Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological findings from older premutation carrier males and their noncarrier siblings from families with fragile X syndrome.

Objective: Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The primary features of FXTAS are late-onset intention tremor and gait ataxia. Previous reports have shown global deficits in neuropsychological measures among males with FXTAS, particularly those related to executive functioning. The purpose of this study was to investigate the neuropsychological profile among older males with the premutation who are at risk for FXTAS. Method: Premutation carriers, 66 with motor symptoms and 23 without, and 18 noncarrier siblings were recruited from pedigrees diagnosed with fragile X syndrome, all over age 50. Subjects were examined with a neurological test battery to identify symptoms of FXTAS and a neuropsychological test battery to investigate cognitive and behavioral profiles. Linear regression and ANCOVA were used to determine the effect of the premutation on outcome measures adjusting for age and education. Results: We identified a significant decrease in scores of general intelligence and a marginally significant decrease in scores of logical memory among premutation carrier males with motor symptoms compared to the noncarrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. Conclusions: Similar to other reports, we found that the FMR1 premutation is associated with deficits in general intelligence and memory among older males with symptoms of FXTAS. However, our results differed in that we found no evidence of premutation-associated executive dysfunction. We provide possible explanations for this difference. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome.

On a series of attention tasks, male mice with a mutation targeted to the fragile X mental retardation 1 (Fmrl) gene (Fmrl knockout [KO] mice) committed a higher rate of premature responses than wild-type littermates, with the largest differences seen when task contingencies changed. This finding indicates impaired inhibitory control, particularly during times of stress or arousal. The KO mice also committed a higher rate of inaccurate responses than controls, particularly during the final third of each daily test session, indicating impaired sustained attention. In the selective attention task, the unpredictable presentation of potent olfactory distractors produced a generalized disruption in the performance of the KO mice, whereas for controls, the disruption produced by the distractors was temporally limited. Finally, the attentional disruption seen following an error was more pronounced for the KO mice than for controls, further implicating impaired regulation of arousal and/or negative affect. The present study provides the first evidence that the Fmrl KO mouse is impaired in inhibitory control, attention, and arousal regulation, hallmark areas of dysfunction in fragile X syndrome. The resistance to change also seen in these mice provides a behavioral index for studying the autistic features of this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociating the role of the parietal cortex and dorsal hippocampus for spatial information processing.

Dorsal hippocampus, parietal cortex, and control lesioned rats were tested on both a metric and topological task. The metric task consisted of 2 different objects placed 68 cm apart on a cheese board. After habituation, the objects were moved to a separation of 38 cm on Day 1 and to a separation of 98 cm on Day 2. The topological task consisted of 4 different objects placed in a square orientation. After habituation, the first 2 objects were switched, and after the rats habituated to that change, the back 2 objects were switched. This was repeated on a different day with 4 new objects. The data suggest that the hippocampus is necessary for metric representations, whereas the parietal cortex is necessary for topological representations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mouse model of fragile X syndrome: Behavioral and hormonal response to stressors.

Fragile X syndrome, a form of mental retardation caused by inadequate levels of fragile X mental retardation protein (FMRP), is characterized by extreme sensitivity to sensory stimuli and increased behavioral and hormonal reactivity to stressors. Fmr1 knockout mice lack FMRP and exhibit abnormal responses to auditory stimuli. This study sought to determine whether Fmr1 knockout mice on an F1 hybrid background are normal in their response to footshock. Knockout mice were also examined for signs of hyperexcitation across an extended trial range, and serum corticosterone levels were evaluated in response to various stressors. The ability to acquire conditioned taste aversion was also assessed. Knockout mice exhibited no impairment in associative aversive learning or memory, since they successfully expressed conditioned taste aversion. Footshock-sensitivity, freezing behavior, and corticosterone response to various stressors did not differ between knockout and wild-type mice. However, knockout mice exhibited significantly increased responses during the extended test. The knockout mice’s increased responsiveness to footshock in the extended test may be an indication of increased vulnerability to stress or enhanced emotional reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of the Fragile X Status Categories and the Fragile X Mental Retardation Protein Levels on Executive Functioning in Males and Females With Fragile X.

The effects of a fragile X disorder on executive function impairment were assessed in 144 extended families, which included individuals with fragile X premutation and full mutation and their relatives without fragile X. A modification of the maximum-likelihood estimators for pedigree data, as well as ordinal logistic regression, were used in data analysis. The most outstanding deficit, occurring especially in males, involved impaired capacity to use an intention to regulate purposeful behavior. This deficit occurred independently of general cognitive impairment but was related to depletion of fragile X mental retardation 1 gene protein product. The other executive function deficits were accounted for by the general cognitive impairment. Possible mechanisms of the effect of fragile X premutation on impairments of executive functioning are considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Body- and environmental-stabilized processing of spatial knowledge.

