The functional anatomy of dystonia: Recent developments.

While dystonia has traditionally been viewed as a disorder of the basal ganglia, the involvement of other key brain structures is now accepted. However, just what these structures are remains to be defined. Neuroimaging has been an especially valuable tool in dystonia, yet traditional cross-sectional designs have not been able to separate causal from compensatory brain activity. Therefore, this chapter discusses recent studies using causal brain lesions, and animal models, to converge upon the brain regions responsible for dystonia with increasing precision. This evidence strongly implicates the basal ganglia, thalamus, brainstem, cerebellum, and somatosensory cortex, yet shows that different types of dystonia involve different nodes of this brain network. Nearly all of these nodes fall within the recently identified two-way networks connecting the basal ganglia and cerebellum, suggesting dysfunction of these specific pathways. Localisation of the functional anatomy of dystonia has strong implications for targeted treatment options, such as deep brain stimulation, and non-invasive brain stimulation.

Large-scale activation likelihood estimation meta-analysis of parkinsonian disorders.

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Neuroimaging studies have yielded insights into parkinsonian disorders; however, due to variability in results, the brain regions consistently implicated in these disorders remain to be characterized. The aim of this meta-analysis was to identify consistent brain abnormalities in individual parkinsonian disorders (Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy) and to investigate any shared abnormalities across disorders. A total of 44 591 studies were systematically screened following searches of two databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 132 neuroimaging studies (69 Parkinson's disease; 23 progressive supranuclear palsy; 17 corticobasal syndrome; and 23 multiple system atrophy) utilizing anatomical MRI, perfusion or metabolism PET and single-photon emission computed tomography. Meta-analyses were performed in each parkinsonian disorder within each imaging modality, as well as across all included disorders. Results in progressive supranuclear palsy and multiple system atrophy aligned with current imaging markers for diagnosis, encompassing the midbrain, and brainstem and putamen, respectively. PET imaging studies of patients with Parkinson's disease most consistently reported abnormality of the middle temporal gyrus. No significant clusters were identified in corticobasal syndrome. When examining abnormalities shared across all four disorders, the caudate was consistently reported in MRI studies, whilst the thalamus, inferior frontal gyrus and middle temporal gyri were commonly implicated by PET. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders and the first to characterize brain regions implicated across parkinsonian disorders.

Mapping a network for tics in Tourette syndrome using causal lesions and structural alterations.

Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.

Effects of non-invasive brain stimulation in dystonia: a systematic review and meta-analysis.

Background: Deep brain stimulation is a highly effective treatment of dystonia but is invasive and associated with risks, such as intraoperative bleeding and infections. Previous research has used non-invasive brain stimulation (NIBS) in an attempt to alleviate symptoms of dystonia. The results of these studies, however, have been variable, leaving efficacy unclear. Objectives: This study aimed to evaluate the effects of NIBS on symptoms of dystonia and determine whether methodological characteristics are associated with variability in effect size. Methods: Web of Science, Embase, and MEDLINE Complete databases were searched for articles using any type of NIBS as an intervention in dystonia patients, with changes in dystonia symptoms the primary outcome of interest. Results: Meta-analysis of 27 studies demonstrated a small effect size for NIBS in reducing symptoms of dystonia (random-effects Hedges' g = 0.21, p = .002). Differences in the type of NIBS, type of dystonia, and brain region stimulated had a significant effect on dystonia symptoms. Meta-regression revealed that 10 sessions of active stimulation and the application of concurrent motor training programs resulted in significantly larger mean effect sizes. Conclusion: NIBS has yielded small improvements to dystonic symptoms, but effect sizes depended on methodological characteristics, with more sessions of stimulation producing a larger response. Future research should further investigate the application of NIBS parallel to motor training, in addition to providing a greater quantity of sessions, to help define optimal parameters for NIBS protocols in dystonia. Registration: PROSPERO 2020, CRD42020175944.

Clinical and Structural Findings in Patients With Lesion-Induced Dystonia: Descriptive and Quantitative Analysis of Published Cases.

BACKGROUND AND OBJECTIVES: Brain lesions are a well-recognized etiology of dystonia. These cases are especially valuable because they offer causal insight into the neuroanatomical substrates of dystonia. To date, knowledge of lesion-induced dystonia comes mainly from isolated case reports or small case series, restricting broader description and analysis. METHODS: Cases of lesion-induced dystonia were first identified from a systematic review of published literature. Latent class analysis then investigated whether patients could be classified into subgroups based on lesion location and body regions affected by dystonia. Regression analyses subsequently investigated whether subgroup membership predicted clinical characteristics of dystonia. RESULTS: Three hundred fifty-nine published cases were included. Lesions causing dystonia occurred in heterogeneous locations, most commonly in the basal ganglia (46.2%), followed by the thalamus (28.1%), brainstem (22.6%), and white matter (21.2%). The most common form of lesion-induced dystonia was focal dystonia (53.2%), with the hand (49.9%) and arm (44.3%) most commonly affected. Of all cases, 86.6% reported co-occurring neurologic manifestations and 26.1% reported other movement disorders. Latent class analysis identified 3 distinct subgroups of patients: those with predominantly limb dystonias, which were associated with basal ganglia lesions; those with hand dystonia, associated with thalamic lesions; and those with predominantly cervical dystonia, associated with brainstem and cerebellar lesions. Regression demonstrated significant differences between these subgroups on a range of dystonia symptoms, including dystonic tremor, symptom latency, other movement disorders, and dystonia variability. DISCUSSION: Although dystonia can be induced by lesions to numerous brain regions, there are distinct relationships between lesion locations and dystonic body parts. This suggests that the affected brain networks are different between types of dystonia.