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New Horizons in Cerebellar Research
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New Horizons in Cerebellar Research

A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601).

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 25744

Special Issue Editors

Dr. Hiroshi Mitoma

E-Mail Website
Guest Editor
Medical Education Promotion Center, Tokyo Medical University, Tokyo 160-0023, Japan
Interests: neurophysiology; movement disorders; cerebellar diseases; immune-mediated cerebellar ataxias; cerebellar physiology; accelerometers; medical signal processing; gait analysis
Special Issues, Collections and Topics in MDPI journals
Dr. Mario Manto

E-Mail Website
Assistant Guest Editor
1. Unité des Ataxies Cérébelleuses, Department of Neurology, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium
2. Service des Neurosciences, University of Mons, 7000 Mons, Belgium
Interests: cerebellum; ataxias; movement disorders; neuroanatomy
Special Issues, Collections and Topics in MDPI journals
Dr. Aasef G. Shaikh

E-Mail Website
Assistant Guest Editor
University Hospitals, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA
Interests: cerebellum; eye movements; dystonia; vestibular function; tremor

Special Issue Information

Dear Colleagues,

The cerebellum is characterized by geometrical circuitry, presents many forms of synaptic plasticity, and shows abundant connections to the other CNS regions. Through this connectivity, the cerebellum coordinates activities along with other CNS regions such as the cerebral cortex. Marked developments in anatomy, physiology, and molecular biology have provided new images of the cerebellum's functions over the last few decades. The current view is that the cerebellum holds internal models acquired through learning and coordinates movements in a predictive fashion. The cerebellum is also involved in cognitive/affective/social control. Furthermore, cross-talk between the environment and the cerebellum is emerging as a new field. This could also be a clue for thinking about relationships between environmental factors and the brain.

Many toxic agents impact the cerebellum. Up to 15% of ataxic patients have toxic- and ethanol-induced cerebellar ataxia (CA). Thus, clinical features of toxic CA should be re-examined systematically from a point of differential diagnosis with other etiologies. Cellular mechanisms of cell death in ethanol-induced CA need to be further examined in an attempt to suggest novel therapeutic targets.

Environmental enrichment (EE) was originally a concept of animal breeding. It is well known that EE improves cognitive functions not only in animals but also in some conditions such as autism. On the other hand, recent studies have shown that the cerebellum can facilitate compensation and restoration to the pathology, which is termed as cerebellar reserve, and, importantly, EE facilitates cerebellar reserve.

This Special Issue calls for manuscripts addressing the following issues:

  1. Clinical profiles and pathomechanisms in toxic- and ethanol-induced cerebellar ataxia, from the fetal period to the elderly period;
  2. Molecular modifications in cerebellar neurons following toxic and ethanol exposure, with an emphasis on cellular/molecular/genetic mechanisms. Animal models of environmental ataxias;
  3. Gadolinium deposits in the cerebellum: from in vitro studies in the laboratory to in vivo investigations in humans;
  4. Actions of EE on cerebellar reserve, with the aim of clarifying how EE impacts cerebellar circuitry both functionally and structurally;
  5. Studies on the effects of toxic agents upon cerebellar motor syndrome, vestibular cerebellar syndrome, and cerebellar cognitive affective syndrome/Schmahmann’s syndrome.

We welcome original research papers using different study designs, as well as systematic reviews and meta-analyses.

Dr. Hiroshi Mitoma
Dr. Mario Manto
Dr. Aasef G. Shaikh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Environmental Research and Public Health is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2500 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cerebellum
  • toxic cerebellar ataxias
  • developmental ataxias
  • ethanol-induced cerebellar ataxia
  • gadolinium deposits in the cerebellum
  • environmental enrichment
  • cerebellar reserve
  • cerebellar cognitive affective syndrome/Schmahmann’s syndrome

Published Papers (7 papers)

