Next Article in Journal
Experimental Approaches for Testing the Hypothesis of the Emergence of Life at Submarine Alkaline Vents
Next Article in Special Issue
Classification of Dystonia
Previous Article in Journal
Biochemical Correlates of Video Game Use: From Physiology to Pathology. A Narrative Review
Previous Article in Special Issue
Psychological Traits and Behavioural Influences in Patients with Dystonia—An Observational Cohort Study in a Romanian Neurology Department
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Dystonia and Cerebellum: From Bench to Bedside

1
Department of Advanced Brain Research, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima 770-8501, Japan
2
Department of Neurosurgery, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima 770-8501, Japan
3
Department of Neurology, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima 770-8501, Japan
*
Author to whom correspondence should be addressed.
Life 2021, 11(8), 776; https://doi.org/10.3390/life11080776
Submission received: 3 June 2021 / Revised: 20 July 2021 / Accepted: 29 July 2021 / Published: 31 July 2021
(This article belongs to the Special Issue Dystonia and Related Disorders: From Bench to Bedside)

Abstract

:
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 studies in dystonia patients continues to provide new pieces of knowledge regarding the role of the cerebellum in dystonia genesis. Herein, we review basic and clinical articles related to dystonia focusing on the cerebellum, and clarify the current understanding of the role of the cerebellum in dystonia pathogenesis. Given the recent evidence providing new hypotheses regarding dystonia pathogenesis, we discuss how the current evidence answers the unsolved clinical questions.

1. Introduction

Dystonia is a clinical syndrome characterized by patterned, directional, sustained, or intermittent muscle contractions that cause abnormal dystonic postures and repetitive twisting dystonic movements [1,2,3,4]. The striking efficacy of pallidal deep brain stimulation suggests the involvement of the cortico-basal ganglia-thalamo-cortical feedback loop in its pathogenesis [5,6]. However, growing evidence extracted from basic and clinical research has additionally elucidated the importance of the cerebellum [5], suggesting that dystonia may arise from a motor network dysfunction, including both the basal ganglia and the cerebellum [7,8]. In this review, we collected research focusing on the relationship between “the cerebellum” and “dystonia”, trying to extract plausible answers to some of the unresolved clinical questions related to dystonia and aiming to gain a better understanding of its pathogenesis.

2. Neuroanatomical Consideration: Interaction between Basal Ganglia and the Cerebellum

Traditionally, the cortico-basal ganglia-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops are considered to be segregated, wherein the interaction between two loops occurs on thalamic relay neuron overlapping [9]. Currently, more direct communication between these two loops is considered to play a critical role in dystonia genesis [5].
The cerebellum can be grossly divided into three sagittal areas, which include the middle portion “vermin” or “vermal zone”, portions lateral to the vermis “the paravermis” or “the intermediate cortex”, and the most lateral parts “hemisphere” or “the lateral cortex” [10,11]. Purkinje cells, the only cerebellar cortex output elements, relay cerebellar cortex information on downstream deep cerebellar nuclei via GABAergic synaptic transmission. The cerebellum has four deep cerebellar nuclei, which lie on each side of the cerebellar midline. From medial to lateral, they are the fastigial, interposed (emboliform and globose), and dentate nuclei [12], which are targeted by the vermis, paravermis, and hemisphere, respectively [11,13]. These nuclei directly project to the thalamus, vestibular nuclei, inferior olive, red nucleus, locus coeruleus, anterior pretectal nucleus, and zona incerta [12,14]. Via the ventrolateral thalamus, these nuclei then connect to the frontal and parietal cortices, including the primary motor, prearcuate, premotor, and supplementary motor areas [13].
The cerebellum contributes to a feedforward system, which controls fast-coordinated movements [15]. Specifically, motor commands from the primary motor cortex to the spinal cord are copied and sent to the deep cerebellar nuclei, wherein the inferior olive nucleus receives predicted future outcome signals from the cerebellar nuclei [15]. The dentate nucleus receives input from the lateral cerebellar hemisphere; exerts a tonic facilitatory influence on downstream structures, controlling multi-joint fast movements [16], and is involved in planning, initiating, modifying voluntary movements, higher-level cognition, and sensory processing [17]. Meanwhile, the interposed and fastigial nuclei, situated in the spinocerebellum, are responsible for agonist–antagonist synergy (posture and gait), stretch reflexes, muscle tone, and slow single-joint movements [11,16]. The fastigial nuclei, especially the rostral division, are related to axial and proximal motor functions and encode the motion of the head and body in space [18,19,20,21].
The deep cerebellar nuclei have also been found to have a polysynaptic short-latency connection to the basal ganglia in rodents and non-human primates [22,23,24,25]. Dentate nucleus stimulation in cats evoked either bilateral caudate nucleus excitation or inhibition via the thalamic intralaminar nuclei [26]. Activation of the thalamic intralaminar centrolateral nucleus specifically induces metabolic contralateral deep cerebellar nuclei activation, and deactivation of the same nucleus elicits metabolic depression in the bilateral cerebellum (cortex and deep cerebellar nuclei) and basal ganglia [27] in rats, which implies functional connections. These nuclei also receive projections from the dorsal raphe nuclei serotonin neurons [28].
A study using retrograde tracing viruses in the monkey brain suggested that neurons in the dentate, interposed, and fastigial nuclei project mainly to D2-type medium spiny neurons in the putamen via the central lateral thalamic nuclei [22]. Other studies using antero- or retrograde tracing viruses in the rodent brain supported the notion that the cerebellar nuclei neurons project to D2-type medium spiny neurons in the dorsolateral striatum via the intralaminar or central lateral thalamic nuclei [23,29]. The intralaminar thalamic nuclei also have stronger innervation to striatal cholinergic and parvalbumin interneurons than cortices [30,31,32,33,34,35]. Furthermore, neurons in the non-human primate subthalamic nucleus (STN) have been found to have disynaptic innervation to the cerebellar cortex via the pontine nuclei or pedunculopontine nucleus, which is less prominent in rodents [24,36,37,38,39]. The red nucleus and zona incerta/field of Forel receive input from both the basal ganglia (entopeduncular nucleus, homologous to the primate globus pallidus interna) and cerebellum, which may integrate them [14,40,41]. In humans, a diffusion tractography study also delineated connections from the dentate nucleus to the basal ganglia, as well as from the subthalamic nucleus to the cerebellar cortex, as suggested by animal studies [42].
Somatotopic mapping is common throughout the cerebellum, including deep cerebellar nuclei, wherein the head is caudal, the tail rostral, the trunk lateral, and the extremities are medial [43]. The deep cerebellar nuclei projections innervate the premotor and motor cortices mainly through the ventrolateral thalamus [44,45,46,47], which comprises the ventral oral nucleus (Vo) and ventral intermediate nucleus (Vim). In particular, the ventrolateral thalamus has two subcortical afferent territories: the pallidothalamic and cerebellothalamic territories [48,49,50,51]. The pallidothalamic territory density decreases in an anterior (Vo side) to posterior (Vim side) gradient, whereas the cerebellothalamic territory density decreases in a posterior (Vim) to anterior (Vo) gradient [52]. Although the basal ganglia influence on supplementary motor areas is significantly greater than that of the cerebellum [53], cerebellar connectivity reduction induces a loss of inhibition in the sensorimotor and supplementary motor cortices [54]. Moreover, the cerebellum plays a role in proprioceptive information to M1 for sensing spatio-temporal aspects, which become deranged in dystonia [5,55]. Given that multiple structures, including the basal ganglia, cerebellum, thalamus, and sensorimotor cortex are disinhibited in dystonia [5], both the cortico-basal ganglia-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops seem to play critical roles in the pathogenesis of dystonia.
Neurons in mice deep cerebellar nuclei exert functional disynaptic innervation to the striatum via dopaminergic neurons in the ventral tegmental area [25]. The dopaminergic neurons in the ventral tegmental area innervate the nucleus accumbens and dorsal striatum [25,56,57]. Functionally, it is unclear whether neurons in deep cerebellar nuclei can directly modulate motor control via dopaminergic neurons in this area. Given that dopamine neurons in the substantia nigra compacta are primarily associated with motor function [58] and that the ventral tegmental area receives relatively little input from deep cerebellar nuclei [57,59], the cerebellum-ventral tegmental area-striatal pathway seems to have only a small contribution to basic motor control. In contrast, GABAergic neurons in the tail of the ventral tegmental area send inhibitory input to the dopaminergic neurons in the substantia nigra compacta, which may modulate motor function more efficiently [60]. Given that both dopaminergic and GABAergic neurons in the ventral tegmental area receive cerebellar afferents [25], cerebellar outputs may affect motor control via GABAergic neurons in the tail of the ventral tegmental area.
The brain loop consists of a continuous divergent-reconvergent architecture [61]. The anatomical hub structures should be a common reconvergent portion of the different loops. The primary hub structure of the two aforementioned loops is the thalamus. When we consider the third loop between the dopaminergic neurons in the substantia nigra compacta and striosome compartment in the striatum, the striatal interneurons could integrate the information from this loop and the thalamus.

3. Research Regarding the Role of the Cerebellum in Dystonia Genesis

3.1. Evidence from Animal Models of Dystonia

Morphological cerebellar abnormalities have been reported in rodent models of dystonia, such as dt rat, tottering mouse, leaner mouse, and Wriggle mouse Sagami [62,63,64,65,66]. Torsin A knockdown, for one, which targets the cerebellum but not the basal ganglia, induced dystonia in a mouse model of DYT1 [67]. Abnormalities in a restricted number of Purkinje cells were also found to be sufficient to cause generalized dystonia and more limited cerebellar regions of dysfunction-induced focal dystonia in mice [68]. Abnormal cerebellar activation was also evident in several different genetic rodent models of dystonia, including both transgenic and knockin DYT1 mice, dystonic (dt) rats, and tottering mice [8,68,69,70,71,72,73,74,75,76,77,78,79,80,81]. In addition, abnormal bursting of cerebellar Purkinje cells or neurons in the deep cerebellar nuclei was identified in rodent models of dystonia and pharmacological models of rapid-onset dystonia-parkinsonism [23,67,77,78,79,82], in which this abnormal cerebellar output drives abnormal high-frequency burst firing in the dorsolateral striatum [23]. Thus, eliminating cerebellar output reduces dystonic symptoms in these animals [8,23,28,74,75,83]. Additionally, abnormal cerebellar activation via the AMPA receptor agonists induces generalized dystonia in normal mice [84,85,86].
Notably, genetic silencing of the glutamatergic output of mice olivocerebellar fibers induces severe dystonia [87]. In contrast, 130-Hz inhibitory stimulation of bilateral interposed nuclei or centrolateral thalamic nuclei immediately abolished dystonia. Similarly, the dorsal raphe nuclei project 5HT-2A serotonergic fibers into the fastigial nucleus, and optogenetic photostimulation of this connection induces dystonia [28]. Thus, optogenetic photoinhibition of this connection or shRNA-mediated knockdown of the ht2ar gene in the fastigial nucleus was found to abolish dystonia in tottering mice [28]. These results might also explain the relationship between dystonia and stress.
Animal models of dystonia support the notion that cerebellar abnormalities, especially the hyperactivity of the cerebellar output, largely contribute to the genesis of dystonia. The clinical heterogeneity of dystonia suggests the involvement of multiple network malfunctions, and the cerebellum might be one of the key structures responsible for this heterogeneity.

