Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Nature Reviews Drug Discovery volume 11, pages 141–168 (2012)Cite this article

Subjects

Key Points

  • Deficits in cognitive function — ranging from decreased attention and working memory to disrupted social cognition and language — are common in psychiatric disorders.

  • They severely compromise quality of life, yet are currently poorly treated.

  • Recent research has identified numerous interacting causes — genetic, epigenetic, developmental and environmental — that collectively disrupt the cerebral and cellular networks integrating and modulating cognition.

  • Several pharmacotherapeutic strategies for the restoration of cognition are under investigation but most drugs have only been evaluated in rodents, and there is limited positive feedback from the clinic.

  • The successful development of improved agents necessitates rigorous validation both in animals and in humans. In this regard, a broad palette of techniques, ranging from behavioural testing to brain imaging, is available for the exploration of innovative concepts and the characterization of new drugs.

  • Despite the key importance of pharmacotherapy, the relevance of alternative strategies should not be neglected. The association of both approaches may emerge to be particularly effective for realizing the goal of enhanced cognitive performance and, accordingly, improved quality of life in patients suffering from psychiatric disorders.

Abstract

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A global view of cognition and its disruption in psychiatric disorders.
Figure 2: Schematic representation of major cerebral circuits underpinning core cognitive domains that are disrupted in psychiatric disorders.
Figure 3: Schematic representation of the principal cerebral circuits integrating social cognition and verbal language, both of which are disrupted in psychiatric disorders.
Figure 4: An overview of molecular substrates targeted by drugs that are designed to enhance cognitive performance in psychiatric disorders.
Figure 5: Overview of translational models for characterizing and predicting the influence of pharmacological agents on cognitive function in humans.

References

  1. Pessoa, L. On the relationship between emotion and cognition. Nature Rev. Neurosci. 9, 148–158 (2008).

    Article  CAS  Google Scholar 

  2. Harmer, C. J. et al. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am. J. Psychiatry 166, 1178–1184 (2009).

    Article  PubMed  Google Scholar 

  3. Hill, S. K., Bichop, J. R., Palumbo, D. & Sweeney, J. A. Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert Rev. Neurother. 10, 43–57 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Millan, M. J. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 110, 135–370 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Dickinson, D. & Harvey, P. D. Systemic hypotheses for generalized cognitive deficits in schizophrenia: a new take on an old problem. Schizophr. Bull. 35, 403–414 (2009).

    Article  PubMed  Google Scholar 

  6. Kalkstein, S., Hurford, I. & Gur, R. C. Neurocognition in schizophrenia. Curr. Top. Behav. Neurosci. 4, 373–390 (2010).

    Article  PubMed  Google Scholar 

  7. Millan, M. J. in Animal and Translational Models for CNS Drug Discovery Vol. 1 (eds McArthur, R. A. & Borsini, F.) 1–57 (Academic Press, Burlington, Massachusetts, 2008).

    Book  Google Scholar 

  8. Baron-Cohen, S. & Belmonte, M. K. Autism: a window onto the development of the social and the analytic brain. Annu. Rev. Neurosci. 28, 109–126 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Barnett, J. H. et al. Assessing cognitive function in clinical trials of schizophrenia. Neurosci. Biobehav. Rev. 34, 1161–1177 (2010).

    Article  PubMed  Google Scholar 

  10. Hauber, W. & Sommer, S. Prefrontostriatal circuitry regulates effort-related decision making. Cereb. Cortex 19, 2240–2247 (2009).

    Article  PubMed  Google Scholar 

  11. Kas, M. J. H. et al. Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders. Eur. Neuropsychopharmacol. 21, 532–544 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Burdick, K. E., Robinson, D. G., Malhotra, A. K. & Szeszko, P. R. Neurocognitive profile analysis in obsessive-compulsive disorder. J. Int. Neuropsychol. Soc. 14, 640–645 (2008).

    Article  PubMed  Google Scholar 

  13. McNally, R. J. Cognitive abnormalities in post-traumatic stress disorder. Trends Cogn. Sci. 10, 271–277 (2006).

    Article  PubMed  Google Scholar 

  14. Liberzon, I. & Sripada, C. S. The functional neuroanatomy of PTSD: a critical review. Prog. Brain Res. 167, 151–169 (2008).

    Article  PubMed  Google Scholar 

  15. Quirk, G. J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).

    Article  PubMed  Google Scholar 

  16. Castaneda, A. E., Tuulio-Henriksson, A., Marttunen, M., Suvisaari, J. & Lönnqvist, J. A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J. Affect. Disord. 106, 1–27 (2008).

    Article  PubMed  Google Scholar 

  17. Coles, M. E., Turks, C. L. & Heimberg, R. G. Memory bias for threat in generalized anxiety disorder: the potential importance of stimulus relevance. Cogn. Behav. Ther. 36, 65–73 (2007).

    Article  PubMed  Google Scholar 

  18. Gordeev, S. A. Cognitive functions and the state of nonspecific brain systems in panic disorders. Neurosci. Behav. Physiol. 38, 707–714 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Dere, E., Pause, B. M. & Pietrowsky, R. Emotion and episodic memory in neuropsychiatric disorders. Behav. Brain Res. 215, 162–171 (2010).

    Article  PubMed  Google Scholar 

  20. Brüne, M. Theory of mind in schizophrenia: a review of the literature. Schizophr. Bull. 31, 21–42 (2005).

    Article  PubMed  Google Scholar 

  21. Crow, T. J. The big bang theory of the origin of psychosis and the faculty of language. Schizophr. Res. 102, 31–52 (2008).

    Article  PubMed  Google Scholar 

  22. Galderisi, S. et al. Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study. Schizophr. Res. 115, 104–114 (2009).

    Article  PubMed  Google Scholar 

  23. Kurtz, M. M. & Gerraty, R. T. A meta-analytic investigation of neurocognitive deficits in bipolar illness: profile and effects of clinical state. Neuropsychology 23, 551–562 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wolf, F., Brüne, M. & Assion, H. J. Theory of mind and neurocognitive functioning in patients with bipolar disorder. Bipolar Disord. 12, 657–666 (2010).

    Article  PubMed  Google Scholar 

  25. Zobel, I. et al. Theory of mind deficits in chronically depressed patients. Depress. Anxiety 27, 821–828 (2010).

    Article  PubMed  Google Scholar 

  26. Marazziti, D., Consoli, G., Picchetti, M., Carlini, M. & Faravelli, L. Cognitive impairment in major depression. Eur. J. Pharmacol. 626, 83–86 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Beevers, C. G., Clasen, P., Stice, E. & Schnyer, D. Depression symptoms and cognitive control of emotion cues: a functional magnetic resonance imaging study. Neuroscience 167, 97–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Vaidya, C. J. & Stollstorff, M. Cognitive neuroscience of attention deficit hyperactivity disorder: current status and working hypotheses. Dev. Disabil. Res. Rev. 14, 261–267 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Uekermann, J. et al. Social cognition in attention-deficit hyperactivity disorder (ADHD). Neurosci. Biobehav. Rev. 34, 734–743 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Sayin, A., Oral, N., Utku, C. Baysak, E. & Candansayar, S. Theory of mind in obsessive-compulsive disorder: comparison with healthy controls. Eur. Psychiatry 25, 116–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Hill, E. L. & Frith, U. Understanding autism: insights from mind and brain. Phil. Trans. R. Soc. Lond. B Biol. Sci. 358, 281–289 (2003).

    Article  Google Scholar 

  32. Robinson, S., Goddard, L. Dritschel, B., Wisley, M. & Howlin, P. Executive functions in children with autism spectrum disorders. Brain Cogn. 71, 362–368 (2009).

    Article  PubMed  Google Scholar 

  33. Krause, J., Ruxton, G. D. & Krause, S. Swarm intelligence in animals and humans. Trends Ecol. Evol. 25, 28–34 (2010).

