Louise A. Corben

The greyscales task: a perceptual measure of attentional bias following unilateral hemispheric damage

The two cerebral hemispheres in humans have been suggested to control contralaterally opposed attentional biases. These biases may be revealed by unilateral hemispheric damage, which often causes contralesional spatial neglect, particularly when the right hemisphere (RH) is affected. Subtle attentional biases have also been observed in normal observers in tasks requiring judgements of horizontal spatial extent, brightness, numerosity and size. Here, we examined attentional biases for judging the darker of two left-right mirror-reversed brightness gradients under conditions of free viewing (the greyscales task). We compared performances of patients with damage to the RH (n=78) and left hemisphere (LH; n=20) with those of normal controls (n=20). Controls showed a small but significant leftward bias, implying a subtle asymmetry favouring the RH. In contrast, RH and LH patients showed extreme rightward and leftward biases, respectively, both of which differed significantly from that of controls. For the patient groups, performance on clinical tests of neglect (cancellation and line bisection) did not predict their greyscales scores. Pathological biases were present in patients without clinical neglect or visual field defects, suggesting that the attentional bias measured by the greyscales task can be dissociated from clinical neglect and visual sensory loss. The greyscales task offers an efficient means of quantifying pathological attentional biases in unilateral lesion patients; it is easy to administer and score, and may be particularly useful for clinical trials of recovery and rehabilitation following stroke.

FXN methylation predicts expression and clinical outcome in Friedreich ataxia

Friedreich ataxia (FA) is the most common ataxia and results from an expanded GAA repeat in the first intron of FXN. This leads to epigenetic modifications and reduced frataxin. We investigated the relationships between genetic, epigenetic, and clinical parameters in a large case–control study of FA.

Speech perception ability in individuals with Friedreich ataxia.

The aim of this study was to investigate auditory pathway function and speech perception ability in individuals with Friedreich ataxia (FRDA). Ten subjects confirmed by genetic testing as being homozygous for a GAA expansion in intron 1 of the FXN gene were included. While each of the subjects demonstrated normal, or near normal sound detection, 3 of the 10 showed electrophysiological evidence of auditory pathway disorder [presenting with the auditory neuropathy/dyssynchrony (AN/AD) result pattern], and 9 of the 10 showed abnormal speech understanding when tested with levels of background noise typical of everyday listening conditions. Information transmission analyses of the speech perception findings for the three FRDA subjects with AN/AD type hearing loss when compared with those of a cohort of individuals with peripheral [sensorineural (SN)] hearing loss, showed a distinct pattern of perceptual disruption. Where the listeners with SN loss confused sounds on the basis of frequency (pitch) differences, the FRDA subjects with AN/AD made errors that reflected an inability to perceive temporal (timing) cues in the speech sounds.

Clinical Features of Friedreich Ataxia

Friedreich ataxia, the most common hereditary ataxia, affects approximately 1 per 29,000 white individuals. In about 98% of these individuals, it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2%, it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this autosomal recessive condition is usually in the first 2 decades of life. Major clinical features include progressive ataxia, absent lower limb reflexes, upgoing plantar responses, and peripheral sensory neuropathy. The main nonneurological sites of morbidity are the heart, resulting in cardiomyopathy, and the pancreas, resulting in diabetes mellitus. In this review, we provide an overview of the clinical features of Friedreich ataxia and discuss differential diagnoses.

Dysarthria in Friedreich’s Ataxia: A Perceptual Analysis

The aims of this study were to: (1) evaluate the perceptual speech dimensions, speech intelligibility and dysarthria severity of a group of individuals diagnosed with Friedreich’s ataxia (FRDA); (2) determine the presence of subgroups within FRDA dysarthria; (3) investigate the relationship between the speech outcome and the clinical factors of disease progression. The study included 38 individuals (21 female, 17 male) with a confirmed diagnosis of FRDA. A group of 20 non-neurologically impaired individuals served as controls. Perceptual analysis, investigating 30 different dimensions of speech, was conducted on a speech sample obtained from each participant. In addition, the Assessment of Intelligibility of Dysarthria Speech was administered. All FRDA participants presented with dysarthria with severities ranging from mild to moderate. Cluster analysis revealed 3 subgroups, the first presenting with mild dysarthric symptoms, the second with increased velopharyngeal involvement and the third characterized by increased laryngeal dysfunction. Dysarthria severity showed a significant correlation to disease duration but to no other clinical measure. The findings support the notion of subgroups in FRDA dysarthria, representing distinct impairments of the speech mechanism and perhaps reflective of differing evolutions beyond the cerebellum.

Towards an understanding of cognitive function in Friedreich ataxia

There is limited documentation regarding cognitive function in individuals with Friedreich ataxia (FRDA), possibly because FRDA is widely held to predominantly affect the spinal cord, peripheral sensory nerves and cerebellum and not to affect cognition. Traditionally, the cerebellum has been thought to coordinate voluntary movement and motor tone, posture and gait. However, recent studies have implicated the cerebellum in a range of cognitive functions including executive function, visuospatial organisation and memory. We review the available data on cognitive function and neuroimaging in FRDA and the role of the cerebellum in cognitive function. We conclude with recommendations for future research including correlating cognitive function in individuals with FRDA with possible determinants of disease severity, such as age of onset and the causative genetic mutation.

