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 work of Mircea Steriade demonstrated that the neocortex could synchronize large regions of the thalamus within 10−100 msec. Unlike the synchrony generated by the cortex, the retinal afferents synchronize a restricted group of neighboring thalamic neurons with <1-msec precision. Here, we use a large sample (n = 372) of simultaneous recordings from neighboring neurons in the lateral geniculate nucleus (LGN) to illustrate the high specificity of the synchrony generated by retinal afferents and its dependency on sensory stimulation. First, we demonstrate that cells sharing a retinal afferent show a balanced receptive field diversity: although slight receptive field mismatches are common, the largest mismatches in a specific property (e.g. receptive field size) are restricted to cells that are precisely matched in other properties (e.g. receptive field overlap). Second, we show that these receptive field mismatches are functionally important and can lead to a 5-fold variation in the percentage of synchronous spikes driven by the shared retinal afferent under different stimulus conditions. Based on these and other findings, we speculate that the precise synchronous firing of cells sharing a retinal afferent might serve to amplify local stimuli that might be too brief and small to generate a large number of thalamic spikes.

The interaction between cortical input frequency and intrinsic thalamic neuron (TN) properties were investigated using intracellular recordings from mice TNs in thalamocortical (TC) slices. Excitatory postsynaptic potentials (EPSPs) of corticothalamic (CT) origin were recorded at TN membrane potentials (Vm) held, by current clamp means, between −59 and −55 mV to avoid low-threshold calcium currents (IT) activation. EPSPs elicited in ventrobasal neurons (n = 25) by stimulation in the internal capsule showed constant latency, relatively fast rise time (2.9 ± 0.56 ms) and short duration (26.6 ± 9.11 ms). EPSPs evoked by threshold stimulation (n = 10) showed similar characteristics (mean rise time, 2.74 ± 0.42 ms; mean duration, 30 ± 8.00 ms). The time course of CT synaptic facilitation was determined using pairs of stimuli. Paired-pulse facilitation (PPF) of CT EPSPs peaked at 25–30 ms stimulus intervals and decayed exponentially with an average time constant of 130 ms (n = 50). Application of the NMDA receptor blocker APV (25 μM, n = 4) did not modify PPF for any interstimulus interval studied but suppressed frequency facilitation evoked by trains of CT stimuli. We compared the number of spikes per stimulus (Fs) evoked in TNs by repetitive CT stimulation over a range of frequencies at different Vm. At hyperpolarized Vm (below −65 mV) and frequencies of stimulation ≥ 10 Hz, Fs decreased along the train while at depolarized Vm (above −59 mV) Fs increased along the train. Decremental patterns resulted from the activation of IT while facilitatory patterns emerged from superposition of synaptic and intrinsic mechanisms. At hyperpolarized Vm, steady-state Fs was maximal for frequencies ≤ 2 Hz, intermediate for frequencies between 2 and 10 Hz and zero at ≥ 10 Hz. At depolarized Vm, steady-state Fs increased with increasing frequencies (from 1 to 40 Hz).

We conclude that the CT–TN junctions are tuned to establish stable thalamocortical resonant dynamics.

This paper provides an overview of the major organizational features of the basal ganglia and related thalamic centers, as delineated by the application of single-axon or single-cell labeling procedures in primates. These studies have revealed that the striatum, the external pallidum and the subthalamic nucleus harbor several types of projection neurons endowed with a highly collateralized axon that allows these neurons to interact with most components of the basal ganglia. In contrast, the internal pallidum, which is a major output structure of the basal ganglia, contains only two types of projection neurons. First, there is a minority of “limbic” pallidal neurons with a poorly branched axon that arborized profusely within the lateral habenula, which stands out as the most densely innervated pallidal target. Second, there is a majority of pallidal “motor” neurons with a long (total axonal length up to 27 cm) and highly branched axon that provides collaterals to the ventral tiers thalamic nuclei, the brainstem pedunculopontine nucleus and the centre médian/parafascicular thalamic complex. This type of axon allows internal pallidal neurons to send efferent copies of the same information to the thalamus and brainstem and hence influence various neuronal systems scattered throughout the neuraxis. Pallidal information is conveyed to the cerebral cortex and the striatum via the thalamus, while it is projected back to different components of the basal ganglia via the numerous reentrant pathways that arise from the pedunculopontine nucleus. Virtually all neurons in the centre médian thalamic nucleus innervate massively the striatum and less prominently the primary motor cortex, which in turn projects to the striatum directly or via a collateral from long-range corticofugal pyramidal axons. The results call for a reappraisal of our current concept of the anatomical and functional organization of basal ganglia, which play a crucial role in sensorimotor integration. Our data indicate that basal ganglia and related thalamic nuclei form a widely distributed neuronal network, whose elements are endowed with a highly patterned set of axon collaterals. This morphological feature allows a complex and exquisitely precise interaction between the various basal ganglia and related thalamic nuclei. The elucidation of this finely tuned network is needed to understand the complex spatiotemporal sequence of neural events that ensures the flow of cortical information through the basal ganglia and thalamus.

