Joseph M. Galea

Dissociating the Roles of the Cerebellum and Motor Cortex during Adaptive Learning: The Motor Cortex Retains What the Cerebellum Learns

Adaptation to a novel visuomotor transformation has revealed important principles regarding learning and memory. Computational and behavioral studies have suggested that acquisition and retention of a new visuomotor transformation are distinct processes. However, this dissociation has never been clearly shown. Here, participants made fast reaching movements while unexpectedly a 30-degree visuomotor transformation was introduced. During visuomotor adaptation, subjects received cerebellar, primary motor cortex (M1) or sham anodal transcranial direct current stimulation (tDCS), a noninvasive form of brain stimulation known to increase excitability. We found that cerebellar tDCS caused faster adaptation to the visuomotor transformation, as shown by a rapid reduction of movement errors. These findings were not present with similar modulation of visual cortex excitability. In contrast, tDCS over M1 did not affect adaptation, but resulted in a marked increase in retention of the newly learnt visuomotor transformation. These results show a clear dissociation in the processes of acquisition and retention during adaptive motor learning and demonstrate that the cerebellum and primary motor cortex have distinct functional roles. Furthermore, they show that is possible to enhance cerebellar function using tDCS.

Modulation of Cerebellar Excitability by Polarity-Specific Noninvasive Direct Current Stimulation

The cerebellum is a crucial structure involved in movement control and cognitive processing. Noninvasive stimulation of the cerebellum results in neurophysiological and behavioral changes, an effect that has been attributed to modulation of cerebello–brain connectivity. At rest, the cerebellum exerts an overall inhibitory tone over the primary motor cortex (M1), cerebello–brain inhibition (CBI), likely through dentate–thalamo–cortical connections. The level of excitability of this pathway before and after stimulation of the cerebellum, however, has not been directly investigated. In this study, we used transcranial magnetic stimulation to determine changes in M1, brainstem, and CBI before and after 25 min of anodal, cathodal, or sham transcranial direct current stimulation (tDCS) applied over the right cerebellar cortex. We hypothesized that anodal tDCS would result in an enhancement of CBI and cathodal would decrease it, relative to sham stimulation. We found that cathodal tDCS resulted in a clear decrease of CBI, whereas anodal tDCS increased it, in the absence of changes after sham stimulation. These effects were specific to the cerebello–cortical connections with no changes in other M1 or brainstem excitability measures. The cathodal effect on CBI was found to be dependent on stimulation intensity and lasted up to 30 min after the cessation of tDCS. These results suggest that tDCS can modulate in a focal and polarity-specific manner cerebellar excitability, likely through changes in Purkinje cell activity. Therefore, direct current stimulation of the cerebellum may have significant potential implications for patients with cerebellar dysfunction as well as to motor control studies.

Speech Facilitation by Left Inferior Frontal Cortex Stimulation

Summary Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3–8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9–13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Brocas area. Our data support the importance of Brocas area within the normal naming network and as such indicate that Brocas area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.

Brain Polarization Enhances the Formation and Retention of Motor Memories

One of the first steps in the acquisition of a new motor skill is the formation of motor memories. Here we tested the capacity of transcranial DC stimulation (tDCS) applied over the motor cortex during motor practice to increase motor memory formation and retention. Nine healthy individuals underwent a crossover transcranial magnetic stimulation (TMS) study designed to test motor memory formation resulting from training. Anodal tDCS elicited an increase in the magnitude and duration of motor memories in a polarity-specific manner, as reflected by changes in the kinematic characteristics of TMS-evoked movements after anodal, but not cathodal or sham stimulation. This effect was present only when training and stimulation were associated and mediated by a differential modulation of corticomotor excitability of the involved muscles. These results indicate that anodal brain polarization can enhance the initial formation and retention of a new motor memory resulting from training. These processes may be the underlying mechanisms by which tDCS enhances motor learning.

Dopamine, Affordance and Active Inference

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinsons disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

Cerebellar modulation of human associative plasticity.

Key point  •  Increases in the strength of synaptic connections in the motor cortex (long term potentiation) can be induced in humans by repetitively pairing peripheral nerve stimuli and motor cortex transcranial magnetic stimuli given 21–25 ms apart – paired associative stimulation (PAS). •  This ‘associative plasticity’ effect has been assumed to relate to synchronicity between sensory input and motor output, with a similar mechanism proposed to underlie effects at all interstimulus intervals. •  Here we show that modulation of cerebellar activity using transcranial direct current stimulation can abolish associative plasticity in the motor cortex, but only for sensory/motor stimuli paired at 25 ms, not at 21.5 ms. •  The results indicate that human associative plasticity can be affected by cerebellar activity and that at least two different mechanisms are involved in the effects previously reported in studies using PAS at different inter‐stimulus intervals.

Human Locomotor Adaptive Learning Is Proportional to Depression of Cerebellar Excitability

Human locomotor adaptive learning is thought to involve the cerebellum, but the neurophysiological mechanisms underlying this process are not known. While animal research has pointed to depressive modulation of cerebellar outputs, a direct correlation between adaptive learning and cerebellar depression has never been demonstrated. Here, we used transcranial magnetic stimulation to assess excitability changes occurring in the cerebellum and primary motor cortex (M1) after individuals learned a new locomotor pattern on a split-belt treadmill. To control for potential changes associated to task performance complexity, the same group of subjects was also assessed after performing 2 other locomotor tasks that did not elicit learning. We found that only adaptive learning resulted in reduction of cerebellar inhibition. This effect was strongly correlated with the magnitude of learning (r = 0.78). In contrast, M1 excitability changes were not specific to learning but rather occurred in association with task complexity performance. Our results demonstrate that locomotor adaptive learning in humans is proportional to cerebellar excitability depression. This finding supports the theory that adaptive learning is mediated, at least in part, by long-term depression in Purkinje cells. This knowledge opens the opportunity to target cerebellar processes with noninvasive brain stimulation to enhance motor learning.

Disruption of the dorsolateral prefrontal cortex facilitates the consolidation of procedural skills

In explicit sequence learning tasks, an improvement in performance (skill) typically occurs after sleep—leading to the recent literature on sleep-dependent motor consolidation. Consolidation can also be facilitated during wakefulness if declarative knowledge for the sequence is reduced through a secondary cognitive task. Accordingly, declarative and procedural consolidation processes appear to mutually interact. Here we used TMS to test the hypothesis that functions in the dorsolateral prefrontal cortex (DLPFC) that support declarative memory formation indirectly reduce the formation of procedural representations. We hypothesize that disrupting the DLPFC immediately after sequence learning would degrade the retention or the consolidation of the sequence within the declarative memory system and thus facilitate consolidation within procedural memory systems, evident as wakeful off-line skill improvement. Inhibitory theta-burst TMS was applied to the left DLPFC (n = 10), to the right DLPFC (n = 10), or to an occipital cortical control site (n = 10) immediately after training on the serial reaction time task (SRTT). All groups were retested after eight daytime hours without sleep. TMS of either left or right DLPFC lead to skill improvements on the SRTT. Increase in skill was greater following right DLPFC stimulation than left DLPFC stimulation; there was no improvement in skill for the control group. Across all participants, free recall of the sequence was inversely related to the improvements in performance on the SRTT. These results support the hypothesis of interference between declarative and procedural consolidation processes and are discussed in the framework of the interactions between memory systems.

Cerebellar Transcranial Direct Current Stimulation (ctDCS) A Novel Approach to Understanding Cerebellar Function in Health and Disease

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.