Ocular motor indicators of executive dysfunction in fragile X and Turner syndromes☆
Introduction
Fragile X and Turner syndromes are two X-chromosome-related disorders associated with neuropsychological deficits. Despite reports of deficits in memory, spatial, and executive function skills for persons with either disorder (as reviewed by Mazzocco & McCloskey, 2005), it remains unclear what primary neurobiological mechanisms underlie these corresponding cognitive phenotypes. The present study of ocular motor behavior was designed to investigate possible mechanisms underlying the impairments associated with fragile X and Turner syndromes. Following a brief introduction to each disorder, we describe how ocular motor studies help to delineate neurological pathways that underlie cognitive deficits.
Section snippets
Fragile X syndrome
Fragile X syndrome is the most common known hereditary cause of mental retardation, occurring in approximately 1 per 4000 to 9000 individuals (Crawford, Acuna, & Sherman, 2001). In most individuals with fragile X, the disorder results from a mutation of a single gene on the X-chromosome (Verkerk et al., 1991). As an X-linked disorder, fragile X affects males more severely than it affects females. Nearly all males with fragile X (Bailey, Hatton, & Skinner, 1998), and approximately half of
Contribution of ocular motor assessment to neuropsychological theory
Eye movement studies can be a useful complement to other diagnostic and exploratory methods, because ocular motor assessments afford a degree of quantification about signal processing and timing (i.e., latencies) that is not found in methods such as MRI and neuropsychological testing alone. Consequently, with judicious use of specific ocular motor paradigms, it is possible to assess involvement of areas known to be associated with ocular motor control. For example, in a study of the cognitive
The present study
In the present study, we used five eye movement testing paradigms based on the model of the ocular motor system described above, in order to measure neuropsychological performance implicated by ocular motor behavior. These paradigms were used to test the ability to generate reflexive saccades (visually guided saccade paradigm), disengage fixation (gap/overlap paradigm), inhibit reflexive saccades and generate a volitional saccades (anti-saccade paradigm), inhibit and initiate volitional
Methods
Informed consent for this study was obtained according to procedures approved by an institutional review board, prior to carrying out any of the procedures. Participants 18 years of age or older signed consent forms, whereas children below 18 years of age signed an assent form in the presence of the examiner. Parents of children under 18 years of age signed consent forms. All consent and assent forms indicated that participation was voluntary.
Preliminary analyses
There was no group difference in age at testing across the three participant groups, p = 0.498. As expected, there was an inverse correlation between age and the other variables measured. Therefore, age was included as a covariate in the subsequent parametric analyses.
Primary analyses using three group comparisons
The results of the three-group MANCOVA were significant for the majority of dependent variables. These are summarized in Table 2. Results of the subsequent planned pairwise comparisons are summarized in Table 3, Table 4, and are
Discussion
The aim of the present study was to use eye movement paradigms to infer differences in the underlying neurobiological mechanisms in children with fragile X or Turner syndrome, two developmental disorders with globally similar cognitive phenotypes. Based upon previous neuropsychological and neuroimaging studies, we hypothesized that girls with Turner syndrome would have difficulty in generating visually guided saccades, but that girls with either syndrome would show deficits in latencies during
References (88)
- et al.
Brain development in Turner syndrome: a magnetic resonance imaging study
Psychiatry Research
(2002) - et al.
FMR1 and the fragile X syndrome: human genome epidemiology review
Genetics in Medicine
(2001) - et al.
Differences in eye movements and reading problems in dyslexic and normal children
Vision Research
(1994) - et al.
Deficits in the initiation of eye movements in the absence of a visual target in adolescents with high functioning autism
Neuropsychologia
(2002) - et al.
Cognitive abilities of adolescent Turner’s syndrome patients
Journal of Adolescent Health Care
(1985) - et al.
Specific frontal lobe deficits among women with the fragile X gene
Journal of the American Academy of Child and Adolescent Psychiatry
(1992) Turner’s syndrome and parietal lobe functions
Cortex
(1973)- et al.
Differential cortical activation during voluntary and reflexive saccades in man
NeuroImage
(2003) MRI and fMRI analysis of oculomotor function
- et al.
