Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: A twin study

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Abstract

A deficit in sensory gating measured by the suppression of P50 auditory event-related potential (ERP) has been implicated in the biological bases of schizophrenia and some other psychiatric disorders and proposed as a candidate endophenotype for genetic studies. More recently, it has been shown that gating deficits in schizophrenics extend to ERP components reflecting early attentive processing (the N1/P2 complex). However, evidence for heritability of sensory gating in the general population is very limited. Heritability of P50, N1, and P2 amplitudes and gating was estimated in 54 monozygotic and 55 dizygotic twin pairs using a dual-click auditory paradigm. Genetic model-fitting analysis showed high heritability of peak amplitudes of P50, N1, and P2 waves. Genetic influences on P50 gating (S2/S1) were modest, while heritability of N1 and P2 gating was high and significant. The alternative gating measure (S1–S2 difference) showed significant heritability for all three ERP components. Weak genetic influences on P50 gating ratio can be related to its poor test–retest reliability demonstrated in previous studies. These results suggest that gating measures derived from the N1/P2 wave complex may be useful endophenotypes for population-based genetic studies of the sensory gating function and its impairments in psychopathology.

Introduction

An impaired ability to filter sensory information has been hypothesized as one of the core dysfunctions in schizophrenia and related spectrum of disorders and cognitive abnormalities (Freedman et al., 1983, Braff and Geyer, 1990). Filtering excessive information can protect limited processing resources against overloading, or “flooding”(Venables, 1964). It has been proposed that one form of such inhibitory regulation is sensory gating, or modulation of the sensitivity to repetitive sensory information (Braff and Geyer, 1990, Adler et al., 1999, Freedman et al., 2000). The hypothesized sensory gating can be studied experimentally in humans using the so-called conditioning-testing paradigm, in which the subject is administered a pair of brief auditory stimuli (clicks) and brain evoked responses are recorded. Click stimuli elicit a cascade of neuroelectric response components reflecting sequential stages of information processing in the auditory pathways and the cerebral cortex. A distinct complex of ERP components including P50, N1, and P2 peaks occurs between the early brainstem responses and late cognitive “endogenous” P300 response. Following the classification suggested by Buchsbaum (1977) and later by Roth et al. (1980), we refer to this wave complex as mid-latency auditory evoked responses (MLAER). The P50 component reflects largely pre-attentive sensory processing, while N1 and P2 components reflect early attentional processing (relative to the late “endogenous” P300 component involving voluntary, controlled attention), although the distinction between preattentional and attention-dependent cognitive functions is not necessarily discrete and categorical (Braff and Light, 2004).

When auditory click stimuli are presented in pairs with inter-click interval of less than 1 s, the P50 response to the second of the two identical clicks is suppressed, or gated out. According to the sensory gating hypothesis, the first stimulus elicits the initial excitatory response of the neuronal population giving rise to the P50 response and also activates inhibitory pathways attenuating the response to the second stimulus (Davis et al., 1966, Freedman et al., 1983, Adler et al., 1999).

Studies have shown that P50 gating is diminished in schizophrenic patients and, importantly, in unaffected first degree relatives of schizophrenics compared to healthy controls, suggesting that P50 suppression can be a marker of familial and, possibly, genetic risk for the disorder (reviewed in Adler et al., 1999, Freedman et al., 2000, Bramon et al., 2004). Other studies reported a genetic linkage between P50 suppression index and the alpha7 neuronal nicotinic receptor subunit gene, as well as association between different mutations in this gene and P50 phenotype (reviewed in Freedman et al., 2003). These studies suggest that P50 suppression can serve as one of the candidate vulnerability markers, or endophenotypes for schizophrenia and schizophrenia spectrum disorders (Freedman et al., 2000). It was suggested that the gating deficit occurring at early stages of sensory processing is primary to more complex cognitive deficits occurring at later processing stages, such as problems with attention and perception, cognitive fragmentation, hypervigilance, etc. (Freedman et al., 1983, Braff and Geyer, 1990).