The P50 potential is a midlatency auditory evoked response which is sleep state-dependent, habituates rapidly and is blocked by the muscarinic cholinergic antagonist scopolamine. It is thought to be generated, at least in part, by ascending projections of the reticular activating system. The amplitude of the P50 potential can be used as a measure of level of arousal, while the degree of habituation to repetitive stimulation can be used as a measure of sensory gating. We studied these processes in three conditions which show sleep-wake cycle dysregulation and attentional disturbance, but differ greatly in their etiology, depression, Huntington’s disease and rotation-induced motion sickness. Subjects with depression and rotation-induced motion sickness showed significant decreases in the habituation of the second of paired evoked responses, while Huntington’s disease subjects showed decreased amplitude as well as decreases in the habituation of the second P50 potential. This waveform may represent the manifestation of pre-attentional processes, and may become a useful measure for monitoring the severity, progression and/or remission of disorders which affect these processes.

Postmortem and in vivo imaging studies have revealed structural and functional pathology in the thalamus in schizophrenia. We have reported a series neurochemical changes in the thalamus in schizophrenia, including decreased expression of NMDA receptor subunit transcripts and increased levels of NMDA receptor-associated intracellular proteins like postsynaptic density protein 95 (PSD95) and neurofilament-light (NF-L) chain that link the NMDA receptor to downstream signal transduction pathways. NF-L, along with the neurofilament subunit proteins NF-medium (NF-M) chain and NF-heavy (NF-H) chain, assemble to form neurofilaments, one of the most abundant cytoskeletal elements. While the neurofilament subunits play a crucial role in sustaining the neuronal cytoskeleton, two subunits, NF-L and NF-M, also participate in neurotransmission, interacting with the NMDA and the dopamine Dl receptors, respectively. In the present study, using in situ hybridization, we determined whether all of the neurofilament subunits (NF-L, NF-M, and NF-H) are abnormally expressed in the thalamus in schizophrenia, or whether the abnormality is specific to NF-L. We found that NF-L and NF-M transcripts are both increased in schizophrenia, but the expression of NF-H is unchanged. Both NF-L and NF-M play an important role in maintaining the neuronal cytoskeleton, so abnormal transcript expression may be associated with structural thalamic pathology. Alternatively, since these proteins are also known to interact with the NMDA and Dl dopamine receptors, abnormal transcript levels may be associated with abnormalities of neurotransmission in the thalamus in schizophrenia.

Chronic pain is an immense, unsolved, clinical problem. Current approaches to this condition are limited by uncertainty about mechanisms of acute and chronic pain in humans. Although much progress has been made toward understanding peripheral neural mechanisms of human nociception, we have a poor understanding of CNS pain mechanisms. Here, we review the anatomy and physiology of the ascending spinal pathways and supraspinal centers with pain-related activity. This review focuses on the primate nervous systems because there are significant differences between pain transmission in primates and other species such as cats and rats.

The terminals formed by the corticothalamic axons are of two types, small and giant endings. This dual mode of corticothalamic projection has been found to be consistent across species (mouse, rat, cat, monkey) and across systems (visual, auditory, somatosensory and motor). In the monkey, this dual mode of projection has been demonstrated for the motor system in the case of the primary motor cortical area, the supplementary motor area and the caudal part of the dorsal premotor cortex. Based on biotinylated dextran amine anterograde tracing experiments, a similar dual mode of termination morphology was found here for corticothalamic axons originating from the other three distinct sub-divisions of the premotor cortex. Furthermore, the pattern of arrangement of giant endings originating from the premotor cortex was found to be similar to that from the supplementary motor area but different to that from the primary motor cortex.

