The genetic impact (C957T-DRD2) on inhibitory control is magnified by aging

Abstract

Healthy aging beyond the age of 65 is characterized by a general decrease in cognitive control over actions: old adults have more difficulty than young adults in stopping overt responses. Responsible for this cognitive decrement is the continuous decline of striatal and extrastriatal dopamine (DA). The resource-modulation hypothesis assumes that genetic variability is more likely to result in performance differences when brain resources move away from close-to-optimal levels, as in aging. To test this hypothesis we investigated, first, whether individual differences in the C957T polymorphism at DRD2 gene (rs6277) contribute to individual differences in the proficiency to inhibit behavioral responses in a stop-signal task. Second, we assessed whether this genetic effect is magnified in older adults, due to the considerable decline in dopamine function. Our findings show that individuals carrying genotype associated with higher density of extrastriatal D2 receptors (C957T CC) were more efficient in inhibiting unwanted action tendencies, but not in term of response execution. This effect was stronger in older than in younger adults. Our findings support the idea that aging-related decline in dopamine availability alters the balance between genotypes and cognitive functions.

Introduction

Healthy aging beyond the age of 65 is characterized by a general decrease in cognitive control: older adults find it increasingly difficult to apply new or coordinate multiple rules, and to discriminate relevant from irrelevant information. Working memory, reasoning (Ball, Vance, Edwards, & Wadley, 2004 (chap. 36); Brehmer, Li, Müller, von Oertzen, & Lindenberger, 2007; Li, Schmiedek, Huxhold, Röcke, Smith, & Lindenberger, 2008; Shing, Werkle-Bergner, Brehmer, Muller, Li, & Lindenberger, 2010), attention abilities and speed of processing (Faust and Balota, 1997, Ball et al., 1998, Colzato et al., 2011) show large decrements with increasing age. Cognitive inhibition also declines throughout the life span (Williams, Ponesse, Schachar, Logan, & Tannock, 1999): old adults have more difficulty than young adults in stopping an overt response and changing to new rules in a categorization task (Kramer, Humphrey, Larish, Logan, & Strayer, 1994). Responsible for this cognitive decline is the general loss of neurochemicals, such as the continuous decline of striatal and extrastriatal dopamine (DA) systems from early to late adulthood and old age (Bäckman et al., 2000, Bäckman et al., 2006, Erixon-Lindroth et al., 2005, Volkow et al., 1998).

Interestingly, individual differences in cognitive performance increase from early to late adulthood reflecting genetic differences (Li et al., 2004, Li et al., 2010, Störmer et al., 2012). The resource-modulation hypothesis (Lindenberger et al., 2008) assumes that aging-related losses in neurochemical and structural brain resources modulate the extent to which common genetic variations affect cognitive functioning. In particular, the function relating brain resources to cognitive performance is assumed to be nonlinear, so that genetic variability is more likely to result in performance differences when resources move away from close-to-optimal levels, as in aging. In other words, the genetic setup of an individual matters more the older he or she gets.

The resource-modulation hypothesis has been supported by a number of studies. First, spatial working memory and executive functions in elderly were associated with individual differences in genetic predispositions of the gene that codes for the catechol-O-methyltransferase (COMT), an enzyme that degrades DA in prefrontal cortex, while no such relation was observed in younger adults (Nagel et al., 2008; Störmer et al., 2012). Second, a similar age magnification effect was observed between brain-derived neurotropic factor (BDNF) genotype and episodic memory performance under high associative demands (Li et al., 2010). The third evidence comes from the genetic modulation of training and transfer in older adults. Colzato, Slagter, de Rover, and Hommel (2011) trained participants genotyped for the brain-derived-neurotrophic factor (BDNF) Val⁶⁶Met polymorphism on cognitive tasks developed to improve dynamic attention. Pre-training (baseline) and post-training measures of attentional processes (divided and selective attention) were acquired. As expected, Val/Val homozygous individuals, associated with increased activity-dependent secretion of BDNF (Egan et al., 2003), showed larger beneficial transfer effects than Met/−carriers.

The current study focused, for the first time, on the inhibition of behavioral responses—another key cognitive control function (Logan and Cowan, 1984, Logan, 1994) that is known to decrease with old age (Kramer et al., 1994, Williams et al., 1999). Recently, Colzato, Waszak, Nieuwenhuis, Posthuma, and Hommel (2010) reported response inhibition (assessed in by means of a stop-signal task) to be predicted by the C957T polymorphism at the DRD2 gene, but not by COMT Val¹⁵⁸Met (a polymorphism related to frontal DA). Healthy young adults pressed a left or right button as soon as a green left- or right-pointing arrow appeared (go trials). However, if the color of the arrow suddenly changed to red, the participants were supposed to refrain from responding (stop trials). This stop-signal task measures both the efficiency of response execution (by means of reaction times to go-signals) and the efficiency in inhibitory control (by means of the stop-signal reaction time or SSRT, where longer SSRT reflect general slowing of inhibitory processes and indicate a lower level of inhibitory efficiency). C/C homozygotes, associated with increased extrastriatal D2 receptor availability (Hirvonen et al., 2009a) and higher striatal DA levels (Hirvonen et al., 2009b), stopped faster on stop trials than T/−carriers. No association between COMT Val¹⁵⁸Met polymorphism and stopping latency was found. This pattern of results was in line with a previous study by Forbes, Brown, Kimak, Ferrell, Manuck, and Hariri (2007), who reported no association between self-reported impulsivity scores (index highly correlated with the inhibitory control) with the COMT gene (Val¹⁵⁸Met polymorphism).

A number of patient studies have provided converging evidence for the involvement of striatal DA in response inhibition. Parkinson's patients, who suffer from loss of dopaminergic neurons in the basal ganglia, showed difficulties in stopping (Gauggel, Rieger, & Feghoff, 2004) and impaired suppression of conflicting responses (Wylie et al., 2009) compared to matched healthy controls. Consistent with this picture, ADHD patients (see, Alderson, Rapport, & Kofler, 2007, for a recent review) and recreational users of cocaine (Colzato, van den Wildenberg, & Hommel, 2007), who are likely to suffer from reduced dopamine D2 receptors in the striatum (Volkow, Fowler, & Wang, 1999), need significantly more time to inhibit responses to stop-signals than non-users. Moreover, spontaneous eyeblink rate, a marker of striatal dopaminergic functioning, reliably predicts the efficiency in inhibiting unwanted action tendencies in a stop-signal task (Colzato, van den Wildenberg, van Wouwe, Pannebakker, & Hommel, 2009).

Given the role of striatal DA in modulating response inhibition, we expected DRD2 C957T C/C homozygotes to be better than T/−carriers in stopping control, replicating Colzato, Waszak, et al. (2010). Moreover, based on the resource-modulation hypothesis (Lindenberger et al., 2008), we expected this effect to be magnified in old age.