Cerebellar Pathology Research Articles

Chapter 34 - Hepatic encephalopathy in alcoholic cirrhosis

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis in alcoholic patients that is characterized clinically by personality changes, sleep abnormalities, and impaired motor coordination, as well as cognitive dysfunction progressing to stupor and coma. Procedures used for diagnosis and grading of HE include neurologic assessment, electroencephalography, psychometric testing, and use of the critical flicker frequency test. Neuropathologically, HE in cirrhosis is principally a disorder of neuroglia characterized by Alzheimer type II astrocytosis and activation of microglia. However, thalamic and cerebellar neuronal pathologies have been noted as well as lesions to globus pallidus and substantia nigra, leading to a condition known as "parkinsonism in cirrhosis." Multiple mechanisms have been proposed to account for the pathogenesis of HE in cirrhosis, including the neurotoxic actions of ammonia and manganese (normally removed via the hepatobiliary route), impaired brain energy metabolism, central proinflammatory mechanisms, and alterations of both excitatory and inhibitory neurotransmission. Treatment of HE in cirrhosis continues to rely on ammonia-lowering strategies such as lactulose, antibiotics, probiotics and l-ornithine l-aspartate with nutritional management consisting of adequate (but not excessive) dietary protein and vitamin B1 supplements. l-DOPA may improve parkinsonian symptoms. Liver transplantation leads to recovery of central nervous system function in the majority of cases.

Protective role of coenzyme Q 10 against high cholesterol dietinduced histological and biochemical changes in cerebellar cortex of adult albino rats

Hypercholesterolemia was known to cause cardiovascular and brain damaging effects; however cholesterol is less known for affecting cerebellar and microvasculature pathology. Coenzyme Q10 (CoQ10) is a naturally occurring potent antioxidant. The aim of this research is to study histological and biochemical alterations occuring in the structure of cerebellum after feeding high cholesterol diet and the possible protective role of CoQ10. Forty male adult albino rats were randomly divided into four groups. Group I, control received a low-cholesterol diet. Group II received normal laboratory diet and CoQ10, Group III fed on 5% cholesterol diet. Group IV fed on 5% cholesterol diet and CoQ10 orally. After 4 months the body weight of all rats was measured and lipid profile was assessed. Rats' cerebelli were removed, cortices were dissected and divided into three parts for histological, tau and GFAB immunohistochemical study and for assessment of endogenous oxidative and antioxidant markers. In cerebellar cortex from rats fed on high cholesterol diet, Purkinje cell number showed significant decrease compared to control group. They had many multi-lysosomes, cytoplasmic vacuoles, dilatation of rough endoplasmic reticulum and most of their nuclei were variable in shape, muddy or appoptotic, while few were euchromatic. In group IV, cerebellar cortex nearly regained the normal architecture but few granular cells still had pyknotic nuclei and few purkinje cells still had positive Tau immune reaction. High cholesterol diet has a deleterious effect on histological and biochemical structure of the cerebellum. Coenzyme-Q10 ameliorates these effects.

Development of the cerebellar white matter is impaired by postnatal hyperoxia and protected by minocycline

Brain injury of preterm infants has widely been ascribed to the cerebrum, but recent studies demonstrate that injury of the cerebellum occurs, too [1]. Causes of cerebellar pathologies in preterm infants and ways of protection are underinvestigated. In general, perinatal infection/inflammation, hypocarbia, and hyperoxia are factors associated with brain damage in preterm infants [1, 2]. We investigate whether oxidative stress induced by postnatal hyperoxia impairs the development of the cerebellar white matter. We used a neonatal hyperoxia model in rats with 80% oxygen exposure for 24h from P6 to P7, and determined development and maturation of oligodendroglial precursor cells (OPCs) in the cerebellum after recovery in room air until P9, P11, P14, and P30. Volume of the cerebellum measured by MRI in P30 rats after exposure to hyperoxia was significantly reduced as compared to control litters always kept in room air (hyperoxia = 209 µL, controls = 232 µL; n=8, t-test p<0.05). Myelination measured by MBP expression in immunostainings and Western blots was significantly reduced from P7 to P30. Numbers of apoptotic TUNEL+NG2+ OPCs were higher in hyperoxia rats; OPC proliferation and maturation towards CC1+ stages were significantly reduced. Analysis of Iba1 immunostainings and of inflammatory cytokine expression did not reveal signs of microglial activation after hyperoxia. Oxidative stress after hyperoxia was indicated by increased nitrotyrosin. Treatment with minocycline significantly attenuated toxic effects of hyperoxia. Postnatal hyperoxia in rats causes critical features of cerebellar pathology seen in preterm infants. A pharmacological approach for prevention seems feasible.

