Cortical networks of procedural learning: evidence from cerebellar damage

The lateral cerebellum plays a critical role in procedural learning that goes beyond the strict motor control functions attributed to it. Patients with cerebellar damage show marked impairment in the acquisition of procedures, as revealed by their performance on the serial reaction time task (SRTT). Here we present the case of a patient affected by ischemic damage involving the left cerebellum who showed a selective deficit in procedural learning while performing the SRTT with the left hand. The deficit recovered when the cortical excitability of an extensive network involving both cerebellar hemispheres and the dorsolateral prefrontal cortex (DLPFC) was decreased by low-frequency repetitive transcranial magnetic stimulation (rTMS). Although inhibition of the right DLPFC or a control fronto-parietal region did not modify the patient's performance, inhibition of the right (unaffected) cerebellum and the left DLPFC markedly improved task performance. These findings could be explained by the modulation of a set of inhibitory and excitatory connections between the lateral cerebellum and the contralateral prefrontal area induced by rTMS. The presence of left cerebellar damage is likely associated with a reduced excitatory drive from sub-cortical left cerebellar nuclei towards the right DLPFC, causing reduced excitability of the right DLPFC and, conversely, unbalanced activation of the left DLPFC. Inhibition of the left DLPFC would reduce the unbalancing of cortical activation, thus explaining the observed selective recovery of procedural memory.     

Lack of prefrontal repetitive transcranial magnetic stimulation effects in time production processing

The aim of the present study was to determine the effects of high frequency repetitive transcranial magnetic stimulation (rTMS) over different neuroanatomical areas [left and right doroslateral prefrontal cortex (DLPFC) and right cerebellar hemisphere] on time production task. The study was performed in 16 healthy right-handed men with a cross-over, within subject repeated measures design. There were four rTMS conditions: baseline without stimulation, high frequency rTMS over right, left DLPFC and over right cerebellum. The volunteers were asked to produce a 3-min interval by internal counting. The rTMS was applied during the task. No significantly differences were observed in absolute error scores in time estimation task with any rTMS condition. This preliminary study does not support the role of the prefrontal lobe in time production processes.     

Involvement of the ipsilateral motor cortex in finger movements of different complexities

Functional imaging and behavioral studies suggest involvement of the ipsilateral hemisphere in hand movements, particularly of the left hand. If this is so, transient disturbance of the motor cortex (M1) with repetitive transcranial magnetic stimulation (rTMS) may affect ipsilateral motor sequences, and the effects may differ on the two sides. We studied 15 right-handed subjects who played a simple and a complex piano sequence for 8 seconds each. Two seconds after the beginning of each sequence, rTMS was delivered to the ipsilateral or contralateral M1, or directed away from the head (control trial). Ipsilateral M1 stimulation on either side induced timing errors in both sequences, and with the complex sequence induced more timing errors in the left hand than in the right hand. Errors of the right hand with both sequences occurred in the stimulation period only, but errors of the left hand with the complex sequence occurred in both the stimulation and poststimulation periods. We conclude that the ipsilateral M1 is involved in fine finger movements. The left hemisphere plays a greater role in timing ipsilateral complex sequences than the right hemisphere and may be more involved in the processing of complex motor programs.     

Stimulating the Cerebellum Affects Visuomotor Adaptation but not Intermanual Transfer of Learning

When systematic movement errors occur, the brain responds with a systematic change in motor behavior. This type of adaptive motor learning can transfer intermanually; adaptation of movements of the right hand in response to training with a perturbed visual signal (visuomotor adaptation) may carry over to the left hand. While visuomotor adaptation has been studied extensively, it is unclear whether the cerebellum, a structure involved in adaptation, is important for intermanual transfer as well. We addressed this question with three experiments in which subjects reached with their right hands as a 30° visuomotor rotation was introduced. Subjects received anodal or sham transcranial direct current stimulation on the trained (experiment 1) or untrained (experiment 2) hemisphere of the cerebellum, or, for comparison, motor cortex (M1). After the training period, subjects reached with their left hand, without visual feedback, to assess intermanual transfer of learning aftereffects. Stimulation of the right cerebellum caused faster adaptation, but none of the stimulation sites affected transfer. To ascertain whether cerebellar stimulation would increase transfer if subjects learned faster as well as a larger amount, in experiment 3 anodal and sham cerebellar groups experienced a shortened training block such that the anodal group learned more than sham. Despite the difference in adaptation magnitude, transfer was similar across these groups, although smaller than in experiment 1. Our results suggest that intermanual transfer of visuomotor learning does not depend on cerebellar activity and that the number of movements performed at plateau is an important predictor of transfer.     

