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Hypofrontality and Posterior Hyperactivity in Early Schizophrenia: Imaging and Behavior in a Preclinical Model

  • Gen Kaneko
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Basavaraju G. Sanganahalli
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Stephanie M. Groman
    Affiliations
    Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut
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  • Helen Wang
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Daniel Coman
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Jyotsna Rao
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Peter Herman
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Lihong Jiang
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut
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  • Katherine Rich
    Affiliations
    Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut
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  • Robin A. de Graaf
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut

    Department of Biomedical Engineering, and, Yale University, Yale University, New Haven, Connecticut
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  • Jane R. Taylor
    Affiliations
    Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut
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  • Fahmeed Hyder
    Correspondence
    Address correspondence to: D. S. Fahmeed Hyder, N143, TAC (MRRC), 300 Cedar Street, New Haven, CT 06520; .
    Affiliations
    Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut

    Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut

    Department of Biomedical Engineering, and, Yale University, Yale University, New Haven, Connecticut
    Search for articles by this author

      Abstract

      Background

      Schizophrenia is a debilitating neuropsychiatric disorder typically diagnosed from late adolescence to adulthood. Subthreshold behavioral symptoms (e.g., cognitive deficits and substance abuse) often precede the clinical diagnosis of schizophrenia. However, these prodromal symptoms have not been consistently associated with structural and functional brain biomarkers, limiting the chance of early diagnosis of schizophrenia.

      Methods

      Using an extensively multimodal range of magnetic resonance methods (for anatomy, metabolism, and function), we screened early biomarkers in a methylazoxymethanol acetate (MAM) rat model of schizophrenia and saline-treated control (SHAM) rats, in conjunction with immunohistochemistry, myelin staining, and a novel three-choice, reversal-learning task to identify early behavioral markers corresponding the subthreshold symptoms.

      Results

      MAM (vs. SHAM) rats had lower/higher structural connectivity in anterior/posterior corpus callosum. The orbitofrontal cortex of MAM rats showed lower resting-state functional magnetic resonance imaging functional connectivity in conjunction with lower neuronal density, lower glucose oxidation, and attenuated neurotransmission (hypofrontality). In contrast, these measures were all higher in visual cortex of MAM rats (posterior hyperactivity), which might parallel perceptual problems in schizophrenia. In behavioral studies, MAM (vs. SHAM) rats displayed abnormal orbitofrontal cortex–mediated decision-making processes, resulting in a novel reward-sensitive hyperflexible phenotype, which might reflect vulnerability of prodromal patients to substance abuse.

      Conclusions

      We identified two novel biomarkers of early schizophrenia in a preclinical rat model: hypofrontality associated with the hyperflexible phenotype, and posterior hyperactivity. Because each of these magnetic resonance methods is clinically translatable, these markers could contribute to early diagnosis and the development of novel therapies of schizophrenia.