    Article  PubMed  Google Scholar 

  34. Adolphs, R. The social brain: neural basis of social knowledge. Annu. Rev. Psychol. 60, 693–716 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Fitch, W. T., Huber, L. & Bugnyar, T. Social cognition and the evolution of language: constructing cognitive phylogenies. Neuron 65, 795–814 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gorwood, P., Corruble, E., Falissard, B. & Goodwin, G. M. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am. J. Psychiatry 165, 731–739 (2008).

    Article  PubMed  Google Scholar 

  37. Goodwin, G. M., Martinez-Aran, A., Glahn, D. C. & Vieta, E. Cognitive impairment in bipolar disorder: neurodevelopment of neurodegeneration? An ECNP expert meeting report. Eur. Neuropsychopharmacol. 18, 787–793 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Sarter, M., Parikh, V. & Howe, W. M. nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms. Biochem. Pharmacol. 10, 658–667 (2009).

    Article  CAS  Google Scholar 

  39. McAfoose, J. & Baune, B. T. Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 33, 355–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Cunha, C., Brambilla, R. & Thomas, K. L. A simple role for BDNF in learning and memory? Front. Mol. Neurosci. 3, 1 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. Robbins, T. W. & Arnsten, A. F. T. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu. Rev. Neurosci. 32, 267–287 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lewis, D. A., Fish, K. N., Arion, D. & Gonzalez-Burgos, G. Perisomatic inhibition and cortical circuit dysfunction in schizophrenia. Curr. Neurobiol. 21, 866–872 (2011).

    Article  CAS  Google Scholar 

  43. Lee, Y. S. & Silva, A. J. The molecular and cell biology of enhanced cognition. Nature Rev. Neurosci. 10, 126–140 (2009).

    Article  CAS  Google Scholar 

  44. Neves, G., Cooke, S. F. & Bliss, T. V. P. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nature Rev. Neurosci. 9, 65–75 (2008).

    Article  CAS  Google Scholar 

  45. Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. Long-term depression in the CNS. Nature Rev. Neurosci. 11, 459–473 (2010).

    Article  CAS  Google Scholar 

  46. Buzsaki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, X. J. Neurophysiological and computational principles of cortical rhythms in cognition. Physiol. Rev. 90, 1195–1268 (2010).

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  49. Lynall, M. E. et al. Functional connectivity and brain networks in schizophrenia. J. Neurosci. 30, 9477–9487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gilmour, G. et al. NMDA receptors, cognition and schizophrenia — testing the validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology 21 Mar 2011 (doi:10.1016/j.neuropharm.2011.03.015).

  51. Heifets, B. D. & Castillo, P. E. Endocannabinoid signaling and long-term synaptic plasticity. Annu. Rev. Physiol. 71, 283–306 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Papaleo, F., Lipska, B. K. & Weinberger, D. R. Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 5 May 2011 (doi:10.1016/j.neuropharm.2011.04.025).

  53. McGuire, P., Howes, O. D., Stone, J. & Fusar-Poli, P. Functional neuroimaging in schizophrenia: diagnosis and drug discovery. Trends Pharmacol. Sci. 29, 91–98 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Minzenberg, M. J. et al. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch. Gen. Psychiatry 66, 811–822 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Pettersson-Yeo, W., Allen, P., Benetti, S., McGuire, P. & Mechelli, A. Dysconnectivity in schizophrenia: where are we now? Neurosci. Biobehav. Rev. 35, 1110–1124 (2011).

    Article  PubMed  Google Scholar 

  56. Li, X., Branch, C. A. & DeLisi, L. E. Language pathway abnormalities in schizophrenia: a review of fMRI and other imaging studies. Curr. Opin. Psychiatry 22, 131–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Knaus, T. A. et al. Language laterality in autism spectrum disorder and typical controls: a functional, volumetric, and diffusion tensor MRI study. Brain Lang. 112, 113–120 (2010).

    Article  PubMed  Google Scholar 

  58. Wass, S. Distortions and disconnections: disrupted brain connectivity in autism. Brain Cogn. 75, 18–28 (2011).

    Article  PubMed  Google Scholar 

  59. Kennedy, D. P. & Courchesne, E. The intrinsic functional organization of the brain is altered in autism. Neuroimage 39, 1877–1885 (2008).

    Article  PubMed  Google Scholar 

  60. Cubillo, A. & Rubia, K. Structural and functional brain imaging in adult attention-deficit/hyperactivity disorder. Expert Rev. Neurother. 10, 603–620 (2010).

    Article  PubMed  Google Scholar 

  61. Harrison, B. J. et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch. Gen. Psychiatry 66, 1189–1200 (2009).

    Article  PubMed  Google Scholar 

  62. Van Marle, H. J. F., Hermans, E. J., Qin, S. & Fernandez, G. Enhanced resting-state connectivity of amygdala in the immediate aftermath of acute psychological stress. Neuroimage 53, 348–354 (2010).

    Article  PubMed  Google Scholar 

  63. Ehninger, D., Li, W., Fox, K., Stryker, M. P. & Silva, A. J. Reversing neurodevelopmental disorders in adults. Neuron 60, 950–960 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Belsky, J. et al. Vulnerability genes or plasticity genes? Mol. Psychiatry 14, 746–754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Penrod, N. M., Cowper-Sallari, R. & Moore, J. H. Systems genetics for drug target discovery. Trends Pharmacol. Sci. 32, 623–630 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  PubMed  Google Scholar 

  67. Jaaro-Peled, H. J. et al. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 32, 485–495 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Markou, A., Chiamulera, C., Geyer, M. A., Tricklebank, M. & Steckler, T. Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 34, 74–89 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Young, J. W., Powell. S. B., Risbrough, V., Marston, H. M. & Geyer, M. A. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol. Ther. 122, 150–202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Balanzá-Martínez, V. et al. Neurocognitive endophenotypes (endophenocognotypes) from studies of relatives of bipolar disorder subjects: a systematic review. Neurosci. Biobehav. Rev. 32, 1426–1438 (2008).

    Article  PubMed  Google Scholar 

  71. Turetsky, B. I. et al. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr. Bull. 33, 64–94 (2007).

    Google Scholar 

  72. Walter, H. et al., Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task. Mol. Psychiatry 16, 462–470 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Mosconi, M. M. et al. Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Arch. Gen. Psychiatry 67, 830–840 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Chamberlain, S. R. & Menzies, L. Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential. Expert. Rev. Neurother. 9, 1133–1146 (2009).

    Article  PubMed  Google Scholar 

  75. Apud, J. A. & Weinberger, D. R. Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors. CNS Drugs 21, 535–557 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Roussos, P., Giakoumaki, S. G. & Bitsios, P. Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818C/G polymorphism. Biol. Psychiatry 66, 997–1004 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Bertolino, A. et al. Prefrontal–hippocampal coupling during memory processing is modulated by COMT Val158Met genotype. Biol. Psychiatry 60, 1250–1258 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Meyer-Lindenberg, A. et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J. Clin. Invest. 117, 672–682 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Esslinger, C. et al. Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. Neuroimage 54, 2514–2523 (2011).

    Article  PubMed  Google Scholar 

  80. Hashimoto, R. et al. The impact of a genome-wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 5, 153B, 1459–1464 (2010).

    Article  Google Scholar 

  81. 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).

    Article  CAS  Google Scholar 

  82. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Joëls, M. & Baram, T. Z. The neuro-symphony of stress. Nature Rev. Neurosci. 10, 459–466 (2009).

    Article  CAS  Google Scholar 

  84. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Rev. Neurosci. 10, 434–445 (2009).

    Article  CAS  Google Scholar 

  85. Wang, X. D. et al. Forebrain CRF1 modulates early-life stress-programmed cognitive deficits. J. Neurosci. 21, 13625–13634 (2011).

    Article  CAS  Google Scholar 

  86. Schwabe, L., Wolf, O. T. & Oitzl, M. S. Memory formation under stress: quantity and quality. Neurosci. Biobehav. Rev. 34, 584–591 (2010).

