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 plac

The role of alpha oscillations in premotor-cerebellar connectivity in motor sequence 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 work 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.:1 List of Abbreviations 2 Introduction 2.1 Motor Learning Stages 2.2 Motor Learning Tasks 2.3 Motor Learning Network 2.4 Theoretical Models of Motor Learning 2.5 Functional Connectivity of Motor Brain Regions 2.6 Effective Connectivity of Motor Brain Regions 2.7 Oscillations in Neuronal Communication 2.8 Alpha Oscillations 2.8.1 Role of Alpha Oscillations in Motor Sequence Learning 2.9 Transcranial Electric Stimulation 2.9.1 Transcranial Alternating Current Stimulation (tACS) 2.10 Summary of Study Rationale 3 Publication 4 Summary 5 List of References 6 Supplementary Materials 7 Contribution of Authors / Darstellung des eigenen Beitrags 8 Declaration of Authorship 9 Curriculum Vitae 10 Publication and Presentation 11 Acknowledgement / Danksagun

Learning temporal statistics for sensory predictions in mild cognitive impairment.

Training is known to improve performance in a variety of perceptual and cognitive skills. However, there is accumulating evidence that mere exposure (i.e. without supervised training) to regularities (i.e. patterns that co-occur in the environment) facilitates our ability to learn contingencies that allow us to interpret the current scene and make predictions about future events. Recent neuroimaging studies have implicated fronto-striatal and medial temporal lobe brain regions in the learning of spatial and temporal statistics. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are characterized by hippocampal dysfunction are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards orientated gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. However, our fMRI results demonstrate that MCI-AD patients recruit an alternate circuit to hippocampus to succeed in learning of predictive structures. In particular, we observed stronger learning-dependent activations for structured sequences in frontal, subcortical and cerebellar regions for patients compared to age-matched controls. Thus, our findings suggest a cortico-striatal-cerebellar network that may mediate the ability for predictive learning despite hippocampal dysfunction in MCI-AD.This work was supported by grants to PB from Birmingham and Solihull Mental Health Foundation Trust Research and Development, and to ZK from the Leverhulme Trust [RF-2011-378] and the [European Community's] Seventh Framework Programme [FP7/2007-2013] under agreement PITN-GA-2011-290011.This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0028393215300506

Investigating the Declarative and Procedural Memory Processes Underlying Acquisition of Tool-Related Knowledge and Skills

It has been proposed that the acquisition of tool-related knowledge and skills (e.g., attributes of a tool, how it is used, how it is grasped) relies on a complex set of memory processes. However, the precise memory representations of different aspects of tool knowledge are still unclear. It has also been argued that some aspects may require an interaction between the declarative and procedural memory systems. However, the nature of this interaction between both memory systems in relation to tool-related knowledge is not well understood. A series of three experiments was carried out in the current dissertation to systematically investigate the role of declarative and procedural memory in mediating complex tool knowledge and skills. In Experiment 1 participants with Parkinson’s disease (PD) showed unimpaired memory for tool attributes and tool grasping relative to controls. In addition, participants with PD showed intact motor skill learning and skilled tool use within sessions, but failed to retain proficiency of these skills after a 3-week delay. In Experiment 2, declarative encoding processes were interrupted in healthy adults by dividing attention during training. Findings showed that dividing attention during training was detrimental for subsequent memory for tool attributes as well as accurate demonstration of tool use and tool grasping. However, dividing attention did not interfere with motor skill learning. In Experiment 3, motor procedural learning among healthy adults was disrupted by limiting access to performance-based feedback during training. Results showed that recall of tool attributes and tool grasping were intact, but limited feedback was detrimental for motor skill learning and skilled tool use. Taken together, the results suggest that memory for tool attributes and tool grasping primarily relies on declarative memory which is associated with the medial temporal lobes. In contrast, findings suggest that motor skill acquisition related to complex tools is primarily supported by striatal-dependent procedural memory. Thus, these results represent a dissociation between declarative and procedural aspects of tool knowledge and skills. Findings from the current studies also provide new insights into the interaction between declarative and procedural memory. The results suggest that skilled tool use requires a cooperative interaction of both systems. The evidence also suggests that the pattern of interaction between memory systems may vary, depending on the learning context

Upregulation of cortico-cerebellar functional connectivity after motor learning

Interactions between the cerebellum and primary motor cortex are crucial for the acquisition of new motor skills. Recent neuroimaging studies indicate that learning motor skills is associated with subsequent modulation of resting-state functional connectivity in the cerebellar and cerebral cortices. The neuronal processes underlying the motor-learning-induced plasticity are not well understood. Here, we investigate changes in functional connectivity in source-reconstructed electroencephalography (EEG) following the performance of a single session of a dynamic force task in twenty young adults. Source activity was reconstructed in 112 regions of interest (ROIs) and the functional connectivity between all ROIs was estimated using the imaginary part of coherence. Significant changes in resting-state connectivity were assessed using partial least squares (PLS). We found that subjects adapted their motor performance during the training session and showed improved accuracy but with slower movement times. A number of connections were significantly upregulated after motor training, principally involving connections within the cerebellum and between the cerebellum and motor cortex. Increased connectivity was confined to specific frequency ranges in the mu- and beta-bands. Post hoc analysis of the phase spectra of these cerebellar and cortico-cerebellar connections revealed an increased phase lag between motor cortical and cerebellar activity following motor practice. These findings show a reorganization of intrinsic cortico-cerebellar connectivity related to motor adaptation and demonstrate the potential of EEG connectivity analysis in source space to reveal the neuronal processes that underpin neural plasticity

