Kainate receptors (KAR) remain the most poorly defined components of the glutamate receptor system in the CNS, mainly because of the difficulty of distinguishing currents gated by KAR from those mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation, and because KAR are expressed at significantly lower levels than AMPA receptors in most parts of the CNS.

The corticothalamic projection exerts its effects on thalamic neurons via NMDA, non-NMDA and metabotropic glutamate receptors. AMPA receptor mediated effects tend to predominate in the mature thalamus, but the involvement of kainate receptors at corticothalamic synapses on relay neurons and reticular nucleus neurons had not been studied.

The present work compared KAR influences on neurons in the ventral posterior nucleus (VP) and reticular nucleus (RTN), using whole-cell recording in P14–P20 mouse thalamocortical slices. The results were correlated with quantitative immuno-electron microscopic localization of kainate receptor sub-units at corticothalamic synapses in these nuclei. Small kainate-induced inward currents could be recorded in thalamic neurons in response to bath application of kainate, but no KAR-mediated pre-synaptic effects could be detected and no synaptic responses could be evoked in these cells by corticothalamic stimulation. Morphologically, GluR5/6/7 sub-units were expressed at low levels in both VP and RTN and were confined to post-synaptic membranes at corticothalamic synapses in both VP and RTN. Many synapses, however, lacked GluR5/6/7 immunoreactivity.

These results suggest that kainate receptor-mediated events are not major components of the responses of thalamic neurons to corticothalamic activation, either because of small numbers or their location in sites inaccessible to glutamate released from corticothalamic terminals.

The suprachiasmatic nucleus (SCN) projections to the midline and intralaminar thalamic nuclei were examined in the rat. Stereotaxic injections of the retrograde tracer cholera toxin-β subunit (CTb) were made in 12 different thalamic sites. These included individual midline thalamic nuclei (anterior, middle, and posterior portions of the paraventricular thalamic nucleus (PVT), intermediodorsal, paratenial, rhomboid, or reuniens nuclei) and intralaminar thalamic nuclei (lateral parafascicular, central lateral, or central medial nuclei) as well as the mediodorsal and anteroventral thalamic nuclei. After 10–14 days survival, the brains from these animals were processed histochemically and the distribution of retrogradely-labeled neurons was mapped throughout the rostralcaudal extent of the SCN. Within this collective group of midline and intralaminar thalamic nuclei, the only region innervated by the SCN was the PVT. Approximately 80% of this projection arose from the dorsomedial SCN, and the remaining projection originated from the ventrolateral SCN which targeted mainly the anterior division of the PVT. Virtually no SCN neurons were labeled after CTb injections centered in any of the other midline thalamic nuclei, which includes the intermediodorsal, mediodorsal, paratenial, rhomboid, or reuniens thalamic nuclei. Similarly, no evidence for a SCN projection to the intralaminar thalamic nuclei was found. The discussion focuses on the role of SCN → PVT pathway in modulating cerebral cortical functions.

The effect of chronic high frequency deep brain stimulation (DBS) on rest tremor was investigated in subjects with Parkinson’s disease (PD). Eight PD subjects with high amplitude tremor (Group 1) and eight PD subjects with low amplitude tremor (Group 2, used as a reference group) were examined by a clinical neurologist and tested with a velocity laser to quantify time and frequency domain characteristics of tremor. Possible rebound effects in rest tremor when DBS was stopped for 60 min were also explored. Participants received DBS of the internal globus pallidus (GPi) (n = 7), the subthalamic nucleus (STN) (n = 6) or the ventrointermediate nucleus of the thalamus (Vim) (n = 3). Tremor was recorded with a velocity laser under two conditions of DBS (on-off) and two conditions of medication (L-Dopa on-off). Correlations between clinical and experimental results for tremor amplitude was 0.70 with no medication and no stimulation. In Group 1, DBS decreased tremor amplitude but also increased spectral concentration and median frequency significantly. Under medication, the changes in tremor with and without stimulation were not statistically significant (Group 1). When stimulation was stopped for 60 min, a rebound in tremor amplitude was observed and median frequency remained stable in Group 1. None of the comparisons examined produced significant effects in Group 2. Taken together, these results suggest that beyond its effect on tremor amplitude DBS acted also on tremor frequency and did not modify tremor characteristics in subjects with low amplitude tremor.

