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Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant...
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Dystonia is the second most common movement disorder next to tremor, but its pathophysiology remains unsettled. Its therapeutic measures include anti-cholingerics and other medications, in addition to botulinum neurotoxin injections, and stereotaxic surgery including deep brain stimulation (DBS), but there still remain a number of patients resistan...
Dystonia pathogenesis remains unclear; however, findings from basic and clinical research suggest the importance of the interaction between the basal ganglia and cerebellum. After the discovery of disynaptic pathways between the two, much attention has been paid to the cerebellum. Basic research using various dystonia rodent models and clinical stu...
Deep brain stimulation is an elective surgical intervention that improves the function and quality of life in children with dystonia and other movement disorders. Both basal ganglia and thalamic nuclei have been found to be relevant targets for treatment of dystonia in children, including the ventral intermediate nucleus of the thalamus, in which s...
Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using deep brain stimulation (DBS) to the internal pallidum.
While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale...
Parkinson’s disease (PD) is associated with abnormal beta oscillations (13-30 Hz) in the basal ganglia and motor cortex (M1). Recent reports show that M1 beta-high gamma (50-200 Hz) phase-amplitude coupling (PAC) is exaggerated in PD and is reduced following acute deep brain stimulation (DBS). Here we analyze invasive M1 electrocorticography record...
Citations
... Similarly, sensorimotor and cerebellar loops have been linked to symptom improvements in DYT by investigations that used comparably causal sources of information (such as lesions) 43,66,67 . The sensorimotor cortex along with its basal ganglia projections 68 but also the cerebellum and cerebello-thalamic pathway 69,70 have been related to dystonic pathophysiology, in the past. ...
The frontal cortex is involved in motor, cognitive, and affective brain functions. In humans, however, neuroanatomy-function mappings are predominantly derived from correlative neuroimaging studies. Hence, exactly which frontal domains causally mediate which function remains largely elusive. Herein, we leverage a strategy that allows for causal inference using invasive neuromodulation. Studying 394 subthalamic deep brain stimulation electrodes in patients suffering from one of four brain disorders, we segregated the frontal cortex into cortical projection sites of modulated circuits by their involvement in specific functions. Modulating projections from sensory and motor cortices in dystonia, from primary motor cortex in Tourette's syndrome, from supplementary motor cortex in Parkinson's disease, and from ventromedial prefrontal, anterior cingulate, dorsolateral prefrontal and orbitofrontal cortices in obsessive-compulsive disorder linked to respective symptom improvements. Our findings showcase the combination of deep brain stimulation and brain connectomics as a tool for causal inference on structure-function mappings within the human brain.
... In the present study, lesion network mapping was applied to investigate the neuroanatomical substrate of RBD. Figure 1 shows the specific experimental process. The specific steps of data analysis refer to previous literature [18,19]. Briefly, the brain lesion of each patient was used as a seed region of interest to calculate the functional connectivity (FC) of the lesion to all brain voxels by calculating the correlated time course between each lesion location and every other brain voxel in a resting-state FC MRI analysis using 1083 healthy subjects' resting-state functional magnetic resonance imaging (fMRI) data from the open access Human Connectome Project (HCP) S1200 data release [20,21]. ...
Objective:
To localize the neuroanatomical substrate of rapid eye movement sleep behavior disorder (RBD) and to investigate the neuroanatomical locational relationship between RBD and α-synucleinopathy neurodegenerative diseases.
Materials and methods:
Using a systematic PubMed search, we identified 19 patients with lesions in different brain regions that caused RBD. First, lesion network mapping was applied to confirm whether the lesion locations causing RBD corresponded to a common brain network. Second, the literature-based RBD lesion network map was validated using neuroimaging findings and locations of brain pathologies at post-mortem in patients with idiopathic RBD (iRBD) who were identified by independent systematic literature search using PubMed. Finally, we assessed the locational relationship between the sites of pathological alterations at the preclinical stage in α-synucleinopathy neurodegenerative diseases and the brain network for RBD.