However, findings in this field have not been entirely consistent: some studies failed to find any significant association between P50 gating and schizophrenia (Arnfred et al., 2003), or found this association only in a subgroup of patients (Jin et al., 1998). Other studies failed to find association between mutations in the nicotinic receptor gene and schizophrenia (Li et al., 2004) or genetic linkage with markers in this chromosomal region (Neves-Pereira et al., 1998, Curtis et al., 1999).

Some studies suggest that increased S2/S1 ratio (indicating poor gating) can in fact be related to smaller response to the first click (S1) in schizophrenics, rather than to deficient suppression of the response to the second click (e.g. Blumenfeld and Clementz, 2001, Clementz and Blumenfeld, 2001, Johannesen et al., 2005). Thus, the amplitude of P50 response to the first click alone (S1) can potentially serve as a marker of genetic vulnerability.

In addition to P50, several studies have also reported similar gating abnormalities in other MLAER components including N1 and P2 related to early attentive stages of processing (Roth et al., 1980, Boutros et al., 1999, Clementz and Blumenfeld, 2001, Boutros et al., 2004a, Boutros et al., 2004b). Characterization of the heritability of gating indices derived from each of these components is important as these components likely reflect different physiological aspects of the sensory gating function (Boutros and Belger, 1999). Moreover, recent studies provided behavioral evidence suggesting that P50 gating and N1 gating correspond to different sensory processing phenomena. Using a self-report measure of sensory experiences, Kisley et al. (2004) have shown that poor P50 suppression was correlated with the dimension of Perceptual Modulation indicating filtering difficulties, while poor N1 suppression was correlated with the dimension of Over-Inclusion indicating increased awareness of background sounds (Kisley et al., 2004).

Sensory gating deficits as measured by P50 suppression are not limited to schizophrenia and have been reported in a broader spectrum of conditions including schizotypal personality disorder (Cadenhead et al., 2000) and questionnaire-measured psychometric schizotypy (Croft et al., 2001), as well as in substance use disorders (Fein et al., 1996, Patrick and Struve, 2000, Marco et al., 2005).

Thus, deficient gating of P50 and perhaps other components (N1, P2) may represent an endophenotype, or biological marker of genetic vulnerability, for schizophrenia and related spectrum of disorders and comorbidities, perhaps including addictions. One of the requirements to an endophenotype is its significant heritability. There have been two small twin studies of P50 suppression (Myles-Worsley et al., 1996, Young et al., 1996). To the best of our knowledge, there have been no genetic studies of other MLAER components (N100, P200) recorded in the dual click paradigm.

Accordingly, the goal of the present study was to estimate heritability of the peak amplitudes and gating measures of MLAER including P50, N100, and P200 components in the general population using a community-based sample of twins.

Section snippets

Methods

Due to space limitations, only a concise description of methods is presented here. For a more detailed description, see Supplementary methods online.

General considerations

Examples of P50 waves (S1 and S1 responses) illustrating strong and poor suppression of S2 are presented on Fig. 1 (note that the amplitudes of N1 and P2 components are attenuated on this waveform due to filter settings that are optimal for P50 detection but not for N1 and P2). Data are presented for the vertex (Cz) electrode location, consistent with previous P50 gating literature. Mean values and standard deviations of peak amplitudes and S2/S1 suppression ratios (Table 1) are in good

Discussion

The present study extends previous studies on heritability of P50 suppression by utilizing a substantially larger twin sample and by applying the model-fitting approach to the estimation of genetic and environmental influences. This study also demonstrated for the first time the heritability of gating effects at early attentive stages of auditory processing (N1 and P2 waves) that have been associated with schizophrenia in recent studies (Boutros et al., 2004a, Boutros et al., 2004b).

Our results

Acknowledgements

This work was supported by the grants DA00421 and DA018899 from the National Institute on Drug Abuse. This work was also partially supported by grant MH58784 from the National Institute of Mental Health. The authors thank Dr. Fred Struve for his contribution to the rating of the ERP components, Dr. Simon Golosheykin for his assistance with ERP analyses, and Erin Myers for her role in the data collection.

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