Cause of Common, Incurable Movement Disorder Pinpointed?

Batya Swift Yasgur, MA, LSW

July 26, 2019

A new brain mapping technique is providing fresh insight into a common, incurable — but relatively unknown — movement disorder that shares some similarities with Parkinson's disease (PD).

It is thought that lesions in a single brain region cause cervical dystonia (CD), but this new research shows there is actually a network of lesions located in multiple areas of the brain.

"There is currently no cure for cervical dystonia, and symptoms can be debilitating for sufferers, so if we can localize the parts of the brain that cause symptoms, we can then try to treat these brain regions and relieve the patient's symptoms," lead investigator Daniel Corp, PhD, a lecturer at the School of Psychology, Deakin University, Victoria, Australia, told Medscape Medical News.

The study was published online June 1 in the journal Brain.

Network Mapping

CD is a chronic neurologic disorder characterized by sustained and involuntary contractions of the neck muscles. It is the most common form of focal dystonia and "has traditionally been ascribed to dysfunction of the basal ganglia," the authors note.

However, previous research has shown there are abnormalities in many other areas of the brains of CD patients, suggesting it is a "network disorder" resulting from dysfunction of yet unidentified brain regions.

Symptoms can emerge not only from a single lesion but also from the effect of the lesion on remote but connected brain regions. However, nodes of this possible network remain "unclear."

To investigate, the researchers used lesion network mapping, "which can link lesions in different locations to a common brain network," they write.

Instead of focusing exclusively on lesion location, the technique uses a database of normative resting state functional magnetic resonance imaging (fMRI) scans to identify the network of brain regions connected to each lesion location.

"We used a novel neuroimaging technique called lesion network mapping to identify two specific parts of the brain we think are involved in cervical dystonia — the cerebellum and the sensory cortex," said Corp.

The researchers also investigated whether the neuroanatomical substrate of CD derived from focal brain lesions is also abnormal in patients with similar symptoms but without brain lesions.

Investigators identified cases of causal CD lesions by searching published literature. Inclusion criteria consisted of neurologic examination documenting CD suspected to be caused by an intraparenchymal brain lesion and a figure or image showing lesion location that could be traced onto a standard brain atlas, the authors report.

Networks of regions functionally connected to each lesion were identified and mapped through a series of complex procedures, culminating in the creation of a network map.

To test for specificity, the results of the mapping were compared to two "control" datasets of lesions not related to CD.

Regions of interest that emerged from the analyses, particularly the specificity tests, were the cerebellar and somatosensory regions, which were then tested to determine whether these regions — identified based on brain lesions — were also abnormal in idiopathic CD.

Two-Hit Model

The researchers identified 25 cases of lesion-induced CD in several different brain locations, including the cerebellum (n = 11), brainstem (n = 9), basal ganglia (n = 8), thalamus (n = 1), and occipital lobe (n = 1). Some patients had lesions in multiple locations.

Despite heterogeneity in lesion locations, the researchers found all lesions causing CD were part of a single, functionally connected brain network. That is, all lesion locations were positively correlated to the cerebellar vermis, dentate nucleus, cerebellar cortex, and midbrain, with more than 90% of lesion locations functionally connected to the thalamus and globus pallidus.

All lesion locations were also functionally connected, but negatively correlated, to the right somatosensory cortex.

Connectivity to the cerebellum and somatosensory cortex was specific to CD-causing lesion locations, compared with control lesion locations.

Cerebellum region of interest connectivity was a strong independent predictor of CD (P = .002), although the somatosensory cortex region of interest connectivity "fell just short" of the statistical threshold for independence (P = .051).

The cerebellar and somatosensory regions of interest were used as "seed regions" to test whether these same regions were abnormal in patients with idiopathic CD (n = 39) vs control subjects (n = 37).

The seed region of interest in the cerebellum showed abnormal connectivity to regions in the lateral sensorimotor cortex and operculum, whereas the seed region of interest in the somatosensory cortex showed abnormal connectivity to regions in the basal ganglia, thalamus, anterior cingulate, occipital cortex, and sensorimotor cortex.

Each abnormality involved a loss of normal negative or positive connectivity and showed greater abnormalities in idiopathic CD than in 19 control regions of interest derived from lesions causing other neurologic symptoms.

The cerebellar regions of interest turned out to be positively connected to sites associated with "good" clinical response to deep brain stimulation (DBS) in patients with dystonia in general (P < .001) and patients with CD (P < .001) in particular.

They also turned out be significantly more connected to DBS sites associated with good (vs "poor") clinical response (P = .002).

Conversely, the somatosensory region of interest was negatively connected with the optimal DBS site for treating dystonia in general (P < .001) and CD in particular (P < .001).

The somatosensory region was also significantly more negatively connected to DBS sites associated with good clinical responses (P < .001).

The authors described the involvement of two distinct brain regions as a "two-hit model" combining dysfunction of the cerebellum and the somatosensory cortex.

"Now that we have identified two specific brain regions that we believe are firing abnormally, we can begin trials to target these regions through methods such as noninvasive brain stimulation, which we hope will alleviate dystonia symptoms," Corp said in a press release.

Highway With Potholes

Commenting on the study for Medscape Medical News, David E. Vaillancourt, PhD, chair and professor of applied physiology and kinesiology, College of Health and Human Performance, University of Florida, Gainesville, said finding consistent structural lesions in CD "has been tough going" because, as shown by this paper, the lesions can occur across a network of connected brain regions.

Vaillancourt, who was not associated with the study, likened this to "a highway that can have potholes in many parts of the highway between 2 connected cities, all associated with a similar outcome."

The take-home message "is that CD seems to associate with lesions along a connected network of brain regions, rather than in one specific brain region, suggesting that altering different parts of the network could help these patients," he said.

The study was supported by the Dorothy Feiss Dystonia Research Fund and the Dystonia Medical Research Foundation. Corp was supported by a Victoria Fellowship awarded by the Veski Foundation. The other authors' sources of funding are listed on the original paper. The authors and Vaillancourt have disclosed no relevant financial relationships.

Brain. Published online June 1, 2019. Abstract

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