Both the thalamocortical and limbic systems generate a variety of brain state-dependent rhythms but the relationship between the oscillatory families is not well understood. Transfer of information across structures can be controlled by oscillations. We suggest that slow oscillation of the neocortex, which was discovered by Mircea Steriade, temporally coordinates the self-organized oscillations in the neocortex, entorhinal cortex, subiculum and hippocampus. Transient coupling between rhythms can guide bidirectional information transfer among these structures and might serve to consolidate memory traces.

Behaviorally relevant brain oscillations relate to each other in a specific manner to allow neuronal networks of different sizes with wide variety of connections to cooperate in a coordinated manner. For example, thalamo-cortical and hippocampal oscillations form numerous frequency bands, which follow a general rule. Specifically, the center frequencies and frequency ranges of oscillation bands with successively faster frequencies, from ultra-slow to ultra-fast frequency oscillations, form an arithmetic progression on the natural logarithmic scale. Due to mathematical properties of natural logarithm, the cycle lengths (periods) of oscillations, as an inverse of frequency, also form an arithmetic progression after natural logarithmic transformation. As a general rule, the neuronal excitability is larger during a certain phase of the oscillation period. Because the intervals between these activation phases and the temporal window of activation vary in proportion to the length of the oscillation period, lower frequency oscillations allow for an integration of neuronal effects with longer delays and larger variability in delays and larger areas of involvement. Neural representations based on these oscillations could therefore be complex. In contrast, high frequency oscillation bands allow for a more precise and spatially limited representation of information by incorporating synaptic events from closely located regions with short synaptic delays and limited variability. The large family of oscillation frequency bands with a constant relation may serve to overcome the information processing limitations imposed by the synaptic delays.

The absence epilepsies are characterized by recurrent episodes of loss of consciousness associated with generalized spike-and-wave discharges, with an abrupt onset and offset, in the thalamocortical system. In the absence of detailed neurophysiological studies in humans, many of the concepts regarding the pathophysiological basis of absence seizures are based on studies in animal models. Each of these models has its particular strengths and limitations, and the validity of findings from these models for the human condition cannot be assumed. Consequently, studies in different models have produced some conflicting findings and conclusions. A long-standing concept, based primarily from studies in vivo in cats and in vitro brain slices, is that these paroxysmal electrical events develop suddenly from sleep-related spindle oscillations. More specifically, it is proposed that the initial mechanisms that underlie absence-related spike-and-wave discharges are located in the thalamus, involving especially the thalamic reticular nucleus. By contrast, more recent studies in well-established, genetic models of absence epilepsy in rats demonstrate that spike-and-wave discharges originate in a cortical focus and develop from a wake-related natural corticothalamic sensorimotor rhythm. In this review we integrate recent findings showing that, in both the thalamus and the neocortex, genetically-determined, absence-related spike-and-wave discharges are the manifestation of hypersynchronized, cellular, rhythmic excitations and inhibitions that result from a combination of complex, intrinsic, synaptic mechanisms. Arguments are put forward supporting the hypothesis that layer VI corticothalamic neurons act as ‘drivers’ in the generation of spike-and-wave discharges in the somatosensory thalamocortical system that result in corticothalamic resonances particularly initially involving the thalamic reticular nucleus. However an important unresolved question is: what are the cellular and network mechanisms responsible for the switch from physiological, wake-related, natural oscillations into pathological spike-and-wave discharges? We speculate on possible answers to this, building particularly on recent findings from genetic models in rats.

Sleep deprivation impairs alertness and cognitive performance, and these deficits suggest decreases in brain activity and function, particularly in the prefrontal cortex, a region subserving alertness, attention, and higher-order cognitive processes and in the thalamus, a subcortical structure involved in alertness and attention. To substantiate this premise, we characterized the effects of 24, 48, and 72 h of progressive sleep deprivation on brain activity by assessing regional cerebral metabolic rate for glucose (CMRglu) during complex cognitive task performance in 17 young, normal, healthy male volunteers using positron emission tomography (PET) and l8Fluoro-2-deoxyglucose (18FDG). The results of prolonged sleep deprivation, 48 and 72 h, are reported here. Compared to rested baseline (RB), global CMRglu decreased by 6% at 48 and 72 h sleep deprivation (SD) and approximated the 8% decrease seen at 24 h SD. Absolute and relative regional CMRglu decreased at 48 and 72 h SD primarily in the prefrontal and parietal cortices and in the thalamus, the same areas that showed decreases at 24 h SD. Compared to 24 h SD, relative regional CMRglu decreased further in the prefrontal cortex and dorsal thalamus at 48 and 72 h, and at 72 h SD in a limited area of medial visual cortex. Relative regional CMRglu increased in lateral superior occipital cortices, lingual and fusiform gyri, anterior cerebellum, and in primary and supplementary motor cortices at 48 and 72 h SD, indicating a rebound CMRglu activity response from 24 h SD. Polysomnographic monitoring confirmed that subjects were awake. Behavioral outcomes showed continuing decreases in alertness, cognitive performance, and saccadic velocity (a measure of oculomotor response) with prolonged sleep deprivation. Progressive decreases in relative CMRglu values in prefrontal, thalamic, and primary visual areas were correlated positively with the impairments in cognitive performance and saccadic velocity across the 72 h sleep deprivation period. Relative thalamic activity was also correlated with the alterations in alertness. The prefrontal and thalamic regions were positively correlated, suggesting that sleep deprivation impacted these areas together as a functional network.

We propose that the decreases in CMRglu induced in the prefrontal-thalamic network by prolonged sleep deprivation underlie the decline in alertness and cognitive performance and signify the brain’s involuntary progression toward sleep onset, while the increases in visual and motor areas express the brain’s exertion of voluntary control to remain awake and perform. This exertion of voluntary control is manifest in increased subject effort and physical movement, and the recruitment of additional brain regions may reflect an attempt to sustain alertness and cognitive performance despite a continuing decline in prefrontal-thalamic activity. Our findings provide support for the notion of a specific sensitivity of the prefrontal cortex to, and a pivotal role of the thalamus in, sleepiness.

The transcriptional mechanisms that govern the development and plasticity of somatopic sensory maps in the cerebral cortex have not been studied extensively. In particular, no studies have addressed the role of epigenetic mechanisms in the development of sensory maps. DNA methylation is one of the main epigenetic mechanisms by which mammalian cells regulate gene transcription. Demethylation results in embryonic lethality, so it has been very difficult to study the role of DNA methylation in brain development. We have used cre-loxP technology to generate forebrain-specific deletion of DNA methyltransferase 1 (Dnmt1), the enzyme required for the maintenance of DNA methylation. We find that DNA hypomethylation of neurons in the cerebral cortex results in the failure of development of somatosensory barrel cortex. We also find that, despite functional thalamocortical neurotransmission, thalamocortical long-term potentiation cannot be induced in slices from Emx1-cre;Dnmt1 mutant mice. These studies emphasize the importance of DNA methylation for the development of sensory maps and indicate that epigenetic mechanisms might play a role in the development of synaptic plasticity.

Enlargement of the forebrain, including elaboration of the thalamus, has occurred independently within different groups of vertebrates. Dorsal and ventral thalamic territories can be identified in most vertebrates, with variations in the presence of GABAergic neuronal components. An inhibitory thalamic reticular nucleus-like input to the dorsal thalamus might be a common feature, as might the organizational plan of two divisions of the dorsal thalamus, the lemnothalamus and collothalamus. Differential, independent elaboration of these divisions occurred in mammals and sauropsids (reptiles and birds), making their evolutionary relationships challenging to discern. Not all of the crucial features identified for mammalian thalamocortical circuitry are present in other vertebrates, but birds share the most features identified to date. These include specific and nonspecific thalamic relay neurons, reciprocal pallial projections, and a GABAergic thalamic reticular nucleus with some but not all hodological features. Because birds share many higher-level cognitive abilities and, thus, possibly higher-level consciousness, with mammals, comparison of the thalamocortical (thalamopallial) circuitry might prove a fruitful resource for testing functional hypotheses. Comparisons with selected other vertebrates that likewise have relatively large brain:body ratios and also exhibit some cognitively sophisticated behaviors, such as cichlid fish, might also prove valuable.

Abnormal thalamocortical dynamics have been proposed as the underlying mechanism for a subset of neurological and psychiatric disorders that include centrally generated pain. Spectral analysis and independent component-based localization of neuromagnetic signals reveal ongoing theta-range activity localized to physiologically significant cortical regions in a group of subjects with well-characterized central and peripheral lesions. In addition, recordings from subjects who failed to obtain relief from spinal cord stimulation (SCS) and from those in whom SCS was successful further delineate thalamocortical dysrhythmias as a mechanism that underlies chronic pain.

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.

We simultaneously recorded local field potentials (LFP) in the thalamus and EEG on the scalp of 17 patients suffering from neurogenic pain, epilepsy and movement disorders. The EEG of 11 patients displayed enhanced power in the theta frequency range (4–8 Hz). The thalamic LFP of 14 patients peaked in the theta range. The theta coherence between EEG and LFP was significant for 12 patients and reached strengths up to 70%. These findings suggest that enhanced theta rhythmicity occurs in tight functional thalamocortical loops and is a major element in all three diseases investigated.

