Auditory and visual cortical activity during selective attention in fragile X syndrome: A cascade of processing deficiencies
Highlights
► Basic information processing in fragile X syndrome (FXS) can be characterized by augmented cortical activity during the early sensory stages in both auditory and visual modalities. ► P3b related activity in FXS is significantly reduced in the auditory relative to the visual modality. ► Deficits in selective attention in FXS on a behavioral level can be traced back to event-related cortical activity.
Introduction
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability with a prevalence of 1:4000 males and 1:8000 females (Turner et al., 1996). FXS is caused by silencing of the fragile X mental retardation 1 (FMR1) gene, resulting in reduction or absence of the FMR1 protein (FMRP) (Pieretti et al., 1991, Verkerk et al., 1991). FMRP plays an important role in early brain development by regulating the translation of proteins important for synaptic development and dendritic refinement (Pfeiffer and Huber, 2007). In full mutation FXS males, absence of FMRP is linked to a global reduction in cognitive performance (Maes et al., 1994, Cornish et al., 2004, Van der Molen et al., 2010) and behavioral problems (Reiss and Freund, 1992, Dykens et al., 1993, Backes et al., 2000, Hagerman and Hagerman, 2002) with deficits most notably in the attentional domain (Munir et al., 2000, Wilding et al., 2002, Scerif et al., 2007). However, few human studies addressed the question whether these attentional deficits can be traced back to impairments at lower-levels of information processing in FXS.
Lower-level information processing has been overlooked as critical factor in contributing to impairments in higher-level cognitive and behavioral deficits (Belmonte and Bourgeron, 2006, Bertone et al., 2010a, Bertone et al., 2010b). There is evidence to suggest, however, that sensitivity to sensory stimuli is enhanced in FXS, in particular in the auditory modality (Chen and Toth, 2001, Castrén et al., 2003, Moon et al., 2006, Hessl et al., 2009). For example, abnormally large sensory evoked brain potentials have been reported to simple auditory stimuli in FXS humans (Rojas et al., 2001, Castrén et al., 2003, Frankland et al., 2004, Hessl et al., 2009), as well as in the FMR1 knockout mouse (Chen and Toth, 2001, Moon et al., 2006). Moreover, recent findings have demonstrated early information processing abnormalities during passive auditory discrimination and involuntary attentional processes. That is, both the mismatch negativity (MMN) and P3a generation were significantly altered during a passive auditory change detection task (Van der Molen et al., in preparation). As the MMN and P3a are associated with sensory change detection (Näätänen et al., 2007) and the involuntary triggering of attention (Escera et al., 2000, Escera et al., 2001), respectively, it could be argued that the observed attentional deficits at the behavioral level can be traced back to early information processing deficiencies in FXS. This notion is supported by recent findings of Hessl et al. (2009), who demonstrated deficient auditory prepulse inhibition in FXS, implicating that information processing shows early perceptual abnormalities, probably impacting on higher-level information processing. To date, it is unclear whether similar information processing abnormalities can be demonstrated in the visual modality.
The primary goal of the present study was to perform an event-related potential (ERP) analysis of the alleged information processing deficits in FXS. To this end, ERPs were investigated during an active two-stimulus auditory and visual discrimination task. ERPs provide a suitable window on stimulus processing in the brain, reflecting both sensory (i.e., bottom–up) and higher-level (i.e., top–down) information processing with high temporal accuracy. Thus, the N1 and P2 components of the ERP are associated with the pre-attentive detection of a stimulus, reflecting sensory processing (Näätänen and Picton, 1987, Crowley and Colrain, 2004), whereas the later occurring N2b is argued to be an electrocortical marker of attentive deviancy detection (Escera et al., 1998, Folstein and Van Petten, 2008). Finally, the P3b is a reflection of attention-driven stimulus evaluation and decision-making processes (Escera et al., 1998, Nieuwenhuis et al., 2005, Polich, 2007, Folstein and Van Petten, 2008, Nieuwenhuis et al., 2010), regulated by stimulus-evoked neuromodulatory mechanisms (e.g., acetylcholine and norepinephrine), which modulate the encoding of rare and potentially important events (Escera et al., 1998, Ranganath and Rainer, 2003, Nieuwenhuis et al., 2005, Folstein and Van Petten, 2008, Nieuwenhuis et al., 2010).
For the first time in FXS, ERPs will be recorded during an oddball paradigm for both auditory and visual modalities. Our ERP analysis should reveal whether FXS abnormalities in early stimulus processing is typical for the auditory modality or can be observed for both the auditory and visual modalities. In addition, the ERP analysis should reveal whether early sensory deficits, as reflected in the N1 and P2 are associated with impairments at higher-level processing as indexed by the N2b and P3b components of the ERP. Finally, we asked whether ERP deficits in FXS males would be related to their task performance.
Section snippets
Participants
Sixteen male participants diagnosed with the FXS full mutation (age range 18–42 years, mean age 29.6 years) and 22 healthy male controls (age range 19–47 years, mean age 29.2 years) participated in this study. FXS participants were recruited with the help of the Dutch Fragile X Parent Network. Prior DNA testing confirmed the diagnosis of the FXS full mutation. Controls were university students or college graduates recruited from or within the proximity of the university, and were rewarded either
Performance data
Five FXS participants (mean age in years = 38.2, SD = 5.7) were excluded from analyses based on their performance below chance level (19% hit rate) on the auditory oddball task (see Table 1). These five participants were significantly p’s < .05) older (mean age difference = 10.2 years) and had lower Raven SPM raw scores (mean difference = 9.4) compared to the FXS participants performing above chance level (55% hit rate). Their exclusion resulted in a reduced sample of 11 FXS participants. Table 1 shows
Discussion
The aim of the present study was threefold. First, we examined the electrocortical correlates of early information processing to assess the alleged information processing deficits in FXS males. Second, we examined whether these deficits are typical for the auditory modality or extend also to the visual modality. Third, we examined whether early sensory processing deficits in FXS males are associated with higher-level information processing. These issues were addressed by recording ERPs to
Acknowledgements
This study was supported by the Cognition Program of The Netherlands Organization for Scientific Research (Grant Number 051.04.090 to G. Ramakers). None of the authors report conflict of interests. We thank Mieke van Leeuwen of The Netherlands Federation of Parent Organizations for assisting in the recruitment of participants, and we thank the participants and their families for their support and contribution to this study.
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