The quest for biomarkers in Schizophrenia: from neuroimaging to machine learning

The diagnosis of schizophrenia still depends exclusively on the detection of symptoms that are also present in other mental disorders. This situation causes overlapping of the boundaries of the diagnostic categories and constitutes a source of diagnostic errors. Moreover, current treatment algorithms do not take into account the substantial interindividual variability in response to antipsychotic drugs. As a result, around one-third of patients are treatment-resistant to first line antipsychotic drugs. This deleterious consequence is associated with poor individual outcomes and elevated healthcare costs.

[1]  O. Howes,et al.  Glutamate and dopamine in schizophrenia: An update for the 21st century , 2015, Journal of psychopharmacology.

[2]  René S. Kahn,et al.  Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings , 2011, Front. Psychiatry.

[3]  T. Laursen Life expectancy among persons with schizophrenia or bipolar affective disorder , 2011, Schizophrenia Research.

[4]  Kristina M. Visscher,et al.  Ventral Tegmental Area/Midbrain Functional Connectivity and Response to Antipsychotic Medication in Schizophrenia , 2014, Neuropsychopharmacology.

[5]  Karl J. Friston Functional and effective connectivity in neuroimaging: A synthesis , 1994 .

[6]  Andre F. Marquand,et al.  An empirical comparison of different approaches for combining multimodal neuroimaging data with support vector machine , 2014, Front. Neurosci..

[7]  R. Murray,et al.  Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. , 2012, The American journal of psychiatry.

[8]  S. Mori,et al.  Principles of Diffusion Tensor Imaging and Its Applications to Basic Neuroscience Research , 2006, Neuron.

[9]  Karl J. Friston The disconnection hypothesis , 1998, Schizophrenia Research.

[10]  S. Kapur,et al.  Molecular imaging as a guide for the treatment of central nervous system disorders , 2013, Dialogues in clinical neuroscience.

[11]  J. McGrath,et al.  Schizophrenia: a concise overview of incidence, prevalence, and mortality. , 2008, Epidemiologic reviews.

[12]  A. Malhotra,et al.  Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia. , 2015, JAMA psychiatry.

[13]  HighWire Press The journal of neuroscience : the official journal of the Society for Neuroscience. , 1981 .

[14]  S. Kapur,et al.  A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). , 2014, The British journal of psychiatry : the journal of mental science.

[15]  C. Altar,et al.  The social and economic burden of treatment-resistant schizophrenia: a systematic literature review , 2014, International clinical psychopharmacology.

[16]  O. Sporns Contributions and challenges for network models in cognitive neuroscience , 2014, Nature Neuroscience.

[17]  M. V. D. Heuvel,et al.  Brain Networks in Schizophrenia , 2014, Neuropsychology Review.

[18]  G. Remington,et al.  Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up , 2015, Schizophrenia Research.

[19]  Stephen M Smith,et al.  Correspondence of the brain's functional architecture during activation and rest , 2009, Proceedings of the National Academy of Sciences.

[20]  Edward T. Bullmore,et al.  Schizophrenia, neuroimaging and connectomics , 2012, NeuroImage.

[21]  J. Gabrieli,et al.  Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia , 2009, Proceedings of the National Academy of Sciences.

[22]  Academisch Proefschrift,et al.  Diffusion Tensor Imaging in the Early Phase of Schizophrenia , 2010 .

[23]  O. Sporns,et al.  Network hubs in the human brain , 2013, Trends in Cognitive Sciences.

[24]  S. Kapur,et al.  Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. , 2000, The American journal of psychiatry.

[25]  Anqi Qiu,et al.  Combined analyses of thalamic volume, shape and white matter integrity in first-episode schizophrenia , 2009, NeuroImage.

[26]  Yuan Zhou,et al.  Anatomical insights into disrupted small-world networks in schizophrenia , 2012, NeuroImage.

[27]  Jong H. Yoon,et al.  General and Specific Functional Connectivity Disturbances in First-Episode Schizophrenia During Cognitive Control Performance , 2011, Biological Psychiatry.

[28]  A. Abi-Dargham,et al.  The search for imaging biomarkers in psychiatric disorders , 2016, Nature Medicine.

[29]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[30]  J. Lauriello,et al.  1H-MRS at 4 Tesla in minimally treated early schizophrenia , 2010, Molecular Psychiatry.

[31]  A. Egerton,et al.  Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review , 2017, BMC Psychiatry.

[32]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[33]  S. Lui,et al.  Network-Level Dysconnectivity in Drug-Naïve First-Episode Psychosis: Dissociating Transdiagnostic and Diagnosis-Specific Alterations , 2016, Neuropsychopharmacology.

[34]  R. Murray,et al.  The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia , 1997, Schizophrenia Research.

[35]  D. Barch,et al.  Brain Network Connectivity in Individuals with Schizophrenia and Their Siblings , 2011, Biological Psychiatry.

[36]  G. Barker,et al.  Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology , 2012, Molecular Psychiatry.

[37]  B. Moghaddam,et al.  NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons , 2007, The Journal of Neuroscience.

[38]  G. Collin,et al.  Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia , 2016, Schizophrenia Research.