3.2. Evidence from Clinical Research in Patients with Dystonia

In humans, dystonia has been reported in patients with cerebellar tumors, infarction, or spinocerebellar ataxia [88,89,90,91,92,93,94,95,96,97]. Dystonia patients with cerebellar atrophy have also been reported [98,99,100,101,102]. These overlapping phenomena of predominant dystonia and ataxia are called “predominant dystonia with marked cerebellar atrophy” or “slowly progressive cerebellar ataxia and cervical dystonia” [98,99,101]. Autopsy of cervical or generalized dystonia cases showed cerebellar abnormalities, including patchy loss [99,103], heterotopic existence, and dendritic swellings [104] of Purkinje cells. In contrast, a systemic review showed that up to 19% of patients with spinocerebellar ataxia (SCA) experienced dystonia during the overall disease course [105]. Dystonia is a relatively common manifestation of SCA2, 3, and 17 [106]. Approximately, 9–18.1% of SCA2, 24.2–24.6% of SCA3, and 52.7% of SCA17 patients manifest dystonia [105,107,108].
Cerebellar involvement in dystonia pathogenesis has been implicated in several imaging studies [62,109,110,111]. Morphologically, increased gray matter density has been observed bilaterally in the cerebellar flocculus or left cerebellum of idiopathic cervical dystonia patients [112,113] and in the bilateral cerebellum of patients with blepharospasm [113]. In contrast, a decrease in cerebellar gray matter in patients with writer’s cramp has also been reported [114]. An increase or decrease in the grey matter may indicate irritative or destructive lesions. These changes in the cerebellum have been considered secondary compensatory changes to the primary basal ganglia pathology; however, accumulating evidence suggests these cerebellar abnormalities are causal for dystonia genesis [115]. Abnormal cerebellar connectivity to the thalamus has been suggested in diffusion tensor imaging of DYT1 and DYT6 dystonia [116,117]. Several studies using positron emission tomography (PET) or functional magnetic resonance imaging have even shown increased cerebellar perfusion or metabolism [118,119,120,121,122,123,124,125,126,127,128]. A PET study using 18F-fluoroethoxybenzovesamicol, a radioligand of vesicular acetylcholine transporter (VAChT), showed that VAChT expression significantly decreased in the cerebellar vermis, which projects GABAergic output to the fastigial nucleus [129] in TOR1A/DYT1 patients as compared to the controls [130]. Moreover, pallidal deep brain stimulation reduces regional cerebral blood flow in the motor, premotor, prefrontal cortices, and cerebellum in tardive dystonia patients [128]. Collectively, it seems that hyperactivity in the cerebellar output might induce dystonia.

3.3. The Effect of Cerebellar Stimulation for Dystonia

Regarding non-invasive stimulation, transcranial magnetic stimulation [131,132,133,134] of the cerebellum temporarily alleviates dystonia, although the results of direct current stimulation [135,136,137] are controversial. Invasive cerebellar stimulation has been reported to be effective in secondary dystonia patients since the 1950s [138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153]. Cooper et al. used anterior lobe stimulation for cerebral palsy and dystonia [140,154,155]. Davis et al. and Galanda et al. have also used anterior cerebellar lobe or superior cerebellar peduncle high-frequency stimulations [142,143,144,146,147,148,149,150,151]. Although pallidal deep brain stimulation is still the gold standard for medically intractable generalized and cervical dystonia [156,157,158,159], Vo thalamic nucleus surgeries, which is innervated by both the pallidum and cerebellum, are effective for some forms of dystonia [160,161,162,163,164,165,166,167,168,169,170,171]. Recently, evidence from basic and clinical research has facilitated the revival of cerebellar surgery for dystonia [172,173,174,175,176,177,178], which mainly targets the deep cerebellar nuclei and superior cerebellar peduncles. The primary target nucleus in the cerebellum is the motor (dorsal) part of the dentate nucleus [173]. In addition, deep brain stimulation (DBS) of the superior cerebellar peduncle is preferred to avoid accompanying side effects, including dizziness, nystagmus, and ipsilateral leaning, as observed in studies of the dentate nucleus [172,175]. Recent studies have used high-frequency stimulations (104–300 Hz), pulse width (50–180 μs), 1.2–2.8V for stimulation of the dentate nucleus [174,178], and 130–200 Hz, 50–180 μs, 1.4–8.0 V for stimulation of the superior cerebellar peduncle [172,175,176]. Evidence also suggests the effectiveness of cerebellar modulation in dystonia treatment; however, the efficacy of GPi or Vo thalamic DBS, not the Vim nucleus, where more abundant cerebellar inputs come, implies the importance of the cortico-basal ganglia-thalamo-cortical circuitry in its pathogenesis [6]. Given that cerebral palsy patients respond well to cerebellar surgery, cerebellar DBS might be more effective for tonic-type dystonia and long-term illness-induced aberrant neuroplasticity as compared to pallidal DBS.
STN DBS is an interesting target for treating dystonia [179,180]. A recent meta-analysis comparing the efficacy of high-frequency STN DBS and GPi DBS suggested that STN DBS is more efficient at suppressing dystonia than GPi DBS in the long term [181]. STN DBS may modulate sensorimotor integration through orthodromic thalamocortical or antidromic hyperdirect pathway activation [182]. Delayed dystonia improvement after STN DBS may indicate the involvement of changes in disynaptic innervation from the STN to the cerebellar cortex via the pontine nuclei or pedunculopontine nucleus. In the future, combined pallidal, thalamic, subthalamic, and cerebellar DBS or personalized DBS treatment options may be considered in patients with various types of dystonia.

4. What Are the Roles of Two Distinct Loops?

The current concept of dystonia may answer some of its clinical questions. We can estimate the roles of two distinct loops, that is, the cortico-striato-pallido-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops. While the efficacy of pallidal-DBS in dystonia patients has been reported, it may take weeks to months to alleviate symptoms, and some patients, especially those who suffer from more chronic illnesses, manifest minimal improvement [111,183,184,185,186,187]. Delayed improvement has been established to be different from rapid improvement, as observed in Parkinson’s disease [115]. Another question is the type of dystonia. In human studies, dystonia patients usually show phasic or tonic dystonia, wherein pallidal-DBS has been found to be more effective for phasic dystonia and improves faster than tonic dystonia [156,186,188,189,190,191].
One hypothesis to explain this delay and insufficient efficacy after pallidal-DBS is that it takes time to modulate the rigid abnormal plastic change in the motor circuitry [111,115,163]. The neuronal activity of patients with dystonia is characterized by enhanced synchronized oscillations in the low-frequency band (4–12 Hz) [187,192,193,194,195,196,197,198]. It has been considered that the pathogeneses of phasic and tonic dystonia are different. Phasic dystonia is related to excessive resting-state pallidal low-frequency alpha oscillation and the cortico-striato-pallido-thalamo-cortical loop [187,194,199]. In contrast, tonic dystonia patients manifested resting-state pallidal delta oscillations, having no coherence with the motor cortex [187]. Liu et al. also showed pallidal low-frequency oscillatory local field potentials coherent with surface electromyograms (EMGs) in patients with phasic dystonia but not in those with tonic dystonia during involuntary dystonic movements [194]. These findings suggest that the mechanisms for developing phasic and tonic dystonic symptoms may differ at the basal ganglia level [194]. High-frequency pallidal-DBS suppresses pathological pallidal low-frequency activity and coherent EMG activity in patients with phasic dystonia [192,199]. Yokochi et al. further hypothesized that the cerebellothalamic pathway dysfunction induces tonic dystonia [187]. Frequent use of cerebellar surgery for dystonia in cerebral palsy patients suggests that tonic dystonia may arise from cerebellar dysfunction [173]. Additionally, DYT6 dystonia, which has been suggested to have abnormal cerebellar connectivity [116], is often treated unsatisfactorily with pallidal DBS [200,201,202]. Interestingly, a failed pallidal-DBS in a DYT6 dystonia patient was successfully treated with thalamic Vo-DBS in one study [163]. Clinically, we often observe both tonic and phasic components in patients with dystonia. Thus, the contribution of the cerebellum may differ from patient to patient depending on the underlying disorder.
Following DBS, tonic dystonia was found to improve slowly, possibly due to rigid maladaptive plasticity, which might partly be due to abnormal cerebellar activities from a loss of inhibition in the sensorimotor and supplementary motor cortices [5,54,109,203]. A high rate of recurrence in essential tremors after thalamic Vim-DBS [204,205,206] may partly support the hypothesis that cerebellothalamic connectivity dysfunction may induce rigid maladaptive plasticity [207].
Dopamine levels in the striatum should also be considered, given that either too little or too much of it can cause dystonia [208]. These two conflicting facts might be explained, in part, using the compartmental hypothesis [209,210,211]. Usually, hyperkinetic movement disorders, including phasic dystonia, are thought to be the consequence of excessive dopamine in the striatum. Given that Parkinson’s disease patients often experience off-tonic dystonia, and dopa-responsive dystonia (DYT5-GCH1) patients also manifest tonic dystonia, a lesser amount of dopamine is one of its causal factors [212]. Reduced dopamine level in the striatum with concomitant cerebellar abnormality induces dystonic movements in animal models [8] or human subjects [127]. Collectively, both loops might be involved in dystonia pathogenesis, wherein tonic dystonia might be more related to the cortico-ponto-cerebello-thalamo-cortical loop than the cortico-basal ganglia-thalamo-cortical loop.

5. Hypothesis for Dystonia Genesis

The reason why cerebellar lesions can cause ataxia and dystonia is still unclear. Prudente et al. hypothesized that destructive (suppressive) lesions are associated with ataxia, irritable (excitatory) lesions may cause dystonia, and these two could simultaneously exist in the cerebellum [115]. This hypothesis is consistent with prior studies suggesting that an increase in cerebellar output, such as an abnormal increase in Purkinje neuron firing or abnormal bursting patterns, can cause dystonia [109,115] and a strong relationship between dystonia and tremor [115]. Fremont and Khodakhah hypothesized that ataxia and dystonia exist on a continuum where modest changes in the regularity of cerebellar output underlie ataxia, while highly irregular firing (erratic bursting) cause dystonia [213]. Both theories could explain the coexistence of ataxia and dystonia due to cerebellar dysfunction.
We should separately evaluate two factors, that is, motor focusing and scaling [209,214]. The critical element for dystonia genesis might be the striatal switching system by the interneurons (Figure 1). In particular, cholinergic and parvalbumin neurons are important due to their powerful inhibition of medium spiny neurons [215,216]. When these interneurons depolarize, both D1 and D2 type medium spiny neurons are deactivated, resulting in direct pathway deactivation and indirect pathway activation. In contrast, interneuron hyperpolarization can activate both D1 and D2 type medium spiny neurons, thereby activating the direct pathways and deactivating the indirect pathways. Indirect pathway deactivation, that is, activation of D2 type medium spiny neurons, focuses the movements to be facilitated in an “intended” manner. Meanwhile, excessive indirect pathway deactivation, that is, excessive deactivation of D2 type medium spiny neurons, induces the loss of broad “unwanted movement” inhibition [217]. Through this switching system using the striatal interneurons, not only the striosome-matrix interconnection in the striatum [218], but also the cortico-striatal and thalamo-striatal innervation could change motor focusing.
Altered cholinergic transmission in a mouse model of dystonia has been reported [219,220]. Furthermore, the cholinergic interneurons are more influenced by the thalamo-striatal innervation than the cortico-striatal connection [30,31,32]. Repetitive stimulation from the intralaminar thalamus increases firing in the cholinergic interneurons [31], and clinically anticholinergic drugs are effective in dystonia patients [221]. The concept that cholinergic interneuron dysfunction induces motor focusing dysfunction in dystonia matches both hypotheses that dysfunction in the striosomes or the cerebellum causes dystonia (Figure 1) [222].
Similar to cholinergic interneurons, parvalbumin interneurons receive glutamatergic inputs from the cortex, centromedian, and parafascicular intralaminar nuclei [223,224,225], and thalamo-striatal synapses have a higher release probability on parvalbumin interneurons than cortico-striatal interneurons [35]. Animal studies showed that developmental delay in the maturation of parvalbumin interneurons causes dystonia in dtsz-mutant Syrian hamsters [226,227,228,229]. Injections of the parvalbumin interneuron inhibitor in the dorsolateral striatum elicit dystonia [230]. These thalamic or cortical modulations on the parvalbumin interneurons do not depend on dopamine or acetylcholine receptors [35]. Thus, the dysfunction of parvalbumin interneurons might determine the extent of abnormal movements.
The amount of dopamine is probably related to movement scaling (Figure 2) [209]. Cholinergic interneuron activation can trigger dopamine release by activating presynaptic nicotinic receptors [231]. When striosome dysfunction occurs, dopamine may also be released via the striosomal circuit between the striosomes and substantia nigra compacta [210,211,232]. Striosomal dysfunction also activates cholinergic interneurons and facilitates dopamine release [231]. Excessive dopamine amounts lead to enlarging movements via direct pathway facilitation. In contrast, off dystonia in Parkinson’s disease and DYT5-GCH1 dystonia patients can be caused by the loss of suppression by the dopamine D2 receptor on the cholinergic interneurons due to decreased dopamine. In this context, a lesser amount of dopamine leads to minifying movements, that is, fixed or tonic dystonia, and thus the amount of dopamine in the striatum might determine the scaling of abnormal movements.