    Article  PubMed  Google Scholar 

  87. Howland, J. G. & Wang, Y. T. Synaptic plasticity in learning and memory: stress effects in the hippocampus. Prog. Brain Res. 169, 145–158 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Mailliet, F. et al. Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signalling. Exp. Neurol. 211, 593–596 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Sandi, C. Glucocorticoids act on glutamatergic pathways to affect memory processes. Trends Neurosci. 34, 165–171 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Sotiropoulos, I. et al. Stress and glucocorticoid footprints in the brain — the path from depression to Alzheimer's disease. Neurosci. Biobehav. Rev. 32, 1161–1173 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Dorey, R. et al. Membrane mineralocorticoid but not glucocorticoid receptors of the dorsal hippocampus mediate the rapid effects of corticosterone on memory retrieval. Neuropsychopharmacology 36, 2639–2649 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cerqueira, J. J., Maillet, F., Almeida, O. F., Jay, T. M. & Sousa, N. The prefrontal cortex as a key target of the maladaptive response to stress, J. Neurosci. 27, 2781–2787 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Holmes, A. & Wellman, C. L. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci. Biobehav. Rev. 33, 773–783 (2009).

    Article  PubMed  Google Scholar 

  94. Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nature Rev. Neurosci. 10, 423–433 (2009).

    Article  CAS  Google Scholar 

  95. Oomen, C. A. et al. Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats. Psychopharmacology 214, 249–260 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Champagne, D. L. et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J. Neurosci. 28, 6037–6045 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Millan, M. J. & Brocco, M. Cognitive impairment in schizophrenia: a review of developmental and genetic models, and pro-cognitive profile of the optimized D3 > D2 antagonist, S33138. Thérapie 63, 187–229 (2008).

    PubMed  Google Scholar 

  98. Barch, D. M. Pharmacological strategies for enhancing cognition in schizophrenia. Curr. Top. Behav. Neurosci. 4, 43–96 (2010).

    Article  PubMed  Google Scholar 

  99. Margulies, C., Tully, T. & Dubnau, J. Deconstructing memory in Drosphila. Curr. Biol. 15, R700–R713 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hawkins, R. D., Kandel, E. R. & Bailey, C. H. Molecular mechanisms of memory storage in Aplysia. Biol. Bull. 210, 174–191 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Champagne, D. L., Hoefnagels, C. C. M., de Kloet, R. E. & Richardson, M. K. Translating rodent behavioral repertoire to zebrafish (Danio rerio); relevance for stress research. Behav. Brain Res. 214, 332–342 (2010).

    Article  PubMed  Google Scholar 

  102. Emery, N. J. & Clayton, N. S. Comparative social cognition. Annu. Rev. Psychol. 60, 87–113 (2009).

    Article  PubMed  Google Scholar 

  103. Bolhuis, J. J., Okanoya, K. & Scharff, C. Twitter evolution: converging mechanisms in birdsong and human speech. Nature Rev. Neurosci. 11, 747–759 (2010).

    Article  CAS  Google Scholar 

  104. Wallace, T., Ballard, T. M., Pouzet, B., Riedel, W. J. & Wettstein, J. G. Drug targets for cognitive enhancement in neuropsychiatric disorders. Pharmacol. Biochem. Behav. 99, 130–145 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Levin, E. D., Bushnell, P. J. & Rezvani, A. H. Attention-modulating effects of cognitive enhancers. Pharmacol. Biochem. Behav. 99, 146–154 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kaplan, G. B. & Moore, K. A. The use of cognitive enhancers in animal models of fear extinction. Pharmacol. Biochem. Behav. 99, 217–228 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Poe, G. R., Walsh, C. M. & Bjorness, T. E. Cognitive neuroscience of sleep. Prog. Brain Res. 185, 1–19 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Kyriacou, C. P. & Hastings, M. H. Circadian clocks: gene, sleep, and cognition. Trends Cogn. Sci. 14, 259–267 (2010).

    Article  PubMed  Google Scholar 

  109. Solas, M. et al. Interactions between age, stress and insulin on cognition: implications for Alzheimer's disease. Neuropsychopharmacology 35, 1664–1673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. El-Ghundi, M., O'Dowd, B. F. & George, S. R. Insights into the role of dopamine receptor systems in learning and memory. Rev. Neurosci. 18, 37–66 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Buchanan, R. W. et al. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol. Psychiatry 69, 442–449 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Graef, S., Schönknecht, P., Sabri, O. & Hegerl, U. Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings. Psychopharmacology, 215, 205–229 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. King, M. V., Marsden, C. A. & Fone, K. C. A role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol. Sci. 29, 482–492 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Codony, X., Vela, J. M. & Ramirez, M. J. 5-HT6 receptors and cognition. Curr. Opin. Pharmacol. 11, 94–100 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Goodson, J. L. & Thompson, R. R. Nonapeptide mechanisms of social cognition, behavior and species-specific social systems Curr. Opin. Neurobiol. 20, 784–794 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Insel, T. R. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behaviour. Neuron 65, 768–779 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Meyer-Lindenberg, A., Domes, G., Kirsch, P. & Heinrichs, M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Rev. Neurosci. 12, 524–538 (2011).

    Article  CAS  Google Scholar 

  118. Garnock-Jones, K. P. & Keating, G. M. Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatr. Drugs 11, 203–226 (2011).

    Article  Google Scholar 

  119. Ramos, B. P. & Arnsten, A. F. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol. Ther. 113, 523–536 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Sallee, F. R. The role of α2-adrenergic agonists in attention-deficit/hyperactivity disorder. Postgrad. Med. 122, 78–87 (2010).

    Article  PubMed  Google Scholar 

  121. Liem-Moolenaar, M. et al. The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects. J. Psychopharmacol. 24, 1671–1679 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Saavedra-Velez, C., Yusim, A., Anbarasan, D. & Lindenmayer, J. P. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J. Clin. Psychiatry 70, 104–112 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Saletu, M. et al. Modafinil improves information processing speed and increases energetic resources for orientation of attention in narcoleptics: double-blind, placebo-controlled ERP studies with low-resolution brain electromagnetic tomography (LORETA). Sleep Med. 10, 850–858 (2009).

    Article  PubMed  Google Scholar 

  124. Uslaner, J. M. et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 57, 531–538 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Zhang, Z., Gong, N., Wang, W., Xu, L. & Xu, T. L. Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval. Cereb. Cortex 18, 2391–2401 (2008).

    Article  PubMed  Google Scholar 

  126. Williams, G. V. & Castner, S. A. Under the curve: critical issues for elucidating D1 receptor function in working memory. Neuroscience 139, 263–276 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Deng, W., Aimone, J. B. & Gage, F. H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Rev. Neurosci. 11, 339–350 (2010).

    Article  CAS  Google Scholar 

  128. Kasai, H., Fukuda, M., Watanabe, S., Hayashi-Takagi, A. & Noguchi, J. Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci. 33, 121–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Mansuy, I. M. & Shenolikar, S. Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci. 29, 689–696 (2006).

    Article  CAS  Google Scholar 

  130. Pertovaara, A., Haapalinna, A., Sirviö, J. & Virtanen, R. Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective α2-adrenoceptor antagonist. CNS Drug Rev. 11, 273–288 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Lapiz, M. D. S. & Morilak, D. A. Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 137, 1039–1049 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Vellano, C. P., Lee, A. E., Dudek, S. M. & Hepler, J. R. RGS14 at the interface of hippocampal signaling and synaptic plasticity. Trends Pharmacol. Sci. 32, 666–674 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vinkers, C. H. et al. The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin. Investig. Drugs 19, 1217–1233 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Dölen, G., Carpenter, R. L., Ocain, T. D. & Bear, M. F. Mechanism-based approaches to treating fragile X. Pharmacol. Ther. 127, 78–93 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Lüscher, C. & Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445–459 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hoeffer, C. A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Franklin, T. & Mansuy, I. M. Epigenetic inheritance in mammals: evidence for the impact of adverse environmental effects. Neurobiol. Dis. 39, 61–65 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Day, J. J. & Sweatt, J. D. Epigenetic treatments for cognitive impairments. Neuropsychopharmacology 18 May 2011 (doi:10.1038/npp.2011.85).

