SA, Vetterling WT, Flannery BP. Numerical Recipes in C: The Art of Scientific Computing. 2nd ed. Cambridge University Press, Cambridge; 1995.
• [39]Srinivasan V, Eswaran C, Sriraam N. Approximate entropy-based epileptic EEG detection using artificial neural networks. IEEE Trans Inf Technol Biomed. 2007; 11(3):288-95.
• [40]Morihisa JM, Duffy FH, Wyatt RJ. Topographic analysis of computer processed electroencephalography in schizophrenia. In: Biological markers in neurology and psychiatry. Usdin E, Hanin I, editors. Pergamon Press, New York; 1982: p.495-504.
• [41]Morstyn R, Duffy FH, McCarley RW. Altered topography of EEG spectral content in schizophrenia. Electroencephalogr Clin Neurophysiol. 1983; 65:263-71.
• [42]Karson CN, Coppola R, Morihisa JM, Weinberger DR. Computed electroencephalographic activity mapping in Schizophrenia: the resting state reconsidered. Arch Gen Psychiatry. 1987; 44(6):514-7.
• [43]Stevens JR. Disturbances of ocular movements and blinking in schizophrenia. J Neurol Neurosurg Psychiatry. 1978; 41(11):1024-30.
• [44]Henshall KR, Sergejew AA, Rance G, McKay CM, Copolov DL. Interhemispheric EEG coherence is reduced in auditory cortical regions in schizophrenia patients with auditory hallucinations. Int J Psychophysiol. 2013; 89(1):63-71.
• [45]Kam JW, Bolbecker AR, O’Donnell BF, Hetrick WP, Brenner CA. Resting state EEG power and coherence abnormalities in bipolar disorder and schizophrenia. J Psychiatr Res. 2013; 47(12):1893-901.
• [46]Mann K, Maier W, Franke P, Roschke J, Gansicke M. Intra- and interhemispheric electroencephalogram coherence in siblings discordant for schizophrenia and healthy volunteers. Biol Psychiatry. 1997; 42(8):655-63.
• [47]Nagase Y, Okubo Y, Matsuura M, Kojima T, Toru M. EEG coherence in unmedicated schizophrenic patients: topographical study of predominantly never medicated cases. Biol Psychiatry. 1992; 32:1028-34.
• [48]Pachou E, Vourkas M, Simos P, Smit D, Stam CJ, Tsirka V et al.. Working memory in schizophrenia: an EEG study using power spectrum and coherence analysis to estimate cortical activation and network behavior. Brain Topogr. 2008; 21(2):128-37.
• [49]Wada Y, Nanbu Y, Jiang ZY, Koshino Y, Hashimoto T. Interhemispheric EEG coherence in never-medicated patients with paranoid schizophrenia: analysis at rest and during photic stimulation. Clin EEG. 1998; 29(4):170-6.
• [50]Wada Y, Nanbu Y, Kikuchi M, Koshino Y, Hashimoto T. Aberrant functional organization in schizophrenia: analysis of EEG coherence during rest and photic stimulation in drug-naive patients. Neuropsychobiology. 1998; 38(2):63-9.
• [51]Andreou C, Nolte G, Leicht G, Polomac N, Hanganu-Opatz IL, Lambert M et al.. Increased resting-state gamma-band connectivity in first-episode schizophrenia. Schizophr Bull. 2015; 41(4):930-9.
• [52]Bandyopadhyaya D, Nizamie SH, Pradhan N, Bandyopadhyaya A. Spontaneous gamma coherence as a possible trait marker of schizophrenia – an explorative study. Asian J Psychiatr. 2011; 4(3):172-7.
• [53]Chen CM, Stanford AD, Mao X, Abi-Dargham A, Shungu DC, Lisanby SH et al.. GABA level, gamma oscillation, and working memory performance in schizophrenia. Neuroimage Clin. 2014; 4:531-9.
• [54]Diez A, Suazo V, Casado P, Martin-Loeches M, Molina V. Gamma power and cognition in patients with schizophrenia and their first-degree relatives. Neuropsychobiology. 2014; 69(2):12012-8.
• [55]Diez A, Suazo V, Casado P, Martin-Loeches M, Perea MV, Molina V. Frontal gamma noise power and cognitive domains in schizophrenia. Psychiatry Res. 2014; 221(1):104-13.
• [56]Herrmann CS, Demiralp T. Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol. 2005; 116(12):2719-33.
• [57]Khan S, Gramfort A, Shetty NR, Kitzbichler MG, Ganesan S, Moran JM et al.. Local and long-range functional connectivity is reduced in concert in autism spectrum disorders. Proc Natl Acad Sci U S A. 2013; 110(8):3107-12.
