Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Consensus paper: roles of the cerebellum in motor control--the diversity of ideas on cerebellar involvement in movement.

Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure.

Slow-waves in the olfactory system: an olfactory perspective on cortical rhythms.

Over the past few years, it has become clear that oscillatory dynamics of cortical networks are closely involved in sensory coding, attention, memory and sleep. Although most experimental and theoretical studies have focused on the neocortex, we believe that progress in understanding cortical oscillations can be advanced by also considering the olfactory system--which shares many basic properties with the neocortex and shows similar oscillatory patterns. Besides offering the advantage of a greater experimental tractability, the olfactory cortex might prove to be instrumental in uncovering general functional principles of neocortical oscillations, by virtue of the potentially important role of olfaction during neocortical evolution. In this article, we illustrate how such an evolution-based comparative approach can provide novel insights into neocortical slow-wave sleep oscillations and their relationship to respiration.

Constructing realistic neural simulations with GENESIS.

The GEneral NEural SImulation System (GENESIS) is an open source simulation platform for realistic modeling of systems ranging from subcellular components and biochemical reactions to detailed models of single neurons, simulations of large networks of realistic neurons, and systems-level models. The graphical interface XODUS permits the construction of a wide variety of interfaces for the control and visualization of simulations. The object-oriented scripting language allows one to easily construct and modify simulations built from the GENESIS libraries of simulation components. Here, we present procedures for installing GENESIS and its supplementary tutorials, running GENESIS simulations, and creating new neural simulations.

The influence of somatosensory cortex on climbing fiber responses in the lateral hemispheres of the rat cerebellum after peripheral tactile stimulation.

This report describes the temporal relationship between the latency of responses to peripheral stimulation in primary somatosensory (SI) cerebral cortex and the timing of climbing fiber inputs to the lateral hemispheres of the rat cerebellum. Examined in the tactilely responsive regions of crus IIa in the rat, the results show that SI influences the timing of both evoked and spontaneous climbing fiber activity in these cerebellar regions without affecting the rate or probability of complex spike discharge. By reversibly blocking SI activity, we demonstrate that the absence of cortical input results in a lengthening of climbing fiber response latency to peripheral stimuli. Similarly, enhancing the cortical input by subthreshold electrical stimulation of SI results in a shortening of climbing fiber response latency. These results provide a new explanation for the tendency of the inferior olive to oscillate at 7-12 Hz and is consistent with the hypothesis that the inferior olive provides the cerebellum information about the timing of cortical computational cycles. Results are discussed in the context of previous and current hypotheses concerning the physiology and function of the inferior olive/climbing fiber system and are interpreted to provide additional evidence of a role for the cerebellum in the tactile somatosensory system.

Ketamine-xylazine-induced slow (< 1.5 Hz) oscillations in the rat piriform (olfactory) cortex are functionally correlated with respiration.

The occurrence of low frequency (<1.5 Hz) cerebral cortical oscillations during slow-wave sleep has recently lead to the suggestion that this pattern of activity is specifically associated with conditions in which the brain is mostly closed to external inputs and running on its own. In the current experiments, we used a combination of in vivo intracellular and extracellular field potential recordings obtained under conditions of ketamine-xylazine anesthesia to examine slow-wave behavior in the olfactory system. We demonstrate the occurrence of low-frequency oscillations in field potentials of both the olfactory bulb and cortex and in the membrane potentials of cortical pyramidal cells. By monitoring ongoing breathing, we also show that these oscillations are all correlated with the natural breathing cycle. Using a tracheotomized preparation, we demonstrate that slow oscillatory patterns could occasionally be produced even when air is no longer entering the nose, supporting the view that the olfactory system has an intrinsic propensity to oscillate. However, in the case of tracheotomized rats, the amplitude and regularity of the oscillations as well as their patterns of correlation are disrupted. All temporal relationships were restored when air was pulsed into the nostrils. We conclude that, in the olfactory system of freely breathing rats, there is a strong relationship between the occurrence and timing of slow oscillations and the ongoing periodic sensory input resulting from respiration. This coupling between olfactory cortex slow oscillations and respiration may result from the interaction between respiratory-related rhythmic input and the tendency for olfactory structures to oscillate intrinsically. We believe this finding has important functional as well as evolutionary implications.

The 40-year history of modeling active dendrites in cerebellar Purkinje cells: emergence of the first single cell "community model".