  139. Raddatz, R., Tao, M. & Hudkins, R. L. Histamine H3 antagonists for treatment of cognitive deficits in CNS diseases. Curr. Top. Med. Chem. 10, 153–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Leiser, S. C., Bowlby, M. R., Comery, T. A. & Dunlop, J. A cog in cognition: how the α7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol. Ther. 122, 302–311 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Reneerkens, O. A. H., Rutten, K., Steinbusch, H. W. M., Blokland, A. & Prickaerts, J. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology 202, 419–443 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. Schmidt, C. J. Phosphodiesterase inhibitors as potential cognition enhancing agents. Curr. Top. Med. Chem. 10, 222–230 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Burgin, A. B. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nature Biotech. 28, 63–70 (2010).

    Article  CAS  Google Scholar 

  144. Sun, M. K. & Alkon, D. L. Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol. Ther. 127, 66–77 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Levallet, G., Hotte, M., Boulouard, M. & Dauphin, F. Increased particulate phosphodiesterase 4 in the prefrontal cortex supports 5-HT4 receptor-induced improvement of object recognition memory in the rat. Psychopharmacology 202, 125–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Puighemanal, E. et al. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nature Neurosci. 12, 1152–1158 (2009).

    Article  CAS  Google Scholar 

  147. Gafford, G. M., Parsons, R. G. & Helmstette, F. J. Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus. Neuroscience 182, 98–104 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Dewachter, I. et al. GSK3β, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9. Neurobiol. Dis. 35, 193–200 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Hooper, C. et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur. J. Neurosci. 25, 81–86 (2007).

    Article  PubMed  Google Scholar 

  150. Taglialatela, G., Hogan, D., Zhang, W. R. & Dineley, K. T. Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav. Brain Res. 200, 95–99 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Baumgärtel, K. et al. Control of the establishment of aversive memory by calcineurin and Zif268. Nature Neurosci. 11, 572–578 (2009).

    Article  CAS  Google Scholar 

  152. Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Lacefield, C. O., Itskov, V., Reardon, T., Hen, R. & Gordon, J. A. Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 29 Sep 2010 (doi:10.1002/hipo.20860).

  154. Rolls, E. T. A computational theory of episodic memory formation in the hippocampus. Behav. Brain Res. 215, 180–196 (2010).

    Article  PubMed  Google Scholar 

  155. Wixted, J. T. & Squire, L. R. The medial temporal lobe and the attributes of memory. Trends Cogn. Sci. 15, 210–217 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Carolis, N. A. & Eisch, A. J. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58, 884–893 (2011).

    Article  CAS  Google Scholar 

  157. Bramham, C. R. et al. The Arc of synaptic memory. Exp. Brain Res. 200, 125–140 (2010).

    Article  PubMed  Google Scholar 

  158. Minichiello, L. TrkB signalling pathways in LTP and learning. Nature Rev. Neurosci. 10, 850–860 (2009).

    Article  CAS  Google Scholar 

  159. Peters, J., Dieppa-Perea, L. M., Melendez, L. M. & Quirk, G. J. Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328, 1288–1290 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wilkinson, L. S., Davies, W. & Isles, A. R. Genomic imprinting effects on brain development and function. Nature Rev. Neurosci. 8, 832–843 (2007).

    Article  CAS  Google Scholar 

  161. Gregory, S. G. et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 7, 62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhang, T. Y. & Meaney, M. Epigenetics and the environmental regulation of the genome and its function. Annu. Rev. Psychol. 61, 439–466 (2010).

    Article  PubMed  Google Scholar 

  163. Guidotti, A. et al. Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology, 60, 1007–1016 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kundakovic, M., Chen. Y., Guidotti, A. & Grayson, D. R. The reelin of GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol. Pharmacol. 75, 342–354 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Guan, J. S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Koshibu, K., Gräff, J. & Mansuy, I. M. Nuclear protein phosphate-1: an epigenetic regulator of fear memory and amygdala long-term potentiation. Neuroscience 173, 30–36 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Torrioli, M. et al. Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys. Am. J. Med. Genet. A 152A, 1420–1427 (2010).

    PubMed  Google Scholar 

  168. Fischbach, S. J. & Carew, T. J. MiRNAs in memory processing. Neuron 63, 714–716 (2009).

    Article  CAS  PubMed  Google Scholar 

  169. Gao, J. et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hunsberger, J. G., Austin, D. R., Chen, G. & Manji, H. K. MiRNAs in mental health: from biological underpinnings to potential therapies. Neuromol. Med. 11, 173–182 (2009).

    Article  CAS  Google Scholar 

  171. Kocerha, J. et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc. Natl Acad. Sci. USA 106, 3507–3512 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  172. DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nature Rev. Neurosci. 9, 788–796 (2008).

    Article  CAS  Google Scholar 

  173. Medalia, A. & Choi, J. Cognitive remediation in schizophrenia. Neuropsychol. Rev. 19, 353–364 (2009).

    Article  PubMed  Google Scholar 

  174. Swerdlow, N. R. Are we studying and treating schizophrenia correctly? Schizophr. Res. 130, 1–10 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Cuijpers, P., van Staten, A., Hollon, S. D. & Andersson, G. The contribution of active medication to combined treatments of psychotherapy and pharmacotherapy for adult depression: a meta-analysis. Acta Psychiatr. Scand. 19, 1–9 (2009).

    Google Scholar 

  176. Myers, K. M., Carlezon, W. A. & Davis, M. Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology 36, 274–293 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Modi, M. E. & Young, L. J. D-cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders. Biol. Psychiatry 70, 298–304 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Keefe, R. S. et al. Characteristics of the MATRICS consensus cognitive battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr. Res. 125, 161–168 (2010).

    Article  PubMed  Google Scholar 

  179. Carter, C. S. & Barch, D. M. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia: the CNTRICS initiative. Schizophr. Bull. 33, 1131–1137 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Heinrichs, R. W., Ammari, N., Miles, A. A. & McDermid Vaz, S. Cognitive performance and functional competence as predictors of community independence in schizophrenia. Schizophr. Bull. 36, 381–387 (2010).

    Article  PubMed  Google Scholar 

  181. Leifker, F. R., Patterson, T. L., Heaton, R. K. & Harvey, P. D. Validating measures of real-world outcome: the results of the VALERO expert survey and RAND panel. Schizophr. Bull. 37, 334–343 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Green, M. F., Kerns, S. R. & Heaton, R. K. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr. Res. 72, 45–51 (2004).

    Google Scholar 

  183. Hill, S. K., Reilly, J. L., Harris, M. S. H., Khine, T. & Sweeney, J. A. Oculomotor and neuropsychological effects of antipsychotic treatment for schizophrenia. Schizophr. Bull. 34, 494–506 (2008).

    Article  PubMed  Google Scholar 

  184. Luna, B., Velanova, K. & Geier, C. F. Development of eye-movement control. Brain Cogn. 68, 293–308 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Reilly, J. L., Lencer, R., Bishop, J., Keedy, S. & Sweeney, J. A. Pharmacological studies of eye movement control. Brain Cogn. 68, 415–435 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Noudoost, B. & Moore, T. Control of visual cortical signals by prefrontal dopamine. Nature 474, 375–379 (2011).

    Article  CAS  Google Scholar 

  187. Keedy, S. K. et al. An fMRI study of visual attention and sensorimotor function before and after antipsychotic treatment in first episode schizophrenia. Psychiatry Res. 172, 16–23 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Sakkalis, V. Applied strategies towards EEG/MEG biomarker identification in clinical and cognitive research. Biomark. Med. 5, 93–105 (2011).

