Cerebellar Pathology Research Articles

Mechanisms of penitrem-induced cerebellar granule neuron death in vitro: Possible involvement of GABAA receptors and oxidative processes

The fungal neurotoxin penitrem A has previously been found to cause neurological disorders in animals and humans after ingestion of contaminated food and/or feed. It penetrates the blood–brain-barrier and causes cerebellar pathology in rats, including mild effects on granule neurons.The aim of the current study was to investigate the potential toxicity of penitrem A in rat cerebellar granule neurons in vitro, and to examine the involvement of the GABAA, AMPA and NMDA receptors, intracellular signalling pathways as well as the role of oxidative stress in penitrem A-induced neuronal death. Cerebellar granule cells were exposed to penitrem A, alone or together with different pharmacological agents, before cell survival was assessed with the MTT assay or formation of reactive oxygen species (ROS) was investigated with the DCF assay.Penitrem A caused a time- and concentration-dependent reduction in cell survival, as well as a concentration-dependent increase in ROS production. Co-incubation with diazepam, GABA, BAPTA-AM, vitamin E, SP600125 and cyclosporine A significantly reduced cell death. Our results show that penitrem A is toxic to cerebellar granule neurons in vitro. Further, ROS production and the GABAA receptor are likely to be involved in the induction of neuronal death following penitrem A exposure. A disruption of calcium homeostasis and activation of the JNK pathway may also play a role in penitrem A neurotoxicity.

A familial FTD associated with C9orf72 repeat expansion and dysplastic gangliocytoma

Background A hexanucleotide repeat expansion, in the chromosome 9 open reading frame 72 gene (C9orf72), has been identified the most common genetic cause of FTD/ALS. Here we describe the clinical, pathologic and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma, a rare hamartoma of cerebellar granule cells, associated with PTEN mutations. In addition to the dysplastic gangliocytoma, the patient showed TDP43-pathology in the cortex and in the substantia nigra, and p62-positive/TDP43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed similar type of TDP43/p62-pathology in her brain. Our findings confirm the clinical and pathological picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrant further studies on the possible involvement of PTEN pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.

Gas Bubble Disease in the Brain of a Living California Sea Lion (Zalophus californianus)

A yearling California sea lion (Zalophus californianus) was admitted into rehabilitation with signs of cerebellar pathology. Diagnostic imaging that included radiography and magnetic resonance imaging (MRI) demonstrated space-occupying lesions predominantly in the cerebellum that were filled partially by CSF-like fluid and partially by gas, and cerebral lesions that were fluid filled. Over a maximum period of 4 months, the brain lesions reduced in size and the gas resorbed and was replaced by CSF-like fluid. In humans, the cerebellum is known to be essential for automating practiced movement patterns (e.g., learning to touch-type), also known as procedural learning or the consolidation of “motor memory.” To test the animal in this study for motor memory deficits, an alternation task in a two-choice maze was utilized. The sea lion performed poorly similar to another case of pneumocerebellum previously reported, and contrary to data acquired from a group of sea lions with specific hippocampal injury. The learning deficits were attributed to the cerebellar injury. These data provide important insight both to the clinical presentation and behavioral observations of cerebellar injury in sea lions, as well as providing an initial model for long-term outcome following cerebellar injury. The specific etiology of the gas could not be determined. The live status of the patient with recovery suggests that the most likely etiologies for the gas are either de novo formation or air emboli secondary to trauma. A small air gun pellet was present within and was removed from soft tissues adjacent to the tympanic bulla. While no evidence to support the pellet striking bone was found, altered dive pattern associated with this human interaction may have provided the opportunity for gas bubble formation to occur. The similarity in distribution of the gas bubble related lesions in this case compared with another previously published case of pneumocerebellum suggests that preferential perfusion of the brain, and more specifically the cerebellum, may occur during diving events.

