Temporal discrimination: Mechanisms and relevance to adult-onset dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis

A Comparison of Stimulus Presentation Methods in Temporal Discrimination Testing

The temporal discrimination threshold (TDT) is the shortest time interval at which an individual detects two stimuli to be asynchronous (normal  =  30-50 ms). It has been shown to be abnormal in patients with disorders affecting the basal ganglia including adult onset idiopathic focal dystonia (AOIFD). Up to 97% of patients have an abnormal TDT with age- and sex-related penetrance in unaffected relatives, demonstrating an autosomal dominant inheritance pattern. These findings support the use of the TDT as a pre-clinical biomarker for AOIFD. The usual stimulus presentation method involves the presentation of progressively asynchronous stimuli; when three sequential stimuli are reported asynchronous is taken as a participant\u27s TDT. To investigate the robustness of the \u27staircase\u27 method of presentation, we introduced a method of randomised presentation order to explore any potential \u27learning effect\u27 that may be associated with this existing method. The aim of this study was to investigate differences in temporal discrimination using two methods of stimulus presentation. Thirty healthy volunteers were recruited to the study (mean age 33.73  ±  3.4 years). Visual and tactile TDT testing using a staircase and randomised method of presentation order was carried out in a single session. There was a strong relationship between the staircase and random method for TDT values. This observed consistency between testing methods suggests that the existing experimental approach is a robust method of recording an individual\u27s TDT. In addition, our newly devised randomised paradigm is a reproducible and more efficient method for data acquisition in the clinic setting. However, the two presentation methods yield different absolute TDT results and either of the two methods should be used uniformly in all participants in any one particular study. doi: 10.1088/1361-6579/38/2/N5

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

Neural Correlates of Abnormal Temporal Discrimination in Unaffected Relatives of Cervical Dystonia Patients

Background: An abnormal temporal discrimination threshold in cervical dystonia (CD) is considered to be a mediational endophenotype; in unaffected relatives it is hypothesized to indicate non-manifesting gene carriage. The pathogenesis underlying this condition remains unknown. Investigation of the neural networks involved in disordered temporal discrimination may highlight its pathomechanisms.Objective: To examine resting state brain function in unaffected relatives of CD patients with normal and abnormal temporal discrimination. We hypothesized that the endophenotype, an abnormal temporal discrimination, would manifest as altered connectivity in relatives in regions associated with CD, thereby illuminating the neural substrates of the link between temporal discrimination and CD.Methods: Rs-fMRI data was analyzed from two sex- and age-matched cohorts: 16 unaffected relatives of CD patients with normal temporal discrimination and 16 with abnormal temporal discrimination. Regional and whole brain functional connectivity measures were extracted via Independent Component Analysis (ICA), Regional Homogeneity (ReHo), and Amplitude of Low Frequency (ALFF) analyses.Results: Our ICA analysis revealed increased connectivity within both the executive control and cerebellar networks and decreased connectivity within the sensorimotor network in relatives with abnormal temporal discrimination when compared to relatives with normal temporal discrimination. The ReHo and ALFF analyses complimented these results and demonstrated connectivity differences in areas corresponding to motor planning, movement coordination, visual information processing, and eye movements in unaffected relatives with abnormal temporal discrimination.Conclusion: Disordered connectivity in unaffected relatives with abnormal temporal discrimination illuminates neural substrates underlying endophenotype expression and supports the hypothesis that genetically determined aberrant connectivity, when later coupled with unknown environmental triggers, may lead to disease penetrance

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 \u3c 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

A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism

Background: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy‐to‐use clinical screening tool to help recognize movement disorders. Objective: The aim is to develop a user‐friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs. Methods: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter‐rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool. Results: A movement disorder was rated as present in 80% of the patients, with a moderate inter‐rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter‐rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool. Conclusions: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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.Health Research BoardFoundation for Dystonia Research (Belgium

Health-Related Quality of Life Is Severely Affected in Primary Orthostatic Tremor

BackgroundPrimary orthostatic tremor (POT) is a movement disorder characterized by unsteadiness upon standing still due to a tremor affecting the legs. It is a gradually progressive condition with limited treatment options. Impairments in health-related quality of life (HQoL) seem to far exceed the physical disability associated with the condition.MethodsA multi-center, mixed-methodology study was undertaken to investigate 40 consecutive patients presenting with POT to four movement disorder centers in France. HQoL was investigated using eight quantitative scales and a qualitative study which employed semi-structured interviews. Qualitative data were analyzed with a combination of grounded-theory approach.ResultsOur results confirm that HQoL in POT is severely affected. Fear of falling was identified as the main predictor of HQoL. The qualitative arm of our study explored our initial results in greater depth and uncovered themes not identified by the quantitative approach.ConclusionOur results illustrate the huge potential of mixed methodology in identifying issues influencing HQoL in POT. Our work paves the way for enhanced patient care and improved HQoL in POT and is paradigmatic of this modern approach for investigating HQoL issues in chronic neurological disorders

Temporal Discrimination: Mechanisms and Relevance to Adult-Onset Dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test–retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis