Motor deficits cannot explain impaired cognitive associative learning in cerebellar patients

There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.     

Topographic organization of the cerebellar nucleocortical projection in the albino rat: an autoradiographic orthograde study

The topography of the cerebellar nucleocortical projection was investigated in the albino rat by experiments employing an autoradiographic orthograde tracing method. The present results indicate that neurons in the deep cerebellar nuclei project to the granule cell layer of cerebellar cortex as mossy fiber terminals in an orderly way. Thus, the medial cerebellar nucleus projects mainly to the bilateral vermis with ipsilateral dominance. The interpositus and lateral cerebellar nuclei project mainly to the intermediate and lateral zones of the anterior and posterior lobes of the cortex, respectively. The paraflocculus and flocculus receive the nucleocortical projection from the caudal and ventral parts of the interpositus nuclei and the dentate nucleus. A mediolateral topography within each subdivision of the cerebellar nuclear complex was observed; the medial and lateral parts of the subdivision project to the more medial and lateral portions of the primary cortical targets of the subdivision, respectively.     

Glutamic acid decar☐ylase activity in micropunches of the deep cerebellar nuclei of the genetically dystonic (dt) rat

Glutamic acid decar☐ylase (GAD) activity was measured in specific divisions of the deep cerebellar nuclei of rats with an inherited dystonia. In 16-day-old dystonic rats there was a significant increase in GAD activity only in the nucleus interpositus (+26%). In 20-day-old dystonic rats GAD activity in all 3 cerebellar nuclei (fastigial, interpositus, dentate) was significantly increased compared to normal controls. The results indicate a spread of the anatomical locus of the neurochemical abnormality with time. During this period (postnatal days 16–20) there is a progressive worsening of the motor disorder in the affected animals.     

The effects of ethanol on the developing cerebellum and eyeblink classical conditioning

In rats, developmental ethanol exposure has been used to model the central nervous system deficits associated with human fetal alcohol syndrome. Binge-like ethanol exposure of neonatal rats depletes cells in the cerebellum, including Purkinje cells, granule cells, and deep nuclear cells, and produces deficits in simple tests of motor coordination. However, the extent to which anatomical damage is related to behavioral deficits has been difficult to estimate. Eyeblink classical conditioning is known to engage a discrete brain stem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental ethanol exposure. Eyeblink conditioning is a simple form of motor learning in which a neutral stimulus (such as a tone) comes to elicit an eyeblink when repeatedly paired with a stimulus that evokes an eyeblink prior to training (such as mild periorbital stimulation). In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for tone conditioned stimulus and somatosensory unconditioned stimulus information, and, together with brain stem nuclei, provide the necessary and sufficient substrate for the learned response. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to ethanol as neonates. In addition, interpositus nucleus neurons from ethanol-exposed rats showed impaired activation during eyeblink conditioning. These deficits are accompanied by a permanent reduction In the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding the underlying neural substrates of behavioral change after developmental ethanol exposure are greatly strengthened.     

Effects of hippocampal lesions on patterned motor learning in the rat

Motor skill learning in rats has been linked to cerebellar function as well as to cortical and striatal influences. The present study evaluated the contribution of the hippocampus to motor learning. Adult male rats received electrolytic lesions designed to selectively destroy the hippocampus; a sham-lesioned group of animals served as a control. The animals with hippocampal lesions acquired a patterned motor learning task as well as sham controls. In contrast, rats with hippocampal lesions were impaired in spatial, but not cued, learning in the Morris water maze. In addition, lesioned rats showed profound impairment in the novel object recognition memory task, when a 1-h delay was used between training and testing. Taken together, these results suggest that the hippocampus is not necessary during acquisition of the motor learning task.     

Cerebellar vermis abnormalities and cognitive functions in individuals with Williams syndrome

In Williams syndrome (WS) cerebellar measures were only indirectly related to behavioral outcomes. T1-weighted magnetic resonance images and neuropsychological data were acquired to investigate whether cerebellar vermis differences were present in 12 WS individuals compared with 13 chronological age-matched controls and whether WS cerebellar vermis measures were related to cognitive scores. In WS participants, we observed a significant increase in the volume of the posterior superior cerebellar vermis (lobules VI–VII) and an atypical ratio between width and height of the cerebellar vermis. Furthermore, we found an inverse correlation between cerebellar posterior vermis volume and scores on implicit learning, phonological fluency and the verbal short-term memory tasks. The present study supported a role for the posterior cerebellar vermis in higher cognitive processes and indicated that the cerebellar vermis abnormalities (enlargement) in WS individuals have an effect in worsening the cognitive performance in specific domains.     