The basal ganglia: motor and cognitive relationships in a clinical neurobehavioral context

New information about the basal ganglia and cerebellar connections with the cerebral cortex has prompted a reevaluation of the role of the basal ganglia in cognition. We know that the relation between the basal ganglia and the cerebral cortical region allows for connections organized into discrete circuits. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia. The properties of neurons within the basal ganglia or cerebellar components of these circuits resemble the properties of neurons within the cortical areas subserved by these loops. For example, neuronal activity within the basal ganglia and cerebellar loops with motor areas of the cerebral cortex is highly correlated with parameters of movement, whereas neuronal activity within the basal ganglia and cerebellar loops with areas of the prefrontal cortex is more related to the aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Studies of the basal ganglia and cerebellar pathology support this conclusion. Damage to the basal ganglia or cerebellar components of circuits with motor areas of the cortex leads to motor symptoms, whereas damage to the subcortical components of circuits with nonmotor areas of the cortex causes higher-order deficits. In this report, we review some of the new anatomic, physiologic, and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex and apply it in clinical applications to obsessive-compulsive disorder, Tourette's syndrome, and attention-deficit/hyperactivity disorder as examples of how compromise at different points in the system may yield similar but different clinical results.

Oromandibular and lingual dystonia associated with spinocerebellar ataxia type 8

Oromandibular and lingual dystonia associated with spinocerebellar ataxia type 8

Lipid mediators in plasma of autism spectrum disorders

BackgroundInflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. Cerebellar pathology occurs in autism, as a neurodevelopmental disorder with genetic and environmental origins. The genesis of this disorder is still not understood but inflammation in utero or early in childhood is an environmental risk factor.MethodsProstaglandin E2 (PGE2), cysteinyl leukotriene as two important lipid mediators together with 8 isoprostane as marker of oxidative stress were measured using ELISA in plasma of 20 male autistic patients compared to 19 age and gender matching control participants.ResultsPGE2, leukotrienes and isoprostanes recorded significantly elevated levels in autistics compared to controls. Role of these measured parameters in inflammation and autoimmunity as two etiological factors in autism were discussed in details.ConclusionReceiver Operating Characteristic (ROC) curve analysis shows satisfactory values of area under the curve (AUC) which could reflect the high degree of specificity and sensitivity of the altered PGE2, leukotrienes and isoprostanes as predictive biomarkers in autistic patients from Saudi Arabia.

Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Editorial

In 1990, Ikeda et al. described an action and postural tremor that originated from the cerebral cortex and was thus termed “cortical tremor.” Due to its peculiar electrophysiological features, this involuntary movement was considered to be a variant of cortical reflex myoclonus [1]. Cortical tremor was then recognized to occur in Japanese families often in association with tonic– clonic seizures, and this observation led to the definition of an autosomal dominant trait named Benign Adult Familial Myoclonic Epilepsy (BAFME), which was mapped on chromosome 8q [2, 3]. Over the past decade, several European kindreds with overlapping clinical features have been reported under different acronyms, such as autosomal dominant cortical myoclonus and epilepsy and familial cortical myoclonic tremor with epilepsy (FCMTE) [4–7]. The available literature now suggests a worldwide distribution (more than 60 families have been reported) and genetic heterogeneity, yet with evidence that 2p11.1-q12.2 is a major locus for the kindreds of European origin [8]. Most affected individuals experience tonic–clonic seizures, which begin later than “tremor.” Seizures are generally rare (about five to ten episodes during life) and are not preceded by any warning. However, in some cases, they may be heralded by progressively increasing myoclonic jerks. Precipitating factors such as sleep deprivation, emotional stress, pain, and photic stimulation are often reported [3, 7]. In some cases, severe myoclonus can alter the quality of life. Although the epilepsy is usually benign, in rare cases, patients may present with drug-resistant complex partial seizures and focal EEG abnormalities [4]. Patients usually have normal cognition; however, mildto-moderate mental retardation may be present in some cases, especially in a more advanced age [6, 9]. Both the severity of seizures and the use of antiepileptic drugs could contribute to cognitive impairment. Cerebellar symptoms are usually mild: postural ataxia, downbeat nystagmus, impaired smooth pursuit. MRI may demonstrate a cerebellar atrophy. A pseudo-parkinsonism has also been reported. FCTME is usually diagnosed between the ages of 20 and 45 years. Myoclonus and EEG abnormalities progressively worsen from early to late adulthood. Clonazepam and sodium valproate are usually effective therapies. Thus far, the pathophysiological and biochemical bases of this condition remain poorly understood. Mutations in genes encoding ion channels have been excluded by several authors [3–7]. Patients typically show giant somatosensory evoked potentials and strong corticoand intermuscular coherence in the 8to 30-Hz range, thus suggesting an underlying cortical hyperexcitability, which can be the result of a decreased cortical inhibition by the cerebellum via its cerebello-thalamocortical projections [6]. Indeed, rare post-mortem histological studies have shown evidence of cerebellar pathology reminiscent of SCA type 6 [3, 5], and although P. Striano (*) Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Largo Gaslini 5, Pediatric Neurology and Muscular Diseases Unit, Padiglione 16, IV Piano, 16147 Genoa, Italy e-mail: pstriano@email.it

Cerebellar Pathology of a Dual Clinical Diagnosis: Patients with Essential Tremor and Dystonia

<strong>Background:</strong> Clinical studies have implicated the cerebellum in the pathogenesis of essential tremor (ET), and recent postmortem studies have identified structural changes in the ET cerebellum. While the basal ganglia have traditionally been implicated in dystonia, cerebellar involvement has been suggested as well, and a recent study showed Purkinje cell (PC) loss. We conducted a detailed postmortem examination of the brain in four individuals with clinical diagnoses of ET and dystonia, and hypothesized that pathological changes in the cerebellum would be greater in these four ET cases than in published ET cases without dystonia. <strong>Methods:</strong> After a complete neuropathological assessment, a standard parasagittal neocerebellar tissue block was harvested in each brain. One 7-μm thick section was stained with luxol fast blue/hematoxylin and eosin, and one section with the Bielschowsky method. We quantified PCs, torpedoes, heterotopic PCs, PC dendritic swellings, and basket cell changes. <strong>Results:</strong> Two ET+dystonia cases had more microscopic changes in the cerebellum than published ET cases; the other two cases had similar changes to published ET cases. <strong>Discussion:</strong> This is the first report that uses human autopsy tissue to study patients with both ET and dystonia. The findings were heterogeneous. Additional studies, with larger samples, are needed.

Cerebellar pathology of a dual clinical diagnosis: patients with essential tremor and dystonia.

Clinical studies have implicated the cerebellum in the pathogenesis of essential tremor (ET), and recent postmortem studies have identified structural changes in the ET cerebellum. While the basal ganglia have traditionally been implicated in dystonia, cerebellar involvement has been suggested as well, and a recent study showed Purkinje cell (PC) loss. We conducted a detailed postmortem examination of the brain in four individuals with clinical diagnoses of ET and dystonia, and hypothesized that pathological changes in the cerebellum would be greater in these four ET cases than in published ET cases without dystonia. After a complete neuropathological assessment, a standard parasagittal neocerebellar tissue block was harvested in each brain. One 7-µm thick section was stained with luxol fast blue/hematoxylin and eosin, and one section with the Bielschowsky method. We quantified PCs, torpedoes, heterotopic PCs, PC dendritic swellings, and basket cell changes. Two ET+dystonia cases had more microscopic changes in the cerebellum than published ET cases; the other two cases had similar changes to published ET cases. This is the first report that uses human autopsy tissue to study patients with both ET and dystonia. The findings were heterogeneous. Additional studies, with larger samples, are needed.

