The Role of the Cerebellum in Degenerative Ataxias and Essential Tremor: Insights From Noninvasive Modulation of Cerebellar Activity

Over the last three decades, measuring and modulating cerebellar activity and its connectivity with other brain regions has become an emerging research topic in clinical neuroscience. The most important connection is the cerebellothalamocortical pathway, which can be functionally interrogated using a paired-pulse transcranial magnetic stimulation paradigm. Cerebellar brain inhibition reflects the magnitude of suppression of motor cortex excitability after stimulating the contralateral cerebellar hemisphere and therefore represents a neurophysiological marker of the integrity of the efferent cerebellar tract. Observations that cerebellar noninvasive stimulation techniques enhanced performance of certain motor and cognitive tasks in healthy individuals have inspired attempts to modulate cerebellar activity and connectivity in patients with cerebellar diseases in order to achieve clinical benefit. We here comprehensively explore the therapeutic potential of these techniques in two movement disorders characterized by prominent cerebellar involvement, namely the degenerative ataxias and essential tremor. The article aims to illustrate the (patho)physiological insights obtained from these studies and how these translate into clinical practice, where possible by addressing the association with cerebellar brain inhibition. Finally, possible explanations for some discordant interstudy findings, shortcomings in our current understanding, and recommendations for future research will be provided. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

The clinical versus radiological diagnosis of alcoholic cerebellar degeneration

We report the clinical characteristics of 65 patients with alcoholic cerebellar degeneration as verified by computerized tomography of the brain. Thirty-two patients (49%) had clear clinical signs of the disease such as broad-based staggering gait, impaired heel-to-toe walking, terminal oscillations in heel-knee test and slow (3/s) leg tremor. These signs were virtually absent in 33 patients (51%) who, nevertheless, had radiological signs of cerebellar degeneration. Traumatic brain injuries were more frequent in those patients who had both clinical and radiological signs of alcoholic cerebellar degeneration. Furthermore, this group showed longer periods of heavy drinking, more severe cerebral atrophy and more profound neuropsychological impairment than a control group of 92 alcoholics with neither clinical nor radiological signs of cerebellar disease. We conclude that careful clinical neurological examination is needed to diagnose alcoholic cerebellar degeneration which is apparently a more common disease than first realized. Subclinical cases can be diagnosed with the help of computerized tomography of the brain.     

Secondary changes in cerebellar perfusion (diaschisis) in hemiplegia during childhood: SPECT study of 55 children

Diaschisis is a functional impairment at a site in the brain remote from the lesion causing it. An investigation of cerebellar diaschisis in childhood was undertaken to better understand the functional maturation of the corticopontocerebellar tract in developing brain. A retrospective study of cerebellar diaschisis in 55 hemiplegic children was conducted using singlephoton emission computed tomography (SPECT) with ¹²³I-IMP. Cerebellar diaschisis was evaluated by 2 authors. Crossed cerebellar diaschisis (CCD) was found in 6 of 55 patients. SPECT findings of patients who presented with CCD disclosed supratentorial hypoperfusion of varying degrees, from focally to the whole hemisphere; however, patients had frontal and/or parietal hypoperfusion in common. A second type of cerebellar diaschisis also was demonstrated. Cerebellar hypoperfusion ipsilateral to supratentorial lesions, ipsilateral cerebellar diaschisis (ICD), was observed in 10 of 55 patients. CCD occurred in the patients who suffered from brain injuries after 7 years, 5 months of age, while ICD manifested in patients whose brain injuries occurred before 3 years, 1 month of age. The production of remote effects, such as CCD and ICD, could be closely related to maturation of the corticopontocerebellar tract in the developing brain during childhood.     

Where is the trace in trace conditioning?

