Vernier acuity and the magnocellular system revisited: Response to Skottun and Skoyles

Skottun and Skoyles (2009) recently presented a comment on Vernier acuity and magnocellular dysfunctions in fragile X premutation carriers (Kéri & Benedek, 2009). The authors concluded that our finding that the magnocellular deficit, as revealed by luminance-contrast sensitivity measurements, is associated with impaired Vernier acuity for achromatic gratings does not mean that this procedure is suitable for the investigation of the magnocellular pathways, given that deficits outside the magnocellular system also lead to impaired Vernier acuity. However, Skottun and Skoyles (2009) did not consider the dissociation between achromatic and isoluminant color Vernier and the convergence of Vernier and luminance-contrast sensitivity measurements.     

The perception of biological and mechanical motion in female fragile X premutation carriers

Previous studies reported impaired visual information processing in patients with fragile X syndrome and in premutation carriers. In this study, we assessed the perception of biological motion (a walking point-light character) and mechanical motion (a rotating shape) in 25 female fragile X premutation carriers and in 20 healthy non-carrier controls. Stimuli were moving stimulus dots embedded among a cloud of noise dots. Sensitivity (d′) for motion detection was determined. Emotional symptoms were assessed by Hamilton’s depression and anxiety rating scales. Results revealed that the premutation carriers displayed lower sensitivities for biological and mechanical motion relative to the non-carriers. This deficit was more pronounced in the case of biological stimuli. The premutation carriers displayed higher depression and anxiety scores relative to the non-carriers. Higher depression, but not anxiety, scores were associated with decreased sensitivity for biological, but not mechanical, motion in the carrier group. These results suggest that motion perception deficits are detectable in fragile X premutation carriers, and that the impairment of biological motion perception is associated with depressive symptoms.     

Visual pathway deficit in female fragile X premutation carriers: a potential endophenotype

Previous studies indicated impaired magnocellular (M) and relatively spared parvocellular (P) visual pathway functioning in patients with fragile X syndrome. In this study, we assessed M and P pathways in 22 female fragile X premutation carriers with normal intelligence and in 20 healthy non-carrier controls. Testing procedure included visual contrast sensitivity and vernier threshold measurements. Results revealed that carriers were selectively impaired on tests of M pathways (low spatial/high temporal frequency contrast sensitivity and frequency-doubling vernier), whereas they showed intact performance on P pathway tests. These results suggest that the deficit of the M pathway is an endophenotype of fragile X syndrome.     

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.     

Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. Previous studies have demonstrated that CGG KI mice have spatiotemporal information processing deficits and impaired visuomotor function that worsen with increasing CGG repeat length. Since skilled forelimb reaching requires integration of information from the visual and motor systems, skilled reaching performance could identify potential visuomotor dysfunction in CGG KI mice. To characterize motor deficits associated with the fragile X premutation, 6 month old female CGG KI mice heterozygous for trinucleotide repeats ranging from 70-200 CGG in length were tested for their ability to learn a skilled forelimb reaching task. The results demonstrate that female CGG KI mice show deficits for learning a skilled forelimb reaching task compared to wildtype littermates, and that these deficits worsen with increasing CGG repeat lengths.     

Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.     

The emerging fragile X premutation phenotype: evidence from the domain of social cognition

Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200) region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP). Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation ("carrier-status") (approximately 55-200 repeats). Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The findings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.     

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.     

Fragile X-associated tremor/ataxia syndrome (FXTAS)

Carriers of fragile X mental retardation 1 (FMR1) premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full-mutation carriers (>200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55-200 repeats) develop a neurological syndrome involving intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. In excess of one-third of male premutation carriers over 50 years of age develop the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS also represents a new form of inclusion disease, with eosinophilic intranuclear inclusions found throughout the brain in both neurons and astrocytes. Because FXTAS appears to be relatively specific to male premutation carriers, who are known to possess elevated levels of FMR1 mRNA, the neuropathology may arise as a consequence of a toxic gain-of-function of the mRNA itself, although this proposal requires additional direct testing. One of the critical needs at present is a better estimate for the prevalence of this disorder, because FXTAS is likely to be underdiagnosed in the adult movement disorders clinics.     

阅读障碍的巨细胞系统缺陷理论之争

近几年诸多研究者认为阅读障碍是由于视觉系统巨细胞功能缺陷引起的。他们从对比度敏感性研究、巨细胞抑制功能研究与视觉运动知觉功能的研究结果中得到了支持证据。就这个问题的研究进行综述,表明不论是巨细胞功能缺陷理论的支持者还是反对者,都从巨细胞的对比度敏感性、视觉运动知觉与巨细胞抑制功能上得到了一些研究结果的支持。巨细胞功能缺陷理论的支持者还从阅读障碍的神经生理学研究和阅读的脑功能研究中得到了一些支持性的证据。新的研究结果揭示了巨细胞系统缺陷理论与阅读之间的关系以及巨细胞系统缺陷理论的应用价值。在巨细胞系统缺陷理论的进一步研究中,还需要统一实验方法与实验标准以获得更多的证据,同时需要有新的方法来有效区分小细胞系统与巨细胞系统     