Type 1 metabotropic glutamate receptors (m G lu1) trigger the gating of G lu D 2 delta glutamate receptors

The orphan GluD2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. Ligand-gated GluD2 currents have never been evidenced, and whether GluD2 operates as an ion channel has been a long-standing question. Here, we show that GluD2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in Purkinje cells. Thus, GluD2 is not only an adhesion molecule at synapses but also works as a channel. This gating mechanism reveals new properties of glutamate receptors that emerge from their interaction and opens unexpected perspectives regarding synaptic transmission and plasticity.

Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders

Neural abnormalities commonly associated with autism spectrum disorders include prefrontal cortex (PFC) dysfunction and cerebellar pathology in the form of Purkinje cell loss and cerebellar hypoplasia. It has been reported that loss of cerebellar Purkinje cells results in aberrant dopamine neurotransmission in the PFC which occurs via dysregulation of multisynaptic efferents from the cerebellum to the PFC. Using a mouse model, we investigated the possibility that developmental cerebellar Purkinje cell loss could disrupt glutamatergic cerebellar projections to the PFC that ultimately modulate DA release. We measured glutamate release evoked by local electrical stimulation using fixed-potential amperometry in combination with glutamate selective enzyme-based recording probes in urethane-anesthetized Lurcher mutant and wildtype mice. Target sites included the mediodorsal and ventrolateral thalamic nuclei, reticulotegmental nuclei, pedunculopontine nuclei, and ventral tegmental area. With the exception of the ventral tegmental area, the results indicated that in comparison to wildtype mice, evoked glutamate release was reduced in Lurcher mutants by between 9 and 72% at all stimulated sites. These results are consistent with the notion that developmental loss of cerebellar Purkinje cells drives reductions in evoked glutamate release in cerebellar efferent pathways that ultimately influence PFC dopamine release. Possible mechanisms whereby reductions in glutamate release could occur are discussed.

Prominent EMA ‘dots’ in tumour‐induced Bergmann gliosis

To describe an unusual pattern of epithelial membrane antigen (EMA) immunoreactivity in highly proliferative human Bergmann glia. An immunohistochemical study was performed of postmortem cerebellar tissue from 18 adult patients with cerebellar damage of various aetiologies and 15 biopsies of diverse adult and paediatric cerebellar tumours. We observed marked proliferation of Bergmann glia with unusual prominent dot-like cytoplasmic EMA immunoreactivity in a case with extensive leptomeningeal sarcomatosis. Similar staining was not observed in association with other types of cerebellar pathology, except for other neoplastic conditions, such as leptomeningeal carcinomatosis, adult medulloblastoma, and pilocytic astrocytoma in children. At an ultrastructural level, the index case showed prominent endoplasmic reticulum with some intermediate filaments and lipofuscin granules, but no structures related to cilia or microvilli were observed. We consider that prominent EMA dots in Bergmann glia might represent excessive activation induced by an overlying leptomeningeal tumour that stimulates the expression of early developmental antigens. This observation suggests modulation of the glial phenotype when exposed to a neoplastic microenvironment that, in turn, might influence the regenerative potential of Bergmann glia.

A familial frontotemporal dementia associated with C9orf72 repeat expansion and dysplastic gangliocytoma

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) was recently identified as the most common genetic cause of frontotemporal dementia/amyotrophic lateral sclerosis. Here we describe the clinical, pathologic, and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma (Lhermitte-Duclos disease), a rare hamartoma/overgrowth syndrome of cerebellar granule cells associated with mutations in the phosphatase and tensin homolog gene. In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with Mr 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed a similar type of TDP-43/p62 pathology in her brain. Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.