The cerebellum and cognition: cerebellar lesions impair sequence learning but not conditional visuomotor learning in monkeys

Claims that the cerebellum contributes to cognitive processing in humans have arisen from both functional neuroimaging and patient studies. These claims challenge traditional theories of cerebellar function that ascribe motor functions to this structure. We trained monkeys to perform both a visuomotor conditional associative learning task and a visually guided sequence task, and studied the effects of bilateral excitotoxic lesions in the lateral cerebellar nuclei. In the first experiment three operated monkeys showed a small impairment in post-operative retention of a visuomotor associative task (A) but were then not impaired in learning a new task (B). However, the impairment on A could have been due to a problem in making the movements themselves. In a second experiment we therefore gave the three control animals a further pre-operative retest on both A and B and then tested after surgery on retention of both tasks. Though again the animals showed motor problems on task A, they reached criterion, and at this stage could clearly make both movements satisfactorily. The critical test was then retention of task B, and they were not impaired. In the final experiment (serial reaction time task) the monkeys response times on a repeating visuomotor sequence were compared with those for a pseudo-random control sequence. After bilateral nuclei lesions they were slow to execute the pre-operatively learned sequence but were still faster on this than on the control task. However, when they were then given a new repeating sequence to learn, they never performed the sequence as quickly as they had on retention of the first sequence. We conclude that the cerebellum is not essential for the learning or recall of stimulus-response associations but that it is crucially involved in the process by which motor sequences become automatic with extended practice.     

Inhibiting cholinergic signalling in the cerebellar interpositus nucleus impairs motor behaviour

The role of neuromodulators in the cerebellum is not well understood. In particular, the behavioural significance of the cholinergic system in the cerebellum is unknown. To investigate the importance of cerebellar cholinergic signalling in behaviour, we infused acetylcholine receptor antagonists, scopolamine and mecamylamine, bilaterally into the rat cerebellum (centred on interpositus nucleus) and observed the motor effects through a battery of behavioural tests. These tests included unrewarded behaviour during open field exploration and a horizontal ladder walking task and reward-based beam walking and pellet reaching tasks. Infusion of a mix of the antagonists did not impair motor learning in the horizontal ladder walking or the reaching task but reduced spontaneous movement during open field exploration, impaired coordination during beam walking and ladder walking, led to fewer reaches in the pellet reaching task, slowed goal-directed reaching behaviour and reduced reward pellet consumption in a free access to food task. Infusion of the muscarinic antagonist scopolamine on its own resulted in deficits in motor performance and a reduction in the number of reward pellets consumed in the free access to food task. By contrast, infusion of the nicotinic antagonist mecamylamine on its own had no significant effect on any task, except beam walking traversal time, which was reduced. Together, these data suggest that acetylcholine in the cerebellar interpositus nucleus is important for the execution and coordination of voluntary movements mainly via muscarinic receptor signalling, especially in relation to reward-related behaviour.     

Two channels in the cerebellothalamocortical system

Two channels of the cerebellothalamocortical system were investigated in cats by using cerebellar-evoked synaptic responses and cortical-evoked antidromic invasion of single thalamic cells. One channel arises in interpositus and dentate cerebellar nuclei and mainly projects through ventroanterior-ventrolateral (VA-VL) thalamic nuclei to cortical motor areas 4 and 6; the other channel arises in cerebellar fastigial nuclei and projects through ventromedial (VM) thalamic nuclei to more widespread cortical areas. The antidromic response latencies of VM neurons to stimuli applied to cortical areas 4 and 6 were longer (medians 2.8 and 3.0 msec, respectively) than the antidromic response latencies of VA-VL neurons to stimulation of the same cortical areas (1.8 and 2.3 msec). This was a statistically significant difference, and it matched the longer latencies of fastigial-evoked synaptic responses of VM cells (2.9 msec) compared to the response latencies of VA-VL cells elicited by stimulation of interpositus or dentate nuclei (1.7 and 2.4 msec). These differences among thalamic nuclei relaying cerebellocortical impulses were corroborated by dissimilar effects exerted on the electroencephalogram (EEG) during high-frequency (300 Hz) pulse trains applied to different deep cerebellar nuclei. The distribution of activated EEG patterns over the cortex depended on the stimulated site. Fastigial stimulation elicited the blockage of slow EEG rhythms and the appearance of fast oscillations (20–40 Hz) over widespread cortical areas in the proreus, pericruciate, and suprasylvian gyri. At variance, the activating influence of interpositus or dentate nuclei was restricted to the motor cortex. It is proposed that, besides their role in controlling the postural axial and proximal musculature, fastigial nuclei are part of diffusely activating systems. © 1995 Wiley-Liss, Inc.     

Physiopathology of the cerebellum in the monkey: Part 2. Motor disturbances associated with partial and complete destruction of cerebellar structures

Profound truncal ataxia, dysmetria, postural tremor of the head, trunk and limbs and hypotonia and intention (acting) tremor of the limbs were displayed by 3 monkeys with total cerebellectomy and 2 monkeys with extensive damage to several structures of the cerebellum. Truncal ataxia, dysmetria, hypotonia and intention tremor gradually diminished during the immediate postoperative period whereas postural tremor became less conspicuous. The administration of harmaline, however, exaggerated or evoked postural tremor of the limbs and trunk for a period of 3–4 hr in these monkeys.On the one hand lesions of the vermis of the posterior lobe and of part of the nodulus in one animal or of the interpositus and fastigial nuclei of both sides and the nodulus in another animal or destruction of the uvula and the interpositus nuclei associated with partial involvement of dentate and fastigial nuclei of both sides in a third animal resulted in truncal ataxia and transient dysmetria. The latter animal repeatedly displayed postural tremor of the two upper limbs in response to harmaline. Harmaline, however, did not produce any peculiar effect in the 2 former animals. On the other hand unilateral or bilateral lesions of the dentate and interpositus nuclei or destruction of the left half of the posterior lobe (with or without involvement of the corresponding dentate nucleus) or interruption of the superior cerebellar peduncle did not result in any marked and/or sustained motor impairment. Nine out of 10 monkeys with such lesions, however, displayed postural tremor of the ipsilateral limbs after the administration of harmaline.Truncal ataxia predominantly involves a disturbance of the uvula and nodulus and/or the fastigial nuclei and their interconnections with the vestibular nuclei and, most likely, with the dorsal and medial accessory olives. Dysmetria (or incoordination of the limbs) is apparently related to a combined impairment of structures of the anterior and posterior lobes of the cerebellum and their corresponding interconnections with the cerebellar nuclei. Postural tremor is partly related to a disturbance at the level of a series of phylogenetically more recent structures including parts of the principal olive, neocerebellar cortex and dentate nucleus and the parvocellular division of the red nucleus as well as their nervous interconnections.     

Spinocerebellar Ataxia Type 2 Neurodegeneration Differentially Affects Error-Based and Strategic-Based Visuomotor Learning

There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error-based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure.     

Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning.

This study compared the morphology of cerebellar cortex in adult female rats exposed for 1 month to repetitive exercise, motor learning, or an inactive condition. In the exercise conditions, rats that were run on a treadmill or housed with access to a running wheel had a shorter diffusion distance from blood vessels in the molecular layer of the paramedian lobule when compared to rats housed individually or rats that participated in a motor skill learning task. Rats taught complex motor skills substantially increased the volume of the molecular layer per Purkinje neuron and increased blood vessel number sufficiently to maintain the diffusion distance. These results dissociate angiogenesis associated with increased neuropil volume (as seen in the motor learning group) from angiogenesis associated with increased metabolic demands (as seen in the exercise groups). While the volume fraction of mitochondria did not differ among groups, the mitochondrial volume fraction per Purkinje cell was significantly increased in the motor skill rats. This appears to parallel the previously reported increase in synapses and associated neuropil volume change.     

Neuropsychological deficits in cerebellar syndromes

Interest in the role of the cerebellum in cognitive functioning has been increasing in recent years, based on both theoretical considerations and empirical evidence. This review attempts to critically evaluate neuropsychological studies based on standardized testing of patients with selective cerebellar dysfunction. Findings are considered which address possible cerebellar influence on motor adaptation and habituation, motor skill acquisition, classical conditioning of motor responses, temporal processing, general intellectual abilities, frontal lobe functions, visuospatial abilities, memory and non-motor skill learning, and language. Deficits in motor learning and temporal processing are consistently observed in patients with cerebellar syndromes, while deficits in frontal lobe functions, visuospatial processing, memory, non-motor skill learning and language dysfunction have been reported in several studies, but have not been replicated in others. Methodological factors which may account for such discrepancies are discussed.     