In 5 experiments, the authors examined the perceptual and cognitive processes used to track the locations of objects during locomotion. Participants learned locations of 9 objects on the outer part of a turntable from a single viewpoint while standing in the middle of the turntable. They subsequently pointed to objects while facing the learning heading and a new heading, using imagined headings that corresponded to their current actual body heading and the other actual heading. Participants in 4 experiments were asked to imagine that the objects moved with them as they turned and were shown or only told that the objects would move with them; in Experiment 5, participants were shown that objects could move with them but were asked to ignore this as they turned. Results showed that participants tracked object locations as though the objects moved with them when shown but not when told about the consequences of their locomotion. Once activated, this processing mode could not be suppressed by instructions. Results indicated that people process object locations in a body- or an environment-stabilized manner during locomotion, depending on the perceptual consequences of locomotion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Executive functions in young males with fragile X syndrome in comparison to mental age-matched controls: Baseline findings from a longitudinal study.

The performance of 54 boys with fragile X syndrome (FXS), ages 7 to 13 years, was compared to that of a group of typically developing boys who were matched on mental age (MA) and ethnicity across multiple measures of executive function (EF). Boys with FXS varied in their ability to complete EF measures, with only 25.9% being able to complete a set-shifting task and 94.4% being able to complete a memory for word span task. When compared to the control group, and controlling for MA and maternal education, boys with FXS showed significant deficits in inhibition, working memory, cognitive flexibility/set-shifting, and planning. No group differences were observed in processing speed. Mental age significantly impacted performance on working memory, set-shifting, planning, and processing speed tasks for both groups. In boys with FXS, MA significantly predicted performance on working memory and set-shifting tasks. Our findings suggest that deficits in EF in boys with FXS are not solely attributable to developmental delays but, rather, present as a true array of neurocognitive deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome.

This study assessed social behavior in a mouse model of Fragile X syndrome (FXS), the Fmr1 tm1Cgr or Fmr1 "knockout" (KO) mouse. Both the KO and wild-type (WT) mice preferred to be near a novel conspecific than to be alone. However, during the initial interaction with a novel conspecific, (1) a greater proportion of the KO mice exhibited high levels of grooming; and (2) the average duration of nose contact with the stimulus mouse was significantly shorter for the KO mice, both indicative of increased arousal and/or anxiety. Both groups exhibited a robust novelty preference when the novel animal was a "preferred" mouse. However, when the novel mouse was a "nonpreferred" animal, both groups showed a diminished novelty preference but this effect was more pronounced for the WT mice. This blunted negative reaction of the KO mice to a nonpreferred animal may indicate that they were less proficient than controls in distinguishing between positive and negative social interactions. These findings provide support for the use of this animal model to study the autistic features of FXS and autism spectrum disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The interactions and dissociations of the dorsal hippocampus subregions: How the dentate gyrus, CA3, and CA1 process spatial information.

Several studies have demonstrated the significance of a spatial cognitive map and its role for guided and accurate navigation through the environment. Learning and recalling spatial knowledge depends upon proper topological and metric spatial information processing. The present objectives are to better characterize the role of the hippocampus for processing topological and metric spatial information. Rats with dorsal hippocampal subregional lesions (dDG, dCA3, dCA1) were tested on a previously established metric task and topological task. The results of the present study suggest that dCA1, but not dDG or dCA3, mediates topological memory. Furthermore, dDG, dCA3, and dCA1 mediate metric memory. Dorsal DG is required for spatial information processing via pattern separation or orthogonalization of sensory inputs to generate metric representations. Dorsal CA3 and dCA1 then receive these metric representations transmitted from dDG along the trisynaptic loop. The present data add to a growing body of literature suggesting a diversity of function among the hippocampal subregions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Revisiting the role of spatial frequencies in the holistic processing of faces.

V. Goffaux and B. Rossion (2006) argued that holistic processing of faces is largely supported by low spatial frequencies (LSFs) but less so by high spatial frequencies (HSFs). We addressed this claim using a sequential matching task with face composites. Observers judged whether the top halves of aligned or misaligned composites were identical. We replicated the V. Goffaux and B. Rossion (2006) results, finding a greater alignment effect in accuracy for LSF compared with HSF faces on same trials. However, there was also a greater bias for responding "same" for HSF compared with LSF faces, indicating that the alignment effects arose from differential response biases. Crucially, comparable congruency effects found for LSF and HSF suggest that LSF and HSF faces are processed equally holistically. These results demonstrate that it is necessary to use measures that take response biases into account in order to fully understand the holistic nature of face processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The modulation of fragile X behaviors by the muscarinic M4 antagonist, tropicamide.

Muscarinic acetylcholine receptors (mAChR) are G protein–coupled receptors (M1–M5), grouped together into two functional classes, based on their G protein interaction. Although ubiquitously expressed in the CNS, the M4 protein shows highest expression in the neostriatum, cortex, and hippocampus. Electrophysiological and biochemical studies have provided evidence for overactive mAChR signaling in the fragile X knock-out (Fmr1KO) mouse model, and this has been hypothesized to contribute to the phenotypes seen in Fmr1KO mice. To address this hypothesis we used an M4 antagonist, tropicamide, to reduce the activity through the M4 mAChR and investigated the behavioral response in the Fmr1KO animals. Data from the marble-burying assay have shown that tropicamide treatment resulted in a decreased number of marbles buried in the wild-type (WT) and in the knockout (KO) animals. Results from the open field assay indicated that tropicamide increases activity in both the WT and KO mice. In the passive avoidance assay, tropicamide treatment resulted in the improvement of performance in both the WT and the KO animals at the lower doses (2 and 5 mg/kg), and the drug was shown to be important for the acquisition and not the consolidation process. Lastly, we observed that tropicamide causes a significant decrease in the percentage of audiogenic seizures in the Fmr1KO animals. These results suggest that pharmacological antagonism of the M4 receptor modulates select behavioral responses in the Fmr1KO mice. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Mental layout extrapolations prime spatial processing of scenes.

Four experiments examined whether scene processing is facilitated by layout representation, including layout that was not perceived but could be predicted based on a previous partial view (boundary extension). In a priming paradigm (after Sanocki, 2003), participants judged objects' distances in photographs. In Experiment 1, full scenes (target), partial scenes, and two control primes were used. Partial scenes excluded the target objects' locations, but these areas could be predicted. Full and partial scenes produced equal performance facilitation. In Experiment 2, task-irrelevant partial scene primes were also tested. These primes did not facilitate performance (i.e. simple scene previews did not help). Experiment 3 showed that a partial prime's utility depended on the area of the scene that would be tested; the task-irrelevant primes used in Experiment 2 were useful for other distance judgments. Experiment 4 showed that partial scene facilitation is not limited to the area immediately surrounding the prime. The study demonstrated that perceived and mentally extrapolated layouts are equally effective. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Discrimination learning and attentional set formation in a mouse model of Fragile X.

Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive function is inconsistent. To address this issue, we trained wild-type and Fmr1 KO mice on an experimental paradigm that assesses attentional set-shifting. Mice learned to discriminate between stimuli differing in two of three perceptual dimensions. Successful discrimination required attending only to the relevant dimension, while ignoring irrelevant dimensions. Mice were trained on three discriminations in the same perceptual dimension, each followed by a reversal. This procedure normally results in the formation of an attentional set to the relevant dimension. Mice were then required to shift attention and discriminate based on a previously irrelevant perceptual dimension. Wild-type mice exhibited the increase in trials to criterion expected when shifting attention from one perceptual dimension to another. In contrast, the Fmr1 KO group failed to show the expected increase, suggesting impairment in forming an attentional set. Fmr1 KO mice also exhibited a general impairment in learning discriminations and reversals. This is the first demonstration that Fmr1 KO mice show a deficit in attentional set formation. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

A spatial frequency account of the detriment that local processing of Navon letters has on face recognition.

Five minutes of processing the local features of a Navon letter causes a detriment in subsequent face-recognition performance (Macrae & Lewis, 2002). We hypothesize a perceptual after effect explanation of this effect in which face recognition is less accurate after adapting to high-spatial frequencies at high contrasts. Five experiments were conducted in which face-recognition performance was compared after processing high-contrast Navon stimuli. The standard recognition deficit was observed for processing the local features of Navon stimuli, but not if the stimuli were blurred (Experiment 1) or if they were of lower contrast (Experiment 2). A face-recognition deficit was observed after processing small, high-contrast letters equivalent to local processing of Navon letters (Experiment 3). Experiments 4 and 5 demonstrated that recognition of bandpass-filtered faces interacted with the type of Navon processing, in which the recognition of low-pass filtered faces was better following local rather than global processing. These results suggest that the Navon effect on subsequent face recognition is a perceptual phenomenon. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