6. Concluding Remarks

Accumulating evidence suggests that the cortico-basal ganglia-thalamo-cortical, as well as cortico-ponto-cerebello-thalamo-cortical loops, are important in dystonia pathogenesis. The interaction between two loops, including each structure, may generate a differential dystonia phenotype. Despite these findings, its precise pathophysiology remains to be elucidated; however, recent evidence suggests that phasic dystonia may be more related to the basal ganglia circuitry, and tonic dystonia may be more affected by the cerebellar circuitry. Moreover, cerebellar circuitry abnormalities may induce rigid neuroplasticity. Specifically, striatal interneurons might be a key element in dystonia genesis, needing further studies to clarify the role of these loops in dystonia genesis. Accordingly, a new therapeutic option, that is, combined DBS or tailormade DBS, may be considered based on neuroimaging and neurophysiological findings in the future.

Author Contributions

Conceptualization, R.M. (Ryoma Morigaki) and R.M. (Ryosuke Miyamoto); writing—original draft preparation, R.M. (Ryoma Morigaki); writing—review and editing, R.M. (Ryosuke Miyamoto), T.M., K.M., N.Y., Y.T.; funding acquisition, R.M. (Ryoma Morigaki) and R.M. (Ryosuke Miyamoto). All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by JSPS KAKENHI Grant Numbers JP16KK0182 and JP20K17932 and Japan Agency for Medical Research and Development (AMED Number 16ek0109182h0001).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge the help provided by members of our team for movement disorders. Department of Advanced Brain Research is supported by Beauty Life Corporation.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Jinnah, H.A.; Factor, S.A. Diagnosis and treatment of dystonia. Neurol. Clin. 2015, 33, 77–100. [Google Scholar] [CrossRef] [Green Version]
  2. Albanese, A.; Asmus, F.; Bhatia, K.P.; Elia, A.E.; Elibol, B.; Filippini, G.; Gasser, T.; Krauss, J.K.; Nardocci, N.; Newton, A.; et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur. J. Neurol. 2011, 18, 5–18. [Google Scholar] [CrossRef]
  3. Geyer, H.L.; Bressman, S.B. The diagnosis of dystonia. Lancet Neurol. 2006, 5, 780–790. [Google Scholar] [CrossRef]
  4. Kaji, R.; Hasegawa, K.; Ugawa, Y.; Osawa, M.; Kashihara, K.; Kawarai, T.; Kobayashi, T.; Sakamoto, T.; Taira, T.; Tamagawa, S.; et al. Practical Guideline for Dystonia 2018, 1st ed.; Nankodo Co., Ltd.: Tokyo, Japan, 2018. [Google Scholar]
  5. Latorre, A.; Rocchi, L.; Bhatia, K.P. Delineating the electrophysiological signature of dystonia. Exp. Brain Res. 2020, 238, 1685–1692. [Google Scholar] [CrossRef] [PubMed]
  6. Kaji, R.; Bhatia, K.; Graybiel, A.M. Pathogenesis of dystonia: Is it of cerebellar or basal ganglia origin? J. Neurol. Neurosurg. Psychiatry 2018, 89, 488–492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Jinnah, H.A.; Hess, E.J. A new twist on the anatomy of dystonia: The basal ganglia and the cerebellum? Neurology 2006, 67, 1740–1741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Neychev, V.K.; Fan, X.; Mitev, V.I.; Hess, E.J.; Jinnah, H.A. The basal ganglia and cerebellum interact in the expression of dystonic movement. Brain 2008, 131, 2499–2509. [Google Scholar] [CrossRef] [PubMed]
  9. Percheron, G.; Francois, C.; Talbi, B.; Yelnik, J.; Fenelon, G. The primate motor thalamus. Brain Res. Brain Res. Rev. 1996, 22, 93–181. [Google Scholar] [CrossRef]
  10. Voogd, J.; Glickstein, M. The anatomy of the cerebellum. Trends Cogn. Sci. 1998, 2, 307–313. [Google Scholar] [CrossRef]
  11. Grimaldi, G.; Manto, M. Topography of cerebellar deficits in humans. Cerebellum 2012, 11, 336–351. [Google Scholar] [CrossRef]
  12. Miterko, L.N.; Baker, K.B.; Beckinghausen, J.; Bradnam, L.V.; Cheng, M.Y.; Cooperrider, J.; DeLong, M.R.; Gornati, S.V.; Hallett, M.; Heck, D.H.; et al. Consensus paper: Experimental neurostimulation of the cerebellum. Cerebellum 2019, 18, 1064–1097. [Google Scholar] [CrossRef] [Green Version]
  13. Voogd, J. The human cerebellum. J. Chem. Neuroanat. 2003, 26, 243–252. [Google Scholar] [CrossRef]
  14. Pong, M.; Horn, K.M.; Gibson, A.R. Pathways for control of face and neck musculature by the basal ganglia and cerebellum. Brain Res. Rev. 2008, 58, 249–264. [Google Scholar] [CrossRef] [PubMed]
  15. Manto, M. Mechanisms of human cerebellar dysmetria: Experimental evidence and current conceptual bases. J. Neuroeng. Rehabil. 2009, 6, 10. [Google Scholar] [CrossRef]
  16. Thach, W.T.; Goodkin, H.P.; Keating, J.G. The cerebellum and the adaptive coordination of movement. Annu. Rev. Neurosci. 1992, 15, 403–442. [Google Scholar] [CrossRef] [PubMed]
  17. Bond, K.M.; Brinjikji, W.; Eckel, L.J.; Kallmes, D.F.; McDonald, R.J.; Carr, C.M. Dentate update: Imaging features of entities that affect the dentate nucleus. AJNR Am. J. Neuroradiol. 2017, 38, 1467–1474. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Kleine, J.F.; Guan, Y.; Kipiani, E.; Glonti, L.; Hoshi, M.; Buttner, U. Trunk position influences vestibular responses of fastigial nucleus neurons in the alert monkey. J. Neurophysiol. 2004, 91, 2090–2100. [Google Scholar] [CrossRef] [Green Version]
  19. Shaikh, A.G.; Meng, H.; Angelaki, D.E. Multiple reference frames for motion in the primate cerebellum. J. Neurosci. 2004, 24, 4491–4497. [Google Scholar] [CrossRef] [Green Version]
  20. Brooks, J.X.; Cullen, K.E. Multimodal integration in rostral fastigial nucleus provides an estimate of body movement. J. Neurosci. 2009, 29, 10499–10511. [Google Scholar] [CrossRef]
  21. Zhang, X.Y.; Wang, J.J.; Zhu, J.N. Cerebellar fastigial nucleus: From anatomic construction to physiological functions. Cerebellum Ataxias 2016, 3, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Hoshi, E.; Tremblay, L.; Feger, J.; Carras, P.L.; Strick, P.L. The cerebellum communicates with the basal ganglia. Nat. Neurosci. 2005, 8, 1491–1493. [Google Scholar] [CrossRef]
  23. Chen, C.H.; Fremont, R.; Arteaga-Bracho, E.E.; Khodakhah, K. Short latency cerebellar modulation of the basal ganglia. Nat. Neurosci. 2014, 17, 1767–1775. [Google Scholar] [CrossRef]
  24. Bostan, A.C.; Dum, R.P.; Strick, P.L. The basal ganglia communicate with the cerebellum. Proc. Natl. Acad. Sci. USA 2010, 107, 8452–8456. [Google Scholar] [CrossRef] [Green Version]
  25. Carta, I.; Chen, C.H.; Schott, A.L.; Dorizan, S.; Khodakhah, K. Cerebellar modulation of the reward circuitry and social behavior. Science 2019, 363. [Google Scholar] [CrossRef]
  26. Ratcheson, R.A.; Li, C.L. Effect of dentate stimulation on neuronal activity in the caudate nucleus. Exp. Neurol. 1969, 25, 268–281. [Google Scholar] [CrossRef]
  27. Raos, V.C.; Dermon, C.R.; Savaki, H.E. Functional anatomy of the thalamic centrolateral nucleus as revealed with the [14C] deoxyglucose method following electrical stimulation and electrolytic lesion. Neuroscience 1995, 68, 299–313. [Google Scholar] [CrossRef]
  28. Kim, J.E.; Chae, S.; Kim, S.; Jung, Y.J.; Kang, M.G.; Do Heo, W.; Kim, D. Cerebellar 5HT-2A receptor mediates stress-induced onset of dystonia. Sci. Adv. 2021, 7, eabb5735. [Google Scholar] [CrossRef] [PubMed]
  29. Ichinohe, N.; Mori, F.; Shoumura, K. A di-synaptic projection from the lateral cerebellar nucleus to the laterodorsal part of the striatum via the central lateral nucleus of the thalamus in the rat. Brain Res. 2000, 880, 191–197. [Google Scholar] [CrossRef]
  30. Ding, J.B.; Guzman, J.N.; Peterson, J.D.; Goldberg, J.A.; Surmeier, D.J. Thalamic gating of corticostriatal signaling by cholinergic interneurons. Neuron 2010, 67, 294–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Doig, N.M.; Magill, P.J.; Apicella, P.; Bolam, J.P.; Sharott, A. Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli. J. Neurosci. 2014, 34, 3101–3117. [Google Scholar] [CrossRef] [Green Version]
  32. Assous, M.; Kaminer, J.; Shah, F.; Garg, A.; Koos, T.; Tepper, J.M. Differential processing of thalamic information via distinct striatal interneuron circuits. Nat. Commun. 2017, 8, 15860. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Lapper, S.R.; Bolam, J.P. Input from the frontal cortex and the parafascicular nucleus to cholinergic interneurons in the dorsal striatum of the rat. Neuroscience 1992, 51, 533–545. [Google Scholar] [CrossRef]
  34. Meredith, G.E.; Wouterlood, F.G. Hippocampal and midline thalamic fibers and terminals in relation to the choline acetyltransferase-immunoreactive neurons in nucleus accumbens of the rat: A light and electron microscopic study. J. Comp. Neurol. 1990, 296, 204–221. [Google Scholar] [CrossRef] [PubMed]
  35. Sciamanna, G.; Ponterio, G.; Mandolesi, G.; Bonsi, P.; Pisani, A. Optogenetic stimulation reveals distinct modulatory properties of thalamostriatal vs corticostriatal glutamatergic inputs to fast-spiking interneurons. Sci. Rep. 2015, 5, 16742. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Bostan, A.C.; Strick, P.L. The cerebellum and basal ganglia are interconnected. Neuropsychol. Rev. 2010, 20, 261–270. [Google Scholar] [CrossRef] [PubMed]
  37. Carpenter, M.B.; Carleton, S.C.; Keller, J.T.; Conte, P. Connections of the subthalamic nucleus in the monkey. Brain Res. 1981, 224, 1–29. [Google Scholar] [CrossRef]
  38. Carpenter, M.B.; Baton, R.R., 3rd; Carleton, S.C.; Keller, J.T. Interconnections and organization of pallidal and subthalamic nucleus neurons in the monkey. J. Comp. Neurol. 1981, 197, 579–603. [Google Scholar] [CrossRef]
