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

Millan, Mark J.; Agid, Yves; Brüne, Martin; Bullmore, Edward T.; Carter, Cameron S.; Clayton, Nicola S.; Connor, Richard C.; Davis, Sabrina; Deakin, Bill; DeRubeis, Robert J.; Dubois, Bruno; Geyer, Mark A.; Goodwin, Guy M.; Gorwood, Philip; Jay, Thérèse M.; Joëls, Marian; Mansuy, Isabelle M.; Meyer‐Lindenberg, Andreas; Murphy, Declan; Rolls, Edmund T.; Saletu, B.; Spedding, Michael; Sweeney, John A.; Whittington, Miles A.; Young, Larry J.

doi:10.1038/nrd3628

Cited by 983 publications

(844 citation statements)

References 268 publications

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“…49,50 Importance of GABA receptors for the regulation of cognition, emotion and memory is increasingly being recognized. 51,52 The Dp427p is expressed in the cerebellar and hippocampal Purkinje cells and in the cortical brain. 53,54 However, exon 45 does not affect three shorter DMD isoforms (Dp140, Dp116 and Dp71) which are known to be associated with cognitive function in DMD.…”

Section: Discussionmentioning

confidence: 99%

The dystrophin gene and cognitive function in the general population

et al. 2014

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The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (Po1 × 10 − 4 ), rs147546024:A4G showed strong association (β = 1.786, P-value = 2.56 × 10 − 4 ) with block-design test in the ERF study, while another variant rs1800273:G4A showed suggestive association (β = − 0.465, P-value = 0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A4G is an intronic variant, whereas rs1800273:G4A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values = 0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.

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Section: Discussionmentioning

confidence: 99%

The dystrophin gene and cognitive function in the general population

et al. 2014

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“…Virtual navigation paradigms have already been successfully used in aged subjects and in clinical populations (Konishi et al, 2013;Sneider et al, 2013;Spieker et al, 2012;Yuan et al, 2014). Although there are currently no established treatments for such deficits, the use of this translational paradigm in affected populations is expected to help identify the neural correlates of WM impairment and may ultimately inform novel treatments (Millan et al, 2012). It is important to keep in mind that this paradigm may have to be modified for different populations depending on the exact research question being asked.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal–Dorsolateral Prefrontal Coupling as a Species-Conserved Cognitive Mechanism: A Human Translational Imaging Study

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Schweiger

et al. 2015

Neuropsychopharmacol

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Hippocampal-prefrontal cortex (HC-PFC) interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging together with a spatial WM paradigm adapted from rodent research to examine HC-PFC coupling in humans. A PFC-parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral PFC (DLPFC), and right supramarginal gyrus explained one-fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC-DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.

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“…Among hierarchically inter-related cognitive dysfunctions associated with schizophrenia (Millan et al 2012), perhaps the best studied is working memory (Park and Holzman 1992, Lee and Park 2005, Lewis and Gonzalez-Burgos 2006, Barch and Ceaser 2012. Working memory, the brain's ability to encode and sustain the neural representation of information in the absence of direct sensory stimulation and to manipulate this information in the service of future action, is a core cognitive function that depends on the PFC (Fuster 2008, GoldmanRakic 1995, D'Esposito 2007, Baddeley 2012.…”

Section: Biophysically-based Neural Circuit Modeling: Understanding Amentioning

confidence: 99%

Computational Psychiatry

2016

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Psychiatric disorders such as autism and schizophrenia arise from abnormalities in brain systems that underlie cognitive, emotional and social functions. The brain is enormously complex and its abundant feedback loops on multiple scales preclude intuitive explication of circuit functions. In close interplay with experiments, theory and computational modeling are essential for understanding how, precisely, neural circuits generate flexible behaviors and their impairments give rise to psychiatric symptoms. This Perspective highlights recent progress in applying computational neuroscience to the study of mental disorders. We outline basic approaches, including identification of core deficits that cut across disease categories, biologically-realistic modeling bridging cellular and synaptic mechanisms with behavior, model-aided diagnosis. The need for new research strategies in psychiatry is urgent. Computational psychiatry potentially provides powerful tools for elucidating pathophysiology that may inform both diagnosis and treatment. To achieve this promise will require investment in cross-disciplinary training and research in this nascent field. © 2014 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Neither Dr. Wang nor Dr. Krystal has any financial interests relevant to the advancement of computational psychiatry. to and engage with psychiatric research. Second, it will be important to develop a cadre of young psychiatrists who learn computational modeling, lest computational psychiatry.

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

Cited by 983 publications

References 268 publications

The dystrophin gene and cognitive function in the general population

The dystrophin gene and cognitive function in the general population

Hippocampal–Dorsolateral Prefrontal Coupling as a Species-Conserved Cognitive Mechanism: A Human Translational Imaging Study

Computational Psychiatry

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