7-nitroindazole attenuates 6-hydroxydopamine-induced spatial learning deficits and dopamine neuron loss in a presymptomatic animal model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder in which loss of dopaminergic (DA) neurons (>50%) in the substantia nigra (SN) precedes most of the overt motor symptoms, making early diagnosis and treatment interventions difficult. Because PD has been associated with free radicals generated by nitric oxide, this study tested whether treatments of 7-nitroindazole (7NI), a nitric-oxide-synthase inhibitor, could reduce cognitive deficits that often emerge before overt motor symptoms in a presymptomatic rat model of PD. Rats were given intraperitoneal injections of 50 mg/kg 7NI (or vehicle) just before receiving bilateral, intrastriatal injections of the DA-toxin, 6-hydroxydopamine (6-OHDA). The rats were then given a battery of motor tasks, and their learning ability was assessed using a spatial reversal task in a water-T maze. Results indicate that 7NI treatments attenuate 6-OHDA-induced spatial learning deficits and protect against DA cell loss in the SN, suggesting that 7NI may have potential as an early, presymptomatic pharmacotherapy for PD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of the dorsal hippocampus or parietal cortex differentially affect spatial information processing.

The present experiments used 2 versions of a modified Hebb-Williams maze to test the role of the dorsal hippocampus (dHip) and parietal cortex (PC) in processing allocentric and egocentric space during acquisition and retention. Bilateral lesions were made to either the dHip or PC before maze testing (acquisition) or after maze testing (retention). The results indicate that lesions of the dHip impair allocentric maze acquisition, whereas lesions of the PC impair egocentric maze acquisition. During retention, lesions of the PC produced a significant impairment on both maze versions, whereas lesions of the dHip produced short-lived, transient impairments on both maze versions. These results suggest that during acquisition, the hippocampus and PC process spatial information in parallel; however, long-term retention of spatial information requires the PC with the dHIP as necessary for retrieval and/or access but not necessarily storage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mental rotation of objects retrieved from memory: A functional MRI study of spatial processing.

This functional MRI study examined how people mentally rotate a 3-dimensional object (an alarm clock) that is retrieved from memory and rotated according to a sequence of auditory instructions. We manipulated the geometric properties of the rotation, such as having successive rotation steps around a single axis versus alternating between 2 axes. The latter condition produced much more activation in several areas. Also, the activation in several areas increased with the number of rotation steps. During successive rotations around a single axis, the activation was similar for rotations in the picture plane and rotations in depth. The parietal (but not extrastriate) activation was similar to mental rotation of a visually presented object. The findings indicate that a large-scale cortical network computes different types of spatial information by dynamically drawing on each of its components to a differential, situation-specific degree. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Category-based errors and the accessibility of unbiased spatial memories: A retrieval model.

Studies have consistently shown a spatial memory bias such that a target location is remembered toward the prototypical location of the region to which the target belongs, indicating a blending between the target’s specific information and the generic information of its region. The authors investigated whether people retain a veridical representation of a target location after a delay by determining the locus of the blending (during encoding, delay, or retrieval). To examine accessibility to the original target location, they used a recognition task, which is less demanding than the traditional reproduction procedure. The results showed that participants were able to recognize the original position of a target over their own biased recalled position after both a short (1,500 ms) and a longer (5,000 ms) delay. These findings reveal that spatial memories can be undistorted despite distorted recall responses. Results are discussed in terms of J. Huttenlocher, L. V. Hedges, and S. Duncan’s (1991) category adjustment model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interference effects by spatial proximity and age-related declines in spatial memory by Japanese monkeys (Macaca fuscata): Deficits in the combined use of multiple spatial cues.

Spatial information processing was assessed in 3 young (4-10 years old) and 4 aged (24-25 years old) Japanese monkeys (Macaca fuscata) on 3 delayed nonmatching-to-position (DNMP) tests with relatively short delays of 5 s. Each test had 3 conditions of different horizontal distances between sample and to-be-nonmatched positions. Experiment 1 demonstrated that the performance on the DNMP test in both age groups was impaired when 2 stimulus positions were located next to each other; however, it was fairly accurate when they were located farther apart, suggesting that interference is introduced by spatial proximity. Experiment 2 revealed age-related differences in the situation in which an additional spatial cue, depth information, was available by extending the stimulus array of the DNMP test to a 4 = 2 matrix. In this test, young monkeys performed accurately irrespective of position distance between stimuli, whereas the aged monkeys' performance remained the same as before. Experiment 3 confirmed that the recognition ability in aged monkeys was well preserved on DNMP tests with different objects. These patterns of results indicate that the ability to use information from multiple spatial cues is not accessible to the aged monkeys. (PsycINFO Database Record (c) 2010 APA, all rights reserved)