    Article  PubMed  Google Scholar 

  189. Braff, D. L. & Light, G. A. Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology 174, 175–185 (2004).

    Article  CAS  Google Scholar 

  190. Bodatsch, M. et al. Prediction of psychosis by mismatch negativity. Biol. Psychiatry 69, 959–966 (2011).

    Article  PubMed  Google Scholar 

  191. Lavoie, S. et al. Glutathione precursor, N-acetyl-cysteine, improved mismatch negativity in schizophrenia patients. Neuropsychopharmacology 33, 2187–2199 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Fell, J. & Axmacher, N. The role of phase synchronisation in memory processes. Nature Rev. Neurosci. 12, 105–118 (2011).

    Article  CAS  Google Scholar 

  193. Whittington, M. A., Cunningham, M. O., LeBeau, F. E. N., Racca, C. & Traub, R. D. Multiple origins of the cortical γ rhythm. Dev. Neurobiol. 71, 92–106 (2010).

    Article  Google Scholar 

  194. Perry, A. et al. Intranasal oxytocin modulates EEG mu/alpha and beta rhythms during perception of biological motion. Psychoneuroendocrinology 35, 1446–1453 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. Hali, S. D., Barnes, G. R., Furlong, P. L., Seri, S. & Hillebrand, A. Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmacomagnetoencephalography. Hum. Brain Mapp. 31, 581–594 (2010).

    Google Scholar 

  196. Higuchi, Y. et al. Electrophysiological basis for the ability of olanzapine to improve verbal memory and functional outcome in patients with schizophrenia: a LORETA analysis of P300. Schizophr. Res. 101, 320–330 (2008).

    Article  PubMed  Google Scholar 

  197. Murphy, S. E. & Mackay, C. E. Using MRI to measure drug action: caveats and new directions. J. Psychopharmacol. 25, 1168–1174 (2011).

    Article  CAS  PubMed  Google Scholar 

  198. Mu, Q. et al. A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. Schizophr. Res. 94, 332–341 (2007).

    Article  PubMed  Google Scholar 

  199. Lui, S. 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 67, 783–792 (2010).

    Article  PubMed  Google Scholar 

  200. Tregellas, J. R. et al. Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia. Neuropsychopharmacology 35, 938–942 (2010).

    Article  CAS  PubMed  Google Scholar 

  201. Riem, M. M. et al. Oxytocin modulates amygdala, insula, and inferior frontal gyrus responses to infant crying: a randomized controlled trial. Biol. Psychiatry 70, 291–297 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Garner, M., Zurowski, B. & Büchel, C. Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans. Proc. Natl Acad. Sci. USA 107, 9400–9405 (2010).

    Article  Google Scholar 

  203. Broyd, S. J. et al. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci. Biobehav. Rev. 33, 279–296 (2009).

    Article  PubMed  Google Scholar 

  204. Sambataro, P. et al. Treatment with olanzapine is associated with modulation of the default mode network in patients with schizophrenia. Neuropsychopharmacology 35, 904–912 (2010).

    Article  CAS  PubMed  Google Scholar 

  205. Tregellas, J. R. et al. Effects of an α7-nicotinic agonist on default network activity in schizophrenia. Biol. Psychiatry 69, 7–11 (2011).

    Article  CAS  PubMed  Google Scholar 

  206. Minzenberg, M. J., Yoon, J. H. & Carter, C. S. Modafinil modulation of the default mode network. Psychopharmacology 215, 23–31 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Szulc, A. et al. Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment. Pharmacopsychiatry 44, 148–157 (2011).

    Article  CAS  PubMed  Google Scholar 

  208. Bustillo, J. R. Glutamate as a marker of cognitive function in schizophrenia: a proton spectroscopic imaging study at 4 Tesla. Biol. Psychiatry 69, 19–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  209. Ertugrul, A. et al. The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: relationship with treatment response. Psychiatry Res. 174, 121–129 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Manganas, L. N. et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Vyas, N. S., Patel, N. H., Nijran, K. S., Al-Nahhas, A. & Puri, B. K. The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia. Expert Rev. Neurother. 11, 37–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  212. Van Overwalle, F. & Baetens, K. Understanding others' actions and goals by mirror and mentalizing systems: a meta-analysis. Neuroimage 48, 564–584 (2009).

    Article  PubMed  Google Scholar 

  213. Young, L. J. & Wang, Z. The neurobiology of pair bonding. Nature Neurosci. 7, 1048–1054 (2004).

    Article  CAS  PubMed  Google Scholar 

  214. Hermann, E., Call, J., Hernandez-Lloreda, M. V., Hare, B. & Tomasello, M. Humans have evolved specialized skills to social cognition: the cultural intelligence hypothesis. Science 317, 1360–1366 (2007).

    Article  CAS  Google Scholar 

  215. Carruthers, P. The cognitive functions of language. Behav. Brain Sci. 25, 657–674 (2002).

    PubMed  Google Scholar 

  216. Nelson, B. & Rawlings, D. Relating schizotypy and personality to the phenomenology of creativity. Schizophr. Bull. 36, 388–399 (2010).

    Article  CAS  PubMed  Google Scholar 

  217. Hart, B. L., Hart, L. A. & Pinter-Wollman, N. Large brains and cognition: where do elephants fit in? Neurosci. Biobehav. Rev. 32, 86–98 (2008).

    Article  PubMed  Google Scholar 

  218. Premack, D. Human and animal cognition: continuity and discontinuity. Proc. Natl Acad. Sci. USA 104, 13861–13867 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. McGraw, L. A. & Young, L. J. The prairie vole: an emerging model organism for understanding the social brain. Trends Neurosci. 33, 106–109 (2009).

    Google Scholar 

  220. Scattoni, M. L., Crawley, J. & Ricceri, L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci. Biobehav. Rev. 33, 508–515 (2009).

    Article  PubMed  Google Scholar 

  221. Arakawa, H., Blanchard, D. C., Arakawa, K., Dunlap, C. & Blanchard, R. J. Scent marking behavior as an odorant communication in mice. Neurosci. Biobehav. Rev. 32, 1236–1248 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Dunbar, R. I. The social role of touch in humans and primates: behavioural function and neurobiological mechanisms. Neurosci. Biobehav. Rev. 34, 260–268 (2010).

    Article  CAS  PubMed  Google Scholar 

  223. Buchanan, R. W. et al. The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209–1217 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Manahan-Vaughan, D., Widlfôrster, V. & Thomsen, C. Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1 (GlyT1). Eur. J. Neurosci. 28, 1342–1350 (2008).

    Article  PubMed  Google Scholar 

  225. Stefani, M. R. & Moghaddam, B. Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur. J. Pharmacol. 639, 26–32 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Ayala, J. E. et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34, 2057–2071 (2009).

    Article  CAS  PubMed  Google Scholar 

  227. Zanto, F. P., Rubens, M. T., Thangavel, A. & Gazzaley, A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory Nature Neurosci. 14, 656–662 (2011).

    Article  CAS  PubMed  Google Scholar 

  228. Belforte, J. E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neurosci. 13, 76–83 (2010).

    Article  CAS  PubMed  Google Scholar 

  229. Moreines, J. L., McClintock, S. M. & Holtzheimer, P. E. Neuropsychologic effects of neuromodulation technique for treatment-resistant depression: a review. Brain Stimul. 4, 17–27 (2010).

    Article  PubMed  Google Scholar 

  230. Matheson, S. L., Green, M. J., Loo, C. & Carr, V. J. Quality assessment and comparison of evidence for electroconvulsive therapy and repetitive transcranial magnetic stimulation for schizophrenia: a systematic meta-review. Schizophr. Res. 118, 201–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  231. Vanderhasselt, M. A., De Raedt, R., Baeken, C., Leyman, L. & D'Haanen, H. A single session of rTMS over the left dorsolateral prefrontal cortex influences attentional control in depressed patients. World J. Biol. Psychiatry 10, 34–42 (2009).

