Mapping the genetic variation of executive attention onto brain  activity

Fan, Jin; Fossella, John; Sommer, Tobias; Wu, Youting; Posner, Michael I.

doi:10.1073/pnas.0732088100

Cited by 415 publications

(272 citation statements)

References 26 publications

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“…In addition, this report marks an important advance in the application of functional neuroimaging to the study of genes, brain and behavior. In contrast to previous studies of genetic effects on brain function, where the molecular and cellular effects of the candidate variants had been previously demonstrated (eg 5-HTTLPR, 13 MAO-A, 31 COMT 32 and BDNF 33 ), our fMRI data provide the first evidence that a single nucleotide polymorphism in the regulatory region of the human TPH2 gene likely affects biological function. In this way, the initial identification of a systems level effect of a specific polymorphism provides impetus for the subsequent characterization of its functional effects at the molecular and cellular level.…”

Section: Discussioncontrasting

confidence: 89%

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

et al. 2005

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Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(À844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors. Keywords: TPH2; amygdala; serotonin; fMRI Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin (5-HT), a key modulator of mood and affect. Thus, the identification of genetic variation contributing to functional changes in TPH enzymatic activity is of great interest in determining the biological pathways underpinning individual differences in emotional behaviors and risk for psychiatric disorders, including depression, anxiety, and suicidality. Recent molecular and cellular studies have revealed the existence of a second TPH isoform, tryptophan hydroxylase-2 (TPH2), exclusively expressed in the murine brain. 1 Functional assays demonstrate that TPH2-and not the original isoform, referred to now as TPH1-is responsible for regulating TPH expression and 5-HT synthesis in the murine central nervous system. 2 In contrast, both TPH1 and TPH2 are expressed in the human brain 3 and genetic variation in both isoforms have been associated with alterations in mood and 5-HT function. 4,5 Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) associated with depression has been shown to alter TPH enzymatic efficiency in vitro. 6 However, the functional consequence of genetic variation in hTPH2 on the neural circuitry of mood and emotional behaviors is unknown.In the current study, we used functional magnetic resonance imaging (fMRI) to examine the effects of a single nucleotide polymorphism (G(À844)T) in the upstream regulatory region of hTPH2 on the reactivity of the amygdala, a central structure in the mediation of behavioral and physiologic arousal associated with emotional behaviors. Although the molecular and cellular effects of the G(À844)T polymorphism are unknown, we focused on this regulatory variant for several reasons. First, unlike other hTPH2 variants with demonstrated impact on enzymatic activity, 6 the G(À844)T has a relatively high minor allele frequency (T allele ¼ 38%) and thus, has the potential to contribute more broadly to brain function and risk for mood disorders. Second, this variant is located within 1 kb (844 bp upstream) of the transcription initiation site of hTPH2 and is likely a constituent of the proximal promoter of the gene. Regulatory variants in general often impact gene expression 7 and several specific promoter polymorphisms in other 5-HT subsystem genes have demonstrated effects on brain function and emotional behaviors. [8][9][10]

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Section: Discussioncontrasting

confidence: 89%

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

et al. 2005

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“…As demonstrated by Fan et al ( 2003Fan et al ( , 2005, the three networks are not only independent at a behavioral level but also at a neuroanatomic level. Therefore, it might be interesting to determine whether the less-segregated nature of the networks observed at a behavioral level could also be observed in preterm children at a neuronal activation level.…”

Section: Discussionmentioning

confidence: 99%

“…Fan, McCandliss, Sommer, Raz, and Posner ( 2002 ) proposed that these three systems could be assessed with a single behavioral task: the Attention Network Task (ANT). Many studies using the ANT have confi rmed the independence of the three systems in terms of cognitive processes and neuronal networks in adults (Fan et al, 2002 ;Fan, Fossella, Sommer, Yanghong, & Posner, 2003 ;Fan McCandliss, Fossella, Flombaum, & Posner, 2005 ;Fernandez-Duque & Posner, 2001 ). Rueda et al ( 2004 ) adapted a version of the ANT for children and used it with children between the ages of 4 and 10 years.…”

Section: Attentional Network Effi Ciency In Preterm Childrenmentioning

confidence: 99%

Attentional networks efficiency in preterm children

Pizzo

Urben

Linden

et al. 2009

J Int Neuropsychol Soc

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Recent studies have reported specifi c executive and attentional defi cits in preterm children. However, the majority of this research has used multidetermined tasks to assess these abilities, and the interpretation of the results lacks an explicit theoretical backdrop to better understand the origin of the diffi culties observed. In the present study, we used the Child Attention Network Task (Child ANT; Rueda et al. 2004 ) to assess the effi ciency of the alerting, orienting and executive control networks. We compared the performance of 25 preterm children (gestational age ≤ 32 weeks) to 25 full-term children, all between 5½ and 6½ years of age. Results showed that, as compared to full-term children, preterm children were slower on all conditions of the Child ANT and had a specifi c defi cit in executive control abilities. We also observed a signifi cantly higher correlation between the orienting and executive control networks in the preterm group, suggesting less differentiation of these two networks in this population. ( JINS , 2010, 16, 130-137.)

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“…To date, three studies have found evidence for an impact of the MAOA u-VNTR on brain function during tasks that index inhibitory control. Fan et al 22,23 found decreased dorsal cingulate activation during conflict resolution in MAOA-L subjects, and Passamonti et al 24 showed diminished ventrolateral prefrontal engagement during response inhibition in these individuals. A recent investigation of the effect of this genetic variant on brain structure and function in a large sample of healthy volunteers found a pronounced impact on amygdala and perigenual cingulate cortex, as well as gender-dimorphic (males only) effects on limbic circuitry for emotional arousal, memory and cognitive control, including orbitofrontal cortex and dorsal anterior cingulate.…”

Section: Introductionmentioning

confidence: 99%

“…However, clinical associations of the MAOA u-VNTR with personality traits and cerbrospinal fluid monoamine metabolite levels are mixed, with heterogeneity in the personality measures used and inconsistent directionality of effects making interpretation difficult. [19][20][21][22][23][24][25][26][27][28][29][30] A more consistent picture has emerged showing the relevance of MAOA genetic variation to a complex behavior, impulsive violence. In a large longitudinal study of at-risk children, Caspi et al 31 found evidence for a gene-environment interaction, whereby childhood abuse predicted later life antisocial behavior in men hemizygous for the MAOA-L allele.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

Buckholtz¹,

Callicott²,

Kolachana³

et al. 2007

Mol Psychiatry

198

170

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Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

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Mapping the genetic variation of executive attention onto brain activity

Cited by 415 publications

References 26 publications

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

Attentional networks efficiency in preterm children

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

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