UNLABELLED: Schizophrenia is a complex disorder characterized by altered brain functional connectivity, detectable during both task and resting state conditions using different neuroimaging methods. To this day, electroencephalography (EEG) studies have reported inconsistent results, showing both hyper- and hypo-connectivity with diverse topographical distributions. Interpretation of these findings is complicated by volume-conduction effects, where local brain activity fluctuations project simultaneously to distant scalp regions (zero-phase lag), inducing spurious inter-electrode correlations. AIM: In the present study, we explored the network dynamics of schizophrenia using a novel functional connectivity metric-corrected imaginary phase locking value (ciPLV)-which is insensitive to changes in amplitude as well as interactions at zero-phase lag. This method, which is less prone to volume conduction effects, provides a more reliable estimate of sensor-space functional network connectivity in schizophrenia. METHODS: We employed a cross-sectional design, utilizing resting state EEG recordings from two adult groups: individuals diagnosed with chronic schizophrenia (n = 30) and a control group of healthy participants (n = 30), all aged between 18 and 55 years old. RESULTS: Our observations revealed that schizophrenia is characterized by a prevalence of excess theta (4-8 Hz) power localized to centroparietal electrodes. This was accompanied by significant alterations in inter- and intra-hemispheric functional network connectivity patterns, mainly between frontotemporal regions within the theta band and frontoparietal regions within beta/gamma bands. CONCLUSIONS: Our findings suggest that patients with schizophrenia demonstrate long-range electrophysiological connectivity abnormalities that are independent of spectral power (i.e., volume conduction). Overall, distinct hemispheric differences were present in frontotemporo-parietal networks in theta and beta/gamma bands. While preliminary, these alterations could be promising new candidate biomarkers of chronic schizophrenia.

Center for Biomedical Imaging Geneva Lausanne Switzerland

Department of Clinical Neuroscience University of Geneva Geneva Switzerland

Department of Psychiatry Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

Doctoral School in the Social Sciences Jagiellonian University Krakow Poland

Institute of Psychology Jagiellonian University Krakow Poland

Life Quality Research Centre Sport Science School of Rio Maior Rio Maior Portugal

Zobrazit více v PubMed

Andreou, C. , Leicht G., Nolte G., et al. 2015. “Resting‐State Theta‐Band Connectivity and Verbal Memory in Schizophrenia and in the High‐Risk State.” Schizophrenia Research 161, no. 2–3: 299–307. 10.1016/j.schres.2014.12.018. PubMed DOI

Andreou, C. , Nolte G., Leicht G., et al. 2015. “Increased Resting‐State Gamma‐Band Connectivity in First‐Episode Schizophrenia.” Schizophrenia Bulletin 41, no. 4: 930–939. 10.1093/schbul/sbu121. PubMed DOI PMC

Baradits, M. , Kakuszi B., Balint S., et al. 2019. “Alterations in Resting‐State Gamma Activity in Patients with Schizophrenia: A High‐Density EEG Study.” European Archives of Psychiatry and Clinical Neuroscience 269, no. 4: 429–437. 10.1007/s00406-018-0889-z. PubMed DOI

Bastos, A. M. , and Schoffelen J. M.. 2015. “A Tutorial Review of Functional Connectivity Analysis Methods and Their Interpretational Pitfalls.” Frontiers in Systems Neuroscience 9: 175. 10.3389/fnsys.2015.00175. PubMed DOI PMC

Bigdely‐Shamlo, N. , Kreutz‐Delgado K., Kothe C., and Makeig S.. 2013. “EyeCatch: Data‐Mining Over Half a Million EEG Independent Components to Construct a Fully‐Automated Eye‐Component Detector.” In Proceedings of the 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), edited by Bigdely‐Shamlo N., Kreutz‐Delgado K., Kothe C., and Makeig S., 5845–5848. IEEE. PubMed PMC

Bigdely‐Shamlo, N. , Mullen T., Kothe C., Su K.‐M., and Robbins K. A.. 2015. “The PREP Pipeline: Standardized Preprocessing for Large‐Scale EEG Analysis.” Frontiers in Neuroinformatics 9: 16. 10.3389/fninf.2015.00016. PubMed DOI PMC

Bowie, C. R. , Reichenberg A., Patterson T. L., Heaton R. K., and Harvey P. D.. 2006. “Determinants of Real‐World Functional Performance in Schizophrenia Subjects: Correlations With Cognition, Functional Capacity, and Symptoms.” American Journal of Psychiatry 163, no. 3: 418–425. 10.1176/appi.ajp.163.3.418. PubMed DOI