Auditory perception in individuals with Friedreich's ataxia.

Introduction: Friedreich’s ataxia (FRDA) is an inherited ataxia with a range of progressive features including axonal degeneration of sensory nerves. The aim of this study was to investigate auditory perception in affected individuals. Methods: Fourteen subjects with genetically defined FRDA participated. Two control groups, one consisting of healthy, normally hearing individuals and another comprised of subjects with sensorineural hearing loss, were also assessed. Auditory processing was evaluated using structured tasks designed to reveal the listeners’ ability to perceive temporal and spectral cues. Findings were then correlated with open-set speech understanding. Results: Nine of 14 individuals with FRDA showed evidence of auditory processing disorder. Gap and amplitude modulation detection levels in these subjects were significantly elevated, indicating impaired encoding of rapid signal changes. Electrophysiologic findings (auditory brainstem response, ABR) also reflected disrupted neural activity. Speech understanding was significantly affected in these listeners and the degree of disruption was related to temporal processing ability. Speech analyses indicated that timing cues (notably consonant voice onset time and vowel duration) were most affected. Conclusion: The results suggest that auditory pathway abnormality is a relatively common consequence of FRDA. Regular auditory evaluation should therefore be part of the management regime for all affected individuals. This assessment should include both ABR testing, which can provide insights into the degree to which auditory neural activity is disrupted, and some functional measure of hearing capacity such as speech perception assessment, which can quantify the disorder and provide a basis for intervention.

The effects of competition and motor reprogramming on visuomotor selection in unilateral neglect

Abstract Patients with unilateral neglect following right hemisphere damage may have difficulty in moving towards contralesional targets. To test the hypothesis that this impairment arises from competing motor programs triggered by irrelevant ipsilesional stimuli, we examined 16 right hemisphere patients, eight with left visual neglect and eight without, in addition to eight healthy control subjects. In experiment 1 subjects performed sequences of movements using their right hand to targets on the contralesional or ipsilesional side of the responding limb. The locations of successive targets in each sequence were either predictable or unpredictable. In separate blocks of trials, targets appeared either alone or with a simultaneous distractor located at the immediately preceding target location. Neglect patients were significantly slower to execute movements to contralesional targets, but only for unpredictable movements and in the presence of a concurrent ipsilesional distractor. In contrast, healthy controls and right hemisphere patients without neglect showed no directional asymmetries of movement execution. In experiment 2 subjects were required to interrupt a predictable, reciprocating sequence of leftward and rightward movements in order to move to an occasional, unpredictable target that occurred either in the direction opposite to that expected, or in the same direction but twice the extent. Neglect patients were significantly slower in reprogramming the direction and extent of movements towards contralesional versus ipsilesional targets, and they also made significantly more errors when executing such movements. Right hemisphere patients without neglect showed a similar bias in reprogramming direction (but not extent) for contralesional targets, whereas healthy controls showed no directional asymmetry in either condition. On the basis of these findings we propose that neglect involves a competitive bias in favour of motor programs for actions directed towards ipsilesional versus contralesional events. We suggest that programming errors and increased latencies for contralesional movements arise because the damaged right hemisphere can no longer effectively inhibit the release of inappropriate motor programs towards ipsilesional events.

Disruption to higher order processes in Friedreich ataxia.

Friedreich ataxia (FRDA), the most common of the genetically inherited ataxias, is characterised by ocular motor deficits largely reflecting disruption to brainstem-cerebellar circuitry. These deficits include fixation instability, saccadic dysmetria, disrupted pursuit, and vestibular abnormalities. Whether higher order or cognitive control processes involved the generation of more volitional eye movements are similarly impaired, has not been explored previously. This research examined antisaccade and memory-guided saccade characteristics in 13 individuals with genetically confirmed FRDA, and contrasted performance with neurologically healthy individuals. We demonstrate, for the first time, a broad range of deficits in FDRA consistent with disruption to higher order processes involved in the control of saccadic eye movement. Significant differences between FDRA and control participants were revealed across all movement parameters (latency, gain, velocity, position error), and across all saccade types, including alterations to velocity profiles. FDRA participants also generated significantly more erroneous responses to non-target stimuli in both saccade paradigms. Finally, a number of correlations between ocular motor and clinical measures were revealed including those between contrast acuity and saccadic latency (all saccade types), disease duration and measures of response inhibition (errors and relative latencies for antisaccades), and neurological scores and error latencies, arguably a reflection of difficulty resolving response conflict. These results suggest a role for the cerebellum in higher order cognitive control processes, and further support the proposal that eye movement markers, which can be measured with accuracy and reliability, may be a useful biomarker in FDRA.

Impairment in motor reprogramming in Friedreich ataxia reflecting possible cerebellar dysfunction

The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three “oddball” stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto-cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two.