MRI-Assessed Volume of Cerebellum Correlates with Associative Learning

Richard F. Thompson's cerebellar model of classical eyeblink conditioning highlights Purkinje cells in cerebellar cortex and principal cells in the deep cerebellar nucleus as the integrating cells for acquisition of conditioned responses (CRs). CR acquisition is significantly slower in rabbits with lesions to cerebellar cortex and in Purkinje cell-deficient mice that lose all cerebellar cortical Purkinje cells. Purkinje cells are the largest neurons in the cerebellum and contribute significantly to cerebellar volume. Magnetic resonance imaging (MRI) was used to assess cerebellar volume in humans. Cerebellar volume was related to eyeblink conditioning (400-ms delay procedure) in 8 adults (21-35 years) and compared to 8 older adults (77-95 years) tested previously (Woodruff-Pak, Goldenberg, Downey-Lamb, Boyko, & Lemieux, 2000). In the young adult sample, there was a high correlation between percentage of CRs in a session and cerebellar volume (corrected for total intracranial volume [TIV], r =.58, p =.066). There were statistically significant age differences in cerebellar volume, t(14) = 8.96, p <.001, and percentage of CRs, t(14) = 3.85, p <.002, but no age difference in TIV. Combining the young and older adult sample, the correlation between percentage of CRs and cerebellar volume (corrected for TIV) was.832 (p <.001). Cerebellar volume showed age-related deficits likely due to Purkinje cell loss. Individual differences in classical eyeblink conditioning are associated with differences in cerebellar volume, supporting Thompson's model of a cerebellar cortical role in facilitating this form of associative learning.     

Incidence of dysarthria in children with cerebellar tumors: a prospective study

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence production tasks. Localization of the cerebellar lesions were defined after manual transfer from individual 2D-MR images onto 3D images of a spatially normalized healthy brain. Cerebellar children showed few and mild clinical signs of dysarthria. No difference was present in the sentence production task compared to controls. In five cerebellar children, syllables were prolonged in the syllable repetition task after surgery. Syllable duration normalized in an additional four-week session in all but one case. The MR-analysis showed that superior paravermal cerebellar areas likely involved in dysarthria in adults (paravermal lobules HVI, Crus I) were not significantly affected. In children, speech impairments appear to be rare after cerebellar surgery because tumors most commonly affect posterior-inferior and medial parts of the cerebellum while critical cerebellar regions are likely spared. The results suggest a similar localization of speech functions in the cerebellum in children and adults.     

The visuospatial functions in children after cerebellar low‐grade astrocytoma surgery: A contribution to the pediatric neuropsychology of the cerebellum

The aim of this study was to specify whether cerebellar lesions cause visuospatial impairments in children. The study sample consisted of 40 children with low‐grade cerebellar astrocytoma, who underwent surgical treatment and 40 healthy controls matched with regard to age and sex. Visuospatial abilities were tested using the spatial WISC‐R subtests (Block Design and Object Assembly), Rey–Osterrieth Complex Figure, Benton Judgment of Line Orientation Test, PEBL Mental Rotation Task, and Benton Visual Retention Test. To exclude general diffuse intellectual dysfunction, the WISC‐R Verbal Intelligence IQ, Performance IQ, and Full‐Scale IQ scores were analysed. Post‐surgical medical consequences were measured with the International Cooperative Ataxia Rating Scale. Compared to controls, the cerebellar group manifested problems with mental rotation of objects, visuospatial organization, planning, and spatial construction processes which could not be explained by medical complications or general intellectual retardation. The intensity of visuospatial syndrome highly depends on cerebellar lesion side. Patients with left‐sided cerebellar lesions display more severe spatial problems than those with right‐sided cerebellar lesions. In conclusion, focal cerebellar lesions in children affect their visuospatial ability. The impairments profile is characterized by deficits in complex spatial processes such as visuospatial organization and mental rotation, requiring reconstruction of visual stimuli using the imagination, while elementary sensory analysis and perception as well as spatial processes requiring direct manipulation of objects are relatively better preserved. This pattern is analogous to the one previously observed in adult population and appears to be typical for cerebellar pathology in general, regardless of age.     

Performance of Dyslexic Children on Cerebellar and Cognitive Tests

In a previous study (A. J. Fawcett, R. I. Nicolson, & P. Dean, 1996), the authors had found strong behavioral evidence for cerebellar deficit in a panel of children with dyslexia. In the present study, the generality of those results was assessed. A battery of clinical tests for cerebellar dysfunction was administered, together with selected cognitive tests, to a further 59 dyslexic and 67 control children. The dyslexic children showed highly significant impairments on the cerebellar tests, with deficits on postural stability and muscle tone comparable in magnitude with their reading and spelling deficits. Furthermore, over 95% of the dyslexic children showed clear evidence of deficit on muscle tone or stability. The findings provide further evidence of the generality of cerebellar impairment in dyslexia. The implications of the cerebellar tests for screening in dyslexia are discussed.     

Performance of Dyslexic Children on Cerebellar and Cognitive Tests

In a previous study (A. J. Fawcett, R. I. Nicolson, & P. Dean, 1996), the authors had found strong behavioral evidence for cerebellar deficit in a panel of children with dyslexia. In the present study, the generality of those results was assessed. A battery of clinical tests for cerebellar dysfunction was administered, together with selected cognitive tests, to a further 59 dyslexic and 67 control children. The dyslexic children showed highly significant impairments on the cerebellar tests, with deficits on postural stability and muscle tone comparable in magnitude with their reading and spelling deficits. Furthermore, over 95&percent; of the dyslexic children showed clear evidence of deficit on muscle tone or stability. The findings provide further evidence of the generality of cerebellar impairment in dyslexia. The implications of the cerebellar tests for screening in dyslexia are discussed.     

Mutism in an Adult Following Hypertensive Cerebellar Hemorrhage: Nosological Discussion and Illustrative Case

Mutism after cerebellar injury has been associated with tumors, hemorrhage, and surgery of midline cerebellar structures. Literature review identified 54 cases, primarily in children after surgical splitting of the inferior vermis. We present a 47-year-old who developed transient mutism after cerebellar hemorrhage. This represents the first report of transient mutism in an adult with neither tumor nor brainstem infarction and documents the importance of cerebellar structures for initiation and production of speech in adulthood. This case further differs from those previous because of the long mute period and the subsequent return of continued ataxic and dysarthric speech.     

The Role of the Cerebellum in Cognition and Emotion: Personal Reflections Since 1982 on the Dysmetria of Thought Hypothesis,and Its Historical Evolution from Theory to Therapy

The cognitive neuroscience of the cerebellum is now an established multidisciplinary field of investigation. This essay traces the historical evolution of this line of inquiry from an emerging field to its current status, with personal reflections over almost three decades on this journey of discovery. It pays tribute to early investigators who recognized the wider role of the cerebellum beyond motor control, traces the origins of new terms and concepts including the dysmetria of thought theory, the universal cerebellar transform, and the cerebellar cognitive affective syndrome, and places these developments within the broader context of the scientific efforts of a growing community of cerebellar cognitive neuroscientists. This account considers the converging evidence from theoretical, anatomical, physiological, clinical, and functional neuroimaging approaches that have resulted in the transition from recognizing the cerebellar incorporation into the distributed neural circuits subserving cognition and emotion, to a hopeful new era of treatment of neurocognitive and neuropsychiatric manifestations of cerebellar diseases, and to cerebellar-based interventions for psychiatric disorders.     

Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei

In Pavlovian eyelid conditioning and adaptation of the vestibulo-ocular reflex, cerebellar cortex lesions fail to completely abolish previously acquired learning, indicating an additional site of plasticity in the deep cerebellar or vestibular nucleus. Three forms of plasticity are known to occur in the deep cerebellar nuclei: formation of new synapses, plasticity at existing synapses, and changes in intrinsic excitability. Only a cell-wide increase in excitability predicts that learning should generalize broadly from a training stimulus to other stimuli capable of supporting learning, whereas the alternatives predict that learning should be relatively specific to the training stimulus. Here we show that deep nucleus plasticity, as assessed by conditioned eyelid responses produced without input from the cerebellar cortex, is relatively specific to the training conditioned stimulus (CS). We trained rabbits to a tone or light CS with periorbital stimulation as the unconditioned stimulus (US), and pharmacologically disconnected the cerebellar cortex during a posttraining generalization test. The short-latency conditioned responses unmasked by this treatment showed strong decrement along the dimension of auditory frequency and did not generalize across stimulus modalities. These results cannot be explained solely by a cell-wide increase in the excitability of deep nucleus neurons, and imply that an input-specific mechanism in the deep cerebellar nucleus operates as well.     

Cerebellar patients demonstrate preserved implicit knowledge of association strengths in musical sequences

Recent findings suggest the involvement of the cerebellum in perceptual and cognitive tasks. Our study investigated whether cerebellar patients show musical priming based on implicit knowledge of tonal-harmonic music. Participants performed speeded phoneme identification on sung target chords, which were either related or less-related to prime contexts in terms of the tonal-harmonic system. As groups, both cerebellar patients and age-matched controls showed facilitated processing for related targets, as previously observed for healthy young adults. The outcome suggests that an intact cerebellum is not mandatory for accessing implicit knowledge stored in long-term memory and for its influence on perception. One patient showed facilitated processing for less-related targets (suggesting sensory priming). The findings suggest directions for future research on auditory perception in cerebellar patients to further our understanding of cerebellar functions.     

Neuroimaging studies of the cerebellum: language, learning and memory

During the decade following a functional neuroimaging study of language that showed cerebellar involvement in a cognitive task, PET and fMRI studies have continued to provide evidence that the role of the cerebellum extends beyond that of motor control and that this structure contributes in some way to cognitive operations. In this review, we describe neuroimaging evidence for cerebellar involvement in working memory, implicit and explicit learning and memory, and language, and we discuss some of the problems and limitations faced by researchers who use neuroimaging to investigate cerebellar function. We also raise a set of outstanding questions that need to be addressed through further neuroimaging and behavioral experiments before differing functional accounts of cerebellar involvement in cognition can be resolved.     

Erratum

The main aims of this study were a) to assess the cerebellar deficit hypothesis examining children's performance in cerebellar and cognitive tasks associated with the dyslexic syndrome and b) to investigate if there is a differentiation in articulation speed in children with dyslexia. A battery consisted of five cerebellar tests, five cognitive tests, and an articulation speed test was administered to three age- and sex-matched groups of dyslexics, children with attention deficit/hyperactivity disorder (ADHD) and normal readers aged 8–12 years. The dyslexics showed significant impairment in one cerebellar test compared with the control group and in two cognitive tests compared with both the control and the ADHD group. Additionally, the dyslexic children performed significantly worse than the control group during the articulation speed test; such a difference was not observed between the control and the ADHD group. The present study provides clues to support the cerebellar deficit hypothesis and the possible relationship between reading impairment and speed of articulation. Further research is considered essential to clarify the relationship between cerebellar function, dyslexia, and oral language speed.     

Structural Stability within the Lateral Cerebellar Nucleus of the Rat Following Complex Motor Learning

Complex motor learning, but not mere motor activity, has been previously shown to induce structural modifications within the cerebellar cortex. The present experiment examined whether similar changes occur within one of the primary output targets of the region of the cerebellar cortex in which these structural changes were described, the lateral cerebellar nucleus (LCN; dentate nucleus). Adult female rats were randomly allocated to one of three training conditions. Acrobatic condition (AC) rats were trained to complete a complex motor learning task consisting of a series of elevated obstacles while motor control (MC) condition animals were forced to traverse a flat obstacle-free runway equal in length to the AC task. Inactive condition (IC) animals received no motor training. Unbiased stereological techniques and electron microscopy were used to obtain estimates of synapse number and postsynaptic density (PSD) length within the LCN. Results showed that neither synapse number nor PSD length was significantly altered as a function of training condition. These results indicate that complex motor skill learning is associated with structural plasticity within the cerebellar cortex and with structural stability within the lateral cerebellar nucleus.     

Reorganization of the cerebro-cerebellar network of language production in patients with congenital left-hemispheric brain lesions

Patients with congenital lesions of the left cerebral hemisphere may reorganize language functions into the right hemisphere. In these patients, language production is represented homotopically to the left-hemispheric language areas. We studied cerebellar activation in five patients with congenital lesions of the left cerebral hemisphere to assess if the language network is reorganized completely in these patients, i.e. including also cerebellar language functions. As compared to a group of controls matched for age, sex, and verbal IQ, the patients recruited an area not in the right but in the left cerebellar hemisphere. The extent of laterality of the cerebellar activation correlated significantly with the laterality of the frontal activation. We suggest that the developing brain reacts to early focal lesions in the left hemisphere with a mirror-image organization of the entire cerebro-cerebellar network engaged in speech production.     

The cerebellum: Its role in language and related cognitive and affective functions

The traditional view on the cerebellum as the sole coordinator of motor function has been substantially redefined during the past decades. Neuroanatomical, neuroimaging and clinical studies have extended the role of the cerebellum to the modulation of cognitive and affective processing. Neuroanatomical studies have demonstrated cerebellar connectivity with the supratentorial association areas involved in higher cognitive and affective functioning, while functional neuroimaging and clinical studies have provided evidence of cerebellar involvement in a variety of cognitive and affective tasks. This paper reviews the recently acknowledged role of the cerebellum in linguistic and related cognitive and behavioral–affective functions. In addition, typical cerebellar syndromes such as the cerebellar cognitive affective syndrome (CCAS) and the posterior fossa syndrome (PFS) will be briefly discussed and the current hypotheses dealing with the presumed neurobiological mechanisms underlying the linguistic, cognitive and affective modulatory role of the cerebellum will be reviewed.     

Verbal Memory Abilities of Children With Brain Tumors

Several critical neuroanatomical structures and pathways for memory performance are located in the third ventricle region. This led us to predict that verbal memory abilities would be more impaired in children treated for third ventricle tumors compared to those treated for cerebellar tumors. Archival data was obtained from 24 pediatric patients with third ventricle region tumors and 18 pediatric patients with cerebellar tumors. Neuroradiological verifications of tumor involvement and hydrocephalus severity (i.e., Evans Index) on preoperative scans and MRIs proximal to the time of the neuropsychological evaluation were conducted. The potential confounds of hydrocephalus severity, seizure medication, age, radiation treatment, and chemotherapy were addressed. Verbal IQ was comparable between tumor groups and in the Average range. The third ventricle region group performed significantly worse on list learning and delayed list recall compared to the cerebellar group. Their mean performance was in the clinically impaired range on both trials. The third ventricle region tumor group performed better than the cerebellar tumor group on Digit Span, a basic repetition, attention span task. These findings support the hypothesis that pediatric patients with third ventricle region brain tumors are more likely to be impaired on verbal recall tasks compared to pediatric patients with cerebellar brain tumors. In contrast, patients who were treated for cerebellar tumors were more impaired on the basic repetition, attention span task compared to patients who were treated for third ventricle tumors. Future studies should examine the specific neuroanatomical structures and pathways that are damaged and may influence differential cognitive impairments in children.     

Using Eyeblink Classical Conditioning as a Test of the Functional Consequences of Exposure of the Developing Cerebellum to Alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Developmental dyslexia and widespread activation across the cerebellar hemispheres

Developmental dyslexia is the most common learning disability in school-aged children with an estimated incidence of five to ten percent. The cause and pathophysiological substrate of this developmental disorder is unclear. Recently, a possible involvement of the cerebellum in the pathogenesis of dyslexia has been postulated. In this study, 15 dyslexic children and 7 age-matched control subjects were investigated by means of functional neuroimaging (fMRI) using a noun-verb association paradigm. Comparison of activation patterns between dyslexic and control subjects revealed distinct and significant differences in cerebral and cerebellar activation. Control subjects showed bilaterally well-defined and focal activation patterns in the frontal and parietal lobes and the posterior regions of the cerebellar hemispheres. The dyslexic children, however, presented widespread and diffuse activations on the cerebral and cerebellar level. Cerebral activations were found in frontal, parietal, temporal and occipital regions. Activations in the cerebellum were found predominantly in the cerebellar cortex, including Crus I, Crus II, hemispheric lobule VI, VII and vermal lobules I, II, III, IV and VII. This preliminary study is the first to reveal a significant difference in cerebellar functioning between dyslexic children and controls during a semantic association task. As a result, we propose a new hypothesis regarding the pathophysiological mechanisms of developmental dyslexia. Given the sites of activation in the cerebellum in the dyslexic group, a defect of the intra-cerebellar distribution of activity is suspected, suggesting a disorder of the processing or transfer of information within the cerebellar cortex.     

Verbal memory abilities of children with brain tumors.

Several critical neuroanatomical structures and pathways for memory performance are located in the third ventricle region. This led us to predict that verbal memory abilities would be more impaired in children treated for third ventricle tumors compared to those treated for cerebellar tumors. Archival data was obtained from 24 pediatric patients with third ventricle region tumors and 18 pediatric patients with cerebellar tumors. Neuroradiological verifications of tumor involvement and hydrocephalus severity (i.e., Evans Index) on preoperative scans and MRIs proximal to the time of the neuropsychological evaluation were conducted. The potential confounds of hydrocephalus severity, seizure medication, age, radiation treatment, and chemotherapy were addressed. Verbal IQ was comparable between tumor groups and in the Average range. The third ventricle region group performed significantly worse on list learning and delayed list recall compared to the cerebellar group. Their mean performance was in the clinically impaired range on both trials. The third ventricle region tumor group performed better than the cerebellar tumor group on Digit Span, a basic repetition, attention span task. These findings support the hypothesis that pediatric patients with third ventricle region brain tumors are more likely to be impaired on verbal recall tasks compared to pediatric patients with cerebellar brain tumors. In contrast, patients who were treated for cerebellar tumors were more impaired on the basic repetition, attention span task compared to patients who were treated for third ventricle tumors. Future studies should examine the specific neuroanatomical structures and pathways that are damaged and may influence differential cognitive impairments in children.     

Using eyeblink classical conditioning as a test of the functional consequences of exposure of the developing cerebellum to alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.