Results:
The lesion network mapping showed lesions causing RBD to be localized to a common brain network defined by connectivity to the pons (including the locus coeruleus, dorsal raphe nucleus, central superior nucleus, and ventrolateral periaqueductal gray), regardless of the lesion location. The positive regions in the pons were replicated by the neuroimaging findings in an independent group of patients with iRBD and it coincided with the reported pathological alterations at post-mortem in patients with iRBD. Furthermore, all brain pathological sites at preclinical stages (Braak stages 1-2) in Parkinson's disease (PD) and at brainstem Lewy body disease in dementia with Lewy bodies (DLB) were involved in the brain network identified for RBD.
Conclusion:
The brain network defined by connectivity to positive pons regions might be the regulatory network loop inducing RBD in humans. In addition, our results suggested that the underlying cause of high phenoconversion rate from iRBD to neurodegenerative α-synucleinopathy might be pathological changes in the preclinical stage of α-synucleinopathy located at the regulatory network loop of RBD.
... Overall, the evidence observed in the animal studies suggests that to cause CD [57]. Deep brain stimulation targeting the cerebellum or basal ganglia nucleus (e.g., global pallidus internus and subthalamic nucleus) significantly improves the symptoms of dystonia [7,58]. ...
Background:
Post-mortem brain study indicated that cerebellar Purkinje cell (PC) loss might be a pathological finding in patients with inherited and idiopathic cervical dystonia (ICD). The analysis of conventional magnetic resonance imaging (MRI) brain scans has failed to yield support for this finding. Previous studies have identified that iron overload can be the consequence of neuron death.
Objectives:
This study aimed to investigate iron distribution and demonstrate changes in axons in the cerebellum, providing evidence for PC loss in patients with ICD.
Methods:
We recruited 28 patients with ICD (20 females) and 28 age- and sex-matched healthy controls. A spatially unbiased infratentorial template was applied to perform cerebellum optimized quantitative susceptibility mapping (QSM) and diffusion tensor analysis based on MRI. Voxel-wise analysis was performed to assess cerebellar tissue magnetic susceptibility and fractional anisotropy (FA) alterations, and the clinical relevance of these findings was investigated in the patients with ICD.
Results:
Increased susceptibility values revealed by QSM in the right lobule CrusI, CrusII, VIIb, VIIIa, VIIIb, and IX were found in the patients with ICD. Reduced FA value was found almost all across the cerebellum; FA value of the significant clusters within right lobule VIIIa significantly correlated with the motor severity of patients with ICD (r = -0.575, P = 0.002).
Conclusions:
Our study provided evidence for cerebellar iron overload and axonal damage in the patients with ICD, which may indicate PC loss and related axonal changes. These results provided evidence for the neuropathological finding in patients with ICD and further highlighted the cerebellar involvement in the pathophysiology of dystonia.
... Once thought to be a sole disorder of the basal ganglia, research has elucidated dystonia to reflect a "circuitopathy", indicating aberrant networks underpinning the pathophysiology. (7,8) Lesion-identification studies have identified spinal cord, basal ganglia, brainstem, cerebellum, and thalamic regions as most affected in patients with cervical dystonia, (9,10) with the brainstem and cerebellum as the most commonly affected regions in a recent study. (11) All lesion sites have been classified to ascertain connectivity with the cerebellum, (10) and surmounting evidence supports cerebellar involvement in dystonic sensorimotor pathophysiology. ...
... (7,8) Lesion-identification studies have identified spinal cord, basal ganglia, brainstem, cerebellum, and thalamic regions as most affected in patients with cervical dystonia, (9,10) with the brainstem and cerebellum as the most commonly affected regions in a recent study. (11) All lesion sites have been classified to ascertain connectivity with the cerebellum, (10) and surmounting evidence supports cerebellar involvement in dystonic sensorimotor pathophysiology. (7,8,(12)(13)(14) Brain-based imaging markers offer a potential avenue to explore variability in patients with cervical dystonia, in relation to therapeutic DBS outcomes. ...
