Early visual sensory deficits as endophenotypes for schizophrenia: High-density electrical mapping in clinically unaffected first-degree relatives

Cognitive Neurophysiology Laboratory, St Vincent's Hospital, Fairview, and Trinity College Institute of Neuroscience, Department of Psychology, Dublin, Ireland.
Archives of General Psychiatry (Impact Factor: 14.48). 12/2006; 63(11):1180-8.
Source: PubMed


The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests.
Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability.
Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland.
Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives.
Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

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    • "Crossvalidation revealed that from the group of patients whose VEPs were within the normal range of controls (10 patients for P1 and 14 patients for N1) VEPs of six patients were also outside the normal range of SZ leaving these patients as misclassified. Early visual processing deficits mostly related to P1 have been repeatedly demonstrated in SZ (Yeap et al., 2006; Foxe et al., 2001; Doniger et al., 2002; Martinez et al., 2012). Evidences exist that vision capability, i.e. visual information processing per se, represents a susceptibility factor (necessary condition) for SZ, not by itself, but rather by the visual processing impairment in lower visual regions involving bottomup mechanisms, which prevent from normal functioning of higher order multisensory integration processes (González-Hernández et al., 2003; Butler et al., 2008; Javitt, 2009; González-Hernández et al., 2006; Silverstein et al., 2013; Landgraf and Osterheider, 2013). "
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    ABSTRACT: Alterations of the visual evoked potential (VEP) component P1 at the occipital region represent the most extended functional references of early visual dysfunctions in schizophrenia (SZ). However, P1 deficits are not reliable enough to be accepted as standard susceptibility markers for use in clinical psychiatry. We have previously reported a novel approach combining a standard checkerboard pattern-reversal stimulus, spectral resolution VEP, source detection techniques and statistical procedures which allowed the correct classification of all patients as SZ compared to controls. Here, we applied the same statistical approach but to a single surface VEP - in contrast to the complex EEG source analyses in our previous report. P1 and N1 amplitude differences among spectral resolution VEPs from a POz-F3 bipolar montage were computed for each component. The resulting F-values were then Z-transformed. Individual comparisons of each component of P1 and N1 showed that in 72% of patients, their individual Z-score deviated from the normal distribution of controls for at least one of the two components. Crossvalidation against the distribution in the SZ-group improved the detection rate to 93%. In all, six patients were misclassified. Clinical validation yielded striking positive (78.13%) and negative (92.69%) predictive values. The here presented procedure offers a potential clinical screening method for increased susceptibility to SZ which should then be followed by high density electrode array and source detection analyses. The most important aspect of this work is represented by the fact that this diagnostic technique is low-cost and involves equipment that is feasible to use in typical community clinics. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 05/2015; 166(1-3). DOI:10.1016/j.schres.2015.05.007 · 3.92 Impact Factor
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    • "In a series of experiments, we have shown that visual-sensory processing deficits are particularly robust in patients with schizophrenia (Foxe et al., 2001, 2005; Doniger et al., 2002; Lalor et al., 2008, 2012; Yeap et al., 2008a), a finding that has been observed across multiple labs (Mukundan, 1986; Spencer et al., 2004; Haenschel et al., 2007). Crucially, these deficits are also seen in first-degree relatives (Yeap et al., 2006), first-episode drug-na€ ıve patients (Yeap et al., 2008b) and in young adults with high schizotypy (Koychev et al., 2010; Bedwell et al., 2013), pointing to their potential utility as risk endophenotypes (Gottesman & Gould, 2003; Magno et al., 2008; Foxe et al., 2011). A drawback of many of these studies, however, is that despite between-group effect sizes that are typically large, intrinsic interindividual variability in the amplitude and morphology of the VEP response reduces their effectiveness as potential classifiers. "
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    ABSTRACT: When sensory inputs are presented serially, response amplitudes to stimulus repetitions generally decrease as a function of presentation rate, diminishing rapidly as inter-stimulus intervals (ISIs) fall below 1 s. This 'adaptation' is believed to represent mechanisms by which sensory systems reduce responsivity to consistent environmental inputs, freeing resources to respond to potentially more relevant inputs. While auditory adaptation functions have been relatively well characterized, considerably less is known about visual adaptation in humans. Here, high-density visual-evoked potentials (VEPs) were recorded while two paradigms were used to interrogate visual adaptation. The first presented stimulus pairs with varying ISIs, comparing VEP amplitude to the second stimulus with that of the first (paired-presentation). The second involved blocks of stimulation (N = 100) at various ISIs and comparison of VEP amplitude between blocks of differing ISIs (block-presentation). Robust VEP modulations were evident as a function of presentation rate in the block-paradigm, with strongest modulations in the 130-150 ms and 160-180 ms visual processing phases. In paired-presentations, with ISIs of just 200-300 ms, an enhancement of VEP was evident when comparing S2 with S1, with no significant effect of presentation rate. Importantly, in block-presentations, adaptation effects were statistically robust at the individual participant level. These data suggest that a more taxing block-presentation paradigm is better suited to engage visual adaptation mechanisms than a paired-presentation design. The increased sensitivity of the visual processing metric obtained in the block-paradigm has implications for the examination of visual processing deficits in clinical populations. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
    European Journal of Neuroscience 02/2015; 41(7). DOI:10.1111/ejn.12849 · 3.18 Impact Factor
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    • "Greater left hemisphere activity in the inferior and orbitofrontal cortices may indicate an alternative, compensatory mechanism in adult autism (Schmitz et al., 2006). The recruitment of additional areas of the brain to aid in task performance and to off-set the negative effects of a deficient network has been illustrated in recent studies, including those investigating aged individuals (Nielson, Langenecker, & Garavan, 2002) and first-degree relatives of patients with schizophrenia (Yeap et al., 2006). Executive dysfunction in ADHD and autism may be related to the compromised workings of the fronto-striatal and fronto-parietal circuits. "

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