Role of the cerebellum in time perception: a TMS study in normal subjects

The aim of this study was to investigate the role of the cerebellum in a temporal-discrimination task without movement production in healthy subjects. Ten healthy subjects underwent a time-perception task with somatosensory stimuli. Two pairs of electrical stimuli: the first considered the reference pair (rp) with a standard interval of 400 ms and the second, the test pair (tp), with variable intervals ranging from 300 to 500 ms, were applied by surface electrodes on the right forearm. Subjects were instructed to compare time intervals of rp and tp and to estimate whether the tp interval was shorter than, equal to, or longer than that of rp. The task was performed in baseline and after 1 Hz rTMS over the right and left cerebellar hemisphere. The right cerebellar rTMS worsened temporal discrimination of cutaneous somatosensory electrical stimuli on the ipsilateral hand. rTMS of the left cerebellar hemisphere did not determine significant changes in the subjects' performance with respect to the baseline. These findings suggest that the cerebellum plays a role in merely perceptive aspects of temporal information processing.     

Left prefrontal repetitive transcranial magnetic stimulation impairs performance in affective go/no-go task

Functional neuroimaging studies have associated affective go/no-go function with lateral prefrontal activation, but they have not established a causal role and have not determined whether one hemisphere is predominantly engaged. In the present study, 11 normal volunteers underwent slow repetitive transcranial magnetic stimulation of the left and right dorsolateral prefrontal cortex, and the occipital cortex prior to performance of a picture-based affective go/no-go task. We found an interfering effect of left prefrontal repetitive transcranial magnetic stimulation compared with both right prefrontal and occipital repetitive transcranial magnetic stimulation. This impairment concerned positive and negative task stimuli to a similar extent, and tended to be greater in shift compared with nonshift blocks. Our findings demonstrate a functionally relevant lateralization of the prefrontal contribution to affective go/no-go tasks.     

Facilitation of Fast Backward Priming After Left Cerebellar Continuous Theta-Burst Stimulation

Traditional theories of backward priming account only for the priming effects found at long stimulus onset asynchronies (SOAs). Here, we suggest that the presence of backward priming at short SOAs may be related to the integrative role of the cerebellum. Previous research has shown that the right cerebellum is involved in forward associative priming. Functional magnetic resonance imaging reveals some activation of the left cerebellar hemisphere during backward priming; but what this activation represents is unclear. Here we explore this issue using continuous theta-burst transcranial magnetic stimulation (cTBS) and associative priming in a lexical decision task. We tested the hypothesis that the left cerebellum plays a role in backward priming and that this is dissociated from the role of the right cerebellum in forward priming. Before and after cTBS was applied to their left and right cerebellar hemispheres, participants completed a lexical decision task. Although we did not replicate the forward priming effect reported in the literature, we did find a significant increase in backward priming after left relative to right cerebellar cTBS. We consider how theories of cerebellar function in the motor domain can be extended to language and cognitive models of backward priming.     

"Do what I do" and "do how I do": different components of imitative learning are mediated by different neural structures.

The involvement of different neural structures in imitative learning was studied in two paradigms. In an experimental paradigm, rats observed actor rats learning spatial procedures in a water maze. After the observational training, the observers underwent a cerebellar lesion, preventing further procedural acquisitions, and then were tested in the water maze previously observed. The cerebellar networks appear to be indispensable for acquiring by imitation the spatial procedures. The procedural sequence was then dissected into the single behavioral units, demonstrating that such units do exist and can be independently acquired. By using repetitive transcranial magnetic stimulation (rTMS), the role of the cerebellum and prefrontal cortex in imitative learning was investigated in humans. Subjects observed an actor detecting a hidden sequence in a matrix and then performed the task detecting either the previously observed sequence or a new one. Cerebellar rTMS applied before the observational training interfered with performance of the new sequence, whereas prefrontal rTMS interfered also with performance of the previously observed one. rTMS delivered after the observational training did not influence task execution. These findings indicate that the cerebellum and prefrontal cortex interact in planning actions, the former by permitting the acquisition by imitation of procedural competencies and the latter by providing flexibility among already acquired solutions.     