The subject of the effects of the active properties of the Purkinje cell dendrite on neuronal function has been an active subject of study for more than 40 years. Somewhat unusually, some of these investigations, from the outset have involved an interacting combination of experimental and model-based techniques. This article recounts that 40-year history, and the view of the functional significance of the active properties of the Purkinje cell dendrite that has emerged. It specifically considers the emergence from these efforts of what is arguably the first single cell "community" model in neuroscience. The article also considers the implications of the development of this model for future studies of the complex properties of neuronal dendrites.

The organization of cerebellar cortical circuitry revisited: implications for function.

For more than 35 years there has been experimental evidence that parallel fiber activity does not generate the beams of activated Purkinje cells hypothesized on the basis of cortical anatomy and assumed by most theories of cerebellar cortical function. This paper first reviews the evidence for and against the parallel fiber beam hypothesis, and then discusses the findings of our recent experimental and model-based investigations intended to better understand parallel fiber effects on Purkinje cells. A principal conclusion of these studies is that the excitatory effects of parallel fibers on Purkinje cell dendrites are modulating and must be considered in the context of a balancing inhibitory influence provided by molecular layer interneurons to these same dendrites. It is proposed that this association of excitation and inhibition can account for the lack of beam-like effects on Purkinje cells. The paper concludes by considering the consequences of this new interpretation of cerebellar cortical circuitry for current theories of cerebellar function.

A Computer Simulation of Oscillatory Behavior in Primary Visual Cortex.

Periodic variations in correlated cellular activity have been observed in many regions of the cerebral cortex. The recent discovery of stimulus-dependent, spatially-coherent oscillations in primary visual cortex of the cat has led to suggestions of neural information encoding schemes based on phase and/or frequency variation. To explore the mechanisms underlying this behavior and their possible functional consequences, we have developed a realistic neural model, based on structural features of visual cortex, which replicates observed oscillatory phenomena. In the model, this oscillatory behavior emerges directly from the structure of the cortical network and the properties of its intrinsic neurons; however, phase coherence is shown to be an average phenomenon seen only when measurements are made over multiple trials. Because average coherence does not ensure synchrony of firing over the course of single stimuli, oscillatory phase may not be a robust strategy for directly encoding stimulus-specific information. Instead, the phase and frequency of cortical oscillations may reflect the coordination of general computational processes within and between cortical areas. Under this interpretation, coherence emerges as a result of horizontal interactions that could be involved in the formation of receptive field properties.

The challenge of connecting the dots in the B.R.A.I.N.

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.

A federated design for a neurobiological simulation engine: the CBI federated software architecture.

Simulator interoperability and extensibility has become a growing requirement in computational biology. To address this, we have developed a federated software architecture. It is federated by its union of independent disparate systems under a single cohesive view, provides interoperability through its capability to communicate, execute programs, or transfer data among different independent applications, and supports extensibility by enabling simulator expansion or enhancement without the need for major changes to system infrastructure. Historically, simulator interoperability has relied on development of declarative markup languages such as the neuron modeling language NeuroML, while simulator extension typically occurred through modification of existing functionality. The software architecture we describe here allows for both these approaches. However, it is designed to support alternative paradigms of interoperability and extensibility through the provision of logical relationships and defined application programming interfaces. They allow any appropriately configured component or software application to be incorporated into a simulator. The architecture defines independent functional modules that run stand-alone. They are arranged in logical layers that naturally correspond to the occurrence of high-level data (biological concepts) versus low-level data (numerical values) and distinguish data from control functions. The modular nature of the architecture and its independence from a given technology facilitates communication about similar concepts and functions for both users and developers. It provides several advantages for multiple independent contributions to software development. Importantly, these include: (1) Reduction in complexity of individual simulator components when compared to the complexity of a complete simulator, (2) Documentation of individual components in terms of their inputs and outputs, (3) Easy removal or replacement of unnecessary or obsoleted components, (4) Stand-alone testing of components, and (5) Clear delineation of the development scope of new components.

Python as a federation tool for GENESIS 3.0.