Stases are associated with blood–brain barrier damage and a restricted activation of coagulation in SHRSP

Cerebral small vessel disease (CSVD) is a chronically proceeding pathology of small brain vessels associated with white matter lesions, lacunar infarcts, brain atrophy and microbleeds. CSVD leads to slowly increasing cognitive and functional deficits but may also cause stroke-like symptoms, if vessels in critical brain areas are affected. Spontaneously hypertensive stroke-prone rats (SHRSP) exhibit several vascular risk factors, develop infarcts and hemorrhages and therefore represent a relevant model for the study of CSVD. Using this animal model, we recently demonstrated that intravasal accumulations of erythrocytes, we interpreted as stases, stand at the beginning of a pathological vascular cascade. After stases microbleeds occur, which are followed by reactive microthromboses. Bleeds and thromboses finally cause hemorrhagic infarcts. Immunohistochemical stainings show, that plasma proteins like IgG are deposited in the walls of vessels affected by stases. Further, we found small clots and thread-shaped aggregations of thrombocytes as well as thread-shaped structures of von Willebrand-Factor within stases. Thus, we conclude that blood–brain barrier damages occur in the neighborhood of stases and stases seem to be associated with a restricted activation of blood coagulation without formation of obstructive thromboses. Finally, we demonstrate that small vessel damage rarely appears in the cerebellum. Even animals with multiple cerebral infarcts may be free of any cerebellar vascular pathology.

A functional MRI study of motor dysfunction in Friedreich's ataxia

Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia. In addition to proximal spinal cord and brain stem atrophy, mild to moderate atrophy of the cerebellum has been reported in advanced FRDA. The aim of this study was to examine dysfunction in motor-related areas involved in the execution of finger tapping tasks in individuals with FRDA, and to investigate functional re-organization of cortico-cerebellar, cortico-striatal and parieto-frontal loops as a result of the cerebellar pathology. Thirteen right-handed individuals with FRDA and fourteen right-handed controls participated. Functional MRI images were acquired during four different finger tapping tasks consisting of visually cued regular and irregular single finger tapping tasks, a self-paced regular finger tapping task, and a visually cued multi-finger tapping task. Both groups showed significant activation of the motor-related network including the pre-central cortex and supplementary motor area bilaterally; the left primary motor cortex, somatosensory cortex and putamen; and the right cerebellum. During the visually cued regular finger tapping task, the right hemisphere of the cerebellar cortex, bilateral supplementary motor areas and right inferior parietal cortex showed higher activation in the healthy control group, while in individuals with FRDA the left premotor cortex, left somatosensory cortex and left inferior parietal cortex were more active. In addition, during the visually cued irregular finger tapping task, the right middle temporal gyrus in the control group and the right superior parietal lobule and left superior and middle temporal gyri in the individuals with FRDA showed higher activation. During visually cued multi-finger tapping task, the control group showed higher activation in the bilateral middle frontal gyri, bilateral somatosensory cortices, bilateral inferior parietal lobules, left premotor cortex, left supplementary area, right superior frontal gyrus and right cerebellum, while individuals with FRDA showed increased activity in the left inferior parietal lobule, left primary motor cortex, left middle occipital gyrus, right somatosensory cortex and the left cerebellum. Only the right crus I/II of the cerebellum showed higher activation in individuals with FRDA during the self-paced regular finger tapping task, whereas wide-spread regions including the left superior frontal gyrus, left central opercular cortex, left somatosensory cortex, left putamen, right cerebellum, bilateral primary motor cortices, bilateral inferior parietal lobules and the left insula were more active in the control group. Although the pattern of the BOLD signal from the putamen was different during the self-paced regular finger tapping task to the other tasks in controls, in individuals with FRDA there was no distinction of the signal between the tasks suggesting that primary cerebellar pathology may cause secondary basal ganglia dysregulation. While individuals with FRDA tapped at a slightly lower rate (0.59Hz) compared with controls (0.74Hz) they showed significantly decreased activity of the SMA and the inferior parietal lobule, which may suggest disruption to the fronto-parietal connections. These findings suggest that the motor impairments in individuals with FRDA result from dysfunction extending beyond the spinal cord and cerebellum to include sub-cortical and cortical brain regions.

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance images

The C57BL mouse is the centerpiece of efforts to use gene-targeting technology to understand cerebellar pathology, thus creating a need for a detailed magnetic resonance imaging (MRI) atlas of the cerebellum of this strain. In this study we present a methodology for systematic delineation of the vermal and hemispheric lobules of the C57BL/6J mouse cerebellum in magnetic resonance images. We have successfully delineated 38 cerebellar and cerebellar-related structures. The higher signal-to-noise ratio achieved by group averaging facilitated the identification of anatomical structures. In addition, we have calculated average region volumes and created probabilistic maps for each structure. The segmentation method and the probabilistic maps we have created will provide a foundation for future studies of cerebellar disorders using transgenic mouse models.

Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults

Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

Functional topography of primary emotion processing in the human cerebellum

The cerebellum has an important role in the control and coordination of movement. It is now clear, however, that the cerebellum is also involved in neural processes underlying a wide variety of perceptual and cognitive functions, including the regulation of emotional responses. Contemporary neurobiological models of emotion assert that a small set of discrete emotions are mediated through distinct cortical and subcortical areas. Given the connectional specificity of neural pathways that link the cerebellum with these areas, we hypothesized that distinct sub-regions of the cerebellum might subserve the processing of different primary emotions. We used functional magnetic resonance imaging (fMRI) to identify neural activity patterns within the cerebellum in 30 healthy human volunteers as they categorized images that elicited each of the five primary emotions: happiness, anger, disgust, fear and sadness. In support of our hypothesis, all five emotions evoked spatially distinct patterns of activity in the posterior lobe of the cerebellum. We also detected overlaps between cerebellar activations for particular emotion categories, implying the existence of shared neural networks. By providing a detailed map of the functional topography of emotion processing in the cerebellum, our study provides important clues to the diverse effects of cerebellar pathology on human affective function.

Hirano body‐rich subtypes of Creutzfeldt–Jakob disease

In definite Creutzfeldt-Jakob disease (CJD), morphological and immunohistochemical patterns are useful to identify molecular subtypes. Severe cerebellar pathology and hippocampal involvement helps to identify VV subtypes. The rare VV1 variant (<1%), more frequent in young individuals, is additionally characterized by the presence of ballooned neurones in affected areas. In 1985, Cartier et al. described a family cluster of three individuals with an ataxic CJD form, showing, in addition to severe cerebellar and hippocampal involvement, the presence of frequent Hirano bodies (HB) in CA1 pyramidal neurones. HB are frequently found in aged individuals with Alzheimer pathology although they are not a specific finding. In this study, we evaluated the presence of HB in hippocampi of 54 genetically and molecularly characterized CJD cases, aiming to elucidate whether additional morphological features could be helpful to point to molecular subtypes. We identified nine cases (four VV1, one out of three MV2K, three out of six MV2K+2C and one MV carrying a 96-base pair insertion) with abundant, partly bizarre and clustered HB in CA1 sector, not observed in other subtypes. The presence of HB was independent of hippocampal involvement by the disease itself. Clusters of abundant HB might be found in rare CJD subtypes such as VV1, MV2K/MV2K+2C and some genetic cases. In addition to histopathological and PrP immunohistochemical deposition patterns, their presence might be a useful additional morphologic feature that could point to the molecular subtype, especially when genetic and/or Western blot analyses are not available.

Commentary on “Bilateral cerebellar stroke presenting with acute dysphonia and late palatal tremor”