An atlas of serial sections stained alternately for one of the three calcium-binding proteins, calbindin, calretinin or parvalbumin, or for markers that demarcate borders of thalamic nuclei in and around the posterior pole of the ventral posterior thalamic nucleus of a macaque monkey is presented. The concentrated focal zone of calbindin-immunoreactive fiber ramifications considered by others to form a specific pain and temperature relay nucleus is shown to be located entirely within the confines of the ventral posterior medial (VPM) nucleus. It contains a large population of calbindin-immunoreactive cells and overlaps a region of dense cell and fiber immunoreactivity for parvalbumin. In other parts of the ventral posterior complex, calbindin and parvalbumin immunoreactivity is complementary rather than co-extensive. It is unlikely that the zone of intense calbindin immunoreactivity in VPM forms the only thalamic relay for noxious thermal and mechanical inputs to the cerebral cortex.

Data based on dual intracellular recordings from neocortical and thalamic neurons in anesthetized cats are presented to support the assumption that bisynaptic inhibition of thalamocortical (TC) neurons, induced by synchronous cortical volleys through a prior synaptic relay in GABAergic thalamic reticular (RE) neurons, may overcome the direct excitation of TC neurons. This effect occurs during cortical augmenting responses mimicking sleep spindles as well as during the self-sustained, post-augmenting activity. Although TC volleys directly produce cortical potentials, the cortex uses its own machinery to elaborate oscillatory responses that outlast thalamic stimuli, whereas, simultaneously, TC neurons remain under a prolonged hyperpolarization arising in RE neurons. This pattern suggests that, during slow-wave sleep, when TC neurons are unable to process faithfully fast recurring signals from the external world because of their inhibition, intracortical activity may underlie processes accounting for some forms of mental activity. Opposite activity patterns in cortical and TC neurons are also observed during spike-wave seizures, which are generated in cortex and are associated with steady inhibition in a majority of TC neurons. The inability of TC neurons to transfer signals from the outside world during spike-wave seizures may account for unconsciousness during absence (petit-mal) seizures.

Thalamic and cortical neurons are richly and reciprocally interconnected and support recurrent functional loops in the intact brain, but the role of this circuitry is still poorly understood. Here, we present evidence—from cellular and from functional neuroimaging in control and clinical domains—that thalamocortical resonance is not only a prerequisite for normal cognition, but that its perturbation, in a dynamic sense (e.g. a dysrhythmia) can underlie a variety of neurological and psychiatric disorders.

The companion paper (Llinás et al., 2001) presents evidence, at both cellular and network levels, for the role of resonant oscillatory thalamocortical properties in normal and pathological brain function. Here we present confirmatory single cell electrophysiology from the thalami of thalamocortical dysrhythmia (TCD) patients and review our surgical approach towards the relief of this chronic disabling condition, in its many forms. The goal of surgery is a rebalancing of the abnormal thalamocortical oscillation responsible for TCD. Our approach uses small strategically placed pre-thalamic and medial thalamic lesions that serve to make subcritical the low frequency thalamocortical reentry network attractor via desinhibition and desamplification. The lesions address classical and new stereotactic targets that provide therapeutic efficiency coupled with the sparing of the specific thalamocortical loops.

Advances in the neurosciences and functional neurosurgery have led to a renaissance in the use of brain stimulation technology. A number of intractable neurological disorders can now be safely and successfully treated with brain stimulation. Although this technique was first performed over 50 years ago, it has only now begun to reach its vast clinical potential. This article will provide a historical overview of brain stimulation, describe state-of-the-art clinical applications, and discuss future prospects in this rapidly advancing field.

High-frequency electrical stimulation (deep brain stimulation (DBS)) of the thalamus and basal ganglia (subthalamic nucleus, internal segment of the globus pallidus) is used to treat motor disorders arising in Parkinson’s disease, multiple sclerosis, and essential tremor. Although clinically effective, the mechanisms of action of DBS are unknown. A number of plausible hypotheses have been offered, however, until the effects of the applied current on the surrounding neurons are understood, it will prove difficult to determine the underlying mechanisms. Computational models of central neurons were used to determine what neural elements are activated by extracellular stimulation. Thresholds for activation of local cells and axons of passage were similar with conventional stimuli. With electrodes positioned over the cell body, action potential initiation invariably occurred in the axon. As a result, activity generated by extracellular stimulation could vary between the soma and axon of the same neuron. Additionally, extracellular chronaxie times were insensitive to the neural element (cell versus axon) that was stimulated. The non-specific activation that occurs with conventional stimuli complicates the determination of the mechanisms of action and may contribute to side effects. Novel asymmetrical stimuli were developed that enable selective stimulation of different populations of neural elements. Understanding the effects of extracellular stimulation on central neurons will limit the plausible hypotheses to explain the effects of DBS, and lead to new stimulation technologies that will improve clinical efficacy.