Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex.

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

Remembering forward: neural correlates of memory and prediction in human motor adaptation.

We used functional MR imaging (FMRI), a robotic manipulandum and systems identification techniques to examine neural correlates of predictive compensation for spring-like loads during goal-directed wrist movements in neurologically-intact humans. Although load changed unpredictably from one trial to the next, subjects nevertheless used sensorimotor memories from recent movements to predict and compensate upcoming loads. Prediction enabled subjects to adapt performance so that the task was accomplished with minimum effort. Population analyses of functional images revealed a distributed, bilateral network of cortical and subcortical activity supporting predictive load compensation during visual target capture. Cortical regions--including prefrontal, parietal and hippocampal cortices--exhibited trial-by-trial fluctuations in BOLD signal consistent with the storage and recall of sensorimotor memories or "states" important for spatial working memory. Bilateral activations in associative regions of the striatum demonstrated temporal correlation with the magnitude of kinematic performance error (a signal that could drive reward-optimizing reinforcement learning and the prospective scaling of previously learned motor programs). BOLD signal correlations with load prediction were observed in the cerebellar cortex and red nuclei (consistent with the idea that these structures generate adaptive fusimotor signals facilitating cancelation of expected proprioceptive feedback, as required for conditional feedback adjustments to ongoing motor commands and feedback error learning). Analysis of single subject images revealed that predictive activity was at least as likely to be observed in more than one of these neural systems as in just one. We conclude therefore that motor adaptation is mediated by predictive compensations supported by multiple, distributed, cortical and subcortical structures.

Basal ganglia contribution to the initiation of corrective submovements.

We investigated the neural processes, with a focus on subcortical circuits, which govern corrective submovements in visually targeted action. During event-related fMRI, subjects moved a cursor to capture targets presented at varying movement amplitudes. Movements were performed in a rehearsed null and a novel viscous (25% random trials) torque field. Movement error feedback was provided after each trial. The viscous field invoked a significantly larger error at the end of the primary movement. Subjects compensated by producing more corrections than they had in the null condition. Corrective submovements were appropriately scaled such that terminal error was similar between the two conditions. Parametric analysis identified two regions where the BOLD signal correlated with the number of submovements per trial: a cerebellar region similar to the one noted in the task contrast and the contralateral dorsal putamen. A separate parametric analysis identified brain regions where activity correlated with movement amplitude. This identified the same cerebellar region as above, bilateral parietal cortex, and left motor and premotor cortex. Our data indicate that the basal ganglia and cerebellum play complementary roles in regulating ongoing actions when precise updating is required. The basal ganglia have a key role in contextually-based motor decision-making, i.e. for deciding if and when to correct a given movement by initiating corrective submovements, and the cerebellum is more generally involved in amplifying and refining the command signals for movements of different amplitudes.

An analysis of immediate serial recall performance in a macaque.

There has been considerable research into the ability of nonhuman primates to process sequential information, a topic that is of interest in part because of the extensive involvement of sequence processing in human language use. Surprisingly, no previous study has unambiguously tested the ability of nonhuman primates to encode and immediately reproduce a novel temporal sequence of perceptual events, the ability tapped in the immediate serial recall (ISR) task extensively studied in humans. We report here the performance of a rhesus macaque on a spatial ISR task, closely resembling tasks widely used in human memory research. Detailed analysis of the monkey's recall performance indicates a number of important parallels with human ISR, consistent with the idea that a single mechanism for short-term serial order memory may be shared across species.

Biological implementation of the temporal difference algorithm for reinforcement learning: theoretical comment on O'Reilly et al. (2007).

The ability to survive in the world depends critically on the brain's capacity to detect earlier and earlier predictors of reward or punishment. The dominant theoretical perspective for understanding this capacity has been the temporal difference (TD) algorithm for reinforcement learning. In this issue of Behavioral Neuroscience, R. C. O'Reilly, M. J. Frank, T. E. Hazy, and B. Watz (2007) propose a new model dubbed primary value and learned value (PVLV) that is simpler than TD, and they claimed that it is biologically more realistic. In this commentary, the author suggests some slight modifications of a previous biological implementation of TD instead of adopting the new PVLV algorithm.

The role of the basal ganglia and cerebellum in language processing.

The roles of the cerebellum and basal ganglia have typically been confined in the literature to motor planning and control. However, mounting evidence suggests that these structures are involved in more cognitive domains such as language processing. In the current study, we looked at effective connectivity (the influence that one brain region has on another) of the cerebellum and basal ganglia with regions thought to be involved in phonological processing, i.e. left inferior frontal gyrus and left lateral temporal cortex. We analyzed functional magnetic resonance imaging data (fMRI) obtained during a rhyming judgment task in adults using dynamic causal modeling (DCM). The results showed that the cerebellum has reciprocal connections with both left inferior frontal gyrus and left lateral temporal cortex, whereas the putamen has unidirectional connections into these two brain regions. Furthermore, the connections between cerebellum and these phonological processing areas were stronger than the connections between putamen and these areas. This pattern of results suggests that the putamen and cerebellum may have distinct roles in language processing. Based on research in the motor planning and control literature, we argue that the putamen engages in cortical initiation while the cerebellum amplifies and refines this signal to facilitate correct decision making.

Signaling patterns of globus pallidus internal segment neurons during forearm rotation.

We recorded extracellular single unit discharges of globus pallidus internal segment (GPi) neurons in monkeys performing a visually driven forearm rotation movement task in order to quantify how discharge patterns changed in relation to kinematic parameters. Subjects grasped a handle that rotated about its axis while facing a video screen displaying visual targets. Continuous visual feedback of handle rotation position was provided. Monkeys generated forearm rotation movements of +/-35 degrees and +/-70 degrees amplitude in order to align the cursor and targets. Trial records were aligned to forearm rotation onset in order to compare the discharge patterns that were associated with movements of different amplitudes, velocities, and directions. In addition, we quantified the depth of modulation of neuronal discharge associated with movements generated in two different task phases. Comparisons of discharge patterns were made between the visually guided, rewarded phase ("cued movements") and the self-paced, unrewarded phase that returned the monkey to the task start position ("return movements") by quantifying the goodness of fit between neuronal discharge during cued and return movements. Our analyses revealed no systematic relationship between the depth of modulation of GPi neurons and forearm rotation amplitude, direction, or velocity. Furthermore, comparisons between the two behavioral contexts revealed a systematic attenuation of modulation that could not be attributed to differences in movement velocity. Collectively, these findings suggest that the GPi neurons that we studied were not significantly involved in mediating movement kinematics, but may have instead been instrumental in the processing of information about the behavioral context during which movements were generated.

Presynaptic Inhibition in the Striatum of the Basal Ganglia Improves Pattern Classification and Thus Promotes Superior Goal Selection.

This review article takes a multidisciplinary approach to understand how presynaptic inhibition in the striatum of the basal ganglia (BG) contributes to pattern classification and the selection of goals that control behavior. It is a difficult problem both because it is multidimensional and because it is has complex system dynamics. We focus on the striatum because, as the main site for input to the BG, it gets to decide what goals are important to consider.

Spatial serial order processing in schizophrenia.

The aim of this study was to examine serial order processing deficits in 21 schizophrenia patients and 16 age- and education-matched healthy controls. In a spatial serial order working memory task, one to four spatial targets were presented in a randomized sequence. Subjects were required to remember the locations and the order in which the targets were presented. Patients showed a marked deficit in ability to remember the sequences compared with controls. Increasing the number of targets within a sequence resulted in poorer memory performance for both control and schizophrenia subjects, but the effect was much more pronounced in the patients. Targets presented at the end of a long sequence were more vulnerable to memory error in schizophrenia patients. Performance deficits were not attributable to motor errors, but to errors in target choice. The results support the idea that the memory errors seen in schizophrenia patients may be due to saturating the working memory network at relatively low levels of memory load.

Modeling signal transduction in classical conditioning with network motifs.

Biological networks are constructed of repeated simplified patterns, or modules, called network motifs. Network motifs can be found in a variety of organisms including bacteria, plants, and animals, as well as intracellular transcription networks for gene expression and signal transduction processes in neuronal circuits. Standard models of signal transduction events for synaptic plasticity and learning often fail to capture the complexity and cooperativity of the molecular interactions underlying these processes. Here, we apply network motifs to a model for signal transduction during an in vitro form of eyeblink classical conditioning that reveals an underlying organization of these molecular pathways. Experimental evidence suggests there are two stages of synaptic AMPA receptor (AMPAR) trafficking during conditioning. Synaptic incorporation of GluR1-containing AMPARs occurs early to activate silent synapses conveying the auditory conditioned stimulus and this initial step is followed by delivery of GluR4 subunits that supports acquisition of learned conditioned responses (CRs). Overall, the network design of the two stages of synaptic AMPAR delivery during conditioning describes a coherent feed-forward loop (C1-FFL) with AND logic. The combined inputs of GluR1 synaptic delivery AND the sustained activation of 3-phosphoinositide-dependent protein-kinase-1 (PDK-1) results in synaptic incorporation of GluR4-containing AMPARs and the gradual acquisition of CRs. The network architecture described here for conditioning is postulated to act generally as a sign-sensitive delay element that is consistent with the non-linearity of the conditioning process. Interestingly, this FFL structure also performs coincidence detection. A motif-based approach to modeling signal transduction can be used as a new tool for understanding molecular mechanisms underlying synaptic plasticity and learning and for comparing findings across forms of learning and model systems.

Differential effects of paced and unpaced responding on delayed serial order recall in schizophrenia.

Working memory for temporal order is a component of working memory that is especially dependent on striatal systems, but has not been extensively studied in schizophrenia. This study was designed to characterize serial order reproduction by adapting a spatial serial order task developed for nonhuman primate studies, while controlling for working memory load and whether responses were initiated freely (unpaced) or in an externally paced format. Clinically stable schizophrenia patients (n=27) and psychiatrically healthy individuals (n=25) were comparable on demographic variables and performance on standardized tests of immediate serial order recall (Digit Span, Spatial Span). No group differences were observed for serial order recall when read sequence reproduction was unpaced. However, schizophrenia patients exhibited significant impairments when responding was paced, regardless of sequence length or retention delay. Intact performance by schizophrenia patients during the unpaced condition indicates that prefrontal storage and striatal output systems are sufficiently intact to learn novel response sequences and hold them in working memory to perform serial order tasks. However, retention for newly learned response sequences was disrupted in schizophrenia patients by paced responding, when read-out of each element in the response sequence was externally controlled. The disruption of memory for serial order in paced read-out condition indicates a deficit in frontostriatal interaction characterized by an inability to update working memory stores and deconstruct 'chunked' information.

Deciding when and how to correct a movement: discrete submovements as a decision making process.

Rapid reaching movements of human and non-human primates are often characterized by irregular multi-peaked velocity profiles. How to interpret these irregularities is still under debate. While some reports assert that these irregularities are the result of a continuous controller interacting with the environment, we and others hold that the velocity irregularities are evidence for a controller that produces discrete movement corrections. Here we analyze rapid pronation/supination wrist movements in monkey during a 1D step-tracking task, where visual perturbations of the target were randomly introduced at movement onset. We use our recently introduced algorithm (Fishbach et al. in Exp Brain Res 164:442-457, 2005) to decompose an irregular movement into a primary movement and one or more discrete, corrective submovements. We first show that the visual perturbation has almost no effect on primary movements. In contrast, this perturbation influences the type and the extent of the corrective submovements that often follow primary movements. Secondly, we show that the highly variable timing of overlapping submovements does not depend directly on the visual perturbation but rather on an estimate of the movement error and on the movement's extent-to-go at the time of correction initiation. These results are consistent with a forward-model based intermittent controller with a non-linearity that depends both on a prediction of the magnitude and direction of the movement's error and on its variance. Corrections are initiated only when the predicted error is statistically significant. A simple abstract model that implements these principles accounts for the type and timing of the corrections observed in our data.

Agents of the mind.

The higher order circuitry of the brain is comprised of a large-scale network of cerebral cortical areas that are individually regulated by loops through subcortical structures, particularly through the basal ganglia and cerebellum. These subcortical loops have powerful computational architectures. Using, as an example, the relatively well-understood processing that occurs in the cortical/basal ganglionic/cerebellar distributed processing module that generates voluntary motor commands, I postulate that a network of analogous agents is an appropriate framework for exploring the dynamics of the mind.

Kinematic properties of on-line error corrections in the monkey.

Despite the abundant experimental evidence for the irregular, multipeaked velocity profiles that often characterize rapid human limb movements, there is currently little agreement on how to interpret these phenomena. While in some studies these irregularities have been interpreted as reflecting a continuous control process, in others the irregularities are considered to be evidence for the existence of discrete movement primitives that are initiated by an intermittent controller. Here we introduce a novel "soft symmetry" method for analyzing irregular movements and decomposing them into their discrete movement primitives. We applied this method to analyze rapid pronation/supination wrist movements in monkeys during a one-dimensional tracking task. We showed that the properties of the extracted overlapping submovements (OSMs) were very similar to those of single, regular movements, despite the fact that the decomposition algorithm did not restrict the extracted submovements to a particular shape. In addition we showed that the movement primitives corrected preceding primitives and that the correction initiation time was highly variable, and thus could not be explained by the relatively fixed sensorimotor delay. These results argue against the interpretation of movement irregularities as reflecting a continuous control process and reinforce the hypothesis that movement irregularities result from an intermittent control mechanism. Demonstrating these phenomena in non-human primates will allow neurophysiological investigation of the neural mechanisms involved in these corrections.

Modulation of striatal single units by expected reward: a spiny neuron model displaying dopamine-induced bistability.

Single-unit activity in the neostriatum of awake monkeys shows a marked dependence on expected reward. Responses to visual cues differ when animals expect primary reinforcements, such as juice rewards, in comparison to secondary reinforcements, such as tones. The mechanism of this reward-dependent modulation has not been established experimentally. To assess the hypothesis that direct neuromodulatory effects of dopamine on spiny neurons can account for this modulation, we develop a computational model based on simplified representations of key ionic currents and their modulation by D1 dopamine receptor activation. This minimal model can be analyzed in detail. We find that D1-mediated increases of inward rectifying potassium and L-type calcium currents cause a bifurcation: the native up/down state behavior of the spiny neuron model becomes truly bistable, which modulates the peak firing rate and the duration of the up state and introduces a dependence of the response on the past state history. These generic consequences of dopamine neuromodulation through bistability can account for both reward-dependent enhancement and suppression of spiny neuron single-unit responses to visual cues. We validate the model by simulating responses to visual targets in a memory-guided saccade task; our results are in close agreement with the main features of the experimental data. Our model provides a conceptual framework for understanding the functional significance of the short-term neuromodulatory actions of dopamine on signal processing in the striatum.