Cerebellar language and cognitive functions in childhood: A comparative review of the clinical research

Background: Recent research addressing evidence from functional neuroimaging studies, neurophysiological research, and new advances in neuropsychology together with traditional cerebellar lesion studies have recently implicated the cerebellum in adult language and cognitive functions. However, more limited information is currently available in describing the functional connectivity present in the paediatric population. Aims: It is the purpose of this paper to review recent clinical research pertaining to paediatric populations, outlining the impact of site of lesion and specific associated clinical changes in children with cerebellar disturbances. Main contribution: The specific contribution of the right cerebellar hemisphere to language function is identified to also exist in the paediatric population, highlighting the existence of functional connections between this region of the brain and left frontal cortical areas early in development. Conclusions: Implications for future research in paediatric populations are extensive, as a greater awareness and an understanding of the recently acknowledged involvement of the cerebellum in cognition and nonmotor linguistic function is anticipated to also add new dimension and direction to the analysis of childhood language outcomes associated with the cerebellum.

Acoustic Investigation of Vocal Quality following Treatment for Childhood Cerebellar Tumour

The aim of the study was firstly to document the acoustic parameters of voice using the Multidimensional Voice Program (MDVP, Kay Elemetrics) in a group of children with dysarthria subsequent to treatment for cerebellar tumour (CT). Then, secondly, compare the acoustic findings to perceptual voice characteristics as described by the GIRBAS (grade, instability, roughness, breathiness, asthenicity, strain). The assessments were performed on 29 voice samples; 9 cerebellar tumour participants with dysarthria, and 20 control participants. None of the control voices were rated as exhibiting any of the six parameters described by the GIRBAS, while 7 of the CT participants were noted to have at least a mild voice disorder. Roughness, instability, breathiness and asthenicity were all identified as voice characteristics in the CT voice samples. Acoustically, the CT voice samples differed significantly from the controls' voices on frequency and amplitude perturbation measures. Our findings confirmed voice dysfunction as a component of dysarthria in children treated for cerebellar tumour, and discussed the links between acoustic and perceptual descriptions. Copyright (C) 2004 S. Karger AG, Basel.

Higher-level language deficits resulting from left primary cerebellar lesions

Background: Contemporary neuropsychological studies suggest that cerebellar lesions may impact upon higher-level cognitive functioning via mechanisms of crossed cerebello-cerebral diaschisis. Accordingly, right cerebellar lesions have been previously associated with linguistic impairments such as reduced word fluency and agrammatic output. Recently, however, neuroimaging investigations have also identified ipsilateral cerebral hypoperfusion as a consequence of cerebellar lesions, implicating a potential role for the left cerebellum in the mediation of language processes. Aims: The purpose of this research was to investigate the effects of left cerebellar lesions of vascular origin, on general as well as high-level language skills. Methods & Procedures: Linguistic profiles were compiled for five individuals with left primary cerebellar lesions utilising a comprehensive language test battery. Individual scores relevant to each subtest were compared to a group of non-neurologically impaired controls. The criterion for anomalous performance was established as greater than or equal to 1.5 SD below the mean of the control group. Outcomes & Results: The findings of this research suggest that higher-level language deficits may result from left primary cerebellar lesions. All participants demonstrated deficits on measures of word fluency, sentence construction within a set context, producing word definitions, and producing multiple definitions for the same word. Deficits were also noted for several participants on measures of understanding figurative language, forming word associations, identifying and correcting semantic absurdities, and producing synonyms and antonyms. Conclusions: The results presented challenge the notion of a lateralised linguistic cerebellum, supporting a potential role for the left as well as right cerebellar hemispheres in the regulation of language processes, presumably via cerebellar-basal ganglia/thalamo-cortical pathways.

The impact of carboxy nitroxide antioxidants on irradiated ataxia telangiectasia cells

Three water-soluble carboxy nitroxide antioxidants, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-yloxyl, and 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-yloxyl, show significant impact on the postirradiation survival rates of ataxia telangiectasia (A-T) cells compared to normal cells, an assay which represents a model for understanding the impact of ROS damage on the A-T phenotype. The effects of these antioxidants are much more significant than those of vitamin E or Trolox (a water-soluble vitamin E analog), studied using the same cell survival model. (C) 2004 Elsevier Inc. All rights reserved.

Articulatory imprecision in dysarthria following childhood cerebellar tumor: A perceptual and acoustic investigation of three male participants

Articulatory imprecision has been documented as a key perceptual feature of the dysarthria associated with childhood cerebellar tumor (CCT). As yet the underlying acoustic and physiological characteristics of motor speech production that contribute to this perceptual feature have not been identified. The aim of the current study was to describe perceptual and acoustic characteristics of consonant production in three children with dysarthria associated with CCT The results indicated that in all three cases the timing of articulatory movements during stop consonant production differed from that measured in a control group of same-age peers. The impact of cerebellar lesions in adulthood on articulatory gestures is used as a reference for discussing the findings of the current study with similarities evident. Also discussed are future research directions for examining the underlying acoustic or physiological basis for articulatory imprecision in children with dysarthria associated with CCT.

Differential motor speech outcomes in children treated for mid-line cerebellar tumour

Primary objective: To investigate the nature of the motor speech impairments and dysarthria that can arise subsequent to treatment for childhood mid-line cerebellar tumours (CMCT). Research design: The motor speech ability of six cases of children with CMCT was analysed using perceptual and physiological measures and compared with that of a group of non-neurologically impaired children matched for age and sex. Main outcome and results: Three of the children with CMCT were perceived to exhibit dysarthric speech, while the remaining three were judged to have normal speech. The speech disorder in three of the children with CMCT was marked by deviances in prosody, articulation and phonation. The underlying pathophysiology was linked to cerebellar damage and expressed as difficulty in co-ordinating the motor speech musculature as required for speech production. These deficits were not identified in the three non-dysarthric children with CMCT. Conclusion: Differential motor speech outcomes occur for children treated for CMCT and these are discussed within the realm of possible mechanisms responsible for these differences. The need for further investigation of the risk factors for development of motor speech impairment in children treated for CMCT is also highlighted.

Defective p53 response and apoptosis associated with an ataxia-telangiectasia-like phenotype

Ataxia-telangiectasia mutated (ATM), the protein defective in ataxia-telangiectasia, plays a central role in DNA damage response and signaling to cell cycle checkpoints. We describe here a cell line from a patient with an ataxia-telangiectasia-like clinical phenotype defective in the p53 response to radiation but with normal ATM activation and efficient downstream phosphorylation of other ATM substrates. No mutations were detected in ATM cDNA. A normal level of interaction between p53 and peptidyl-prolyl-isomerase Pin1 suggests that posttranslational modification was intact in these cells but operating at reduced level. Defective p53 stabilization was accompanied by defective induction of p53 effector genes and failure to induce apoptosis in response to DNA-damaging agents. Continued association between p53 and murine double minute-2 (Mdm2) occurred in irradiated ATL2ABR cells in response to DNA damage, and incubation with Mdm2 antagonists, nutlins, increased the stabilization of p53 and its transcriptional activity but failed to induce apoptosis. These results suggest that ATM-dependent stabilization of p53 and induction of apoptosis by radiation involve an additional factor(s) that is defective in ATL2ABR cells.

Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.

Detection of elevated protein modification in human cerebellum in alcoholic cerebellar degeneration

Modification of proteins by reactive ethanol metabolites has been known for some time to occur in the liver, the main site of ethanol metabolism. In more recent studies of laboratory animals, similar modifications have been detected in organs with lesser ability to metabolize ethanol, such as skeletal and cardiac muscle and brain. Such modification may alter protein function or form a neoantigen, making it a target for immune attack. We now report an analysis of protein modification derived from ethanol metabolites in human brain tissue by ELISA using adduct-specific antibodies. We obtained autopsy cerebellum samples from 10 alcoholic cerebellar degeneration cases and 10 matched controls under informed written consent from the next of kin and clearance from the UQ Human Ethics Committee. Elevated levels of protein modifications derived from acetaldehyde (unreduced-acetaldehyde and acetaldehyde-advanced glycation end-product adducts), from malondialdehyde (malondialdehyde adducts) and from combined adducts (malondialdehydeacetaldehyde (MAA) adducts) were detected in alcoholic cerebellar degeneration samples when compared to controls. Other adduct types found in liver samples, such as reduced-acetaldehyde and those derived from hydroxyethyl radicals, were not detected in brain samples. This may reflect the different routes of ethanol metabolism in the two tissues. This is the first report of elevated protein modification in alcoholic cerebellar degeneration, and suggests that such modification may play a role in the pathogenesis of brain injury. Supported by NIAAA under grant NIH AA12404 and the NHMRC (Australia) under grant #981723.