Intensive mapping of the essential cerebellar brain circuits for Pavlovian eyeblink conditioning appeared relatively complete by 2000, but new data indicate the need for additional differentiation of cerebellar regions and mechanisms coding delay and trace conditioning. This is especially important, as trace conditioning is an experimentally tractable model of declarative learning. The temporal gap in trace eyeblink conditioning may be bridged by forebrain regions through pontine-cerebellar nuclear connections that can bypass cerebellar cortex, whereas a cerebellar cortical long-term-depression-like process appears to be required to support normal delay conditioning. Experiments focusing on the role of cerebellar cortex and deep nuclei in delay versus trace conditioning add perspective on brain substrates of these seemingly similar paradigms, which differ only by a brief stimulus-free time gap between conditioned and unconditioned stimuli. This temporal gap appears to impose forebrain dependencies and differentially engage different cerebellar circuitry during acquisition of conditioned responses.     

Acute cerebellar ataxia in children

Acute cerebellar ataxia is a benign syndrome usually occurring after an acute febrile disease. In a few cases neuroradiological investigations reveal cerebellar alterations. Clinical and neuroradiological involvement of the brain stem has rarely been reported in the literature. We present five cases of acute cerebellar ataxia. In two cases the cerebellar symptomatology was associated with neurological signs of brain stem involvement. CT scans did not show any pathologic findings in three patients. MRI disclosed cerebellar or brain stem alterations in all the patients. Clinical and neuroradiological findings allow differentiation of this pathologic entity from other demyelinating or dysmyelinating diseases. The value of MRI in detection and localization of the lesions and in following their evolution is emphasized. Received: 4 December 1996 Revised: 20 May 1997     

Psychiatric symptoms and cerebellar pathology

The authors describe three patients hospitalized for psychiatric disorders, all of whom had cerebellar lesions. Referring to recent research on nonmotor cerebellar functions, the authors suggest that patients with cerebellar lesions may develop an organic brain syndrome that closely resembles the organic brain syndrome associated with cerebral cortical lesions.     

Isolated hemiataxia after supratentorial brain infarction.

Acute isolated hemiataxia is in most cases due to infratentorial (cerebellar) stroke. It has only twice been described in supratentorial stroke--namely, after thalamic infarction and a capsular haemorrhage. Three patients with isolated hemiataxia after a supratentorial brain infarct are described. These patients were seen in a period of five years during which 899 patients with a first supratentorial brain infarct were registered. Clinically the hemiataxia was of the cerebellar type. In two patients, CT and MRI showed a small, deep (lacunar) infarct restricted to the posterior limb of the internal capsule, a site not previously reported in isolated hemiataxia. The third patient had a small, deep (lacunar) infarct in the thalamus extending into the adjacent posterior limb of the internal capsule. Isolated hemiataxia after a supratentorial brain infarct is a very rare clinical stroke syndrome. The cerebellar type hemiataxia was most likely caused by interruption of the cerebellar pathways at the level of the internal capsule. Our cases confirm prior observations that the cerebellar pathways run through the posterior part of the posterior limb of the internal capsule separately from the motor and sensory pathways.     

Comparative Evaluation of the Cerebral and Cerebellar White Matter Development in Pediatric Age Group using Quantitative Diffusion Tensor Imaging

Age-dependent changes in the normal cerebral white matter have been reported; however, there is no study on normal cerebellar white matter maturation in developing brain using diffusion tensor imaging (DTI). We performed DTI in 21 children who had normal neurological assessment along with no evidence of any abnormality on imaging. The aim of this study was to compare the age-related changes in fractional anisotropy (FA) and mean diffusivity (MD) quantified from cerebral white matter (splenium and genu of the corpus callosum and posterior limb of the internal capsule) and cerebellar white matter (middle cerebellar peduncles, superior cerebellar peduncles, and inferior cerebellar peduncles) regions in healthy children ranging in age from birth to 132 months. Log-linear regression model showed best fit to describe the age-related changes in FA and MD both for cerebral and cerebellar white matter. In cerebral white matter, an initial sharp increase in FA was observed up to the age of 24 months followed by a gradual increase up to 132 months. In cerebellar white matter, sharp increase in FA was observed up to 36 months, which then followed a gradual increase. However, MD showed a sharp decrease in cerebral white matter up to 24 months followed by a more gradual decrease thereafter, while in cerebellar white matter after an initial decrease (6 months), it followed a stable pattern. This study provides normative database of brain white matter development from neonates to childhood. This quantitative information may be useful for assessing brain maturation in patients with developmental delay of the cerebral and cerebellar white matter.     

