Visuomotor Adaptation Deficits in Patients with Essential Tremor.

Essential tremor (ET) is a progressive movement disorder whose pathophysiology is not fully understood. Current evidence supports the view that the cerebellum is critically involved in the genesis of the tremor in ET. However, it is still unknown whether cerebellar dysfunction affects not only the control of current movements but also the prediction of future movements through dynamic adaptation toward a changed environment. Here, we tested the capacity of 28 patients with ET to adapt in a visuomotor adaptation task known to depend on intact cerebellar function. We found specific impairments in that task compared to age-matched healthy controls. Adaptation to the visual perturbation was disrupted in ET patients, while de-adaptation, the phase after abrupt removal of the perturbation, developed similarly to control subjects. Baseline tremor-independent motor performance was as well similar to healthy controls, indicating that adaptation deficits in ET patients were not rooted in an inability to perform goal-directed movements. There was no association between clinical severity scores of ET and early visuomotor adaptation abilities. These results provide further evidence that the cerebellum is dysfunctional in ET.

Coherent theta oscillations in the cerebellum and supplementary motor area mediate visuomotor adaptation.

The cerebellum and its interaction with cortical areas play a key role in our ability to flexibly adapt a motor program in response to sensory input. Current knowledge about specific neural mechanisms underlying the process of visuomotor adaptation is however lacking. Using a novel placement of EEG electrodes to record electric activity from the cerebellum, we studied local cerebellar activity, as well as its coupling with neocortical activity to obtain direct neurophysiological markers of visuomotor adaptation in humans. We found increased theta (4-8 Hz) power in "cerebellar" as well as cortical electrodes, when subjects first encountered a visual manipulation. Theta power decreased as subjects adapted to the perturbation, and rebounded when the manipulation was suddenly removed. This effect was observed in two distinct locations: a cerebellar cluster and a central cluster, which were localized in left cerebellar crus I (lCB) and right supplementary motor area (rSMA) using linear constrained minimum variance beamforming. Importantly, we found that better adaptation was associated with increased theta power in left cerebellar electrodes and a right sensorimotor cortex electrode. Finally, increased rSMA -> lCB connectivity was significantly decreased with adaptation. These results demonstrate that: (1) cerebellar theta power is markedly modulated over the course of visuomotor adaptation and (2) theta oscillations could serve as a key mechanism for communication within a cortico-cerebellar loop.

Mini-review: The Role of the Cerebellum in Visuomotor Adaptation.

The incredible capability of the brain to quickly alter performance in response to ever-changing environment is rooted in the process of adaptation. The core aspect of adaptation is to fit an existing motor program to altered conditions. Adaptation to a visuomotor rotation or an external force has been well established as tools to study the mechanisms underlying sensorimotor adaptation. In this mini-review, we summarize recent findings from the field of visuomotor adaptation. We focus on the idea that the cerebellum plays a central role in the process of visuomotor adaptation and that interactions with cortical structures, in particular, the premotor cortex and the parietal cortex, may be crucial for this process. To this end, we cover a range of methodologies used in the literature that link cerebellar functions and visuomotor adaptation; behavioral studies in cerebellar lesion patients, neuroimaging and non-invasive stimulation approaches. The mini-review is organized as follows: first, we provide evidence that sensory prediction errors (SPE) in visuomotor adaptation rely on the cerebellum based on behavioral studies in cerebellar patients. Second, we summarize structural and functional imaging studies that provide insight into spatial localization as well as visuomotor adaptation dynamics in the cerebellum. Third, we discuss premotor - cerebellar interactions and how these may underlie visuomotor adaptation. And finally, we provide evidence from transcranial direct current and magnetic stimulation studies that link cerebellar activity, beyond correlational relationships, to visuomotor adaptation .

Alpha oscillations modulate premotor-cerebellar connectivity in motor learning: Insights from transcranial alternating current stimulation.

Alpha oscillations (8-13 Hz) have been suggested to play an important role in dynamic neural processes underlying learning and memory. The goal of this study was to scrutinize the role of alpha oscillations in communication within a cortico-cerebellar network implicated in motor sequence learning. To this end, we conducted two EEG experiments using a serial reaction time task. In the first experiment, we explored changes in alpha power and cross-channel alpha coherence as subjects learned a motor sequence. We found a gradual decrease in spectral alpha power over left premotor cortex (PMC) and sensorimotor cortex (SM1) during learning blocks. In addition, alpha coherence between left PMC/SM1 and left cerebellar crus I was specifically decreased during sequence learning, possibly reflecting a functional decoupling in the broader motor learning network. In the second experiment in a different cohort, we applied 10Hz transcranial alternating current stimulation (tACS), a method shown to entrain local oscillatory activity, to left M1 (lM1) and right cerebellum (rCB) during sequence learning. We observed a tendency for diminished learning following rCB tACS compared to sham, but not following lM1 tACS. Learning-related alpha power following rCB tACS was increased in left PMC, possibly reflecting increase in local inhibitory neural activity. Importantly, learning-specific alpha coherence between left PMC and right cerebellar lobule VIIb was enhanced following rCB tACS. These findings provide strong evidence for a causal role of alpha oscillations in controlling information transfer in a premotor-cerebellar loop during motor sequence learning. Our findings are consistent with a model in which sequence learning may be impaired by enhancing premotor cortical alpha oscillation via external modulation of cerebellar oscillations.

Effective connectivity underlying reward-based executive control.

Motivational influences on cognitive control play an important role in shaping human behavior. Cognitive facilitation through motivators such as prospective reward or punishment is thought to depend on regions from the dopaminergic mesocortical network, primarily the ventral tegmental area (VTA), inferior frontal junction (IFJ), and anterior cingulate cortex (ACC). However, how interactions between these regions relate to motivated control remains elusive. In the present functional magnetic resonance imaging study, we used dynamic causal modeling (DCM) to investigate effective connectivity between left IFJ, ACC, and VTA in a task-switching paradigm comprising three distinct motivational conditions (prospective monetary reward or punishment and a control condition). We found that while prospective punishment significantly facilitated switching between tasks on a behavioral level, interactions between IFJ, ACC, and VTA were characterized by modulations through prospective reward but not punishment. Our DCM results show that IFJ and VTA modulate ACC activity in parallel rather than by interaction to serve task demands in reward-based cognitive control. Our findings further demonstrate that prospective reward and punishment differentially affect neural control mechanisms to initiate decision-making.

Cerebellar - Premotor cortex interactions underlying visuomotor adaptation.

Visuomotor adaptation (VMA) is a form of motor learning essential for performing day to day routines. Theoretical models and empirical evidence suggest a specific cortico-striato-cerebellar loop that mediates early and late learning in VMA. Here, we investigated dynamic changes in neural activity and connectivity when learning a novel visuomotor rotation using fMRI. We found that motor cortical regions, parietal cortex and cerebellum are recruited in the early phase of VMA, gradually reduce their activity as learning reaches plateau and rebound when the visuomotor rotation is removed. At this phase, dubbed de-adaptation, individual performance correlated with activity in motor and parietal cortex such that stronger activity was associated with better performance. Theory suggests that VMA is governed by the cortico-striato-cerebellar network during the early phase of learning and by the cortico-cerebellar loop at later stages. We tested this hypothesis using dynamic causal modelling and found distinct modulation of a cerebellar to dorsal premotor cortex (dPMC) loop. Specifically, the cerebellar to dPMC connection was modulated during adaptation, suggesting a release of inhibition and net excitatory effect of cerebellum on dPMC. The modulation of cerebellar to dPMC connection during de-adaptation was specifically related to behavioral learning parameter: stronger release of inhibition of the cerebellar to dPMC connection was associated with better de-adaptation. We interpret these findings to reflect dynamic interactions between representation of movement in cerebellum and visuomotor integration in dPMC.

Beneficial effects of cerebellar tDCS on motor learning are associated with altered putamen-cerebellar connectivity: A simultaneous tDCS-fMRI study.

Non-invasive transcranial stimulation of cerebellum and primary motor cortex (M1) has been shown to enhance motor learning. However, the mechanisms by which stimulation improves learning remain largely unknown. Here, we sought to shed light on the neural correlates of transcranial direct current stimulation (tDCS) during motor learning by simultaneously recording functional magnetic resonance imaging (fMRI). We found that right cerebellar tDCS, but not left M1 tDCS, led to enhanced sequence learning in the serial reaction time task. Performance was also improved following cerebellar tDCS compared to sham in a sequence production task, reflecting superior training effects persisting into the post-training period. These behavioral effects were accompanied by increased learning-specific activity in right M1, left cerebellum lobule VI, left inferior frontal gyrus and right inferior parietal lobule during cerebellar tDCS compared to sham. Despite the lack of group-level changes comparing left M1 tDCS to sham, activity increase in right M1, supplementary motor area, and bilateral middle frontal cortex, under M1 tDCS, was associated with better sequence performance. This suggests that lack of group effects in M1 tDCS relate to inter-individual variability in learning-related activation patterns. We further investigated how tDCS modulates effective connectivity in the cortico-striato-cerebellar learning network. Using dynamic causal modelling, we found altered connectivity patterns during both M1 and cerebellar tDCS when compared to sham. Specifically, during cerebellar tDCS, negative modulation of a connection from putamen to cerebellum was decreased for sequence learning only, effectively leading to decreased inhibition of the cerebellum. These results show specific effects of cerebellar tDCS on functional activity and connectivity in the motor learning network and may facilitate the optimization of motor rehabilitation involving cerebellar non-invasive stimulation.

Alpha-gamma phase amplitude coupling subserves information transfer during perceptual sequence learning.

Cross-frequency coupling is suggested to serve transfer of information between wide-spread neuronal assemblies and has been shown to underlie many cognitive functions including learning and memory. In previous work, we found that alpha (8-13 Hz) - gamma (30-48 Hz) phase amplitude coupling (αγPAC) is decreased during sequence learning in bilateral frontal cortex and right parietal cortex. We interpreted this to reflect decreased demands for visuo-motor mapping once the sequence has been encoded. In the present study, we put this hypothesis to the test by adding a "simple" condition to the standard serial reaction time task (SRTT) with minimal needs for visuo-motor mapping. The standard SRTT in our paradigm entailed a perceptual sequence allowing for implicit learning of a sequence of colors with randomly assigned motor responses. Sequence learning in this case was thus not associated with reduced demands for visuo-motor mapping. Analysis of oscillatory power revealed a learning-related alpha decrease pointing to a stronger recruitment of occipito-parietal areas when encoding the perceptual sequence. Replicating our previous findings but in contrast to our hypothesis, αγPAC was decreased in sequence compared to random trials over right frontal and parietal cortex. It also tended to be smaller compared to trials requiring a simple motor sequence. We additionally analyzed αγPAC in resting-state data of a separate cohort. PAC in electrodes over right parietal cortex was significantly stronger compared to sequence trials and tended to be higher compared to simple and random trials of the SRTT data. We suggest that αγPAC in right parietal cortex reflects a "default-mode" brain state, which gets perturbed to allow for encoding of visual regularities into memory.

Reduced alpha-gamma phase amplitude coupling over right parietal cortex is associated with implicit visuomotor sequence learning.

Implicit visuomotor sequence learning is important for our daily life, e.g., when writing or playing an instrument. Previous research identified a network of cortical regions that is relevant for motor sequence learning, namely primary motor cortex, premotor cortex, superior parietal cortex, and subcortical regions, including basal ganglia and cerebellum. Here, we investigated learning-related changes in oscillatory activity (theta, alpha and gamma power) and cross-frequency interactions (theta- and alpha-gamma phase-amplitude coupling) within cortical regions during sensorimotor memory formation. EEG was recorded from a large group of participants (n=73) performing the serial reaction time task (SRTT). Posterior parietal alpha power was larger early-on during sequence learning and smaller in later sessions. Alpha/low-gamma (8-13Hz and 30-48Hz) phase-amplitude coupling (PAC) was significantly smaller during sequence learning over right superior parietal cortex and frontal cortex. During the transition from sequential stimuli to random stimuli, participants made more errors, indicating that they still implicitly attempted to implement the learned motor sequence. At the same time, alpha/low-gamma phase-amplitude coupling was found to be smaller during the transition relative to later random trials. Our results show that learning and implementing a learned motor sequence reduces alpha/low-gamma PAC over parietal and frontal cortex. Fronto-parietal alpha/low-gamma PAC might be relevant for visuomotor mapping which becomes less relevant once the motor sequence has been encoded.

Frontal and motor cortex contributions to response inhibition: evidence from electrocorticography.

Changes in the environment require rapid modification or inhibition of ongoing behavior. We used the stop-signal paradigm and intracranial recordings to investigate response preparation, inhibition, and monitoring of task-relevant information. Electrocorticographic data were recorded in eight patients with electrodes covering frontal, temporal, and parietal cortex, and time-frequency analysis was used to examine power differences in the beta (13-30 Hz) and high-gamma bands (60-180 Hz). Over motor cortex, beta power decreased, and high-gamma power increased during motor preparation for both go trials (Go) and unsuccessful stops (US). For successful stops (SS), beta increased, and high-gamma was reduced, indexing the cancellation of the prepared response. In the middle frontal gyrus (MFG), stop signals elicited a transient high-gamma increase. The MFG response occurred before the estimated stop-signal reaction time but did not distinguish between SS and US trials, likely signaling attention to the salient stop stimulus. A postresponse high-gamma increase in MFG was stronger for US compared with SS and absent in Go, supporting a role in behavior monitoring. These results provide evidence for differential contributions of frontal subregions to response inhibition, including motor preparation and inhibitory control in motor cortex and cognitive control and action evaluation in lateral prefrontal cortex.

Striatal-cerebellar networks mediate consolidation in a motor sequence learning task: An fMRI study using dynamic causal modelling.

The fast and slow learning stages of motor sequence learning are suggested to be realized through plasticity in a distributed cortico-striato-cerebellar network. To better understand the causal interactions within this network in the different phases of motor sequence learning, we investigated the effective connectivity within this network during encoding (Day 1) and after consolidation (Day 2) of a serial reaction time task. Using Dynamic Causal Modelling of fMRI data, we found general changes in network connections reflected in altered input nodes and endogenous connections when comparing the early and fast learning session to the late and slow learning session. Whereas encoding of a motor memory early on modulated several connections in a distributed network, slow learning resulted in a pruned network. More specifically, we found a negative modulation of connections from left M1 to right cerebellum, right premotor cortex to left cerebellum, as well as backward connections from putamen to cerebellum bilaterally in the encoding session. While connections during pre-sleep were significantly modulated by learning per se (i.e., specifically modulated by performance on sequence conditions), the connections observed after sleep were rather modulated by general performance (i.e., modulated by performance on both sequence and random conditions). A forward connection from left cerebellum to right putamen was found to be consistent across participants for the sequence condition only during slow learning. Together these findings suggest that whereas encoding in the fast learning phase requires plasticity in several connections implementing both motor and perceptual learning components, slow learning is mediated through connectivity from left cerebellum to right putamen.

Delineating the cortico-striatal-cerebellar network in implicit motor sequence learning.

Theoretical models and experimental evidence suggest that cortico-striatal-cerebellar networks play a crucial role in mediating motor sequence learning. However, how these different regions interact in order to mediate learning is less clear. In the present fMRI study, we used dynamic causal modeling to investigate effective connectivity within the cortico-striatal-cerebellar network while subjects performed a serial reaction time task. Using Bayesian model selection and family wise inference, we show that the cortico-cerebellar loop had higher model evidence than the cortico-striatal loop during motor learning. We observed significant negative modulatory effects on the connections from M1 to cerebellum bilaterally during learning. The results suggest that M1 causes the observed decrease in activity in the cerebellum as learning progresses. The current study stresses the significant role that the cerebellum plays in motor learning as previously suggested by fMRI studies in healthy subjects as well as behavioral studies in patients with cerebellar dysfunction. These results provide important insight into the neural mechanisms underlying motor learning.

Neuronavigated Cerebellar 50 Hz tACS: Attenuation of Stimulation Effects by Motor Sequence Learning.

Cerebellar transcranial alternating current stimulation (tACS) is an emerging non-invasive technique that induces electric fields to modulate cerebellar function. Although the effect of cortical tACS seems to be state-dependent, the impact of concurrent motor activation and the duration of stimulation on the effects of cerebellar tACS has not yet been examined. In our study, 20 healthy subjects received neuronavigated 50 Hz cerebellar tACS for 40 s or 20 min, each during performance using a motor sequence learning task (MSL) and at rest. We measured the motor evoked potential (MEP) before and at two time points after tACS application to assess corticospinal excitability. Additionally, we investigated the online effect of tACS on MSL. Individual electric field simulations were computed to evaluate the distribution of electric fields, showing a focal electric field in the right cerebellar hemisphere with the highest intensities in lobe VIIb, VIII and IX. Corticospinal excitability was only increased after tACS was applied for 40 s or 20 min at rest, and motor activation during tACS (MSL) cancelled this effect. In addition, performance was better (shorter reaction times) for the learned sequences after 20 min of tACS, indicating more pronounced learning under 20 min of tACS compared to tACS applied only in the first 40 s.

Motor learning is independent of effects of subthalamic deep brain stimulation on motor execution.

Motor learning is defined as an improvement in performance through practice. The ability to learn new motor skills may be particularly challenged in patients with Parkinson's disease, in whom motor execution is impaired by the disease-defining motor symptoms such as bradykinesia. Subthalamic deep brain stimulation is an effective treatment in advanced Parkinson's disease, and its beneficial effects on Parkinsonian motor symptoms and motor execution have been widely demonstrated. Much less is known about whether deep brain stimulation directly interacts with motor learning independent of modulation of motor execution. We investigated motor sequence learning in 19 patients with Parkinson's disease treated with subthalamic deep brain stimulation and 19 age-matched controls. In a cross-over design, patients performed an initial motor sequence training session with active and inactive stimulation, respectively (experiments separated by ≥14 days). Performance was retested after 5 min and after a 6 h consolidation interval with active stimulation. Healthy controls performed a similar experiment once. We further investigated neural correlates underlying stimulation-related effects on motor learning by exploring the association of normative subthalamic deep brain stimulation functional connectivity profiles with stimulation-related differences in performance gains during training. Pausing deep brain stimulation during initial training resulted in the inhibition of performance gains that could have been indicative of learning at the behavioural level. Task performance improved significantly during training with active deep brain stimulation, but did not reach the level of learning dynamics of healthy controls. Importantly, task performance after the 6 h consolidation interval was similar across patients with Parkinson's disease independent of whether the initial training session had been performed with active or inactive deep brain stimulation. This indicates that early learning and subsequent consolidation were relatively intact despite severe impairments of motor execution during training with inactive deep brain stimulation. Normative connectivity analyses revealed plausible and significant connectivity of volumes of tissue activated by deep brain stimulation with several cortical areas. However, no specific connectivity profiles were associated with stimulation-dependent differences in learning during initial training. Our results show that motor learning in Parkinson's disease is independent of modulation of motor execution by subthalamic deep brain stimulation. This indicates an important role of the subthalamic nucleus in regulating general motor execution, whereas its role in motor learning appears negligible. Because longer-term outcomes were independent of performance gains during initial training, patients with Parkinson's disease may not need to wait for an optimal motor state to practice new motor skills.

Classification of EEG Signals Reveals a Focal Aftereffect of 10 Hz Motor Cortex Transcranial Alternating Current Stimulation.

Transcranial alternating current stimulation (tACS) modulates oscillations in a frequency- and location-specific manner and affects cognitive and motor functions. This effect appears during stimulation as well as "offline," following stimulation, presumably reflecting neuroplasticity. Whether tACS produces long-lasting aftereffects that are physiologically meaningful, is still of current debate. Thus, for tACS to serve as a reliable method for modulating activity within neural networks, it is important to first establish whether "offline" aftereffects are robust and reliable. In this study, we employed a novel machine-learning approach to detect signatures of neuroplasticity following 10-Hz tACS to two critical nodes of the motor network: left motor cortex (lMC) and right cerebellum (rCB). To this end, we trained a classifier to distinguish between signals following lMC-tACS, rCB-tACS, and sham. Our results demonstrate better classification of electroencephalography (EEG) signals in both theta (θ, 4-8 Hz) and alpha (α, 8-13 Hz) frequency bands to lMC-tACS compared with rCB-tACS/sham, at lMC-tACS stimulation location. Source reconstruction allocated these effects to premotor cortex. Stronger correlation between classification accuracies in θ and α in lMC-tACS suggested an association between θ and α efffects. Together these results suggest that EEG signals over premotor cortex contains unique signatures of neuroplasticity following 10-Hz motor cortex tACS.

Cerebellar rTMS and PAS effectively induce cerebellar plasticity.

Non-invasive brain stimulation techniques including repetitive transcranial magnetic stimulation (rTMS), continuous theta-burst stimulation (cTBS), paired associative stimulation (PAS), and transcranial direct current stimulation (tDCS) have been applied over the cerebellum to induce plasticity and gain insights into the interaction of the cerebellum with neo-cortical structures including the motor cortex. We compared the effects of 1 Hz rTMS, cTBS, PAS and tDCS given over the cerebellum on motor cortical excitability and interactions between the cerebellum and dorsal premotor cortex / primary motor cortex in two within subject designs in healthy controls. In experiment 1, rTMS, cTBS, PAS, and tDCS were applied over the cerebellum in 20 healthy subjects. In experiment 2, rTMS and PAS were compared to sham conditions in another group of 20 healthy subjects. In experiment 1, PAS reduced cortical excitability determined by motor evoked potentials (MEP) amplitudes, whereas rTMS increased motor thresholds and facilitated dorsal premotor-motor and cerebellum-motor cortex interactions. TDCS and cTBS had no significant effects. In experiment 2, MEP amplitudes increased after rTMS and motor thresholds following PAS. Analysis of all participants who received rTMS and PAS showed that MEP amplitudes were reduced after PAS and increased following rTMS. rTMS also caused facilitation of dorsal premotor-motor cortex and cerebellum-motor cortex interactions. In summary, cerebellar 1 Hz rTMS and PAS can effectively induce plasticity in cerebello-(premotor)-motor pathways provided larger samples are studied.

Motor learning deficits in cervical dystonia point to defective basal ganglia circuitry.

Dystonia is conceptualized as a network disorder involving basal ganglia, thalamus, sensorimotor cortex and the cerebellum. The cerebellum has been implicated in dystonia pathophysiology, but studies testing cerebellar function in dystonia patients have provided equivocal results. This study aimed to further elucidate motor network deficits in cervical dystonia with special interest in the role of the cerebellum. To this end we investigated motor learning tasks, that differ in their dependence on cerebellar and basal ganglia functioning. In 18 cervical dystonia patients and 18 age matched healthy controls we measured implicit motor sequence learning using a 12-item serial reaction time task mostly targeting basal ganglia circuitry and motor adaptation and eyeblink conditioning as markers of cerebellar functioning. ANOVA showed that motor sequence learning was overall impaired in cervical dystonia (p = 0.01). Moreover, unlike healthy controls, patients did not show a learning effect in the first part of the experiment. Visuomotor adaptation and eyeblink conditioning were normal. In conclusion, these data lend support to the notion that motor learning deficits in cervical dystonia relate to basal ganglia-thalamo-cortical loops rather than being a result of defective cerebellar circuitry.

Abnormal effective connectivity in the sensory network in writer's cramp.

BACKGROUND: Writer's cramp (WC), a task specific form of dystonia, is considered to be a motor network disorder, but abnormal sensory tactile processing has also been acknowledged. The sensory spatial discrimination threshold (SDT) can be determined with a spatial acuity test (JVP domes). In addition to increased SDT, patients with WC exhibited dysfunctional sensory processing in the sensory cortex, insula, basal ganglia and cerebellum in a functional magnetic resonance imaging (fMRI) study while performing the spatial acuity test. OBJECTIVES: To assess whether effective connectivity (EC) in the sensory network including cortical, basal ganglia, thalamic and cerebellar regions of interest in WC patients is abnormal. METHODS: We used fMRI and applied a block design, while 19 WC patients and 13 age-matched healthy controls performed a spatial discrimination task. Before we assessed EC using dynamic causal modelling, we compared three model structures based on the current literature. We enclosed regions of interest that are established for sensory processing during right hand stimulation: Left thalamus, somatosensory, parietal and insular cortex, posterior putamen, and right cerebellum. RESULTS: The EC analysis revealed task-dependent decreased unidirectional connectivity between the insula and the posterior putamen. The connectivity involving the primary sensory cortex, parietal cortex and cerebellum were not abnormal in WC. The two groups showed no differences in their behavioural data. CONCLUSIONS: Perception and integration of sensory information requires the exchange of information between the insula cortex and the putamen, a sensory process that was disturbed in WC patients.

Motor Sequence Learning Deficits in Idiopathic Parkinson's Disease Are Associated With Increased Substantia Nigra Activity.

Previous studies have shown that persons with Parkinson's disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differences between the groups were found during sequence learning. We speculate that learning-specific SN recruitment leads to a relative increase in SN- > putamen connectivity, which returns to a pathological reduced state when no learning takes place.

Cerebello-striatal interaction mediates effects of subthalamic nucleus deep brain stimulation in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), dopamine replacement therapy (DRT) enhances the effective connectivity of the prefrontal cortex (PFC) and supplementary motor area (SMA). The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) go beyond DRT effects including highly beneficial tremor suppression. OBJECTIVES: Here, we aimed to determine DBS-related changes of a motor network using resting state fMRI in PD patients with chronic STN DBS. METHODS: In a repeated-measurement design, 26 medicated PD patients (60.9 years (SD 8.9)) were investigated using resting state fMRI while bipolar STN stimulation was (i) active or (ii) switched off, and dynamic causal modelling was subsequently performed. RESULTS: DBS improved the MDS-UPDRS-III score by 26.4% (DBS ON/Med ON vs. DBS OFF/Med ON). Active stimulation resulted in an increased effective connectivity from cerebellum to putamen (p = 0.00118). In addition, there was a stronger coupling from PFC to cerebellum (p = 0.021), as well as from cerebellum to SMA (p = 0.043) on an uncorrected level. Coupling strength from PFC to cerebellum correlated with the DBS-related change of the resting tremor subscore (r = 0.54, p = 0.031). Self-connections increased as a function of DBS in the right PFC, PMC, SMA, M1, thalamus and left cerebellum. CONCLUSIONS: DBS-related improvement of Parkinsonian signs appears to be driven by an interaction between the cerebellum and the putamen. Resting tremor suppression may be related to an enhanced prefronto-cerebellar network. Activation of the mesial premotor loop (PFC-SMA) as seen in DRT may thus be secondary due to the primary modulation of cerebellar networks.