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From maps to mechanisms through neuroimaging of schizophrenia

Nature volume 468, pages 194–202 (2010)Cite this article

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Abstract

Functional and structural brain imaging has identified neural and neurotransmitter systems involved in schizophrenia and their link to cognitive and behavioural disturbances such as psychosis. Mapping such abnormalities in patients, however, cannot fully capture the strong neurodevelopmental component of schizophrenia that pre-dates manifest illness. A recent strategy to address this issue has been to focus on mechanisms of disease risk. Imaging genetics techniques have made it possible to define neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants, and mechanisms for environmental risk and gene–environment interactions are emerging. Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments.

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Figure 1: Functional neuroimaging methods and their temporal and spatial resolution.
Figure 2: Brain regions functionally and/or structurally affected in schizophrenia.
Figure 3: Schematic summary of putative alterations in dorsolateral prefrontal cortex circuitry in schizophrenia.
Figure 4: A systems-level phenotype in patients relates to genetic risk and animal models.

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References

  1. Editorial A decade for psychiatric disorders. Nature 463, 9 (2010)

    Google Scholar 

  2. Weinberger, D. R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660–669 (1987)A landmark conceptualization of schizophrenia as a neurodevelopmental disorder.

    CAS  PubMed  Google Scholar 

  3. Ellison-Wright, I., Glahn, D. C., Laird, A. R., Thelen, S. M. & Bullmore, E. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am. J. Psychiatry 165, 1015–1023 (2008)

    PubMed  PubMed Central  Google Scholar 

  4. Boos, H. B., Aleman, A., Cahn, W., Hulshoff Pol, H. & Kahn, R. S. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch. Gen. Psychiatry 64, 297–304 (2007)

    PubMed  Google Scholar 

  5. Goldman, A. L. et al. Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol. Psychiatry 63, 475–483 (2008)

    PubMed  Google Scholar 

  6. Lewis, D. A. & Sweet, R. A. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J. Clin. Invest. 119, 706–716 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Selemon, L. D. & Goldman-Rakic, P. S. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45, 17–25 (1999)

    CAS  PubMed  Google Scholar 

  8. Hashimoto, T. et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J. Neurosci. 23, 6315–6326 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Byne, W., Hazlett, E. A., Buchsbaum, M. S. & Kemether, E. The thalamus and schizophrenia: current status of research. Acta Neuropathol. 117, 347–368 (2009)

    PubMed  Google Scholar 

  10. Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995)

    CAS  PubMed  Google Scholar 

  11. Goldman-Rakic, P. S. Working memory dysfunction in schizophrenia. J. Neuropsychiatry Clin. Neurosci. 6, 348–357 (1994)

    CAS  PubMed  Google Scholar 

  12. Callicott, J. H. et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb. Cortex 10, 1078–1092 (2000)

    CAS  PubMed  Google Scholar 

  13. Tan, H. Y. et al. Dysfunctional prefrontal regional specialization and compensation in schizophrenia. Am. J. Psychiatry 163, 1969–1977 (2006)

    PubMed  Google Scholar 

  14. Fusar-Poli, P. et al. Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 31, 465–484 (2007)

    PubMed  Google Scholar 

  15. Achim, A. M. & Lepage, M. Episodic memory-related activation in schizophrenia: meta-analysis. Br. J. Psychiatry 187, 500–509 (2005)

    PubMed  Google Scholar 

  16. Murray, G. K. et al. Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol. Psychiatry 13, 267–276 (2008)Evidence for abnormal salience processing in midbrain in schizophrenia.

    CAS  Google Scholar 

  17. Juckel, G. et al. Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 29, 409–416 (2006)

    PubMed  Google Scholar 

  18. Simon, J. J. et al. Neural correlates of reward processing in schizophrenia—Relationship to apathy and depression. Schizophr. Res. 118, 154–161 (2009)

    PubMed  Google Scholar 

  19. Aleman, A. & Kahn, R. S. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Prog. Neurobiol. 77, 283–298 (2005)

    PubMed  Google Scholar 

  20. Rasetti, R. et al. Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk. Am. J. Psychiatry 166, 216–225 (2009)

    PubMed  Google Scholar 

  21. Gur, R. E. et al. Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia. Arch. Gen. Psychiatry 64, 1356–1366 (2007)

    PubMed  Google Scholar 

  22. Brunet-Gouet, E. & Decety, J. Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res. 148, 75–92 (2006)

    PubMed  Google Scholar 

  23. Walter, H. Dysfunction of the social brain is modulated by intention type: an FMRI study. Soc. Cogn. Affect. Neurosci. 4, 166–176 (2009)

