Neuropeptides and Their Roles in the Cerebellum.

Although more than 30 different types of neuropeptides have been identified in various cell types and circuits of the cerebellum, their unique functions in the cerebellum remain poorly understood. Given the nature of their diffuse distribution, peptidergic systems are generally assumed to exert a modulatory effect on the cerebellum via adaptively tuning neuronal excitability, synaptic transmission, and synaptic plasticity within cerebellar circuits. Moreover, cerebellar neuropeptides have also been revealed to be involved in the neurogenetic and developmental regulation of the developing cerebellum, including survival, migration, differentiation, and maturation of the Purkinje cells and granule cells in the cerebellar cortex. On the other hand, cerebellar neuropeptides hold a critical position in the pathophysiology and pathogenesis of many cerebellar-related motor and psychiatric disorders, such as cerebellar ataxias and autism. Over the past two decades, a growing body of evidence has indicated neuropeptides as potential therapeutic targets to ameliorate these diseases effectively. Therefore, this review focuses on eight cerebellar neuropeptides that have attracted more attention in recent years and have significant potential for clinical application associated with neurodegenerative and/or neuropsychiatric disorders, including brain-derived neurotrophic factor, corticotropin-releasing factor, angiotensin II, neuropeptide Y, orexin, thyrotropin-releasing hormone, oxytocin, and secretin, which may provide novel insights and a framework for our understanding of cerebellar-related disorders and have implications for novel treatments targeting neuropeptide systems.

A missense variant in EXOSC8 causes exon skipping and expands the phenotypic spectrum of pontocerebellar hypoplasia type 1C.

Pontocerebellar hypoplasia (PCH) is a rare heterogeneous neurodegenerative disorder affecting the pons and cerebellum and is currently classified into 17 types (PCH1-PCH17). PCH1 is distinguishable from other types by the association of spinal motor neuron dysfunction. Based on the underlying genetic etiology, PCH1 is further classified into 6 different subtypes (PCH1 A-F). Of them, PCH type 1C is caused by pathogenic variants in EXOSC8 gene and so far, only four families have been described in the literature. In this study, we report a new patient with PCH1 who proved by whole-exome sequencing to harbor a novel homozygous missense variant in the splice region of EXOSC8 gene (c.238 G > A; p.Val80Ile). Studying mRNA of the patient confirmed that this variant results in skipping of exon 5 of the gene and early protein truncation. Our patient presented with the main clinical findings of PCH type 1C including psychomotor retardation, spasticity, spinal muscle atrophy, and respiratory problems. However, unlike most of the reported cases, he did not develop hearing or visual impairment and displayed a longer survival. In addition, our patient had dysmorphic facies, nystagmus, congenital esotropia and contractures which were infrequently described in patients with EXOSC8. Diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, and thinning of the brain stem were additional new findings noted in our patient. This study presents the fifth family with this extremely rare type of PCH and expands the associated clinical and brain imaging findings.

The CODECS study: COgnitive DEficits in Cerebellar Stroke.

Part of the extra-pyramidal system, the cerebellum is more and more recognized by its non-motor functions known as the cerebellar cognitive affective syndrome. Several studies have identified disturbances specifically in executive and attentional functions after focal cerebellar lesions. However, most studies were performed in small and heterogeneous patient groups. Furthermore, there is a substantial variation in the methodology of assessment. Here, we present the results of a large and homogeneous cohort of patients with isolated uniform cerebellar lesions. After three months post-stroke all patients underwent structural neuroimaging to confirm an isolated lesion and were given neuropsychological testing. The results show that cerebellar lesions relate to mild but long-term cognitive impairment in a broad spectrum of neurocognitive functions compared to normative values. These findings confirm involvement of the cerebellum in cognitive processing and supports the theory of 'dysmetria of thought' based upon uniform cerebellar processing in multiple cognitive domains. This study highlights the following results: 1-Cognitive impairments after isolated cerebellar stroke is confirmed in several cognitive domains. 2-Semantic and phonemic fluency are most affected in cerebellar stroke patients. 3-Verbal deficits show an age-independent long term effect post-stroke and should be studied further in depth. 4-Cognitive disorders after cerebellar stroke are more prominent in women than men.