... When normative structural connectivity was mapped from the surface area showing inwards deflation, probabilistic streamlines connected with cerebellar, subcortical and cortical motor regions, which corroborate a literature-defined network in cervical dystonia. (10,15) Analysis of electric field overlap with cerebellar tracts revealed that the non-decussating DRTT was significantly correlated with clinical outcome. Importantly, differences in clinical outcomes between patient groups appeared to not be driven by the accuracy of electrode placement, further enforcing the need to identify biomarkers beyond surgical accuracy. ...
Background: Cervical dystonia is a movement disorder, characterised by involuntary head and neck muscle contractions. Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment option, motor outcomes can vary even when sufficient targeting accuracy is achieved. Increasing evidence supports a role of brainstem and cerebellum dysfunction in cervical dystonia pathogenesis.
Objective: To determine whether morphometry of brainstem and dentate nuclei, and DBS stimulatory overlap with cerebello-thalamic tracts modelled from normative connectivity, were related to DBS clinical motor outcomes.
Methods: 27 patients with idiopathic cervical dystonia underwent bilateral targeting of the GPi. and were separated into suboptimal and optimal motor outcome groups. Dentate nuclei and brainstem volumes were quantified in association with clinical outcomes. A brainstem shape analysis was conducted and used as a seed to assess connectivity from a normative structural connectome. Patient-specific electrodes were modelled to quantify stimulatory overlap with the GPi and proximity to cerebellothalamic tracts.
Results: GPi implantation accuracy did not significantly differ between groups. Significantly reduced dentate nuclei and brainstem volumes were observed in patients with poorer clinical outcomes. Regional surface shape change of the brainstem was also observed in patients with poorer responses. Fibre tracking from this area intersected cerebellar, pallidal and cortical motor regions. Electrode field intersection with the non-decussating dentatorubrothalamic tract in the right, and in both hemispheres were also positively associated with clinical outcome.
Conclusions: Variability in cerebellar and brainstem morphometry, and stimulation of non-decussating cerebello-thalamic pathways may contribute to the mediation of DBS motor outcomes.
... Regardless of the cause of the lesion, its size or precise location, evidence has accumulated in recent years in favor of the connectome hypothesis whereby the specific network(s) affected by the lesion can predict many of the patient's responses through motor, non-motor, cognitive and behavioral domains 1-23 , leading to lesion-driven disconnectivity analyses 24 . A common computational framework was developed recently 2 , and successfully applied to several conditions and pathologies 3,4,6,7,[9][10][11][12][13][14][15][16][17][18]22,25 . Due to the simplicity of this method to correlate behavioral outcomes with the extent of lesion-driven disconnection, the strategy was referred to as lesion network mapping (LNM). ...
Beyond the characteristics of a brain lesion, such as its etiology, size or location, lesion network mapping (LNM) has shown that similar symptoms after a lesion reflects similar dis-connectivity patterns, thereby linking symptoms to brain networks. Here, we extend LNM by using a multimodal strategy, combining functional and structural networks from 1000 healthy participants in the Human Connectome Project. We apply multimodal LNM to a cohort of 54 stroke patients with the aim of predicting sensorimotor behavior, as assessed through a combination of motor and sensory tests. Results are two-fold. First, multimodal LNM reveals that the functional modality contributes more than the structural one in the prediction of sensorimotor behavior. Second, when looking at each modality individually, the performance of the structural networks strongly depended on whether sensorimotor performance was corrected for lesion size, thereby eliminating the effect that larger lesions generally produce more severe sensorimotor impairment. In contrast, functional networks provided similar performance regardless of whether or not the effect of lesion size was removed. Overall, these results support the extension of LNM to its multimodal form, highlighting the synergistic and additive nature of different types of network modalities, and their corresponding influence on behavioral performance after brain injury.
... Recently, a possible mechanism has been proposed, in which a focal brain lesion causes abnormalities in a network that includes the cerebellum and somatosensory cortex -which are involved in the generation of cervical dystonia. [3] It is possible that amelioration of the dysfunction of the network involved in the development of cervical dystonia does not necessarily require treatment of the bilateral GPi. In the future, examination of such network abnormalities may be a critical factor in determining which side of the brain to operate on, the left or right. ...