    Article  PubMed  Google Scholar 

  232. Barr, M. S. et al. Potentiation of γ oscillatory activity through repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex. Neuropsychopharmacology 34, 2359–2367 (2009).

    Article  PubMed  Google Scholar 

  233. Sokhadze, E. M. et al. Effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on γ frequency oscillations and event-related potentials during processing of illusory figures in autism. J. Autism Dev. Disord. 39, 619–634 (2009).

    Article  PubMed  Google Scholar 

  234. Treffart, D. A. The savant syndrome: an extraordinary condition. A synopsis: past, present, future. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 1351–1358 (2009).

    Article  Google Scholar 

  235. Cattaneo, Z., Pisoni, A. & Papagno, C. Transcranial direct current stimulation over Broca's region improves phonemic and semantic fluency in healthy individuals. Neuroscience 183, 64–70 (2011).

    Article  CAS  PubMed  Google Scholar 

  236. De Carvalho, M. R., Rozenthal, M. & Nardi, A. E. The fear circuitry in panic disorder and its modulation by cognitive-behaviour therapy interventions. World J. Biol. Psychiatry 11, 188–198 (2009).

    Article  Google Scholar 

  237. Wykes, T., Huddy, V., Cellard, C., McGurk, S. R. & Czobor, P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168, 472–485 (2011).

    Article  PubMed  Google Scholar 

  238. Naismith, S. L. Enhancing memory in late-life depression: the effects of a combined psychoeducation and cognitive training program. Am. J. Psychiatry 19, 240–248 (2011).

    Google Scholar 

  239. Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).

    Article  CAS  PubMed  Google Scholar 

  240. Jung, R. E. & Haier, R. J. The parieto-frontal integration theory (P-FIT) of intelligence: converging neuroimaging evidence. Behav. Brain Sci. 30, 135–187 (2007).

    Article  PubMed  Google Scholar 

  241. Van Strien, N. M., Cappaert, N. L. M. & Witter, M. P. The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nature Rev. Neurosci. 10, 272–282 (2009).

    Article  CAS  Google Scholar 

  242. Strick, P. L., Dum, R. P. & Fiez, J. A. Cerebellum and non-motor function. Annu. Rev. Neurosci. 32, 413–434 (2009).

    Article  CAS  PubMed  Google Scholar 

  243. Price, C. J. The anatomy of language: a review of 100 fMRI studies published in 2009. Ann. NY Acad. Sci. 1191, 62–88 (2010).

    Article  PubMed  Google Scholar 

  244. Saur, D. et al. Ventral and dorsal pathways for language. Proc. Natl Acad. Sci. USA 105, 18035–18040 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Fusar-Poli, P. et al. Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J. Psychiatry Neurosci. 34, 418–432 (2009).

    PubMed  PubMed Central  Google Scholar 

  246. Ishai, A., Schmidt, C. F. & Boesiger, P. Face perception is mediated by a distributed cortical network. Brain Res. Bull. 67, 87–93 (2005).

    Article  PubMed  Google Scholar 

  247. Cattaneo, L. & Rizzolatti, G. The mirror neuron system. Arch. Neurol. 66, 557–560 (2009).

    Article  PubMed  Google Scholar 

  248. Fadiga, L., Craighero, L. & D'Ausilio, A. Broca's area in language, action, and music. Ann. NY Acad. Sci. 1169, 448–458 (2009).

    Article  PubMed  Google Scholar 

  249. Doron, K. W., Funk, C. M. & Glickstein, M. Fronto-cerebellar circuits and eye movement control: a diffusion imaging tractography study on human cortico-pontine projections. Brain Res. 1307, 63–71 (2010).

    Article  CAS  PubMed  Google Scholar 

  250. Beaton, A. & Mariën P. Language, cognition and the cerebellum: grappling with an enigma. Cortex 46, 811–820 (2010).

    Article  PubMed  Google Scholar 

  251. Watson, D. J. G., Marsden, M. A., Millan, M. J. & Fone, K. F. C. Blockade of dopamine D3 but not D2 receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment. Int. J. Neuropsychopharmacol. 18 Mar 2011 (doi:10.1017/S1461145711000435).

  252. Loiseau F. & Millan M. J. Blockade of dopamine D3 receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: similar actions of D1 receptor agonists, but not of D2 antagonists. Eur. Neuropsychopharmacol. 19, 23–33 (2009).

    Article  CAS  PubMed  Google Scholar 

  253. Brioni, J. D., Esbenshade, T. A., Garrison, T. R., Bitner, S. R. & Cowart, M. D. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer's disease. J. Pharmacol. Exp. Ther. 336, 38–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  254. Sellin, A. K., Shad, M. & Tamminga, C. Muscarinic agonists for the treatment of cognition in schizophrenia. CNS Spectr. 13, 985–996 (2008).

    Article  PubMed  Google Scholar 

  255. McArthur, R. A., Gray, J. & Schreiber, R. Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials. Curr. Opin. Invest. Drugs 11, 740–760 (2011).

    Google Scholar 

  256. Shimazaki, T., Kaku, A. & Chaki, S. D-serine and a glycine transporter-1 inhibitor enhance social memory in rats. Psychopharmacology 20, 263–270 (2010).

    Article  CAS  Google Scholar 

  257. Smith, S. M., Uslaner, J. M. & Hutson, P. H. The therapeutic potential of D-amino acid oxidase (DAAO) inhibitors. Open Med. Chem. J. 4, 3–9 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Labrie, V. et al. Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. Learn. Mem. 16, 28–37 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Roberts, B. M. et al. Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction. Behav. Brain Res. 212, 41–48 (2010).

    Article  CAS  PubMed  Google Scholar 

  260. O'Neill, M. J. & Dix, S. AMPA receptor potentiatiors as cognitive enhancers. IDrugs 10, 185–192 (2007).

    CAS  PubMed  Google Scholar 

  261. Simonyi, A., Schachtman, T. R. & Christoffersen, G. R. J. Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur. J. Pharmacol. 639, 17–25 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Castner, S. A. et al. Reversal of ketamine-induced working memory impairments by the GABAAα2/3 agonist TPA023. Biol. Psychiatry 15, 998–1001 (2010).

    Article  CAS  Google Scholar 

  263. Takahashi, R. N., Pamplona, F. A. & Prediger, R. D. Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. Front. Biosci. 13, 2614–2632 (2008).

    Article  CAS  PubMed  Google Scholar 

  264. Wei, C. J. et al. Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning. Learn. Mem. 21, 459–474 (2011).

    Article  CAS  Google Scholar 

  265. de Bruin, N. M. W. et al. SVL330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and social recognition tasks in rodents. Neurobiol. Learn. Mem. 217, 408–415 (2010).

    Google Scholar 

  266. Egashira, N., Mishima, K., Iwasaki, K., Oishi, R. & Fujiwara, M. New topics in vasopressin receptors and approach to novel drugs: role of the vasopressin receptor in psychological and cognitive functions. J. Pharmacol. Sci. 109, 44–49 (2009).

    Article  CAS  PubMed  Google Scholar 

  267. Hongpaisan, J., Sun, M. K. & Alkon, D. L. PKCɛ activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J. Neurosci. 12, 630–643 (2011).

    Article  CAS  Google Scholar 

  268. Gozes, I. Microtubules, schizophrenia and cognitive behaviour: preclinical development of davunetide (NAP) as a peptide-drug candidate. Peptides 32, 428–431 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M. Soubeyran is thanked for excellent secretarial assistance, S.-M. Rivet for the excellent graphics, and A. Gobert and A. Dekeyne are likewise thanked for their logistical help. We would like to thank three anonymous reviewers for their insightful comments that helped to improve the manuscript. This paper emerged from a Congress that took place in France, 2009, organized by 'Advances in Neuroscience for Medical Innovation' and supported by an educational grant from Institut de Recherche Servier.