      Keywords

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      References

        • World Health Organization
        The Global Burden of Disease: 2004 Update.
        WHO, Geneva, Switzerland2008
        • Palmer B.A.
        • Pankratz V.S.
        • Bostwick J.M.
        The lifetime risk of suicide in schizophrenia: A reexamination.
        Arch Gen Psychiatry. 2005; 62: 247-253
        • Schmidt M.J.
        • Mirnics K.
        Neurodevelopment, GABA system dysfunction, and schizophrenia.
        Neuropsychopharmacology. 2015; 40: 190-206
        • Limosin F.
        Neurodevelopmental and environmental hypotheses of negative symptoms of schizophrenia.
        BMC Psychiatry. 2014; 14: 88
        • van Os J.
        • Kenis G.
        • Rutten B.P.
        The environment and schizophrenia.
        Nature. 2010; 468: 203-212
        • Baum K.M.
        • Walker E.F.
        Childhood behavioral precursors of adult symptom dimensions in schizophrenia.
        Schizophr Res. 1995; 16: 111-120
        • Cannon M.
        • Murray R.M.
        Neonatal origins of schizophrenia.
        Arch Dis Child. 1998; 78: 1-3
        • Rossi A.
        • Pollice R.
        • Daneluzzo E.
        • Marinangeli M.G.
        • Stratta P.
        Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL).
        Schizophr Res. 2000; 44: 121-128
        • Miller P.M.
        • Byrne M.
        • Hodges A.
        • Lawrie S.M.
        • Johnstone E.C.
        Childhood behaviour, psychotic symptoms and psychosis onset in young people at high risk of schizophrenia: Early findings from the Edinburgh High Risk Study.
        Psychol Med. 2002; 32: 173-179
        • Weiser M.
        • Reichenberg A.
        • Grotto I.
        • Yasvitzky R.
        • Rabinowitz J.
        • Lubin G.
        • et al.
        Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: A historical-prospective cohort study.
        Am J Psychiatry. 2004; 161: 1219-1223
        • Weiser M.
        • Reichenberg A.
        • Rabinowitz J.
        • Kaplan Z.
        • Caspi A.
        • Yasvizky R.
        • et al.
        Self-reported drug abuse in male adolescents with behavioral disturbances, and follow-up for future schizophrenia.
        Biol Psychiatry. 2003; 54: 655-660
        • Welch K.A.
        • McIntosh A.M.
        • Job D.E.
        • Whalley H.C.
        • Moorhead T.W.
        • Hall J.
        • et al.
        The impact of substance use on brain structure in people at high risk of developing schizophrenia.
        Schizophr Bull. 2011; 37: 1066-1076
        • Davidson M.
        • Caspi A.
        • Noy S.
        The treatment of schizophrenia: From premorbid manifestations to the first episode of psychosis.
        Dialogues Clin Neurosci. 2005; 7: 7
        • Gilmore J.H.
        • Smith L.C.
        • Wolfe H.M.
        • Hertzberg B.S.
        • Smith J.K.
        • Chescheir N.C.
        • et al.
        Prenatal mild ventriculomegaly predicts abnormal development of the neonatal brain.
        Biol Psychiatry. 2008; 64: 1069-1076
        • Li G.
        • Wang L.
        • Shi F.
        • Lyall A.E.
        • Ahn M.
        • Peng Z.
        • et al.
        Cortical thickness and surface area in neonates at high risk for schizophrenia.
        Brain Struct Func. 2016; 221: 447-461
        • Le Pen G.
        • Gourevitch R.
        • Hazane F.
        • Hoareau C.
        • Jay T.
        • Krebs M.-O.
        Peri-pubertal maturation after developmental disturbance: A model for psychosis onset in the rat.
        Neuroscience. 2006; 143: 395-405
        • Moore H.
        • Jentsch J.D.
        • Ghajarnia M.
        • Geyer M.A.
        • Grace A.A.
        A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.
        Biol Psychiatry. 2006; 60: 253-264
        • Gourevitch R.
        • Rocher C.
        • Le Pen G.
        • Krebs M.-O.
        • Jay T.M.
        Working memory deficits in adult rats after prenatal disruption of neurogenesis.
        Behav Pharmacol. 2004; 15: 287-292
        • Hazane F.
        • Krebs M.-O.
        • Jay T.M.
        • Le Pen G.