  39. Giolli, R.A.; Gregory, K.M.; Suzuki, D.A.; Blanks, R.H.; Lui, F.; Betelak, K.F. Cortical and subcortical afferents to the nucleus reticularis tegmenti pontis and basal pontine nuclei in the macaque monkey. Vis. Neurosci. 2001, 18, 725–740. [Google Scholar] [CrossRef] [Green Version]
  40. Hendry, S.H.; Jones, E.G.; Graham, J. Thalamic relay nuclei for cerebellar and certain related fiber systems in the cat. J. Comp. Neurol. 1979, 185, 679–713. [Google Scholar] [CrossRef]
  41. Ilinsky, I.A.; Kultas-Ilinsky, K. An autoradiographic study of topographical relationships between pallidal and cerebellar projections to the cat thalamus. Exp. Brain Res. 1984, 54, 95–106. [Google Scholar] [CrossRef]
  42. Pelzer, E.A.; Hintzen, A.; Goldau, M.; von Cramon, D.Y.; Timmermann, L.; Tittgemeyer, M. Cerebellar networks with basal ganglia: Feasibility for tracking cerebello-pallidal and subthalamo-cerebellar projections in the human brain. Eur. J. Neurosci. 2013, 38, 3106–3114. [Google Scholar] [CrossRef] [PubMed]
  43. Asanuma, C.; Thach, W.R.; Jones, E.G. Anatomical evidence for segregated focal groupings of efferent cells and their terminal ramifications in the cerebellothalamic pathway of the monkey. Brain Res. 1983, 286, 267–297. [Google Scholar] [CrossRef]
  44. Middleton, F.A.; Strick, P.L. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994, 266, 458–461. [Google Scholar] [CrossRef] [PubMed]
  45. Middleton, F.A.; Strick, P.L. Cerebellar output channels. Int. Rev. Neurobiol. 1997, 41, 61–82. [Google Scholar] [PubMed]
  46. Middleton, F.A.; Strick, P.L. Dentate output channels: Motor and cognitive components. Prog. Brain Res. 1997, 114, 553–566. [Google Scholar] [PubMed]
  47. Dum, R.P.; Li, C.; Strick, P.L. Motor and nonmotor domains in the monkey dentate. Ann. N. Y. Acad. Sci. 2002, 978, 289–301. [Google Scholar] [CrossRef]
  48. Ilinsky, I.A.; Kultas-Ilinsky, K. Sagittal cytoarchitectonic maps of the macaca mulatta thalamus with a revised nomenclature of the motor-related nuclei validated by observations on their connectivity. J. Comp. Neurol. 1987, 262, 331–364. [Google Scholar] [CrossRef]
  49. Nakano, K. Neural circuits and topographic organization of the basal ganglia and related regions. Brain Dev. 2000, 22 (Suppl. 1), S5–S16. [Google Scholar] [CrossRef]
  50. Kuo, J.S.; Carpenter, M.B. Organization of pallidothalamic projections in the rhesus monkey. J. Comp. Neurol. 1973, 151, 201–236. [Google Scholar] [CrossRef]
  51. Sidibe, M.; Bevan, M.D.; Bolam, J.P.; Smith, Y. Efferent connections of the internal globus pallidus in the squirrel monkey: I. Topography and synaptic organization of the pallidothalamic projection. J. Comp. Neurol. 1997, 382, 323–347. [Google Scholar] [CrossRef]
  52. Sakai, S.T.; Inase, M.; Tanji, J. Comparison of cerebellothalamic and pallidothalamic projections in the monkey (macaca fuscata): A double anterograde labeling study. J. Comp. Neurol. 1996, 368, 215–228. [Google Scholar] [CrossRef]
  53. Akkal, D.; Dum, R.P.; Strick, P.L. Supplementary motor area and presupplementary motor area: Targets of basal ganglia and cerebellar output. J. Neurosci. 2007, 27, 10659–10673. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Abbruzzese, G.; Berardelli, A. Further progress in understanding the pathophysiology of primary dystonia. Mov. Disord. 2011, 26, 1185–1186. [Google Scholar] [CrossRef] [PubMed]
  55. Quartarone, A.; Cacciola, A.; Milardi, D.; Ghilardi, M.F.; Calamuneri, A.; Chillemi, G.; Anastasi, G.; Rothwell, J. New insights into cortico-basal-cerebellar connectome: Clinical and physiological considerations. Brain 2020, 143, 396–406. [Google Scholar] [CrossRef]
  56. Beier, K.T.; Gao, X.J.; Xie, S.; DeLoach, K.E.; Malenka, R.C.; Luo, L. Topological organization of ventral tegmental area connectivity revealed by viral-genetic dissection of input-output relations. Cell Rep. 2019, 26, 159–167.e6. [Google Scholar] [CrossRef] [Green Version]
  57. Beier, K.T.; Steinberg, E.E.; DeLoach, K.E.; Xie, S.; Miyamichi, K.; Schwarz, L.; Gao, X.J.; Kremer, E.J.; Malenka, R.C.; Luo, L. Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell 2015, 162, 622–634. [Google Scholar] [CrossRef] [Green Version]
  58. Trutti, A.C.; Mulder, M.J.; Hommel, B.; Forstmann, B.U. Functional neuroanatomical review of the ventral tegmental area. Neuroimage 2019, 191, 258–268. [Google Scholar] [CrossRef] [Green Version]
  59. Watabe-Uchida, M.; Zhu, L.; Ogawa, S.K.; Vamanrao, A.; Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 2012, 74, 858–873. [Google Scholar] [CrossRef] [Green Version]
  60. Bourdy, R.; Sanchez-Catalan, M.J.; Kaufling, J.; Balcita-Pedicino, J.J.; Freund-Mercier, M.J.; Veinante, P.; Sesack, S.R.; Georges, F.; Barrot, M. Control of the nigrostriatal dopamine neuron activity and motor function by the tail of the ventral tegmental area. Neuropsychopharmacology 2014, 39, 2788–2798. [Google Scholar] [CrossRef] [Green Version]
  61. Flaherty, A.W.; Graybiel, A.M. Input-output organization of the sensorimotor striatum in the squirrel monkey. J. Neurosci. 1994, 14, 599–610. [Google Scholar] [CrossRef]
  62. Filip, P.; Lungu, O.V.; Bares, M. Dystonia and the cerebellum: A new field of interest in movement disorders? Clin. Neurophysiol. 2013, 124, 1269–1276. [Google Scholar] [CrossRef]
  63. Stratton, S.E.; Lorden, J.F. Effect of harmaline on cells of the inferior olive in the absence of tremor: Differential response of genetically dystonic and harmaline-tolerant rats. Neuroscience 1991, 41, 543–549. [Google Scholar] [CrossRef]
  64. Isaacs, K.R.; Abbott, L.C. Cerebellar volume decreases in the tottering mouse are specific to the molecular layer. Brain Res. Bull. 1995, 36, 309–314. [Google Scholar] [CrossRef]
  65. Heckroth, J.A.; Abbott, L.C. Purkinje cell loss from alternating sagittal zones in the cerebellum of leaner mutant mice. Brain Res. 1994, 658, 93–104. [Google Scholar] [CrossRef]
  66. Matsui, K.; Mukoyama, M.; Adachi, K.; Ando, K. Fundamental study on ataxic mice (wriggle mouse sagami). Jikken Dobutsu 1987, 36, 185–189. [Google Scholar] [PubMed] [Green Version]
  67. Fremont, R.; Tewari, A.; Angueyra, C.; Khodakhah, K. A role for cerebellum in the hereditary dystonia DYT1. eLife 2017, 6, e22775. [Google Scholar] [CrossRef] [PubMed]
  68. Raike, R.S.; Pizoli, C.E.; Weisz, C.; van den Maagdenberg, A.M.; Jinnah, H.A.; Hess, E.J. Limited regional cerebellar dysfunction induces focal dystonia in mice. Neurobiol. Dis. 2013, 49, 200–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Brown, L.L.; Lorden, J.F. Regional cerebral glucose utilization reveals widespread abnormalities in the motor system of the rat mutant dystonic. J. Neurosci. 1989, 9, 4033–4041. [Google Scholar] [CrossRef] [Green Version]
  70. Calderon, D.P.; Fremont, R.; Kraenzlin, F.; Khodakhah, K. The neural substrates of rapid-onset dystonia-parkinsonism. Nat. Neurosci. 2011, 14, 357–365. [Google Scholar] [CrossRef]
  71. Ulug, A.M.; Vo, A.; Argyelan, M.; Tanabe, L.; Schiffer, W.K.; Dewey, S.; Dauer, W.T.; Eidelberg, D. Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice. Proc. Natl. Acad. Sci. USA 2011, 108, 6638–6643. [Google Scholar] [CrossRef] [Green Version]
  72. Zhao, Y.; Sharma, N.; LeDoux, M.S. The DYT1 carrier state increases energy demand in the olivocerebellar network. Neuroscience 2011, 177, 183–194. [Google Scholar] [CrossRef] [Green Version]
  73. Campbell, D.B.; Hess, E.J. Cerebellar circuitry is activated during convulsive episodes in the tottering (tg/tg) mutant mouse. Neuroscience 1998, 85, 773–783. [Google Scholar] [CrossRef]
  74. Campbell, D.B.; North, J.B.; Hess, E.J. Tottering mouse motor dysfunction is abolished on the purkinje cell degeneration (pcd) mutant background. Exp. Neurol. 1999, 160, 268–278. [Google Scholar] [CrossRef] [PubMed]
  75. Devanagondi, R.; Egami, K.; LeDoux, M.S.; Hess, E.J.; Jinnah, H.A. Neuroanatomical substrates for paroxysmal dyskinesia in lethargic mice. Neurobiol. Dis. 2007, 27, 249–257. [Google Scholar] [CrossRef] [PubMed]
  76. LeDoux, M.S.; Lorden, J.F. Abnormal cerebellar output in the genetically dystonic rat. Adv. Neurol. 1998, 78, 63–78. [Google Scholar]
  77. LeDoux, M.S.; Hurst, D.C.; Lorden, J.F. Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat. Neuroscience 1998, 86, 533–545. [Google Scholar] [CrossRef]
  78. Fremont, R.; Calderon, D.P.; Maleki, S.; Khodakhah, K. Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. J. Neurosci. 2014, 34, 11723–11732. [Google Scholar] [CrossRef] [Green Version]
  79. Fremont, R.; Tewari, A.; Khodakhah, K. Aberrant purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of rapid onset dystonia-parkinsonism. Neurobiol. Dis. 2015, 82, 200–212. [Google Scholar] [CrossRef] [Green Version]
  80. Stratton, S.E.; Lorden, J.F.; Mays, L.E.; Oltmans, G.A. Spontaneous and harmaline-stimulated purkinje cell activity in rats with a genetic movement disorder. J. Neurosci. 1988, 8, 3327–3336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Xiao, J.; Ledoux, M.S. Caytaxin deficiency causes generalized dystonia in rats. Brain Res. Mol. Brain Res. 2005, 141, 181–192. [Google Scholar] [CrossRef]
  82. Alvarez-Fischer, D.; Grundmann, M.; Lu, L.; Samans, B.; Fritsch, B.; Moller, J.C.; Schaefer, M.K.; Hartmann, A.; Oertel, W.H.; Bandmann, O. Prolonged generalized dystonia after chronic cerebellar application of kainic acid. Brain Res. 2012, 1464, 82–88. [Google Scholar] [CrossRef]