Bruna, R. , Maestu F., and Pereda E.. 2018. “Phase Locking Value Revisited: Teaching New Tricks to an Old Dog.” Journal of Neural Engineering 15, no. 5: 056011. 10.1088/1741-2552/aacfe4. PubMed DOI

Buzsaki, G. , and Draguhn A.. 2004. “Neuronal Oscillations in Cortical Networks.” Science 304, no. 5679: 1926–1929. 10.1126/science.1099745. PubMed DOI

Cao, Y. , Han C., Peng X., et al. 2022. “Correlation Between Resting Theta Power and Cognitive Performance in Patients With Schizophrenia.” Frontiers in Human Neuroscience 16: 853994. 10.3389/fnhum.2022.853994. PubMed DOI PMC

Castellanos, N. P. , and Makarov V. A.. 2006. “Recovering EEG Brain Signals: Artifact Suppression With Wavelet Enhanced Independent Component Analysis.” Journal of Neuroscience Methods 158, no. 2: 300–312. 10.1016/j.jneumeth.2006.05.033. PubMed DOI

Chang, Y. , Wang X., Liao J., et al. 2024. “Temporal Hyper‐Connectivity and Frontal Hypo‐Connectivity Within Gamma Band in Schizophrenia: A Resting State EEG Study.” Schizophrenia Research 264: 220–230. 10.1016/j.schres.2023.12.017. PubMed DOI

de Cheveigné, A. 2020. “ZapLine: A Simple and Effective Method to Remove Power Line Artifacts.” Neuroimage 207: 116356. 10.1016/j.neuroimage.2019.116356. PubMed DOI

di Lorenzo, G. , Daverio A., Ferrentino F., et al. 2015. “Altered Resting‐State EEG Source Functional Connectivity in Schizophrenia: The Effect of Illness Duration.” Frontiers in Human Neuroscience 9: 234. 10.3389/fnhum.2015.00234. PubMed DOI PMC

Fingelkurts, A. A. , Fingelkurts A. A., and Kahkonen S.. 2005. “Functional Connectivity in the Brain–Is It an Elusive Concept?” Neuroscience and Biobehavioral Reviews 28, no. 8: 827–836. 10.1016/j.neubiorev.2004.10.009. PubMed DOI

Ford, J. M. , Palzes V. A., Roach B. J., and Mathalon D. H.. 2014. “Did I Do That? Abnormal Predictive Processes in Schizophrenia When Button Pressing to Deliver a Tone.” Schizophrenia Bulletin 40, no. 4: 804–812. 10.1093/schbul/sbt072. PubMed DOI PMC

Ford, J. M. , Roach B. J., Palzes V. A., and Mathalon D. H.. 2016. “Using Concurrent EEG and fMRI to Probe the State of the Brain in Schizophrenia.” NeuroImage: Clinical 12: 429–441. 10.1016/j.nicl.2016.08.009. PubMed DOI PMC

Fornito, A. , Zalesky A., and Breakspear M.. 2015. “The Connectomics of Brain Disorders.” Nature Reviews Neuroscience 16, no. 3: 159–172. 10.1038/nrn3901. PubMed DOI

Fries, P. 2015. “Rhythms for Cognition: Communication Through Coherence.” Neuron 88, no. 1: 220–235. 10.1016/j.neuron.2015.09.034. PubMed DOI PMC

Friston, K. J. , and Frith C. D.. 1995. “Schizophrenia: a Disconnection Syndrome?” Clinical Neuroscience 3, no. 2: 89–97. https://www.ncbi.nlm.nih.gov/pubmed/7583624. PubMed

He, B. , Dai Y., Astolfi L., Babiloni F., Yuan H., and Yang L.. 2011. “eConnectome: a MATLAB Toolbox for Mapping and Imaging of Brain Functional Connectivity.” Journal of Neuroscience Methods 195, no. 2: 261–269. 10.1016/j.jneumeth.2010.11.015. PubMed DOI PMC

Hinkley, L. B. , Vinogradov S., Guggisberg A. G., Fisher M., Findlay A. M., and Nagarajan S. S.. 2011. “Clinical Symptoms and Alpha Band Resting‐State Functional Connectivity Imaging in Patients With Schizophrenia: Implications for Novel Approaches to Treatment.” Biological Psychiatry 70, no. 12: 1134–1142. 10.1016/j.biopsych.2011.06.029. PubMed DOI PMC

