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Research Paper

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

Vicente Molina, Alba Lubeiro, Rodrigo de Luis Garcia, Javier Gomez-Pilar, Oscar Martín-Santiago, María Iglesias-Tejedor, Pedro Holgado-Madera, Rafael Segarra-Echeverría, María Recio-Barbero, Pablo Núñez, Mahmoud Karim Haidar, Jessica Fernández-Sevillano and Javier Sanz-Fuentenebro
J Psychiatry Neurosci September 01, 2020 45 (5) 322-333; DOI: https://doi.org/10.1503/jpn.190032
Vicente Molina
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Alba Lubeiro
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Rodrigo de Luis Garcia
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Javier Gomez-Pilar
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Oscar Martín-Santiago
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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María Iglesias-Tejedor
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Pedro Holgado-Madera
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Rafael Segarra-Echeverría
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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María Recio-Barbero
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Pablo Núñez
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Mahmoud Karim Haidar
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Jessica Fernández-Sevillano
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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Javier Sanz-Fuentenebro
From the Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain (Molina, Lubeiro); the Psychiatry Service, Clinical Hospital of Valladolid, Valladolid, Spain (Molina, Martín-Santiago); the Neurosciences Institute of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain (Molina); the Imaging Processing Laboratory, University of Valladolid, Valladolid, Spain (de Luis Garcia); the Biomedical Engineering Group, University of Valladolid, Valladolid, Spain (Gomez-Pilar, Núñez); the Neurophysiology Service, Clinical Hospital of Valladolid, Valladolid, Spain (Iglesias-Tejedor); the Psychiatry Service, Doce de Octubre University Hospital, Madrid, Spain (Holgado-Madera, Sanz-Fuentenebro); the Psychiatry Service, Cruces Hospital, Bilbao, Spain (Segarra-Echeverría, Recio-Barbero); and the Psychiatry Service, Santiago Apostol Hospital, Vitoria, Spain (Haidar, Fernández-Sevillano)
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    Fig. 1

    Spectral entropy modulation (factor scores): individual distributions and 95% confidence intervals (CI).

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    Fig. 2

    Spatial distribution of spectral entropy (SE) and median frequency (MF) at baseline and response windows, and its difference (modulation) in each group, with corresponding intragroup statistical significance difference between windows (Wilcoxon test). Shading depicts the corresponding regional values in Hertz for median frequency. Between-group comparisons are shown in the text.

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    Fig. 3

    Spectral entropy modulation 95% confidence intervals (CI) at frontal (F), frontocentral (Fc), and parietal (P) electrodes.

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    Fig. 4

    Graphs showing the absence of a relation between spectral entropy modulation and treatment. (A) Spectral entropy modulation values in patients with bipolar disorder receiving antipsychotic treatment or not. (B) Association between current treatment antipsychotic doses and spectral entropy modulation. (C) Association between illness duration and spectral entropy modulation.

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    Fig. 5

    Scatterplots showing the relationship between spectral entropy modulation and (A) negative symptom scores and performance in (B) verbal and (C) working memory in patients with schizophrenia (p < 0.05; see text). BACS = Brief Assessment of Cognition in Schizophrenia; PANSS = Positive and Negative Syndrome Scale.