Pontocerebellar Hypoplasia 7 with Novel Compound Heterozygous Variants of TOE1 in a Boy with Micropenis, Developmental Delay, and Ataxia: The First Korean Case Report.

Pontocerebellar hypoplasia (PCH) is a rare neurodegenerative disorder characterized by hypoplasia of the pons and cerebellum and global developmental delay. Among several PCH types, PCH7 is a characteristic type that manifests with not only brain lesions but also sexual developmental disorders. The causative gene, TOE1, encodes a protein involved in small ribonucleic acid maturation and processing. TOE1 mutation is associated with neuronal survival that causes hypoplasia of the cerebellum and pons. We report the case of a male patient with PCH7, developmental delay, ataxia, micropenis, and undescended testis. Genetic analysis revealed compound heterozygous missense variants (c.955C>T and c.533T>G) in the TOE1 gene.

Advances in cerebellar disorders: pre-clinical models, therapeutic targets, and challenges.

INTRODUCTION: Cerebellar ataxias (CAs) represent neurological disorders with multiple etiologies and a high phenotypic variability. Despite progress in the understanding of pathogenesis, few therapies are available so far. Closing the loop between preclinical studies and therapeutic trials is important, given the impact of CAs upon patients' health and the roles of the cerebellum in multiple domains. Because of a rapid advance in research on CAs, it is necessary to summarize the main findings and discuss future directions. AREAS COVERED: We focus our discussion on preclinical models, cerebellar reserve, the therapeutic management of CAs, and suitable surrogate markers. We searched Web of Science and PubMed using keywords relevant to cerebellar diseases, therapy, and preclinical models. EXPERT OPINION: There are many symptomatic and/or disease-modifying therapeutic approaches under investigation. For therapy development, preclinical studies, standardization of disease evaluation, safety assessment, and demonstration of clinical improvements are essential. Stage of the disease and the level of the cerebellar reserve determine the goals of the therapy. Deficits in multiple categories and heterogeneity of CAs may require disease-, stage-, and symptom-specific therapies. More research is needed to clarify how therapies targeting the cerebellum influence both basal ganglia and the cerebral cortex, poorly explored domains in CAs.

Pearls & Oy-sters: Cognitive and Affective Dysfunction Caused by a Small Cerebellar Hemangioblastoma.

The primary function of the cerebellum is the coordination and regulation of movement; therefore, cerebellar tumors usually present with ataxia, dysarthria, and vertigo. Large tumors also cause elevated intracranial pressure that may lead to a disturbance of consciousness. Furthermore, it has become increasingly evident that the cerebellum plays a substantial role in cognitive and affective processing. A 44-year-old female patient presented with a 1-month history of depression and flat affect. She had no cerebellar symptoms including no coordination dysfunction or dysarthria. Cognitive function tests revealed impairments in attention, execution, and processing speed. Hamilton Depression Scale and Hospital Anxiety Depression Scale indicated moderate-to-severe depression. Magnetic resonance (MR) imaging revealed a 7-mm enhancing lesion in the culmen of the cerebellar vermis with surrounding edema. Technetium-99m ethyl cysteinate dimer single-photon emission tomography (SPECT) showed hypoperfusion in the left frontal lobe. Although she was initially treated with corticosteroids for presumed sero-negative autoimmune encephalitis, her symptoms persisted. She then underwent cerebellar lesion resection. The histologic diagnosis was hemangioblastoma. The patient's symptoms dramatically improved within 1 week of resection, including improved batteries for cognitive function and depression. Complete regression of cerebellar edema and left frontal lobe hypoperfusion was observed on MR and SPECT images, respectively. This case reiterates the crucial influence of the cerebellum on cognitive and affective function. Moreover, cognitive dysfunction may be masked in cases with focal cerebellar symptoms or elevated intracranial pressure and, consequently, not adequately evaluated.

Vestibulo-spatial navigation: pathways and sense of direction.

Aims of the present article are: 1) assessing vestibular contribution to spatial navigation, 2) exploring how age, global positioning systems (GPS) use, and vestibular navigation contribute to subjective sense of direction (SOD), 3) evaluating vestibular navigation in patients with lesions of the vestibular-cerebellum (patients with downbeat nystagmus, DBN) that could inform on the signals carried by vestibulo-cerebellar-cortical pathways. We applied two navigation tasks on a rotating chair in the dark: return-to-start (RTS), where subjects drive the chair back to the origin after discrete angular displacement stimuli (path reversal), and complete-the-circle (CTC) where subjects drive the chair on, all the way round to origin (path completion). We examined 24 normal controls (20-83 yr), five patients with DBN (62-77 yr) and, as proof of principle, two patients with early dementia (84 and 76 yr). We found a relationship between SOD, assessed by Santa Barbara Sense of Direction Scale, and subject's age (positive), GPS use (negative), and CTC-vestibular-navigation-task (positive). Age-related decline in vestibular navigation was observed with the RTS task but not with the complex CTC task. Vestibular navigation was normal in patients with vestibulo-cerebellar dysfunction but abnormal, particularly CTC, in the demented patients. We conclude that vestibular navigation skills contribute to the build-up of our SOD. Unexpectedly, perceived SOD in the elderly is not inferior, possibly explained by increased GPS use by the young. Preserved vestibular navigation in cerebellar patients suggests that ascending vestibular-cerebellar projections carry velocity (not position) signals. The abnormalities in the cognitively impaired patients suggest that their vestibulo-spatial navigation is disrupted.NEW & NOTEWORTHY Our subjective sense-of-direction is influenced by how good we are at spatial navigation using vestibular cues. Global positioning systems (GPS) may inhibit sense of direction. Increased use of GPS by the young may explain why the elderly's sense of direction is not worse than the young's. Patients with vestibulo-cerebellar dysfunction (downbeat nystagmus syndrome) display normal vestibular navigation, suggesting that ascending vestibulo-cerebellar-cortical pathways carry velocity rather than position signals. Pilot data indicate that dementia disrupts vestibular navigation.

The frequency and characteristics of saccadic dysmetria in isolated cerebellar infarction.

OBJECTIVES: To investigate the frequency and pattern of horizontal saccadic dysmetria in unilateral cerebellar infarction and identify the responsible region for horizontal saccadic dysmetria. METHODS: From the acute stroke registry of Keimyung University Dongsan Medical Center between July 2016 and October 2020, 43 patients with acute unilateral cerebellar infarction were enrolled. Eye movements were recorded during the acute period and the lesion was mapped using MRIcron software for subtraction analysis. Saccadic dysmetria was marked as hypometric when the gain is < 0.85 and hypermetric when > 1.0. RESULTS: Among the 43 participants, 30 patients (69.8%) demonstrated saccadic dysmetria. The age was significantly higher in patients with dysmetria (66.87 ± 12.82 vs. 53.54 ± 14.09, p = 0.004). Type of dysmetria showed a significant difference according to the vascular territory of the lesion. The posterior inferior cerebellar artery (PICA) infarction group presented ipsiversive saccadic dysmetria, while the superior cerebellar artery (SCA) group showed contraversive dysmetria (p < 0.001). In the SCA group, the culmen, fastigium, and dentate were the most frequently damaged regions, while the tonsil and inferior semilunar lobule were in the PICA group. CONCLUSION: Saccadic dysmetria was observed in a large proportion of cerebellar stroke patients, and the types of saccades were distinctive according to the vascular territory of the lesion.

Analysis of the Clinical Features and Imaging Findings of Pontocerebellar Hypoplasia Type 2D Caused by Mutations in SEPSECS Gene.

