Neuromodulation in Dystonia - Harnessing the Network.

Adult-onset isolated focal dystonia (AOIFD) is a network disorder characterised by abnormalities of sensory processing and motor control. These network abnormalities give rise to both the phenomenology of dystonia and the epiphenomena of altered plasticity and loss of intracortical inhibition. Existing modalities of deep brain stimulation effectively modulate parts of this network but are limited both in terms of targets and invasiveness. Novel approaches using a variety of non-invasive neuromodulation techniques including transcranial stimulation and peripheral stimulation present an interesting alternative approach and may, in conjunction with rehabilitative strategies, have a role in tailored therapies targeting the underlying network abnormality behind AOIFD.

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.

Characterizing Brain Network Topology in Cervical Dystonia Patients and Unaffected Relatives via Graph Theory.

Cervical Dystonia (CD) is a neurological movement disorder characterized by intermittent muscle contractions in the head and neck. The pathophysiology and neural networks underpinning this condition are incompletely understood. There is increasing evidence that isolated focal dystonias are due to network-wide functional alterations. An abnormal temporal discrimination threshold (TDT) is believed to be a mediational endophenotype due to its prevalence in unaffected first-degree relatives as well as patients. However the neural correlates linking abnormal TDT and CD remain poorly understood. Probing changes in large-scale network topology via graph theory with resting state fMRI data from relatives and patients may provide further insight into the pathophysiology of CD. In this study, resting state fMRI data were acquired and analyzed from 16 CD patients with abnormal TDT, 32 unaffected first degree relatives (16 with normal TDT and 16 with abnormal TDT) and 16 healthy controls. Graph theory metrics demonstrating network topology were extracted. The results indicate large-scale functional reorganization of networks in relatives (with abnormal TDT) along with a manifestation of topological aberrations similar to patients.

A Study of the Midbrain Network for Covert Attentional Orienting in Cervical Dystonia Patients using Dynamic Causal Modelling.

Understanding the neuronal network dynamics underlying the third most common movement disorder, cervical dystonia, can be achieved using dynamic causal modelling. Current literature establishes structures of the midbrain network for covert attentional orienting as dysfunctional in patients with cervical dystonia. One of these structures is the superior colliculus, for which it is hypothesised that deficient GABAergic activity therein causes cervical dystonia. To understand the role that this node plays in cervical dystonia, various connectivity models of the midbrain network were compared under the influence of a loom-recede visual stimulus fMRI paradigm. These models included the thalamus and striatum, crucial nodes in the direct/indirect pathways for motor movement and inhibition. The parametric empirical Bayes approach was used to quantify the difference in connection strengths across the winning models between patients and controls. Our findings demonstrated greater modulation by a looming stimulus event on the strength of connection from the striatum to the superior colliculus in patients. These results offer new means to understanding the pathophysiology of cervical dystonia.

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.

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.