Modulating Human Procedural Learning by Cerebellar Transcranial Direct Current Stimulation

Neuroimaging studies suggest that the cerebellum contributes to human cognitive processing, particularly procedural learning. This type of learning is often described as implicit learning and involves automatic, associative, and unintentional learning processes. Our aim was to investigate whether cerebellar transcranial direct current stimulation (tDCS) influences procedural learning as measured by the serial reaction time task (SRTT), in which subjects make speeded key press responses to visual cues. A preliminary modeling study demonstrated that our electrode montage (active electrode over the cerebellum with an extra-cephalic reference) generated the maximum electric field amplitude in the cerebellum. We enrolled 21 healthy subjects (aged 20–49 years). Participants did the SRTT, a visual analogue scale and a visual attention task, before and 35 min after receiving 20-min anodal and sham cerebellar tDCS in a randomized order. To avoid carry-over effects, experimental sessions were held at least 1 week apart. For our primary outcome measure (difference in RTs for random and repeated blocks) anodal versus sham tDCS, RTs were significantly slower for sham tDCS than for anodal cerebellar tDCS (p?=?0.04), demonstrating that anodal tDCS influenced implicit learning processes. When we assessed RTs for procedural learning across the one to eight blocks, we found that RTs changed significantly after anodal stimulation (interaction “time”?×?“blocks 1/8”: anodal, p?=?0.006), but after sham tDCS, they remained unchanged (p?=?0.094). No significant changes were found in the other variables assessed. Our finding that anodal cerebellar tDCS improves an implicit learning type essential to the development of several motor skills or cognitive activity suggests that the cerebellum has a critical role in procedural learning. tDCS could be a new tool for improving procedural learning in daily life in healthy subjects and for correcting abnormal learning in neuropsychiatric disorders.     

The what and how of observational learning

Neuroimaging evidence increasingly supports the hypothesis that the same neural structures subserve the execution, imagination, and observation of actions. We used repetitive transcranial magnetic stimulation (rTMS) to investigate the specific roles of cerebellum and dorsolateral prefrontal cortex (DLPFC) in observational learning of a visuomotor task. Subjects observed an actor detecting a hidden sequence in a matrix and then performed the task detecting either the previously observed sequence or a new one. rTMS applied over the cerebellum before the observational training interfered with performance of the new sequence, whereas rTMS applied over the DLPFC interfered with performance of the previously observed one. When rTMS applied over cerebellar or prefrontal site was delivered after the observational training, no influence was observed on the execution of the task. These results furnish new insights on the neural circuitry involved in the single component of observational learning and allow us to hypothesize that cerebellum and DLPFC interact in planning actions, the former by permitting the acquisition of procedural competencies and the latter by providing flexibility among already acquired solutions.     

The functional nature of cerebellar diaschisis

We report a patient who presented with transient clumsiness of his right hand due to a small hemorrhage in the left globus pallidus. Ten days later, positron emission tomography performed at rest showed decreased oxygen metabolism and blood flow at the site of the anatomic lesion and in remote areas such as the ipsilateral frontotemporoparietal cortex and the contralateral cerebellar hemisphere. Cerebellar hypometabolism has been ascribed to functional disconnection of the contralateral hemisphere from the cerebral cortex and has been termed crossed cerebellar diaschisis. One month later, positron emission tomography performed during unilateral motor activation (finger opposition) showed increased blood flow in the sensorimotor and supplementary motor areas contralateral to the hand engaged in the motor task. An at-rest study at this time showed resolution of the crossed cerebellar diaschisis observed acutely, but cerebellar asymmetry was demonstrated during performance of the motor task with the normal as well as with the previously paretic hand. Our activation study demonstrated cerebellar asymmetry in the chronic phase during a motor task, even though resting cerebellar blood flow was symmetrical. This observation reveals the dynamic, functional nature of crossed cerebellar diaschisis and may partially explain the lack of any clinical counterpart in functional studies of the cerebellum performed with the patient at rest.     

Distinct cerebellar regions for body motion discrimination

Visual processing of human movements is critical for adaptive social behavior. Cerebellar activations have been observed during biological motion discrimination in prior neuroimaging studies, and cerebellar lesions may be detrimental for this task. However, whether the cerebellum plays a causal role in biological motion discrimination has never been tested. Here, we addressed this issue in three different experiments by interfering with the posterior cerebellar lobe using transcranial magnetic stimulation (TMS) during a biological discrimination task. In Experiments 1 and 2, we found that TMS delivered at onset of the visual stimuli over the vermis (vermal lobule VI), but not over the left cerebellar hemisphere (left lobule VI/Crus I), interfered with participants’ ability to distinguish biological from scrambled motion compared to stimulation of a control site (vertex). Interestingly, when stimulation was delivered at a later time point (300 ms after stimulus onset), participants performed worse when TMS was delivered over the left cerebellar hemisphere compared to the vermis and the vertex (Experiment 3). Our data show that the posterior cerebellum is causally involved in biological motion discrimination and suggest that different sectors of the posterior cerebellar lobe may contribute to the task at different time points.     

Cerebellar function in autism: functional magnetic resonance image activation during a simple motor task.