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.

The anterior thalamic nuclei are a key link in pathways associated with emotions and memory. In the preceding study we found that one of the anterior nuclei, the anterior medial (AM), had particularly robust connections with specific medial prefrontal and orbitofrontal cortices and moderate connections with frontal polar cortices. The goal of this study was to use a direct approach to determine the sources of projections to the AM nucleus from all prefrontal cortices, as well as from temporal structures and the hypothalamic mammillary body, known for their role in distinct aspects of memory and emotion. We addressed this issue with targeted injections of retrograde fluorescent tracers in the AM nucleus to determine its sources of input.

Projection neurons directed to the AM nucleus were found in the deep layers of most prefrontal cortices (layers V and VI), and were most densely distributed in medial areas 24, 32 and 25, orbitofrontal areas 13 and 25, and lateral areas 10 and 46. Most projection neurons were found in layer VI, though in medial prefrontal cortices and dorsal area 9 about a third were found in layer V, a significantly higher proportion than in lateral and orbitofrontal cortices. In the temporal lobe, projection neurons originated mostly from the hippocampal formation (ammonic field CA3 and subicular complex), and the amygdala (basolateral, lateral, and basomedial nuclei). In the hypothalamus, a significant number of neurons in the ipsilateral medial mammillary body projected to the AM nucleus, some of which were positive for calbindin (CB) or parvalbumin (PV), markers expressed, respectively, in “diffuse” and “specific” pathways in the thalamus [Adv. Neurol. 77 (1998a) 49]. As recipient of diverse signals, the AM nucleus is in a key position to link pathways associated with emotions, and may be an important interface for systems associated with retrieval of information from long-term memory in the process of solving problems within working memory. Finally, the internal segment of the globus pallidus (GPi) issued projections to AM, suggesting direct linkage with executive systems through the basal ganglia. The diverse connections of the AM nucleus may help explain the varied deficits in memory and emotions seen in neurodegenerative and psychiatric diseases affecting the anterior thalamic nuclei.

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl-D-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

We compared the developmental periods in the mouse when projections from the two eyes become segregated in the dorsal lateral geniculate nucleus with the time when this nucleus becomes innervated by cholinergic fibers from the brainstem. Changes in labeling patterns of different tracers injected into each eye revealed that segregation of retinogeniculate inputs commences at postnatal day five (P5) and is largely complete by P8. Immunocytochemical staining showed that cholinergic neurons are present in the parabrachial region of the brain stem on the day of birth. However, cholinergic fibers are not evident in the geniculate until P5, and these are sparse at this age, increasing in density to form well-defined clusters by P12. These results indicate that segregation of eye-specific projections during normal development is unlikely to be regulated by cholinergic inputs from the brainstem.

In a systematic study of thalamocortical relay neuron responses to sinusoidal current injection [J. Neurophysiol. 83 (1), 588], we found that the Fourier fundamental of tonic responses was regularly phase advanced during low temporal frequency stimulation (1/10 cycle at 0.1 Hz). We hypothesized that such phase advances of the Fourier fundamental response were due to a slow spike-frequency adaptation. Here we measure the time-dependence of the instantaneous firing rate during a current pulse protocol, confirm the presence of a slow spike-frequency adaptation, and quantify the adaptation time constant (0.6–2.0 s) and percentage adaptation of spike rate (40–60%). In light of these results, we augment a previously reported minimal integrate-and-fire-or-burst (IFB) neuron model with an adaptation current. When the parameters for this current are fit using a quantitative theory of spike-frequency adaptation [J. Neurophysiol. 79, 1549], the IFB model reproduces the experimentally observed phase advance of the Fourier fundamental response during sinusoidal current injection. Using fast-slow variable analysis, we develop a firing-rate reduction of the IFB model and perform parameter studies to investigate the dependence of the Fourier fundamental response (amplitude and phase) on the maximum conductance and recovery time constant for the adaptation current. Analytical calculations clarify the relationship between dc and ac measures of the suppression of response due to spike-frequency adaptation, show how the latter depends on stimulation frequency, and confirm the adaptation-induced phase advance of the Fourier fundamental observed in both experiment and simulation.

The goal of the present study was to determine if the medial agranular cortex (AGm) that is thought to contain the supplementary motor area in the rat receives the pallidothalamocortical pathway. A double labeling paradigm was employed whereby injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) into the entopeduncular nucleus (EN) were combined with injections of the retrograde tracer cholera toxin subunit B into either the rostral or caudal part AGm in the rat. We found that the pallidothalamic projections occupied a crescent shaped arc within the thalamic ventral anterior-ventral lateral nuclear complex (VAL) and ventral medial nucleus (VM). Additional efferents projected to LD/LP, MD, Pf and CL. Dense projections were also found to LHb. In addition, we found that a wide band of cells extending from rostral thalamus including VAL and VM through caudal thalamus including MD, Po, LD/LP, Pf and CL projected to either the rostral or caudal parts of the AGm. The greatest coincidence of the pallidothalamic efferents and AGm thalamocortical cells was found in VAL and VM where numerous PHA-L varicosities were found in close apposition to CTB labeled cells. Synaptic contacts between VAL thalamocortical neurons and pallidal terminals were verified in the electron microscope. These results demonstrate for the first time the pallidothalamocortical pathway by way of VAL to the AGm in the rat.

Previous studies have demonstrated that peripheral inflammation leads to long-term increases in spinal dorsal horn neuronal excitability (i.e. central sensitization) and behavioral hyperalgesia that is mediated by glutamate receptor activation. The present study has examined spinal cord changes in serine phosphorylation of the NMDA receptor NR1 and AMPA receptor GluR1 subunits after peripheral inflammation. Using site-specific antibodies, Western blots showed a significant increase in phosphorylation at serine residues 896 and 897 of the NR1 and at serine residues 831 and 845 of the GluR1 subunits in the rat spinal cord after injection of complete Freund's adjuvant into the hindpaw. For all four serine sites, the increased phosphoserine NR1 and GluR1 levels occurred as early as 10 minutes, lasted for at least 3 days, and returned to control level 7–14 days following inflammation. There was also an increase in total NR1 and GluR1 proteins after inflammation, but with a different time course. The phosphorylation of different serine residues of NR1 and GluR1 depended on input from the injured site. Local anesthesia of the inflamed paw with lidocaine (2%), blocked the increase in phosphoserine 896 (NR1) and phosphoserine 831 (GluR1) with a time course corresponding to the duration of anesthesia. However, the increased phosphoserine 845 (GluR1) was blocked only transiently and the concentration of phosphoserine 897 (NR1) was not affected by local anesthesia. Consistent with previous biochemical analysis, phosphorylation of serine 896 NR1 and serine 831 of GluR1 was blocked by intrathecal chelerythrine (0.01–1 nmol), a PKC inhibitor, and phosphorylation of serine 897 NR1 was blocked by H-89 (0.01–1 nmol), a PKA inhibitor. In addition, there appeared to be an interaction between the PKC and PKA cellular pathways because phosphorylation of serine 897 of NR1, a substrate of PKA, was also blocked by chelerythrine. These findings correlate serine phosphorylation of the NR1 and GluR1 subunits to spinal hyperexcitability and hyperalgesia, and indicate a role of serine phosphorylation of NMDA and AMPA receptors in initiating central sensitization.