    PubMed  PubMed Central  Google Scholar 

  24. Dierks, T. et al. Activation of Heschl’s gyrus during auditory hallucinations. Neuron 22, 615–621 (1999)

    CAS  PubMed  Google Scholar 

  25. Hubl, D. et al. Pathways that make voices: white matter changes in auditory hallucinations. Arch. Gen. Psychiatry 61, 658–668 (2004)

    PubMed  Google Scholar 

  26. Wolf, R. C. et al. Temporally anticorrelated brain networks during working memory performance reveal aberrant prefrontal and hippocampal connectivity in patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 1467–1473 (2009)

    Google Scholar 

  27. Whitfield-Gabrieli, S. et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc. Natl Acad. Sci. USA 106, 1279–1284 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379–386 (2005)

    PubMed  Google Scholar 

  29. Crossley, N. A. et al. Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first-episode psychosis. Hum. Brain Mapp. 30, 4129–4137 (2009)

    PubMed  PubMed Central  Google Scholar 

  30. Meyer-Lindenberg, A. et al. Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am. J. Psychiatry 158, 1809–1817 (2001)

    CAS  PubMed  Google Scholar 

  31. Friston, K. J., Frith, C. D., Fletcher, P., Liddle, P. F. & Frackowiak, R. S. Functional topography: multidimensional scaling and functional connectivity in the brain. Cereb. Cortex 6, 156–164 (1996)

    CAS  PubMed  Google Scholar 

  32. Bullmore, E. & Sporns, O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nature Rev. Neurosci. 10, 186–198 (2009)

    CAS  Google Scholar 

  33. Bassett, D. S. et al. Hierarchical organization of human cortical networks in health and schizophrenia. J. Neurosci. 28, 9239–9248 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bertolino, A. et al. Altered development of prefrontal neurons in rhesus monkeys with neonatal mesial temporo-limbic lesions: a proton magnetic resonance spectroscopic imaging study. Cereb. Cortex 7, 740–748 (1997)

    CAS  PubMed  Google Scholar 

  35. Braff, D. L. & Geyer, M. A. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch. Gen. Psychiatry 47, 181–188 (1990)

    CAS  PubMed  Google Scholar 

  36. Jaskiw, G. E., Karoum, F. K. & Weinberger, D. R. Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain Res. 534, 321–323 (1990)

    CAS  PubMed  Google Scholar 

  37. Seeman, P. & Lee, T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219 (1975)

    ADS  CAS  PubMed  Google Scholar 

  38. Davis, K. L., Kahn, R. S., Ko, G. & Davidson, M. Dopamine in schizophrenia: a review and reconceptualization. Am. J. Psychiatry 148, 1474–1486 (1991)

    CAS  PubMed  Google Scholar 

  39. Laruelle, M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q. J. Nucl. Med. 42, 211–221 (1998)

    CAS  PubMed  Google Scholar 

  40. Howes, O. D. et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66, 13–20 (2009)

    PubMed  Google Scholar 

  41. Meyer-Lindenberg, A. et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nature Neurosci. 5, 267–271 (2002)

    CAS  PubMed  Google Scholar 

  42. Fusar-Poli, P. et al. Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol. Psychiatry 10.1038/mp.2009.108 (1 December 2009)Striatal dopamine dysfunction correlates with prefrontal activation abnormalities in high-risk subjects.

  43. Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am. J. Psychiatry 160, 13–23 (2003)An important conceptualization of psychosis linking it to dopamine-related salience signalling.

    PubMed  Google Scholar 

  44. Munafo, M. R., Brown, S. M. & Hariri, A. R. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol. Psychiatry 63, 852–857 (2008)

    CAS  PubMed  Google Scholar 

  45. Mier, D., Kirsch, P. & Meyer-Lindenberg, A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol . Psychiatry 15, 918–927 (2010)

    CAS  Google Scholar 

  46. Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009)One of three large GWAS of schizophrenia in 2009, this paper also provides evidence for multiple common variants contributing to risk for schizophrenia that overlap with bipolar disorder.

    ADS  CAS  PubMed  Google Scholar 

  47. Nicodemus, K. K. et al. Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging. Hum. Genet. 127, 441–452 (2010)

    CAS  PubMed  Google Scholar 

  48. Liu, J. et al. Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA. Hum. Brain Mapp. 30, 241–255 (2009)

    ADS  PubMed  Google Scholar 

  49. Gottesman, I. I. & Gould, T. D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003)

    PubMed  Google Scholar 

  50. Fan, J. B. et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol. Psychiatry 57, 139–144 (2005)

    CAS  PubMed  Google Scholar 

  51. Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Egan, M. F. et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98, 6917–6922 (2001)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gogos, J. A. et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl Acad. Sci. USA 95, 9991–9996 (1998)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen, J. et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 75, 807–821 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Honea, R. et al. Impact of interacting functional variants in COMT on regional gray matter volume in human brain. Neuroimage 45, 44–51 (2009)

