COMT Val^108/158Met genotype modulates human sensory gating

Abstract

Background

The catechol-O-methyltransferase (COMT) Val^108/158Met polymorphism of the dopamine system is essential for prefrontal cortex processing capacity and efficiency. In addition, dopaminergic neurotransmission is also associated with the sensory gating phenomenon protecting the cerebral cortex from information overload. It is however unclear if COMT genotype as a predictor of prefrontal efficiency modulates sensory gating on the level of the auditory cortex, i.e. the gating of the auditory evoked P50 and N100 components.

Methods

P50 and N100 gating and COMT Val^108/158Met genotype were determined in 282 healthy subjects of German descent carefully screened for psychiatric or neurological disorders.

Results

A significant effect of the COMT genotype was observed for N100 gating (F = 4.510, df = 2, p = 0.012) but not for P50 gating (F = 0.376, df = 2, p = 0.687). Contrast analysis showed that Met/Met individuals had poorer N100 gating compared to Val/Met (F = − 12.931, p = 0.003) and the Val/Val individuals (F = − 11.056, p = 0.057).

Conclusion

The results indicate that a high prefrontal efficiency as suggested by the COMT Met/Met genotype is associated with to a poor sensory gating of the N100 component. This would fit in a model where a high prefrontal processing capacity allows a pronounced afferent input of sensory information from the auditory cortex as reflected by a poor sensory gating. The more pronounced prefrontal contribution to the N100 compared to the P50 component may explain the exclusive genotype association with the N100 sensory gating. This preliminary model should be replicated and validated in future investigations.

Introduction

Sensory gating, a core feature of information processing is suggested to be a filter mechanism protecting the central nervous system from sensory overload (McGhie and Chapman, 1961, Braff et al., 1992, Boutros et al., 2004). In this concept, the cerebral response to a repeated identical stimulus is inhibited, which is mediated by pre-attentional habituation to irrelevant sensory input. Therefore, humans are able to differentiate between important and unwanted sensory information and thereby to adapt rapidly to different contextual situations (Fruhstorfer et al., 1970, Braff and Geyer, 1990, Freedman et al., 1991, Grunwald et al., 2003, Potter et al., 2006). A disturbed sensory gating function may cause inadequate sensory information processing and results in a flooding of higher cortical areas with irrelevant information (Boutros et al., 2004). This was implicated as a pathobiological mechanism in severe disturbances of perception, emotion and behaviour (Freedman et al., 1991, McDowd et al., 1993, Kumari et al., 2008) and is one of the most robust biological findings in schizophrenia (Siegel et al., 1984, Baker et al., 1987; Braff et al., 1992, Bramon et al., 2004) and among other psychiatric disorders (Franks et al., 1983, Lijffijt et al., 2009b).

Sensory gating deficits in schizophrenia and other psychiatric disorders were primarily investigated for the auditory evoked P50 and N100 component (Adler et al., 1982, Freedman et al., 1991, Boutros et al., 1993). The P50 is probably the earliest component—about 50 ms after stimulus onset—of the auditory evoked potential that represents sensory gating (Grunwald et al., 2003). The somewhat later N100 potential is known to be the largest mid-latency component of the auditory evoked potentials with a peak between 80 and 120 ms after the presentation of an acoustic stimulus (Spreng, 1980, Gallinat et al., 2002). In comparison to the P50 component, it might be more influenced by arousal and was associated with early attentional processing (Nash and Williams, 1982, Putnam and Roth, 1987, Young et al., 2001, Gallinat et al., 2003). A decreased degree of suppression of the N100 is a relatively stable physiological abnormality in subjects suffering from schizophrenia, though the N100 has not been studied as intensively as the P50 (Strik et al., 1992, Frodl et al., 1998, Laurent et al., 1999, Brockhaus-Dumke et al., 2008).

However, neither the neurophysiological mechanism underlying sensory gating nor the exact anatomical locus of its generation have yet been fully identified. Indirect evidence has been gained by lesion studies indicating an association of deficits in auditory response inhibition with lateral prefrontal cortex (Knight et al., 1999). Studies on patients suffering from temporal lobe epilepsy showed reduced P50 gating; suggesting that anatomical structures mediating P50 gating might be located in temporal structures (Weate et al., 1995). In rat brains, the response of hippocampal pyramidal interneurons, to the second stimulus was found to be almost completely suppressed above all in the CA3 region, indicating that the hippocampus might be an essential mediator of sensory gating (Bickford-Wimer et al., 1990, Freedman et al., 1996). In studies employing magnetencephalography (MEG), a method with high spatial resolution, the M50 was localized in the auditory cortex of the superior temporal gyrus but also to several sources in the frontal lobes (Garcia-Rill et al., 2008, Thoma et al., 2008, Weiland et al., 2008).

Regarding its neurochemical bases, different systems of neurotransmitters have been suggested to be involved as mediators of sensory gating (Laruelle et al., 2003). Most of the findings in this field have been achieved by animal studies in mice, rats and rodents, formerly by administering specific psychotropic drugs and measuring the effect on sensory gating (Geyer et al., 2001, Swerdlow et al., 2006). Amphetamine is known to augment intrasynaptic dopamine concentrations by amplifying its release and inhibiting the reuptake. Its application to healthy humans was associated with a disrupted suppression of the P50 (Adler et al., 1986, Light et al., 1999). This effect was reversible when dopamine receptor (D2) antagonists like haloperidol was administered. Typical antipsychotics as haloperidol and flupenthixol might ameliorate poor sensory gating in drug-free subjects (Adler et al., 1986, Csomor et al., 2008). Other hypotheses suggest different synergic constellations of neurotransmitters as a base of functioning sensory gating, e.g. serotonin and dopamine (Mann et al., 2008), or monoamine inhibition and nicotine antagonism (Siegel et al., 2005).

The catechol-O-methyltransferase (COMT) is one of the major enzymes that methylate the catecholamine's dopamine, norepinephrine and epinephrine to homovanillic acid especially in the prefrontal cortex (Karoum et al., 1994, Gogos et al., 1998). An intensively studied single nucleotide polymorphism (SNP)(Val^108/158Met) of the COMT gene has been suggested to predict executive cognition (Goldberg et al., 2003) and the efficiency of prefrontal functions in humans (Egan et al., 2001, Gallinat et al., 2003; Winterer et al., 2006). At the q11 band of chromosome 22 in humans, valine (val) is replaced by methionine (met), thus diminishing dopamine methylation 3 or 4 times (Gogos et al., 1998), leading to increased prefrontal dopamine concentrations.

Due to the previously observed effects of the dopaminergic neurotransmission on sensory gating as investigated with pharmacological challenges, the objective of our work was to study whether the COMT Val^108/158Met polymorphism is associated with the most common investigated surrogate parameters of sensory gating, the auditory evoked P50 and N100 component. The P50 and to a lesser degree the N100 sensory gating represent intermediate phenotypes because of underlying genetic factors (Siegel et al., 1984, Waldo et al., 1988, Turetsky et al., 2008) associating with diseases e.g. schizophrenia (Bramon et al., 2004), co-segregation with schizophrenia within families (Clementz et al., 1998a, Clementz et al., 1998b); Siegel et al., 1984, Waldo et al., 1992) and sufficient test-retest-reliability (Boutros et al., 1991, Rentzsch et al., 2008a). We studied sensory gating of the P50 and N100 component in a large sample of 282 healthy subjects carefully screened for mental disorders.