Physical mechanisms may be as important as brain mechanisms in evolution of speech [Commentary on Ackerman, Hage, & Ziegler. Brain Mechanisms of acoustic communication in humans and nonhuman primates: an evolutionary perspective]

We present two arguments why physical adaptations for vocalization may be as important as neural adaptations. First, fine control over vocalization is not easy for physical reasons, and modern humans may be exceptional. Second, we present an example of a gorilla that shows rudimentary voluntary control over vocalization, indicating that some neural control is already shared with great apes

Brain mechanisms of acoustic communication in humans and nonhuman primates: An evolutionary perspective

Any account of “what is special about the human brain” (Passingham 2008) must specify the neural basis of our unique ability to produce speech and delineate how these remarkable motor capabilities could have emerged in our hominin ancestors. Clinical data suggest that the basal ganglia provide a platform for the integration of primate-general mechanisms of acoustic communication with the faculty of articulate speech in humans. Furthermore, neurobiological and paleoanthropological data point at a two-stage model of the phylogenetic evolution of this crucial prerequisite of spoken language: (i) monosynaptic refinement of the projections of motor cortex to the brainstem nuclei that steer laryngeal muscles, presumably, as part of a “phylogenetic trend” associated with increasing brain size during hominin evolution; (ii) subsequent vocal-laryngeal elaboration of cortico-basal ganglia circuitries, driven by human-specific FOXP2 mutations.;>This concept implies vocal continuity of spoken language evolution at the motor level, elucidating the deep entrenchment of articulate speech into a “nonverbal matrix” (Ingold 1994), which is not accounted for by gestural-origin theories. Moreover, it provides a solution to the question for the adaptive value of the “first word” (Bickerton 2009) since even the earliest and most simple verbal utterances must have increased the versatility of vocal displays afforded by the preceding elaboration of monosynaptic corticobulbar tracts, giving rise to enhanced social cooperation and prestige. At the ontogenetic level, the proposed model assumes age-dependent interactions between the basal ganglia and their cortical targets, similar to vocal learning in some songbirds. In this view, the emergence of articulate speech builds on the “renaissance” of an ancient organizational principle and, hence, may represent an example of “evolutionary tinkering” (Jacob 1977)

Consensus paper:Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research. The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson\u2019s disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum. The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders

Functional neuroimaging of human vocalizations and affective speech

Neuroimaging studies have verified the important integrative role of the basal ganglia during affective vocalizations. They, however, also point to additional regions supporting vocal monitoring, auditory-motor feedback processing, and online adjustments of vocal motor responses. For the case of affective vocalizations, we suggest partly extending the model to fully consider the link between primate-general and human-specific neural component

The Role Of The Prelimbic, Infralimbic, And Cerebellar Cortices In Operant Behavior

Operant (instrumental) conditioning is a laboratory method for investigating voluntary behavior and involves training a particular response, such as pressing a lever, to earn a reinforcer. Operant behavior is generally divided into two categories: actions and habits. Actions are goal-directed and controlled by response-outcome (R-O) associations. Habits are stimulus-driven and controlled by stimulus-response associations (S-R). Behavior is determined to be goal-directed or habitual by whether or not it is sensitive (action) or insensitive (habit) to reinforcer/outcome devaluation. Many brain regions have been linked to the learning and/or expression of actions and/or habits. This dissertation investigates a few different brain regions in goal-directed and habitual behavior, and determines more specific roles for the prelimbic cortex, infralimbic cortex, prelimbic cortex to dorsomedial striatum pathway, and Crus I/II of the cerebellum. Chapter two investigates the prelimbic and infralimbic cortices in goal-directed behavior. We trained rats on a two-response paradigm, where one response was extensively-trained, and a second response was minimally-trained in a separate context. This maintained both responses as goal-directed. In experiment 1, inactivation of the prelimbic cortex at time of test resulted in an attenuation of responding, but only for the minimally-trained response. This implicates the prelimbic cortex in the expression of goal-directed behavior, but only when that goal-directed behavior is minimally-trained. In experiment 2, we repeated the procedure with infralimbic cortex inactivation and found an attenuation of the extensively-trained response. This implicates the infralimbic cortex in the expression of extensively-trained behavior that is goal-directed. The third chapter examines the role of the prelimbic cortex-to-dorsomedial striatal pathway in minimally-trained operant behavior. Both regions have been implicated in operant behaviors and have strong anatomical connections, but few studies have directly linked them together in the mediation of operant behaviors. After minimal instrumental conditioning, we silenced projections from the prelimbic cortex to the dorsomedial striatum and found that instrumental behavior was reduced, implicating this PL-DMS pathway in the expression of minimally-trained operant responding. The final chapter examines the role of Crus I/II of the cerebellar cortex in the expression of goal-directed and habitual behavior. The cerebellum is well-characterized as a mediator of motor coordination via its connections with the motor cortex. There is also evidence of connections between Crus I/II and non-motor regions of the prefrontal cortex. Additionally, recent studies have pointed towards a role for Crus I/II in non-motor function. In experiment 1, rats learned one minimally-trained and one extensively-trained response, and both responses were goal-directed. Inactivation of Crus I/II attenuated responding only in rats that had undergone reinforcer devaluation. Residual responding in rats that have undergone reinforcer devaluation is attributed to habit, suggesting that Crus I/II may be involved in habit expression. In a follow-up experiment, we extensively-trained a single response and verified that it was expressed as a habit. This time, Crus I/II inactivation at time of test had no effect. Overall, this complex pattern of results suggests the possibility that Crus I/II of the cerebellar cortex is only engaged in habit expression when two responses are trained, but further experiments will be necessary to verify this