Cerebellar thalamic activity in the macaque monkey encodes the duration but not the force or velocity of wrist movement.

The way in which the cerebellum influences the output of the motor cortex is not known. The aim of this study was to establish whether information about force, velocity or duration of movement is encoded in cerebellar thalamic discharge and could therefore be involved in the modulation of motor cortical activity. Extracellular single cell recordings were made from the cerebellar thalamus (66 neurones) and VPLc (49 neurones) of four conscious macaques performing simple wrist movements with various load and gain conditions imposed. A significant correlation (Spearman's; P<0.05) was found between movement duration and the duration of neuronal discharge of most cerebellar thalamic neurones (65%), the velocity of movement and rate of neuronal discharge of some cerebellar thalamic neurones (23%), but not between force of movement and rate of neuronal discharge of any cerebellar thalamic neurones. Similar relationships were found between the activity of VPLc neurones and these movement parameters. The strength of the correlations increased when many cells were grouped and analysed as an ensemble, suggesting that populations of cerebellar thalamic (and VPLc) neurones can encode a signal with higher fidelity than single neurones alone. The ensemble data confirmed that the most robust association was between the duration of neuronal discharge and movement duration. We propose that the cerebellum does not provide the motor cortex with specific information about movement force or velocity, but rather that its major role is in activating many motor cortical regions for a specific duration, thus influencing the timing of complex movements involving many muscles and joints.

Timecourse of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat.

Previously we described the extent of sprouting that axons of the rat substantia nigra pars compacta (SNpc) undergo to grow new synapses and re-innervate the dorsal striatum 16 weeks after partial lesions. Here we provide insights into the timing of events related to the re-innervation of the dorsal striatum by regenerating dopaminergic nigrostriatal axons over a 104-week period after partial SNpc lesioning. Density of dopamine transporter and tyrosine hydroxylase immunoreactive axonal varicosities (terminals) decreased up to 80% 4 weeks after lesioning but returned to normal by 16 weeks, unless SNpc lesions were greater than 75%. Neuronal tracer injections into the SNpc revealed a 119% increase in axon fibres (4 mm rostral to the SNpc) along the medial forebrain bundle 4 weeks after lesioning. SNpc cells underwent phenotypic changes. Four weeks after lesioning the proportion of SNpc neurons that expressed tyrosine hydroxylase fell from 90% to 38% but returned to 78% by 32 weeks. We discuss these phenotype changes in the context of neurogenesis. Significant reductions in dopamine levels in rats with medium (30-75%) lesions returned to normal by 16 weeks whereas recovery was not observed if lesions were larger than 75%. Finally, rotational behaviour of animals in response to amphetamine was examined. The clear rightward turning bias observed after 2 weeks recovered by 16 weeks in animals with medium (30-75%) lesions but was still present when lesions were larger. These studies provide insights into the processes that regulate sprouting responses in the central nervous system following injury.

The activity of primate ventrolateral thalamic neurones during motor adaptation.

Three monkeys were trained to perform stereotyped wrist movements to track a target (phase 1). Changing the gain between the wrist movement and visual display required the monkey to adapt its wrist movement. This adaptation consisted of progressive reduction of movement amplitude over a number of trials (phase 2) until a stereotyped movement accommodating the new gain was learned (phase 3). The experiment's aim was to investigate whether cerebellar thalamic neuronal discharge (ND) changed during motor adaptation and whether this change was related to scaling of kinematic parameters or movement error. Extracellular single-cell recordings were made from "wrist-related" neurones in the cerebellar thalamus (59) and the nucleus ventro-posterior lateralis caudalis (VPLc) (37) of each monkey while they performed the movement paradigm. Neurones were selected for further analysis (37/59 cerebellar thalamic and 23/37 VPLc) if phase-1 movements were stereotyped and motor adaptation occurred in phase 2 (according to statistical definitions). When the gain initially changed, there were positional errors in the form of overshoot. Adaptation to the new gain was achieved by a variety of strategies, including modification of the amplitude of kinematic parameters and positional error in addition to reduction of time to peak velocity and movement time. During stereotyped movements, most cerebellar thalamic neurones fired before movement onset and before VPLc neurones. During adaptation, this order of onset of firing was reversed, and cerebellar thalamic neurones discharged after VPLc neurones and close to the onset of movement. During motor adaptation, the mean rate of phasic ND rose in a large proportion of cerebellar thalamic and VPLc neurones, and the proportion of cerebellar thalamic neurones that encoded a signal about positional error and movement amplitude also increased. In addition, there is set-related activity in the discharge of a majority of cerebellar thalamic and VPLc neurones. This does not appear to be specifically related to motor adaptation, but is related to the movement amplitude. We have discussed the role of the cerebello-thalamo-cortical pathway in error detection in the light of the similarities between discharge patterns of cerebellar thalamic and VPLc neurones. We speculate that, when learned movements are performed, the discharge of cerebellar thalamic neurones occurs before movement, perhaps representing an efference copy of the intended movement. During adaptation, this signal is gated out, and later-arriving peripheral afferent input dominates cerebellar thalamic discharge.

Automatic detection of bursts in spike trains recorded from the thalamus of a monkey performing wrist movements.

In a previous paper (Churchward PR, Butler EG, Finkelstein DI, Aumann TD, Sudbury A, Horne MK. J Neurosci Methods 1997;76:203-210), we showed that a simple back propagation neural network could reliably model visual inspection by human observers in detecting the point of change of neuronal discharge patterns. The data for that study was deliberately chosen so that the point of change was readily detected and there would be high concordance between human observers. We wished to extend this investigation by comparing a variety of automatic analysis methods on more complex data sets. Two automatic analysis methods have been discussed in this paper. The knowledge based spike train analysis (KBSTA) was designed to emulate the detection of bursts by human observers. The self-organizing feature map (SOFM) spike train analysis determined a burst by classifying the patterns of neuronal discharge. Neuronal discharge was recorded from the motor thalamus and nucleus ventralis posterior lateralis caudalis (VPLc) of a monkey performing consecutive trials of skilled wrist movements. Recordings were made from 36 neurons whose discharge patterns were related to wrist movement. Three hundred and sixty trials performed during the recording of these 36 neurons were chosen at random and used to compare the three methods, KBSTA, SOFM, and visual inspection. The main results of this study show that for the 360 trials the three detection methods have very similar results in detecting the onset and offset of neuronal bursts. The SOFM method is not the best first approach for detecting a burst, but it does provides independent evidence to support the KBSTA and visual inspection methods. In conclusion we propose the KBSTA method as a practical, automatic technique to identify bursts of neuronal discharge.

The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys.

This study was designed to further investigate the role of the subthalamic nucleus (STN) and globus pallidus internus (GPi) in the pathophysiology of Parkinson's disease. The prevailing theory about the pathophysiology of Parkinson's disease (PD) predicts that there is overactivity of the subthalamo-pallidal pathway. In order to inactivate that pathway, naive and hemiparkinsonian monkeys were locally administered either muscimol (to reversibly inactivate the contralateral STN) or kynurenic acid (to reduce glutamatergic activity in the contralateral GPi). Three naive and 2 hemiparkinsonian monkeys were studied. Intra-carotid MPTP was administered to produce 2 hemiparkinsonian monkeys. Injection sites of muscimol and kynurenic acid in the brain were confirmed electrophysiologically and histologically. Injections of muscimol into the STN in naive and hemiparkinsonian monkeys caused reversible contralateral dystonia, but did not alleviate Parkinsonism. Only one kynurenic acid injection into GPi partially alleviated Parkinsonism. On the basis of the results in this study, aspects of the currently accepted hypothesis of the pathophysiology of PD cannot be confirmed. However, this study reports that the STN has an important role in the production of dystonia. This experimental model of dystonia will prove suitable for further study of both the mechanisms causing dystonia as well as for possible therapeutic approaches to its treatment.