Abstract
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.
Highlights
The sensory temporal discrimination threshold (TDT) is defined as the shortest interval at which two sequential sensory stimuli are perceived as asynchronous (Lacruz et al, 1991); stimuli may be visual, tactile, or auditory
Significant between-group differences (FWE corrected p < 0.017) in the spatial distribution of the functional connectivity maps were found in the sensory-motor and the executive control networks (Figures 2a,b)
The results revealed significant differences in connectivity within the cerebellum between subjects with abnormal and normal TDTs; those with abnormal TDTs showed an increase in functional connectivity compared to those with normal TDTs
Summary
The sensory temporal discrimination threshold (TDT) is defined as the shortest interval at which two sequential sensory stimuli are perceived as asynchronous (Lacruz et al, 1991); stimuli may be visual, tactile, or auditory. The precise neural circuitry involved in temporal discrimination remains unknown. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia. 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
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