Abstract
Schizophrenia is a psychotic disorder characterized by alterations in perception, thought, and behavior. Although it is widely accepted to be a disorder of neuropathology, definitive biomarkers have yet to be established. This chapter provides a review of the current state of the field for biomarkers of psychosis research, with a focus on findings in schizophrenia. The review is limited to two broad domains, neuroanatomy and neurophysiology, as measured by three well-established methodologies, structural and function magnetic resonance imaging and electroencephalography. Studies of the neuroanatomy of schizophrenia consistently report volume reductions in temporal, medial temporal, and frontal cortices. Cognitive functional magnetic resonance imaging studies highlight prefrontal cortex inefficiency associated with executive functioning and cognitive control impairments, while functional connectivity magnetic resonance imaging studies highlight aberrant connectivity within and between intrinsic brain networks. Finally, electroencephalography studies in schizophrenia have established sensory gating deficits and impaired deviance detection as reflective of core deficits observed in the disorder. For each measure, the use as a potential biomarker is discussed in terms of treatment effects, clinical course, and specificity to psychosis. Current limitations and future directions of the field are discussed.
Abbreviations
- BOLD:
-
Blood-Oxygenation-Level-Dependent Contrast
- EEG:
-
Electroencephalography
- EMG:
-
Electromyography
- ERP:
-
Event-Related Potential
- fMRI:
-
Functional Magnetic Resonance Imaging
- IBN:
-
Intrinsic Brain Networks
- MMN:
-
Mismatch Negativity
- MRI:
-
Magnetic Resonance Imaging
- NPV:
-
Negative Predictive Value
- PPI:
-
Prepulse Inhibition
- PPV:
-
Positive Predictive Value
- sMRI:
-
Structural Magnetic Resonance Imaging
- UHR:
-
Ultra-High Risk
- VBM:
-
Voxel-Based Morphometry
References
Abel K, Waikar M, Pedro B, et al. Repeated testing of prepulse inhibition and habituation of the startle reflex: a study in healthy human controls. J Psychopharmacol. 1998;12:330–7.
Aylward EH, Roberts-Twillie JV, Barta PE, et al. Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry. 1994;151:687–93.
Barch DM, Carter CS, Braver TS, et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry. 2001;58:280–8.
Barch DM, Sheline YI, Csernansky JG, et al. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol Psychiatry. 2003;53:376–84.
Barch DM, Carter CS, Arnsten A, et al. Selecting paradigms from cognitive neuroscience for translation into use in clinical trials: proceedings of the third CNTRICS meeting. Schizophr Bull. 2009;35:109–14.
Beyer JL, Krishnan KRR. Volumetric brain imaging findings in mood disorders. Bipolar Disord. 2002;4:89–104.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.
Braff DL, Light GA. The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues Clin Neurosci. 2005;7:125–35.
Braff DL, Geyer M, Swerdlow N. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl). 2001;156:234–58.
Bramon E, Rabe-Hesketh S, Sham P, et al. Meta-analysis of the P300 and P50 waveforms in schizophrenia. Schizophr Res. 2004;70:315–29.
Braus DF, Ende G, Weber-fahr W, et al. Antipsychotic drug effects on motor activation measured by functional magnetic resonance imaging in schizophrenic patients. Schizophr Res. 1999;39:19–29.
Broyd SJ, Demanuele C, Debener S, et al. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2009;33:279–96.
Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008;1124:1–38.
Calhoun VD, Kiehl K, Liddle PF, et al. Aberrant localization of synchronous hemodynamic activity in auditory cortex reliably characterizes schizophrenia. Biol Psychiatry. 2004;55:842–9.
Calhoun VD, Maciejewski PK, Pearlson GD, et al. Temporal lobe and “default” hemodynamic brain modes discriminate between schizophrenia and bipolar disorder. Hum Brain Mapp. 2008;29:1265–75.
Callicott JH, Mattay VS, Verchinski B, et al. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry. 2003;160:2209–15.
Cannon TD, Van Erp TGM, Huttunen MO, et al. Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 1998;55:1084–91.
Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk. Arch Gen Psychiatry. 2008;65:28–37.
Carter CS, Barch DM. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia: the CNTRICS initiative. Schizophr Bull. 2007;33:1131–7.
Carter CS, Barch DM, Bullmore E, et al. Cognitive neuroscience treatment research to improve cognition in schizophrenia II: developing imaging biomarkers to enhance treatment development for schizophrenia and related disorders. Biol Psychiatry. 2011;70:7–12.
Cohen MS, Bookheimer SY. Localization of brain function using magnetic resonance imaging. Trends Cogn Sci. 1994;17:268–77.
Davatzikos C, Shen D, Gur RC, et al. Whole-brain morphometric study of schizophrenia revealing a spatially complex set of focal abnormalities. Arch Gen Psychiatry. 2005;62:1218–27.
Dean CE. Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia? Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:174–89.
DeLisi LE, Sakuma M, Maurizio AM, et al. Cerebral ventricular change over the first 10 years after the onset of schizophrenia. Psychiatry Res. 2004;130:57–70.
DeLisi LE, Szulc KU, Bertisch HC, et al. Understanding structural brain changes in schizophrenia. Dialogues Clin Neurosci. 2006;8:71–8.
Demirci O, Clark VP, Magnotta VA, et al. A review of challenges in the use of fMRI for disease classification/characterization and a projection pursuit application from multi-site fMRI schizophrenia study. Brain Imaging Behav. 2008;2:147–226.
Elkis H, Friedman L, Wise A, et al. Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry. 1995;52:735–46.
Ellison-Wright I, Glahn DC, Laird AR, et al. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry. 2008;165:1015–23.
Falkai P, Schneider T, Greve B, et al. Reduced frontal and occipital lobe asymmetry on the CT-scans of schizophrenic patients. Its specificity and clinical significance. J Neural Transm. 1995;99:63–77.
Fornito A, Yücel M, Patti J, et al. Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies. Schizophr Res. 2009;108:104–13.
Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8:700–11.
Friston KJ, Mechelli A, Turner R, et al. Nonlinear responses in fMRI: the balloon model, volterra kernels, and other hemodynamics. Neuroimage. 2000;12:466–77.
Garrido MI, Kilner JM, Stephan KE, et al. The mismatch negativity: a review of underlying mechanisms. Clin Neurophysiol. 2009;120:453–63.
Garrity AG, Pearlson GD, McKiernan KA, et al. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry. 2007;164:450–7.
Goldberg TE, Gold JM, Greenberg R, et al. Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery. Am J Psychiatry. 1993;150:1355–62.
Gur RE, Cowell P, Turetsky BI, et al. A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry. 1998;55:145–52.
Haroun N, Dunn L, Haroun A, et al. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophr Bull. 2006;32:166–78.
Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12:426–45.
Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull. 2008;34:354–66.
Ison JR, Hoffman HS. Reflex modification in the domain of startle: II. The anomalous history of a robust and ubiquitous phenomenon. Psychol Bull. 1983;94:3–17.
James ACD, Javaloyes A, James S, et al. Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic resonance imaging study. Br J Psychiatry. 2002;180:339–44.
Javitt DC, Shelley A-M, Silipo G, et al. Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern. Arch Gen Psychiatry. 2000;57:1131–7.
Javitt DC, Spencer KM, Thaker GK, et al. Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov. 2008;7:68–83.
Job DE, Whalley HC, McIntosh AM, et al. Grey matter changes can improve the prediction of schizophrenia in subjects at high risk. BMC Med. 2006;4:29.
Karlsgodt KH, Sanz J, van Erp TGM, Bearden CE, Nuechterlein KH, Cannon TD. Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia. Schizophr Res. 2009;108:143–50.
Kasai K, Shenton ME, Salisbury DF, et al. Progressive decrease of left heschl gyrus and planum temporal gray matter volume in first-episode schizophrenia. Arch Gen Psychiatry. 2003;60:766–75.