Specific messenger RNA changes in Joseph disease cerebella

Joseph disease is an autosomal-dominant, spinocerebellar degeneration characterized at the biochemical level by elevations in the steady-state levels of several abundant proteins (H, J, and L) in affected brain areas such as the cerebellar cortex. The increased levels of these proteins could either be a consequence of a relative increase in their de novo synthesis or result from altered rates of proteolysis in degenerating brain cells. These alternatives can be distinguished by comparing the in vitro protein-synthetic capacities of the messenger ribonucleic acid populations isolated from cerebellar cortex of control subjects and patients with Joseph disease. Protein H (glial fibrillary acidic protein) is synthesized at detectable levels by all messenger ribonucleic acid isolates, and the levels of its translatable messenger ribonucleic acid are reproducibly increased in ribonucleic acids isolated from cerebellar cortex of patients with Joseph disease as compared with those isolated from cerebellar cortex of control subjects. Thus, the increased level of protein H in Joseph disease is a consequence of an increase in its de novo synthesis and is correlated with the increased number of cerebellar glial cells. In contrast to these results, there is no detectable synthesis of proteins J and L by messenger ribonucleic acid populations isolated from cerebellar cortex of either Joseph disease patients or control subjects, suggesting that the increased levels of these proteins in affected cerebellar cortex are a consequence of posttranslational protein modifications.     

Cerebellum volume and eyeblink conditioning in schizophrenia

Although accumulating evidence suggests that cerebellar abnormalities may be linked to the symptoms and course of schizophrenia, few studies have related structural and functional indices of cerebellar integrity. The present study examined the relationship between the volume of specific subregions of the cerebellum and cerebellar function, as measured by eyeblink conditioning (EBC). Nine individuals with schizophrenia and six healthy comparison participants completed structural magnetic resonance imaging of the brain and a delay EBC procedure. Volumetric measurements were taken for the whole brain, whole cerebellum, cerebellar anterior lobules I-V and posterior lobules VI-VII. The schizophrenia group had smaller cerebellar anterior lobes and exhibited impaired EBC relative to the comparison group. In the comparison group, larger anterior volume correlated with earlier conditioned response onset latencies and increased amplitudes of the unconditioned blink response during paired trials (i.e., when the conditioned and unconditioned stimuli co-occurred). The findings that smaller anterior cerebellar volumes and EBC impairments were associated with schizophrenia are consistent with non-human studies showing that anterior cerebellar abnormalities are associated with deficits in delay EBC. The lack of a significant correlation between indices of EBC and cerebellar volume within the schizophrenia group suggests an aberrant relationship between cerebellar structure and function.     

Long-term changes in cerebellar activation during functional recovery from transient peripheral motor paralysis

Localized altered cerebellar cortical activity can be associated with short-term changes in motor learning that take place in the course of hours, but it is unknown whether it can be correlated to long-term recovery from transient peripheral motor diseases, and if so, whether it occurs concomitantly in related brain regions. Here we show in a longitudinal fMRI study of patients with unilateral Bell's palsy that increases in ipsilateral cerebellar activity follow the recovery course of facial motor functions over at least one and a half years. These findings hold true for changes in brain activity related to both oral and peri-orbital activation, even though these processes are differentially mediated by unilateral and bilateral brain connectivities, respectively. Activation of non-facial musculature, which was studied for control, does not show any change in cerebellar activity over time. The localized changes in cerebellar activities following activation of facial functions occur concomitantly with increases in activity of the facial region in the contralateral primary motor cortex suggesting that the cerebellum acts together with the cerebral cortex in long-term adaptation to transient pathological sensorimotor processing.     

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.     