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    Table 1

    Demographic, clinical, cognitive and EEG characteristics for each study group*

    CharacteristicChronic schizophrenia (n = 48)First-episode schizophrenia (n = 31)Bipolar disorder (n = 29)Control (n = 48)
    Sex, M/F29/1919/1217/1226/22
    Age, yr38.93 ± 9.4930.61 ± 10.14†46.40 ± 10.4541.77 ± 8.97
    Illness duration, mo156.17 ± 115.6223.375 ± 58.70§189.21 ± 106.04NA
    Antipsychotic dose, CPZ eq, mg/d447.48 ± 412.95357.40 ± 227.11166.1 ± 155.87‡NA
    Atypical antipsychotic, n483117NA
    Benzodiazepine, n2097NA
    Antidepressant, n1246NA
    Lithium, nNANA17NA
    Anticonvulsant, nNANA5NA
    Education, yr13.71 ± 4.0915.47 ± 3.0015.80 ± 1.7813.20 ± 5.44
    Parental education, yr11.00 ± 4.5113.21 ± 4.1710.00 ± 2.449.63 ± 3.92
    PANSS positive score11.4 ± 4.2510.63 ± 2.777.36 ± 0.83‡NA
    PANSS negative score17.75 ± 8.7314.83 ± 4.229.05 ± 2.48‡NA
    PANSS total score56.07 ± 21.2547.6 ± 11.1830.57 ± 3.32‡NA
    Young Mania Rating Scale score0.83 ± 1.910.22 ± 0.711.81 ± 1.34NA
    Hamilton Depression Rating Scale score5.77 ± 4.295.91 ± 4.184.98 ± 3.81NA
    Brief Assessment of Cognition in Schizophrenia score
     Verbal memory32.75 ± 14.87‡37.62 ± 10.57‡36.00 ± 9.25‡48.55 ± 8.53
     Working memory15.97 ± 4.85‡16.38 ± 4.62‡17.57 ± 4.03‡22.04 ± 3.35
     Motor speed61.42 ± 21.29‡55.57 ± 15.16‡66.10 ± 13.67‡76.90 ± 13.79
     Verbal fluency17.37 ± 7.04‡16.79 ± 7.31‡19.78 ± 7.87†27.21 ± 7.41
     Performance speed39.76 ± 15.30‡45.11 ± 13.12‡41.84 ± 12.40‡65.76 ± 14.57
     Problem-solving16.52 ± 4.6015.24 ± 3.9315.94 ± 3.3017.18 ± 3.23
    MSCEIT score92.38 ± 23.51‡101.27 ± 18.69‡104.05 ± 22.09‡120.61 ± 22.27
    Total IQ95.27 ± 14.07‡87.50 ± 14.70‡98.31 ± 10.23‡115.11 ± 10.39
    P300 amplitude, mV1.04 ± 0.611.20 ± 0.701.23 ± 0.631.58 ± 0.76
    P300 latency, ms423.22 ± 95.43455.13 ± 87.39464.69 ± 96.11458.54 ± 71.40
    Spectral entropy modulation, factor score0.198 ± 0.134‡0.067 ± 0.183†0.536 ± 0.185§−0.345 ± 0.134
    Structural small-world index0.97 ± 0.01†(n = 21)0.98 ± 0.00 (n = 18)0.97 ± 0.01† (n = 21)0.98 ± 0.00 (n = 20)
    Structural connectivity strength0.31 ± 0.03§ (n = 21)0.34 ± 0.01 (n = 18)0.30 ± 0.03§ (n = 21)0.34 ± 0.03 (n = 20)
    • CPZ eq = chlorpromazine equivalent; EEG = electroencephalogram; IQ = intelligence quotient; MSCEIT = Meyer, Salovey and Caruso Emotional Intelligence Test; NA = not applicable; PANSS = Positive and Negative Syndrome Scale.

    • ↵* Spectral entropy modulation values correspond to factor scores from the factor analysis (see text).

    • Findings are presented as mean ± standard deviation, unless otherwise indicated.

      Significant differences with respect to controls are highlighted (†p < 0.05; ‡p < 0.01; §p < 0.001). For PANSS scores, illness duration and treatment doses, differences were calculated between patient groups only.

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Journal of Psychiatry and Neuroscience: 45 (5)
J Psychiatry Neurosci
Vol. 45, Issue 5
1 Sep 2020
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Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?
Vicente Molina, Alba Lubeiro, Rodrigo de Luis Garcia, Javier Gomez-Pilar, Oscar Martín-Santiago, María Iglesias-Tejedor, Pedro Holgado-Madera, Rafael Segarra-Echeverría, María Recio-Barbero, Pablo Núñez, Mahmoud Karim Haidar, Jessica Fernández-Sevillano, Javier Sanz-Fuentenebro
J Psychiatry Neurosci Sep 2020, 45 (5) 322-333; DOI: 10.1503/jpn.190032

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Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?
Vicente Molina, Alba Lubeiro, Rodrigo de Luis Garcia, Javier Gomez-Pilar, Oscar Martín-Santiago, María Iglesias-Tejedor, Pedro Holgado-Madera, Rafael Segarra-Echeverría, María Recio-Barbero, Pablo Núñez, Mahmoud Karim Haidar, Jessica Fernández-Sevillano, Javier Sanz-Fuentenebro
J Psychiatry Neurosci Sep 2020, 45 (5) 322-333; DOI: 10.1503/jpn.190032
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