Ocular flutter in essential tremor: clinical course and response to primidone

Essential tremor (ET) is generally regarded as a benign monosymptomatic condition with tremor being the sole neurological manifestation. Structural brain abnormalities are not considered part of the syndrome. Over recent years, however, it has become increasingly clear that a cerebellar pathology might be involved in the disease process [1, 2]. Neuropathological studies associated Purkinje cell loss with ET [3], whereas brain imaging demonstrated in many cases atrophic changes in different lobules of the cerebellum [4]. It should be mentioned, however, that there are also studies which failed to show an association of ET and cerebellar pathology [5]. Reports on clinical cerebellar signs in ET are sparse [1, 6]. Here, we present an ET case exhibiting saccadic intrusions with features of ocular flutter (OF). A 74-year-old woman presented with gradual onset of hand tremor over the last three decades. The tremor worsened with stress or intense physical exercise and improved after ingestion of small amounts of alcohol. Her father had similar symptoms but never sought medical advice. She also complained of dizziness and oscillopsia lasting ‘‘a few seconds’’ many times a day for at least 10 years. On examination, a postural tremor of both hands, more pronounced on the left, was noted. Finger-to-nose test was slightly impaired, but heel–knee–shin was unremarkable. The eyes showed infrequent (1–2/min), rapid, conjugate, horizontal oscillations occurring in bursts, leading to the clinical diagnosis of OF. No other ocular motor abnormalities were noted. Recording of eye movements confirmed the clinical impression, showing bursts of fast phases without intersaccadic intervals (Fig. 1a). Intraburst frequency was 10 Hz, and interburst frequency was 0.5 Hz in a 4-min record. Surface electromyography (EMG) recordings of the wrist extensors revealed a postural tremor frequency of 6–6.5 Hz (Fig. 1c). We put the patient on primidone, slowly titrated up to a daily dose of 375 mg. Upon reexamination 2 months later, hand tremor had virtually disappeared (Fig. 1d), although the patient reported a mild tremor of the left hand during emotional excitement. Interestingly, ocular flutter was also absent both clinically and in a 7-min-long record (Fig. 1b). Importantly, she could not recall any oscillopsias in the last couple of weeks. OF is a pathological form of saccadic intrusions consisting of back-to-back horizontal saccades [7]. It is considered a subtype of opsoclonus, the former being characterized by multidirectional fast phases of varying amplitudes. The pathophysiology of OF and opsoclonus is still controversial. It is assumed that abnormal Purkinje cell activity in the cerebellum leads to reduced inhibition on the fastigial nucleus. This results in enhanced inhibition of brainstem omnipause neurons, which, in turn, renders saccadic burst neurons free to oscillate [8, 9]. Recent modeling, however, is based on a dysfunction of the brainstem saccadic generator while cerebellar abnormalities are believed to be secondary to brainstem oscillations [10]. Nonetheless, available functional neuroimaging data conform to the cerebellar hypothesis of OF genesis [11, 12]. The present case exhibited ocular flutter linked with mild oscillopsia for presumably more than 10 years. Thus, this long period largely rules out causes such as encephalitis or paraneoplastic disease. The fact that both tremor E. Anagnostou (&) E. Kararizou I. Evdokimidis Department of Neurology, Eginition Hospital, University of Athens, Vas. Sophias Avenue 74, 11528 Athens, Greece e-mail: granavan@yahoo.com

Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39weeks, however, were distinguished from wild types by MRS starting at 6weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.

Clinical and Neurophysiological Profile of Four German Families with Spinocerebellar Ataxia Type 14

Spinocerebellar ataxia type 14 (SCA14) is an autosomal-dominant ataxia caused by point mutations of the Protein Kinase C Gamma gene. In addition to slowly progressive cerebellar ataxia, it is characterised by dystonia and myoclonus. With scant neuropathological data and no detailed neurophysiological examinations little is known on extracerebellar consequences of SCA14 related cerebellar pathology. To this end, we here delineate clinical phenomenology and neurophysiology of four German SCA14 families. Detailed clinical examination including ataxia severity evaluation by means of the Scale for the Assessment and Rating of Ataxia (SARA) was carried out in 9 affected family members (mean age 49.8years ± 14.4 SD). Motor thresholds (MT), the contralateral silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF), interhemispheric inhibition (IHI) and short afferent inhibition (SAI) were determined using transcranial magnetic stimulation (TMS). Somatosensory evoked potentials (SEP) of the median nerve, and acoustic and visual evoked potentials (AEP, VEP) were also performed. Most patients reported symptoms since early childhood. There was a positive correlation between age and SARA scores (r = .721, P < 0.05). Patients had cerebellar ataxia, mild dystonia (focal, task-specific or segmental), subtle pyramidal signs and myoclonus. SICI increased with increasing conditioning pulse intensities in healthy controls but not in patients. Other neurophysiological parameters did not differ between groups. SCA14 is a slowly progressive ataxia associated with mild dystonia and myoclonus. Reduced SICI reflects abnormalities of intracortical inhibitory circuits.

Glial scaffold required for cerebellar granule cell migration is dependent on dystroglycan function as a receptor for basement membrane proteins

BackgroundCobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD. In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated.ResultsHere we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, yet causes malformations associated with glia limitans disruptions and granule cell heterotopia that recapitulate phenotypes found in dystroglycanopathy patients. Cerebellar pathology in these mice is not evident until birth even though dystroglycan is lost during the second week of embryogenesis. The severity and spatial distribution of glia limitans disruption, Bergmann glia disorganization, and heterotopia exacerbate during postnatal development. Astrogliosis becomes prominent at these same sites by the time cerebellar development is complete. Interestingly, there is spatial heterogeneity in the glia limitans and granule neuron migration defects that spares the tips of lobules IV-V and VI.ConclusionsThe full spectrum of developmental pathology is caused by loss of dystroglycan from Bergmann glia, as neither granule cell- nor Purkinje cell-specific deletion of dystroglycan results in similar pathology. These data illustrate the importance of dystroglycan function in radial/Bergmann glia, not neurons, for normal cerebellar histogenesis. The spatial heterogeneity of pathology suggests that the dependence on dystroglycan is not uniform.

Executive Functions and Cerebellar Development in Children

This article examines the role of the cerebellum in processing executive functions in developmental age. The areas implicated in its elaboration are interconnected in a network that includes the prefrontal cortex, the basal ganglia, and the cerebellum. Implementation of the capacities to plan and to control corresponds to the development of the network and its structures. The development, from an evolutionary point of view, of the most recent parts of the cerebellum and of its connections with the prefrontal cortex is tied to the crucial role that it plays in an inexorable way in action execution with implicit mechanisms of anticipation and control. Deficits in executive functions are present in many cerebellar pathologies and there is also an important link between motor development and the development of many higher-order cognitive and functional domains. Further studies are needed to clarify the role of the cerebellum in executive functions both in pathological or normal conditions in the developmental age.

Cerebellar Syndromes: A Medical Student Guide

The cerebellum is central to normal motor function and co-ordination, and can be frequently affected in a number of common disease processes. However, medical student teaching relating to cerebellar anatomy and pathology is lacking, leaving many graduates with a significant knowledge gap. Junior doctors need to be able to recognize ‘cerebellar syndromes’ on presentation to hospitals, and to identify and manage reversible causes rapidly and effectively. After review of relevant literature, a simple approach to the functional anatomy and practical classifications of common cerebellar pathology is presented here, with a focus on symptoms, signs and examination techniques essential to medical school final exams.