Author information

Authors and Affiliations

  1. Institut de Recherche Servier, Croissy/Seine, 78290, France

    Mark J. Millan

  2. ICM, Pitié-Salpétrière University Hospital, 47 boulevard de l'Hôpital, Paris, 75013, France

    Yves Agid

  3. Research Department of Cognitive Neuropsychiatry and Psychiatric Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Alexandrinenstr. 1, Bochum, 44791, Germany

    Martin Brüne

  4. University of Cambridge and GlaxoSmithKline, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK

    Edward T. Bullmore

  5. University of California, Davis, Sacramento, 95817, California, USA

    Cameron S. Carter

  6. Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, UK

    Nicola S. Clayton

  7. Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, 02747, USA

    Richard Connor

  8. Centre National de la Recherche Scientifique, University of Paris-Sud, Orsay, 91400, France

    Sabrina Davis

  9. Neuroscience and Psychiatry Unit, University of Manchester, Manchester, M13 9PT, UK

    Bill Deakin

  10. University of Pennsylvania, Philadelphia, 19104, USA

    Robert J. DeRubeis

  11. Institut du Cerveau et de la Moelle Epinière (ICM), Université Pierre et Marie Curie, Paris 6, Paris, UMR-S975, France

    Bruno Dubois

  12. University of California San Diego, La Jolla, 92093-0804, California, USA

    Mark A. Geyer

  13. University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK

    Guy M. Goodwin

  14. INSERM; Université Paris, Descartes, Centre de Psychiatrie et Neurosciences U894,

    Philip Gorwood & Thérèse M. Jay

  15. Université Paris, Descartes, Centre de Psychiatrie et Neurosciences U894, Paris, 75014, France

    Philip Gorwood & Thérèse M. Jay

  16. Department of Neuroscience and Pharmacology, Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, 3584, CG, The Netherlands

    Marian Joëls

  17. Brain Research Institute, University of Zürich and ETHZ, Zürich, 8057, Switzerland

    Isabelle M. Mansuy

  18. Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, Mannheim, D-68159, Germany

    Andreas Meyer-Lindenberg

  19. Institute of Psychiatry, King's College London, Denmark Hill, London, SE5 8AF, UK

    Declan Murphy

  20. Oxford Centre for Computational Neuroscience and Department of Computer Science, University of Warwick, Coventry, CV4 7AL, UK

    Edmund Rolls

  21. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Gürtel 18-20, Vienna, A-1090, Austria

    Bernd Saletu

  22. Les Laboratoires Servier, 50 Rue Carnot, Suresnes Cedex, 92284, France

    Michael Spedding

  23. University of Texas Southwestern, Dallas, 75235, Texas, USA

    John Sweeney

  24. Newcastle University, Newcastle, NE2 4HH, UK

    Miles Whittington

  25. Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, 30329, Georgia, USA

    Larry J. Young

Authors
  1. Mark J. Millan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yves Agid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Brüne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward T. Bullmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cameron S. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicola S. Clayton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sabrina Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bill Deakin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert J. DeRubeis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bruno Dubois
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mark A. Geyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Guy M. Goodwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Philip Gorwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Thérèse M. Jay
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Marian Joëls
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Isabelle M. Mansuy
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Andreas Meyer-Lindenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Declan Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Edmund Rolls
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Bernd Saletu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Michael Spedding
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. John Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Miles Whittington
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Larry J. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark J. Millan.

Ethics declarations

Competing interests

Mark J. Millan is a full-time employee of the Institut de Recherche Servier.

Yves Agid carried out a consultancy at the department of neuroscience of Servier.

Martin Brüne declares no competing financial interests.

Edward T. Bullmore is employed half-time by GlaxoSmithKline (GSK) and holds shares in GSK.

Cameron S. Carter has received a research grant from GlaxoSmithKline (GSK) and is an advisory board consultant at Pfizer.

Nicola S. Clayton declares no competing financial interests.

Richard Connor declares no competing financial interests.

Sabrina Davis declares no competing financial interests.

Bill Deakin has carried out consultancy and speaking engagements for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag and Servier. All fees are paid to the University of Manchester to reimburse them for the time taken. He has share options in P1vital.

Robert J. DeRubeis declares no competing financial interests.

Bruno Dubois declares no competing financial interests.

Mark A. Geyer has received consulting compensation from Abbott, Acadia, Addex, Cerca, Medivation, Merck, Omeros, Takeda and Teva, and holds an equity interest in San Diego Instruments.

In the past 3 years, Guy M. Goodwin has had grants from Servier; received honoraria for speaking or chairing educational meetings from AstraZeneca, Bristol-Myers Squibb, Eisai, Lundbeck, Sanofi-Aventis and Servier; and advised AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen-Cilag, Lilly, Lundbeck, P1vital, Roche, Sanofi-Aventis and Servier. He holds shares in P1vital and acted as an expert witness for Lilly.

During the past 5 years, Philip Gorwood received research grants from Eli Lilly and Servier, and fees for presentations at congresses or participation in scientific boards from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Roche and Servier.

Thérèse M. Jay has received grant support from the Institut de Recherche Servier.

Marian Joëls declares no competing financial interests.

Isabelle M. Mansuy declares no competing financial interests.

Andreas Meyer-Lindenberg declares no competing financial interests.

Declan Murphy declares no competing financial interests.

Edmund Rolls declares no competing financial interests.

Bernd Saletu has received research support from Abiogen Pharma, Actelion, AstraZeneca, Cephalon, GlaxoSmithKline, Sanofi-Aventis, Schwarz Pharma, Servier and Takeda; he has received honoraria (not exceeding US$10,000 per year) for serving on the scientific advisory boards of Nycomed, Servier, Takeda, UCB and Sanofi-Aventis, for being a consultant for Merck and XenoPort and for being a speaker for AstraZeneca, Cephalon, IXICO, Janssen and Lundbeck. He is a shareholder of The Siesta Group Schlafanalyse GmbH, Austria.

Michael Spedding is employed by Les Laboratoires Servier.

John Sweeney declares no competing financial interests.

Miles Whittington declares no competing financial interests.

Larry J. Young declares no competing financial interests.

Supplementary information

Supplementary information S1 (figure)

Cellular substrates and susceptibility genes influencing synaptic plasticity and cognitive processes in psychiatric disorders. (PDF 1364 kb)

Supplementary information S2 (figure)

Cellular networks underpinning cognitive processes, potential targets for countering the cognitive impairment of psychiatric disorders. (PDF 953 kb)

Supplementary information S3 (box)

Complex social alliances in dolphins and other cetaceans: relevance to human social cognition (PDF 192 kb)

Supplementary information S4 (box)

Prairie voles, social cognition and the key pro-social role of oxytocin. (PDF 146 kb)

Supplementary information S5 (box)

Complex cognitive capacities of birds: focus on temporal and social dimensions. (PDF 195 kb)

Glossary

Cognition

A suite of interrelated conscious (and unconscious) mental activities, including: pre-attentional sensory gating; attention; learning and memory; problem solving, planning, reasoning and judgment; understanding, knowing and representing; creativity, intuition and insight; 'spontaneous' thought; introspection; as well as mental time travel, self-awareness and meta-cognition (thinking and knowledge about cognition).

Learning

The active, experience- and/or training-driven acquisition of information or behaviour. The term 'conditioning' is usually used in an experimental context of associative learning. Learning necessitates complementary and distinct processes of encoding and acquisition that can be perturbed and modulated independently.

Memory

Partly separate mechanisms permitting consolidation, retention and retrieval of information from various sensory domains. Short-term memory relates to immediately available information maintained for ∼30 seconds. Information retained for longer periods must be consolidated into mechanistically different long-term memory; in principle, this relates to the unlimited (in quantity and in time) capacity to store information.

Extinction

The progressive reduction of a response to a stimulus — for example, owing to discontinuation of reinforcement or loss of association between an unconditioned and conditioned stimulus. Extinction does not just refer to forgetting (a loss or weakening of memory) or 'un-learning' (a decay of the processes involved in retention and recall); rather, it refers to a special form of learning that involves active processes of suppression. The extinguished response may reappear following a change of context or exposure to stress.