  83. LeDoux, M.S.; Lorden, J.F.; Ervin, J.M. Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat. Exp. Neurol. 1993, 120, 302–310. [Google Scholar] [CrossRef] [PubMed]
  84. Fan, X.; Hughes, K.E.; Jinnah, H.A.; Hess, E.J. Selective and sustained alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation in cerebellum induces dystonia in mice. J. Pharm. Exp. 2012, 340, 733–741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Pizoli, C.E.; Jinnah, H.A.; Billingsley, M.L.; Hess, E.J. Abnormal cerebellar signaling induces dystonia in mice. J. Neurosci. 2002, 22, 7825–7833. [Google Scholar] [CrossRef] [Green Version]
  86. Ellen, J.H.; Jinnah, H.A. Mouse model of dystonia. In Animal Models of Movement Disorder, 1st ed.; LeDoux, M., Ed.; Elsevier Academic Press: Amsterdam, The Netherlands, 2005; pp. 265–277. [Google Scholar]
  87. White, J.J.; Sillitoe, R.V. Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat. Commun. 2017, 8, 14912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. LeDoux, M.S.; Brady, K.A. Secondary cervical dystonia associated with structural lesions of the central nervous system. Mov. Disord. 2003, 18, 60–69. [Google Scholar] [CrossRef]
  89. Seidel, K.; Siswanto, S.; Brunt, E.R.; den Dunnen, W.; Korf, H.W.; Rub, U. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012, 124, 1–21. [Google Scholar] [CrossRef] [PubMed]
  90. Fletcher, N.A.; Stell, R.; Harding, A.E.; Marsden, C.D. Degenerative cerebellar ataxia and focal dystonia. Mov. Disord. 1988, 3, 336–342. [Google Scholar] [CrossRef] [PubMed]
  91. Manto, M.U. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005, 4, 2–6. [Google Scholar] [CrossRef]
  92. Anheim, M.; Tranchant, C.; Koenig, M. The autosomal recessive cerebellar ataxias. N. Engl. J. Med. 2012, 366, 636–646. [Google Scholar] [CrossRef]
  93. Muzaimi, M.B.; Wiles, C.M.; Robertson, N.P.; Ravine, D.; Compston, D.A. Task specific focal dystonia: A presentation of spinocerebellar ataxia type 6. J. Neurol. Neurosurg. Psychiatry 2003, 74, 1444–1445. [Google Scholar] [CrossRef] [Green Version]
  94. Saunders-Pullman, R.; Raymond, D.; Stoessl, A.J.; Hobson, D.; Nakamura, K.; Pullman, S.; Lefton, D.; Okun, M.S.; Uitti, R.; Sachdev, R.; et al. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology 2012, 78, 649–657. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Bodensteiner, J.B.; Goldblum, R.M.; Goldman, A.S. Progressive dystonia masking ataxia in ataxia-telangiectasia. Arch. Neurol. 1980, 37, 464–465. [Google Scholar] [CrossRef] [PubMed]
  96. Krauss, J.K.; Seeger, W.; Jankovic, J. Cervical dystonia associated with tumors of the posterior fossa. Mov. Disord. 1997, 12, 443–447. [Google Scholar] [CrossRef] [PubMed]
  97. O’Rourke, K.; O’Riordan, S.; Gallagher, J.; Hutchinson, M. Paroxysmal torticollis and blepharospasm following bilateral cerebellar infarction. J. Neurol. 2006, 253, 1644–1645. [Google Scholar] [CrossRef]
  98. Le Ber, I.; Clot, F.; Vercueil, L.; Camuzat, A.; Viemont, M.; Benamar, N.; De Liege, P.; Ouvrard-Hernandez, A.M.; Pollak, P.; Stevanin, G.; et al. Predominant dystonia with marked cerebellar atrophy: A rare phenotype in familial dystonia. Neurology 2006, 67, 1769–1773. [Google Scholar] [CrossRef]
  99. Miyamoto, R.; Sumikura, H.; Takeuchi, T.; Sanada, M.; Fujita, K.; Kawarai, T.; Mure, H.; Morigaki, R.; Goto, S.; Murayama, S.; et al. Autopsy case of severe generalized dystonia and static ataxia with marked cerebellar atrophy. Neurology 2015, 85, 1522–1524. [Google Scholar] [CrossRef]
  100. Hagenah, J.; Reetz, K.; Zuhlke, C.; Rolfs, A.; Binkofski, F.; Klein, C. Predominant dystonia with marked cerebellar atrophy: A rare phenotype in familial dystonia. Neurology 2006, 67, 1769–1773. [Google Scholar] [CrossRef]
  101. van de Warrenburg, B.P.; Giunti, P.; Schneider, S.A.; Quinn, N.P.; Wood, N.W.; Bhatia, K.P. The syndrome of (predominantly cervical) dystonia and cerebellar ataxia: New cases indicate a distinct but heterogeneous entity. J. Neurol. Neurosurg. Psychiatry 2007, 78, 774–775. [Google Scholar] [CrossRef] [Green Version]
  102. Batla, A.; Sanchez, M.C.; Erro, R.; Ganos, C.; Stamelou, M.; Balint, B.; Brugger, F.; Antelmi, E.; Bhatia, K.P. The role of cerebellum in patients with late onset cervical/segmental dystonia?--evidence from the clinic. Parkinsonism Relat. Disord. 2015, 21, 1317–1322. [Google Scholar] [CrossRef]
  103. Prudente, C.N.; Pardo, C.A.; Xiao, J.; Hanfelt, J.; Hess, E.J.; Ledoux, M.S.; Jinnah, H.A. Neuropathology of cervical dystonia. Exp. Neurol. 2013, 241, 95–104. [Google Scholar] [CrossRef] [Green Version]
  104. Ma, K.; Babij, R.; Cortes, E.; Vonsattel, J.P.; Louis, E.D. Cerebellar pathology of a dual clinical diagnosis: Patients with essential tremor and dystonia. Tremor Other Hyperkinet Mov. 2012, 2, tre-12-107-677-1. [Google Scholar] [CrossRef]
  105. Rossi, M.; Perez-Lloret, S.; Cerquetti, D.; Merello, M. Movement disorders in autosomal dominant cerebellar ataxias: A systematic review. Mov. Disord. Clin. Pr. 2014, 1, 154–160. [Google Scholar] [CrossRef] [PubMed]
  106. van Gaalen, J.; Giunti, P.; van de Warrenburg, B.P. Movement disorders in spinocerebellar ataxias. Mov. Disord. 2011, 26, 792–800. [Google Scholar] [CrossRef] [PubMed]
  107. Cancel, G.; Durr, A.; Didierjean, O.; Imbert, G.; Burk, K.; Lezin, A.; Belal, S.; Benomar, A.; Abada-Bendib, M.; Vial, C.; et al. Molecular and clinical correlations in spinocerebellar ataxia 2: A study of 32 families. Hum. Mol. Genet. 1997, 6, 709–715. [Google Scholar] [CrossRef] [PubMed]
  108. Kuo, P.H.; Gan, S.R.; Wang, J.; Lo, R.Y.; Figueroa, K.P.; Tomishon, D.; Pulst, S.M.; Perlman, S.; Wilmot, G.; Gomez, C.M.; et al. Dystonia and ataxia progression in spinocerebellar ataxias. Parkinsonism Relat. Disord. 2017, 45, 75–80. [Google Scholar] [CrossRef] [PubMed]
  109. Neychev, V.K.; Gross, R.E.; Lehericy, S.; Hess, E.J.; Jinnah, H.A. The functional neuroanatomy of dystonia. Neurobiol. Dis. 2011, 42, 185–201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Zoons, E.; Booij, J.; Nederveen, A.J.; Dijk, J.M.; Tijssen, M.A. Structural, functional and molecular imaging of the brain in primary focal dystonia—A review. Neuroimage 2011, 56, 1011–1020. [Google Scholar] [CrossRef] [PubMed]
  111. Tewari, A.; Fremont, R.; Khodakhah, K. It’s not just the basal ganglia: Cerebellum as a target for dystonia therapeutics. Mov. Disord. 2017, 32, 1537–1545. [Google Scholar] [CrossRef]
  112. Draganski, B.; Thun-Hohenstein, C.; Bogdahn, U.; Winkler, J.; May, A. "Motor circuit" gray matter changes in idiopathic cervical dystonia. Neurology 2003, 61, 1228–1231. [Google Scholar] [CrossRef]
  113. Obermann, M.; Yaldizli, O.; De Greiff, A.; Lachenmayer, M.L.; Buhl, A.R.; Tumczak, F.; Gizewski, E.R.; Diener, H.C.; Maschke, M. Morphometric changes of sensorimotor structures in focal dystonia. Mov. Disord. 2007, 22, 1117–1123. [Google Scholar] [CrossRef]
  114. Delmaire, C.; Vidailhet, M.; Elbaz, A.; Bourdain, F.; Bleton, J.P.; Sangla, S.; Meunier, S.; Terrier, A.; Lehericy, S. Structural abnormalities in the cerebellum and sensorimotor circuit in writer’s cramp. Neurology 2007, 69, 376–380. [Google Scholar] [CrossRef] [PubMed]
  115. Prudente, C.N.; Hess, E.J.; Jinnah, H.A. Dystonia as a network disorder: What is the role of the cerebellum? Neuroscience 2014, 260, 23–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Argyelan, M.; Carbon, M.; Niethammer, M.; Ulug, A.M.; Voss, H.U.; Bressman, S.B.; Dhawan, V.; Eidelberg, D. Cerebellothalamocortical connectivity regulates penetrance in dystonia. J. Neurosci. 2009, 29, 9740–9747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Carbon, M.; Kingsley, P.B.; Tang, C.; Bressman, S.; Eidelberg, D. Microstructural white matter changes in primary torsion dystonia. Mov. Disord. 2008, 23, 234–239. [Google Scholar] [CrossRef]
  118. Eidelberg, D.; Moeller, J.R.; Antonini, A.; Kazumata, K.; Nakamura, T.; Dhawan, V.; Spetsieris, P.; deLeon, D.; Bressman, S.B.; Fahn, S. Functional brain networks in DYT1 dystonia. Ann. Neurol. 1998, 44, 303–312. [Google Scholar] [CrossRef]
  119. Ceballos-Baumann, A.O.; Passingham, R.E.; Marsden, C.D.; Brooks, D.J. Motor reorganization in acquired hemidystonia. Ann. Neurol. 1995, 37, 746–757. [Google Scholar] [CrossRef] [PubMed]
  120. Kluge, A.; Kettner, B.; Zschenderlein, R.; Sandrock, D.; Munz, D.L.; Hesse, S.; Meierkord, H. Changes in perfusion pattern using ecd-spect indicate frontal lobe and cerebellar involvement in exercise-induced paroxysmal dystonia. Mov. Disord. 1998, 13, 125–134. [Google Scholar] [CrossRef]
  121. Odergren, T.; Stone-Elander, S.; Ingvar, M. Cerebral and cerebellar activation in correlation to the action-induced dystonia in writer’s cramp. Mov. Disord. 1998, 13, 497–508. [Google Scholar] [CrossRef] [PubMed]
  122. Preibisch, C.; Berg, D.; Hofmann, E.; Solymosi, L.; Naumann, M. Cerebral activation patterns in patients with writer’s cramp: A functional magnetic resonance imaging study. J. Neurol. 2001, 248, 10–17. [Google Scholar] [CrossRef] [PubMed]
  123. Galardi, G.; Perani, D.; Grassi, F.; Bressi, S.; Amadio, S.; Antoni, M.; Comi, G.C.; Canal, N.; Fazio, F. Basal ganglia and thalamo-cortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol. Scand. 1996, 94, 172–176. [Google Scholar] [CrossRef]