Spinocerebellar Ataxia Type 2 (SCA2): Identification of Early Brain Degeneration in One Monozygous Twin in the Initial Disease Stage

Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3?years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3?years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.     

Topographic organization of the corticonuclear fibers from the tuber vermis and paramedian lobule in the albino rat

The topographic organization of the corticonuclear fibers from the tuber vermis and paramedian lobule in the albino rat was investigated by autoradiographic anterograde tracing method. The medial portion of the tuber vermis projects to the dorsal part of the caudomedial subdivision of the medial cerebellar nucleus (MNcm), whereas the lateral portion of the tuber vermis projects to the dorsal part of the MNcm and the caudal part of the middle subdivision of the medial nucleus. The intermediate cortex of the paramedian lobule can be subdivided mediolaterally into three portions which project to the dorsolateral protuberance of the medial cerebellar nucleus, the rostrodorsal part of the posterior interpositus nucleus, and the caudodorsal part of the lateral anterior interpositus nucleus, respectively. The lateral cortex of the paramedian lobule can also be subdivided mediolaterally into two portions: the medial portion projects to the dorsolateral hump, and the lateral one to the lateral cerebellar nucleus. These results indicate that the cortical efferent fibers from the tuber vermis and paramedian lobule are clearly organized in the mediolateral direction in the albino rat.     

Changes in brain activation patterns according to cross-training effect in serial reaction time task An functional MRI study

Cross-training is a phenomenon related to motor learning, where motor performance of the untrained limb shows improvement in strength and skill execution following unilateral training of the homologous contralateral limb. We used functional MRI to investigate whether motor performance of the untrained limb could be improved using a serial reaction time task according to motor sequential learning of the trained limb, and whether these skill acquisitions led to changes in brain activation patterns. We recruited 20 right-handed healthy subjects, who were randomly allocated into training and control groups. The training group was trained in performance of a serial reaction time task using their non-dominant left hand, 40 minutes per day, for 10 days, over a period of 2 weeks. The control group did not receive training. Measurements of response time and percentile of response accuracy were performed twice during pre- and post-training, while brain functional MRI was scanned during performance of the serial reaction time task using the untrained right hand. In the training group, prominent changes in response time and percentile of response accuracy were observed in both the untrained right hand and the trained left hand between pre- and post-training. The control group showed no significant changes in the untrained hand between pre- and post-training. In the training group, the activated volume of the cortical areas related to motor function (i.e., primary motor cortex, premotor area, posterior parietal cortex) showed a gradual decrease, and enhanced cerebellar activation of the vermis and the newly activated ipsilateral dentate nucleus were observed during performance of the serial reaction time task using the untrained right hand, accompanied by the cross-motor learning effect. However, no significant changes were observed in the control group. Our findings indicate that motor skills learned over the 2-week training using the trained limb were transferred to the opposite homologous limb, and motor skill acquisition of the untrained limb led to changes in brain activation patterns in the cerebral cortex and cerebellum.     

Cerebellar posterior superior vermis and cognitive cluster scores in drug-naive patients with first-episode schizophrenia

Previously, we performed an MRI study that revealed smaller volumes of the subregions of the cerebellar vermis in men and women with chronic schizophrenia. An issue that arose from that study was whether similar structural changes in the cerebellum are found in patients with first-episode schizophrenia. In the present study, MRI scans were acquired from 14 drug-naive patients with first-episode schizophrenia and 16 healthy subjects, and used to measure the volumes of their cerebellar subregions. Positive symptom, negative symptom and cognitive cluster scores were attained using the Positive and Negative Syndrome Scale. Patients with first-episode schizophrenia had reduced volumes of the anterior vermis and posterior superior vermis compared with healthy subjects. We confirmed that there was a volume reduction of the cerebellar vermis in drug-naive patients with first-episode schizophrenia. Smaller volumes of the posterior superior vermis were associated with worse cognitive cluster scores in patients with first-episode schizophrenia.     

Firing activities of identified posterior interpositus nucleus neurons during associative learning in behaving cats

On the basis of stimulation and permanent or transient lesions of putatively involved structures, and using transgenic mice with defective functional circuits, it has been proposed that cerebellar cortex and/or nuclei could be the sites where classically conditioned nictitating membrane/eyelid responses are acquired and stored. Here, we review recent information regarding the electrical activities of deep cerebellar nuclei neurons recorded during the performance of reflex and acquired eyeblinks. In particular, the rostral pole of the dorsolateral region of the posterior interpositus nucleus contains neurons significantly related to reflexively evoked and classically conditioned eyelid responses. Thus, type A interpositus neurons increase their discharge rate during eyelid movements, modulating it depending upon eyelid motorics. In contrast, type B neurons decrease their firing, even to a stop, during the same eyelid responses. However, as these changes in firing start after the onset of eyelid conditioned responses (CRs), and because they do not seem to encode eyelid position and velocity during the CR, the interpositus nucleus cannot be conclusively considered the site where eyelid learned responses are generated and stored. Additional microstimulation and pharmacological blockage of the recorded sites support the suggestion that posterior interpositus neurons contribute to the enhancement of CRs. Moreover, interpositus neurons probably contribute to the proper damping of newly acquired eyelid responses. The contributing role of other neuronal centers and circuits related to the eyelid motor system are also discussed.     

Clinical manifestation of focal cerebellar disease as related to the organization of neural pathways

Neural pathways connect different parts of the cerebellum to different parts of the central nervous system. The cerebellum may be divided anatomically and functionally into three major regions. The cerebellar hemispheres and a small part of the posterior lobe vermis form the pontocerebellum, which receives inputs from the cerebral cortex via the pontine nuclei. The anterior lobe and most of the posterior lobe vermis make up the spinocerebellum, which receives afferents from the spinal cord. The nodulus and flocculus are connected with the vestibular nuclei and constitute the vestibulocerebellum. Most cases of cerebellar disease affect more than one region and different pathways. Hence, they cause generalized cerebellar symptoms dominated by impaired motor control and balance. Focal syndromes after restricted cerebellar lesions are rare. Isolated spinocerebellar affection may give gait ataxia. Vestibulocerebellar disease causes equilibrium disturbances with truncal ataxia and nystagmus. Pontocerebellar lesions typically give ipsilateral limb ataxia, but also dysartria and oculomotor dysfunction if vermal parts are involved. The clinical picture is in most cases of cerebellar disease dominated by motor disturbances, but the cerebellum also participates in the modulation of autonomic and affective responses and in cognitive functions. The cerebrocerebellar and hypothalamocerebellar circuits may be important for these tasks.     

Trace conditioning: Abolished by cerebellar nuclear lesions but not lateral cerebellar cortex aspirations

The trace conditioning paradigm in which the conditioned stimulus-unconditioned stimulus (CS-US) interval is longer and the US and CS do not overlap requires retention of a ‘trace’ of the CS to associate it with the US. This task is difficult, requiring for learning about 5 times the number of trials to criterion as the standard delay task. The present study was undertaken to determine if: (1) the cerebellar interpositus nucleus is essential in trace as well as in delay conditioning; and (2) the lateral cerebellar cortex is involved when CS-US association over longer time intervals is required. Sixteen adult male New Zealand white rabbits had recording and in some cases lesion electrodes surgically implanted before training. They were trained daily with 126 paired trials of tone CS and airpuff US. The trace period between CS offset and US onset was 500 ms. Mean number of trials to criterion of 8/9 CRs was 466.9 trials. After a day of overtraining the animals had one of 3 surgeries: (1) electrolytic lesion of the left cerebellar interpositus nucleus (n= 3); (2) aspiration of the left lateral cerebellar cortex (HVI and HVIIA) and underlying cerebellar nuclei (n= 4); or (3) aspiration of HVI and HVIIA only (n= 9). Rabbits with only HVI and HVIIA removed exhibited a transient decrease in CRs but relearned with significant savings. The amplitude, area and latency of pre- and postlesion conditioned responses (CRs) was similar. When the interpositus nucleus was damaged, the animals' capacity for CRs on the side ipsilateral to the lesion was permanently abolished. It is concluded that the cerebellar interpositus nucleus but not the overlying lateral cerebellar cortex is essential for retention of trace classical conditioning. Nevertheless, the temporary abolition of CRs by removal of lateral cerebellar cortex suggests that the cerebellar cortex does play an important role in learning and retention of the trace conditioned response.