Page 66 - The prevalence of the Val66Met polymorphism in musicians: Possible evidence for compensatory neuroplasticity from a pilot study

COMT Genotype Affects Language Processing in Children Sugiura et al. | 105

Introduction shift should be particularly pronounced in individuals with rela-
tively low dopamine signaling efficacy in young Val carriers. By
Language is one of the higher cognitive functions unique to contrast, Mattay et al. (2003) suggested that excess dopamine
humans. It consists of phonology, syntax, and semantics, and
shifts individuals toward the right-hand side of the curve where
these independent components interact and together promote the Met allele is associated with impaired cognitive function.
comprehension and utterances. Language is formed by interac-
Despite the abundance of studies that have investigated the
tions between genes and experience; however, the genetic basis effects of COMT on prefrontally guided functions in adults,
and signaling pathways controlling language development
similar studies of children and adolescents are sparse.
remain largely elusive. Behavioral studies have indicated an association between
Here, we focus on the gene for catechol-O-methyltransferase
working memory performance and the COMT polymorphism in
(COMT), which has been widely investigated regarding its children and adolescents (Diamond et al. 2004; Wahlstrom
involvement in cognitive function and psychiatric illnesses.
et al. 2007; Barnett et al. 2009). Of the few relevant neuroima-
Evidence has implied a dopaminergic influence on language
ging studies, Dumontheil et al. (2011) investigated PFC func-
ability (Barnett et al. 2007a; Prata et al. 2009; Gaysina et al. 2013);
tioning and working memory performance in a normal
however, dopaminergic influences on language ability, percep- population with an age range of 6–20 years. They identified
tion, or processing have not been actively explored, which moti-
COMT genotype effects (superior performance for individuals
vated us to investigate their impact on language functions. The with the Met allele compared with the Val allele) after the age
human COMT gene on chromosome 22q11 has a functional
of 10 years. These studies focused on prefrontally guided work-
Val 158 Met polymorphism, in which the Val allele exhibits ing memory functions. The effects of the COMT polymorphism
enhanced enzymatic activity relative to the Met allele (Lotta
on posterior and prefrontal cognitive functions other than
et al. 1995; Lachman et al. 1996). Thus, the high-activity Val working memory during development (before brain system
allele results in faster inactivation of extracellular dopamine in
maturity) are largely unknown.
the brain, particularly the prefrontal cortex (PFC) (Chen et al. Another question is whether the effects of the COMT geno-
2004). Therefore, Val 158 Met influences the efficiency of prefron-
type are static or variable during development. In the previ-
tally guided cognitive function, specifically executive function- ously discussed study by Dumontheil et al. (2011), an age-
ing, working memory, fluid intelligence, and attentional control
dependent COMT effect was highlighted for both behavioral
(Egan et al. 2001; Barnett et al. 2007a, 2007b; Flint and Munafo
performance and cortical activation. They reported that the Val
2007; Barnett et al. 2008, see review for Witte and Flöel 2012).
allele tended to be associated with superior performance on a
Previous studies have extensively investigated prefrontally visuospatial working memory task at younger ages (6–10 years)
mediated cognitive functions (Mier et al. 2010). Moreover, an
and the Met allele was beneficial after the age of 10. In the
association between the COMT genotype and cognitive perform- study by Barnett et al. (2007a), the genotype significantly
ance has also been identified in the peri-Sylvian cortex during a
affected executive function and verbal IQ, and subsequent ana- Downloaded from https://academic.oup.com/cercor/article-abstract/27/1/104/2617708 by guest on 24 November 2018
verbal fluency task (Prata et al. 2009) and the parietal region dur- lyses that included sex as a factor indicated that significant
ing an arithmetic working memory task (Tan et al. 2007) and a
genotype effects were identified in boys and, importantly, were
visuospatial working memory task (Dumontheil et al. 2011). significantly greater in pubertal compared with prepubertal
Therefore, catecholamines may affect the activity of multiple
boys. Furthermore, another relevant study of the COMT gene in
cortical regions depending on the cognitive domains. children (Gaysina et al. 2013) assessed verbal and non-verbal
Egan et al. (2001) reported that the COMT 158 Val allele was
cognition at ages 8 and 15 years using a longitudinal design. In
associated with reduced performance on the Wisconsin Card this study, COMT rs737865 was associated with reading com-
Sorting Test and increased task-related prefrontal activation
prehension, verbal ability, and global cognition at age 15 years
assessed via functional magnetic resonance imaging (fMRI). in pubescent boys, but not at age 8; however, these differences
Several studies using cognitive tasks assessing memory and
were not significant following multiple comparison analyses.
executive functions have subsequently indicated better perform- Given the previous findings, we aimed to investigate the
ance in Met carriers compared with Val carriers (Mattay et al. 158
role of the Val Met COMT polymorphism as an underlying
2003; Bishop et al. 2006; Caldu et al. 2007; Bertolino et al. 2008; genetic mechanism in the development of language function.
Enoch et al. 2009). In these studies, a better performance was
More specifically, the present study examined whether the
associated with lower brain activation in the PFC. Increased brain
COMT polymorphism affected language functions in children
activation in Val carriers was interpreted as less efficient process-
6–10 years of age (preadolescence) and whether a potential
ing because of lower dopamine transmission efficacy (Bertolino effect was age-dependent. We measured cortical hemodynamic
et al. 2006, 2008; see review for Witte and Flöel 2012); however,
changes in a sample of 246 normally developing elementary
not all studies are consistent (Barnett et al. 2008; Prata et al. 2009). school-aged children using functional near-infrared spectros-
Recent studies have suggested that the effects of the COMT
copy (fNIRS) while the children performed a word repetition
genotype on cognitive function may vary over a specific age task in their first language (Japanese). Notably, previous studies
range, possibly as a result of age-related changes in the brain
have reported that dopaminergic neurotransmission dynamic-
dopamine system (Witte and Flöel 2012). Previous findings sup- ally changes during the preadolescent and adolescent years
port the hypothesis that optimal cognitive function is asso-
and increases to peak levels during this period (Kalsbeek et al.
ciated with optimal brain dopamine signaling efficacy, thereby 1988; Rosenberg and Lewis 1994; Koga et al. 2016).
suggesting an inverted U-shaped response curve (Goldman-
Rakic et al. 2000; Lindenberger et al. 2008; Nagel et al. 2008).
Advancing age is assumed to shift individuals toward the left- Materials and Methods
hand side of the curve that relates dopamine signaling to cogni-
Participants
tive performance based on an age-related decline in dopamine
signaling efficacy (Volkow et al. 1998; Erixon-Lindroth et al. Participants were 246 healthy Japanese elementary school chil-
2005; Floel et al. 2005). The deleterious effects of this leftward dren (123 boys and 123 girls, aged between 6 and 10 years, with