Cerebellum and Autism

The accumulation of published literature clearly indicates that the cerebellum is involved in the pathology of autism [1–3]. As to whether cerebellar pathology is primal or only part of an important brain circuitry involved in autism, the data are incomplete. What is clearly new and relevant to the etiology of autism is that cerebellar function is not limited to motor coordination but involves processing of cognition which is at the heart of autistic pathology [1, 4]. Fatemi et al. [5] recently reviewed the existing literature with respect to the pathological involvement of cerebellum in autism. The preponderance of evidence supports the involvement of this important brain area in etiology of autism. Recent supportive literature links developmental cerebellar pathology with decreased prefrontal dopamine transmission [3] and autistic behavior [6] in various animal models of autism. In a series of experiments, Rogers et al. [3] showed that despite having different cerebellar abnormalities, both the Lurcher and fragile X mental retardation 1 mutant mice exhibited abnormalities involving the cerebellar–prefrontal circuitry which resulted in abnormal dopamine transmission that underlie cognitive deficits in both mutant mouse models reminiscent of autistic phenotype. By the same token, Tsai et al. [6] showed that loss of tuberous sclerosis complex 1 protein in mouse cerebellar Purkinje cells in both heterozygous and homozygous mutants results in autistic behavior. Treatment with the mTOR inhibitor, rapamycin, prevented both biochemical and behavioral deficits, further supporting a cerebellar contribution to the autistic etiology [6]. Ziats and Rennert [7] question the cerebellar contribution to autistic pathology and suggest that cerebellum may simply act as an anatomic beacon that reflects or exaggerates brain-wide manifestations of autistic disease but do not provide any data to support their claim. Indeed experimental evidence provided by Tsai et al. [6] and Rogers et al. [3] further support the notion that the cerebellum is partially causative for autistic behavior and pathology. Furthermore, Ziats and Rennert’s hypothesis, while plausible, clearly needs further supportive evidence and experimental and clinical verification. Finally, as Ziats and Rennert have shown in their report, cerebellar complexity is no less than in neocortex, showing that it is a site capable of modulating multiple cortical functions including cognition.

The Cerebellum in Autism: Pathogenic or an Anatomical Beacon?

To The Editor: In the September 2012 issue of The Cerebellum, Fatemi et al. presented a comprehensive literature analysis of the putative role of the cerebellum in autism pathogenesis [1]. While this is an important work, which synthesizes the main findings of cerebellar research in autism spectrum disorders (ASD), we believe there is an alternative hypothesis to the role of the cerebellum in autism that is more parsimonious. The conclusion that the cerebellum is pathogenic in ASD is predicated on the notion that the cerebellum functions in the cognitive processes disrupted in autism, although such pathways remain undiscovered. While the cerebellar contribution to higher cognition has been debated for decades [2], a clear mechanistic understanding of how the cerebellum may integrate with processes affected in autism, such as theory of mind, is not well established—as Fatemi et al. noted. Human studies that have consistently implicated the cerebellum in ASD do so mostly on the basis of volumetric imaging studies, or postmortem histologic and molecular changes, including our own work [3]. However, as opposed to the notion that these changes are pathogenic—which would require an as yet undiscovered mechanism for the cerebellum in the higher cognitive functions affected in ASD—we propose instead that the unique anatomy, physiology, and development of the cerebellum may result in an exaggerated manifestation of the brain-wide pathologic changes that underlie autism, without being causal for the clinical phenotype. In this sense, then, the cerebellum in autism may be acting as an “anatomical beacon” of more subtle changes in other brain regions where the functional pathology actually rests. The unique anatomy, physiology, and development of the cerebellum make it a distinct part of the human brain. The cerebellum has the highest cell density of any brain area, approximately four times that of the neocortex [4, 5], and cerebellar Purkinje cells have more synapses than any other cell type by orders of magnitude [6]. As building synapses requires the appropriate molecular “toolkit,” the cerebellum's molecular complexity of transcripts [7, 8] and proteins [9, 10] rivals that of the cerebral cortex. Underlying the heightened synaptogenesis of the cerebellum is the need for energy to carry out this process, resulting in oxidative metabolic demand that is similar to the cerebral cortex as well [11]. The implications of these well-recognized cerebellar properties to autism are profound. The ASD phenotype is considered to ultimately result from synaptic dysfunction [12], which derives from underlying genetic changes that manifest in aberrant RNA and protein production [13, 14]. Additionally, autism has a strong and growing association with related problems in oxidative metabolism [15]. Is it possible that cerebellar pathology in ASD is more evident than other brain areas purely because the cerebellum contains more of the components that are disrupted in autism? If the molecular and cellular processes that are abnormal in ASD are dysfunctional throughout the brain, then these observations suggest that the cerebellum may have properties that result in an exaggerated manifestation of ASD pathology compared to other brain regions. Therefore, we hypothesize that the cerebellum may not be etiological in the pathogenesis of autism spectrum disorders; rather its unique anatomic and physiologic properties may accentuate the mechanisms that are aberrant throughout the autistic brain. Consequently, investigations into autism pathology may be more readily observed in the cerebellum because the changes are more obvious than the concomitant changes in other brain areas responsible for the clinical phenotype. This hypothesis does not diminish the potential importance of the cerebellum to autism research. Harnessing this unique property has serious implications in diagnostic testing, for example with neuroimaging. Diagnostic tests may be able to identify biological changes in ASD patients earlier in life, which is known to correlate with improved patient outcomes [16, 17], by focusing on the cerebellum. While cerebellar changes may not directly cause the cognitive deficits of ASD, they could serve as an “internal biomarker” for the more subtle alterations that must therefore be ongoing in other brain areas but would require more sensitive techniques to detect. Until it is understood how the cerebellum functions in the higher cognitive processes that are abnormal in autism, the field must consider the alternative hypothesis that changes found in the cerebellum of autistic patients are not pathogenic, but rather are collateral manifestations of the cellular and molecular deficits that are present throughout the autistic brain. The distinctive nature of the cerebellum may exaggerate changes that are more subtle in other brain areas, without being causal of the ASD phenotype. However, such an interpretation does not diminish the importance of cerebellar research in autism, as this unique characteristic may make the cerebellum an ideal diagnostic target.

Cerebello-cerebral connectivity deficits in Friedreich ataxia

Brain pathology in Friedreich ataxia is characterized by progressive degeneration of nervous tissue in the brainstem, cerebellum and cerebellar peduncles. Evidence of cerebral involvement is however equivocal. This brain imaging study investigates cerebello-cerebral white matter connectivity in Friedreich ataxia with diffusion MRI and tractography performed in 13 individuals homozygous for a GAA expansion in intron one of the frataxin gene and 14 age- and gender-matched control participants. New evidence is presented for disrupted cerebello-cerebral connectivity in the disease, leading to secondary effects in distant cortical and subcortical regions. Remote regions affected by primary cerebellar and brainstem pathology include the supplementary motor area, cingulate cortex, frontal cortices, putamen and other subcortical nuclei. The connectivity disruptions identified provide an explanation for some of the non-ataxic symptoms observed in the disease and support the notion of reverse cerebellar diaschisis. This is the first study to comprehensively map white matter connectivity disruptions in Friedreich ataxia using tractography, connectomic techniques and super-resolution track density imaging.

Cerebellum-dependent associative learning deficits in primary dystonia are normalized by rTMS and practice

Eyeblink classical conditioning (EBCC) is a cerebellum-dependent paradigm of associative motor learning, and abnormal EBCC is a neurophysiological indicator of cerebellar dysfunction. We have previously demonstrated impaired EBCC in patients with primary dystonia, but it remains uncertain if this represents actual cerebellar pathology or reflects a functional cerebellar disruption. We examined this further by: (1) studying acquisition and retention of EBCC in a second session in eight patients with cervical dystonia (CD) who had a first session 7-10days earlier; and (2) by investigating the potential of continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere to modify a first-ever EBCC session in 11 patients with CD. EBCC data of eight healthy controls previously studied were used for additional between-group comparisons. We observed an improvement of EBCC in a second session in patients with CD, which is in contrast to patients with proven cerebellar pathology who do not show further improvement of EBCC in additional sessions. We also found that cerebellar cTBS paradoxically normalized EBCC in patients with CD, while we previously showed that it disrupts EBCC in healthy volunteers. Combined, these two experiments are in keeping with a functional and reversible disruption of the cerebellum in dystonia, a phenomenon that is probably secondary to either cerebellar compensation or to cerebellar recruitment in the abnormal sensorimotor network.