Hirano, Y. , Oribe N., Kanba S., Onitsuka T., Nestor P. G., and Spencer K. M.. 2015. “Spontaneous Gamma Activity in Schizophrenia.” JAMA Psychiatry 72, no. 8: 813–821. 10.1001/jamapsychiatry.2014.2642. PubMed DOI PMC

Iglesias‐Tejedor, M. , Díez Á., Llorca‐Bofí V., et al. 2022. “Relation Between EEG Resting‐State Power and Modulation of P300 Task‐Related Activity in Theta Band in Schizophrenia.” Progress in Neuro‐Psychopharmacology and Biological Psychiatry 116: 110541. 10.1016/j.pnpbp.2022.110541. PubMed DOI

Kam, J. W. , Bolbecker A. R., O'Donnell B. F., Hetrick W. P., and Brenner C. A.. 2013. “Resting State EEG Power and Coherence Abnormalities in Bipolar Disorder and Schizophrenia.” Journal of Psychiatric Research 47, no. 12: 1893–1901. 10.1016/j.jpsychires.2013.09.009. PubMed DOI PMC

Kikuchi, M. , Hashimoto T., Nagasawa T., et al. 2011. “Frontal Areas Contribute to Reduced Global Coordination of Resting‐State Gamma Activities in Drug‐Naive Patients With Schizophrenia.” Schizophrenia Research 130, no. 1‐3: 187–194. 10.1016/j.schres.2011.06.003. PubMed DOI

Kirino, E. , Tanaka S., Fukuta M., et al. 2017. “Simultaneous Resting‐State Functional MRI and Electroencephalography Recordings of Functional Connectivity in Patients With Schizophrenia.” Psychiatry and Clinical Neurosciences 71, no. 4: 262–270. 10.1111/pcn.12495. PubMed DOI

Kirkpatrick, B. , Strauss G. P., Nguyen L., et al. 2011. “The Brief Negative Symptom Scale: Psychometric Properties.” Schizophrenia Bulletin 37, no. 2: 300–305. 10.1093/schbul/sbq059. PubMed DOI PMC

Knyazeva, M. G. , Jalili M., Meuli R., Hasler M., de Feo O., and Do K. Q.. 2008. “Alpha Rhythm and Hypofrontality in Schizophrenia.” Acta Psychiatrica Scandinavica 118, no. 3: 188–199. 10.1111/j.1600-0447.2008.01227.x. PubMed DOI

Koessler, L. , Maillard L., Benhadid A., et al. 2009. “Automated Cortical Projection of EEG Sensors: Anatomical Correlation via the International 10‐10 System.” Neuroimage 46, no. 1: 64–72. 10.1016/j.neuroimage.2009.02.006. PubMed DOI

Korthauer, K. , Kimes P. K., Duvallet C., et al. 2019. “A Practical Guide to Methods Controlling False Discoveries in Computational Biology.” Genome Biology 20, no. 1: 118. 10.1186/s13059-019-1716-1. PubMed DOI PMC

Landis, J. 1977. “The Measurement of Observer Agreement for Categorical Data.” Biometrics 33, no. 1: 159–174. 10.2307/2529310. PubMed DOI

Mahjoory, K. , Nikulin V. V., Botrel L., Linkenkaer‐Hansen K., Fato M. M., and Haufe S.. 2017. “Consistency of EEG Source Localization and Connectivity Estimates.” Neuroimage 152: 590–601. 10.1016/j.neuroimage.2017.02.076. PubMed DOI

McGrath, J. , Saha S., Chant D., and Welham J.. 2008. “Schizophrenia: A Concise Overview of Incidence, Prevalence, and Mortality.” Epidemiologic Reviews 30, no. 1: 67–76. 10.1093/epirev/mxn001. PubMed DOI

McLoughlin, G. , Gyurkovics M., Palmer J., and Makeig S.. 2022. “Midfrontal Theta Activity in Psychiatric Illness: An Index of Cognitive Vulnerabilities Across Disorders.” Biological Psychiatry 91, no. 2: 173–182. 10.1016/j.biopsych.2021.08.020. PubMed DOI

Meyer, M. , Lamers D., Kayhan E., Hunnius S., and Oostenveld R.. 2021. “Enhancing Reproducibility in Developmental EEG Research: BIDS, Cluster‐Based Permutation Tests, and Effect Sizes.” Developmental Cognitive Neuroscience 52: 101036. 10.1016/j.dcn.2021.101036. PubMed DOI PMC