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Research

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21 pages, 5122 KiB  
Article
Cerebellar Agenesis and Bilateral Polimicrogyria Associated with Rare Variants of CUB and Sushi Multiple Domains 1 Gene (CSMD1): A Longitudinal Neuropsychological and Neuroradiological Case Study
by Floriana Costanzo, Ginevra Zanni, Elisa Fucà, Margherita Di Paola, Sabina Barresi, Lorena Travaglini, Giovanna Stefania Colafati, Antonio Gambardella, Emanuele Bellacchio, Enrico Bertini, Deny Menghini and Stefano Vicari
Int. J. Environ. Res. Public Health 2022, 19(3), 1224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph19031224 - 22 Jan 2022
Cited by 1 | Viewed by 2388
Abstract
Cerebellar agenesis is an extremely rare condition characterized by a near complete absence of the cerebellum. The pathogenesis and molecular basis remain mostly unknown. We report the neuroradiological, molecular, neuropsychological and behavioral characterization of a 5-year-old girl, with cerebellar agenesis associated with parietal [...] Read more.
Cerebellar agenesis is an extremely rare condition characterized by a near complete absence of the cerebellum. The pathogenesis and molecular basis remain mostly unknown. We report the neuroradiological, molecular, neuropsychological and behavioral characterization of a 5-year-old girl, with cerebellar agenesis associated with parietal and peri-Sylvian polymicrogyria, followed-up for 10 years at four time points. Whole exome sequencing identified two rare variants in CSMD1, a gene associated with neurocognitive and psychiatric alterations. Mild intellectual impairment, cerebellar ataxia and deficits in language, memory and executive functions, with relatively preserved adaptive and psychopathological domains, were initially showed. Phonological awareness and verbal memory declined at 11 years of age, and social and anxiety problems emerged. Adaptive and psychopathological characteristics dramatically worsened at 15 years. In summary, the developmental clinical outcome showed impairment in multiple cognitive functions in childhood, with a progressive decline in cognitive and adaptive abilities and the emergence of psychopathological symptoms in adolescence. The observed phenotype could be the result of a complex interplay between cerebellar abnormality, brain malformation and the relations with CSMD1 variants. These findings may provide insights into the developmental clinical outcomes of a co-occurrence between rare brain malformation and rare genetic variants associated to neurodevelopmental disorders. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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7 pages, 626 KiB  
Communication
Identification of the Prodromal Symptoms and Pre-Ataxic Stage in Cerebellar Disorders: The Next Challenge
by Mario Manto, Aasef G. Shaikh and Hiroshi Mitoma
Int. J. Environ. Res. Public Health 2021, 18(19), 10057; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph181910057 - 24 Sep 2021
Cited by 2 | Viewed by 2260
Abstract
Cerebellar ataxias (CAs) manifest with a combination of motor incoordination, cognitive, affective and recently identified social symptoms. Novel therapies aim to stop the progression of the subgroup of the degenerative ataxias, or even to cure the disease with a functional and anatomical restoration [...] Read more.
Cerebellar ataxias (CAs) manifest with a combination of motor incoordination, cognitive, affective and recently identified social symptoms. Novel therapies aim to stop the progression of the subgroup of the degenerative ataxias, or even to cure the disease with a functional and anatomical restoration of the cerebellar circuitry in the near future. The goal of stopping the progression of the disease is particularly relevant if applied at a very early stage of the disease, when the cerebellar reserve is only slightly impaired. Therefore, the search of the prodromal phase or pre-ataxic stage of CAs represents a very important challenge for the scientific community. The identification of pre-manifest individuals and the recruitment of individuals at risk has become a key-challenge to address neuroprotective therapies. The feasibility is high due to the recent progress in the biological and morphological biomarkers of CAs. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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11 pages, 2994 KiB  
Article
Two-Photon Laser Ablation and In Vivo Wide-Field Imaging of Inferior Olive Neurons Revealed the Recovery of Olivocerebellar Circuits in Zebrafish
by Kanae Hiyoshi, Kaito Saito, Narumi Fukuda, Takahisa Matsuzaki, Hiroshi Y. Yoshikawa and Sachiko Tsuda
Int. J. Environ. Res. Public Health 2021, 18(16), 8357; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph18168357 - 06 Aug 2021
Cited by 3 | Viewed by 2614
Abstract
The cerebellum, a brain region with a high degree of plasticity, is pivotal in motor control, learning, and cognition. The cerebellar reserve is the capacity of the cerebellum to respond and adapt to various disorders via resilience and reversibility. Although structural and functional [...] Read more.
The cerebellum, a brain region with a high degree of plasticity, is pivotal in motor control, learning, and cognition. The cerebellar reserve is the capacity of the cerebellum to respond and adapt to various disorders via resilience and reversibility. Although structural and functional recovery has been reported in mammals and has attracted attention regarding treatments for cerebellar dysfunction, such as spinocerebellar degeneration, the regulatory mechanisms of the cerebellar reserve are largely unidentified, particularly at the circuit level. Herein, we established an optical approach using zebrafish, an ideal vertebrate model in optical techniques, neuroscience, and developmental biology. By combining two-photon laser ablation of the inferior olive (IO) and long-term non-invasive imaging of “the whole brain” at a single-cell resolution, we succeeded in visualization of the morphological changes occurring in the IO neuron population and showed at a single-cell level that structural remodeling of the olivocerebellar circuit occurred in a relatively short period. This system, in combination with various functional analyses, represents a novel and powerful approach for uncovering the mechanisms of the cerebellar reserve, and highlights the potential of the zebrafish model to elucidate the organizing principles of neuronal circuits and their homeostasis in health and disease. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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Review