Background
Reports on the long-term effects of pallidotomy for cervical dystonia remain scarce.
Case Description
We report a case of cervical dystonia successfully treated by unilateral pallidotomy. The patient was a 29-year-old man without past medical and family history of cervical dystonia. At the age of 28 years, neck rotation to the right with right shoulder elevation developed and gradually became worse. After symptoms failed to respond to repetitive botulinum toxin injections and oral medications, he underwent left pallidotomy, which resulted in significant improvement of cervical dystonia and shoulder elevation without surgical complications. At the 3-month evaluation, the symptoms completely improved. The Toronto Western Spasmodic Torticollis Rating Scale score dramatically improved from 39 points before surgery to 0 points at 7-year postoperative evaluation.
Conclusion
This case suggests that unilateral pallidotomy can be an alternative treatment option for cervical dystonia.
... Several studies have demonstrated loss of inhibition, increased excitability, or abnormal plasticity in dystonia, in cortical regions associated with sensorimotor function including the somatosensory cortex (S1), primary motor cortex (M1), dorsal premotor cortex (dPM), and cerebellum. [15][16][17][18][19][20] However, NIBS to these cortical areas has returned variable results. While previous research has suggested that rTMS and transcranial direct current stimulation (tDCS) provide some relief from symptoms of dystonia, 21 other studies suggest little to no effect on dystonia symptoms in comparison to sham stimulation. ...
... The fact that stimulation of the M1 and dPM and the use of inhibitory NIBS protocols significantly predicted an effect of NIBS on dystonia symptoms is in line with prior research, demonstrating increased excitability in sensorimotor areas including the motor, premotor, and somatosensory cortices in dystonia. [18][19][20] This can be seen through the excessive contraction of both agonist and antagonist muscles in dystonia, leading to unwanted muscle spasms and motor overflow. 87 Thus, the application of inhibitory NIBS protocols to these cortical areas may downregulate cortical and network activity, leading to a reduction in symptoms. ...
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.
... Furthermore, the SMA modulated the process of sensorimotor integration during sensory trick performance and imagination. Sensory trick effect may involve high order sensorimotor processing that are ultimately connected to GPi 23 , and SMA may play a critical role in sensory tricks by engaging with known dystonia network 24 . ...
Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.
... No pathogenetic mechanisms of decreased cognition are known in depressive patients with focal muscular dystonia. Even more, the precise mechanisms of muscular dystonia developing are still unknown-earlier studies described reduced inhibition at the level of the primary motor cortex, brainstem and spinal cord [42], while more recent studies suggest the involvement of the basal ganglia [43]. Certainly there is one possibility, that the same depression mechanisms that induce cognitive decline in the muscular-dystonia-free population are engaged also in focal dystonia patients as independent factors, but there is also another possibility that affected muscular dystonia regions induce cognitive decline on their own, such as in the case of described dementia associated with disorders of the basal ganglia [44]. ...
Background: Cervical dystonia is a highly disabling hyperkinetic movement disorder with a lot of nonmotor symptoms. One symptom with a high prevalence is depression, which may negatively affect dystonia patients. The aim of the study was to investigate the impact of depression on disease severity and cognitive functions in cervical dystonia patients. Methods: Patients with cervical dystonia were interviewed and divided into two groups, based on the Patient Health Questionnaire-9: those with no depression or mild depressive features and those with moderate, moderately severe, and severe depression. The severity of dystonia and cognitive functions were assessed and compared in both groups. Results: A total of 52 patients were investigated. Self-assessment of the disease was more negative in clinically significant depressive signs group (p = 0.004), with a tendency for patients with clinically significant depressive features to have a slightly higher score on objective dystonia scales (TSUI and TWSTRS), but without statistically significant differences (p = 0.387 and p = 0.244, respectively). Although not statistically significant, a slightly higher MoCA scale score was registered in cervical dystonia patients with clinically insignificant depressive signs. There was a tendency for worse results in the abstraction category in patients with clinically significant depression (p = 0.056). Conclusions: Patients with clinically significant depression have a more negative self-assessment of the disease and perform worse in abstraction tasks.
