Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models

Kalueff, Allan V.; Stewart, Adam; Song, Cai; Gottesman, Irving I.

doi:10.1016/j.neubiorev.2015.03.007

Cited by 52 publications

(19 citation statements)

References 132 publications

(144 reference statements)

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“…We conclude by identifying issues that merit further investigation. Figure 1 illustrates the core features of our integrated decision-making model and highlights the complex interplay underpinning neuropsychological systems (see also Kalueff, Stewart, Song, and Gottesman, 2015). The model has several general characteristics.…”

Section: Introductionmentioning

confidence: 99%

Annual Research Review: Transdiagnostic neuroscience of child and adolescent mental disorders – differentiating decision making in attention‐deficit/hyperactivity disorder, conduct disorder, depression, and anxiety

Sonuga‐Barke

Cortese

Fairchild

et al. 2015

Child Psychology Psychiatry

146

119

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BackgroundIneffective decision making is a major source of everyday functional impairment and reduced quality of life for young people with mental disorders. However, very little is known about what distinguishes decision making by individuals with different disorders or the neuropsychological processes or brain systems underlying these. This is the focus of the current review.Scope and methodologyWe first propose a neuroeconomic model of the decision‐making process with separate stages for the prechoice evaluation of expected utility of future options; choice execution and postchoice management; the appraisal of outcome against expectation; and the updating of value estimates to guide future decisions. According to the proposed model, decision making is mediated by neuropsychological processes operating within three domains: (a) self‐referential processes involved in autobiographical reflection on past, and prospection about future, experiences; (b) executive functions, such as working memory, inhibition, and planning, that regulate the implementation of decisions; and (c) processes involved in value estimation and outcome appraisal and learning. These processes are underpinned by the interplay of multiple brain networks, especially medial and lateralized cortical components of the default mode network, dorsal corticostriatal circuits underpinning higher order cognitive and behavioral control, and ventral frontostriatal circuits, connecting to brain regions implicated in emotion processing, that control valuation and learning processes.Findings and conclusionBased on clinical insights and considering each of the decision‐making stages in turn, we outline disorder‐specific hypotheses about impaired decision making in four childhood disorders: attention‐deficit/hyperactivity disorder (ADHD), conduct disorder (CD), depression, and anxiety. We hypothesize that decision making in ADHD is deficient (i.e. inefficient, insufficiently reflective, and inconsistent) and impulsive (biased toward immediate over delayed alternatives). In CD, it is reckless and insensitive to negative consequences. In depression, it is disengaged, perseverative, and pessimistic, while in anxiety, it is hesitant, risk‐averse, and self‐deprecating. A survey of current empirical indications related to these disorder‐specific hypotheses highlights the limited and fragmentary nature of the evidence base and illustrates the need for a major research initiative in decision making in childhood disorders. The final section highlights a number of important additional general themes that need to be considered in future research.

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Section: Introductionmentioning

confidence: 99%

Annual Research Review: Transdiagnostic neuroscience of child and adolescent mental disorders – differentiating decision making in attention‐deficit/hyperactivity disorder, conduct disorder, depression, and anxiety

Sonuga‐Barke

Cortese

Fairchild

et al. 2015

Child Psychology Psychiatry

146

119

View full text Add to dashboard Cite

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“…Endophenotypes are the heritable and quantifiable – neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive or behavioural – markers of psychiatric conditions ( Gottesman and Gould, 2003 ). Endophenotypes are found in patients and their asymptomatic relatives, and thus simplify the search for causes of complex psychiatric conditions by identifying genetically mediated and quantifiable traits that bind together diverse clinical presentations ( Kalueff et al, 2015 ). Here we search for endophenotypes in a matched sample of males with ASC, unaffected siblings of people with ASC, and typically developing controls.…”

Section: Introductionmentioning

confidence: 99%

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents

Moseley

Ypma

Holt

et al. 2015

NeuroImage: Clinical

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Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.

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“…We posit that the proposed regulation via the "interlinking" genes differs markedly from pleiotropy and epistasis, because such novel putative genes do not affect disordered endophenotypes per se (Kalueff et al, 2015b). For example, they cannot make anhedonia and low mood worse, but can make them better correlated and integrated, thereby rendering the entire depressive pathogenesis more severe, better orchestrated, and more debilitating (Kalueff et al, 2015b). Pleiotropy occurs when a candidate gene causes multiple deficits in various systems, simultaneously affecting several, seemingly unrelated neural endophenotypes (Kalueff et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

“…For example, they cannot make anhedonia and low mood worse, but can make them better correlated and integrated, thereby rendering the entire depressive pathogenesis more severe, better orchestrated, and more debilitating (Kalueff et al, 2015b). Pleiotropy occurs when a candidate gene causes multiple deficits in various systems, simultaneously affecting several, seemingly unrelated neural endophenotypes (Kalueff et al, 2015b). While pleotropic genes exert shared influence on several endophenotypes, the proposed interlinking genes are associated not with endophenotypes per se, but with the interconnectedness (pathogenetic linkage) between them (Kalueff et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

Understanding the genetic architectonics of complex CNS traits: Lost by the association, but found in the interaction?

Stewart¹,

Nguyen

Song

et al. 2015

J Psychopharmacol

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Recent evidence supports the value of endophenotypes and genome-wide association studies in psychiatric genetics, and their importance for dissecting the neural pathways and molecular mechanisms of complex neuropsychiatric disorders. Continuing this important discussion, here we outline three new mechanisms by which novel classes of genes may facilitate CNS pathogenesis without directly worsening its individual 'established' endophenotypes. These putative genetic mechanisms can apply to other human disorders in general, and may also be used for designing novel effective CNS drug treatments.

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Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models

Cited by 52 publications

References 132 publications

Annual Research Review: Transdiagnostic neuroscience of child and adolescent mental disorders – differentiating decision making in attention‐deficit/hyperactivity disorder, conduct disorder, depression, and anxiety

Annual Research Review: Transdiagnostic neuroscience of child and adolescent mental disorders – differentiating decision making in attention‐deficit/hyperactivity disorder, conduct disorder, depression, and anxiety

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents

Understanding the genetic architectonics of complex CNS traits: Lost by the association, but found in the interaction?

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