  124. Hutchinson, M.; Nakamura, T.; Moeller, J.R.; Antonini, A.; Belakhlef, A.; Dhawan, V.; Eidelberg, D. The metabolic topography of essential blepharospasm: A focal dystonia with general implications. Neurology 2000, 55, 673–677. [Google Scholar] [CrossRef] [Green Version]
  125. Carbon, M.; Raymond, D.; Ozelius, L.; Saunders-Pullman, R.; Frucht, S.; Dhawan, V.; Bressman, S.; Eidelberg, D. Metabolic changes in DYT11 myoclonus-dystonia. Neurology 2013, 80, 385–391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Lehericy, S.; Gerardin, E.; Poline, J.B.; Meunier, S.; Van de Moortele, P.F.; Le Bihan, D.; Vidailhet, M. Motor execution and imagination networks in post-stroke dystonia. Neuroreport 2004, 15, 1887–1890. [Google Scholar] [CrossRef]
  127. Asanuma, K.; Ma, Y.; Huang, C.; Carbon-Correll, M.; Edwards, C.; Raymond, D.; Bressman, S.B.; Moeller, J.R.; Eidelberg, D. The metabolic pathology of dopa-responsive dystonia. Ann. Neurol. 2005, 57, 596–600. [Google Scholar] [CrossRef]
  128. Thobois, S.; Ballanger, B.; Xie-Brustolin, J.; Damier, P.; Durif, F.; Azulay, J.P.; Derost, P.; Witjas, T.; Raoul, S.; Le Bars, D.; et al. Globus pallidus stimulation reduces frontal hyperactivity in tardive dystonia. J. Cereb. Blood Flow Metab 2008, 28, 1127–1138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Bostan, A.C.; Strick, P.L. The basal ganglia and the cerebellum: Nodes in an integrated network. Nat. Rev. Neurosci. 2018, 19, 338–350. [Google Scholar] [CrossRef] [PubMed]
  130. Mazere, J.; Dilharreguy, B.; Catheline, G.; Vidailhet, M.; Deffains, M.; Vimont, D.; Ribot, B.; Barse, E.; Cif, L.; Mazoyer, B.; et al. Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia. Brain 2021, 144, 909–923. [Google Scholar] [CrossRef] [PubMed]
  131. Koch, G.; Porcacchia, P.; Ponzo, V.; Carrillo, F.; Caceres-Redondo, M.T.; Brusa, L.; Desiato, M.T.; Arciprete, F.; Di Lorenzo, F.; Pisani, A.; et al. Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients. Brain Stimul. 2014, 7, 564–572. [Google Scholar] [CrossRef] [PubMed]
  132. Brighina, F.; Romano, M.; Giglia, G.; Saia, V.; Puma, A.; Giglia, F.; Fierro, B. Effects of cerebellar TMS on motor cortex of patients with focal dystonia: A preliminary report. Exp. Brain Res. 2009, 192, 651–656. [Google Scholar] [CrossRef]
  133. Bradnam, L.V.; McDonnell, M.N.; Ridding, M.C. Cerebellar intermittent theta-burst stimulation and motor control training in individuals with cervical dystonia. Brain Sci. 2016, 6, 56. [Google Scholar] [CrossRef] [Green Version]
  134. Hoffland, B.S.; Kassavetis, P.; Bologna, M.; Teo, J.T.; Bhatia, K.P.; Rothwell, J.C.; Edwards, M.J.; van de Warrenburg, B.P. Cerebellum-dependent associative learning deficits in primary dystonia are normalized by rTMS and practice. Eur. J. Neurosci. 2013, 38, 2166–2171. [Google Scholar] [CrossRef] [PubMed]
  135. Bradnam, L.V.; Frasca, J.; Kimberley, T.J. Direct current stimulation of primary motor cortex and cerebellum and botulinum toxin a injections in a person with cervical dystonia. Brain Stimul. 2014, 7, 909–911. [Google Scholar] [CrossRef] [PubMed]
  136. Bradnam, L.V.; Graetz, L.J.; McDonnell, M.N.; Ridding, M.C. Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia. Front. Hum. Neurosci. 2015, 9, 286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Sadnicka, A.; Hamada, M.; Bhatia, K.P.; Rothwell, J.C.; Edwards, M.J. Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia. Mov. Disord. 2014, 29, 1304–1307. [Google Scholar] [CrossRef] [PubMed]
  138. Cooper, I.S. Dystonia: Slrgical approaches to treatment and physiologic implications. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 1976, 55, 369–383. [Google Scholar]
  139. Cooper, I.S. 20-year followup study of the neurosurgical treatment of dystonia musculorum deformans. Adv. Neurol. 1976, 14, 423–452. [Google Scholar]
  140. Cooper, I.S.; Riklan, M.; Amin, I.; Waltz, J.M.; Cullinan, T. Chronic cerebellar stimulation in cerebral palsy. Neurology 1976, 26, 744–753. [Google Scholar] [CrossRef]
  141. Penn, R.D.; Gottlieb, G.L.; Agarwal, G.C. Cerebellar stimulation in man. Quantitative changes in spasticity. J. Neurosurg. 1978, 48, 779–786. [Google Scholar] [CrossRef]
  142. Galanda, M.; Hovath, S. Different effect of chronic electrical stimulation of the region of the superior cerebellar peduncle and the nucleus ventralis intermedius of the thalamus in the treatment of movement disorders. Stereotact. Funct. Neurosurg. 1997, 69, 116–120. [Google Scholar] [CrossRef]
  143. Galanda, M.; Mistina, L.; Zoltan, O. Behavioural responses to cerebellar stimulation in cerebral palsy. Acta Neurochir. Suppl. 1989, 46, 37–38. [Google Scholar]
  144. Galanda, M.; Zoltan, O. Motor and psychological responses to deep cerebellar stimulation in cerebral palsy (correlation with organization of cerebellum into zones). Acta Neurochir. Suppl. 1987, 39, 129–131. [Google Scholar]
  145. Schulman, J.H.; Davis, R.; Nanes, M. Cerebellar stimulation for spastic cerebral palsy: Preliminary report; on-going double blind study. Pacing Clin. Electrophysiol. 1987, 10, 226–231. [Google Scholar] [CrossRef] [PubMed]
  146. Davis, R.; Schulman, J.; Delehanty, A. Cerebellar stimulation for cerebral palsy--double blind study. Acta Neurochir. Suppl. 1987, 39, 126–128. [Google Scholar] [PubMed]
  147. Davis, R.; Gray, E.; Ryan, T.; Schulman, J. Bioengineering changes in spastic cerebral palsy groups following cerebellar stimulation. Appl. Neurophysiol. 1985, 48, 111–116. [Google Scholar] [CrossRef] [PubMed]
  148. Davis, R.; Cullen, R.F., Jr.; Flitter, M.A.; Duenas, D.; Engle, H.; Papazian, O.; Weis, B. Control of spasticity and involuntary movements--cerebellar stimulation. Appl. Neurophysiol. 1977, 40, 135–140. [Google Scholar] [CrossRef]
  149. Davis, R.; Barolat-Romana, G.; Engle, H. Chronic cerebellar stimulation for cerebral palsy--five-year study. Acta Neurochir. Suppl. 1980, 30, 317–332. [Google Scholar]
  150. Davis, R. Cerebellar stimulation for cerebral palsy spasticity, function, and seizures. Arch. Med. Res. 2000, 31, 290–299. [Google Scholar] [CrossRef]
  151. Galanda, M.; Horvath, S. Effect of stereotactic high-frequency stimulation in the anterior lobe of the cerebellum in cerebral palsy: A new suboccipital approach. Stereotact. Funct. Neurosurg. 2003, 80, 102–107. [Google Scholar] [CrossRef]
  152. Galanda, M.; Horvath, S. Stereotactic stimulation of the anterior lobe of the cerebellum in cerebral palsy from a suboccipital approach. Acta Neurochir. Suppl. 2007, 97, 239–243. [Google Scholar]
  153. Harat, M.; Radziszewski, K.; Rudas, M.; Okon, M.; Galanda, M. Clinical evaluation of deep cerebellar stimulation for spasticity in patients with cerebral palsy. Neurol. Neurochir. Pol. 2009, 43, 36–44. [Google Scholar]
  154. Cooper, I.S. Effect of chronic stimulation of anterior cerebellum on neurological disease. Lancet 1973, 1, 206. [Google Scholar] [CrossRef]
  155. Rosenow, J.; Das, K.; Rovit, R.L.; Couldwell, W.T. Irving s. Cooper and his role in intracranial stimulation for movement disorders and epilepsy. Stereotact. Funct. Neurosurg. 2002, 78, 95–112. [Google Scholar] [CrossRef]
  156. Vidailhet, M.; Vercueil, L.; Houeto, J.L.; Krystkowiak, P.; Benabid, A.L.; Cornu, P.; Lagrange, C.; Tezenas du Montcel, S.; Dormont, D.; Grand, S.; et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 2005, 352, 459–467. [Google Scholar] [CrossRef] [Green Version]
  157. Vidailhet, M.; Vercueil, L.; Houeto, J.L.; Krystkowiak, P.; Lagrange, C.; Yelnik, J.; Bardinet, E.; Benabid, A.L.; Navarro, S.; Dormont, D.; et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: A prospective 3 year follow-up study. Lancet Neurol. 2007, 6, 223–229. [Google Scholar] [CrossRef]
  158. Volkmann, J.; Wolters, A.; Kupsch, A.; Muller, J.; Kuhn, A.A.; Schneider, G.H.; Poewe, W.; Hering, S.; Eisner, W.; Muller, J.U.; et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol. 2012, 11, 1029–1038. [Google Scholar] [CrossRef]
  159. Volkmann, J.; Mueller, J.; Deuschl, G.; Kuhn, A.A.; Krauss, J.K.; Poewe, W.; Timmermann, L.; Falk, D.; Kupsch, A.; Kivi, A.; et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: A randomised, sham-controlled trial. Lancet Neurol. 2014, 13, 875–884. [Google Scholar] [CrossRef]
  160. Fukaya, C.; Katayama, Y.; Kano, T.; Nagaoka, T.; Kobayashi, K.; Oshima, H.; Yamamoto, T. Thalamic deep brain stimulation for writer’s cramp. J. Neurosurg. 2007, 107, 977–982. [Google Scholar] [CrossRef]
  161. Goto, S.; Shimazu, H.; Matsuzaki, K.; Tamura, T.; Murase, N.; Nagahiro, S.; Kaji, R. Thalamic Vo-complex vs pallidal deep brain stimulation for focal hand dystonia. Neurology 2008, 70, 1500–1501. [Google Scholar] [CrossRef]
  162. Goto, S.; Tsuiki, H.; Soyama, N.; Okamura, A.; Yamada, K.; Yoshikawa, M.; Hashimoto, Y.; Ushio, Y. Stereotactic selective Vo-complex thalamotomy in a patient with dystonic writer’s cramp. Neurology 1997, 49, 1173–1174. [Google Scholar] [CrossRef]
  163. Mure, H.; Morigaki, R.; Koizumi, H.; Okita, S.; Kawarai, T.; Miyamoto, R.; Kaji, R.; Nagahiro, S.; Goto, S. Deep brain stimulation of the thalamic ventral lateral anterior nucleus for DYT6 dystonia. Stereotact. Funct. Neurosurg. 2014, 92, 393–396. [Google Scholar] [CrossRef]
  164. Horisawa, S.; Ochiai, T.; Goto, S.; Nakajima, T.; Takeda, N.; Fukui, A.; Hanada, T.; Kawamata, T.; Taira, T. Safety and long-term efficacy of ventro-oral thalamotomy for focal hand dystonia: A retrospective study of 171 patients. Neurology 2019, 92, e371–e377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Horisawa, S.; Taira, T.; Goto, S.; Ochiai, T.; Nakajima, T. Long-term improvement of musician’s dystonia after stereotactic ventro-oral thalamotomy. Ann. Neurol. 2013, 74, 648–654. [Google Scholar] [CrossRef] [PubMed]
  166. Horisawa, S.; Goto, S.; Nakajima, T.; Ochiai, T.; Kawamata, T.; Taira, T. Stereotactic thalamotomy for hairdresser’s dystonia: A case series. Stereotact. Funct. Neurosurg. 2016, 94, 201–206. [Google Scholar] [CrossRef]
  167. Horisawa, S.; Goto, S.; Nakajima, T.; Kawamata, T.; Taira, T. Bilateral stereotactic thalamotomy for bilateral musician’s hand dystonia. World Neurosurg. 2016, 92, 585.e21–585.e25. [Google Scholar] [CrossRef]
  168. Shimizu, T.; Maruo, T.; Miura, S.; Kishima, H.; Ushio, Y.; Goto, S. Stereotactic lesioning of the thalamic Vo nucleus for the treatment of writer’s cramp (focal hand dystonia). Front. Neurol. 2018, 9, 1008. [Google Scholar] [CrossRef]
  169. Morishita, T.; Foote, K.D.; Haq, I.U.; Zeilman, P.; Jacobson, C.E.; Okun, M.S. Should we consider Vim thalamic deep brain stimulation for select cases of severe refractory dystonic tremor. Stereotact. Funct. Neurosurg. 2010, 88, 98–104. [Google Scholar] [CrossRef]
  170. Hedera, P.; Phibbs, F.T.; Dolhun, R.; Charles, P.D.; Konrad, P.E.; Neimat, J.S.; Davis, T.L. Surgical targets for dystonic tremor: Considerations between the globus pallidus and ventral intermediate thalamic nucleus. Parkinsonism Relat. Disord. 2013, 19, 684–686. [Google Scholar] [CrossRef]
  171. Morigaki, R.; Nagahiro, S.; Kaji, R.; Goto, S. Current use of thalamic surgeries for treating movement disorders. In Thalamus: Anatomy, Functions and Disorders; Song, J.L., Ed.; Nova Science Publishers, Inc.: New York, NY, USA, 2011; pp. 1–31. [Google Scholar]
  172. Lin, S.; Zhang, C.; Li, H.; Wang, Y.; Wu, Y.; Wang, T.; Pan, Y.; Sun, B.; Wu, Y.; Li, D. High frequency deep brain stimulation of superior cerebellar peduncles in a patient with cerebral palsy. Tremor. Other Hyperkinet. Mov. 2020, 10, 38. [Google Scholar] [CrossRef]
  173. Nicholson, C.L.; Coubes, P.; Poulen, G. Dentate nucleus as target for deep brain stimulation in dystono-dyskinetic syndromes. Neurochirurgie 2020, 66, 258–265. [Google Scholar] [CrossRef]
  174. Horisawa, S.; Kohara, K.; Nonaka, T.; Mochizuki, T.; Kawamata, T.; Taira, T. Case report: Deep cerebellar stimulation for tremor and dystonia. Front. Neurol. 2021, 12, 642904. [Google Scholar] [CrossRef] [PubMed]
  175. Horisawa, S.; Arai, T.; Suzuki, N.; Kawamata, T.; Taira, T. The striking effects of deep cerebellar stimulation on generalized fixed dystonia: Case report. J. Neurosurg. 2019, 132, 712–716. [Google Scholar] [CrossRef]
  176. Sokal, P.; Rudas, M.; Harat, M.; Szylberg, L.; Zielinski, P. Deep anterior cerebellar stimulation reduces symptoms of secondary dystonia in patients with cerebral palsy treated due to spasticity. Clin. Neurol. Neurosurg. 2015, 135, 62–68. [Google Scholar] [CrossRef]
  177. Elia, A.E.; Bagella, C.F.; Ferre, F.; Zorzi, G.; Calandrella, D.; Romito, L.M. Deep brain stimulation for dystonia due to cerebral palsy: A review. Eur. J. Paediatr. Neurol. 2018, 22, 308–315. [Google Scholar] [CrossRef] [PubMed]
  178. Brown, E.G.; Bledsoe, I.O.; Luthra, N.S.; Miocinovic, S.; Starr, P.A.; Ostrem, J.L. Cerebellar deep brain stimulation for acquired hemidystonia. Mov. Disord. Clin. Pr. 2020, 7, 188–193. [Google Scholar] [CrossRef]
  179. Lin, S.; Wu, Y.; Li, H.; Zhang, C.; Wang, T.; Pan, Y.; He, L.; Shen, R.; Deng, Z.; Sun, B.; et al. Deep brain stimulation of the globus pallidus internus versus the subthalamic nucleus in isolated dystonia. J. Neurosurg. 2019, 132, 721–732. [Google Scholar] [CrossRef]
  180. Macerollo, A.; Sajin, V.; Bonello, M.; Barghava, D.; Alusi, S.H.; Eldridge, P.R.; Osman-Farah, J. Deep brain stimulation in dystonia: State of art and future directions. J. Neurosci. Methods 2020, 340, 108750. [Google Scholar] [CrossRef]
  181. Wu, Y.S.; Ni, L.H.; Fan, R.M.; Yao, M.Y. Meta-regression analysis of the long-term effects of pallidal and subthalamic deep brain stimulation for the treatment of isolated dystonia. World Neurosurg. 2019, 129, e409–e416. [Google Scholar] [CrossRef]
  182. Wagle Shukla, A.; Ostrem, J.L.; Vaillancourt, D.E.; Chen, R.; Foote, K.D.; Okun, M.S. Physiological effects of subthalamic nucleus deep brain stimulation surgery in cervical dystonia. J. Neurol. Neurosurg. Psychiatry 2018, 89, 1296–1300. [Google Scholar] [CrossRef]
  183. Toda, H.; Saiki, H.; Nishida, N.; Iwasaki, K. Update on deep brain stimulation for dyskinesia and dystonia: A literature review. Neurol. Med. Chir. 2016, 56, 236–248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Isaias, I.U.; Alterman, R.L.; Tagliati, M. Outcome predictors of pallidal stimulation in patients with primary dystonia: The role of disease duration. Brain 2008, 131, 1895–1902. [Google Scholar] [CrossRef] [Green Version]
  185. Yianni, J.; Bain, P.G.; Gregory, R.P.; Nandi, D.; Joint, C.; Scott, R.B.; Stein, J.F.; Aziz, T.Z. Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur. J. Neurol. 2003, 10, 239–247. [Google Scholar] [CrossRef]
  186. Krauss, J.K.; Yianni, J.; Loher, T.J.; Aziz, T.Z. Deep brain stimulation for dystonia. J. Clin. Neurophysiol. 2004, 21, 18–30. [Google Scholar] [CrossRef]
  187. Yokochi, F.; Kato, K.; Iwamuro, H.; Kamiyama, T.; Kimura, K.; Yugeta, A.; Okiyama, R.; Taniguchi, M.; Kumada, S.; Ushiba, J. Resting-state pallidal-cortical oscillatory couplings in patients with predominant phasic and tonic dystonia. Front. Neurol. 2018, 9, 375. [Google Scholar] [CrossRef]
  188. Kupsch, A.; Benecke, R.; Muller, J.; Trottenberg, T.; Schneider, G.H.; Poewe, W.; Eisner, W.; Wolters, A.; Muller, J.U.; Deuschl, G.; et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N. Engl. J. Med. 2006, 355, 1978–1990. [Google Scholar] [CrossRef] [Green Version]
  189. Volkmann, J.; Benecke, R. Deep brain stimulation for dystonia: Patient selection and evaluation. Mov. Disord. 2002, 17 (Suppl. 3), S112–S115. [Google Scholar] [CrossRef] [PubMed]
  190. Hung, S.W.; Hamani, C.; Lozano, A.M.; Poon, Y.Y.; Piboolnurak, P.; Miyasaki, J.M.; Lang, A.E.; Dostrovsky, J.O.; Hutchison, W.D.; Moro, E. Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Neurology 2007, 68, 457–459. [Google Scholar] [CrossRef] [PubMed]
  191. Wang, S.; Liu, X.; Yianni, J.; Green, A.L.; Joint, C.; Stein, J.F.; Bain, P.G.; Gregory, R.; Aziz, T.Z. Use of surface electromyography to assess and select patients with idiopathic dystonia for bilateral pallidal stimulation. J. Neurosurg. 2006, 105, 21–25. [Google Scholar] [CrossRef]
  192. Liu, X.; Griffin, I.C.; Parkin, S.G.; Miall, R.C.; Rowe, J.G.; Gregory, R.P.; Scott, R.B.; Aziz, T.Z.; Stein, J.F. Involvement of the medial pallidum in focal myoclonic dystonia: A clinical and neurophysiological case study. Mov. Disord. 2002, 17, 346–353. [Google Scholar] [CrossRef]
  193. Liu, X.; Wang, S.; Yianni, J.; Nandi, D.; Bain, P.G.; Gregory, R.; Stein, J.F.; Aziz, T.Z. The sensory and motor representation of synchronized oscillations in the globus pallidus in patients with primary dystonia. Brain 2008, 131, 1562–1573. [Google Scholar] [CrossRef] [Green Version]
  194. Liu, X.; Yianni, J.; Wang, S.; Bain, P.G.; Stein, J.F.; Aziz, T.Z. Different mechanisms may generate sustained hypertonic and rhythmic bursting muscle activity in idiopathic dystonia. Exp. Neurol. 2006, 198, 204–213. [Google Scholar] [CrossRef]
  195. Chen, C.C.; Kuhn, A.A.; Hoffmann, K.T.; Kupsch, A.; Schneider, G.H.; Trottenberg, T.; Krauss, J.K.; Wohrle, J.C.; Bardinet, E.; Yelnik, J.; et al. Oscillatory pallidal local field potential activity correlates with involuntary EMG in dystonia. Neurology 2006, 66, 418–420. [Google Scholar] [CrossRef]
  196. Chen, C.C.; Kuhn, A.A.; Trottenberg, T.; Kupsch, A.; Schneider, G.H.; Brown, P. Neuronal activity in globus pallidus interna can be synchronized to local field potential activity over 3–12 Hz in patients with dystonia. Exp. Neurol. 2006, 202, 480–486. [Google Scholar] [CrossRef]
  197. Silberstein, P.; Kuhn, A.A.; Kupsch, A.; Trottenberg, T.; Krauss, J.K.; Wohrle, J.C.; Mazzone, P.; Insola, A.; Di Lazzaro, V.; Oliviero, A.; et al. Patterning of globus pallidus local field potentials differs between parkinson’s disease and dystonia. Brain 2003, 126, 2597–2608. [Google Scholar] [CrossRef]
  198. Weinberger, M.; Hutchison, W.D.; Alavi, M.; Hodaie, M.; Lozano, A.M.; Moro, E.; Dostrovsky, J.O. Oscillatory activity in the globus pallidus internus: Comparison between parkinson’s disease and dystonia. Clin. Neurophysiol. 2012, 123, 358–368. [Google Scholar] [CrossRef] [PubMed]
  199. Barow, E.; Neumann, W.J.; Brucke, C.; Huebl, J.; Horn, A.; Brown, P.; Krauss, J.K.; Schneider, G.H.; Kuhn, A.A. Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements. Brain 2014, 137, 3012–3024. [Google Scholar] [CrossRef]
  200. Groen, J.L.; Ritz, K.; Contarino, M.F.; van de Warrenburg, B.P.; Aramideh, M.; Foncke, E.M.; van Hilten, J.J.; Schuurman, P.R.; Speelman, J.D.; Koelman, J.H.; et al. Dyt6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation. Mov. Disord. 2010, 25, 2420–2427. [Google Scholar] [CrossRef]
  201. Panov, F.; Tagliati, M.; Ozelius, L.J.; Fuchs, T.; Gologorsky, Y.; Cheung, T.; Avshalumov, M.; Bressman, S.B.; Saunders-Pullman, R.; Weisz, D.; et al. Pallidal deep brain stimulation for DYT6 dystonia. J. Neurol. Neurosurg. Psychiatry 2012, 83, 182–187. [Google Scholar] [CrossRef]
