The interplay between the intrinsic properties of thalamocortical (TC) neurons and synaptic potentials was investigated in vivo, in decorticated and intact-cortex cats, as well as in computational models to elucidate the possible mechanisms underlying the disruption of the spindle oscillation, a network phenomenon. We found that the low-threshold spikes (LTSs) in TC neurons were graded in their amplitude and latency to peak when elicited by current pulses or synaptic potentials from physiological levels of hyperpolarization. IPSPs could either delay or shunt the LTSs. Although the onset of spindles was rhythmic and did not include rebound LTSs, the end of spindles was highly aperiodic suggesting that desynchronization could contribute to the spindle termination. The desynchronization could have several sources, the main of which are (a) intrinsically generated rebound LTSs in TC neurons that occur with different delays and keep thalamic reticular (RE) neurons relatively depolarized, and/or (b) out-of-phase firing of cortical neurons due to intracortical processes that would result in depolarization of both TC and RE neurons. The present study suggests that an active cortical network participates in disrupting the spindle activities. We propose that the progression of spindles contains at least three different phases, with different origins: (a) the onset is generated by RE neurons that impose their activity onto TC neurons, without participation of cortical neurons; (b) the middle part is produced by the interplay between RE and TC neurons, with potentiation from the cortical network; and (c) the waning of spindles is due to the out-of-phase firing of TC and particularly cortical neurons that participate in the spindle termination.

This work is focused on the study of neuronal circuits arising from the rodent caudal intralaminar nuclei and their presumed role on basal ganglia function. Emphasis was placed on the analysis of the architecture of thalamostriatal and thalamo-subthalamic projections in albino rats. Our major interest was to elucidate whether thalamic inputs were related to projection neurons or local circuit neurons within targeted structures (striatum and subthalamic nucleus). Projections coming from the parafascicular nucleus (PF) to the striatum displayed a patchy organization throughout the matrix compartment. These patches are composed by dense terminal axonal arborizations, often containing striatal neurons projecting to the entopeduncular nucleus (ENT) (medial globus pallidus in primates) and neurons projecting to the substantia nigra reticulata (SNR). The thalamostriatal projections under scrutiny were also seen to be in register with all the major classes of striatal interneurons (nitrergic neurons, neurons containing the calcium binding protein parvalbumin (PV) and cholinergic interneurons). Subthalamic neurons projecting to the ENT are the presumed postsynaptic target for fibers coming from the sensorimotor part (dorsolateral) of the PF. In summary, glutamatergic axons arising from the PF might exert a dual control of the striatal output, either by directly exciting striatal projection neurons or indirectly by means of a previous synaptic contact onto an striatal interneuron which in turn modulates the activity of projection neurons. Furthermore, thalamic inputs can also gain access to basal ganglia output nuclei via subthalamo-pallidal projecting neurons, neurons receiving glutamatergic thalamo-subthalamic projections. Thus, activation of either circuit has an opposite physiological effect on the basal ganglia output nucleus. Taken together, these data suggest that the PF may influence neuronal activity in the direct and indirect circuits and could be considered as an additional component of the basal ganglia motor loops.

We studied the synchronous cortical and thalamic activities induced by low (0.5–1 mM) and high (50–100 mM) concentrations of the K+ channel blocker 4-aminopyridine (4AP) in a rat thalamocortical preparation. The presence of reciprocal thalamocortical connectivity was documented by diffusion of the fluorescent tracer Di-IC18 between the somatosensory cortex and the ventrobasal complex (VB) of the thalamus in vitro. Functional reciprocal connectivity was also demonstrated by stimulating the cortical middle-deep layers (which elicited orthodromic responses in VB) or the VB (which induced orthodromic and antidromic responses in the cortex). Spontaneous field potentials were not recorded in either the thalamus or cortex in control medium. Low concentrations of 4AP produced local spindle-like rhythmic oscillations in cortex and VB (duration = 0.4–3.5 s; frequency = 9–16 Hz). In contrast, high concentrations of 4AP induced widespread ictal-like epileptiform discharges (duration = 8–45 s) characterised by lsquo ‘tonic’ component followed by a period of ‘clonic’ discharges in both cortex and VB. Spindle-like activity was abolished in cortex and thalamus by applying the excitatory amino acid receptor antagonist kynurenic acid in VB. In contrast, the same procedure exacerbated ictal-like discharges, while depressing VB activity. Our results indicate that thalamus and cortex can produce synchronous activities in this in vitro thalamocortical network: spindle-like rhythmic oscillations are generated at the thalamic level and imposed upon the cortical network whereas ictal-like discharges have a cortical origin and are modulated by the thalamic network activity. In addition, we have shown that it is possible to preserve reciprocal projections between cortex and thalamus in an in vitro rat slice preparation that could be a valuable tool to study epileptic-prone rat strains.