Inconsistent terminology for cerebellar mutism

Dear Editor:We would like to thank Gudrunardottir and coworkers forcommenting on our paper “Fronto-cerebellar fiber tractographyin pediatric patients following posterior fossa tumor surgery”[1]. We admit that the paper entitled “Cerebellar mutism:review of the literature” by Gudrunardottir et al. [2] shouldhave been cited at the respective passage instead of or eventogether with “Cerebellar mutism: definitions, classificationand grading of symptoms” by the same group [ 3]whichwere published both in 2011.The issue raised by Gudrunardottir et al. is the ambiguoususe of the term of “cerebellar mutism (CM)” and its exactdefinition. In our report, we used CM and CM syndrome(CMS)assynonymsandtherebymaynothaveclearlyenoughexpressed that we agree that posterior fossa syndrome (PFS)describes a broader symptomatology complex of which CMSorCMisanintegralpart.Inthiscontextandtobetterelucidatethe problem of inconsistent terminology, we scrutinized theterminology used in the literature in the period between 2000and2013byperformingaMedlinesearchusingthephrases“cerebellar mutism” and “cerebellar mutism syndrome.” Weexcluded all non-English papers and all publications, whichdid not primarily deal with cerebellar pathology. The searchrevealed 86 publications: 12 reviews, 13 letters to the editors,26 case reports, and 35 original papers. Among these, weevaluated the terminology used for the clinical picture dealingwith mutism caused by cerebellar pathology. Eventually, wefound up to nine different specifications (Table 1). The major-ity of papers used only one or two terms (n=57) for thesymptomatology. The mean number of terms used was 2.2ranging from one up to five terms per paper. CM and CMSwere used most often as synonyms (n=14). Even more con-fusing synonymous descriptions were CM together with“posterior fossa syndrome” (n=5) or together with“akinetic mutism” (n=4). In contrast, clear delineation be-tween the terms CM and CMS was performed in onlyseven publications.This wide spectrum of terms employed clearly shows thatthe definition of CM and its associated syndromes is stillwithout clear definition. Thus, wesupport theneedfor a clearandwidelyacceptedterminologyproposedbyGudrunardottiret al. [3]. We agree with their definition of CM as a mutenessfollowing lesion of the cerebellum as opposed to occurrencewith lesions of the cerebrum or the lower cranial nerves. WealsoagreethatCMisonlyonesymptomoftheCMScomplexthatalsoincludesataxia,hypotonia,andirritabilityorthatCMand CMS are part of PFS that additionally includes cranialnervedeficits,neurobehavioralchanges,andurinaryretentionor incontinence [3]. In our view for future discussions, threeissues need further clarification: firstly, any symptoms ofdecreasedimpetusmaybebetterclassifiedwithinCMSratherthaninthecontextofPFSasproposedbyGudrunardottiretal.[3].Thisincludesimpairedimpulsionofmotormovements(aslong as no brainstem lesion is present) or impaired impulsionof eye opening, which may be similar in its cerebellar originlike impaired impulsion of speech production. Secondly,neurobehavioral changes like apathy and deficits of atten-tion or memory may resemble lack of cerebellar controlon higher prefrontal function, which is yet not fully un-derstood. As long as anatomical correlates are not clearlyidentified, an exact and sustainable terminology cannot befound. Nevertheless, it seems reasonable to distinguishCMS with neurological deficits being related to cerebellarfunctions from PFS that includes symptoms related tocranial nerves or brainstem deficits. Thirdly, grading ofseverity of CMS is still ill defined. Robertson et al. usedthe duration of symptoms as a measure for severity [4].The future goal may be to grade the severity of mutenessitself as well as to grade the amount of symptoms withinCMS. This may be relevant to evaluate even mild

Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Burial of the Polymorphic Residue 129 in Amyloid Fibrils of Prion Stop Mutants

Misfolding of the natively α-helical prion protein into a β-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. In humans, the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene. Using a combination of hydrogen/deuterium exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry, and site-directed mutagenesis, we demonstrate that stop mutants of the human prion protein have a conserved amyloid core. The 129 residue is deeply buried in the amyloid core structure, and its mutation strongly impacts aggregation. Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease.