Impaired Saccade Adaptation in Tremor-Dominant Cervical Dystonia—Evidence for Maladaptive Cerebellum

Mahajan, Abhimanyu; Gupta, Palak; Jacobs, Joseph B.; Marsili, Luca; Sturchio, Andrea; Jinnah, Hyder A.; Espay, Alberto J.; Shaikh, Aasef G.

doi:10.1007/s12311-020-01104-y

Cited by 13 publications

(13 citation statements)

References 66 publications

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“…In future applications, this will allow to tune the MF toward specific functional or dysfunctional states that affect the cerebellum. Among these it is worth mentioning ataxias (Pedroso et al, 2019; Rosenthal, 2022), paroxysmal dyskinesia (Mendonça and Alves da Silva, 2021; Ekmen et al, 2022), dystonia (Mahajan et al, 2021; Morigaki et al, 2021), autistic spectrum disorders (Bruchhage et al, 2018; Kelly et al, 2020) as well as other pathologies like and multiple sclerosis (Tornes et al, 2014; Schreck et al, 2018), dementia (Monteverdi et al, 2022) and Parkinson disease (Wu and Hallett, 2013; Shen et al, 2020), in which a cerebellum involvement has been reported. The cerebellar MF could be applied to whole-brain simulators using TVB and DCM, as much as it has been done before for the isocortical MF in TVB (Pinotsis et al, 2012; Goldman et al, 2019; Sadeghi et al, 2020; Ruffini and Deco, 2021).…”

Section: Discussionmentioning

confidence: 99%

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

Lorenzi

Geminiani

Zerlaut

et al. 2022

Preprint

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Mean-field (MF) models can be used to summarize in a few statistical parameters the salient properties of an inter-wired neuronal network incorporating different types of neurons and synapses along with their topological organization. MF are crucial to efficiently implement the modules of large-scale brain models maintaining the specificity of local microcircuits. While MFs have been generated for the isocortex, they are still missing for other parts of the brain. Here we have designed and simulated a multi-layer MF of the cerebellar network (including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells) and validated it against experimental data and the corresponding spiking neural network (SNN) microcircuit model. The cerebellar MF was built using a system of equations, where properties of neuronal populations and topological parameters are embedded in inter-dependent transfer functions. The model time constant was optimised using local field potentials recorded experimentally from acute mouse cerebellar slices as a template. The MF satisfactorily reproduced the average dynamics of the different neuronal populations in response to various input patterns and predicted the modulation of Purkinje Cells firing depending on cortical plasticity, which drives learning in associative tasks, and the level of feedforward inhibition. The cerebellar MF provides a computationally efficient tool that will allow to investigate the causal relationship between microscopic neuronal properties and ensemble brain activity in virtual brain models addressing both physiological and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

Lorenzi

Geminiani

Zerlaut

et al. 2022

Preprint

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“…If classical genetic mechanisms were at play, not only would have other families with these genetic etiologies would have been reported but other genes might have been identified. Based on the recent successes of LRS technologies, and in line with precision medicine principles, a new molecular approach is required ( 102 – 105 ). Conditions traditionally grouped under such clinical categories as “ET,” “ET plus tremor,” “orthostatic tremor” (OT), “pseudo-OT,” and “indeterminate tremor” could be phenotypic expressions of several genetic etiologies ( 106 ).…”

Section: Long-read Sequencing In Tremor-related Disordersmentioning

confidence: 99%

Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing

et al. 2022

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Long-read sequencing (LRS) technologies have been recently introduced to overcome intrinsic limitations of widely-used next-generation sequencing (NGS) technologies, namely the sequencing limited to short-read fragments (150–300 base pairs). Since its introduction, LRS has permitted many successes in unraveling hidden mutational mechanisms. One area in clinical neurology in need of rethinking as it applies to genetic mechanisms is essential tremor (ET). This disorder, among the most common in neurology, is a syndrome often exhibiting an autosomal dominant pattern of inheritance whose large phenotypic spectrum suggest a multitude of genetic etiologies. Exome sequencing has revealed the genetic etiology only in rare ET families (FUS, SORT1, SCN4A, NOS3, KCNS2, HAPLN4/BRAL2, and USP46). We hypothesize that a reason for this shortcoming may be non-classical genetic mechanism(s) underpinning ET, among them trinucleotide, tetranucleotide, or pentanucleotide repeat disorders. In support of this hypothesis, trinucleotide (e.g., GGC repeats in NOTCH2NLC) and pentanucleotide repeat disorders (e.g., ATTTC repeats in STARD7) have been revealed as pathogenic in patients with a past history of what has come to be referred to as “ET plus,” bilateral hand tremor associated with epilepsy and/or leukoencephalopathy. A systematic review of LRS in neurodegenerative disorders showed that 10 of the 22 (45%) genetic etiologies ascertained by LRS include tremor in their phenotypic spectrum, suggesting that future clinical applications of LRS for tremor disorders may uncover genetic subtypes of familial ET that have eluded NGS, particularly those with associated leukoencephalopathy or family history of epilepsy. LRS provides a pathway for potentially uncovering novel genes and genetic mechanisms, helping narrow the large proportion of “idiopathic” ET.

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“…We must take into account the contribution of coexisting tremor when tackling prediction of spread in adult‐onset isolated dystonia as its frequency in this patient population is relatively high [9‐14]. Neurophysiological studies suggest that coexisting tremor may be the clinical hallmark of an "oscillatory" pathophysiological subtype of adult‐onset isolated dystonia, in which cerebellar outflow is more dysfunctional than in other subtypes [15‐18]. Tremor may occur in a body region manifesting dystonia (labeled in the Movement Disorders Society 1998 [19] and 2018 [20] classification of tremor as "dystonic tremor") and/or in a region not affected by dystonia (labeled in the same classifications as "tremor associated with dystonia").…”

Section: Introductionmentioning

confidence: 99%

Predictive modeling of spread in adult‐onset isolated dystonia: Key properties and effect of tremor inclusion

Wang

Sajobi

Morgante

et al. 2021

Euro J of Neurology

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Background and purpose Several clinical and demographic factors relate to anatomic spread of adult‐onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult‐onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. Methods Adult‐onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation (“dystonia‐only”) and one accepting dystonia OR tremor in any body part as disease manifestations (“dystonia OR tremor”). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. Results Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62–0.70 and 0.62–0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. Conclusions This predictive modeling of spread in adult‐onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals’ risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

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Impaired Saccade Adaptation in Tremor-Dominant Cervical Dystonia—Evidence for Maladaptive Cerebellum

Cited by 13 publications

References 66 publications

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing

Predictive modeling of spread in adult‐onset isolated dystonia: Key properties and effect of tremor inclusion

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