[39]  R. Murray,et al.  Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study , 2011, Psychological Medicine.

[40]  R. Murray,et al.  White matter integrity as a predictor of response to treatment in first episode psychosis , 2013, Brain : a journal of neurology.

[41]  A. Mechelli,et al.  Dysconnectivity in schizophrenia: Where are we now? , 2011, Neuroscience & Biobehavioral Reviews.

[42]  A. Malhotra,et al.  Baseline Striatal Functional Connectivity as a Predictor of Response to Antipsychotic Drug Treatment. , 2015, The American journal of psychiatry.

[43]  D. Rujescu,et al.  Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics , 2016, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[44]  A. Egerton,et al.  Anterior Cingulate Glutamate Levels Related to Clinical Status Following Treatment in First-Episode Schizophrenia , 2012, Neuropsychopharmacology.

[45]  Yong He,et al.  Disrupted small-world networks in schizophrenia. , 2008, Brain : a journal of neurology.

[46]  R. Murray,et al.  Antipsychotic Treatment Resistance in Schizophrenia Associated with Elevated Glutamate Levels but Normal Dopamine Function , 2014, Biological Psychiatry.

[47]  W. Carpenter,et al.  Deficit and nondeficit forms of schizophrenia: the concept. , 1988, The American journal of psychiatry.

[48]  Steven C. R. Williams,et al.  Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level , 2013, Psychological Medicine.

[49]  Susumu Mori,et al.  Fiber tracking: principles and strategies – a technical review , 2002, NMR in biomedicine.

[50]  A. Wheeler,et al.  A review of structural neuroimaging in schizophrenia: from connectivity to connectomics , 2014, Front. Hum. Neurosci..

[51]  P. Falkai A desperate search for biomarkers in schizophrenia. What is going wrong? , 2011, World psychiatry : official journal of the World Psychiatric Association.

[52]  R. Murray,et al.  Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study , 2014, Psychological Medicine.

[53]  René S. Kahn,et al.  Impaired Rich Club Connectivity in Unaffected Siblings of Schizophrenia Patients , 2013, Schizophrenia bulletin.

[54]  E. Bullmore,et al.  Reconciling abnormalities of brain network structure and function in schizophrenia , 2015, Current Opinion in Neurobiology.

[55]  A. Mechelli,et al.  Using Support Vector Machine to identify imaging biomarkers of neurological and psychiatric disease: A critical review , 2012, Neuroscience & Biobehavioral Reviews.

[56]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  O. Howes,et al.  Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. , 2016, The lancet. Psychiatry.

[58]  F. Turkheimer,et al.  Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging , 2008, Schizophrenia Research.

[59]  B. Franke,et al.  From estimating activation locality to predicting disorder: A review of pattern recognition for neuroimaging-based psychiatric diagnostics , 2015, Neuroscience & Biobehavioral Reviews.

[60]  Robin M. Murray,et al.  Connectomic correlates of response to treatment in first-episode psychosis , 2017, Brain : a journal of neurology.

[61]  P. Falkai,et al.  Detecting Neuroimaging Biomarkers for Schizophrenia: A Meta-Analysis of Multivariate Pattern Recognition Studies , 2015, Neuropsychopharmacology.

[62]  Karl J. Friston,et al.  Dysconnectivity in the Frontoparietal Attention Network in Schizophrenia , 2013, Front. Psychiatry.

[63]  P. McGuire,et al.  Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research , 2015, Front. Hum. Neurosci..

[64]  Liang Wang,et al.  Impaired Efficiency of Functional Networks Underlying Episodic Memory-for-Context in Schizophrenia , 2010, The Journal of Neuroscience.

[65]  Danielle S Bassett,et al.  Brain graphs: graphical models of the human brain connectome. , 2011, Annual review of clinical psychology.

[66]  O. Sporns,et al.  The economy of brain network organization , 2012, Nature Reviews Neuroscience.

[67]  B. Pollock,et al.  Neuroimaging evidence for the deficit subtype of schizophrenia. , 2013, JAMA psychiatry.

[68]  E. Bleuler [Dementia praecox or the group of schizophrenias]. , 1968, Vertex.

[69]  Edward T. Bullmore,et al.  Frontiers in Systems Neuroscience Systems Neuroscience , 2022 .

[70]  V. Calhoun,et al.  Multimodal fusion of brain imaging data: A key to finding the missing link(s) in complex mental illness. , 2016, Biological psychiatry. Cognitive neuroscience and neuroimaging.

[71]  Mark Slifstein,et al.  The nature of dopamine dysfunction in schizophrenia and what this means for treatment. , 2012, Archives of general psychiatry.

[72]  Ravi S. Menon,et al.  Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. , 2002, The American journal of psychiatry.

[73]  Peter A. Bandettini,et al.  Twenty years of functional MRI: The science and the stories , 2012, NeuroImage.

[74]  Olaf Sporns,et al.  Network attributes for segregation and integration in the human brain , 2013, Current Opinion in Neurobiology.

[75]  Peter B. Jones,et al.  Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis. , 2013, JAMA psychiatry.