Michel, C. M. , and Brunet D.. 2019. “EEG Source Imaging: A Practical Review of the Analysis Steps.” Frontiers in Neurology 10: 325. 10.3389/fneur.2019.00325. PubMed DOI PMC

Nasreddine, Z. S. , Phillips N. A., Bedirian V., et al. 2005. “The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool for Mild Cognitive Impairment.” Journal of the American Geriatrics Society 53, no. 4: 695–699. 10.1111/j.1532-5415.2005.53221.x. PubMed DOI

Newson, J. J. , and Thiagarajan T. C.. 2018. “EEG Frequency Bands in Psychiatric Disorders: A Review of Resting State Studies.” Frontiers in Human Neuroscience 12: 521. 10.3389/fnhum.2018.00521. PubMed DOI PMC

Nolan, H. , Whelan R., and Reilly R. B.. 2010. “FASTER: Fully Automated Statistical Thresholding for EEG Artifact Rejection.” Journal of Neuroscience Methods 192, no. 1: 152–162. 10.1016/j.jneumeth.2010.07.015. PubMed DOI

Nolte, G. , Bai O., Wheaton L., Mari Z., Vorbach S., and Hallett M.. 2004. “Identifying True Brain Interaction From EEG Data Using the Imaginary Part of Coherency.” Clinical Neurophysiology 115, no. 10: 2292–2307. 10.1016/j.clinph.2004.04.029. PubMed DOI

Northoff, G. , and Duncan N. W.. 2016. “How Do Abnormalities in the Brain's Spontaneous Activity Translate Into Symptoms in Schizophrenia? From an Overview of Resting State Activity Findings to a Proposed Spatiotemporal Psychopathology.” Progress in Neurobiology 145: 26–45. 10.1016/j.pneurobio.2016.08.003. PubMed DOI

Northoff, G. , and Qin P.. 2011. “How Can the Brain's Resting State Activity Generate Hallucinations? A ‘Resting State Hypothesis’ of Auditory Verbal Hallucinations.” Schizophrenia Research 127, no. 1–3: 202–214. 10.1016/j.schres.2010.11.009. PubMed DOI

Nunez, P. L. , Silberstein R. B., Cadusch P. J., Wijesinghe R. S., Westdorp A. F., and Srinivasan R.. 1994. “A Theoretical and Experimental Study of High Resolution EEG Based on Surface Laplacians and Cortical Imaging.” Electroencephalography and Clinical Neurophysiology 90, no. 1: 40–57. 10.1016/0013-4694(94)90112-0. PubMed DOI

Peirce, J. W. 2008. “Generating Stimuli for Neuroscience Using PsychoPy.” Frontiers in Neuroinformatics 2: 10. 10.3389/neuro.11.010.2008. PubMed DOI PMC

Peirce, J. W. , Gray J. R., Simpson S., et al. 2019. “PsychoPy2: Experiments in Behavior Made Easy.” Behavior Research Methods 51: 195–203. 10.3758/s13428-018-01193-y. PubMed DOI PMC

Pettersson‐Yeo, W. , Allen P., Benetti S., McGuire P., and Mechelli A.. 2011. “Dysconnectivity in Schizophrenia: Where Are We Now?” Neuroscience & Biobehavioral Reviews 35, no. 5: 1110–1124. 10.1016/j.neubiorev.2010.11.004. PubMed DOI

Pion‐Tonachini, L. , Kreutz‐Delgado K., and Makeig S.. 2019. “ICLabel: An Automated Electroencephalographic Independent Component Classifier, Dataset, and Website.” Neuroimage 198: 181–197. 10.1016/j.neuroimage.2019.05.026. PubMed DOI PMC

Ranlund, S. , Nottage J., Shaikh M., et al. 2014. “Resting EEG in Psychosis and At‐Risk Populations—A Possible Endophenotype?” Schizophrenia Research 153, no. 1–3: 96–102. 10.1016/j.schres.2013.12.017. PubMed DOI PMC

Schaefer, J. , Giangrande E., Weinberger D. R., and Dickinson D.. 2013. “The Global Cognitive Impairment in Schizophrenia: Consistent Over Decades and Around the World.” Schizophrenia Research 150, no. 1: 42–50. 10.1016/j.schres.2013.07.009. PubMed DOI PMC

Shin, Y. W. , O'Donnell B. F., Youn S., and Kwon J. S.. 2011. “Gamma Oscillation in Schizophrenia.” Psychiatry Investigation 8, no. 4: 288–296. 10.4306/pi.2011.8.4.288. PubMed DOI PMC