  202. Zittel, S.; Moll, C.K.; Bruggemann, N.; Tadic, V.; Hamel, W.; Kasten, M.; Lohmann, K.; Lohnau, T.; Winkler, S.; Gerloff, C.; et al. Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Mov. Disord. 2010, 25, 2405–2412. [Google Scholar] [CrossRef]
  203. Quartarone, A.; Hallett, M. Emerging concepts in the physiological basis of dystonia. Mov. Disord. 2013, 28, 958–967. [Google Scholar] [CrossRef]
  204. Benabid, A.L.; Pollak, P.; Gao, D.; Hoffmann, D.; Limousin, P.; Gay, E.; Payen, I.; Benazzouz, A. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J. Neurosurg. 1996, 84, 203–214. [Google Scholar] [CrossRef] [PubMed]
  205. Tasker, R.R. Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg. Neurol. 1998, 49, 145–153. [Google Scholar] [CrossRef]
  206. Pilitsis, J.G.; Metman, L.V.; Toleikis, J.R.; Hughes, L.E.; Sani, S.B.; Bakay, R.A. Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor. J. Neurosurg. 2008, 109, 640–646. [Google Scholar] [CrossRef]
  207. Morigaki, R.; Goto, S. Deep brain stimulation for essential tremor. In Deep Brain Stimulation for Neurological Disorders; Itakura, T., Ed.; Springer: Berlin/Heidelberg, Germany, 2015; pp. 135–155. [Google Scholar]
  208. Breakefield, X.O.; Blood, A.J.; Li, Y.; Hallett, M.; Hanson, P.I.; Standaert, D.G. The pathophysiological basis of dystonias. Nat. Rev. Neurosci. 2008, 9, 222–234. [Google Scholar] [CrossRef] [PubMed]
  209. Morigaki, R.; Goto, S. Striatal vulnerability in huntington’s disease: Neuroprotection versus neurotoxicity. Brain Sci. 2017, 7, 63. [Google Scholar] [CrossRef]
  210. Kawarai, T.; Morigaki, R.; Kaji, R.; Goto, S. Clinicopathological phenotype and genetics of x-linked dystonia-parkinsonism (XDP; DYT3; lubag). Brain Sci. 2017, 7, 72. [Google Scholar] [CrossRef]
  211. Goto, S.; Lee, L.V.; Munoz, E.L.; Tooyama, I.; Tamiya, G.; Makino, S.; Ando, S.; Dantes, M.B.; Yamada, K.; Matsumoto, S.; et al. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann. Neurol. 2005, 58, 7–17. [Google Scholar] [CrossRef]
  212. Goto, S.; Nagahiro, S.; Kaji, R. Striosome-matrix pathology of dystonias: A new hypothesis for dystonia genesis. In Dystonia: Causes, Symptoms, and Treatment; Kurstot, J., Forsström, M., Eds.; Nova Science: New York, NY, USA, 2010; pp. 1–22. [Google Scholar]
  213. Shakkottai, V.G.; Batla, A.; Bhatia, K.; Dauer, W.T.; Dresel, C.; Niethammer, M.; Eidelberg, D.; Raike, R.S.; Smith, Y.; Jinnah, H.A.; et al. Current opinions and areas of consensus on the role of the cerebellum in dystonia. Cerebellum 2017, 16, 577–594. [Google Scholar] [CrossRef] [Green Version]
  214. Morigaki, R.; Okita, S.; Goto, S. Dopamine-induced changes in Galphaolf protein levels in striatonigral and striatopallidal medium spiny neurons underlie the genesis of l-dopa-induced dyskinesia in parkinsonian mice. Front. Cell Neurosci. 2017, 11, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  215. Assous, M.; Tepper, J.M. Excitatory extrinsic afferents to striatal interneurons and interactions with striatal microcircuitry. Eur. J. Neurosci. 2019, 49, 593–603. [Google Scholar] [CrossRef]
  216. Koos, T.; Tepper, J.M. Inhibitory control of neostriatal projection neurons by GABAergic interneurons. Nat. Neurosci. 1999, 2, 467–472. [Google Scholar] [CrossRef]
  217. Mink, J.W. The basal ganglia: Focused selection and inhibition of competing motor programs. Prog. Neurobiol. 1996, 50, 381–425. [Google Scholar] [CrossRef]
  218. Amemori, K.; Gibb, L.G.; Graybiel, A.M. Shifting responsibly: The importance of striatal modularity to reinforcement learning in uncertain environments. Front. Hum. Neurosci. 2011, 5, 47. [Google Scholar] [CrossRef] [Green Version]
  219. Pisani, A.; Martella, G.; Tscherter, A.; Bonsi, P.; Sharma, N.; Bernardi, G.; Standaert, D.G. Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia. Neurobiol. Dis. 2006, 24, 318–325. [Google Scholar] [CrossRef]
  220. Martella, G.; Tassone, A.; Sciamanna, G.; Platania, P.; Cuomo, D.; Viscomi, M.T.; Bonsi, P.; Cacci, E.; Biagioni, S.; Usiello, A.; et al. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: Role of endogenous acetylcholine. Brain 2009, 132, 2336–2349. [Google Scholar] [CrossRef] [PubMed]
  221. Bonsi, P.; Cuomo, D.; Martella, G.; Madeo, G.; Schirinzi, T.; Puglisi, F.; Ponterio, G.; Pisani, A. Centrality of striatal cholinergic transmission in basal ganglia function. Front. Neuroanat. 2011, 5, 6. [Google Scholar] [CrossRef] [Green Version]
  222. Bruggemann, N. Contemporary functional neuroanatomy and pathophysiology of dystonia. J. Neural Transm. 2021, 128, 499–508. [Google Scholar] [CrossRef] [PubMed]
  223. Smith, Y.; Raju, D.V.; Pare, J.F.; Sidibe, M. The thalamostriatal system: A highly specific network of the basal ganglia circuitry. Trends Neurosci. 2004, 27, 520–527. [Google Scholar] [CrossRef] [PubMed]
  224. Sidibe, M.; Smith, Y. Thalamic inputs to striatal interneurons in monkeys: Synaptic organization and co-localization of calcium binding proteins. Neuroscience 1999, 89, 1189–1208. [Google Scholar] [CrossRef]
  225. Rudkin, T.M.; Sadikot, A.F. Thalamic input to parvalbumin-immunoreactive GABAergic interneurons: Organization in normal striatum and effect of neonatal decortication. Neuroscience 1999, 88, 1165–1175. [Google Scholar] [CrossRef]
  226. Bennay, M.; Gernert, M.; Richter, A. Spontaneous remission of paroxysmal dystonia coincides with normalization of entopeduncular activity in dt(SZ) mutants. J. Neurosci. 2001, 21, RC153. [Google Scholar] [CrossRef]
  227. Gernert, M.; Richter, A.; Loscher, W. In vivo extracellular electrophysiology of pallidal neurons in dystonic and nondystonic hamsters. J. Neurosci. Res. 1999, 57, 894–905. [Google Scholar] [CrossRef]
  228. Gernert, M.; Richter, A.; Loscher, W. Alterations in spontaneous single unit activity of striatal subdivisions during ontogenesis in mutant dystonic hamsters. Brain Res. 1999, 821, 277–285. [Google Scholar] [CrossRef]
  229. Gernert, M.; Hamann, M.; Bennay, M.; Loscher, W.; Richter, A. Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia. J. Neurosci. 2000, 20, 7052–7058. [Google Scholar] [CrossRef]
  230. Gittis, A.H.; Leventhal, D.K.; Fensterheim, B.A.; Pettibone, J.R.; Berke, J.D.; Kreitzer, A.C. Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. J. Neurosci. 2011, 31, 15727–15731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  231. Threlfell, S.; Lalic, T.; Platt, N.J.; Jennings, K.A.; Deisseroth, K.; Cragg, S.J. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 2012, 75, 58–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  232. Crittenden, J.R.; Tillberg, P.W.; Riad, M.H.; Shima, Y.; Gerfen, C.R.; Curry, J.; Housman, D.E.; Nelson, S.B.; Boyden, E.S.; Graybiel, A.M. Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons. Proc. Natl. Acad. Sci. USA 2016, 113, 11318–11323. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Possible hypothesis of the common mechanism underlying unwanted movements from several different sources. (A): normal condition, (B): aberrant condition; multiple structures (striosome, cortex, thalamus, cerebellum) can cause unwanted movements via hyperactivity of the cholinergic interneurons. S: striosome, IN: cholinergic interneurons, PN: pontine nucleus, DCN: deep cerebellar nuclei, Drd2 MSN: dopamine D2 receptor type medium spiny neurons.
Figure 1. Possible hypothesis of the common mechanism underlying unwanted movements from several different sources. (A): normal condition, (B): aberrant condition; multiple structures (striosome, cortex, thalamus, cerebellum) can cause unwanted movements via hyperactivity of the cholinergic interneurons. S: striosome, IN: cholinergic interneurons, PN: pontine nucleus, DCN: deep cerebellar nuclei, Drd2 MSN: dopamine D2 receptor type medium spiny neurons.
Life 11 00776 g001
Figure 2. Hypothesis of excessive and insufficient dopamine releases in the striatum. (A): normal dopamine release, (B): increased dopamine release due to hyperactive cholinergic transmission, (C): excessive dopamine release due to striosomal dysfunction, (D): insufficient dopamine release due to dysfunction in the dopaminergic neurons. S: striosome, IN: interneurons, DA: dopamine, Drd1 MSN: dopamine D1 receptor type medium spiny neurons.
Figure 2. Hypothesis of excessive and insufficient dopamine releases in the striatum. (A): normal dopamine release, (B): increased dopamine release due to hyperactive cholinergic transmission, (C): excessive dopamine release due to striosomal dysfunction, (D): insufficient dopamine release due to dysfunction in the dopaminergic neurons. S: striosome, IN: interneurons, DA: dopamine, Drd1 MSN: dopamine D1 receptor type medium spiny neurons.
Life 11 00776 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Morigaki, R.; Miyamoto, R.; Matsuda, T.; Miyake, K.; Yamamoto, N.; Takagi, Y. Dystonia and Cerebellum: From Bench to Bedside. Life 2021, 11, 776. https://doi.org/10.3390/life11080776

AMA Style

Morigaki R, Miyamoto R, Matsuda T, Miyake K, Yamamoto N, Takagi Y. Dystonia and Cerebellum: From Bench to Bedside. Life. 2021; 11(8):776. https://doi.org/10.3390/life11080776

Chicago/Turabian Style

Morigaki, Ryoma, Ryosuke Miyamoto, Taku Matsuda, Kazuhisa Miyake, Nobuaki Yamamoto, and Yasushi Takagi. 2021. "Dystonia and Cerebellum: From Bench to Bedside" Life 11, no. 8: 776. https://doi.org/10.3390/life11080776

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop