Forms Of Motor Learning Research Articles

The acute effects of aerobic exercise on sensorimotor adaptation in chronic stroke.

Background:Sensorimotor adaptation, or the capacity to adapt movement to changes in the moving body or environment, is a form of motor learning that is important for functional independence (e.g., regaining stability after slips or trips). Aerobic exercise can acutely improve many forms of motor learning in healthy adults. It is not known, however, whether acute aerobic exercise has similar positive effects on sensorimotor adaptation in stroke survivors as it does in healthy individuals.Objective:The aim of this study was to determine whether acute aerobic exercise promotes sensorimotor adaptation in people post stroke.Methods:A single-blinded crossover study. Participants attended two separate sessions, completing an aerobic exercise intervention in one session and a resting control condition in the other session. Sensorimotor adaptation was assessed before and after each session, as was brain derived neurotrophic factor. Twenty participants with chronic stroke completed treadmill exercise at moderate to high intensity for 30 minutes.Results:Acute aerobic exercise in chronic stroke survivors significantly increased sensorimotor adaptation from pre to post treadmill intervention. The 30-minute treadmill intervention resulted in an averaged 2.99 ng/ml increase in BDNF levels (BDNF pre-treadmill = 22.31 + /–2.85 ng/ml, post-treadmill was = 25.31 + /–2.46 pg/ml; t(16) = 2.146, p = 0.048, cohen’s d = 0.521, moderate effect size).Conclusions:These results indicate a potential role for aerobic exercise to promote the recovery of sensorimotor function in chronic stroke survivors.

Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum.

NMDA receptors (NMDARs) are required for long-term depression (LTD) at parallel fibre-Purkinje cell synapses, but their cellular localization and physiological functions invivo are unclear. NMDARs in molecular-layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long-term potentiation induced by low-frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Long-term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N-methyl-d-aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)-Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD invitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning invivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular-layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC-, PC- and MLI/PC-specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF-PC synapses in GC- and PC-specific Grin1 (GC-Grin1 and PC-Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC-specific Grin1 (MLI/PC-Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC-Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC-Grin1 cKO and PC-Grin1 cKO mice, but not in MLI/PC-Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD invitro and motor learning invivo.

Modulation of motor learning by a paired associative stimulation protocol inducing LTD-like effects

BackgroundPaired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21–25 ms (PASLTP). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PASLTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PASLTD) on motor learning and its dependency on current direction have not yet been tested. ObjectiveTo investigate whether, and how, PASLTD affects distinct types of motor learning. MethodsEighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PASLTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs). ResultsPASLTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PASLTD protocols tested here showed no effects on model-based learning. ConclusionsPASLTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning.

T124. Effect of subthreshold paired associative stimulation during voluntary contraction on different forms of motor learning

Introduction Paired associative stimulation can induce long-term potentiation (LTP)-like or long-term depression (LTD)-like synaptic plasticity changes in the human primary motor cortex (M1) by repeated pairing of an electrical stimulus to the median nerve with a suprathreshold transcranial magnetic stimulation (TMS) pulse to M1. The effective interstimulus intervals (ISIs) between electric stimulation and TMS for inducing LTP-like plasticity are approximately 21–25 ms, while ISI of about 10 ms is suitable for inducing LTD-like changes. We previously reported that standard PAS with ISI of 21.5 ms (PAS21.5) and 25 ms (PAS25) differentially modulate two types of motor learning, that is, model-free motor learning was facilitated by PAS21.5 while model-based motor learning was inhibited by PAS25. We argued that standard PAS at different ISIs might involve different inputs to corticospinal neurons, which are sensitive to current direction of TMS applied in PAS. This is because the facilitatory effects of subthreshold PAS during target muscle voluntary contraction (sub-PAS) on motor evoked potentials (MEP) depended on current direction by TMS (i.e. sub-PAS21.5 required posterior-to-anterior (PA) currents, while sub-PAS25 was only effective when applied with anterior-to-posterior (AP) currents). In this study, we examined the effects of sub-PAS on model-free and model-based motor learning. We hypothesized that sub-PAS might be more effective to modulate motor learning than standard PAS, since selective stimulation by sub-PAS would reduce the interindividual variability of PAS effects. In addition to LTP-inducing protocols, we examined whether and how LTD-inducing sub-PAS protocol affects motor learning in this study. Methods Forty healthy volunteers (11 females) participated. We examined changes of performance of model-free learning (i.e. acceleration of repeated rapid thumb abduction) and model-based learning (i.e. visuomotor gain adaptation of pincer grip) after different PAS interventions. ISIs in PAS were adjusted in each subject using the latency of the individual N20 of the right median nerve somatosensory evoked potentials. Results Model-free learning was specifically facilitated by sub-PAS with ISI equaling N20 (sub-PASN20) when applied with PA currents, while this learning was exclusively inhibited by sub-PAS with ISI of N20-8.5 (sub-PASN20−8.5) when applied with AP currents. In contrast, model-based learning was interfered by sub-PAS only when ISI equals N20 + 5 (sub-PASN20+5), irrespective of current direction of TMS. Conclusion These findings showed that model-free and model-based motor learning are mediated in M1 by considerably different procedures, since modulation of model-free learning is likely to depend on specific combination between current direction and ISI adopted in sub-PAS, while model-based motor learning appears to be associated with interneuron circuits dependent only on ISI, but not on current direction applied in sub-PAS.

Current direction in TMS revisited: Behavior

Introduction: A recent experiment investigated for the first time whether the excitatory synaptic inputs to corticospinal neurons (CSNs) activated by posterior-anterior (PA) and anterior-posterior (AP) currents participated in different types of behaviour. Putatively preconditioning the excitability of PA- and AP-inputs affected learning of a ballistic thumb acceleration task and a visuomotor adaptation task, respectively. The implication is that different inputs to CSNs subserve different forms of motor learning. Here we used a more direct approach to examining the functional role of PA- and AP-inputs, by testing whether MEPs evoked by AP and PA pulses were modulated differently during the warning and reaction period of various reaction time tasks (choice, simple and Go/No Go).

Motor Learning Enhances Use-Dependent Plasticity.

Motor behaviors are shaped not only by current sensory signals but also by the history of recent experiences. For instance, repeated movements toward a particular target bias the subsequent movements toward that target direction. This process, called use-dependent plasticity (UDP), is considered a basic and goal-independent way of forming motor memories. Most studies consider movement history as the critical component that leads to UDP (Classen et al., 1998; Verstynen and Sabes, 2011). However, the effects of learning (i.e., improved performance) on UDP during movement repetition have not been investigated. Here, we used transcranial magnetic stimulation in two experiments to assess plasticity changes occurring in the primary motor cortex after individuals repeated reinforced and nonreinforced actions. The first experiment assessed whether learning a skill task modulates UDP. We found that a group that successfully learned the skill task showed greater UDP than a group that did not accumulate learning, but made comparable repeated actions. The second experiment aimed to understand the role of reinforcement learning in UDP while controlling for reward magnitude and action kinematics. We found that providing subjects with a binary reward without visual feedback of the cursor led to increased UDP effects. Subjects in the group that received comparable reward not associated with their actions maintained the previously induced UDP. Our findings illustrate how reinforcing consistent actions strengthens use-dependent memories and provide insight into operant mechanisms that modulate plastic changes in the motor cortex.SIGNIFICANCE STATEMENT Performing consistent motor actions induces use-dependent plastic changes in the motor cortex. This plasticity reflects one of the basic forms of human motor learning. Past studies assumed that this form of learning is exclusively affected by repetition of actions. However, here we showed that success-based reinforcement signals could affect the human use-dependent plasticity (UDP) process. Our results indicate that learning augments and interacts with UDP. This effect is important to the understanding of the interplay between the different forms of motor learning and suggests that reinforcement is not only important to learning new behaviors, but can shape our subsequent behavior via its interaction with UDP.

Are There Age-Related Differences in the Ability to Learn Configural Responses?

Age is often associated with a decline in cognitive abilities that are important for maintaining functional independence, such as learning new skills. Many forms of motor learning appear to be relatively well preserved with age, while learning tasks that involve associative binding tend to be negatively affected. The current study aimed to determine whether age differences exist on a configural response learning task, which includes aspects of motor learning and associative binding. Young (M = 24 years) and older adults (M = 66.5 years) completed a modified version of a configural learning task. Given the requirement of associative binding in the configural relationships between responses, we predicted older adults would show significantly less learning than young adults. Older adults demonstrated lower performance (slower reaction time and lower accuracy). However, contrary to our prediction, older adults showed similar rates of learning as indexed by a configural learning score compared to young adults. These results suggest that the ability to acquire knowledge incidentally about configural response relationships is largely unaffected by cognitive aging. The configural response learning task provides insight into the task demands that constrain learning abilities in older adults.

Two distinct interneuron circuits in human motor cortex are linked to different subsets of physiological and behavioral plasticity.

How does a single brain region participate in multiple behaviors? Here we argue that two separate interneuron circuits in the primary motor cortex (M1) contribute differently to two varieties of physiological and behavioral plasticity. To test this in human brain noninvasively, we used transcranial magnetic stimulation (TMS) of M1 hand area to activate two independent sets of synaptic inputs to corticospinal neurons by changing the direction of current induced in the brain: posterior-to-anterior current (PA inputs) and anterior-to-posterior current (AP inputs). We demonstrate that excitability changes produced by repetitive activation of AP inputs depend on cerebellar activity and selectively alter model-based motor learning. In contrast, the changes observed with repetitive stimulation of PA inputs are independent of cerebellar activity and specifically modulate model-free motor learning. The findings are highly suggestive that separate circuits in M1 subserve different forms of motor learning.

A PILOT CASE SERIES OF MAGNETIC SEIZURE THERAPY IN REFRACTORY SCHIZOPHRENIA

Activity-dependent changes in synaptic properties are considered key neural mechanisms of learning and memory. Most studies focus on changes in synaptic function such as long-term potentiation (LTP) and long-term depression (LTD), while changes in synaptic structure have been largely ignored. However, structural synaptic changes are also important. In fact, LTP and LTD are often associated with structural alterations of dendritic spines. Furthermore, experimental evidence indicates that behavioral learning often induces structural rewiring of synaptic circuitry through the formation of new synapses and elimination of existing ones. To discuss the role of structural plasticity in cerebellar learning, this chapter mainly focuses on parallel fiber–Purkinje cell synapses in the cerebellar cortex and reviews their structural changes under several different forms of motor learning.

Chapter One - Learning-Induced Structural Plasticity in the Cerebellum

Activity-dependent changes in synaptic properties are considered key neural mechanisms of learning and memory. Most studies focus on changes in synaptic function such as long-term potentiation (LTP) and long-term depression (LTD), while changes in synaptic structure have been largely ignored. However, structural synaptic changes are also important. In fact, LTP and LTD are often associated with structural alterations of dendritic spines. Furthermore, experimental evidence indicates that behavioral learning often induces structural rewiring of synaptic circuitry through the formation of new synapses and elimination of existing ones. To discuss the role of structural plasticity in cerebellar learning, this chapter mainly focuses on parallel fiber-Purkinje cell synapses in the cerebellar cortex and reviews their structural changes under several different forms of motor learning.

P 178. Reversal of motor learning-related effects in humans

The induction of long-term potentiation (LTP) like plasticity in the human primary motor cortex (M1) using repetitive Transcranial Magnetic Stimulation can be reversed (depotentiated) if another intervention, by itself ineffective in inducing plastic changes (for example a short form of continuous theta burst stimulation-cTBS150) is delivered immediately after an experimentally inducing plasticity protocol. We here investigated if it is also possible to depotentiate the LTP-like after-effects of motor learning in the M1 and the behavioural outcome of learning (i.e. motor learning retention) using the cTBS150 as a depotentiation protocol. We used a well-characterized motor training task in which behavioural improvement is known to be associated with LTP-like plasticity changes of M1, as measured by increased M1 excitability after motor training. Eleven healthy participants were given 15 learning blocks (15 movements each) to maximize the initial acceleration of ballistic finger movements. Participants improved their motor performance during the training task and, as expected, this behavioural improvement was associated with increased M1 excitability. We found that the motor learning-related LTP-like effects were reversed if cTBS150 was given immediately after the end of the training. A control experiment confirmed that cTBS150 alone did not modify the M1 excitability. The analysis of the behavioural data showed that cTBS150 did not modify the motor-learning related behavioural outcome, supporting the hypothesis that M1 is not involved in motor retention. The present study demonstrate that is possible to reverse, i.e. depotentiate, motor learning-related LTP-like effects in the human M1 but this effect does not have a behavioural counterpart. A similar approach could be adopted to investigate if it is also possible to reverse LTP-like effect of more complex forms of motor learning, or to reverse abnormal cortical excitability associated with inappropriate motor learning in pathological conditions.

Polarity Independent Effects of Cerebellar tDCS on Short Term Ankle Visuomotor Learning

BackgroundTranscranial direct current stimulation (tDCS), an emerging technique of noninvasive brain stimulation, has shown to produce beneficial neural effects in consequence with improvements in motor behavior. There are not many studies examining the use of tDCS for lower limb motor control and learning. Most studies using tDCS for facilitating lower limb motor coordination have applied tDCS to the lower limb motor cortex (M1). As the cerebellum is also critically involved in movement control, it is important to dissociate the effect of tDCS on the cerebellum and M1 with respect to lower limb motor control before we begin the application of tDCS as a neuromodulatory tool. Objective/HypothesisThe purpose of this study was to determine the effects of cerebellar vs. motor cortical tDCS on short term ankle visuomotor learning in healthy individuals. MethodsEight healthy individuals practiced a skilled ankle motor tracking task while receiving either facilitatory anodal tDCS to cerebellum, inhibitory cathodal tDCS to cerebellum, facilitatory anodal tDCS to M1, inhibitory cathodal tDCS to M1 or sham stimulation. Pre- and post-measures of changes in cortical excitability of the tibialis anterior muscle and measures of tracking accuracy were assessed. ResultsAnodal cerebellar, cathodal cerebellar, and anodal M1 stimulation improved target-tracking accuracy of the ankle. This was not dependent on the observed changes in motor cortical excitability of the tibialis anterior muscle. Conclusion(s)Polarity independent effects of tDCS on cerebellum were observed. The present study shows that modulation effects of tDCS can occur because of changes in the cerebellum, a structure implicated in several forms of motor learning, providing an additional way in which tDCS can be used to improve motor coordination.

Estrategias para potenciar el aprendizaje motor en el tratamiento vocal de las enfermedades neurodegenerativas

Sensorimotor deficits have a devastating effect on the quality of life of people with neurodegenerative diseases, especially disruptions of craniofacial nerves. These disorders affect voice, speech, facial expression and deglutition. Scientific evidence indicates that targeted training of laryngeal and respiratory muscle groups may reverse or slow disease progression as well as its cranial sensorimotor deficits. However there is still a lack of specifically designed strategies to achieve motor learning and to enhance the generalization of therapeutic results; e.g. there is a need for specific treatment protocols that improve the transfer of motor abilities from the clinical setting to the patient's actual environment. The purpose of this study is primarily aimed at reviewing the principles, phases and forms of motor learning and the application of motor learning requisites to the treatment of vocal problems in neurodegenerative diseases. In the second part of the article we analyze how the Lee Silverman Voice Treatment (LSVT®) method applies theories of motor learning to the treatment of voice problems in persons with Parkinson's disease. This method has been shown to improve the neurological lesion, vocal function, speech intelligibility and deglutition, with most of its effects being maintained in the short, medium and long term.

Brain activations underlying different patterns of performance improvement during early motor skill learning

Motor learning plays a central role in daily life and in neurorehabilitation. Several forms of motor learning have been described, among which motor skill learning, i.e. reaching a superior level of performance (a skill) through a shift of the speed/accuracy trade-off. During the first stage of learning a visuomotor skill, we observed differential patterns of evolution of the speed/accuracy trade-off in normal subjects. Half of the subjects rapidly achieved successful motor skill learning with an early shift of the speed/accuracy trade-off leading to a superior level of performance (shift pattern). The other subjects attained only minimal global improvement due to a converse evolution of speed and accuracy (i.e. a respect of the speed/accuracy trade-off: fit pattern). Functional magnetic resonance imaging (fMRI) was used to explore the neural substrates underlying these differential patterns during the first stage of motor skill learning in normal subjects. Twenty right-handed normal subjects performed an implicit visuomotor learning task with their non-dominant hand. The task ("circuit game") consisted in learning to navigate a pointer along a circuit as quickly and accurately as possible using a fMRI-compatible mouse. Velocity, accuracy, and performance indexes were used to characterise the motor learning pattern (shift/fit) and to perform fMRI correlation analysis in order to find the neural substrate associated with the shift and fit patterns during early motor skill learning. Nine subjects showed a fit pattern (fitters), and eleven, a shift pattern ("shifters"). fMRI analyses at whole group level (ANOVA) and at sub-group level demonstrated that the supplementary motor area (SMA) was more activated in "shifters" than in the "fitters" groups and that the BOLD activation within the SMA correlated significantly with the on-line shift of the speed/accuracy trade-off in the "shifters" group. Despite identical instructions and experimental conditions, during the first stage of motor skill learning normal subjects spontaneously adopted different patterns that can be differentiated based on distinct fMRI activation patterns. In this implicit visuomotor task, the SMA proper was the key area underlying the achievement of early successful motor skill learning, i.e. on-line shift of the speed/accuracy trade-off.

Cerebellar long‐term depression requires dephosphorylation of TARP in Purkinje cells

Cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is thought to play an essential role in certain forms of motor learning. Like hippocampal LTD, cerebellar LTD is mediated by the endocytosis of AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors at postsynaptic sites. However, similar sets of kinases and phosphatases have opposite regulatory effects on hippocampal and cerebellar LTD, although the mechanisms responsible for this difference remain largely unclear. Activity-dependent dephosphorylation of stargazin (an AMPA receptor auxiliary protein) by calcineurin regulates hippocampal LTD, but whether and how stargazin is involved in cerebellar LTD is unknown. In this study, we showed that stargazin is highly phosphorylated at basal states and is dephosphorylated by the application of high KCl plus glutamate (K-glu) or of a metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), both of which chemically induced LTD in cerebellar slices. This chemically induced dephosphorylation of stargazin was specifically blocked by a calcineurin inhibitor. Indeed, inclusion of the calcineurin auto-inhibitory peptide in the patch pipette solution completely inhibited the LTD induced by the conjunctive stimulation of PFs and Purkinje cells. Furthermore, in Purkinje cells expressing stargazin-9D, in which all nine serine residues are mutated to aspartate, neither conjunctive stimulus nor DHPG treatment induced LTD. Finally, immunohistochemical analyses revealed that neither K-glu nor DHPG induced the endocytosis of AMPA receptors in Purkinje cells expressing stargazin-9D. Together, these results indicate that hippocampal and cerebellar LTD share a common pathway, namely dephosphorylation of stargazin by calcineurin.

Early neural responses to strength training

The neural adaptations that accompany strength training have yet to be fully determined. Here we sought to address this topic by testing the idea that strength training might share similar mechanisms with some forms of motor learning. Since ballistic motor learning is accompanied by a shift in muscle twitches induced by transcranial magnetic stimulation (TMS) toward the training direction, we sought to investigate if these changes also occur after single isometric strength training sessions with various contraction duration and rate of force development characteristics (i.e., brief or sustained ballistic contractions or slow, sustained contractions). Twitch force resultant vectors and motor-evoked potentials (MEPs) induced by TMS were measured before and after single sessions of strength training involving the forearm muscles. Participants (n = 12) each performed three training protocols (each consisting of 4 sets of 10 repetitions) and served as their own control in a counterbalanced order. All three training protocols caused a significant (P < 0.05) shift in TMS-induced twitch force resultant vectors toward the training direction, followed by a gradual shift back toward the pretraining direction. The strongest effect was found when training involved both ballistic and sustained force components. There were no large or consistent changes in the direction of twitches evoked by motor nerve stimulation for any of the three training protocols. We suggest that these early neural responses to strength training, which share similar corticospinal changes to motor learning, might reflect an important process that precedes more long-term neural adaptation that ultimately enhance strength.

Modulatory effects of serotonin on glutamatergic synaptic transmission and long-term depression in the deep cerebellar nuclei

The deep cerebellar nuclei (DCN) are the terminal components of the cerebellar circuitry and constitute its primary output structure. Their activity is important for certain forms of motor learning as well as generation and control of movement. DCN neurons receive glutamatergic excitatory inputs from the pontine nuclei via mossy fibres (MFs) and concomitantly receive inputs from 5-HT-containing neurons of the raphe nuclei. We aimed to explore the roles of 5-HT at MF–DCN synapses by using cerebellar slices from 11 to 15-day-old rats. Bath application of 5-HT reversibly decreased the amplitude of stimulation-evoked excitatory postsynaptic currents (eEPSCs) via the activation of 5-HT 1B receptors at the presynaptic terminals of the MFs. Burst stimulation of the MFs elicited long-term depression (LTD) at the MF–DCN synapses that require activation of the group I metabotropic glutamate receptor (mGluR). In the presence of 5-HT, the extent of burst-induced LTD of MF EPSCs was significantly reduced. Application of 5-HT also decreased the amplitude of mGluR-dependent slow EPSCs evoked by similar burst stimulation. Furthermore, (S)-3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, induced chemical LTD of MF EPSCs, and 5-HT had no significant effect on this LTD. Taken together, the results suggest that 5-HT not only has transitory inhibitory effects on MF EPSCs but also plays a role in regulating the long-term synaptic efficacy.

Timing of conditioned eyeblink responses is impaired in children with attention-deficit/hyperactivity disorder

Structural changes of the cerebellum have been reported in several psychiatric diseases like schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). Beside behavioral deficits children with ADHD often show slight motor abnormalities. Cerebellar malfunction may contribute. The cerebellum is a structure essential for motor coordination, various forms of motor learning and timing of motor responses. In the present study, eyeblink conditioning was applied to investigate learning and timing of motor responses both in children with ADHD and children with cerebellar lesions. Acquisition, timing and extinction of conditioned eyeblink responses were investigated in children with ADHD, children with chronic surgical cerebellar lesions and controls using a standard delay paradigm with two different interstimulus intervals. Timing of conditioned eyeblink responses was significantly impaired in children with ADHD in the long interstimulus interval condition. Also in children with cerebellar lesions conditioned responses (CR) tended to occur earlier than in controls. Incidences of CRs were significantly reduced in children with cerebellar lesions and tended to be less in children with ADHD than in controls. Extinction of the CRs was impaired in children with cerebellar lesions in both interstimulus interval conditions and in children with ADHD in the long interstimulus interval condition. Cerebellar malfunction may contribute to disordered eyeblink conditioning in ADHD. However, because CR abnormalities differed between ADHD and cerebellar subjects, dysfunction of non-cerebellar structures cannot be excluded.

What does the cerebellum really do?

Summary The cerebellum is a large part of the brain in all vertebrates. In humans it constitutes about ten percent of the total brain weight, but the small granule cells of the cerebellar cortex are densely packed so that the cerebellum contains more neurons than all of the rest of the brain. Although it has a uniform cellular structure in mammals and birds, there is great variability in the relative size of its parts. In mammals the cerebellum can be roughly divided into three parasagittal divisions; a midline vermis (Latin: a worm) and two lateral hemispheres. The hemispheres are large in the higher primates and they are very large in the human brain. Because the cerebellar hemispheres are particularly large in humans and the higher primates, from time to time claims have been made that in addition to its role in motor control, the cerebellum is important for cognitive functions, such as learning, attention, and language. Here I review some of the evidence for and against that claim.

Induction of cerebellar long-term depression requires activation of calcineurin in Purkinje cells

Cerebellar long-term depression (LTD) is an activity-dependent depression of synaptic transmission from parallel fibers to Purkinje cells underlying certain forms of motor learning. LTD is induced by the conjunctive stimulation of parallel fibers and climbing fibers, both of which supply excitatory inputs to Purkinje cells. The conjunctive stimulation induces a large increase in intracellular Ca 2+ concentration ([Ca 2+] i) in Purkinje cells. Although the increase in [Ca 2+] i is essential for LTD induction, the downstream signal transduction mechanism remains elusive. In this study, we show that LTD induction requires the activation of the Ca 2+/calmodulin-dependent protein phosphatase 2B calcineurin. In acute cerebellar slices of mice, the LTD amplitude was significantly reduced in the presence of calcineurin inhibitors (cyclosporin A or FK506), whereas the basic electrophysiological properties of the parallel fiber-Purkinje cell synaptic transmission remained constant. Furthermore, a calcineurin autoinhibitory peptide perfused into Purkinje cells completely blocked LTD induction. On the other hand, microcystin LR, an inhibitor of protein phosphatase 1 and 2A, did not affect the induction of LTD. These results indicate that calcineurin activation is essential for LTD induction downstream of the conjunctive-stimulation-induced Ca 2+ signal in Purkinje cells.