The GENESIS simulation platform was one of the first broad-scale modeling systems in computational biology to encourage modelers to develop and share model features and components. Supported by a large developer community, it participated in innovative simulator technologies such as benchmarking, parallelization, and declarative model specification and was the first neural simulator to define bindings for the Python scripting language. An important feature of the latest version of GENESIS is that it decomposes into self-contained software components complying with the Computational Biology Initiative federated software architecture. This architecture allows separate scripting bindings to be defined for different necessary components of the simulator, e.g., the mathematical solvers and graphical user interface. Python is a scripting language that provides rich sets of freely available open source libraries. With clean dynamic object-oriented designs, they produce highly readable code and are widely employed in specialized areas of software component integration. We employ a simplified wrapper and interface generator to examine an application programming interface and make it available to a given scripting language. This allows independent software components to be 'glued' together and connected to external libraries and applications from user-defined Python or Perl scripts. We illustrate our approach with three examples of Python scripting. (1) Generate and run a simple single-compartment model neuron connected to a stand-alone mathematical solver. (2) Interface a mathematical solver with GENESIS 3.0 to explore a neuron morphology from either an interactive command-line or graphical user interface. (3) Apply scripting bindings to connect the GENESIS 3.0 simulator to external graphical libraries and an open source three dimensional content creation suite that supports visualization of models based on electron microscopy and their conversion to computational models. Employed in this way, the stand-alone software components of the GENESIS 3.0 simulator provide a framework for progressive federated software development in computational neuroscience.

Functional implications of tactile projection patterns to the lateral hemispheres of the cerebellum of the albino rat: the legacy of Wally Welker.

In the late 1970s, Wally Welker and his colleagues published a series of papers describing the first high-resolution physiological maps of tactile mossy fiber projections to the granule cell layer of the rat. Over the subsequent decade, his laboratory continued to explore the implications of these results for cerebellar connectivity and function while also extending the basic mapping results to a number of additional mammalian species. In each case, the maps revealed several surprising features, including a dominance of tactile (cutaneous inputs), robust short latency responses from the sensory periphery, and a fractured patchy somatotopic organization of receptive fields. This paper summarizes the major results of these micromapping experiments and reconsiders their implications for cerebellar function in light of more recent experimental data. The paper also explores the relationship between these fundamental discoveries and Wally Welker's theory-neutral approach to experimental science.

Increased activation of the human cerebellum during pitch discrimination: a positron emission tomography (PET) study.

Recent years have seen a growing debate concerning the function of the cerebellum. Here we used a pitch discrimination task and PET to test for cerebellar involvement in the active control of sensory data acquisition. Specifically, we predicted greater cerebellar activity during active pitch discrimination compared to passive listening, with the greatest activity when pitch discrimination was most difficult. Ten healthy subjects were trained to discriminate deviant tones presented with a slightly higher pitch than a standard tone, using a Go/No Go paradigm. To ensure that discrimination performance was matched across subjects, individual psychometric curves were assessed beforehand using a two-step psychoacoustic procedure. Subjects were scanned while resting in the absence of any sounds, while passively listening to standard tones, and while detecting deviant tones slightly higher in pitch among these standard tones at four different performance levels. Consistent with our predictions, 1) passive listening alone elicited cerebellar activity (lobule IX), 2) cerebellar activity increased during pitch discrimination as compared to passive listening (crus I and II, lobules VI, VIIB, and VIIIB), and 3) this increase was correlated with the difficulty of the discrimination task (lobules V, VI, and IX). These results complement recent findings showing pitch discrimination deficits in cerebellar patients (Parsons et al., 2009) and further support a role for the cerebellum in sensory data acquisition. The data are discussed in the light of anatomical and physiological evidence functionally connecting auditory system and cerebellum.

Model-founded explorations of the roles of molecular layer inhibition in regulating purkinje cell responses in cerebellar cortex: more trouble for the beam hypothesis.

For most of the last 50 years, the functional interpretation for inhibition in cerebellar cortical circuitry has been dominated by the relatively simple notion that excitatory and inhibitory dendritic inputs sum, and if that sum crosses threshold at the soma the Purkinje cell generates an action potential. Thus, inhibition has traditionally been relegated to a role of sculpting, restricting, or blocking excitation. At the level of networks, this relatively simply notion is manifest in mechanisms like "surround inhibition" which is purported to "shape" or "tune" excitatory neuronal responses. In the cerebellum, where all cell types except one (the granule cell) are inhibitory, these assumptions regarding the role of inhibition continue to dominate. Based on our recent series of modeling and experimental studies, we now suspect that inhibition may play a much more complex, subtle, and central role in the physiological and functional organization of cerebellar cortex. This paper outlines how model-based studies are changing our thinking about the role of feed-forward molecular layer inhibition in the cerebellar cortex. The results not only have important implications for continuing efforts to understand what the cerebellum computes, but might also reveal important features of the evolution of this large and quintessentially vertebrate brain structure.

3D electron microscopic reconstruction of segments of rat cerebellar Purkinje cell dendrites receiving ascending and parallel fiber granule cell synaptic inputs.

Growing physiological evidence suggests that there are functional differences between synapses made by the ascending and parallel fiber segments of the granule axon on cerebellar Purkinje cells. Supporting this view, our previous electron microscopic studies suggested that these synapses also contacted different regions of the Purkinje cell dendrite, and in particular that ascending segment synapses are made exclusively on the smallest diameter Purkinje cell dendrites. In the current study we used serial electron microscopic techniques to reconstruct Purkinje cell dendritic segments up to almost 10 mum in length. Using a combination of anatomical and immunological labeling techniques we identified the ascending or parallel fiber origins of the excitatory synaptic inputs onto dendritic spines, as well as the location of inhibitory synapses made directly on the dendritic shaft. The results confirmed that there are regions of the Purkinje cell dendrite receiving exclusively ascending or parallel fiber synapses and that ascending segment synapses are only found on small-diameter dendrites. In addition, we describe for the first time small-diameter dendritic regions contacted by both types of excitatory synapses. While our data suggest that the majority of inhibitory inputs to the Purkinje cell tree are associated with parallel fiber synaptic inputs, we also found inhibitory inputs on dendritic regions with mixed ascending and parallel fiber inputs, or exclusively parallel fiber inputs. The finding that ascending and parallel fiber inputs can be segregated on the Purkinje cell dendritic tree provides further evidence that these excitatory granule cell synaptic inputs may be functionally distinct.

Pitch discrimination in cerebellar patients: evidence for a sensory deficit.

In the last two decades, a growing body of research showing cerebellar involvement in an increasing number of nonmotor tasks and systems has prompted an expansion of speculations concerning the function of the cerebellum. Here, we tested the predictions of a hypothesis positing cerebellar involvement in sensory data acquisition. Specifically, we examined the effect of global cerebellar degeneration on primary auditory sensory function by means of a pitch discrimination task. The just noticeable difference in pitch between two tones was measured in 15 healthy controls and in 15 high functioning patients afflicted with varying degrees of global cerebellar degeneration caused by hereditary, idiopathic, paraneoplastic, or postinfectious pancerebellitis. Participants also performed an auditory detection task assessing sustained attention, a test of verbal auditory working memory, and an audiometric test. Patient pitch discrimination thresholds were on average five and a half times those of controls and were proportional to the degree of cerebellar ataxia assessed independently. Patients and controls showed normal hearing thresholds and similar performance in control tasks in sustained attention and verbal auditory working memory. These results suggest there is an effect of cerebellar degeneration on primary auditory function. The findings are consistent with other recent demonstrations of cerebellar-related sensory impairments, and with robust cerebellar auditorily evoked activity, confirmed by quantitative meta-analysis, across a range of functional neuroimaging studies dissociated from attention, motor, affective, and cognitive variables. The data are interpreted in the context of a sensory hypothesis of cerebellar function.

Feedforward inhibition controls the spread of granule cell-induced Purkinje cell activity in the cerebellar cortex.

Synapses associated with the parallel fiber (pf) axons of cerebellar granule cells constitute the largest excitatory input onto Purkinje cells (PCs). Although most theories of cerebellar function assume these synapses produce an excitatory sequential "beamlike" activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex.

Simulation of networks of spiking neurons: a review of tools and strategies.

We review different aspects of the simulation of spiking neural networks. We start by reviewing the different types of simulation strategies and algorithms that are currently implemented. We next review the precision of those simulation strategies, in particular in cases where plasticity depends on the exact timing of the spikes. We overview different simulators and simulation environments presently available (restricted to those freely available, open source and documented). For each simulation tool, its advantages and pitfalls are reviewed, with an aim to allow the reader to identify which simulator is appropriate for a given task. Finally, we provide a series of benchmark simulations of different types of networks of spiking neurons, including Hodgkin-Huxley type, integrate-and-fire models, interacting with current-based or conductance-based synapses, using clock-driven or event-driven integration strategies. The same set of models are implemented on the different simulators, and the codes are made available. The ultimate goal of this review is to provide a resource to facilitate identifying the appropriate integration strategy and simulation tool to use for a given modeling problem related to spiking neural networks.