X-chromosome effects on female brain: a magnetic resonance imaging study of Turner’s syndrome
Lancet
(1993)
The neuropsychological phenotype in Turner syndrome
Cortex
Intention-related activity in the posterior parietal cortex: a review
Vision Research
Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington’s disease
Brain Research Molecular Brain Research
Abnormal prefrontal cortex function during response inhibition in Turner syndrome: functional magnetic resonance imaging evidence
Biological Psychiatry
Oral fluency and narrative production in children with Turner’s syndrome
Neuropsychologia
Patterns of spatial functioning in Turner’s syndrome
Cortex
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome
Cell
Molecular-neurobehavioral associations in females with the fragile X full mutation
American Journal of Medical Genetics
Defective figure drawing, geometric and human, in Turner’s syndrome
Journal of Nervous and Mental Disease
Early developmental trajectories of males with fragile X syndrome
American Journal of Mental Retardation
Cognitive functions in Turner’s syndrome
Minerva Pediatrica
Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities
American Journal of Medical Genetics
Profile of cognitive functioning in women with the fragile X mutation
Neuropsychology
The dorsomedial frontal cortex of the macaca monkey: fixation and saccade-related activity
Experimental Brain Research
Predictive ocular motor control in Parkinson’s disease
Brain
A re-examination of the visuospatial deficit in Turner syndrome: contributions of working memory
Developmental Neuropsychology
Neural substrate of antisaccades: role of subcortical structures
Neurology
Differential impact of the FMR-1 full mutation on memory and attention functioning: a neuropsychological perspective
Journal of Cognitive Neuroscience
Electrical microstimulation of primate posterior parietal cortex initiates orienting and alerting components of covert attention
Experimental Brain Research
The effect of electromagnetic stimulation of the posterior parietal cortex on eye movements
Eye
Positron emission tomography and neuropsychological correlates in children with Turner’s syndrome
Developmental Neuropsychology
Health supervision for children with Turner syndrome
Pediatrics
Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic “scotomas”
Journal of Neuroscience
A direct prefrontotectal tract against distractibility in the human brain
Annals of Neurology
The frontal eye field is involved in spatial short-term memory but not in reflexive saccade inhibition
Experimental Brain Research
Cortical control of saccades
Experimental Brain Research
Effects of anterior cingulate cortex lesions on ocular saccades in humans
Experimental Brain Research
Evidence of normal cerebellar control of the vestibulo-ocular reflex (VOR) in children with high-functioning autism
Journal of Autism and Developmental Disorders
Role of the basal ganglia in the control of purposive saccadic eye movements
Physiological Reviews
Cognitive control of predictive eye tracking: influence of instructions
Experimental Brain Research
Cortical control of vestibular-guided saccades in man
Brain
Fragile-X: neuropsychological test performance, CGG triplet repeat lengths, and hippocampal volumes
Journal of Clinical Investigation
Differentiating aspects of executive dysfunction in girls with fragile X or Turner syndrome using the Contingency Naming Test
Developmental Neuropsychology
Ocular motor behavior of children with neurofibromatosis 1
Journal of Child Neurology
Cited by (31)
Eye-movement Patterns of Chinese Children with Developmental Dyslexia during the Stroop Test
2018, Biomedical and Environmental SciencesCharacterizing Emergent Anxiety Through the Lens of Fragile X
2016, International Review of Research in Developmental DisabilitiesCitation Excerpt :At a more basic level, FXS is also associated with pervasive attention orienting difficulties that may contribute to anxiety emergence by restricting social experiences of affected individuals. A number of studies have reported atypical attention orienting in individuals with FXS across the lifespan, with longer latencies to disengage attention from visual stimuli reported among infants (Roberts, Hatton, Long, Anello, & Colombo, 2011; Tonnsen et al., under review), school-aged individuals (Lasker, Mazzocco, & Zee, 2007), and young adults (Lasker et al., 2007). Indeed, flexible orienting of attention is a core component of self-regulation and, when impaired, compromises an individual's ability to effectively interact with his or her environment.
Genetic Syndromes as Model Pathways to Mathematical Learning Difficulties: Fragile X, Turner, and 22q Deletion Syndromes
2015, Development of Mathematical Cognition: Neural Substrates and Genetic Influences: Volume 2Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements
2014, Brain and CognitionCitation Excerpt :One of the most sensitive behavioural methods for investigating neural (dys)function is assessment of ocular motility. Ocular motor paradigms have been used extensively in a range of neurodevelopmental and neurodegenerative conditions to examine not only control of lower level motor control processes, but of higher order cognitive control processes, in particular response inhibition and working memory (Fielding, Georgiou-Karistianis, Millist, & White, 2006; Fielding et al., 2010; Lasker, Mazzocco, & Zee, 2007). The networks and nodes implicated in generating saccadic eye movement are well defined, spanning almost the entire brain: distributed throughout the neocortex (particularly prefrontal areas), subcortical and cerebellar regions (Leigh & Zee, 2006).
Exceptional lexical skills but executive language deficits in school starters and young adults with Turners syndrome: Implications for X chromosome effects on brain function
2012, Brain and LanguageCitation Excerpt :The dominant focus in exploration of neuropsychological function in TS has been of non-verbal deficits in space form perception (McGlone, 1985; Money, 1963); directional sense (Alexander, Walker & Money, 1964) drawing (Alexander, Erhardt, & Money, 1966; Temple & Carney, 1995); right–left discrimination (Rovet & Netley, 1981; Shucard et al., 1992); visuo-spatial memory (Bishop et al., 2000; Cornoldi et al., 2001; Pennington et al., 1985; Shucard et al., 1992); locating objects in space (Shucard et al., 1992); memory for matrix positions (Rovet & Netley, 1981, 1982) and visuo-motor integration (McCauley, Kay, Ito, & Treder, 1987; Temple & Carney, 1995), though there is intact performance on measures of tactile spatial skill and on some traditional measures of visuo-perceptual skill (Mazzocco, Bhatia, & Lesniak-Karpiak, 2006; Temple & Carney, 1995). The cognitive phenotype also includes impaired executive functions, though different studies focus upon different tasks (Haberecht et al., 2001; Kirk, Mazzocco, & Kover, 2005; Lasker, Mazzocco, & Zee, 2007; Romans, Roeltgen, Kushner, & Ross, 1997; Tamm et al., 2003; Temple, 2002; Temple, Carney, & Mullarkey, 1996). It has been argued that there is a motor deficit (e.g. Nijhuis-van der Sanden, Eling, & Otten, 2003), though motor response times are intact (Simon et al., 2008).
Effects of age, intelligence and executive control function on saccadic reaction time in persons with intellectual disabilities
2011, Research in Developmental Disabilities
- ☆
This work was supported by Grants NS 35356 awarded to Dr. M.B. Denckla and Grant RO1 HD 34061 awarded to Dr. Mazzocco. The authors thank the children who participated in this study and the children’s parents; and acknowledge Research Assistants D. Lanham, J. Teisl, and G.F. Myers.