Emotional Reaction to Fragile X Premutation Carrier Tests Among Infertile Women

Female fragile X premutation carriers are at ∼10-fold increased risk of premature ovarian failure (follicle stimulating hormone >40 mIU/mL, amenorrhea, age <40). A milder degree of premature ovarian aging (diminished ovarian reserve, where follicle stimulating hormone levels are typically 10–20 mIU/mL) results in infertility. Approximately 10% of fertility clinic patients have this diagnosis. A cohort of 20 women diagnosed with diminished ovarian reserve provided a blood specimen (confidential results), and completed structured questionnaires that assessed emotional reactions to potentially being a premutation carrier (pretest questionnaire, n = 20) and the posttest known carrier status (3 month follow-up questionnaire, n = 18 non-carriers). Responses were measured using 9-point scales, and analyzed with Fisher exact and Wilcoxon exact tests. While most participants did not view fragile X premutations as a serious medical condition, perceptions of seriousness were positively correlated with anger and regret about not knowing sooner of the potential association of these premutations with infertility. Overall, when women (pretest) imagined themselves as carriers, their self-esteem and Health Orientation Scale responses were unchanged with the exception of feeling more afraid (p = 0.004). Despite strongly wishing for negative test results, they were glad to know there might be a medical explanation for their infertility. Financial Support: This work was financially supported by a University of Virginia School of Medicine Research & Development Award.     

On the prevalence of magnocellular deficits in the visual system of non-dyslexic individuals

Numerous studies have found visual deficits associated with dyslexia. This has made it important to understand how these deficits may be related to reading difficulties. A widely held theory is that dyslexia is the result of a deficit in the magnocellular part of the visual system (earlier called the transient system). In support for this theory, the prevalence of magnocellular deficits has been reported to be high among dyslexic readers and very low among non-dyslexic ones. This creates the impression that in the population as a whole dyslexic individuals have magnocellular deficits and non-dyslexic individuals do not. However, we show that because the prevalence of dyslexia itself is low this need not be the case. On the basis of previously published data we have estimated the number of non-dyslexic and dyslexic individuals with magnocellular deficits. Our estimates indicate that there should be a large number of non-dyslexic individuals with magnocellular deficits. Paradoxically more individuals without dyslexia have magnocellular deficits than individuals with dyslexia. This poses a challenge to the view that dyslexia is the result of a magnocellular deficit.     

Improving Health Education for Women Who Carry an <Emphasis Type="Italic">FMR1</Emphasis> Premutation

Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive – inductive approach to determine the prominent themes related to the participants’ experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.     

Mapping self-reports of working memory deficits to executive dysfunction in Fragile X Mental Retardation 1 (FMR1) gene premutation carriers asymptomatic for FXTAS

Fragile X Syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation 1 (FMR1) gene. In recent years, the premutation (“carrier”) status has received considerable attention and there is now an emerging consensus that despite intellectual functioning being within the average range premutation males present with subtle executive function impairments that include poor inhibitory control, working memory deficits, and poor planning skills. The ranges of these skills, although not nearly as severe as seen in the full mutation, nonetheless serve to differentiate males with the premutation from males in the unaffected population. In the present study we extend these findings to suggest that behavioral markers, specifically self-report on the Brown Attention-Deficit Disorder Rating Scales, may serve as a clinically useful indicator or “signature” of the Fragile X Premutation status. We discuss the possibility that this measure provides a means to identify those at greatest risk for developing the newly identified neurodegenerative disorder that affects some premutation males – Fragile X Tremor/Ataxia Syndrome (FXTAS).     

Advances in research on the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that results from a single gene mutation on the X chromosome. The purpose of this review is to summarize key advances made in understanding the fragile X premutation gene seen in carriers and the full mutation gene seen in persons with the syndrome. DNA testing has replaced cytogenetic testing as the primary method for identification of fragile X, although the efficacy of protein level screening is being explored. The premutation is associated with no effects, although there is evidence of physical effects-primarily premature menopause and mild outward features of the fragile X syndrome-among premutation carriers. There is much controversy regarding premutation effects on psychological development. The few experimental studies carried out to date do not suggest noticeable or significant effects. One challenge in addressing this controversy is the sometimes ambiguous differentiation between premutation and full mutation genes. There is a well-established yet highly variable phenotype of the full mutation. Research from this decade has helped to address specific aspects of this phenotype, including the early course of its development in males, the influence of home and family environments, the nature of social difficulties and autistic features seen in boys and girls with fragile X, and the potential role of hyperarousal or hyper-reactivity. Studies in these areas, and on the role of FMR protein, will contribute towards ongoing advances in our understanding of fragile X syndrome and its mechanisms. The variability in physical, social, and cognitive features, as described in this review, is one that prohibits clear-cut screening guidelines designed to avoid high rates of both false positives and false negatives. Results from recent studies indicate the need to consider behavioral features in selecting candidates for fragile X screening. MRDD Research Reviews 2000;6:96-106.     

Cortical locus of coherent motion deficits in deaf poor readers

Samar and Parasnis [Samar, V. J., & Parasnis, I. (2005). Dorsal stream deficits suggest hidden dyslexia among deaf poor readers: correlated evidence from reduced perceptual speed and elevated coherent motion detection thresholds. Brain and Cognition, 58, 300-311.] reported that correlated measures of coherent motion detection and perceptual speed predicted reading comprehension in deaf young adults. Because deficits in coherent motion detection have been associated with dyslexia in the hearing population, and because coherent motion detection is strongly dependent on extrastriate cortical area MT, these results are consistent with the claim that hidden dyslexia occurs within the deaf population and is associated with deficits in MT. However, coherent motion detection can also be influenced by subcortical deficits in both magnocellular and parvocellular pathways. To confirm the putative cortical locus of coherent motion perception deficits, we measured contrast thresholds for detecting the direction of movement of drifting sine wave gratings in the same participant group as [Samar, V. J., & Parasnis, I. (2005). Dorsal stream deficits suggest hidden dyslexia among deaf poor readers: correlated evidence from reduced perceptual speed and elevated coherent motion detection thresholds. Brain and Cognition, 58, 300-311.], under stimulus conditions that selectively biased for input from the subcortical magnocellular and parvocellular pathways, respectively. Contrast thresholds were not related to reading comprehension performance under either the magnocellular or parvocellular conditions. Furthermore, the previously reported correlations among reading comprehension, coherent motion thresholds, and perceptual speed remained significant even after contrast thresholds and non-verbal IQ were controlled in partial correlation analyses. In addition, coherent motion detection thresholds were found to correlate specifically with a reading-IQ discrepancy score, one commonly used indicator of dyslexia. These results provide direct psychophysical evidence that the previously reported deficit in coherent motion detection in deaf poor readers does not involve subcortical pathway deficits, but rather is associated with a cortical deficit likely involving area MT. They also strengthen the argument for the existence of hidden dyslexia in the deaf adult population.     

Lifespan changes in working memory in fragile X premutation males

Fragile X syndrome is the world’s most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18–69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.     

发展性阅读障碍与知觉加工

近年来许多行为实验和神经生理学实验都发现 ,发展性阅读障碍与基本知觉障碍有关。在视觉领域研究者提出了巨细胞障碍假设 ,这种假设认为阅读障碍者视觉神经系统中的巨细胞障碍导致他们对某种类型的视觉刺激加工存在困难 ,进而影响阅读。在听觉领域研究发现阅读障碍者加工快速、系列、短暂呈现的声音刺激存在障碍。研究者认为阅读障碍者加工快速刺激输入障碍反映了普遍的时间知觉障碍。这方面的研究发展非常迅速 ,理论观点非常明确 ,并且直接与内在的神经机制相联系 ,形成了与传统的“语言障碍”理论迥然不同的“知觉障碍”理论。“知觉障碍”理论综合了行为、认知和神经等多个层次的研究 ,反映了神经科学发展所带来的巨大影响和认知加工模块化理论的渐渐衰退。     

Aging and reflective processes of working memory: binding and test load deficits

It was hypothesized that age-related deficits in episodic memory for feature combinations (e.g., B. L. Chalfonte & M. K. Johnson, 1996) signal, in part, decrements in the efficacy of reflective component processes (e.g., M. K. Johnson, 1992) that support the short-term maintenance and manipulation of information during encoding (e.g., F. 1. M. Craik. R. G. Morris. & M. L. Gick, 1990; T. A. Salthouse, 1990). Consistent with this, age-related binding deficits in a working memory task were found in 2 experiments. Evidence for an age-related test load deficit was also found: Older adults had greater difficulty than young adults when tested on 2 features rather than 1, even when binding was not required. Thus, disruption of source memory in older adults may involve deficits in both encoding processes (binding deficits) and monitoring processes (difficulty accessing multiple features, evaluating them, or both).     

Effects of age simulation and age on motor sequence learning: Interaction of age-related cognitive and motor decline

Aging is known to lead to decrements in sensory and cognitive functioning and motor performance. The purpose of the present experiment was twofold: a) We assessed the influence of wearing an age simulation suit on motor sequence learning, cognitive speed tasks and far visual acuity in healthy, younger adults. b) We evaluated the interaction of cognitive aging and declining motor sequence learning in older adults. In a between-subjects design we tested 11 younger adults (M_age = 23.6 years) without the age suit, 12 younger adults wearing the age suit (M_age = 23.2 years), and 23 older adults (M_age = 72.6 years). All participants learned a simple, spatial-temporal movement sequence on two consecutive days, and we assessed perceptual processing speed (Digit Symbol Substitution test and Figural Speed test) and far visual acuity. Wearing an age simulation suit neither affected the learning of the simple motor sequence nor the performance at the cognitive speed tasks in younger adults. However, far visual acuity suffered from wearing the suit. Younger adults with and without the suit showed better motor sequence learning compared to older adults. The significant correlations between the cognitive speed tests and the motor learning performance in older adults indicated that cognitive aging partially explains some of the variance in age-related motor learning deficits.