Sponheim, S. R. , Clementz B. A., Iacono W. G., and Beiser M.. 2000. “Clinical and Biological Concomitants of Resting state EEG Power Abnormalities in Schizophrenia.” Biological Psychiatry 48, no. 11: 1088–1097. 10.1016/s0006-3223(00)00907-0. PubMed DOI

Srinath, R. , and Ray S.. 2014. “Effect of Amplitude Correlations on Coherence in the Local Field Potential.” Journal of Neurophysiology 112, no. 4: 741–751. 10.1152/jn.00851.2013. PubMed DOI PMC

Stam, C. J. , Nolte G., and Daffertshofer A.. 2007. “Phase Lag Index: Assessment of Functional Connectivity From Multi Channel EEG and MEG With Diminished Bias From Common Sources.” Human Brain Mapping 28, no. 11: 1178–1193. 10.1002/hbm.20346. PubMed DOI PMC

Stephan, K. E. , Friston K. J., and Frith C. D.. 2009. “Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self‐Monitoring.” Schizophrenia Bulletin 35, no. 3: 509–527. 10.1093/schbul/sbn176. PubMed DOI PMC

Tandon, R. , Gaebel W., Barch D. M., et al. 2013. “Definition and Description of Schizophrenia in the DSM‐5.” Schizophrenia Research 150, no. 1: 3–10. 10.1016/j.schres.2013.05.028. PubMed DOI

Tauscher, J. , Fischer P., Neumeister A., Rappelsberger P., and Kasper S.. 1998. “Low Frontal Electroencephalographic Coherence in Neuroleptic‐Free Schizophrenic Patients.” Biological Psychiatry 44, no. 6: 438–447. 10.1016/S0006-3223(97)00428-9. PubMed DOI

Uhlhaas, P. J. , and Singer W.. 2010. “Abnormal Neural Oscillations and Synchrony in Schizophrenia.” Nature Reviews Neuroscience 11, no. 2: 100–113. 10.1038/nrn2774. PubMed DOI

Uhlhaas, P. J. , and Singer W.. 2012. “Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large‐Scale Networks.” Neuron 75, no. 6: 963–980. 10.1016/j.neuron.2012.09.004. PubMed DOI

van der Gaag, M. , Hoffman T., Remijsen M., et al. 2006. “The Five‐factor Model of the Positive and Negative Syndrome Scale II: A Ten‐Fold Cross‐Validation of a Revised Model.” Schizophrenia Research 85, no. 1‐3: 280–287. 10.1016/j.schres.2006.03.021. PubMed DOI

van Os, J. , and Kapur S.. 2009. “Schizophrenia.” Lancet 374, no. 9690: 635–645. 10.1016/S0140-6736(09)60995-8. PubMed DOI

Venables, N. C. , Bernat E. M., and Sponheim S. R.. 2009. “Genetic and Disorder‐Specific Aspects of Resting State EEG Abnormalities in Schizophrenia.” Schizophrenia Bulletin 35, no. 4: 826–839. 10.1093/schbul/sbn021. PubMed DOI PMC

Whitfield‐Gabrieli, S. , and Ford J. M.. 2012. “Default Mode Network Activity and Connectivity in Psychopathology.” Annual Review of Clinical Psychology 8: 49–76. 10.1146/annurev-clinpsy-032511-143049. PubMed DOI

Winterer, G. , Egan M. F., Rädler T., Hyde T., Coppola R., and Weinberger D. R.. 2001. “An Association Between Reduced Interhemispheric EEG Coherence in the Temporal Lobe and Genetic Risk for Schizophrenia.” Schizophrenia Research 49, no. 1‐2: 129–143. 10.1016/S0920-9964(00)00128-6. PubMed DOI

World Medical Association . 2013. “World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.” Jama 310, no. 20: 2191–2194. 10.1001/jama.2013.281053. PubMed DOI

Xiao, Y. , Liao W., Long Z., et al. 2022. “Subtyping Schizophrenia Patients Based on Patterns of Structural Brain Alterations.” Schizophrenia Bulletin 48, no. 1: 241–250. 10.1093/schbul/sbab110. PubMed DOI PMC

Yadav, S. , Haque Nizamie S., Das B., Das J., and Tikka S. K.. 2021. “Resting State Quantitative Electroencephalogram Gamma Power Spectra in Patients With First Episode Psychosis: An Observational Study.” Asian Journal of Psychiatry 57: 102550. 10.1016/j.ajp.2021.102550. PubMed DOI