Ines Beiser

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland.

Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well‐characterized cohorts are important to our understanding of this disorder.

Sun exposure is an environmental factor for the development of blepharospasm

Background Adult-onset isolated focal dystonia may present with various phenotypes including blepharospasm and cervical dystonia. Although inherited in an autosomal dominant manner with a markedly reduced penetrance, environmental factors are considered important in disease penetrance and expression. We observed a marked variation by latitude in the reports of the frequency of patients with blepharospasm relative to those with cervical dystonia; we hypothesised that sun exposure is an environmental risk factor for the development of blepharospasm in genetically susceptible individuals. Methods From published clinic cohorts and epidemiological reports, the ratio of the number of cases of blepharospasm to cervical dystonia (phenotype case ratio) at each study site was analysed with regard to latitude and measures of annual insolation. Meta-regression analyses of the phenotype case ratio to these environmental factors were performed. Results The phenotype case ratio in 15 eligible study sites over 41° of latitude demonstrated a statistically significant inverse association with latitude (p=0.0004, R2=53.5%). There were significant positive associations between the phenotype case ratio and quarter-one (January–March) insolation (p=0.0005, R2=53%) and average annual insolation (p=0.003, R2=40%). Conclusion The increase in the blepharospasm: cervical dystonia case ratio with decreasing latitude and increasing insolation suggests that sunlight exposure is an environmental risk factor for the development of blepharospasm (rather than cervical dystonia) in individuals genetically susceptible to adult-onset dystonia.

Young Women do it Better: Sexual Dimorphism in Temporal Discrimination

The temporal discrimination threshold (TDT) is the shortest time interval at which two sensory stimuli presented sequentially are detected as asynchronous by the observer. TDTs are known to increase with age. Having previously observed shorter thresholds in young women than in men, in this work we sought to systematically examine the effect of sex and age on temporal discrimination. The aims of this study were to examine, in a large group of men and women aged 20–65 years, the distribution of TDTs with an analysis of the individual participant’s responses, assessing the “point of subjective equality” and the “just noticeable difference” (JND). These respectively assess sensitivity and accuracy of an individual’s response. In 175 participants (88 women) aged 20–65 years, temporal discrimination was faster in women than in men under the age of 40 years by a mean of approximately 13 ms. However, age-related decline in temporal discrimination was three times faster in women so that, in the age group of 40–65 years, the female superiority was reversed. The point of subjective equality showed a similar advantage in younger women and more marked age-related decline in women than men, as the TDT. JND values declined equally in both sexes, showing no sexual dimorphism. This observed sexual dimorphism in temporal discrimination is important for both (a) future clinical research assessing disordered mid-brain covert attention in basal-ganglia disorders, and (b) understanding the biology of this sexual dimorphism which may be genetic or hormonal.

Age-Related Sexual Dimorphism in Temporal Discrimination and in Adult-Onset Dystonia Suggests GABAergic Mechanisms.

Background Adult-onset isolated focal dystonia (AOIFD) presenting in early adult life is more frequent in men, whereas in middle age it is female predominant. Temporal discrimination, an endophenotype of adult-onset idiopathic isolated focal dystonia, shows evidence of sexual dimorphism in healthy participants. Objectives We assessed the distinctive features of age-related sexual dimorphism of (i) sex ratios in dystonia phenotypes and (ii) sexual dimorphism in temporal discrimination in unaffected relatives of cervical dystonia patients. Methods We performed (i) a meta-regression analysis of the proportion of men in published cohorts of phenotypes of adult-onset dystonia in relation to their mean age of onset and (ii) an analysis of temporal discrimination thresholds in 220 unaffected first-degree relatives (125 women) of cervical dystonia patients. Results In 53 studies of dystonia phenotypes, the proportion of men showed a highly significant negative association with mean age of onset (p < 0.0001, pseudo-R2 = 59.6%), with increasing female predominance from 40 years of age. Age of onset and phenotype together explained 92.8% of the variance in proportion of men. Temporal discrimination in relatives under the age of 35 years is faster in women than men but the age-related rate of deterioration in women is twice that of men; after 45 years of age, men have faster temporal discrimination than women. Conclusion Temporal discrimination in unaffected relatives of cervical dystonia patients and sex ratios in adult-onset dystonia phenotypes show similar patterns of age-related sexual dimorphism. Such age-related sexual dimorphism in temporal discrimination and adult-onset focal dystonia may reflect common underlying mechanisms. Cerebral GABA levels have been reported to show similar age-related sexual dimorphism in healthy participants and may be the mechanism underlying the observed age-related sexual dimorphism in temporal discrimination and the sex ratios in AOIFD.

Disrupted Superior Collicular Activity May Reveal Cervical Dystonia Disease Pathomechanisms

Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant’s superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans.

Menstrual cycle and the temporal discrimination threshold

The temporal discrimination threshold (TDT) is a proposed pre-clinical biomarker (endophenotype) for adult onset isolated focal dystonia (AOIFD). Age- and sex-related effects on temporal discrimination demonstrate that women, before the age of 40 years, have faster temporal discrimination than men but their TDTs worsen with age at almost three times the rate of men. Thus after 40 years the TDT in women is progressively worse than in men. AOIFD is an increasingly female-predominant disorder after the age of 40; it is not clear whether this age-related sexually-dimorphic difference observed for both the TDT and sex ratio at disease onset in AOIFD is a hormonal or chromosomal effect. The aim of this study was to examine temporal discrimination at weekly intervals during two consecutive menstrual cycles in 14 healthy female volunteers to determine whether physiological hormonal changes affected temporal discrimination. We observed no significant differences in weekly temporal discrimination threshold values during the menstrual cycles and no significant correlation with the menstrual cycle stage. This observed stability of temporal discrimination during cyclical hormonal change raises interesting questions concerning the age-related sexually-dimorphic decline observed in temporal discrimination. Our findings pave the way for future studies exploring potential pathomechanisms for this age-related deterioration.

Practice does not make perfect: Temporal discrimination in musicians with and without dystonia: Temporal Discrimination in Musicians

Musician’s dystonia (MD), characterized by loss of voluntary control while playing an instrument, is a phenotype of adult-onset isolated focal dystonia (AOIFD). Abnormal sensory processing is a common finding in AOIFD; the temporal discrimination threshold (TDT) is a marker of this. TDT is a measure of the shortest time interval at which 2 stimuli are perceived as asynchronous. It is abnormally elevated in non-MD phenotypes of AOIFD. Abnormal TDTs occur less frequently in MD. Musicians perform better than nonmusicians at various timing tasks. However, compared with healthy musicians, MD subjects exhibit intact timing abilities. We hypothesized that the nonmusician control subjects might have masked an underlying abnormality in TDTs in the MD subjects, which could be discerned on comparison with control musicians. We hypothesized that (1) compared with a control population of healthy musicians, musicians with dystonia would have abnormal TDTs; and (2) healthy musicians would have faster, “betterthan-normal” TDTs compared with healthy nonmusicians. We measured TDTs in 20 patients with musician’s dystonia (group 1), 20 healthy musicians (group 2), and 94 healthy nonmusicians (group 3) according to a method previously described. Briefly, subjects were asked to report when they perceived a delay between a pair of flashing lightemitting diodes positioned on a table in front of them. Repeated trials were averaged, and Z scores were obtained for each subject. Two Z scores were derived using musician and nonmusician controls as reference populations. The number of abnormal controls in each group was assessed for significance using Fisher’s exact test, with a threshold for significance of P 5 0.025. All subjects gave informed consent, and ethical approval was obtained for the study. All participants had normal cognition, visual acuity, and no sensory impairments or history of significant neurological conditions. There were no significant differences in age among the 3 groups. Figure 1 plots the TDT results for subjects in each group. The MD group had a mean TDT of 47.3 milliseconds (SD, 23.3 milliseconds). The control musician group had a mean TDT of 23 milliseconds (SD, 7.3 milliseconds), and the nonmusician control group had a mean TDT of 32.9 milliseconds (SD, 15.9 milliseconds). Using Z scores derived from nonmusician controls as the reference, only 20% of the MD group (4 of 20) was

