Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia

Donohoe, Gary; Morris, Derek W.; Sanctis, Pierfilippo De; Magno, Elena; Montesi, Jennifer L.; Garavan, Hugh; Robertson, Ian H.; Javitt, Daniel C.; Gill, Michael; Corvin, Aiden; Foxe, John J.

doi:10.1016/j.biopsych.2007.07.022

Cited by 62 publications

(52 citation statements)

References 30 publications

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“…In the present study, we again found a substantial reduction in the P1 amplitude in 52 patients compared to healthy age-matched controls (P = 0.016) with a large effect size of d = 0.70 (Cohen's Criteria). Together with our recent finding of a similar P1 deficit in unaffected first-degree relatives [68], the present finding of no effects of age, length of illness or medication dose, reinforces the view that these marked deficits in P1 are linked to the underlying genetic liability for schizophrenia rather than a function of the disease state itself [22]. As such, the P1 deficit appears to be a very promising candidate as an endophenotype for schizophrenia [27].…”

Section: Discussionsupporting

confidence: 88%

Visual sensory processing deficits in Schizophrenia and their relationship to disease state

Yeap

Kelly

Sehatpour

et al. 2008

Eur Arch Psychiatry Clin Neurosc

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Context Visual Evoked Potential (VEP) abnormalities have been a fairly consistent finding in patients with schizophrenia, and it has been suggested that electrophysiological markers of early sensory processing may be useful as trait markers for the illness, and for development as potential diagnostic measures. Objective Clear amplitude reductions in the occipital P1 component of the VEP (~100 ms), have been repeatedly demonstrated in patients with schizophrenia. Here, we investigated whether the extent of this deficit was related to age, clinical symptoms, medication status and length of illness, in a large cohort of ethnically homogenous patients. Design, setting and participants VEP responses to simple isolated-check stimuli were examined in 52 DSM-IV diagnosed patients with schizophrenia, and compared with responses from 26 healthy age-matched control subjects. Using high-density electrical scalp recordings, we assessed the integrity of the visual P1 component across the two groups. This study was conducted at St.Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. Results Substantially reduced P1 amplitude was demonstrated in the patient group compared to controls. The deficit was not linked to age, length of illness or medication status. A small positive correlation, accounting for about 11% of the variance, was found between P1 amplitude and clinical symptoms scales (BPRS and SANS). In addition, we found that a slightly later (~110 ms) fronto-central component was relatively increased in the patient group, and was inversely correlated with the occipital P1 amplitude in the patients, but not in the healthy control subjects.Conclusions Our findings clearly demonstrate a deficit in early visual processing in patients with schizophrenia (with a large effect size; Cohen's d = 0.7) that is unrelated to chronicity. The results are consistent with recent findings showing that the P1 deficit is endophenotypic of the disorder and related to genetic risk factors rather than the disease process itself.j Key words visual-evoked potential AE VEP AE ERP AE P1 deficit AE schizophrenia AE Ireland AE hyperfrontality

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Section: Discussionsupporting

confidence: 88%

Visual sensory processing deficits in Schizophrenia and their relationship to disease state

Yeap

Kelly

Sehatpour

et al. 2008

Eur Arch Psychiatry Clin Neurosc

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“…In terms of effect size, calculation of differences in brain volume associated with dysbindin genotype (based on the reported F-statistics) resulted in an effect size d ¼ 0.60, usually considered a 'medium' effect size as described by Cohen (1992). In our own study, effect sizes associated with the T-values observed for prefrontal and occipital differences were 1.36 and 1.34, respectively, both large effects based on Cohen's criteria, comparable with the earlier effect sizes observed in our previous EEG study of early visual processing associated with dysbindin (Donohoe et al 2008). Given the likelihood that many genetic variants are likely to influence gene function, this suggests that dysbindin, in addition to other schizophrenia-risk variants such as NRG1 for which similar effects sizes have been reported (Mata et al, 2009), is among the more important genetic determinants of structural alterations in brain volume in schizophrenia.…”

Section: Discussionsupporting

confidence: 88%

“…Investigation of the C-A-T-risk haplotype reported by Williams et al was associated with reduced dysbindin mRNA expression in human postmortem analysis of homogenized brain tissue (Bray et al, 2005). The same risk haplotype has also been associated with phenotypic alternations, such as neuropsychological impairments in spatial working memory (Donohoe et al, 2007) and electrophysiological impairments in early visual processing (Donohoe et al, 2008). These findings are complimented by studies of other risk variants and haplotypes at this locus associated with both reduced expression, particularly in the prefrontal and hippocampal cortex (Talbot et al, 2004;Weickert et al, 2004) and variation in neuropsychological function in both patients and healthy controls (Burdick et al, 2006;Zinkstok et al, 2007;Luciano et al, 2009).…”

Section: Introductionmentioning

confidence: 94%

Reduced Occipital and Prefrontal Brain Volumes in Dysbindin-Associated Schizophrenia

Donohoe

Frodl

Morris

et al. 2009

Neuropsychopharmacol

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A three-marker C-A-T dysbindin haplotype identified by Williams et al (PMID: 15066891) is associated with increased risk for schizophrenia, decreased mRNA expression, poorer cognitive performance, and early sensory processing deficits. We investigated whether this same dysbindin risk haplotype was also associated with structural variation in the gray matter volume (GMV). Using voxelbased morphometry, whole-volume analysis revealed significantly reduced GMVs in both the right dorsolateral prefrontal and left occipital cortex, corresponding to the behavioral findings of impaired spatial working memory and EEG findings of impaired visual processing already reported. These data provide important evidence of the influence of dysbindin risk variants on brain structure, and suggest a possible mechanism by which disease risk is being increased.

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“…1B). This trend to a reduction in the S1 P1 amplitude that likely drives the significant reduction in the S2/S1 ratio is consistent with the clinical observations, including a reduction in visually evoked P1 found in nonsymptomatic carriers of DTNBP1 risk alleles (43). To rule out the potential confound that such findings could be caused by differences in hearing threshold between WT and transgenic mice, an additional cohort of animals was tested for acoustic brainstem responses (ABRs; Fig.…”

Section: Resultssupporting

confidence: 80%

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Carlson

Talbot²,

Halene³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.GABAergic | γ-oscillation | hippocampus | evoked response spectral perturbation | Sandy mouse P atients with schizophrenia have reduced amplitude and gating of auditory event-related potentials (ERPs) (1, 2). Recent clinical studies also show abnormal γ-band oscillations (30-100 Hz) as an endophenotype of the illness that is associated with reduced cognitive function (3-7). Work in animal models shows a prominent role of cortical inhibitory networks in generating γ-oscillations (8, 9), which in turn, supports the role of aberrant GABAergic inhibition as an important potential component of schizophrenia (4,7,10,11). The GABA-producing enzyme glutamic acid decarboxylase is dysregulated in schizophrenia, and postsynaptic GABA A receptors are dysregulated as well (4). Risk alleles for GABA A receptor subunits are also associated with the disease (12, 13), although linkage is weaker than the linkage found with dysbindin-1 and other candidate genes such as DISC1 (14). At the anatomical level, there is a loss of immunoreactivity for parvalbumin (PV) in schizophrenia. PV is a calcium-binding protein marker for a class of fast-spiking GABAergic neurons. It is debated whether reduced PV in postmortem studies is caused by reduction in cell number or merely loss of protein expression. In either case, reduced PV immunoreactivity suggests disruption of an important source of local circuit inhibition (4, 15).Although clinical electrophysiological and postmortem anatomical findings support the role of GABA dysfunction in schizophrenia, a larger set of schizophrenia risk haplotypes are thought to confer reduced NMDA receptor-mediated function and changes in glutamatergic transmission [e.g., DISC1; Neuregu...

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Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia

Cited by 62 publications

References 30 publications

Visual sensory processing deficits in Schizophrenia and their relationship to disease state

Visual sensory processing deficits in Schizophrenia and their relationship to disease state

Reduced Occipital and Prefrontal Brain Volumes in Dysbindin-Associated Schizophrenia

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

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