Neuropsychiatric surgery has had a long and complex history with examples of less than optimal surgical procedures implemented in wrong settings. Such past errors have raised important philosophical and ethical issues that remain with us for good reasons. However, the existence of enormous suffering due to chronic therapy-resistant disabling neuropsychiatric disorders compels a search for alternative surgical approaches based on a sound understanding of the underlying physiopathological mechanisms. We bring evidence, from single cell physiology and magnetoencephalography, for the existence of a set of neuropsychiatric disorders characterized by localized and protracted low frequency spontaneous recurrent activation of the thalamocortical system. This condition, labeled thalamocortical dysrhythmia, underlies certain chronic psychotic, affective, obsessive compulsive, anxiety and impulse control disorders. Considering the central role of recurrent oscillatory thalamocortical properties in the generation of normal hemispheric functions, we propose a surgical approach that provides a reestablishment of normal thalamocortical oscillations without reduction of cortical tissue and its specific thalamic connectivity. It consists of small strategically placed pallidal and medial thalamic lesions that serve to make subcritical the increased low frequency thalamocortical recurrent network activity. This result is attained via reduction of both thalamic overinhibition and low frequency over-synchronization. Thalamic disinhibition is obtained by a lesion in the anterior medial paralimbic pallidum. The medial thalamic lesion is localized in the posterior part of the central lateral nucleus, where a large majority of cells have been shown to be locked in low frequency production and to have lost their normal activation patterns. We present here our experience with 11 patients, including clinical follow ups and pre- and postsurgical magnetoencephalographic studies. The evidence speaks (1) for a benign and efficient surgical approach, and (2) for the relevance of the patient’s presurgical cognitive and social settings, making them more or less prone to postoperative psychoreactive manifestations upon rekindling of personal goals and social reentry.

Cerebro–cerebellar interactions are becoming progressively more focused in their anatomical substrate but their functional meaning is still elusive. Here, we review current data on the cerebellar influence on cortical function, with special emphasis on the importance of the cerebellar input for cortical processing in primary motor and sensorimotor areas. Differences in the intracortical processing of cerebellar information are described and the possible role of the thalamus in controlling cerebro–cerebellar loops discussed.

Recent findings in two rat models of absence epilepsy, the Wistar Albino Glaxo Rats from Rijswik (WAG/Rij) and the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), support the idea that defects in the function of hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCN1-4) and the resulting membrane current, Ih, in thalamocortical relay neurons are crucially involved in epilepsy. After a developmental evolution the expression of HCN1, which is relatively insensitive to cAMP, is elevated significantly in epileptic rats with no changes in expression of the other isoforms. This is accompanied by a hyperpolarizing shift in Ih activation and reduced sensitivity to cAMP. Thus, modification of thalamic Ih occurs at pre-epileptic stages and seems to be crucial to the development of spike-and-wave-discharges that characterize absence seizures.

The anterior thalamic nuclei occupy a central position in pathways associated with emotions and memory [AMA Arch. Neurol. Psychiatry 38 (1937) 725]. The goal of this study was to determine the anatomic interaction of the anterior nuclei with distinct prefrontal cortices that have been implicated in emotion and specific aspects of memory. To address this issue, we investigated the relationship of input and output zones in the anterior thalamic nuclei linking them with functionally distinct orbitofrontal, medial, and lateral prefrontal cortices. We identified input zones by mapping the pattern and topography of terminations of prefrontal axons, and the output zones by mapping projection neurons in the anterior nuclei, after injection of anterograde and bidirectional tracers in distinct prefrontal cortices.

The results showed that the anterior nuclei were preferentially connected with some orbitofrontal and medial prefrontal areas. In contrast, the anterior nuclei had comparatively sparse connections with most lateral prefrontal cortices, with the notable exception of frontal polar cortex, which had moderate but consistent connections with the anterior nuclei. Prefrontal cortices were connected mostly with the anterior medial nucleus, though medial areas 32 and 25 as well as the frontal polar cortex were also connected with the anterior ventral nucleus. The zones of axonal terminations were more expansive than the sites with projection neurons in the anterior nuclei, suggesting extensive influence of feedback projections from prefrontal cortices. The results suggest that the anterior thalamic nuclei may act in concert with orbitofrontal and medial prefrontal cortices in processes underlying emotions and long-term memory, and with the frontal polar cortex in prospective aspects of working memory.

These studies in fetal monkeys and ferrets show that the two fundamental types of thalamic GABA neuron populate the thalamus during widely separated developmental epochs. Those of the ventral thalamus (VT) and epithalamus (ET) appear very early in conjunction with the GABA cells of the substantia nigra, globus pallidus, and pretectum (PT). GABA neurons intrinsic to the dorsal thalamus (DT) appear later, long after proliferative activity has ceased in the wall of the third ventricle, after dorsal thalamic nuclei have differentiated and at the same time as principal neurons are acquiring a glutamatergic phenotype. The exact origins of the two waves of GABA cells are uncertain but some appear to arrive from extrinsic sources that include the ganglionic eminence (GE) of the basal forebrain.