    PubMed  Google Scholar 

  57. Meyer-Lindenberg, A. et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nature Neurosci. 8, 594–596 (2005)

    CAS  PubMed  Google Scholar 

  58. Stefansson, H. et al. Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877–892 (2002)

    PubMed  PubMed Central  Google Scholar 

  59. Barros, C. S. et al. Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc. Natl Acad. Sci. USA 106, 4507–4512 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mei, L. & Xiong, W. C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Rev. Neurosci. 9, 437–452 (2008)

    CAS  Google Scholar 

  61. Hall, J. et al. A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nature Neurosci. 9, 1477–1478 (2006)

    CAS  PubMed  Google Scholar 

  62. Gruber, O. et al. Neuregulin-1 haplotype HAP(ICE) is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members. J. Psychiatr. Res. 43, 1–6 (2008)

    ADS  PubMed  Google Scholar 

  63. Mata, I. et al. A neuregulin 1 variant is associated with increased lateral ventricle volume in patients with first-episode schizophrenia. Biol. Psychiatry 65, 535–540 (2009)

    CAS  PubMed  Google Scholar 

  64. McIntosh, A. M. et al. The effects of a neuregulin 1 variant on white matter density and integrity. Mol. Psychiatry 13, 1054–1059 (2008)

    CAS  PubMed  Google Scholar 

  65. Millar, J. K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000)

    CAS  PubMed  Google Scholar 

  66. Ishizuka, K., Paek, M., Kamiya, A. & Sawa, A. A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol. Psychiatry 59, 1189–1197 (2006)

    CAS  PubMed  Google Scholar 

  67. Callicott, J. H. et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc. Natl Acad. Sci. USA 102, 8627–8632 (2005)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Prata, D. P. et al. Effect of disrupted-in-schizophrenia-1 on pre-frontal cortical function. Mol. Psychiatry 13, 915–917 (2008)

    CAS  PubMed  Google Scholar 

  69. Di Giorgio, A. et al. Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. Eur. J. Neurosci. 28, 2129–2136 (2008)

    PubMed  PubMed Central  Google Scholar 

  70. Cannon, T. D. et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch. Gen. Psychiatry 62, 1205–1213 (2005)

    CAS  PubMed  Google Scholar 

  71. Nicodemus, K. K. et al. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum. Genet. 120, 889–906 (2007)

    CAS  PubMed  Google Scholar 

  72. Harrison, P. J. & Weinberger, D. R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10, 40–68 (2005)

    CAS  PubMed  Google Scholar 

  73. Garcia, R. A., Vasudevan, K. & Buonanno, A. The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Natl Acad. Sci. USA 97, 3596–3601 (2000)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mata, I. et al. Additive effect of NRG1 and DISC1 genes on lateral ventricle enlargement in first episode schizophrenia. Neuroimage 53, 1016–1022 (2009)

    PubMed  Google Scholar 

  75. O’Donovan, M. C. et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genet. 40, 1053–1055 (2008)Identification of the ZNF804A variant with genome-wide support.

    PubMed  Google Scholar 

  76. Esslinger, C. et al. Neural mechanisms of a genome-wide supported psychosis variant. Science 324, 605 (2009)The first imaging genetics study on a genome-wide significant variant, showing effects on dorsolateral prefrontal cortex connectivity mirroring those in patients with schizophrenia.

    ADS  CAS  PubMed  Google Scholar 

  77. Walters, J. T. et al. Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia. Arch. Gen. Psychiatry 67, 692–700 (2010)

    CAS  PubMed  Google Scholar 

  78. Lencz, T. et al. A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes. Neuropsychopharmacology 35, 2284–2291 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Walter, H. et al. Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task. Mol. Psychiatry 10.1038/mp.2010.18 (16 March 2010)

  80. Ferreira, M. A. et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nature Genet. 40, 1056–1058 (2008)

    CAS  PubMed  Google Scholar 

  81. Erk, S. et al. Brain function in carriers of a genome-wide supported bipolar disorder variant. Arch. Gen. Psychiatry 67, 803–811 (2010)

    PubMed  Google Scholar 

  82. Wessa, M. et al. The CACNA1C risk variant for bipolar disorder influences limbic activity. Mol. Psychiatry 10.1038/mp.2009.103 (30 March 2010)

  83. Ben-Shachar, S. et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J. Med. Genet. 46, 382–388 (2009)

    CAS  PubMed  Google Scholar 

  84. Karayiorgou, M., Simon, T. J. & Gogos, J. A. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nature Rev. Neurosci. 11, 402–416 (2010)

    CAS  Google Scholar 

  85. Meechan, D. W., Maynard, T. M., Gopalakrishna, D., Wu, Y. & LaMantia, A. S. When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr. 13, 299–310 (2007)

    CAS  PubMed  Google Scholar 

  86. Kempf, L. et al. Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. PLoS Genet. 4, e1000252 (2008)

    PubMed  PubMed Central  Google Scholar 

  87. Lieberman, J. A., Sheitman, B. B. & Kinon, B. J. Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 17, 205–229 (1997)

    CAS  PubMed  Google Scholar 

  88. Selten, J. P. & Cantor-Graae, E. Social defeat: risk factor for schizophrenia? Br. J. Psychiatry 187, 101–102 (2005)

    PubMed  Google Scholar 

  89. Pruessner, J. C., Champagne, F., Meaney, M. J. & Dagher, A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J. Neurosci. 24, 2825–2831 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Soliman, A. et al. Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study. Neuropsychopharmacology 33, 2033–2041 (2008)

    CAS  PubMed  Google Scholar 

  91. Zink, C. F. et al. Know your place: neural processing of social hierarchy in humans. Neuron 58, 273–283 (2008)An environmental stressor (unstable hierarchy) impacts on circuitry for regulation of negative affect.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Caspi, A. et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene × environment interaction. Biol. Psychiatry 57, 1117–1127 (2005)

    CAS  PubMed  Google Scholar 

  93. Stokes, P. R. et al. Significant decreases in frontal and temporal [11C]-raclopride binding after THC challenge. Neuroimage 52, 1521–1527 (2010)

    CAS  PubMed  Google Scholar 

  94. Insel, T. R. & Scolnick, E. M. Cure therapeutics and strategic prevention: raising the bar for mental health research. Mol. Psychiatry 11, 11–17 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Durstewitz, D. & Seamans, J. K. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol. Psychiatry 64, 739–749 (2008)

    CAS  PubMed  Google Scholar 

  96. Apud, J. A. et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 32, 1011–1020 (2007)Proof of principle of genotype-directed personalized therapy guided by neuroimaging mechanisms in psychiatry.

    CAS  PubMed  Google Scholar 

  97. Bertolino, A. et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am. J. Psychiatry 161, 1798–1805 (2004)

    PubMed  Google Scholar 

  98. Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A. & Gordon, J. A. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010)A mouse model of a genetic high-risk microdeletion for schizophrenia exhibits a prefrontal-hippocampal connectivity phenotype.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tost, H. et al. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nature Neurosci. 13, 920–922 (2010)

    CAS  PubMed  Google Scholar 

  100. Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004)

    ADS  CAS  PubMed  Google Scholar 

  101. Sohal, V. S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  102. von Stein, A., Chiang, C. & Konig, P. Top-down processing mediated by interareal synchronization. Proc. Natl Acad. Sci. USA 97, 14748–14753 (2000)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lisman, J. & Buzsaki, G. A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophr. Bull. 34, 974–980 (2008)

    PubMed  PubMed Central  Google Scholar 

  104. Sirota, A. et al. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron 60, 683–697 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ito, H. T. & Schuman, E. M. Frequency-dependent gating of synaptic transmission and plasticity by dopamine. Front Neural Circuits 1, 1 (2007)

    PubMed  PubMed Central  Google Scholar 

  107. Cho, R. Y., Konecky, R. O. & Carter, C. S. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc. Natl Acad. Sci. USA 103, 19878–19883 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hong, L. E. et al. Sensory gating endophenotype based on its neural oscillatory pattern and heritability estimate. Arch. Gen. Psychiatry 65, 1008–1016 (2008)

    PubMed  PubMed Central  Google Scholar 

  109. Markram, H., Lubke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997)

    CAS  PubMed  Google Scholar 

  110. Gurden, H., Tassin, J. P. & Jay, T. M. Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation. Neuroscience 94, 1019–1027 (1999)

    CAS  PubMed  Google Scholar 

  111. Uhlhaas, P. J. et al. The development of neural synchrony reflects late maturation and restructuring of functional networks in humans. Proc. Natl Acad. Sci. USA 106, 9866–9871 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  112. Giorgio, A. et al. Longitudinal changes in grey and white matter during adolescence. Neuroimage 49, 94–103 (2010)

    CAS  PubMed  Google Scholar 

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Acknowledgements

I acknowledge grant support by Deutsche Forschungsgemeinschaft (SFB 636), BMBF (NGFN-MooDs, Bernstein-Programme), EU (NEWMEDS, OPTIMIZE, EU-GEI) and NARSAD (Distinguished Investigator Award) during the preparation of this manuscript.

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  1. Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, J5, 68159 Mannheim, Germany ,

    Andreas Meyer-Lindenberg

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Meyer-Lindenberg, A. From maps to mechanisms through neuroimaging of schizophrenia. Nature 468, 194–202 (2010). https://doi.org/10.1038/nature09569

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