        Behavioral perturbations after prenatal neurogenesis disturbance in female rat.
        Neurotox Res. 2009; 15: 311-320
        • Jenks K.R.
        • Lucas M.M.
        • Duffy B.A.
        • Robbins A.A.
        • Gimi B.
        • Barry J.M.
        • et al.
        Enrichment and training improve cognition in rats with cortical malformations.
        PLoS ONE. 2013; 17: e84492
        • Flagstad P.
        • Glenthøj B.Y.
        • Didriksen M.
        Cognitive deficits caused by late gestational disruption of neurogenesis in rats: A preclinical model of schizophrenia.
        Neuropsychopharmacology. 2005; 30: 250-260
        • Featherstone R.E.
        • Rizos Z.
        • Nobrega J.N.
        • Kapur S.
        • Fletcher P.J.
        Gestational methylazoxymethanol acetate treatment impairs select cognitive functions: Parallels to schizophrenia.
        Neuropsychopharmacology. 2007; 32: 483-492
        • Ewing S.G.
        • Grace A.A.
        Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia.
        J Psychiatr Res. 2013; 47: 1630-1635
        • Lavin A.
        • Moore H.M.
        • Grace A.A.
        Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats.
        Neuropsychopharmacology. 2005; 30: 1426-1435
        • Lodge D.J.
        • Grace A.A.
        Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
        J Neurosci. 2007; 27: 11424-11430
        • Lodge D.J.
        • Behrens M.M.
        • Grace A.A.
        A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia.
        J Neurosci. 2009; 29: 2344-2354
        • Esmaeili B.
        • Grace A.A.
        Afferent drive of medial prefrontal cortex by hippocampus and amygdala is altered in MAM-treated rats: evidence for interneuron dysfunction.
        Neuropsychopharmacology. 2013; 38: 1871-1880
        • Goto Y.
        • Grace A.A.
        Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.
        Biol Psychiatry. 2006; 60: 1259-1267
        • Gastambide F.
        • Cotel M.-C.
        • Gilmour G.
        • O’Neill M.J.
        • Robbins T.W.
        • Tricklebank M.D.
        Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator.
        Neuropsychopharmacology. 2012; 37: 1057-1066
        • Fiore M.
        • Di Fausto V.
        • Iannitelli A.
        • Aloe L.
        Clozapine or Haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins’ concentrations.
        Ann Ist Super Sanita. 2008; 44: 167-177
        • Le Pen G.
        • Jay T.M.
        • Krebs M.-O.
        Effect of antipsychotics on spontaneous hyperactivity and hypersensitivity to MK-801-induced hyperactivity in rats prenatally exposed to methylazoxymethanol.
        J Psychopharm. 2011; 25: 822-835
        • Belujon P.
        • Patton M.H.
        • Grace A.A.
        Disruption of prefrontal cortical–hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride.
        Int J Neuropsychopharmacol. 2013; 16: 507-512
        • Chin C.L.
        • Curzon P.
        • Schwartz A.J.
        • O’Connor E.M.
        • Rueter L.E.
        • Fox G.B.
        • et al.
        Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia.
        Synapse. 2011; 65: 393-403
        • Gill K.M.
        • Lodge D.J.
        • Cook J.M.
        • Aras S.
        • Grace A.A.
        A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia.
        Neuropsychopharmacology. 2011; 36: 1903-1911
        • Hradetzky E.
        • Sanderson T.M.
        • Tsang T.M.
        • Sherwood J.L.
        • Fitzjohn S.M.
        • Lakics V.
        • et al.
        The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus.
        Neuropsychopharmacology. 2012; 37: 364-377
        • Zimmerman E.C.
        • Bellaire M.
        • Ewing S.G.
        • Grace A.A.
        Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.
        Neuropsychopharmacology. 2013; 38: 2131-2139
        • Du Y.
        • Grace A.A.
        Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia.
        Neuropsychopharmacology. 2013; 38: 1881-1888
        • Gill K.M.
        • Grace A.A.
        Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model.
        Int J Neuropsychopharmacol. 2014; 17: 1609-1619