Application of Virtual Reality Head Mounted Display for Investigation of Movement: a Novel Effect of Orientation of Attention

OBJECTIVE To date human kinematics research has relied on video processing, motion capture and magnetic search coil data acquisition techniques. However, the use of head mounted display virtual reality systems, as a novel research tool, could facilitate novel studies into human movement and movement disorders. These systems have the unique ability of presenting immersive 3D stimulus while also allowing participants to make ecologically valid movement-based responses. APPROACH We employed one such system (Oculus Rift DK2) in this study to present visual stimulus and acquire head-turn data from a cohort of 40 healthy adults. Participants were asked to complete head movements towards eccentrically located visual targets following valid and invalid cues. Such tasks are commonly employed for investigating the effects orientation of attention and are known as Posner cueing paradigms. Electrooculography was also recorded for a subset of 18 participants. MAIN RESULTS A delay was observed in onset of head movement and saccade onset during invalid trials, both at the group and single participant level. We found that participants initiated head turns 57.4 ms earlier during valid trials. A strong relationship between saccade onset and head movement onset was also observed during valid trials. SIGNIFICANCE This work represents the first time that the Posner cueing effect has been observed in onset of head movement in humans. The results presented here highlight the role of head-mounted display systems as a novel and practical research tool for investigations of normal and abnormal movement patterns.

Measurement & Analysis of the Temporal Discrimination Threshold Applied to Cervical Dystonia

The temporal discrimination threshold (TDT) is the shortest time interval at which an observer can discriminate two sequential stimuli as being asynchronous (typically 30-50 ms). It has been shown to be abnormal (prolonged) in neurological disorders, including cervical dystonia, a phenotype of adult onset idiopathic isolated focal dystonia. The TDT is a quantitative measure of the ability to perceive rapid changes in the environment and is considered indicative of the behavior of the visual neurons in the superior colliculus, a key node in covert attentional orienting. This article sets out methods for measuring the TDT (including two hardware options and two modes of stimuli presentation). We also explore two approaches of data analysis and TDT calculation. The application of the assessment of temporal discrimination to the understanding of the pathogenesis of cervical dystonia and adult onset idiopathic isolated focal dystonia is also discussed.

COMPARING STIMULUS-PRESENTATION METHODS IN TEMPORAL DISCRIMINTATION TESTING

Objective To investigate any differences in temporal discrimination using two methods of stimulus presentation. Background Temporal discrimination threshold (TDT) is a measure of the point at which an individual determines two sensory stimuli to be asynchronous (normal=30–50 ms). The classic approach involves presentation of progressively-asynchronous stimuli to an individual. The TDT is taken as the first of three consecutively-reported asynchronous stimuli. Due to the potential for a learned effect from this method of presentation, a method of constant stimuli with randomised presentation order was also employed. Methods Ten healthy volunteers were recruited to the study. Visual and tactile TDT testing using the classic and random method of presentation was carried out in a single session. The mean TDT score was calculated for each participant. The data was fitted to a cumulative Gaussian function from which the point of subjective equality (PSE) and the just noticeable difference (JND) was calculated. Results The mean values for the sequential method are as follows; TDT=32.03 ms, PSE=23.11 ms, JND=13.71 ms. The mean values for the random method are as follows; TDT 52.26 ms, PSE 33.35 ms, JND 28.58 ms. Conclusion Although a difference was observed in the results between stimulus presentation, there was a trending correlation between the PSE values for the two stimulus presentation types. This suggests that while the absolute values were different, the relative values were consistent. While our study is limited by number size and future research is required, preliminary results suggest the TDT is a robust measure.