The case report by Walsh et al. described the development of spasmodic dysphonia (SD) secondary to cerebellar stroke. The patient was presented with hyperfunctional, hyperadductive voice disorder affecting supraglottis, including ventricular (false) cords. Speech was incomprehensible with strained-strangled quality and occasional voice arrests. The diagnosis of SD was made based on these speech symptoms, hyperfunctional supraglottis visualized with fiberoptic laryngoscopy, the lack of benefits from voice and speech therapy, and some improvement of voice problems following unilateral botulinum toxin injection into the thyroarytenoid muscle. As such, this is an atypical SD case due to several reasons. Laryngeal spasms in SD primarily affect (true) vocal cords rather than ventricular cords, although supraglottic hyperadduction involving ventricular cords may also be present. While SD patients have problems with coordinating voice onset and offset during connected speech due to SD-specific voice breaks, they usually are able to sustain sound, and their speech remains comprehensible. The lack of response to speech therapy and the benefits from botulinum toxin injections into the laryngeal muscles are typical but not specific to SD only. On the other hand, speech therapy is beneficial in patients with supraglottic hyperadduction, whereas persistent supraglottic squeeze may be managed more successfully with botulinum toxin injections into the supraglottic musculature1. This case report further suggests that cerebellar lesion without functional, structural or dopaminergic abnormalities in any other brain regions may cause SD. Conversely, previous studies have shown relief of dystonia symptoms following cerebellar lesions and cerebellectomy2, 3, and SD has been characterized as a brain network disorder, involving abnormalities in the basal ganglia, thalamus, sensorimotor cortex, and cerebellum4, 5. In conclusion, the diagnosis of SD in this patient is complicated by unusual clinical presentation, atypical diagnostic criteria, and the presence of cerebellar pathology without abnormalities in other dystonia-related brain regions. The differential diagnosis is more likely to include other cerebellar disorders, such as spinocerebellar atrophy, other movement disorders, such as chorea, and muscle tension dysphonia, as a compensatory voice disorder secondary to cerebellar pathology.

Consensus paper: pathological role of the cerebellum in autism.

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Cerebellar theta burst stimulation impairs eyeblink classical conditioning

Theta burst stimulation (TBS) protocols of repetitive transcranial magnetic stimulation (rTMS) have after-effects on excitability of motor areas thought to be due to LTP- and LTD-like processes at cortical synapses. The present experiments ask whether, despite the low intensities of stimulation used and the anatomy of the posterior fossa, TBS can also influence the cerebellum. Acquisition and retention of eyeblink classical conditioning (EBCC) was examined in 30 healthy volunteers after continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere. In subjects who received cerebellar cTBS, conditioned responses were fewer and their onsets were earlier (in the last half of the acquisition blocks) than those from control subjects. There was, however, no effect of cerebellar cTBS on the re-acquisition of EBCC in another session of EBCC 7–10 days later. There was also no effect of cerebellar cTBS on the re-acquisition of EBCC in subjects not naïve to EBCC when the stimulation was delivered immediately before a re-acquisition session. Control experiments verified that suppressive effects of cTBS on EBCC were not due to changes in motor cortical excitability or sensory disturbance caused by cTBS. Based on previous EBCC studies in various cerebellar pathologies, our data are compatible with the hypothesis that cerebellar cTBS has a focal cerebellar cortical effect, and are broadly in line with data from studies of EBCC in various animal models. These results confirm that cerebellar TBS has measurable effects on the function of the cerebellum, and indicate it is a useful non-invasive technique with which to explore cerebellar physiology and function in humans.

New Challenges in CNS Repair: The Immune and Nervous Connection

The Central Nervous System (CNS) is the organ with the least capacity for repair in mammals. Diseases of the CNS may follow developmental deficits, inappropriate environmental factors and acquired damages after maturation. The latter damages may consist of neuronal cell death, like Alzheimers disease and/or to a lesion of the axon, like in the paraplegic patients. Hopes of obtaining a functional recovery after trauma or neurodegeneration, are very low and clinicians have very low possibilities for therapeutic interventions. The causes of the regenerative block in the adult CNS are only partially attributable to the neural component. Direct or indirect interactions with glial cells, the resident CNS immune cells, and with the extracellular matrix play a crucial role in determining the relative inability of adult CNS connections to be modified: adult neurites find themselves within an environment rich in molecules strongly inhibitory for regrowth and sprouting. A further complication arises from the fact that regenerative processes are always accompanied by an inflammatory reaction with the consequent activation of astrocytes and microglia; this activation alters the properties of the extracellular milieu. Thus, research on post lesional plasticity must not only study the molecular mechanisms active in neurons but also consider the role of glial cells and the extracellular environment. Keywords: Axon regeneration, myelination, neuron survival, neuronal growth factors, Central Nervous System, neurological medicine, Neurodegenerative disease, oligodendrocytes, cerebellar pathology