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.

Reactualization of the medial thalamotomy, performed since the fifties in cases of neurogenic pain, has been guided by the discovery of low threshold calcium spike bursts at frequencies in the delta-theta range in the posterior part of the central lateral (CL) nucleus. This thalamic rhythmicity is transmitted to the cortex through thalamocortical resonant properties, giving rise to the thalamocortical dysrhythmia, proposed to be the mechanism of neurogenic pain as well as other central nervous system (CNS) dysfunctions. Magnetic resonance- and microelectrode-guided stereotactic CL thalamotomy was implemented in 96 patients suffering from chronic therapy-resistant peripheral or central neurogenic pain (mean age: 56 ± 15 years; pain duration before surgery: 7.5 ± 8 years). At a mean follow-up of 3 years, 9 months ± 2 years, 9 months, 53% of the patients benefited from a relief superior to 50% (complete relief in 18.7%). Further analysis of the results demonstrated a significant difference between patients suffering from intermittent as compared with continuous pain. Patients with continuous pain showed only a mean relief of 20.4 ± 25.8% in contrast to the 66 ± 39.2% obtained for patients with intermittent (episodic or paroxysmal) pain manifestations. This was confirmed by the pre- and postoperative visual analogue scale scores showing a significant decrease (59.2%) only in the patient group with intermittent pain. Allodynia was suppressed in 57.3% of the patients. Parameters such as the preoperative pain duration or the site of the causal lesion did not affect the surgical outcome. In 28 patients suffering from unilateral continuous pain, the addition of an ipsilateral CL thalamotomy provided a further significant pain relief. A suppression of drug intake was observed in 31.6% of the patients. Complications occurred in 11.5% of the patients and led to a long term significant disability in only one case. In conclusion, CL thalamotomy is a safe neurosurgical option for neurogenic pain, especially for patients suffering from intermittent pain or allodynia. Its limitation in cases of continuous pain indicates the necessity to explore other stereotactic targets outside of the medial thalamus.

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.

Nucleus-specific expression of five gene transcripts related to the inhibitory, gamma-aminobutyric acid (GABA), neurotransmitter system (GABAA receptor subunits αl, α5, β2, γ2, and 67kDa glutamic acid decarboxylase (GAD67)), and of seven transcripts related to the excitatory, glutamatergic, system (GluR2,4–6, NR1 and NR2A, and α-type II calcium/calmodulin-dependent protein kinase (CAMKII-α)), were examined by quantitative in situ hybridization histochemistry in the thalami of brains from normal controls and from patients suffering from schizophrenia. Although there is evidence for cell loss and functional hypoactivity in the thalamus in schizophrenia, it was striking that quantitative levels and expression patterns of the transcripts studied showed only minor differences between schizophrenics and matched controls. Expression patterns of the transcripts had many similarities to the patterns seen in the thalamus of non-human primates. Abundant GABAA-αl, GABAA-(β2, and GABAA-γ2 subunit mRNAs levels were found in most nuclei. Expression levels of the NMDA receptor subunit, NR1, were higher than those seen for NR2A, AMPA (GluR2 and 4) or kainate (GluR5 and 6) receptor subunit mRNAs. Expression of NR2A mRNA was extremely low. CAMKII-α expression was restricted to glutamatergic neurons. Unlike in monkeys, GluR2 subunit mRNA expression was higher than GluR4 expression. These expression patterns form the beginning of a comprehensive database of patterns of gene expression at high resolution in the human forebrain in health and disease.

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.

Voltage-sensitive dye imaging (VDI) of cortical activation patterns generated by electrical stimulation of thalamocortical afferents axons at different frequencies was studied, in vitro, using mouse brain slices. The study demonstrated that thalamocortical afferent axons stimulation could follow frequencies as high as 120 Hz without marked reduction. By contrast the power spectral density amplitude ratio in cortical layer 4 demonstrated a rapidly sigmoidal reduction at frequencies above 60 Hz. Similar findings were obtained with direct cortical afferent axons stimulation that obviated possible interactions at thalamic level. As pre-synaptic afferent field potentials, simultaneously recorded with the VDI at cortical level, followed higher stimulation frequency, it is concluded that cortical activity reduction is secondary to synaptic transmission failure. This interpretation agrees with the result from deep-brain stimulation (DBS) in humans in which high-frequency stimulation produces comparable therapeutic results, as does stereotaxic brain lesioning.