Keshavan MS, Tandon R, Boutros NN, et al. Schizophrenia, “just the facts”: what we know in 2008 part 3: neurobiology. Schizophr Res. 2008;106:89–107.
Key APF, Dove GO, Maguire MJ. Linking brainwaves to the brain: an ERP primer. Dev Neuropsychol. 2005;27:183–215.
Kim D, Sui J, Rachakonda S, et al. Identification of imaging biomarkers in schizophrenia: a coefficient-constrained independent component analysis of the mind multi-site schizophrenia study. Neuroinformatics. 2010;8:213–29.
Koutsouleris N, Meisenzahl EM, Davatzikos C, et al. Use of neuroanatomical pattern classification to identify subjects in at-risk mental states of psychosis and predict disease transition. Arch Gen Psychiatry. 2009;66:700–12.
Koutsouleris N, Borgwardt S, Meisenzahl EM, et al. Disease prediction in the at-risk mental state for psychosis using neuroanatomical biomarkers: results from the FePsy study. Schizophr Bull. 2012;38:1234–46.
Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry. 1998;172:110–20.
Lawrie SM, Buechel C, Whalley HC, et al. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry. 2002;51:1008–11.
Lieberman JA, Chakos M, Wu H, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49:487–99.
Light GA, Braff DL. Do self-reports of perceptual anomalies reflect gating deficits in schizophrenia patients? Biol Psychiatry. 2000;47:463–7.
Lorenzetti V, Allen NB, Fornito A, et al. Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies. J Affect Disord. 2009;117:1–17.
Ludewig K, Geyer M, Etzensberger M, et al. Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia. Schizophr Res. 2002;55:129–37.
Lui S, Li T, Deng W, et al. Short-term effects of antipsychotic treatment on cerebral function in drug-naive first-episode schizophrenia revealed by “resting state” functional magnetic resonance imaging. Arch Gen Psychiatry. 2010;67:783–92.
Marder SR, Fenton W. Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res. 2004;72:5–9.
Mathalon DH, Pfefferbaum A, Lim KO, et al. Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Arch Gen Psychiatry. 2003;60:245–52.
McGlashan TH. Early detection and intervention in psychosis: an ethical paradigm shift. Br J Psychiatry Suppl. 2005;187:s113–1155.
McKiernan KA, Kaufman JN, Kucera-Thompson J, et al. A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci. 2003;15:394–408.
Minzenberg MJ, Laird AR, Thelen S, et al. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry. 2009;66:811–22.
Näätänen R, Kähkönen S. Central auditory dysfunction in schizophrenia as revealed by the mismatch negativity (MMN) and its magnetic equivalent MMNm: a review. Int J Neuropsychopharmacol. 2009;12:125–35.
Näätänen R, Paavilainen P, Rinne T, et al. The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clin Neurophysiol. 2007;118:2544–90.
Nakamura M, Salisbury DF, Hirayasu Y, et al. Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study. Biol Psychiatry. 2007;62:773–83.
Navari S, Dazzan P. Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol Med. 2009;39:1763–77.
Noble WS. What is a support vector machine? Nat Biotechnol. 2006;24:1565–7.
Olejniczak P. Neurophysiologic basis of EEG. J Clin Neurophysiol. 2006;23:186–9.
Ongür D, Lundy M, Greenhouse I, et al. Default mode network abnormalities in bipolar disorder and schizophrenia. Psychiatry Res. 2010;183:59–68.
Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361:281–8.
Pantelis C, Yücel M, Wood SJ, et al. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull. 2005;31:672–96.
Parwani A, Duncan EJ, Bartlett E, et al. Impaired prepulse inhibition of acoustic startle in schizophrenia. Biol Psychiatry. 2000;47:662–9.
Patterson JV, Hetrick WP, Boutros NN, et al. P50 sensory gating ratios in schizophrenics and controls: a review and data analysis. Psychiatry Res. 2008;158:226–47.
Phillips LJ, Leicester SB, O’Dwyer LE, et al. The PACE clinic: identification and management of young people at “ultra” high risk of psychosis. J Psychiatr Pract. 2002;8:255–69.
Pomarol-Clotet E, Salvador R, Sarró S, et al. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network? Psychol Med. 2008;38:1185–93.
Power JD, Cohen AL, Nelson SM, et al. Functional network organization of the human brain. Neuron. 2011;72:665–78.
Ptolemy AS, Rifai N. What is a biomarker? Research investments and lack of clinical integration necessitate a review of biomarker terminology and validation schema. Scand J Clin Lab Invest Suppl. 2010;242:6–14.
Raichle ME, Macleod AM, Snyder AZ, et al. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:676–82.
Reichenberg A, Harvey PD, Bowie CR, et al. Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr Bull. 2009;35:1022–9.
Salisbury DF, Shenton ME, Griggs CB, et al. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Arch Gen Psychiatry. 2002;59:686–94.
Seifritz E, Esposito F, Hennel F, et al. Spatiotemporal pattern of neural processing in the human auditory cortex. Science. 2002;297:1706–8.
Shehzad Z, Kelly MC, Reiss PT, et al. The resting brain: unconstrained yet reliable. Cereb Cortex. 2009;19:2209–29.
Shen H, Wang L, Liu Y, et al. Discriminative analysis of resting-state functional connectivity patterns of schizophrenia using low dimensional embedding of fMRI. Neuroimage. 2010;49:3110–21.
Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49:1–52.
Shung KK, Smith MB, Tsui B. Principles of medical imaging. San Diego: Academic; 1992.
Skudlarski P, Jagannathan K, Anderson K, et al. Brain connectivity is not only lower but different in schizophrenia: a combined anatomical and functional approach. Biol Psychiatry. 2010;68:61–9.
Sommer I, Ramsey N, Kahn R, et al. Handedness, language lateralisation and anatomical asymmetry in schizophrenia: meta-analysis. Br J Psychiatry. 2001;178:344–51.
Sun D, van Erp TGM, Thompson PM, et al. Elucidating a magnetic resonance imaging-based neuroanatomic biomarker for psychosis: classification analysis using probabilistic brain atlas and machine learning algorithms. Biol Psychiatry. 2009;66:1055–60.
Swerdlow N, Geyer M, Braff D. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001;156:194–215.
Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res. 2005;76:1–23.
Umbricht D, Koller R, Schmid L, et al. How specific are deficits in mismatch negativity generation to schizophrenia? Biol Psychiatry. 2003;53:1120–31.
Umbricht D, Bates JA, Lieberman JA, et al. Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biol Psychiatry. 2006;59:762–72.
Van de Ven VG, Formisano E, Prvulovic D, et al. Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest. Hum Brain Mapp. 2004;22:165–78.
Van Haren NEM, Hulshoff Pol HE, Schnack HG, et al. Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biol Psychiatry. 2008;63:106–13.
Vercammen A, Knegtering H, den Boer J, et al. Auditory hallucinations in schizophrenia are associated with reduced functional connectivity of the temporo-parietal area. Biol Psychiatry. 2010;67:912–8.
Weinberger DR, McClure RK. Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry. 2002;59:553–8.
Whitfield-Gabrieli S, Ford JM. Default mode network activity and connectivity in psychopathology. Annu Rev Clin Psychol. 2012;8:49–76.
Wood SJ, Velakoulis D, Smith DJ, et al. A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res. 2001;52:37–46.
Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22:353–70.
Yung AR, Nelson B, Stanford C, et al. Validation of “prodromal” criteria to detect individuals at ultra high risk of psychosis: 2 year follow-up. Schizophr Res. 2008;105:10–7.
Zhou Y, Liang M, Tian L, et al. Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophr Res. 2007;97:194–205.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media Dordrecht
About this entry
Cite this entry
Jimenez, A.M. (2014). Biomarkers of Psychosis . In: Preedy, V., Patel, V. (eds) General Methods in Biomarker Research and their Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7740-8_51-1
Download citation
DOI: https://doi.org/10.1007/978-94-007-7740-8_51-1
Received:
Accepted:
Published:
Publisher Name: Springer, Dordrecht
Online ISBN: 978-94-007-7740-8
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences