小脑的非运动功能

近年来,人们逐渐认识到小脑的非运动功能,就有关小脑的非运动功能研究进展进行了概述,并指出深入研究小脑的非运动功能对于认识脑功能具有重要意义。     

Cerebellar learning in the vestibulo-ocular reflex

The vestibulo-ocular reflex, because of its close relationship with the cerebellum and its marked adaptiveness, has become a model system for studying the functions of the cerebellum. It has been hypothesized that an evolutionarily old part of the cerebellum, the flocculus, forms a modifiable accessory pathway for the vestibulo-ocular reflex arc for adaptive control, and that the modification is due to the synaptic plasticity induced by retinal errors conveyed by a unique structure of the cerebellum, the climbing fibers. The flocculus hypothesis has been supported by several lines of evidence, including lesioning or functionally impairing the flocculus and recording the activity of flocculus Purkinje cells, and, more recently, from pharmacologically or genetically inhibited synaptic plasticity, which produces long-term depression. There has also been debate on a possible site for memory retention in vestibulo-ocular-reflex adaptation, and about the signal content in flocculus Purkinje cells. This article reviews recent studies on the learning mechanisms of the cerebellum that underlie the adaptation of the vestibulo-ocular reflex.     

Cerebellar neurophysiology in Gilles de la Tourette syndrome and its role as a target for therapeutic intervention

Therapy resistance of approximately one‐third of patients with Gilles de la Tourette syndrome (GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning‐induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non‐invasive and invasive brain stimulation techniques as a novel platform for non‐pharmacological neuromodulation of GTS symptoms.     

The Lateralized Linguistic Cerebellum: A Review and a New Hypothesis

During the past 2 decades the collaboration across disciplines and the methodologic and conceptual advances of contemporary neuroscience have brought about a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Growing insights in the neuroanatomy of the cerebellum and its interconnections, evidence from functional neuroimaging and neurophysiological research, and advancements in clinical and experimental neuropsychology have established the view that the cerebellum participates in a much wider range of functions than conventionally accepted. This increase of insight has brought to the fore that the cerebellum modulates cognitive functioning of at least those parts of the brain to which it is reciprocally connected. This article reviews the recently acknowledged role of the cerebellum in cognition and addresses in more detail experimental and clinical data disclosing the modulatory role of the cerebellum in various non-motor language processes such as lexical retrieval, syntax, and language dynamics. In agreement with the findings indicating a topographical organization of the cerebellar structures involved in language pathology we advance the concept of a "lateralized linguistic cerebellum." In our view crossed cerebral diaschisis processes, reflecting a functional depression of supratentorial language areas due to reduced input via cerebellocortical pathways, might represent the relevant pathomechanism for linguistic deficits associated with cerebellar pathology.     

Ablation of cerebellar nuclei prevents H-reflex down-conditioning in rats

While studies of cerebellar involvement in learning and memory have described plasticity within the cerebellum, its role in acquisition of plasticity elsewhere in the CNS is largely unexplored. This study set out to determine whether the cerebellum is needed for acquisition of the spinal cord plasticity that underlies operantly conditioned decrease in the H-reflex, the electrical analog of the spinal stretch reflex. Rats in which the cerebellar output nuclei dentate and interpositus (DIN) had been ablated were exposed for 50 d to the H-reflex down-conditioning protocol. DIN ablation, which in itself had no significant long-term effect on H-reflex size, entirely prevented acquisition of a smaller H-reflex. Since previous studies show that corticospinal tract (CST) transection also prevents down-conditioning while transection of the rubrospinal tract and other major descending tracts does not, this result implies that DIN output that affects cortex is essential for generation of the CST activity that induces the spinal cord plasticity, which is, in turn, directly responsible for the smaller H-reflex. The result extends the role of the cerebellum in learning and memory to include participation in induction of plasticity elsewhere in the CNS, specifically in the spinal cord. The cerebellum might simply support processes in sensorimotor cortex or elsewhere that change the spinal cord, or the cerebellum itself might undergo plasticity similar to that occurring with vestibulo-ocular reflex (VOR) or eyeblink conditioning.     

Cerebellum and processing of negative facial emotions: cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness

Some evidence suggests that the cerebellum participates in the complex network processing emotional facial expression. To evaluate the role of the cerebellum in recognising facial expressions we delivered transcranial direct current stimulation (tDCS) over the cerebellum and prefrontal cortex. A facial emotion recognition task was administered to 21 healthy subjects before and after cerebellar tDCS; we also tested subjects with a visual attention task and a visual analogue scale (VAS) for mood. Anodal and cathodal cerebellar tDCS both significantly enhanced sensory processing in response to negative facial expressions (anodal tDCS, p=.0021; cathodal tDCS, p=.018), but left positive emotion and neutral facial expressions unchanged (p>.05). tDCS over the right prefrontal cortex left facial expressions of both negative and positive emotion unchanged. These findings suggest that the cerebellum is specifically involved in processing facial expressions of negative emotion.     

Solving the Mystery of the Human Cerebellum

The mystery of the human cerebellum is this: Why did it enlarge so dramatically in the last million years of human evolution, concomitantly with the greater enlargement of the cerebral cortex? A solution to this mystery was proposed in the 20th century as a result of research by several groups of scientists who investigated the contributions of the cerebellum to the cerebral cortex. In contrast to the 19th century investigations, which were focused on the motor functions of the cerebellum, the focus of the subsequent investigations was expanded to include some mental functions because evidence was produced that the cerebellum contributes to cognition. It was proposed that the combination in the cerebellum of motor and mental capabilities enables the cerebellum to confer on humans some adaptive advantages of great value, and this ability would explain why the human cerebellum has continued to enlarge so dramatically. A valuable adaptive advantage that is included in the proposal is the possibility that the cerebellum couples the motor function of articulating speech to the mental function that selects the language to be spoken, thus helping to produce fluent human speech and language. The validity of this proposal about linguistic processing has not yet been verified. Therefore the mystery of cerebellar enlargement in humans is not yet solved and requires further research.     

Inferior colliculus lesions impair eyeblink conditioning in rats

The neural plasticity necessary for acquisition and retention of eyeblink conditioning has been localized to the cerebellum. However, the sources of sensory input to the cerebellum that are necessary for establishing learning-related plasticity have not been identified completely. The inferior colliculus may be a source of sensory input to the cerebellum through its projection to the medial auditory thalamus. The medial auditory thalamus is necessary for eyeblink conditioning in rats and projects to the lateral pontine nuclei, which then project to the cerebellar nuclei and cortex. The current experiment examined the role of the inferior colliculus in auditory eyeblink conditioning. Rats were given bilateral or unilateral (contralateral to the conditioned eye) lesions of the inferior colliculus prior to 10 d of delay eyeblink conditioning with a tone CS. Rats with bilateral or unilateral lesions showed equivalently impaired acquisition. The extent of damage to the contralateral inferior colliculus correlated with several measures of conditioning. The findings indicate that the contralateral inferior colliculus provides auditory input to the cerebellum that is necessary for eyeblink conditioning.     

Is the cerebellum a smith predictor?

The motor system may use internal predictive models of the motor apparatus to achieve better control than would be possible by negative feedback. Several theories have proposed that the cerebellum may form these predictive representations. In this article, we review these theories and try to unify them by reference to an engineering control model known as a Smith Predictor. We suggest that the cerebellum forms two types of internal model. One model is a forward predictive model of the motor apparatus (e.g., limb and muscle), providing a rapid prediction of the sensory consequences of each movement. The second model is of the time delays in the control loop (due to receptor and effector delays, axonal conductances, and cognitive processing delays). This model delays a copy of the rapid prediction so that it can be compared in temporal register with actual sensory feedback from the movement. The result of this comparison is used both to correct for errors in performance and as a training signal to learn the first model. We discuss evidence that the cerebellum could form both of these models and suggest that the cerebellum may hold at least two separate Smith Predictors. One, in the lateral cerebellum, would predict the movement outcome in visual, egocentric, or peripersonal coordinates. Another, in the intermediate cerebellum, would predict the consequences in motor coordinates. Generalization of the Smith Predictor theory is discussed in light of cerebellar involvement in nonmotor control systems, including autonomic functions and cognition.     

Cerebellum and processing of negative facial emotions: Cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness

Some evidence suggests that the cerebellum participates in the complex network processing emotional facial expression. To evaluate the role of the cerebellum in recognising facial expressions we delivered transcranial direct current stimulation (tDCS) over the cerebellum and prefrontal cortex. A facial emotion recognition task was administered to 21 healthy subjects before and after cerebellar tDCS; we also tested subjects with a visual attention task and a visual analogue scale (VAS) for mood. Anodal and cathodal cerebellar tDCS both significantly enhanced sensory processing in response to negative facial expressions (anodal tDCS, p=.0021; cathodal tDCS, p=.018), but left positive emotion and neutral facial expressions unchanged (p>.05). tDCS over the right prefrontal cortex left facial expressions of both negative and positive emotion unchanged. These findings suggest that the cerebellum is specifically involved in processing facial expressions of negative emotion.     

Ontogenetic changes in the neural mechanisms of eyeblink conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that estavlish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

The Cerebellum and Basal Ganglia are Interconnected

The cerebellum and the basal ganglia are major subcortical nuclei that control multiple aspects of behavior largely through their interactions with the cerebral cortex. Discrete multisynaptic loops connect both the cerebellum and the basal ganglia with multiple areas of the cerebral cortex. Interactions between these loops have traditionally been thought to occur mainly at the level of the cerebral cortex. Here, we review a series of recent anatomical studies in nonhuman primates that challenge this perspective. We show that the anatomical substrate exists for substantial interactions between the cerebellum and the basal ganglia. Furthermore, we discuss how these pathways may provide a useful framework for understanding cerebellar contributions to the manifestation of two prototypical basal ganglia disorders, Parkinson’s disease and dystonia.     

运动、语言和学习：小脑的功能磁共振成像研究

对小脑功能的认识在过去的100年里经历了缓慢而稳定的发展。在最近20年,随着活体神经影像技术尤其是功能磁共振成像（fMRI）的出现,这一领域取得了更加显著的进展。文章简要总结了我们最近关于小脑的fMRI研究,考察了该结构在运动、语言和学习任务中的作用;并通过回顾相关文献,讨论了这些研究的理论意义。小脑的功能本质似乎是一般性的而非通道特异的,动态的而非静态的,联系的而非孤立的。作者提出,研究小脑与大脑之间的相互作用和合作机制将是小脑研究领域的新的生长点     

Functional Topography of the Cerebellum in Verbal Working Memory

Speech—both overt and covert—facilitates working memory by creating and refreshing motor memory traces, allowing new information to be received and processed. Neuroimaging studies suggest a functional topography within the sub-regions of the cerebellum that subserve verbal working memory. Medial regions of the anterior cerebellum support overt speech, consistent with other forms of motor execution such as finger tapping, whereas lateral portions of the superior cerebellum support speech planning and preparation (e.g., covert speech). The inferior cerebellum is active when information is maintained across a delay, but activation appears to be independent of speech, lateralized by modality of stimulus presentation, and possibly related to phonological storage processes. Motor (dorsal) and cognitive (ventral) channels of cerebellar output nuclei can be distinguished in working memory. Clinical investigations suggest that hyper-activity of cerebellum and disrupted control of inner speech may contribute to certain psychiatric symptoms.     

The detection and generation of sequences as a key to cerebellar function: experiments and theory

Starting from macroscopic and microscopic facts of cerebellar histology, we propose a new functional interpretation that may elucidate the role of the cerebellum in movement control. The idea is that the cerebellum is a large collection of individual lines (Eccles's "beams": Eccles et al. 1967a) that respond specifically to certain sequences of events in the input and in turn produce sequences of signals in the output. We believe that the sequence-in/sequence-out mode of operation is as typical for the cerebellar cortex as the transformation of sets into sets of active neurons is typical for the cerebral cortex, and that both the histological differences between the two and their reciprocal functional interactions become understandable in the light of this dichotomy. The response of Purkinje cells to sequences of stimuli in the mossy fiber system was shown experimentally by Heck on surviving slices of rat and guinea pig cerebellum. Sequential activation of a row of eleven stimulating electrodes in the granular layer, imitating a "movement" of the stimuli along the folium, produces a powerful volley in the parallel fibers that strongly excites Purkinje cells, as evidenced by intracellular recording. The volley, or "tidal wave," has maximal amplitude when the stimulus moves toward the recording site at the speed of conduction in parallel fibers, and much smaller amplitudes for lower or higher "velocities." The succession of stimuli has no effect when they "move" in the opposite direction. Synchronous activation of the stimulus electrodes also had hardly any effect. We believe that the sequences of mossy fiber activation that normally produce this effect in the intact cerebellum are a combination of motor planning relayed to the cerebellum by the cerebral cortex, and information about ongoing movement, reaching the cerebellum from the spinal cord. The output elicited by the specific sequence to which a "beam" is tuned may well be a succession of well timed inhibitory volleys "sculpting" the motor sequences so as to adapt them to the complicated requirements of the physics of a multijointed system.     

The representation of predictive force control and internal forward models: evidence from lesion studies and brain imaging

Force control on the basis of prediction avoids time delays from sensory feedback during motor performance. Thus, self-produced loads arising from gravitational and inertial forces during object manipulation can be compensated for by simultaneous anticipatory changes in grip force. It has been suggested that internal forward models predict the consequences of our movements, so that grip force can be programmed in anticipation of movement-induced loads. The cerebellum has been proposed as the anatomical correlate of such internal models. Here, we present behavioural data from patients with cerebellar damage and data from brain imaging in healthy subjects further elucidating the role of the cerebellum in predictive force control. Patients with cerebellar damage exhibited clear deficits in the coupling between grip force and load. A positron-emission-tomography (PET) paradigm that separated the process of the grip force/load coupling from the isolated production of similar grip forces and loads was developed. Interaction and conjunction analyses revealed a strong activation peak in the ipsilateral posterior cerebellum particularly devoted to the predictive coupling between grip force and load. Both approaches clearly demonstrate that the cerebellum plays a major role in force prediction that cannot be compensated for by other sensorimotor structures in case of cerebellar disease. However, evidence suggests that also extra-cerebellar structures may significantly contribute to predictive force control: (1) grip force/load coupling may also be impaired after cerebral and peripheral sensorimotor lesions, (2) a coupling-related activation outside the cerebellum was observed in our PET study, and (3) the scaling of the grip force level and the dynamic grip force coupling are dissociable aspects of grip force control.     

Short-term effects of postnatal manipulation on central beta-adrenoceptor transmission

Neonatal handling is known to induce long-lasting changes in behavioral and neuroendocrine responses to stress. Since the central noradrenergic system participates in the adaptive responses to stressful conditions we have analyzed the effects of postnatal handling on beta-adrenoceptor binding sites and isoprenaline- and forskolin-stimulated cyclic AMP accumulation in cerebral cortex, hippocampus and cerebellum of rats at 1 and 3 months of age. Handled animals showed reduced emotional reactivity and lower ACTH and corticosterone secretion after stress. Binding studies using [(3) H]CGP12-177 revealed increased beta-adrenoceptor binding sites in handled rats in cerebellum and cerebral cortex with no changes in hippocampus, and decreased affinity in all cerebral regions. Handling reduced basal levels of cyclic AMP in hippocampus and cerebellum but not in cerebral cortex. The concentration-response curves of cyclic AMP to isoprenaline were displaced to the right in cerebellum of handled rats without differences in Emax; however, Emax was significantly reduced in cerebral cortex and hippocampus. Direct stimulation of the catalytic subunit of adenylyl cyclase by forskolin reduced the efficiency in hippocampus and cerebellum, but not in cerebral cortex of handled animals. It is concluded that neonatal handling reduces the binding properties of beta-adrenoceptor and its primary biochemical responses in the young rat brain, which may account for the reduced responsiveness to stress attained in the handled rats, and may explain the persistence of the effect. The present study emphasizes the role of the central noradrenergic system in modulating the behavioral and neurendocrine responses to neonatal handling.     

The effects of stimulating the cerebellum on social sequences: A tDCS-fMRI pilot study

Research on the involvement of the cerebellum in social behavior and its relationship with social mentalizing has just begun. Social mentalizing is the ability to attribute mental states such as desires, intentions, and beliefs to others. This ability involves the use of social action sequences which are believed to be stored in the cerebellum. In order to better understand the neurobiology of social mentalizing, we applied cerebellar transcranial direct current stimulation (tDCS) on 23 healthy participants in the MRI scanner, immediately followed by measuring their brain activity during a task that required to generate the correct sequence of social actions involving false (i.e., outdated) and true beliefs, social routines and non-social (control) events. The results revealed that stimulation decreased task performance along with decreased brain activation in mentalizing areas, including the temporoparietal junction and the precuneus. This decrease was strongest for true belief sequences compared to the other sequences. These findings support the functional impact of the cerebellum on the mentalizing network and belief mentalizing, contributing to the understanding of the role of the cerebellum in social sequences.     

Ontogenetic Changes in the Neural Mechanisms of Eyeblink Conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that establish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.