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.

It has been demonstrated in juvenile rodents that the inhibitory neurons of the nucleus reticularis thalami (NRT) communicate with each other via connexin 36-based electrical synapses. However, whether functional electrical synapses persist into adulthood is not fully known. Here we show that in the presence of the metabotropic glutamate receptor agonists, either trans-ACPD (100 μM) or DHPG (100 μM), 15% of neurons in slices of the adult cat NRT maintained in vitro exhibit stereotypical spikelets with several properties that indicate that they reflect action potentials that have been communicated through an electrical synapse. In particular, these spikelets (1) display a conserved, all-or-nothing waveform with a pronounced after-hyperpolarization (AHP), (2) exhibit an amplitude and time to peak that are unaffected by changes in membrane potential, (3) always occur rhythmically with the precise frequency increasing with depolarization, and (4) are resistant to blockers of conventional, fast, chemical synaptic transmission. Thus, these results indicate that functional electrical synapses in the NRT persist into adulthood where they are likely to serve as an effective synchronizing mechanism for the wide variety of physiological and pathological rhythmic activities displayed by this nucleus.

Anterior thalamic lesions are thought to produce ‘covert pathology’ in retrosplenial cortex, but the causes are unknown. Using microarray analyses we tested the hypothesis that thalamic damage causes a chronic, hypofunction of metabolic and plasticity-related pathways (Experiment 1). Rats with unilateral, anterior thalamic lesions were exposed to a novel environment for 20 min, and granular retrosplenial tissue sampled from both hemispheres 30 min, 2 hours and 8 hours later. Complementary statistical approaches (analyses of variance, predictive patterning and gene set-enrichment analysis) revealed pervasive gene expression differences between retrosplenial cortex ipsilateral to the thalamic lesion and contralateral to the lesion. Selected gene differences were validated by QPCR, immunohistochemistry (Experiment 1) and in situ hybridization (Experiment 2). Following thalamic lesions, the retrosplenial cortex undergoes profuse cellular transcriptome changes including lower relative levels of specific mRNAs that are involved in energy metabolism and neuronal plasticity. These changes in functional gene expression might be driven largely by decreases in the expression of genes encoding transcription factors including brd8, c-fos, fra-2, klf5, nfix, nr4a1, smad3, smarcc2 and zfp9, with far fewer (nfat5, neuroD1 and RXRγ) showing increases. These findings have implications for conditions such as diencephalic amnesia and Alzheimer's disease in which both anterior thalamic pathology and retrosplenial cortex hypometabolism are prominent.

Layer 4 of the mouse somatosensory (barrel) cortex has a diversity of interneuron cell types. Tonic inhibition in other regions is cell type-specific and mediated, in part, by δ-subunit containing, extrasynaptic, GABAA receptors. We have investigated tonic inhibition in LTS cells, a major type of inhibitory neuron, and excitatory cells in layer 4 of the mouse barrel cortex using 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridine-3-ol (THIP), a superagonist of these receptors. Bath application of 20 µM THIP produced baseline shifts, which indicates activation of tonic inhibition of both excitatory and LTS cells. The baseline shift was significantly larger in LTS cells. This finding of greater induced current in LTS cells was paralleled by a significantly greater increase in conductance with THIP application in LTS cells. The increase in conductance resulted in LTS cells requiring more current to reach threshold. Because of the differential effects of tonic inhibition on LTS cells and excitatory cells, bath application of THIP increased the network excitability, measured by multi-unit recordings. Thus, the network effect of tonic inhibition in horizontal layer 4 circuits is a paradoxical increase in excitation.

Mechanisms underlying seizure cessation remain elusive. The Lennox-Gastaut syndrome, a severe childhood epileptic disorder, is characterized by episodes of seizure with alternating epochs of spike-wave and fast run discharges. In a detailed computational model that incorporates extracellular potassium dynamics, we studied the dynamics of these state transitions between slow and fast oscillations. We show that dynamic modulation of synaptic transmission can cause termination of paroxysmal activity. An activity-dependent shift in the balance between synaptic excitation and inhibition towards more excitation caused seizure termination by favoring the slow oscillatory state, which permits recovery of baseline extracellular potassium concentration. We found that slow synaptic depression and change in chloride reversal potential can have similar effects on the seizure dynamics. Our results indicate a novel role for synaptic dynamics during epileptic neural activity patterns.