Pontocerebellar hypoplasia type 2D (PCH2D) caused by SEPSECS gene mutations is very rare and only described in a few case reports. In this study, we analyzed the clinical features and imaging findings of these individuals, so as to provide references for the clinic. We reported a case of PCH2D caused by a new complex heterozygote mutation in SEPSECS gene, and reviewed the literatures to summarize the clinical features and imaging findings and compare the differences between early-onset patients (EOPs) and late-onset patients (LOPs). Of 23 PCH2D patients, 19 cases were early-onset and 4 cases were late-onset, with average ages of 4.1 ± 4.0 years and 21.8 ± 9.4 years, females were more prevalent (14/19). EOPs mainly distributed in Arab countries (10/14) and Finland (4/14), while LOPs in East Asia (3/3). EOPs develop severe initial symptoms at the average age of 4.1 ± 7.8 months or shortly after birth, while LOPs experienced mild developmental delay in infancy. Microcephaly (10/11), intellectual disability (10/11), decreased motor function (10/11), and spastic or dystonic quadriplegia (8/10) were the common clinical features of EOPs and LOPs. EOPs also presented with visual impairment (5/7), seizures (4/7), neonatal irritability/opisthotonus (3/7), tremors/myoclonus (3/7), dysmorphic features (3/7), and other symptoms. EOPs were characterized by cerebellar symptoms (4/4). Magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy followed by less pronounced cerebral atrophy, and there was no pons atrophy in LOPs. Most patients of PCH2D were severe early-onset, and a few were late-onset with milder symptoms. EOPs and LOPs shared some common clinical features and MRI findings, but also had their own characteristics.

The Discovery of Anti-Yo (Anti-PCA1) Antibody in Patients with Paraneoplastic Cerebellar Degeneration: Opening a Window into Autoimmune Neurological Disease.

Prior to 1982, ovarian and certain other cancers were known to have a rare complication of progressive cerebellar ataxia, a disorder characterized pathologically by severe-often total-obliteration of cerebellar Purkinje cells. However, the cause of cerebellar injury in these patients was unknown. In that year, we began studies in which sera from individuals with this disorder were reacted with frozen sections of human cerebellum. These studies revealed that patients with ovarian cancer and cerebellar degeneration had high titers of antibodies directed against cytoplasmic antigens of Purkinje cells and deep cerebellar nuclei-a previously undescribed pattern of antibody response which was subsequently found not to be present in ovarian cancer patients who remained neurologically normal. This antibody, now known as "anti-Yo" or "anti-PCA1" provides a marker for rapidly progressive cerebellar ataxia and is heavily associated with gynecological and breast malignancies. Although the role of anti-Yo antibody in cerebellar injury has not been established in living animals, in vitro studies have demonstrated that anti-Yo antibody causes Purkinje cell death in the absence of T lymphocytes. In this commentary, we describe our studies leading to initial discovery of anti-Yo antibody, discuss the relationship of this discovery to current knowledge of paraneoplastic neurological disease, and outline some important questions which remain to be resolved before we fully understand the pathogenesis and optimal treatment of this disorder.

Cerebello-cerebral resting-state functional connectivity in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by progressive motor and nonmotor deficits concomitant with degenerative pathophysiological changes within the cerebellum. The cerebellum is topographically organized into cerebello-cerebral circuits that create distinct functional networks regulating movement, cognition, and affect. SCA3-associated motor and nonmotor symptoms are possibly related not only to intracerebellar changes but also to disruption of the connectivity within these cerebello-cerebral circuits. However, to date, no comprehensive investigation of cerebello-cerebral connectivity in SCA3 has been conducted. The present study aimed to identify cerebello-cerebral functional connectivity alterations and associations with downstream clinical phenotypes and upstream topographic markers of cerebellar neurodegeneration in patients with SCA3. This study included 45 patients with SCA3 and 49 healthy controls. Voxel-based morphometry and resting-state functional magnetic resonance imaging (MRI) were performed to characterize the cerebellar atrophy and to examine the cerebello-cerebral functional connectivity patterns. Structural MRI confirmed widespread gray matter atrophy in the motor and cognitive cerebellum of patients with SCA3. We found reduced functional connectivity between the cerebellum and the cerebral cortical networks, including the somatomotor, frontoparietal, and default networks; however, increased connectivity was observed between the cerebellum and the dorsal attention network. These abnormal patterns correlated with the CAG repeat expansion and deficits in global cognition. Our results indicate the contribution of cerebello-cerebral networks to the motor and cognitive impairments in patients with SCA3 and reveal that such alterations occur in association with cerebellar atrophy. These findings add important insights into our understanding of the role of the cerebellum in SCA3.

Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy.

Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed. We report a case that presented to the hospital with a flare-up of the disease. We describe the brain magnetic resonance imaging findings, which are still not well characterized, to raise awareness of this diagnosis.

The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia.

AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

A Systematic Review on Anti-Yo/PCA-1 Antibody: Beyond Cerebellar Ataxia in Middle-Aged Women with Gynecologic Cancer.

Current understanding of anti-Yo/PCA1 antibody-associated cerebellar ataxia is based on case reports and small case series. Our goal was to summarize clinical features, highlighting atypical presentations and gaps of knowledge. Following the PRISMA guidelines, we systematically screened Pubmed/MEDLINE, Embase, Scopus, and Web of Science from inception to April 2022 for all case reports and series concerning anti-Yo antibody-associated cerebellar ataxia. We collected data on clinical presentation, investigation findings, and treatment outcomes. Of 379 included patients, 96% were female with gynecologic cancer (82%). Among men, 87% had an associated tumor, mainly of gastrointestinal origin. The median age was 60 years old. Pancerebellar ataxia was the main clinical feature, but extracerebellar findings were frequent during the disease course. Vertigo and imbalance can be present early in the disease course in about two thirds of patients, as a prodromal phase. Although neuroimaging usually is normal or shows cerebellar atrophy, inflammatory changes may also be present. More than half of the patients reported some improvement after immunotherapy. However, despite treatment, 84% of survivors were unable to walk unassisted on follow-up. Our study provides objective data and advances in current knowledge of anti-Yo antibody-associated cerebellar ataxia such as the description of prodromal symptoms, extracerebellar findings, and its presentations in males.

[Transient changes in food preference in a patient with cerebellar infarction].

A 44-year-old woman was admitted to our hospital due to dizziness and ataxia of the trunk and right upper limb. Brain MRI revealed an acute infarct lesion in the right posterior inferior cerebellar artery territory. In addition to the cognitive deterioration observed in the subacute phase, a change was noted in her food preference-from light-tasting, low-caloric Japanese cuisine, sugarless coffee, and hot drinks to strong-tasting, high-caloric Western cuisine, sugar-rich coffee, and iced drinks. Single-photon emission computed tomography showed hypoperfusion in the bilateral frontal lobes and right cerebellum. These cognitive and food preference-related changes were gradually restored over six months after the onset. The reduced cerebral blood flow in the bilateral frontal lobes also restored along with the clinical improvement, with the maximal changes in the bilateral subcallosal areas. This case suggests that changes in food preference can occur as a symptom of cerebellar infarction, possibly by the mechanism similar to cerebellar cognitive affective syndrome.

A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity.

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1ß, we sought to uncover causes of cerebellar damage. In this model, IL-1ß is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL-1ß treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI-detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL-1ß leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target.

Cognitive Dysfunction following Cerebellar Stroke: Insights Gained from Neuropsychological and Neuroimaging Research.

Although the cerebellum has been consistently noted in the process of cognition, the pathophysiology of this link is still under exploration. Cerebellar stroke, in which the lesions are focal and limited, provides an appropriate clinical model disease for studying the role of the cerebellum in the cognitive process. This review article targeting the cerebellar stroke population (1) describes a cognitive impairment profile, (2) identifies the cerebellar structural alterations linked to cognition, and (3) reveals possible mechanisms of cerebellar cognition using functional neuroimaging. The data indicates the disruption of the cerebro-cerebellar loop in cerebellar stroke and its contribution to cognitive dysfunctions. And the characteristic of cognitive deficits are mild, span a broad spectrum, dominated by executive impairment. The consideration of these findings could contribute to deeper and more sophisticated insights into the cognitive function of the cerebellum and might provide a novel approach to cognitive rehabilitation. The goal of this review is to spread awareness of cognitive impairments in cerebellar disorders.

Spatiotemporal changes in along-tract profilometry of cerebellar peduncles in cerebellar mutism syndrome.

Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome. In this retrospective study, twenty-eight children with medulloblastoma (mean age 8.8 ± 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy (FA) at 30 nodes along each tract. Thirteen patients developed cerebellar mutism syndrome. FA was significantly lower in the distal third of the left superior cerebellar peduncle pre-operatively in all patients compared to controls (FA in proximal third 0.228, middle and distal thirds 0.270, p = 0.01, Cohen's d = 0.927). Pre-operative differences in FA did not predict cerebellar mutism syndrome. However, post-operative reductions in FA were highly specific to the distal left superior cerebellar peduncle, and were most pronounced in children with cerebellar mutism syndrome compared to those without at the 1-4 month follow up (0.325 vs 0.512, p = 0.042, d = 1.36) and at the 1-year follow up (0.342, vs 0.484, p = 0.038, d = 1.12). High spatial resolution cerebellar profilometry indicated a site-specific alteration of the distal segment of the superior cerebellar peduncle seen in cerebellar mutism syndrome which may have important surgical implications in the treatment of these devastating tumours of childhood.

Differences in hippocampal plasticity and memory outcomes in anterior versus posterior cerebellar stroke.

Neurological symptoms following cerebellar stroke can range from motor to cognitive-affective impairments. Topographic imaging studies from patients with lesions confined to the cerebellum have shown evidence linking anterior cerebellar lobules with motor function and posterior lobules with cognitive function. Damage to the cerebellum can disrupt functional connectivity in cerebellar stroke patients, as it is highly interconnected with forebrain motor and cognitive areas. The hippocampus plays a key role in memory acquisition, a cognitive domain that is negatively impacted by posterior cerebellar stroke, and there is increasing evidence that the cerebellum can affect hippocampal function in health and disease. To study these topographical dissociations, we developed a mouse photo-thrombosis model to produce unilateral strokes in anterior (lobules III-V) or posterior (lobules VI-VIII) cerebellar cortex to examine hippocampal plasticity and behavior. Histological and MRI data demonstrate reproducible injury that is confined to the targeted lobules. We then measured hippocampal long-term potentiation (LTP) ex-vivo with extracellular field recording experiments in acute brain slices obtained from mice 7 days post-cerebellar stroke. Interestingly, we found that a unilateral posterior stroke resulted in a contralateral hippocampal impairment, matching the cerebellothalamic pathway trajectory, while LTP was intact in both hippocampi of mice with anterior strokes. We also assessed motor coordination and memory function at 7 days post-stroke using a balance beam, contextual and delay fear conditioning (CFC and DFC), and novel object recognition (NOR) tasks. Mice with anterior strokes showed lack of coordination evaluated as an increased number of missteps, while mice with posterior strokes did not. Mice with anterior or posterior cerebellar strokes demonstrated similar freezing behavior to shams in CFC and DFC, while only posterior stroke mice displayed a reduced discrimination index in the NOR task. These data suggest that a unilateral LTP impairment observed in mice with posterior strokes produces a mild memory impairment. Our results demonstrate that our model recapitulates aspects of clinical lesion-symptom mapping, with anterior cerebellar strokes producing impaired motor coordination and posterior cerebellar strokes producing an object-recognition memory impairment. Further studies are warranted to interrogate other motor and cognitive-affective behaviors and brain region specific alterations following focal cerebellar stroke. The novel model presented herein will allow for future preclinical translational studies to improve neurological deficits after cerebellar stroke.