Temporal discrimination, a cervical dystonia endophenotype: Penetrance and functional correlates

Abstract

The pathogenesis of adult-onset primary dystonia remains poorly understood. There is variable age-related and gender-related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)-the shortest time interval at which two separate stimuli can be detected as being asynchronous-is abnormal both in patients with cervical dystonia and in their unaffected first-degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activation positively correlates with the ease of temporal discrimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age-related and gender-related penetrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first-degree relatives of 84 patients with cervical dystonia. In 24 unaffected first-degree relatives, fMRI scanning was performed during a temporal discrimination task. The prevalence of abnormal TDTs in unaffected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endophenotype was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits.

Sensory-motor integration in focal dystonia

“…This hypothesis is mainly supported by the observation that deficits in somatosensory SDT and TDT are present also in some patients' unaffected relatives, who could carry a mutated known (e.g. DYT1; or unknown gene Kimmich et al, 2014;O'Dwyer et al, 2005;. In this regard, however, a distinction should be made between spatial and temporal discrimination abnormalities.…”

“…In this regard, however, a distinction should be made between spatial and temporal discrimination abnormalities. For instance, treatment of cervical dystonia with botulinum toxin improves spatial discrimination , suggesting that spatial Higher TDT in different forms of dystonia than in healthy controls Higher TDT also in unaffected DYT1-carriers and relatives of adult-onset dystonia patients TDT does not improve with botulinum toxin or with pallidal stimulation Aglioti et al, 2003Bradley et al, 2009Fiorio et al, 2003Kimmich et al, 2014Sadnicka et al, 2013Sanger et al, 2001Scontrini et al, 2009Tinazzi et al, 1999 Fiorio et al, 2006 Temporal prediction of movements Focal hand Cervical Temporal prediction of a movement performed by a human body segment (i.e., hand writing a sentence) is impaired in dystonia Avanzino et al, 2013Martino et al, 2015 Sensory-motor integration Grip-force adjustments Focal hand Impaired visuomotor tracking control and force-matching performance in both hands Increased grip force in patients than controls with stronger modulation in the affected than unaffected hand Bleton et al, 2014Odergren et al, 1996Serrien et al, 2000 Reaching movements Focal hand Cervical Impaired upper limb trajectories toward a target Inzelberg et al, 1995Marinelli et al, 2011Pelosin et al, 2009 SDT¼ spatial discrimination threshold; TDT¼ temporal discrimination threshold; TVR ¼ tonic vibration reflex; RHI ¼rubber hand illusion.…”

Endophenotyping in idiopathic adult onset cervical dystonia

“…(Bradley et al, 2009;Scontrini et al, 2009;Tinazzi et al, 2004;Kimmich et al, 2014;Kagi et al, 2013) 5 out of 14 (36%) non-affected 1 st degree relatives had abnormal visuotactile temporal discrimination thresholds. Considering that only 50% of 1 st degree relatives are expected to be gene mutation carriers, the finding supports previous reports that subtle sensory abnormalities represent a trait or endophenotype of gene mutation carriage.…”

“…The fact that the latter research group found the largest differences in the visual and tactile compared to mixed (visuo-tactile) paradigm is intriguing and hard to explain. (Bradley et al, 2009;Kimmich et al, 2014) (Tinazzi et al, 2002)patients with IAOCD multimodal (visuo-tactile) temporal discrimination might be more affected compared to the unimodal temporal discrimination; i) the parietal lobe as an important center of multimodal sensory integration is part of the dystonia network (Lacruz et al, 1991;Leon and Shadlen, 2003;Neychev et al, 2011;Pastor et al, 2004), ii) this notion receives support by the finding that patients with a good effect to a sensory trick perform significantly better in the visuo-tactile sensory discrimination and that the parietal lobe is activated while performing an effective sensory trick (Kagi et al, 2013;Naumann et al, 2000), iii) the superior colliculi, where multisensory (visual, tactile, auditory) inputs converge are involved in head-turn generation with its cephalomotor premotor neurons (Hutchinson et al, 2014).…”

“…Compared to controls, both, manifesting and non-manifesting DYT1 gene mutation carriers share common features like deficient inhibition on a cortical level, (Edwards et al, 2003) impaired sensory temporal processing, (Fiorio et al, 2007a) and impaired body movement representation in the mental rotation task. (Fiorio et al, 2008) Several of these characteristics can also be found in patients with cervical dystonia: i) sensory discrimination: studies have shown that spatial (Molloy et al, 2003;O'Dwyer et al, 2005;Walsh et al, 2007) and temporal sensory discrimination (Bradley et al, 2009;Scontrini et al, 2009;Tinazzi et al, 2004;Kimmich et al, 2014) is impaired in patients with cervical dystonia with the latter being more discriminative. (Bradley et al, 2009;Bradley et al, 2010;Walsh et al, 2007) Impaired sensory discrimination has been found in 1 st degree relatives of patients with cervical dystonia (Bradley et al, 2009;Walsh et al, 2007;Kimmich et al, 2014) ii) impaired inhibition: Impaired intracortical inhibition using transcranial magnetic stimulation is present in both hemispheres (ipsi-and contralateral to the dystonic hand) suggesting that this abnormality is likely to be a substrate or trait for dystonia.…”