Following earlier stereotactic experiences, we re-explored the possibilities of a therapeutic lesion of the pallidothalamic tract in the fields H1 and H2 of Forel in patients with parkinsonian signs. The physiopathological rationale of the pallidothalamic tractotomy (PTT) is based on the presence in the parkinsonian brain of a state of thalamic overinhibition due to an increased output of the internal pallidum. This causes the development of a thalamocortical dysrhythmia characterized by increased low frequencies in the relevant thalamic and frontal cortical areas. The fields of Forel are strategically placed to control this thalamic overinhibition, as they give passage to the majority of the pallidothalamic fibres. Magnetic resonance- and microelectrode-guided stereotactic PTT was proposed to 21 parkinsonian patients (mean age: 60 ± 10 years; mean Hoehn and Yahr in on-condition: 3.5 ± 1; mean disease duration: 11 ± 5 years). At a follow-up of 14 ± 6 months and in on-medication condition, a significant (P < 0.001) postoperative improvement of the motor part of the UPDRS (64.6%) and of the activities of daily living (ADL; 75.8%) was observed. Rest tremor, on-chorea and rigidity were reduced by 77.9, 92.2 and 82.3%, respectively. Distal and axial hypobradykinesias showed an improvement of 72.9 and 64%, respectively. Gait and postural stability also improved (57.5 and 66%, respectively) but at a lower level of significance (P < 0.005). Voice was not statistically influenced. L-dopa intake was decreased by 52.2% (P < 0.001) and 33% of the patients could be freed from treatment. In conclusion, PTT is an effective treatment for chronic therapy-resistant Parkinson's disease, improving symptoms in both on- and off-conditions.

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.

Disruptions in the thalamocortical circuit have been related to several psychiatric disorders, such as schizophrenia and obsessive-compulsive disorders. The dopaminergic/GABAergic afferents to the limbic thalamocortical circuit originate in the ventral tegmental area (VTA) and play a crucial role in the regulation of the normal cognitive functions mediated by this circuit. Moreover, it has been shown that the dopaminergic modulatory system is altered in schizophrenics. Despite the strong clinical and behavioral evidence of the importance of the thalamocortical circuit and the mesocortical dopamine (DA) system for normal cognitive function, little is known about the basic synaptic interactions between the thalamus and VTA. This research hypothesized that VTA stimulation would evoke DAergic and/or GABAergic-mediated responses in the MD thalamic neurons. Using intracellular recordings in vivo, it was found that VTA stimulation evoked short latency EPSPs in 73% of the recorded MD neurons and IPSPs-like responses in 16% of the MD cells. The nature of the VTA-MD projection was explored using DAergic and GABAergic drugs. It was found that the indirect DAergic agonist amphetamine affects the spontaneous and VTA-mediated responses recorded in the MD thalamus. These results indicate that the VTA projection contributes to the modulation of MD activity and that the disruption of such modulation may be relevant in neuropsychiatry disorders.

A series of 49 cases with difficult to control seizures and non-candidates for ablation of the epileptic focus has been treated with electrical stimulation of the centromedian thalamic nuclei (ESCM).

Selected cases were: (1) epilepsia partialis continua (EPC) (n = 5); (2) partial complex seizures (n = 16); (3) bilateral frontal parasagittal seizures (n = 6); (4) Lennox-Gastaut syndrome (n = 22). All patients had four contact electrodes placed bilaterally through frontal parasagittal burr holes and guided by ventriculograms. Plotting of electrodes on sagittal and frontal sections of the Schaltenbrand and Bailey’s atlas permitted to determine their location. Electrodes were left externalized for periods of weeks to months to carry out the following tests. (1) Recordings of spontaneous seizures occurring during wakefulness and sleep. (2) Electrophysiological confirmation of their position by means of recruiting responses and desynchronization induced by low and high frequency stimulation. (3) Effects of high frequency stimulation on interictal and ictal activities. Electrodes were internalized and connected to a subcutaneous pulse generator programmed for alternating right and left ESCM 1 min ON and 4 min OFF at 60–130 Hz, 0.21–0.45 ms, 3–5 V forward and backward for 24 h per day. Repeated EEG recordings and a calendar of seizures were used for follow-up from 1 to 9 years.

CM paroxysmal discharges followed the initiation of seizures in cortical areas, occurred simultaneously with spike wave (SKW) complexes in cortical areas in Lennox-Gastaut syndrome and preceded the initiation of cortical SKW and clinical seizures in typical absences. Low frequency stimulation (6–8 cps) induced recruiting responses that were associated with those electrodes that produced best seizure control. Good to excellent results were obtained in cases of EPC and Lennox-Gastaut syndrome and on generalized tonic clonic convulsions (GTCs) and atypical absences (AA) with tonic or clonic components.

Consequently, we came to the conclusions that the CM participates in the propagation of most seizure types and also in the genesis of some of them and that ESCM is a safe and useful alternative for the treatment of some of the most difficult cases of uncontrollable seizures.

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.