Attention

The awareness and attendance to a stimulus or set of stimuli. It depends on the perception, selection and filtering of sensory input and information. Sustained attention (vigilance) is the capacity to maintain attention over an extended period. Selective (focused) attention is the ability to preferentially attend to a subset of stimuli, thus avoiding distraction. Divided attention is the capacity to respond to multiple stimuli simultaneously, and may involve executive shifts in focused attention according to the demands of the situation.

Processing speed

The rapidity with which a cognitive operation is undertaken successfully. Although this is usually related to the speed of information processing, it may also apply to the speed of retrieval. Processing speed affects performance in many tasks and is operationally related to reaction time.

Working memory

Permits the transient 'online' evaluation, manipulation and synthesis of newly acquired and/or stored information. Working memory operates in short-term memory but the two terms are not synonymous. Working memory is closely interrelated to, and interacts with, attention and executive function.

Top-down cortical cognitive control

Related to executive function. Refers to cortically integrated (in the prefrontal cortex, cingulate cortex and parietal cortex) top-down processes that favour goal-directed behaviours by flexibly investing resources (such as sustained attention) that are needed for goal accomplishment. It also involves the suppression of interference from irrelevant information, habitual actions, negative emotions, and so on.

Procedural learning

The progressive assimilation (learnt association between a stimulus and a response), by practice, of an appropriate behaviour generally involving a motor skill, such as driving a car, which may become an automatic habit. It is closely related to non-declarative (implicit) memory — a form of long-term memory that involves non-conscious recollection of skills, behaviours, habits and preferences such as cycling or one's favourite colour.

Executive function

A purposeful, goal-directed operation such as planning, decision making, problem solving, reasoning, concept formation, self-monitoring or cognitive flexibility (adaptive alternation between different strategies, responses and behaviours). Executive function reciprocally interacts with attention and working memory. It includes both initiation of appropriate and suppression of inappropriate responses.

Declarative memory

A form of long-term memory that demands conscious learning. It is divided into episodic and semantic memory.

Semantic memory

A form of long-term memory that involves the learning and storing of immutable facts, information, ideas, and so on. In contrast to episodic memory, semantic memory cannot — in principle — be modified by questions and alternative accounts.

Episodic memory

The conscious recollection of experiences linked to times and places in the past — what happened, where and when. It may involve mental time-travel back into a situation (known as autobiographical re-experiencing), mirrored by projection into an imagined future (prospective envisioning). As such, it is related to the theory of mind ('travel into' or simulation of other minds). Fully-fledged episodic memory may be a uniquely human trait, but there is evidence for its presence in primates, corvids and even some rodents.

Prosody

The use (and interpretation) of features such as stress, intonation and rhythm that lend additional meaning and emotion to speech.

Pragmatics

The appropriate social use of spoken language.

Verbal fluency

The ability to use written and spoken language, to choose the right word at the right time and to make appropriate associations.

Semantics

The meaning of what is said, written, read or heard.

Epigenetic control

A somatic and/or germline modification of chromatin (DNA plus nuclear proteins) that leads to long-lasting alterations in gene expression but not in the DNA sequence. DNA methylation silences genes and occurs mainly in CpG-rich promoter islands. Histone tails are subject to interacting processes of methylation (lysine and/or arginine residues), acetylation (lysine residues), phosphorylation, sumoylation, ubiquitylation and ADP ribosylation. Acetylation causes decondensation (unwinding), increased access for transcription factors and enhanced gene expression.

Default-mode network

A functionally interconnected network of cortical regions that is active under wakeful, resting conditions in functional magnetic resonance imaging paradigms, yet is consistently deactivated by goal-directed activity such as cognitive tasks. It includes the posterior cingulate cortex, precuneus, medial prefrontal cortex and inferior parietal cortex, and is characterized by synchronised, low-frequency oscillations of less than 1.0 Hz.

Neurogenesis

The continuous generation of new neurons from neural precursor cells in humans and other mammals. It is seen mainly in two regions. First, the subventricular zone of the lateral ventricle gives rise to neurons that migrate to become granule neurons and periglomerular neurons mainly in the olfactory bulb. Second, neurogenesis in the subgranular zone of the hippocampal dentate gyrus yields neurons, some of which are integrated into local neural networks once they have matured.

Fragile X syndrome

A disease that is usually caused by the expansion of a trinucleotide sequence in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene. This leads to FMR1 promoter hypermethylation, transcriptional silencing and loss of the RNA-binding protein FMR1. Abnormal translation of mRNAs, including those regulated by metabotropic glutamate receptor 5, results in excessive long-term depression. Affected individuals have defects in speech, language, attention, working memory and social cognition.

Tuberous sclerosis

An autosomal dominant disorder, usually caused by sporadic mutations, leading to inactivation of the tumour suppressor genes tuberous sclerosis 1 (TSC1; also known as hamartin) and TSC2 (also known as tuberin), which normally inhibit RHEB (a GTPase that is an activator of mammalian target of rapamycin). Loss of TSC1 or TSC2 leads to disinhibition of cell growth, cortical tubers and giant astrocytomas in the brain. Patients have deficits in attention, executive function and memory, as well as symptoms resembling autism spectrum disorder and attention deficit hyperactivity disorder.

Rett's syndrome

An X-linked developmental disorder, mainly seen in females, caused by de novo mutations in the gene encoding methyl CpG binding protein 2 (MECP2). MECP2 normally binds to methylated DNA to transcriptionally repress genes, although some are activated. MECP2 also interacts with histone deacetylases, so its loss leads to gene-dependent histone hypo- and hyperacetylation. Patients with Rett's syndrome suffer from retardation, loss of verbal learning and speech, and impaired social cognition.

Rubinstein–Taybi syndrome

A rare disorder characterized by autistic features, learning difficulties and poor attention. In approximately 50% of cases, it is caused by de novo mutations or deletions in the genes encoding CREB-binding protein or, rarely, histone acetyltransferase p300. These CREB-binding proteins and transcriptional co-activators are also histone acetylases, so patients display histone hypoacetylation and reduced gene transcription.

MicroRNAs

(miRNAs). Small, non-protein-coding sequences (22–24 nucleotides) of RNA, mostly derived from intergenic regions, although some are found in introns. An individual species of miRNA can bind to the 3′-untranslated regions of up to hundreds of different species of mRNA. Translation is usually suppressed but it is sometimes enhanced, and in certain cases mRNA may even be degraded.

Savant syndrome

A rare syndrome that is closely associated with high-functioning autism spectrum disorder but also found in other developmental disorders and following damage to or disease of the central nervous system. It alludes to 'islands of genius' in one or a few cognitive domains such as mathematics despite broader deficits in others, and is usually associated with prodigious memory. Savant-like abilities can partially be reproduced by transcranial magnetic stimulation over the cortex.

Functional magnetic resonance imaging

(fMRI). A technique that exploits the differential paramagnetic properties of oxy- and deoxyhaemoglobin to estimate local cerebral blood oxygenation level-dependent (BOLD) activity. Increased oxygen supply compensates for (and transiently exceeds) energy needs, so the BOLD signal is proportional to neuronal activity. Interpretation of data is challenging as BOLD integrates changes both in neurons and in glia, pre- and postsynaptic changes in excitability, as well as local and upstream effects of drugs. Furthermore, BOLD signals can be affected by energy balance and haemodynamic parameters.

Graph theory

A mathematical approach for modelling complex networks whereby individual elements, like cerebral regions, neurons or cellular proteins, are considered as 'nodes' linked by 'edges'. Brain graphs (derived from neuroimaging data) and cellular graphs (derived from studies of protein networks) reveal non-random topological properties such as modularity (clusters of nodes highly connected to each other) and hubs (nodes with numerous connections). These properties help to optimize network function, including cognitive processing.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Millan, M., Agid, Y., Brüne, M. et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 11, 141–168 (2012). https://doi.org/10.1038/nrd3628

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3628

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research