[76]  Wen-tian Dong,et al.  Diffusion tensor imaging study of the anterior limb of internal capsules in neuroleptic-naive schizophrenia. , 2008, Academic radiology.

[77]  A. Mechelli,et al.  Using deep learning to investigate the neuroimaging correlates of psychiatric and neurological disorders: Methods and applications , 2017, Neuroscience & Biobehavioral Reviews.

[78]  E. Bullmore,et al.  Meta-analysis of diffusion tensor imaging studies in schizophrenia , 2009, Schizophrenia Research.

[79]  A. Lawrence,et al.  Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. , 2004, Archives of general psychiatry.

[80]  R. Conley,et al.  Management of treatment resistance in schizophrenia , 2001, Biological Psychiatry.

[81]  Dimitris Mavridis,et al.  Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis , 2013, The Lancet.

[82]  Edward T. Bullmore,et al.  Altered Hub Functioning and Compensatory Activations in the Connectome: A Meta-Analysis of Functional Neuroimaging Studies in Schizophrenia , 2015, Schizophrenia bulletin.

[83]  H. Möller,et al.  Individualized differential diagnosis of schizophrenia and mood disorders using neuroanatomical biomarkers. , 2015, Brain : a journal of neurology.

[84]  Joy A. Thomas,et al.  White matter deficits in first episode schizophrenia: An activation likelihood estimation meta-analysis , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[85]  M. Yücel,et al.  Mapping grey matter reductions in schizophrenia: An anatomical likelihood estimation analysis of voxel-based morphometry studies , 2009, Schizophrenia Research.

[86]  E. Bullmore,et al.  Disrupted Axonal Fiber Connectivity in Schizophrenia , 2011, Biological Psychiatry.

[87]  Olaf Sporns,et al.  THE HUMAN CONNECTOME: A COMPLEX NETWORK , 2011, Schizophrenia Research.

[88]  Davide Anguita,et al.  K-Fold Cross Validation for Error Rate Estimate in Support Vector Machines , 2009, DMIN.

[89]  S. Paradiso,et al.  "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? , 1998, Schizophrenia bulletin.

[90]  A. Graff-Guerrero,et al.  Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis , 2011, Neuropsychopharmacology.

[91]  P. Liddle,et al.  Neural Primacy of the Salience Processing System in Schizophrenia , 2013, Neuron.

[92]  Patrick R Hof,et al.  Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. , 2008, The American journal of psychiatry.

[93]  J. Kwon,et al.  Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [18F]DOPA PET Study , 2017, Neuropsychopharmacology.

[94]  Paul M. Thompson,et al.  Association of White Matter With Core Cognitive Deficits in Patients With Schizophrenia , 2017, JAMA psychiatry.

[95]  J. Lauriello,et al.  Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. , 2005, The American journal of psychiatry.

[96]  R. Iniesta,et al.  Machine learning, statistical learning and the future of biological research in psychiatry , 2016, Psychological Medicine.

[97]  Cheng-Ta Li,et al.  Schizophrenia and the brain's control network: Aberrant within- and between-network connectivity of the frontoparietal network in schizophrenia , 2013, Schizophrenia Research.

[98]  Tom M. Mitchell,et al.  Machine learning classifiers and fMRI: A tutorial overview , 2009, NeuroImage.

[99]  T. Su,et al.  Abnormal topological organization of structural brain networks in schizophrenia , 2012, Schizophrenia Research.

[100]  Michelle Hampson,et al.  Elevated Functional Connectivity Along a Corticostriatal Loop and the Mechanism of Auditory/Verbal Hallucinations in Patients with Schizophrenia , 2011, Biological Psychiatry.

[101]  E. Ganz,et al.  A Hitchhiker's Guide to Functional Magnetic Resonance Imaging , 2016, Front. Neurosci..

[102]  The nature of dopamine dysfunction in schizophrenia and what this means for treatment , 2013 .

[103]  Andrea Mechelli,et al.  Why are psychiatric imaging methods clinically unreliable? Conclusions and practical guidelines for authors, editors and reviewers , 2012, Behavioral and Brain Functions.

[104]  Mark W. Woolrich,et al.  Network modelling methods for FMRI , 2011, NeuroImage.

[105]  Talma Hendler,et al.  Regional axonal abnormalities in first episode schizophrenia: Preliminary evidence based on high b-value diffusion-weighted imaging , 2006, Psychiatry Research: Neuroimaging.

[106]  R. Kahn,et al.  Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis , 2010, The Journal of Neuroscience.

[107]  O. Sporns,et al.  Rich-Club Organization of the Human Connectome , 2011, The Journal of Neuroscience.

[108]  Hugo Alexandre Ferreira,et al.  Multimodal Imaging Brain Connectivity Analysis (MIBCA) toolbox , 2015, PeerJ.

[109]  P. Skudlarski,et al.  Brain Connectivity Is Not Only Lower but Different in Schizophrenia: A Combined Anatomical and Functional Approach , 2010, Biological Psychiatry.

[110]  J. Kane Treatment-resistant schizophrenia patients , 1996 .

[111]  J. Krystal,et al.  First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients , 2006, Molecular Psychiatry.