An open-source MRI compatible frame for multimodal presurgical mapping in macaque and capuchin monkeys.

BACKGROUND: High-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomical mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. NEW METHOD: We developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. COMPARISON WITH EXISTING METHODS: With the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. RESULTS: We demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of a viral vector. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. CONCLUSIONS: The computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.

A cerebro-cerebellar network for learning visuomotor associations.

Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.

Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum.

Medium spiny neurons (MSNs) constitute the vast majority of striatal neurons and the principal interface between dopamine reward signals and functionally diverse cortico-basal ganglia circuits. Information processing in these circuits is dependent on distinct MSN types: cell types that are traditionally defined according to their projection targets or dopamine receptor expression. Single-cell transcriptional studies have revealed greater MSN heterogeneity than predicted by traditional circuit models, but the transcriptional landscape in the primate striatum remains unknown. Here, we set out to establish molecular definitions for MSN subtypes in Rhesus monkeys and to explore the relationships between transcriptionally defined subtypes and anatomical subdivisions of the striatum. Our results suggest at least nine MSN subtypes, including dorsal striatum subtypes associated with striosome and matrix compartments, ventral striatum subtypes associated with the nucleus accumbens shell and olfactory tubercle, and an MSN-like cell type restricted to µ-opioid receptor rich islands in the ventral striatum. Although each subtype was demarcated by discontinuities in gene expression, continuous variation within subtypes defined gradients corresponding to anatomical locations and, potentially, functional specializations. These results lay the foundation for achieving cell-type-specific transgenesis in the primate striatum and provide a blueprint for investigating circuit-specific information processing.

The basal ganglia and the cerebellum: nodes in an integrated network.

The basal ganglia and the cerebellum are considered to be distinct subcortical systems that perform unique functional operations. The outputs of the basal ganglia and the cerebellum influence many of the same cortical areas but do so by projecting to distinct thalamic nuclei. As a consequence, the two subcortical systems were thought to be independent and to communicate only at the level of the cerebral cortex. Here, we review recent data showing that the basal ganglia and the cerebellum are interconnected at the subcortical level. The subthalamic nucleus in the basal ganglia is the source of a dense disynaptic projection to the cerebellar cortex. Similarly, the dentate nucleus in the cerebellum is the source of a dense disynaptic projection to the striatum. These observations lead to a new functional perspective that the basal ganglia, the cerebellum and the cerebral cortex form an integrated network. This network is topographically organized so that the motor, cognitive and affective territories of each node in the network are interconnected. This perspective explains how synaptic modifications or abnormal activity at one node can have network-wide effects. A future challenge is to define how the unique learning mechanisms at each network node interact to improve performance.

Functional Anatomy of Basal Ganglia Circuits with the Cerebral Cortex and the Cerebellum.

The neural connections of the basal ganglia provide important insights into their function. Here, we discuss the current perspective on basal ganglia connections with the cerebral cortex and with the cerebellum. We review the evidence that the basal ganglia participate in functionally segregated circuits with motor and non-motor areas of the cerebral cortex. We then discuss the data that the basal ganglia are interconnected with the cerebellum. These results provide the anatomical substrate for basal ganglia contributions not only to the control of movement, but also to a variety of cognitive and affective functions. Furthermore, these findings indicate that abnormal activity in basal ganglia circuits with the cerebral cortex and with the cerebellum may contribute to both motor and non-motor deficits associated with several neurologic and psychiatric conditions.

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia.

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

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.

Cerebellar networks with the cerebral cortex and basal ganglia.

The dominant view of cerebellar function has been that it is exclusively concerned with motor control and coordination. Recent findings from neuroanatomical, behavioral, and imaging studies have profoundly changed this view. Neuroanatomical studies using virus transneuronal tracers have demonstrated that cerebellar output reaches vast areas of the neocortex, including regions of prefrontal and posterior parietal cortex. Furthermore, it has recently become clear that the cerebellum is reciprocally connected with the basal ganglia, which suggests that the two subcortical structures are part of a densely interconnected network. Taken together, these findings elucidate the neuroanatomical substrate for cerebellar involvement in non-motor functions mediated by the prefrontal and posterior parietal cortex, as well as in processes traditionally associated with the basal ganglia.

The cerebellum and basal ganglia are interconnected.

The cerebellum and the basal ganglia are major subcortical nuclei that control multiple aspects of behavior largely through their interactions with the cerebral cortex. Discrete multisynaptic loops connect both the cerebellum and the basal ganglia with multiple areas of the cerebral cortex. Interactions between these loops have traditionally been thought to occur mainly at the level of the cerebral cortex. Here, we review a series of recent anatomical studies in nonhuman primates that challenge this perspective. We show that the anatomical substrate exists for substantial interactions between the cerebellum and the basal ganglia. Furthermore, we discuss how these pathways may provide a useful framework for understanding cerebellar contributions to the manifestation of two prototypical basal ganglia disorders, Parkinson's disease and dystonia.

The basal ganglia communicate with the cerebellum.

The basal ganglia and cerebellum are major subcortical structures that influence not only movement, but putatively also cognition and affect. Both structures receive input from and send output to the cerebral cortex. Thus, the basal ganglia and cerebellum form multisynaptic loops with the cerebral cortex. Basal ganglia and cerebellar loops have been assumed to be anatomically separate and to perform distinct functional operations. We investigated whether there is any direct route for basal ganglia output to influence cerebellar function that is independent of the cerebral cortex. We injected rabies virus (RV) into selected regions of the cerebellar cortex in cebus monkeys and used retrograde transneuronal transport of the virus to determine the origin of multisynaptic inputs to the injection sites. We found that the subthalamic nucleus of the basal ganglia has a substantial disynaptic projection to the cerebellar cortex. This pathway provides a means for both normal and abnormal signals from the basal ganglia to influence cerebellar function. We previously showed that the dentate nucleus of the cerebellum has a disynaptic projection to an input stage of basal ganglia processing, the striatum. Taken together these results provide the anatomical substrate for substantial two-way communication between the basal ganglia and cerebellum. Thus, the two subcortical structures may be linked together to form an integrated functional network.

Self-paced movements induce high-frequency gamma oscillations in primary motor cortex.

There has been increasing interest in the functional role of high-frequency (>30 Hz) cortical oscillations accompanying various sensorimotor and cognitive tasks in humans. Similar "high gamma" activity has been observed in the motor cortex, although the role of this activity in motor control is unknown. Using whole-head MEG recordings combined with advanced source localization methods, we identified high-frequency (65 to 80 Hz) gamma oscillations in the primary motor cortex during self-paced movements of the upper and lower limbs. Brief bursts of gamma activity were localized to the contralateral precentral gyrus (MI) during self-paced index finger abductions, elbow flexions and foot dorsiflexions. In comparison to lower frequency (10-30 Hz) sensorimotor rhythms that are bilaterally suppressed prior to and during movement (Jurkiewicz et al., 2006), high gamma activity increased only during movement, reaching maximal increase 100 to 250 ms following EMG onset, and was lateralized to contralateral MI, similar to findings from intracranial EEG studies. Peak frequency of gamma activity was significantly lower during foot dorsiflexion (67.4+/-5.2 Hz) than during finger abduction (75.3+/-4.4 Hz) and elbow flexion (73.9+/-3.7 Hz) although markedly similar for left and right movements of the same body part within subjects, suggesting activation of a common underlying network for gamma oscillations in the left and right motor cortex. These findings demonstrate that voluntary movements elicit high-frequency gamma oscillations in the primary motor cortex that are effector specific, and possibly reflect the activation of cortico-subcortical networks involved in the feedback control of discrete movements.

Event-related beamforming: a robust method for presurgical functional mapping using MEG.

OBJECTIVE: We describe the application of a new spatial filtering technique--event-related beamforming (ERB)--for presurgical functional mapping of primary sensory areas using MEG. This method provides an alternative to equivalent current dipole (ECD) modeling that potentially eliminates problems of intracranial magnetic artifacts due to movement of ferromagnetic materials (e.g., orthodontic braces) or eye movements. METHODS: We compared localization results for ERB and ECD localization of primary somatosensory (M20) and auditory (M100) evoked responses in 12 healthy control subjects and four subjects with metallic dental implants. Data were recorded with a 151-channel CTF MEG system using standard presurgical mapping protocols. RESULTS: We found a high level of agreement between the two methods in control subjects (overall localization difference was 5.9+/-2.2 mm for M20 and 10.4+/-5.6 mm for M100). Subjects with dental implants showed severely distorted evoked responses that could not be analyzed using ECD, whereas the ERB method localized sources to expected anatomical locations. CONCLUSIONS: MEG functional mapping may be carried out without removal of orthodontic or other metallic implants using event-related beamformer analysis. SIGNIFICANCE: Spatial filtering methods can overcome some of the limitations associated with MEG expanding its applicability, particularly in pediatric clinical environments.

Post-movement beta rebound is generated in motor cortex: evidence from neuromagnetic recordings.

Voluntary movements are accompanied by amplitude changes in cortical rhythms presumably as a result of functional activation of sensorimotor areas. Recently, the location of the neural generators involved in increasing power within the beta (15-30 Hz) frequency band following movement (post-movement beta rebound, PMBR) has come into question [Parkes, L.M, Bastiaansen, M.C.M, Norris, D.G., 2006. Combining EEG and fMRI to investigate the post-movement beta rebound. NeuroImage 29, 685-696.]. We used the synthetic aperture magnetometry (SAM) spatial filtering method to identify the time course and location of oscillatory changes within the beta and mu (8-14 Hz) frequency bands during the performance of voluntary movements. Neuromagnetic activity was recorded from 10 adult subjects during abduction of the right index finger. Changes in beta and mu source power were calculated for periods during and following movement, relative to pre-movement baseline activity. Decreases in beta band activity (event-related desynchronization, ERD) were observed during movement, with a strong increase (PMBR) beginning 230+/-170 ms following movement, lasting for 680+/-170 ms. Mu band ERD was observed both during and following movement, with little to no post-movement rebound. Beta and mu ERD were localized bilaterally to the hand region of postcentral gyrus whereas PMBR was localized bilaterally to the hand region of precentral gyrus (motor cortex). Both PMBR and beta ERD were strongest contralateral to the side of movement. These results provide further evidence that movement influences independent cortical rhythms in sensorimotor areas, and confirm previous reports of precentral generators of PMBR in the region of motor cortex, with postcentral generators of beta and mu ERD during movement.