        • Gaisler-Salomon I.
        • Schobel S.A.
        • Small S.A.
        • Rayport S.
        How high-resolution basal-state functional imaging can guide the development of new pharmacotherapies for schizophrenia.
        Schizophr Bull. 2009; 35: 1037-1044
        • van den Heuvel M.P.
        • Fornito A.
        Brain networks in schizophrenia.
        Neuropsychol Rev. 2014; 24: 32-48
        • Mason G.F.
        • Rothman D.L.
        • Behar K.L.
        • Shulman R.G.
        NMR determination of the TCA cycle rate and α-ketoglutarate/glutamate exchange rate in rat brain.
        J Cereb Blood Flow Metab. 1992; 12: 434-447
        • de Graaf R.A.
        • Rothman D.L.
        • Behar K.L.
        State of the art direct 13C and indirect 1H‐[13C] NMR spectroscopy in vivo. A practical guide.
        NMR Biomed. 2011; 24: 958-972
        • Fitzpatrick S.M.
        • Hetherington H.P.
        • Behar K.L.
        • Shulman R.G.
        The flux from glucose to glutamate in the rat brain in vivo as determined by 1H-observed, 13C-edited NMR spectroscopy.
        J Cereb Blood Flow Metab. 1990; 10: 170-179
        • Hyder F.
        • Chase J.R.
        • Behar K.L.
        • Mason G.F.
        • Siddeek M.
        • Rothman D.L.
        • et al.
        Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H [13C] NMR.
        Proc Natl Acad Sci USA. 1996; 93: 7612-7617
        • Dunnett S.B.
        • Meldrum A.
        • Muir J.L.
        Frontal-striatal disconnection disrupts cognitive performance of the frontal-type in the rat.
        Neuroscience. 2005; 135: 1055-1065
        • Chahboune H.
        • Ment L.R.
        • Stewart W.B.
        • Ma X.
        • Rothman D.L.
        • Hyder F.
        Neurodevelopment of C57B/L6 mouse brain assessed by in vivo diffusion tensor imaging.
        NMR Biomed. 2007; 20: 375-382
        • Tomasi D.
        • Volkow N.D.
        Functional connectivity density mapping.
        Proc Natl Acad Sci USA. 2010; 107: 9885-9890
        • Barraclough D.J.
        • Conroy M.L.
        • Lee D.
        Prefrontal cortex and decision making in a mixed-strategy game.
        Nat Neurosci. 2004; 7: 404-410
        • Ito M.
        • Doya K.
        Validation of decision-making models and analysis of decision variables in the rat basal ganglia.
        J Neurosci. 2009; 29: 9861-9874
        • Pietrasanta M.
        • Restani L.
        • Caleo M.
        The corpus callosum and the visual cortex: Plasticity is a game for two.
        Neural Plast. 2012; 2012: 838672
        • Volkow N.D.
        • Wang G.-J.
        • Fowler J.S.
        • Tomasi D.
        • Telang F.
        Addiction: Beyond dopamine reward circuitry.
        Proc Natl Acad Sci USA. 2011; 108: 15037-15042
        • Wallis J.D.
        Orbitofrontal cortex and its contribution to decision-making.
        Annu Rev Neurosci. 2007; 30: 31-56
        • Krystal J.H.
        • D’Souza D.C.
        • Gallinat J.
        • Driesen N.
        • Abi-Dargham A.
        • Petrakis I.
        • et al.
        The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia.
        Neurotox Res. 2006; 10: 235-252
        • Ouzir M.
        Impulsivity in schizophrenia: a comprehensive update.
        Aggr Violent Behav. 2013; 18: 247-254
        • Volkow N.D.
        • Chang L.
        • Wang G.-J.
        • Fowler J.S.
        • Ding Y.-S.
        • Sedler M.
        • et al.
        Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.
        Am J Psychiatry. 2001; 158: 2015-2021
        • Volkow N.D.
        • Li T.-K.
        Drug addiction: The neurobiology of behaviour gone awry.
        Nat Rev Neurosci. 2004; 5: 963-970
        • Wolkin A.
        • Sanfilipo M.
        • Wolf A.P.
        • Angrist B.
        • Brodie J.D.
        • Rotrosen J.
        Negative symptoms and hypofrontality in chronic schizophrenia.
        Arch Gen Psychiatry. 1992; 49: 959-965
        • Molina V.
        • Sanz J.
        • Sarramea F.
        • Palomo T.
        Marked hypofrontality in clozapine-responsive patients.
        Pharmacopsychiatry. 2007; 40: 157-162
        • Swedo S.E.
        • Pietrini P.
