Auditory and visual cortical activity during selective attention in fragile X syndrome: A cascade of processing deficiencies

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Abstract

Objective

This study examined whether attention deficits in fragile X syndrome (FXS) can be traced back to abnormalities in basic information processing.

Method

Sixteen males with FXS and 22 age-matched control participants (mean age 29 years) performed a standard oddball task to examine selective attention in both auditory and visual modalities. Five FXS males were excluded from analysis because they performed below chance level on the auditory task. ERPs were recorded to investigate the N1, P2, N2b, and P3b components.

Results

N1 and N2b components were significantly enhanced in FXS males to both auditory and visual stimuli. Interestingly, in FXS males, the P3b to auditory stimuli was significantly reduced relative to visual stimuli. These modality differences in information processing corresponded to behavioral results, showing more errors on the auditory than on the visual task.

Conclusions

The current findings suggest that attentional impairments in FXS at the behavioral level can be traced back to abnormalities in event-related cortical activity. These information processing abnormalities in FXS may hinder the allocation of attentional resources needed for optimal processing at higher-levels.

Significance

These findings demonstrate that auditory information processing in FXS males is critically impaired relative to visual information processing.

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.

References (65)

  • R. Näätänen et al.

    The mismatch negativity (MMN) in basic research of central auditory processing: a review

    Clin Neurophysiol

    (2007)
  • M. Pieretti et al.

    Absence of expression of the FMR-1 gene in fragile X syndrome

    Cell

    (1991)
  • J. Polich

    Updating P300: an integrative theory of P3a and P3b

    Clin Neurophysiol

    (2007)
  • G.J. Ramakers

    Rho proteins, mental retardation and the cellular basis of cognition

    Trends Neurosci

    (2002)
  • G. Scerif et al.

    Delineation of early attentional control difficulties in fragile X syndrome: focus on neurocomputational changes

    Neuropsychologia

    (2007)
  • D.M. St Clair et al.

    P3 abnormality in fragile X syndrome

    Biol Psychiatry

    (1987)
  • J.E. Stauder et al.

    Multi-modal P3 deflation of event-related brain activity in Prader-Willi syndrome

    Neurosci Lett

    (2002)
  • J.E. Stauder et al.

    The development of visual- and auditory processing in Rett syndrome: an ERP study

    Brain Dev

    (2006)
  • A. Strobel et al.

    Novelty and target processing during an auditory novelty oddball: a simultaneous event-related potential and functional magnetic resonance imaging study

    Neuroimage

    (2008)
  • M.J.W. Van der Molen et al.

    Profiling Fragile X Syndrome in males: strengths and weaknesses in cognitive abilities

    Res Dev Disabil

    (2010)
  • A.J. Verkerk et al.

    Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome

    Cell

    (1991)
  • J. Wilding et al.

    Further delineation of the executive deficit in males with fragile-X syndrome

    Neuropsychologia

    (2002)
  • M. Backes et al.

    Cognitive and behavioral profile of fragile X boys: correlations to molecular data

    Am J Med Genet

    (2000)
  • M.F. Bear

    Therapeutic implications of the mGluR theory of fragile X mental retardation

    Genes Brain Behav

    (2005)
  • M.K. Belmonte et al.

    Fragile X syndrome and autism at the intersection of genetic and neural networks

    Nat Neurosci

    (2006)
  • Y. Ben-Ari et al.

    GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations

    Physiol Rev

    (2007)
  • A. Bertone et al.

    Associating Neural Alterations and Genotype in Autism and Fragile X Syndrome: Incorporating Perceptual Phenotypes in Causal Modeling

    J Autism Dev Disord

    (2010)
  • A. Bertone et al.

    Using Perceptual Signatures to Define and Dissociate Condition-Specific Neural Etiology: Autism and Fragile X Syndrome as Model Conditions

    J Autism Dev Disord

    (2010)
  • M. Castrén et al.

    Augmentation of auditory N1 in children with fragile X syndrome

    Brain Topogr

    (2003)
  • K. Cornish et al.

    Attention and language in fragile X

    Ment Retard Dev Disabil Res Rev

    (2004)
  • V.S. Dani et al.

    Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome

    J Neurosci

    (2009)
  • M. Dierssen et al.

    Dendritic pathology in mental retardation: from molecular genetics to neurobiology

    Genes Brain Behav

    (2006)
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