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18 pages, 481 KiB  
Review
Environmental Enrichment Enhances Cerebellar Compensation and Develops Cerebellar Reserve
by Francesca Gelfo and Laura Petrosini
Int. J. Environ. Res. Public Health 2022, 19(9), 5697; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph19095697 - 07 May 2022
Cited by 9 | Viewed by 1876
Abstract
The brain is able to change its structure and function in response to environmental stimulations. Several human and animal studies have documented that enhanced stimulations provide individuals with strengthened brain structure and function that allow them to better cope with damage. In this [...] Read more.
The brain is able to change its structure and function in response to environmental stimulations. Several human and animal studies have documented that enhanced stimulations provide individuals with strengthened brain structure and function that allow them to better cope with damage. In this framework, studies based on the exposure of animals to environmental enrichment (EE) have provided indications of the mechanisms involved in such a beneficial action. The cerebellum is a very plastic brain region that responds to every experience with deep structural and functional rearrangement. The present review specifically aims to collect and synthesize the evidence provided by animal models on EE exposure effects on cerebellar structure and function by considering the studies on healthy subjects and on animals exposed to EE both before and after damage involving cerebellar functionality. On the whole, the evidence supports the role of EE in enhancing cerebellar compensation and developing cerebellar reserve. However, since studies addressing this issue are still scarce, large areas of inconsistency and lack of clarity remain. Further studies are required to provide suggestions on possible mechanisms of enhancement of compensatory responses in human patients following cerebellar damage. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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14 pages, 1740 KiB  
Review
Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum
by Hiroshi Mitoma, Mario Manto and Aasef G. Shaikh
Int. J. Environ. Res. Public Health 2021, 18(16), 8678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph18168678 - 18 Aug 2021
Cited by 21 | Viewed by 6431
Abstract
Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, [...] Read more.
Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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12 pages, 1233 KiB  
Review
Effects of Gadolinium Deposits in the Cerebellum: Reviewing the Literature from In Vitro Laboratory Studies to In Vivo Human Investigations
by Miski Aghnia Khairinisa, Winda Ariyani, Yoshito Tsushima and Noriyuki Koibuchi
Int. J. Environ. Res. Public Health 2021, 18(14), 7214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph18147214 - 06 Jul 2021
Cited by 6 | Viewed by 4578
Abstract
Gadolinium (Gd)-based contrast agents (GBCAs) are chemicals injected intravenously during magnetic resonance imaging (MRI) to enhance the diagnostic yield. The repeated use of GBCAs can cause their deposition in the brain, including the cerebellum. Such deposition may affect various cell subsets in the [...] Read more.
Gadolinium (Gd)-based contrast agents (GBCAs) are chemicals injected intravenously during magnetic resonance imaging (MRI) to enhance the diagnostic yield. The repeated use of GBCAs can cause their deposition in the brain, including the cerebellum. Such deposition may affect various cell subsets in the brain and consequently cause behavioral alterations due to neurotoxicity. Caution should thus be exercised in using these agents, particularly in patients who are more likely to have repeated enhanced MRIs during their lifespan. Further studies are required to clarify the toxicity of GBCAs, and potential mechanisms causing neurotoxicity have recently been reported. This review introduces the effects of GBCAs in the cerebellum obtained from in vitro and in vivo studies and considers the possible mechanisms of neurotoxicity involved. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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16 pages, 452 KiB  
Review
Cerebellar Degeneration in Epilepsy: A Systematic Review
by Manar Ibdali, Marios Hadjivassiliou, Richard A. Grünewald and Priya D. Shanmugarajah
Int. J. Environ. Res. Public Health 2021, 18(2), 473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph18020473 - 08 Jan 2021
Cited by 16 | Viewed by 4354
Abstract
Introduction: Cerebellar degeneration has been associated in patients with epilepsy, though the exact pathogenic mechanisms are not understood. The aim of this systematic review was to identify the prevalence of cerebellar degeneration in patients with epilepsy and identify any pathogenic mechanisms. Methodology: A [...] Read more.
Introduction: Cerebellar degeneration has been associated in patients with epilepsy, though the exact pathogenic mechanisms are not understood. The aim of this systematic review was to identify the prevalence of cerebellar degeneration in patients with epilepsy and identify any pathogenic mechanisms. Methodology: A systematic computer-based literature search was conducted using the PubMed database. Data extracted included prevalence, clinical, neuroradiological, and neuropathological characteristics of patients with epilepsy and cerebellar degeneration. Results: We identified three consistent predictors of cerebellar degeneration in the context of epilepsy in our review: temporal lobe epilepsy, poor seizure control, and phenytoin as the treatment modality. Whole brain and hippocampal atrophy were also identified in patients with epilepsy. Conclusions: Cerebellar degeneration is prevalent in patients with epilepsy. Further prospective studies are required to confirm if the predictors identified in this review are indeed linked to cerebellar degeneration and to establish the pathogenic mechanisms that result in cerebellar insult. Full article
(This article belongs to the Special Issue New Horizons in Cerebellar Research)
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