Cerebellar Hypometabolism in Focal Epilepsy Is Related to Age of Onset and Drug Intoxication

Summary: Purpose: We wished to investigate the cerebellar depression of regional cerebral glucose metabolism (rCMRGlu) in patients with focal epilepsy.
Method: In 170 consecutive patients with medically refractory, focal epilepsy the rCMRGlu was measured in cerebellum and brain.
Results: rCMRGlu was markedly decreased in both cerebellar hemispheres and slightly in brain. The cerebellum to brain rCMRGlu ratio was significantly decreased in patients with seizure manifestation in infancy, but was normal due to a progressive decrease in brain rCMRGlu in later age. A subgroup of patients with focal epilepsy involving the frontal lobe had a reduced cerebellum/brain rCMRGlu ratio, whereas in patients with mesiotemporal lobe epilepsy (MTLE), the rCMRGlu was decreased to the same degree in cerebellum and brain. The difference in the cerebellum/brain rCMRGlu ratio between the two groups was accounted for by the younger age of the patients with focal epilepsy involving the frontal lobe, however. In another subgroup of patients with a documented history of critical drug intoxications, the cerebellar rCMRGlu was severely decreased, resulting in a significantly reduced cerebellum/brain rCMRGlu ratio.
Conclusion: Our retrospective study suggests that the cerebellum is particularly vulnerable in infancy to ongoing epileptic activity and high dosage of antiepileptic drugs (AEDs).     

Wallerian degeneration of the descending tracts. CT and MRI features of the brain stem

The authors have studied by CT brain infarcts of different ages in 16 patients, two of whom were also examined by MRI. The early and CT signs of wallerian degeneration of the descending tracts within the brain stem are described. Three cases of crossed cerebellar atrophy are reported; in one of them, the cerebral lesion had been present for less than 8 years. The physiopathology of pontine hemiatrophy and crossed cerebellar atrophy is discussed.     

Clinical improvements in higher brain function and rapid functional recovery in a case of cerebellar hemorrhage treated by neurocognitive rehabilitation

Cerebellar stroke rarely causes disorders of higher brain function such as cognitive deficits and emotional dysfunction; hence, the prognosis of these patients is uncertain. We report the case of a 34-year-old patient with cerebellar hemorrhage due to arteriovenous malformation causing higher brain dysfunction who was able to return to full-time employment after neurocognitive rehabilitation. Cerebellar stroke caused by nonatherosclerotic diseases or diaschisis may lead to cognitive deficits but these symptoms can be reversed by appropriate therapy. It is important to assess higher brain function in cerebellar stroke patients and to tailor neurocognitive rehabilitation programs appropriately to promote functional recovery.     

Linking novelty seeking and harm avoidance personality traits to cerebellar volumes

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions, and neuroimaging studies showed structural or functional abnormalities of cerebellum in subjects with personality disorders, suggesting a cerebellar role in affective processing and an effect on personality characteristics. To test the hypothesis that cerebellar [white matter (WM) and cortex] volumes are correlated with scores obtained in the four temperamental scales of the Temperament and Character Inventory (TCI) by Cloninger, a total of 125 healthy participants aged 18–67 years of both genders (males = 52) completed the TCI and underwent magnetic resonance imaging. The scores obtained in each temperamental scale were associated with the volumes of cerebellar WM and cortex of right and left hemispheres separately by using linear regression analyses. In line with our hypothesis, novelty seeking (NS) scores were positively associated with WM and cortex cerebellar volumes. Harm avoidance (HA) scores were negatively associated with WM and cortex cerebellar volumes. The range of individual differences in NS and HA scores reflects the range of variances of cerebellar volumes. The present data indicating a cerebellar substrate for some personality traits extend the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. Hum Brain Mapp 35:285–296, 2014. © 2012 Wiley Periodicals, Inc.     

Dominantly inherited nonprogressive cerebellar hypoplasia identified in utero

Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation.     

Cerebellular calcification in tuberous sclerosis.

A rarely observed pattern of cerebellar calcification was noted in the skull roentgenograms of a child with tuberous sclerosis in the absence of cerebellar dysfunction. The computerized tomographic brain scan was useful in defining the extent of the cerebellar lesion and in detecting two additional foci of calcification that were not detected by standard roentgenographic methods.     

Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism

Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic–repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p?=?0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r?=?0.83; p?=?0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.