The detection and generation of sequences as a key to cerebellar function: experiments and theory

Starting from macroscopic and microscopic facts of cerebellar histology, we propose a new functional interpretation that may elucidate the role of the cerebellum in movement control. The idea is that the cerebellum is a large collection of individual lines (Eccles's "beams": Eccles et al. 1967a) that respond specifically to certain sequences of events in the input and in turn produce sequences of signals in the output. We believe that the sequence-in/sequence-out mode of operation is as typical for the cerebellar cortex as the transformation of sets into sets of active neurons is typical for the cerebral cortex, and that both the histological differences between the two and their reciprocal functional interactions become understandable in the light of this dichotomy. The response of Purkinje cells to sequences of stimuli in the mossy fiber system was shown experimentally by Heck on surviving slices of rat and guinea pig cerebellum. Sequential activation of a row of eleven stimulating electrodes in the granular layer, imitating a "movement" of the stimuli along the folium, produces a powerful volley in the parallel fibers that strongly excites Purkinje cells, as evidenced by intracellular recording. The volley, or "tidal wave," has maximal amplitude when the stimulus moves toward the recording site at the speed of conduction in parallel fibers, and much smaller amplitudes for lower or higher "velocities." The succession of stimuli has no effect when they "move" in the opposite direction. Synchronous activation of the stimulus electrodes also had hardly any effect. We believe that the sequences of mossy fiber activation that normally produce this effect in the intact cerebellum are a combination of motor planning relayed to the cerebellum by the cerebral cortex, and information about ongoing movement, reaching the cerebellum from the spinal cord. The output elicited by the specific sequence to which a "beam" is tuned may well be a succession of well timed inhibitory volleys "sculpting" the motor sequences so as to adapt them to the complicated requirements of the physics of a multijointed system.     

Synchronized cortical potentials and wavelet packets: a potential mechanism for perceptual binding and conveying information

Temporal synchronization in neuronal assemblies has been linked to the functional roles of perceptual binding, sensory-motor integration, attention, and information coding. We report new evidence for a common underlying mechanism that uses specific temporal patterns of synchronized neuronal activity as a basis for conveying information. The temporal patterns of stimulus-related synchronized neuronal discharges are structured to closely resemble specific members of the Symlet wavelet packet family employed in a computational framework. Together, these results suggest that temporal patterns of synchronized activity may act as a parallel, distributed code for information through a mechanism computationally equivalent to wavelet packet analysis.     

Generalization as a behavioral window to the neural mechanisms of learning internal models

In generating motor commands, the brain seems to rely on internal models that predict physical dynamics of the limb and the external world. How does the brain compute an internal model? Which neural structures are involved? We consider a task where a force field is applied to the hand, altering the physical dynamics of reaching. Behavioral measures suggest that as the brain adapts to the field, it maps desired sensory states of the arm into estimates of force. If this neural computation is performed via a population code, i.e., via a set of bases, then activity fields of the bases dictate a generalization function that uses errors experienced in a given state to influence performance in any other state. The patterns of generalization suggest that the bases have activity fields that are directionally tuned, but directional tuning may be bimodal. Limb positions as well as contextual cues multiplicatively modulate the gain of tuning. These properties are consistent with the activity fields of cells in the motor cortex and the cerebellum. We suggest that activity fields of cells in these motor regions dictate the way we represent internal models of limb dynamics.     

The human Turing machine: a neural framework for mental programs

In recent years much has been learned about how a single computational processing step is implemented in the brain. By contrast, we still have surprisingly little knowledge of the neuronal mechanisms by which multiple such operations are sequentially assembled into mental algorithms. We outline a theory of how individual neural processing steps might be combined into serial programs. We propose a hybrid neuronal device: each step involves massively parallel computation that feeds a slow and serial production system. Production selection is mediated by a system of competing accumulator neurons that extends the role of these neurons beyond the selection of a motor action. Productions change the state of sensory and mnemonic neurons and iteration of such cycles provides a basis for mental programs.     

Ontogenetic changes in the neural mechanisms of eyeblink conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that estavlish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

Mapping of interneurons that contribute to food aversive conditioning in the slug brain

To determine the distribution of neurons that contribute to memory formation induced by odor-taste associative conditioning in the slug's brain, we examined neuronal activity of the central nervous system of the slug Limax marginatus using a fluorescent activity marker [Lucifer yellow (LY)]. When LY was injected into the body cavity just after the conditioning, many of the procerebral (PC) interneurons were labeled. The PC lobe was considered to play important roles in the olfaction of the slug, because the olfactory afferent fibers from both the inferior and the superior tentacular noses innervate it. Such strong dye-uptake activity of PC interneurons was not observed when LY was injected just after unpaired control treatment. Thus, it was suggested that enhancement of dye-uptake activity upon conditioning was caused by the association of a conditioning stimulus (CS) with an unconditioned stimulus (UCS). The distribution patterns of PC interneurons that were labeled by LY after conditioning showed a characteristic feature: They usually formed a belt-shaped cluster parallel to the dorsoventral axis. This feature of the distribution was maintained when different odors were used as a CS. Furthermore, the number of the clusters reflected the number of CS odors but not the number of conditioning sessions. From these observations, we considered that enhancement of the neural activity involving dye uptake in each belt-shaped cluster contributed to formation of each odor memory.     

Ontogenetic Changes in the Neural Mechanisms of Eyeblink Conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that establish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

The relationship of neuronal activity within the sensori-motor region of the subthalamic nucleus to speech

Microelectrode recordings of human sensori-motor subthalamic neuronal activity during spoken sentence and syllable-repetition tasks provided an opportunity to evaluate the relationship between changes in neuronal activities and specific aspects of these vocal behaviors. Observed patterns of neuronal activity included a build up of activity in anticipation of the start of the utterance, a marked reduction in activity associated with the start of the utterance, and a burst of activity during the course of the sentence between the noun phrase and the verb phrase. Overall, changes of neuronal activity were more robust for the sentence repetition task. These data suggest that the basal ganglia play a role in generating meaningful speech utterances, which may parallel its role in complex sequential limb movements. It is possible that the basal ganglia play a role in generating the syntactical structure of language.     

Variability in infant motor behavior: A hallmark of the healthy nervous system

Application of the concepts of the Neuronal Group Selection Theory (NGST) may shed a new light on motor development. According to NGST, normal motor development is characterized by two phases of variability. Variation is not random, but determined by criteria set by genetic information. Development starts with the phase of primary variability, during which variation in motor behavior is not geared to external conditions. At function-specific ages secondary variability starts, during which motor performance can be adapted to specific situations. In both forms of variability selection on the basis of afferent information plays a significant role. From the NGST point of view, children with pre- or perinatally acquired brain damage suffer from stereotyped motor behavior produced by a limited repertoire of primary (sub)cortical neuronal networks. These children also have problems in selecting the most efficient neuronal activity due to deficits in the processing of sensory information.     

What is the role of the cerebellum in motor learning and cognition?

The exact role of the cerebellum in motor learning and cognition is controversial. Nonetheless, recent ideas and facts have prompted an attempt at building and testing a more unified and coherent conceptualization. This article will suggest that the cerebellum might indeed participate in both motor control and cognition, and in motor adaptation, motor learning, and procedural learning. The proposed process would entail stimulus-response linkage through trial and error learning, and would consist of groupings of single-response elements-motor and cognitive-into large combinations. After practice, the occurrence of a sensory or experiential `context' would automatically trigger the combined response. The parallel fiber is the proposed agent of stimulus-response linkage and of combining the response elements. The attempt here is to focus on the role of the parallel fiber as a possible combiner of downstream motor and cognitive elements.     

Cerebellar neurophysiology in Gilles de la Tourette syndrome and its role as a target for therapeutic intervention

Therapy resistance of approximately one‐third of patients with Gilles de la Tourette syndrome (GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning‐induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non‐invasive and invasive brain stimulation techniques as a novel platform for non‐pharmacological neuromodulation of GTS symptoms.     

Cerebellar output: motor and cognitive channels

The input to the cerebellum has long been known to originate from widespread regions of the cerebral cortex including the frontal, parietal and temporal lobes. The output of the cerebellum, however, was thought to project mainly to the primary motor cortex. Recent anatomical observations have challenged this view. It is now apparent that cerebellar output goes to multiple cortical areas, including not only the primary motor cortex, but also areas of premotor and prefrontal cortex. In fact, there is growing evidence that each of the areas of cerebral cortex that project to the cerebellum is also the target of cerebellar output. The cerebellar output to individual cortical areas originates from distinct clusters of neurons in the deep nuclei which we have termed `output channels'. The individual output channels to the cortical areas we have examined display little or no overlap. Physiological recordings in awake trained primates indicate that neurons in different output channels appear to be involved in distinct aspects of behavior, and in both motor and cognitive functions. These observations indicate that the cerebellar influence on the cerebral cortex is more extensive than previously recognized.     

Synchronized neuronal oscillations and their role in motor processes

Recant data on the relationship of brain rhythms and the simultaneous oscillatory discharge of single units to motor preparation and performance have largely come from monkey and human studies and have failed to converge on a function. However, when these data are viewed in the context of older data from cats and rodents, some consistent patterns begin to emerge. Synchronous oscillatory activity, at any frequency, may be an integrative sensorimotor mechanism for gathering information that can be used to guide subsequent motor actions. There is also considerable evidence that brain rhythms can entrain motor unit activity. It is not clear yet whether the latter influence is a means of organizing muscle phase relationships within motor acts, or is simply a 'test pulse' strategy for checking current muscle conditions. Moreover, although the traditional association of faster brain rhythms with higher levels of arousal remains valid, arousal levels are correlated so tightly with the dynamics of sensorimotor control that it may not be possible to dissociate the two.     

Is the cerebellum a smith predictor?

The motor system may use internal predictive models of the motor apparatus to achieve better control than would be possible by negative feedback. Several theories have proposed that the cerebellum may form these predictive representations. In this article, we review these theories and try to unify them by reference to an engineering control model known as a Smith Predictor. We suggest that the cerebellum forms two types of internal model. One model is a forward predictive model of the motor apparatus (e.g., limb and muscle), providing a rapid prediction of the sensory consequences of each movement. The second model is of the time delays in the control loop (due to receptor and effector delays, axonal conductances, and cognitive processing delays). This model delays a copy of the rapid prediction so that it can be compared in temporal register with actual sensory feedback from the movement. The result of this comparison is used both to correct for errors in performance and as a training signal to learn the first model. We discuss evidence that the cerebellum could form both of these models and suggest that the cerebellum may hold at least two separate Smith Predictors. One, in the lateral cerebellum, would predict the movement outcome in visual, egocentric, or peripersonal coordinates. Another, in the intermediate cerebellum, would predict the consequences in motor coordinates. Generalization of the Smith Predictor theory is discussed in light of cerebellar involvement in nonmotor control systems, including autonomic functions and cognition.     

On the possibility of universal neural coding of subjective experience

Various neurophysiological experiments have revealed remarkable correlations between cortical neuronal activity and subjective experiences. However, the mere presence of neuronal electrical activity does not appear to be sufficient to produce these experiences. It has been suggested that the explanation for the neural basis of consciousness might lie in understanding the reason that some types of neuronal activity possess subjective correlates and others do not. Here I propose and develop the idea that this difference may be caused by the existence of an elementary nonarbitrary linkage between temporal or spatiotemporal patterns of neuronal activity and their subjective attributes. I also show how cortical neural circuits capable of generating experience-coding patterns could emerge during evolution and brain development, due to the presence of spontaneous stochastic neuronal activity and activity-dependent synaptic plasticity. This hypothesis leads to several testable predictions, principal among which is the idea that the neural correlates of consciousness are essentially innate and universal.     

In defense of experience-coding nonarbitrary temporal neural activity patterns

Various neurophysiological experiments have revealed remarkable correlations between cortical neuronal activity and subjective experiences. However, the mere presence of neuronal electrical activity does not appear to be sufficient to produce these experiences. It has been suggested that the explanation for the neural basis of consciousness might lie in understanding the reason that some types of neuronal activity possess subjective correlates and others do not. Here I propose and develop the idea that this difference may be caused by the existence of an elementary nonarbitrary linkage between temporal or spatiotemporal patterns of neuronal activity and their subjective attributes. I also show how cortical neural circuits capable of generating experience-coding patterns could emerge during evolution and brain development, due to the presence of spontaneous stochastic neuronal activity and activity-dependent synaptic plasticity. This hypothesis leads to several testable predictions, principal among which is the idea that the neural correlates of consciousness are essentially innate and universal.     

Brain weights correlate with behavioral parameters in individual inbred mice housed in a common and enriched environment

Fifty 8-week-old Balb/c mice were individually identified and housed together in a large and enriched environment for 5 months. Maze and open field exploration, response to an aversive noise, swimming, and induced grooming tests were applied to each mouse in an initial search for possible relationships between brain morphology and spontaneous behavior in isogenic individuals living in a complex social and physical environment. The tasks generated 39 quantitative behavioral indices which include locomotion, rearing, still, and grooming bout frequencies, latencies, total, and mean bout durations. At the end of the tests, the 7-month-old mice were sacrificed and the fresh weights of their whole brain, cerebellum, brain stem, diencephalon, telencephalon, and prosencephalon were rapidly obtained. Behavioral data have wide variations and do not adjust to normal population distributions. Means of the same parameter differ between tests. A Spearman correlation matrix of all data yielded many significant correlations between indices of the same task which can be interpreted in terms of time budget and sequence probability. Significant correlations between indices of different tests suggest diverse emotionalities, exploratory strategies, and motor skills. The correlations between body and brain weights and among separate brain regions were not significant. There were several low but significant correlations between brain weights and behavioral indices. Such correlations, the resulting factors, and significant behavioral differences between mice with large and small brains suggest that mice displaying low motor activity in novel environments have larger brains and forebrain/hindbrain ratios than mice with high activity, and that animals with high scores of some specific behaviors have larger brain areas physiologically related to such behaviors.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cerebellum and the timing of coordinated eye and hand tracking.

The cerebellum is known to have important functions in motor control, coordination, motor learning, and timing. It may have other "higher" functions as well, up to and including cognitive processing independent of motor behavior. In this article, we will review some of the evidence from functional imaging, lesion studies, electrophysiological recordings, and anatomy which support the theory that the cerebellum provides a "forward model" of the motor system. This forward model would be used for control of movement; it could also underlie a cerebellar role in coordination. In this role, the forward model would generate time-specific signals predicting the motion of each motor effector, essential for predictive control of, for example, eye and hand movements. Data are presented from human eye and hand tracking that support this. Tracking performance is better if eye and hand follow the same spatial trajectory, but better still if the eye leads the hand by about 75 to 100 ms. This suggests that information from the ocular control system feeds into the manual control system to assist its tracking.     

Neural dynamics of autistic behaviors: cognitive, emotional, and timing substrates

What brain mechanisms underlie autism, and how do they give rise to autistic behavioral symptoms? This article describes a neural model, called the Imbalanced Spectrally Timed Adaptive Resonance Theory (iSTART) model, that proposes how cognitive, emotional, timing, and motor processes that involve brain regions such as the prefrontal and temporal cortex, amygdala, hippocampus, and cerebellum may interact to create and perpetuate autistic symptoms. These model processes were originally developed to explain data concerning how the brain controls normal behaviors. The iSTART model shows how autistic behavioral symptoms may arise from prescribed breakdowns in these brain processes, notably a combination of underaroused emotional depression in the amygdala and related affective brain regions, learning of hyperspecific recognition categories in the temporal and prefrontal cortices, and breakdowns of adaptively timed attentional and motor circuits in the hippocampal system and cerebellum. The model clarifies how malfunctions in a subset of these mechanisms can, through a systemwide vicious circle of environmentally mediated feedback, cause and maintain problems with them all.     

A framework for local cortical oscillation patterns

Oscillations are a pervasive feature of neuronal activity in the cerebral cortex. Here, we propose a framework for understanding local cortical oscillation patterns in cognition: two classes of network interactions underlying two classes of cognitive functions produce different local oscillation patterns. Local excitatory-inhibitory interactions shape neuronal representations of sensory, motor and cognitive variables, and produce local gamma-band oscillations. By contrast, the linkage of such representations by integrative functions such as decision-making is mediated by long-range cortical interactions, which yield more diverse local oscillation patterns often involving the beta range. This framework reconciles different cortical oscillation patterns observed in recent studies and helps to understand the link between cortical oscillations and the fMRI signal. Our framework highlights the notion that cortical oscillations index the specific circuit-level mechanisms of cognition.