        • Leonard H.L.
        • Schapiro M.B.
        • Rettew D.C.
        • Goldberger E.L.
        • et al.
        Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder: Revisualization during pharmacotherapy.
        Arch Gen Psychiatry. 1992; 49: 690-694
        • Ben-Shachar D.
        • Bonne O.
        • Chisin R.
        • Klein E.
        • Lester H.
        • Aharon-Peretz J.
        • et al.
        Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study.
        Prog Neuro-Psychopharmacol Biol Psychiatry. 2007; 31: 807-813
        • Waltz J.A.
        • Gold J.M.
        Probabilistic reversal learning impairments in schizophrenia: Further evidence of orbitofrontal dysfunction.
        Schizophr Res. 2007; 93: 296-303
        • Doremus-Fitzwater T.L.
        • Varlinskaya E.I.
        • Spear L.P.
        Motivational systems in adolescence: Possible implications for age differences in substance abuse and other risk-taking behaviors.
        Brain Cogn. 2010; 72: 114-123
        • Ota M.
        • Yasuno F.
        • Ito H.
        • Seki C.
        • Nozaki S.
        • Asada T.
        • et al.
        Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[β-11 C] DOPA.
        Life Sci. 2006; 79: 730-736
        • Somerville L.H.
        • Jones R.M.
        • Casey B.J.
        A time of change: Behavioral and neural correlates of adolescent sensitivity to appetitive and aversive environmental cues.
        Brain Cogn. 2010; 72: 124-133
        • Padmanabhan A.
        • Luna B.
        Developmental imaging genetics: Linking dopamine function to adolescent behavior.
        Brain Cogn. 2014; 89: 27-38
        • Floresco S.B.
        • Zhang Y.
        • Enomoto T.
        Neural circuits subserving behavioral flexibility and their relevance to schizophrenia.
        Behav Brain Res. 2009; 204: 396-409
        • Barkus C.
        • Feyder M.
        • Graybeal C.
        • Wright T.
        • Wiedholz L.
        • Izquierdo A.
        • et al.
        Do GluA1 knockout mice exhibit behavioral abnormalities relevant to the negative or cognitive symptoms of schizophrenia and schizoaffective disorder?.
        Neuropharmacology. 2012; 62: 1263-1272
        • Butler P.D.
        • Silverstein S.M.
        • Dakin S.C.
        Visual perception and its impairment in schizophrenia.
        Biol Psychiatry. 2008; 64: 40-47
        • Amad A.
        • Cachia A.
        • Gorwood P.
        • Pins D.
        • Delmaire C.
        • Rolland B.
        • et al.
        The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations.
        Mol Psychiatry. 2014; 19: 184-191
        • Ford J.M.
        • Palzes V.A.
        • Roach B.J.
        • Potkin S.G.
        • van Erp T.G.
        • Turner J.A.
        • et al.
        Visual hallucinations are associated with hyperconnectivity between the amygdala and visual cortex in people with a diagnosis of schizophrenia.
        Schizophr Bull. 2014; 41: 223-232
        • Silbersweig D.A.
        • Stern E.
        • Frith C.
        • Cahill C.
        • Holmes A.
        • Grootoonk S.
        • et al.
        A functional neuroanatomy of hallucinations in schizophrenia.
        Nature. 1995; 378: 176-179
        • Oertel V.
        • Rotarska-Jagiela A.
        • van de Ven V.G.
        • Haenschel C.
        • Maurer K.
        • Linden D.E.
        Visual hallucinations in schizophrenia investigated with functional magnetic resonance imaging.
        Psychiatry Res. 2007; 156: 269-273
        • Feifel D.
        • Shilling P.D.
        Promise and pitfalls of animal models of schizophrenia.
        Curr Psychiatry Rep. 2010; 12: 327-334
        • Williams K.A.
        • Magnuson M.
        • Majeed W.
        • LaConte S.M.
        • Peltier S.J.
        • Hu X.
        • et al.
        Comparison of α-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat.
        Magn Reson Imaging. 2010; 28: 995-1003
        • Kochunov P.
        • Chiappelli J.
        • Hong L.E.
        Permeability–diffusivity modeling vs. fractional anisotropy on white matter integrity assessment and application in schizophrenia.
        NeuroImage: Clinical. 2013; 3: 18-26