Temporal Discrimination Threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia

Abstract

Familial adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary torsion dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary torsion dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary torsion dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary torsion dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary torsion dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary torsion dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder.

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.…”

Advances in Our Understanding of Dystonia - Pathophysiology and Treatment Options

“…38,39 Studies of sensory processing in dystonia patients using spatial discrimination thresholds (SDT) or temporal discrimination thresholds (TDT) (tests of discrimination between two close-interval sensory stimuli) have found abnormal SDTs and TDTs in patients with adult-onset sporadic primary dystonia and in their unaffected relatives. 40,41 Notably, a recent study comparing SDT and TDT as potential endophenotypes found that TDT was a much more reliable measurement. 42 'Double pulse' repetitive transmagnetic stimulation (rTMS) studies have demonstrated evidence of decreased cortical inhibition and increased excitability in various forms of dystonia, including in both DYT1 dystonia patients and DYT1 non-manifesting carriers, 43 and in the hand motor cortex in both focal hand dystonia patients as well as in patients with blephorospasm.…”

Advances in Our Understanding of Dystonia—Pathophysiology and Treatment Options

“…38,39 Studies of sensory processing in dystonia patients using spatial discrimination thresholds (SDT) or temporal discrimination thresholds (TDT) (tests of discrimination between two close-interval sensory stimuli) have found abnormal SDTs and TDTs in patients with adult-onset sporadic primary dystonia and in their unaffected relatives. 40,41 Notably, a recent study comparing SDT and TDT as potential endophenotypes found that TDT was a much more reliable measurement. 42 'Double pulse' repetitive transmagnetic stimulation (rTMS) studies have demonstrated evidence of decreased cortical inhibition and increased excitability in various forms of dystonia, including in both DYT1 dystonia patients and DYT1 non-manifesting carriers, 43 and in the hand motor cortex in both focal hand dystonia patients as well as in patients with blephorospasm.…”