BACKGROUND: The cerebellum is one of the most consistent sites of neuroanatomic abnormality in autism, yet it is still unclear how such pathology impacts cerebellar function. In normal subjects, we previously demonstrated with functional magnetic resonance imaging (fMRI) a dissociation between cerebellar regions involved in attention and those involved in a simple motor task, with motor activation localized to the anterior cerebellum ipsilateral to the moving hand. The purpose of the present investigation was to examine activation in the cerebella of autistic patients and normal control subjects performing this motor task. METHODS: We studied eight autistic patients and eight matched normal subjects, using fMRI. An anatomic region-of-interest approach was used, allowing a detailed examination of cerebellar function. RESULTS: Autistic individuals showed significantly increased motor activation in the ipsilateral anterior cerebellar hemisphere relative to normal subjects, in addition to atypical activation in contralateral and posterior cerebellar regions. Moreover, increased activation was correlated with the degree of cerebellar structural abnormality. CONCLUSIONS: These findings strongly suggest dysfunction of the autistic cerebellum that is a reflection of cerebellar anatomic abnormality. This neurofunctional deficit might be a key contributor to the development of certain diagnostic features of autism (e.g., impaired communication and social interaction, restricted interests, and stereotyped behaviors).     

The role of the cerebellum in subsecond time perception: evidence from repetitive transcranial magnetic stimulation

In three experiments, we investigated the role of the cerebellum in sub- and suprasecond time perception by using repetitive transcranial magnetic stimulation (rTMS). In Experiment 1, subjects underwent four 8-min 1-Hz rTMS sessions in a within-subject design. rTMS sites were the medial cerebellum (real and sham rTMS), left lateral cerebellum, and right lateral cerebellum. Following each rTMS session, subjects completed a subsecond temporal bisection task (stimuli in the range 400-800 msec). Compared with sham rTMS, rTMS applied over the right lateral or medial cerebellum induced a leftward shift of the psychophysical function (perceived lengthening of time). In Experiment 2, a separate sample of subjects underwent the identical rTMS procedure and completed a suprasecond bisection task (stimuli in the 1000-2000 msec range). In this experiment, rTMS to the cerebellar sites did not produce any significant changes compared with sham rTMS. Experiment 3 employed a within-subject design to replicate findings from Experiments 1 and 2. Subjects underwent four rTMS conditions (sub- and suprabisection tasks following medial cerebellar and sham rTMS). rTMS induced a significant leftward shift of psychophysical function in the subsecond bisection, but not in the suprasecond bisection. In this study, we have demonstrated that transient cerebellar stimulation can differently affect the ability to estimate time intervals below and above a duration of 1 sec. The results of this study provide direct evidence for the role of the cerebellum in processing subsecond time intervals. This study further suggests that the perception of sub- and suprasecond intervals is likely to depend upon distinct neural systems.     

Influence of repetitive magnetic stimuli on verbal comprehension

The influence of repetitive magnetic transcranial stimulation over the temporo-parietal cortex on verbal comprehension was investigated in 44 healthy subjects. In right-handed subjects, trains of 50 Hz magnetic stimuli over the left hemisphere produced more errors than stimulation over the right hemisphere. The result is not very clearcut, however; thus the test cannot be used for diagnostic investigation of language dominance.     

Metabolic Changes of Cerebrum by Repetitive Transcranial Magnetic Stimulation over Lateral Cerebellum: A Study with FDG PET

To better understand the functional role of cerebellum within the large-scale cerebellocerebral neural network, we investigated the changes of neuronal activity elicited by cerebellar repetitive transcranial magnetic stimulation (rTMS) using (18)F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twelve right-handed healthy volunteers were studied with brain FDG PET under two conditions: active rTMS of 1?Hz frequency over the left lateral cerebellum and sham stimulation. Compared to the sham condition, active rTMS induced decreased glucose metabolism in the stimulated left lateral cerebellum, the areas known to be involved in voluntary motor movement (supplementary motor area and posterior parietal cortex) in the right cerebral hemisphere, and the areas known to be involved in cognition and emotion (orbitofrontal, medial frontal, and anterior cingulate gyri) in the left cerebral hemisphere. Increased metabolism was found in cognition- and language-related brain regions such as the left inferior frontal gyrus including Broca's area, bilateral superior temporal gyri including Wernicke's area, and bilateral middle temporal gyri. Left cerebellar rTMS also led to increased metabolism in the left cerebellar dentate nucleus and pons. These results demonstrate that rTMS over the left lateral cerebellum modulates not only the target region excitability but also excitability of remote, but interconnected, motor-, language-, cognition-, and emotion-related cerebral regions. They provide further evidence that the cerebellum is involved not only in motor-related functions but also in higher cognitive abilities and emotion through the large-scale cerebellocereberal neural network.     

Prefrontal and parietal cortex in human episodic memory: an interference study by repetitive transcranial magnetic stimulation

Neuroimaging findings, including repetitive transcranial magnetic stimulation (rTMS) interference, point to an engagement of prefrontal cortex (PFC) in learning and memory. Whether parietal cortex (PC) activity is causally linked to successful episodic encoding and retrieval is still uncertain. We compared the effects of event-related active or sham rTMS (a rapid-rate train coincident to the very first phases of memoranda presentation) to the left or right intraparietal sulcus, during a standardized episodic memory task of visual scenes, with those obtained in a fully matched sample of subjects who received rTMS on left or right dorsolateral PFC during the same task. In these subjects, specific hemispheric effects of rTMS included interference with encoding after left stimulation and disruption of retrieval after right stimulation. The interference of PC-rTMS on encoding/retrieval performance was negligible, lacking specificity even when higher intensities of stimulation were applied. However, right PC-rTMS of the same intensity lengthened reaction times in the context of a purely attentive visuospatial task. These results suggest that the activity of intraparietal sulci shown in several functional magnetic resonance studies on memory, unlike that of the dorsolateral PFC, is not causally engaged to a useful degree in memory encoding and retrieval of visual scenes. The parietal activations accompanying the memorization processes could reflect the engagement of a widespread brain attentional network, in which interference on a single 'node' is insufficient for an overt disruption of memory performance.     

Processing past tense in the left cerebellum

We report the case of a patient with ischemic lesion of the left cerebellum, who showed specific deficits in processing past versus future tense of action verbs. These findings confirm, in the presence of cerebellar damage, previous results obtained with transcranial magnetic stimulation in healthy subjects and suggest a specificity of the left cerebellum for preparation of responses to the past tense of action verbs. As part of the procedural brain, the cerebellum could play a role in applying the linguistic rules for selection of morphemes typical of past and future tense formation.     

Hemispheric asymmetry of ipsilateral motor cortex activation during unimanual motor tasks: further evidence for motor dominance.

OBJECTIVES: To test to which extent the increase in ipsilateral motor cortex excitability during unimanual motor tasks shows hemispheric asymmetry. METHODS: Six right-handed healthy subjects performed one of several motor tasks of different complexity (including rest) with one hand (task hand) while the other hand (non-task hand) was relaxed. Focal transcranial magnetic stimulation was applied to the motor cortex ipsilateral to the task hand and the amplitude of the motor evoked potential (MEP) in the non-task hand was measured. In one session, the task hand was the right hand, in the other session it was the left hand. The effects of motor task and side of the task hand were analyzed. Spinal motoneuron excitability was assessed using F-wave measurements. RESULTS: Motor tasks, in particular complex finger sequences, resulted in an increase in MEP amplitude in the non-task hand. This increase was significantly less when the right hand rather than the left hand was the task hand. This difference was seen only in muscles homologous to primary task muscles. The asymmetry could not be explained by changes in F-wave amplitudes. CONCLUSIONS: Hemispheric asymmetry of ipsilateral motor cortex activation either supports the idea that, in right handers, the left motor cortex is more active in ipsilateral hand movements, or alternatively, that the left motor cortex exerts more effective inhibitory control over the right motor cortex than vice versa. We suggest that hemispheric asymmetry of ipsilateral motor cortex activation is one property of motor dominance of the left motor cortex.     

Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory

How the cerebellum is involved in the practice and proficiency of non-motor functions is still unclear. We tested whether transcranial direct current stimulation (tDCS) over the cerebellum (cerebellar tDCS) induces after-effects on the practice-dependent increase in the proficiency of a working memory (WM) task (Sternberg test) in 13 healthy subjects. We also assessed the effects of cerebellar tDCS on visual evoked potentials (VEPs) in four subjects and compared the effects of cerebellar tDCS on the Sternberg test with those elicited by tDCS delivered over the prefrontal cortex in five subjects. Our experiments showed that anodal or cathodal tDCS over the cerebellum impaired the practice-dependent improvement in the reaction times in a WM task. Because tDCS delivered over the prefrontal cortex induced an immediate change in the WM task but left the practice-dependent proficiency unchanged, the effects of cerebellar tDCS are structure-specific. Cerebellar tDCS left VEPs unaffected, its effect on the Sternberg task therefore seems unlikely to arise from visual system involvement. In conclusion, tDCS over the cerebellum specifically impairs the practice-dependent proficiency increase in verbal WM.