... For dystonia, 46 articles were included, Pan et al., 2019;Jochim et al., 2018;Putzel et al., 2018;Mantel et al., 2018;Ni et al., 2017;Huang et al., 2017;Li et al., 2017;Long et al., 2017;Haslinger et al., 2017;Kiyuna et al., 2017;Battistella et al., 2016;Sarasso et al., 2020;Liu et al., 2016;Ren et al., 2015;Bharath et al., 2015;Dresel et al., 2014;Delnooz et al., 2015;Hinkley et al., 2013;Delnooz et al., 2013;Delnooz et al., 2012;Mohammadi et al., 2012;Wei et al., 2021;Pan et al., 2021;Feng, 2021;de Faria et al., 2020;Norris et al., 2020;Glickman et al., 2020;Mantel et al., 2020;Ma et al., 2021;Corp et al., 2019;Fang et al., 2021;Giannì et al., 2022;Qin et al., 2019;Zito et al., 2022;Kim et al., 2022;Hou et al., 2022;Ekmen et al., 2022;Nieuwhof et al., 2022;Filip et al., 2022;Battistella and Simonyan, 2019;Bianchi et al., 2019;Kita et al., 2018;Fuertinger and Simonyan, 2018;Qin et al., 2018) concerning cervical dystonia (CD; n = 14), writer's cramp (n = 10), laryngeal dystonia (n = 8), musician's dystonia (n = 5), paroxysmal kinesigenic dyskinesia (n = 6), blepharospasm (n = 6), oromandibular dystonia (n = 2), dyskinetic cerebral palsy (n = 2), spastic cerebral palsy (n = 1), dystonic tremor (n = 1), and generalized dystonia (n = 1). Most studies matched patients and healthy participants for age and gender. ...
Background
Hyperkinetic movement disorders (HMD) manifest as abnormal and uncontrollable movements. Despite reported involvement of several neural circuits, exact connectivity profiles remain elusive.
Objectives
Providing a comprehensive literature review of resting-state brain connectivity alterations using resting-state fMRI (rs-fMRI). We additionally discuss alterations from the perspective of brain networks, as well as correlations between connectivity and clinical measures.
Methods
A systematic review was performed according to PRISMA guidelines and searching PubMed until October 2022. Rs-fMRI studies addressing ataxia, chorea, dystonia, myoclonus, tics, tremor, and functional movement disorders (FMD) were included. The standardized mean difference was used to summarize findings per region in the Automated Anatomical Labeling atlas for each phenotype. Furthermore, the activation likelihood estimation meta-analytic method was used to analyze convergence of significant between-group differences per phenotype. Finally, we conducted hierarchical cluster analysis to provide additional insights into commonalities and differences across HMD phenotypes.
Results
Most articles concerned tremor (51), followed by dystonia (46), tics (19), chorea (12), myoclonus (11), FMD (11), and ataxia (8). Altered resting-state connectivity was found in several brain regions: in ataxia mainly cerebellar areas; for chorea, the caudate nucleus; for dystonia, sensorimotor and basal ganglia regions; for myoclonus, the thalamus and cingulate cortex; in tics, the basal ganglia, cerebellum, insula, and frontal cortex; for tremor, the cerebello-thalamo-cortical circuit; finally, in FMD, frontal, parietal, and cerebellar regions. Both decreased and increased connectivity were found for all HMD. Significant spatial convergence was found for dystonia, FMD, myoclonus, and tremor. Correlations between clinical measures and resting-state connectivity were frequently described.
Conclusion
Key brain regions contributing to functional connectivity changes across HMD often overlap. Possible increases and decreases of functional connections of a specific region emphasize that HMD should be viewed as a network disorder. Despite the complex interplay of physiological and methodological factors, this review serves to gain insight in brain connectivity profiles across HMD phenotypes.