Neuroanatomical tracers were injected into two functionally distinct areas in the lateral sulcus of macaque monkeys, the parietal ventral area (PV) and the second somatosensory area (S2). Three of the four injection sites were electrophysiologically determined by defining the receptive fields of neurons at the injection site prior to the placement of the anatomical tracers. Additionally, all locations were confirmed myeloarchitectonically. Labeled cell bodies and axon terminals were identified in the ipsilateral dorsal thalamus and related to nuclear boundaries in tissue stained for cytochrome oxidase (CO) and Nissl substance. Our results indicate that PV receives substantial input from the inferior division of the ventral posterior nucleus (VPi), the anterior pulvinar (Pla), and from the ventral portion of the magnocellular division of the mediodorsal nucleus (MDm), which also is interconnected with prefrontal cortex, the entorhinal cortex and the amygdala. S2 receives input predominantly from VPi, the ventral posterior superior nucleus (VPs), and Pla. These results indicate that PV and S2 are involved in processing inputs from deep receptors in the muscles and joints. Because PV and S2 receive little if any cutaneous input from the thalamus, cutaneous input to these fields must arise mainly through cortical connections. Connectional data supports the proposition that PV and S2 integrate motor and somatic information necessary for proprioception, goal directed reaching and grasping and tactile object identification. Further, PV may play a role in tactile learning and memory.

Neurophysiological studies at the cellular level (microelectrode unit activity recordings and local field potentials) as well as electro- and magnetoencephalographic recordings provide converging evidence for a thalamocortical dysregulation at the source of chronic neurogenic pain of both peripheral and central origin. These indicate an increase of low frequency thalamocortical rhythmicity originating in disfacilitation of thalamic relay neurons, followed by cortical activation due to asymmetries of corticocortical inhibition. This process, called thalamocortical dysrhythmia, might become self-sustained and, thus, chronic due to recurrent thalamoreticulothalamic and corticoreticulothalamic feedback inhibition. Our surgical approach is centered on re-establishment of normal thalamocortical oscillatory activity using small, strategically placed medial thalamic and prethalamic lesions. These reduce the increased low frequency thalamocortical recurrent network activity via low frequency desamplification and thalamic disinhibition, providing long term therapeutic efficiency coupled with sparing of the specific thalamocortical loops.

This physiopathological framework should be helpful when considering differential mechanisms and treatment modalities for different types of chronic pain. It underscores the risks of any surgical procedure aiming at reducing further the activation of specific thalamic relay cells and, thus, increasing thalamic disfacilitation and dysrhythmic pain mechanisms. In addition, the normal low frequency generation by activation of the paralimbic and high order association networks provides, in the context of a well established thalamocorticothalamic divergent and, thus, interactive organization, a basis for understanding the relevance of the conceptual-affective internal environment in the maintenance and amplification of many chronic neurogenic pain situations.

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.

AMPA receptors mediate fast synaptic transmission at collateral synapses of corticothalamic and thalamocortical axons in the thalamic reticular nucleus (RTN). These synapses are important in generating synchrony in the thalamocortical network. Whole cell recording in the mouse thalamocortical slice preparation was combined with high-resolution immunoelectron microscopy to characterize AMPA-mediated conductances at the two synapses and to correlate these with differential expression of GluR3 and GluR4 subunits. Thalamocortical collateral (TC) synapses had larger mean EPSC amplitudes (1914 ± 1814pS) than corticothalamic (CT) synapses (400 ± 257 pS), and rise and decay times of TC EPSCs were faster and less variable than CT EPSCs, probably reflecting proximal and dispersed locations of TC and CT terminals, respectively, on RTN cells. In situ hybridization and immunocytochemical studies revealed that GluRl and GluR2 subunits are not expressed in the RTN and GluR4 subunits are expressed at higher levels than GluR3 subunits. Immunoelectron microscopy revealed gold particles representing GluR3 or GluR4 subunits concentrated at single postsynaptic densities (PSD) characteristic of CT synapses and at the two to seven split PSD segments characteristic of TC synapses. At CT synapses the number and density of GluR4 particles were 2.5 times greater than GluR3 particles. At the larger TC synapses, the number of GluR3 particles exceeded that of GluR4 particles but density of GluR4 particles was lower than at CT synapses while density of GluR3 particles was similar. Despite enrichment of GluR4 subunits at CT synapses, larger conductances prevailed at thalamocortical collateral synapses, probably reflecting both larger overall numbers of AMPA receptors and a greater number of release sites represented by the split PSDs. Variability in amplitudes of TC EPSCs may reflect variability in the number of release sites; lower variability in CT EPSC amplitudes may reflect a more constant number of release sites.

We have studied circuit activities in layer IV of rat somatosensory barrel cortex that contains microgyri induced by neonatal freeze lesions. Structural abnormalities in GABA-containing interneurons are present in the epileptogenic paramicrogyral area (PMG). We therefore tested the hypothesis that decreased postsynaptic inhibition within barrel microcircuits occurs in the PMG and contributes to epileptogenesis when thalamocortical afferents are activated. In thalamocortical (TC) slices from naïve animals, single electrical stimuli within the thalamic ventrobasal (VB) nucleus evoked transient cortical multi-unit activity lasting 65 ± 42 msec. Similar stimuli in TC slices from lesioned barrel cortex elicited prolonged (850 ± 100 msec) paroxysmal discharges that originated in the PMG and propagated laterally over several mm. The duration of paroxysmal discharges were shortened by ∼70% when APV was applied and were abolished by CNQX. The cortical paroxysmal discharges did not evoke thalamic oscillations. Whole-cell patch-clamp recordings show that there is a shift in the balance of TC-evoked responses in the PMG that favors excitation over inhibition. Dual, whole-cell recordings in layer IV of the PMG indicated that selective loss of inhibition from fast-spiking interneurons to spiny neurons in the barrel circuits is likely to contribute to unconstrained cortical recurrent excitation with generation and spread of paroxysmal discharges.

Having shown a decrease in muscarinic M1 receptors in Brodmann’s area (BA) 9 from subjects with schizophrenia we have extended our studies to determine if this receptor is decreased in the thalamus from the same cohort of subjects. Levels of [3H]pirenzepine binding to and mRNA encoding for M1 and M4 receptors were measured throughout the thalamus. Levels of M1 and M4 receptor proteins were measured in the mediodorsal nucleus. Two-way ANOVA revealed a variance in [3H]pirenzepine binding (F = 4.69, d.f. = 1.190, P = 0.03), but there was no significant change in radioligand binding in any thalamic region in schizophrenia. Neither levels of mRNA encoding the thalamic M1 or M4 receptor nor levels of M1 or M4 receptor protein in the mediodorsal nucleus differed between the schizophrenic and control subjects. We therefore conclude that the M1 and M4 receptor are not altered in the thalamus from subjects with schizophrenia. These data add weight to the hypothesis that changes in M1 receptors in selective regions of the CNS are associated with the pathology of schizophrenia.

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.

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.

Recent work on the visual thalamic relays provides two key properties reviewed here. First, ∼95% of input to lateral geniculate relay cells is non-retinal and dynamically modulates the relay based on behavioral state, including attention. Part of this relates to control of a voltage-gated, low-threshold Ca2+ conductance that controls the relay cell response mode (tonic or burst). Second, the lateral geniculate nucleus and pulvinar are examples of two relay types: the former is a first order relay, transmitting subcortical (retinal) information, while the latter is mostly a higher order relay, transmitting information from layer 5 of one cortical area to another. Higher order relays seem to be important to corticocortical communication, which challenges the dogma that such communication is based on direct cortico–cortical connections. Other examples of first order and higher order relays also exist. Interesting differences in functional circuitry between first and higher order thalamic relays are beginning to accumulate, which indicate extramodulatory functions for higher order relays. Thus, the thalamus provides a behaviorally relevant, dynamic control over the nature of information relayed, and also plays a key role in basic cortico–cortical communication.

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.

Ca2+-dependent inactivation of Ca2+ channels represents a feedback mechanism to limit the influx of Ca2+ into cells. Since large Ca2+ transients are present in thalamocortical relay neurons and Ca2+-dependent mechanisms play a pivotal role for thalamic physiology, the existence of this inactivation mechanism and the involvement of different Ca2+ channel subtypes was investigated. The use of subtype-specific antibodies revealed the expression of α1A–α1E channel proteins on the cell body and proximal dendrites of acutely isolated cells from the rat dorsolateral geniculate nucleus (dLGN). In addition, subtype-specific channel blocking agents were used in whole cell patch clamp experiments: nifedipine (1–5 μM; L-type) blocked 35 ± 3%, ω-conotoxin GVIA (1 μM; N-type) blocked 27 ± 8%, and ω-conotoxin MVIIC (4 μM; P/Q-type) blocked 33 ± 5% of the total HVA Ca2+ current. The blocker-resistant current constituted about 12 ± 3% of the total Ca2+ current. The degree of Ca2+ current inactivation was assessed by using a two-pulse protocol. Under control conditions the post-pulse I/V was U-shaped with 35 ± 4% of the current undergoing inactivation. Inclusion of BAPTA to the internal pipette solution reduced the degree of inactivation to 15 ± 1%. When L- and P/Q-type current was blocked, the degree of inactivation was lowered to 20 ± 2 and 27 ± 3%, respectively. In the presence of ω-agatoxin TK (35 ± 6%) and ω-conotoxin GVIA (32 ± 1%) there was no change in inactivation. These data suggest that Ca2+-dependent inactivation is involved in the fine tuning of Ca2+ entry into relay neurons mediated by L- and Q-type channels locally operated by Ca2+ beneath the plasma membrane.

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl-D-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow.

Anesthetics are used extensively clinically and in research. However, the mechanisms by which anesthetics act to produce the desired end-points of unconsciousness, amnesia and immobility are only beginning to be understood. Recent evidence indicates that the immobilizing effect of anesthetics occurs largely in the spinal cord, whereas it is assumed that the sedative and amnesic actions occur in the brain. Our recent studies, however, indicate that anesthetics exert an indirect, spinal effect on reticulo-thalamo-cortical mechanisms of arousal and, thus, might affect consciousness and memory. These data are consistent with reports of reduced anesthetic requirements for sedation during neuroaxial blockade by spinal anesthesia. The presumed mechanism is decreased afferent impulses to the brain, which reduces arousal and, thereby, reduces sedative requirements. We have used the complementary approaches of single-unit recording and intracranial electrical stimulation to investigate the effects of a common inhaled anesthetic, isoflurane, on reticulo-thalamo-cortical arousal in a goat preparation. The excitatory responses of single neurons in the midbrain reticular formation (MRF) to noxious somatic stimulation are significantly attenuated when the concentration of systemically delivered isoflurane was increased above 1 MAC (the minimum alveolar concentration required to prevent coordinated movement in response to a noxious stimulus), in parallel with a loss of stimulus-evoked desynchronization of the cortical electroencephalogram (EEG). Part of this depressant effect is mediated indirectly in the spinal cord because selectively reducing the concentration of isoflurane delivered differentially to the spinal cord enhances MRF neuronal responses and cortical arousal. In goats anesthetized with isoflurane at ∼1 MAC, electrical stimulation at distinct sites, including the MRF, peduncolopontine tegmentum (PTT), and medial/intralaminar thalamus, elicits desynchronization of the cortical EEG. Increasing the concentration of isoflurane above 1 MAC abolished this effect. In goats prepared for differential delivery of anesthetic to the cranial and torso (spinal) circulations, electrical stimulation in the medial thalamus elicits greater cortical desynchronization at lower currents when the concentration of isoflurane delivered to the spinal cord is reduced while maintaining the cranial isoflurane concentration ≥1 MAC. These results indicate that the depressant effect of isoflurane anesthesia on spinal somatosensory transmission indirectly influences the threshold for reticulo-thalamo-cortical arousal.

Thalamic relay neurons have homogeneous, adult-like firing properties and similar morphology by 12 days postnatally (PN 12). Parafascicular (Pf) neurons have a different morphology compared with typical thalamic relay neurons, but the development of their electrophysiological properties is not well studied. Intracellular recordings in PN 12–50 Pf neurons revealed several heterogeneous firing patterns different from those in thalamic relay neurons. Two types of cells were identified: Type I cells displayed a fast afterhyperpolarization (AHP) followed by a large-amplitude, slow AHP; whereas Type II cells had only a fast AHP. These cell types had overlapping membrane properties but differences in excitability. Some properties of Pf neurons were adult-like by PN 12, but, unlike thalamic relay neurons, there were significant maturational changes thereafter, including decreased action potential (AP) duration, increased fast AHP amplitude and increased excitability. Pf neurons did not exhibit rhythmic bursting and generally lacked low-threshold spike (LTS) responses that characterize thalamic relay neurons. Pf neurons exhibited non-linear I-V relationships, and only a third of the cells expressed the time and voltage-dependent hyperpolarization activated (Ih) current, which declined with age. These results indicate that the morphological differences between Pf neurons and typical thalamic relay neurons are paralleled by electrophysiological differences, and that Pf membrane properties change during postnatal development.

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.