• [58]McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry Rep. 2013; 15(3):346.
• [59]Roach BJ, Ford JM, Hoffman RE, Mathalon DH. Converging evidence for gamma synchrony deficits in schizophrenia. Suppl Clin Neurophysiol. 2013; 62:163-80.
• [60]Roach BJ, Mathalon DH. Event-related EEG time-frequency analysis: an overview of measures and an analysis of early gamma band phase locking in schizophrenia. Schizophr Bull. 2008; 34(5):907-26.
• [61]Whitham EM, Pope KJ, Fitzgibbon SP, Lewis T, Clark CR, Loveless S et al.. Scalp electrical recording during paralysis: quantitative evidence that EEG frequencies above 20 Hz are contaminated by EMG. Clin Neurophysiol. 2007; 118(8):1877-88.
• [62]Whitham EM, Lewis T, Pope KJ, Fitzgibbon SP, Clark CR, Loveless S et al.. Thinking activates EMG in scalp electrical recordings. Clin Neurophysiol. 2008; 119(5):1166-75.
• [63]Yuval-Greenberg S, Tomer O, Keren AS, Nelken I, Deouell LY. Transient induced gamma-band response in EEG as a manifestation of miniature saccades. Neuron. 2008; 58(3):429-41.
• [64]Yuval-Greenberg S, Deouell LY. The broadband-transient induced gamma-band response in scalp EEG reflects the execution of saccades. Brain Topogr. 2009; 22(1):3-6.
• [65]Melloni L, Schwiedrzik CM, Wibral M, Rodriguez E, Singer W. Response to: Yuval-Greenberg et al., ‘Transient induced gamma-band response in EEG as a manifestation of miniature saccades.’ Neuron 58, 429–441. Neuron. 2009; 62(1):8-10.
• [66]Yuval-Greenberg S, Deouell LY. Scalp-recorded induced gamma-band responses to auditory stimulation and its correlations with saccadic muscle-activity. Brain Topogr. 2011; 24(1):30-9.
• [67]Oertel-Knochel V, Bittner RA, Knochel C, Prvulovic D, Hampel H. Discovery and development of integrative biological markers for schizophrenia. Prog Neurobiol. 2011; 95(4):686-702.
• [68]Duffy FH, Eksioglu YZ, Rotenberg A, Madsen JR, Shankardass A, Als H. The frequency modulated auditory evoked response (FMAER), a technical advance for study of childhood language disorders: cortical source localization and selected case studies. BMC Neurol. 2013; 13(1):1-22.
• [69]Duffy FH, Shankardass A, McAnulty GB, Eksioglu YZ, Coulter D, Rotenberg A et al.. Corticosteroid therapy in regressive autism: a retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol. 2014; 14:70.
• [70]Fulham WR, Michie PT, Ward PB, Rasser PE, Todd J, Johnston PJ et al.. Mismatch negativity in recent-onset and chronic schizophrenia: a current source density analysis. PloS One. 2014; 9(6):e100221.
• [71]Oertel-Knochel V, Knochel C, Matura S, Stablein M, Prvulovic D, Maurer K et al.. Association between symptoms of psychosis and reduced functional connectivity of auditory cortex. Schizophr Res. 2014; 160(1–3):35-42.
• [72]Oertel-Knochel V, Knochel C, Matura S, Prvulovic D, Linden DE, van de Ven V. Reduced functional connectivity and asymmetry of the planum temporale in patients with schizophrenia and first-degree relatives. Schizophr Res. 2013; 147(2–3):331-8.
• [73]Bartels PH. Numerical evaluation of cytologic data. IX. Search for data structure by principal components transformation. Anal Quant Cytol. 1981; 3(3):167-77.
• [74]Duffy FH, Jones K, Bartels P, McAnulty G, Albert M. Unrestricted principal components analysis of brain electrical activity: Issues of data dimensionality, artifact, and utility. Brain Topogr. 1992; 4(4):291-307.
• [75]Duffy FH. Issues facing the clinical use of brain electrical activity. In: Functional Brain Imaging. Pfurtscheller G, Lopes Da Silva F, editors. Hans Huber Publishers, Stuttgart; 1988: p.149-60.
• [76]Diagnostic Interview: Kiddie-Sads-Present and Lifetime. Version (K-SADS-PL). http://www. psychiatry.pitt.edu/sites/default/files/Documents/assessments/ksads-pl.pdf webcite
• [77]Lu Z, Heeramun-Aubeeluck A. Cognitive markers in schizophrenia prodrome: a review. ASEAN J Psychiatry. 2012; 13:1-21.
• [78]Miller TJ, McGlashan TH, Woods SW, Stein K, Driesen N, Corcoran CM et al.. Symptom assessment in schizophrenic prodromal states. Psychiatr Q. 1999; 70(4):273-87.
• [79]McGlashan TH, Miller TJ, Woods SW, Hoffman RE, Davidson L. A scale for the assessment of prodromal symptoms and states. In: Early Intervention in Psychotic Disorders. Miller TJ, Mednick SA, McGlashan TH, Libiger J, Johannessen JO, editors. Kluwer Academic Publishing, Dordrecht; 2001: p.135-50.
• [80]McGlashan TH, Walsh BC, Woods DL. Structured Interview for Psychosis – Risk Syndromes, Version 5.0. Prime Research Clinic; Yale School of Medicine, New Haven; 2010.
• [81]Bruininks R, Woodcock R, Weatherman R. Scales of independent behavior – revised. Riverside Publishing, Rolling Meadows; 1997.
• [82]Green GGR, Kay RH, Rees A. Responses evoked by frequency-modulated sounds recorded from the human scalp. J Physiol. 1979; 296:21-22P.
• [83]Green GGR, Rees A, Stefanatos GA. A method for recording evoked responses to frequency modulated sounds in man. J Physiol. 1980; 307:10p.
• [84]Stefanatos GA. Speech perceived through a damaged temporal window: lessons from word deafness and aphasia. Semin Speech Lang. 2008; 29(3):239-52.
• [85]Stefanatos GA, Foley C, Grover W, Doherty B. Steady-state auditory evoked responses to pulsed frequency modulations in children. Electroencephalogr Clin Neurophysiol. 1997; 104:31-42.
• [86]Stefanatos GA, Green GGR, Ratcliff GG. Neurophysiological evidence of auditory channel anomalies in developmental dysphasia. Arch Neurol. 1989; 46(8):871-5.
• [87]Berg P, Scherg M. Dipole modeling of eye activity and its application to the removal of eye artifacts from EEG and MEG. Clin Phys Physiol Meas. 1991; 12 Suppl A:49-54.
• [88]Berg P, Scherg M. A multiple source approach to the correction of eye artifacts. Electroencephalogr Clin Neurophysiol. 1994; 90:229-41.
• [89]Lins OG, Picton TW, Berg P, Scherg M. Ocular artefacts in recording EEGs and event related potentials II: Source dipoles and source components. Brain Topogr. 1993; 6:65-78.
• [90]Srinvasan R, Winter WR, Ding J, Nunez PL. EEG and MEG coherence: measures of functional connectivity at distinct spatial scales of neocortical dynamics. J Neurosci Methods. 2007; 166(1):41-52.
• [91]Semlitsch HV, Anderer P, Schuster P, Presslich O. A solution for reliable and valid reduction of ocular artifacts, applied to the P300 ERP. Psychophysiology. 1986; 23(6):695-703.
• [92]Dixon WJ. BMDP Statistical Software Manual: To accompany BMDP 7.0 software release. University of California Press, Berkeley; 1992.
• [93]Bartels PH. Numerical evaluation of cytologic data VIII. Computation of the principal components. Anal Quant Cytol. 1981; 3(2):83-90.
• [94]Martinez LM, Martinez AR, Solka JL. Exploratory Data Analysis with MATLAB. nth ed. Chapman and Hall/CRC, London; 2011.
• [95]Han J, Kamber M, Pei J. Data Mining, Concepts and Techniques. 3rd ed. Morgan Kaufmann, Boston; 2012.
• [96]Cooley WW, Lohnes PR. Multivariate Data Analysis. Wiley, New York; 1971.
• [97]Duffy FH, Burchfiel JL, Lombroso CT. Brain electrical activity mapping (BEAM): a method for extending the clinical utility of EEG and evoked potential data. Ann Neurol. 1979; 5:309-21.
• [98]Duffy FH, Bartels PH, Burchfiel JL. Significance probability mapping: an aid in the topographic analysis of brain electrical activity. Electroencephalogr Clin Neurophysiol. 1981; 51:455-62.
• [99]Duffy FH, Jones KH, McAnulty GB, Albert MS. Spectral coherence in normal adults: unrestricted principal components analysis – relation of factors to age, gender, and neuropsychologic data. Clin EEG. 1995; 26(1):30-46.
• [100]Duffy FH, Als H, McAnulty GB. Infant EEG spectral coherence data during quiet sleep: unrestricted principal components analysis – relation of factors to gestational age, medical risk, and neurobehavioral status. Clin EEG. 2003; 34(2):54-69.
• [101]Duffy FH, McAnulty GM, McCreary MC, Cuchural GJ, Komaroff AL. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients – a case control study. BMC Neurol. 2011; 11:82.
• [102]Duffy F, Shankardass A, McAnulty G, Als H. The relationship of Asperger’s syndrome to autism: a preliminary EEG coherence study. BMC Med. 2013; 11:175.
• [103]Bartels PH. Numerical evaluation of cytologic data IV. Discrimination and classification. Anal Quant Cytol. 1980; 2(1):19-24.
• [104]Marascuilo LA, Levin JR. Multivariate Statistics in the Social Sciences: A Researchers Guide. Brooks/Cole Publishing Co., Monterey; 1983.
• [105]Lachenbruch PA, Mickey RM. Estimation of error rates in discriminant analysis. Technometrics. 1968; 10:1-11.
• [106]Lachenbruch PA. Discriminant Analysis. Hafner Press, New York; 1975.
• [107]Chernick MR. Bootstrap Methods: A Guide for Practitioners and Researchers. 2nd ed. Wiley, Hoboken; 2008.
• [108]Dixon WJ. BMDP Statistical Software (revised edition). University of California Press, Berkeley; 1985.
• [109]Foley DH. Consideration of sample and feature size. IEEE Trans Inform Theory. 1972; 18(5):618-26.
• [110]Bartels PH. Numerical evaluation of cytologic data III. Selection of features for discrimination. Anal Quant Cytol. 1979; 1:153-9.
• [111]Arnold SE. The medial temporal lobe in schizophrenia. J Neuropsychiatry Clin Neurosci. 1997; 9(3):460-70.
• [112]Cullen AE, De Brito SA, Gregory SL, Murray RM, Williams SC, Hodgins S et al.. Temporal lobe volume abnormalities precede the prodrome: a study of children presenting antecedents of schizophrenia. Schizophr Bull. 2013; 39(6):1318-27.
• [113]Lawrie SM, Whalley HC, Abukmeil SS, Kestelman JN, Miller P, Best JJ et al.. Temporal lobe volume changes in people at high risk of schizophrenia with psychotic symptoms. Br J Psychiatry. 2002; 181:138-43.
• [114]Mathew I, Gardin TM, Tandon N, Eack S, Francis AN, Seidman LJ et al.. Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. JAMA Psychiatry. 2014; 71(7):769-77.
• [115]Roth WT, Pfefferbaum A. Abnormalities of the left temporal lobe in schizophrenia. N Engl J Med. 1992; 327(23):1689-90.
• [116]Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG et al.. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. NEJM. 1992; 327(9):604-12.
• [117]Smiley JF, Rosoklija G, Mancevski B, Pergolizzi D, Figarsky K, Bleiwas C et al.. Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains. Psychiatry Res. 2011; 192(1):1-11.
• [118]Suddath RL, Casanova MF, Goldberg TE, Daniel DG, Kelsoe JR, Weinberger DR. Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. Am J Psychiatry. 1989; 146(4):464-72.
• [119]Sundram F, Cannon M, Doherty CP, Barker GJ, Fitzsimons M, Delanty N et al.. Neuroanatomical correlates of psychosis in temporal lobe epilepsy: voxel-based morphometry study. Br J Psychiatry. 2010; 197(6):482-92.
• [120]Covington MA, He C, Brown C, Naci L, McClain JT, Fjordbak BS et al.. Schizophrenia and the structure of language: the linguist’s view. Schizophr Res. 2005; 77(1):85-98.
• [121]Thermenos HW, Whitfield-Gabrieli S, Seidman LJ, Kuperberg G, Juelich RJ, Divatia S et al.. Altered language network activity in young people at familial high-risk for schizophrenia. Schizophr Res. 2013; 151(1–3):229-37.
• [122]Mou X, Bai F, Xie C, Shi J, Yao Z, Hao G et al.. Voice recognition and altered connectivity in schizophrenic patients with auditory hallucinations. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 44:265-70.
• [123]Lisman J. Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr Opin Neurobiol. 2012; 22:537-44.
• [124]Lisman JE, Pi HJ, Zhang Y, Otmakhova NA. A thalamo-hippocampal-ventral tegmental area Loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol Psychiatry. 2010; 68:17-24.
• [125]Zhang Y, Llinas RR, Lisman JE. Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting. Front Neural Circuits. 2009; 3:1-9.