To investigate second-order phase-coupling between LFP frequency components, we computed the bicoherence and averaged over the group of patients. We found peaks in the theta band and the beta band (14–30 Hz), indicating phase correlations of oscillatory events in these frequency ranges with their first harmonic. A further peak indicates that phase coupling occurred also between theta and beta frequencies. This indicates a strong functional interaction between the generators of these oscillations. We also computed the cross-correlation between LFP spectral power at different frequencies. Although this measure is independent of phase, we found good agreement with the bicoherence patterns, pointing again to strong interaction between theta and beta rhythmicity. The overproduction of theta rhythms, the thalamocortical coherence and the correlation of theta with beta rhythms are key elements for the understanding of thalamocortical dysrhythmia (TCD).

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.

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 over-inhibition of thalamic relay cells by hyperactivity of the internal part of the globus pallidus is a cornerstone of the parkinsonian pathophysiology that leads to a distortion of the thalamocortical dynamics called thalamocortical dysrhythmia (TCD). Here, we present the results of the stereotactic pallidothalamic tractotomy (PTT), which interrupts selectively the enhanced pallidal output to the thalamus in a restricted location in the fields of Forel. This operation represents a reactualization of Spiegel's campotomy. PTT was offered to 41 patients (66.1±8.5 years) suffering from chronic, therapy-resistant Parkinson's disease. It was performed bilaterally in 21 patients. Forty patients displayed mixed, i.e. tremulent and akinetic parkinsonian signs, and seven had drug-induced dyskinesias. One patient had only rest tremor. The evaluation was based on the Unified Parkinson's Disease Rating Scale (UPDRS) scores, comparing the patients' preoperative medicated state with the state at the last postoperative follow-up. We, thus, tested surgical success in terms of superiority to drug treatment. Mean follow-up was 22.4 months with 15 patients followed for >2 years. Mean improvement was 60% (P<0.001) for UPDRS III and 51% (P<0.001) for UPDRS II. Significant improvement (P<0.001) appeared in subscores for tremor (87%), limb akinesia (58%) and axial akinesia (33%). Improvement of postural stability and gait was at the limit of significance (P<0.05). Improvement of hypomimia and hypophonia did not reach statistical significance. Increase of dysarthria was significant (P<0.01). Intake of L-DOPA was reduced significantly and 21 patients were able to stop intake. Median improvement of the Quality of Life score was 67%. Improvement remained, independent of follow-up length. In conclusion, PTT provides a high, stable level of relief to parkinsonian patients whose condition cannot be controlled with pharmacotherapy. The rationale of the surgical therapy is based on a selective extrathalamic regulation of the parkinsonian TCD.

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.

The anterior thalamus (ATh) is a key structure of the limbic system and serves a direct role in spatial memory. We examined the discharge properties of neurons of the anterior thalamus during states of the hippocampal electroencephalogram (theta and non-theta states). Units were recorded in the anteroventral (AV, n = 96), the anterodorsal (AD, n = 44) and the anteromedial (AM, n = 48) nuclei of the thalamus. The majority of theta-related cells fired at higher rates in the presence than absence of theta (theta-on cells); while a small percentage (∼ 13%) discharge at reduced rates with theta (theta-off cells). Theta-off cells were found in AD and AM but not in AV. Mean discharge rates for theta-on cells during control and theta conditions were 6.0 plusmn; 0.52 and 14.48 plusmn; 0.96 Hz for AV cells; 4.43 plusmn; 1.25 and 10.05 plusmn; 1.28 Hz for AD cells, and 2.60 plusmn; 0.3 and 6.42 plusmn; 0.9 Hz for AM cells. Approximately 40% of AV cells, 21.9% of AD units, and 5.7% of AM cells discharged rhythmically, synchronous with the theta rhythm. A subpopulation of ATh cells fired slightly rhythmicity, but with activity strongly phase-locked to EEG oscillations in the crosscorrelogram, indicating a modulation at theta frequency. Cells were classified as: rhythmic (R), non-rhythmic (N, and intermediate (I) based on quantitative criteria. About 75% of theta-on cells (i.e. R and I cells) showed significant coherence with theta. These cells were distributed throughout the extent of the anterior thalamus. The present findings of theta rhythmic cells in the anterior thalamus, together with previous demonstrations of ‘theta’ cells in other structures of Papez’s circuit, suggests that a theta rhythmic signal may reverberate throughout the circuit, possibly involved in memory processing functions of this limbic network.

It may soon be possible to adapt the use of deep brain stimulation (DBS) technologies developed to treat movement disorders to improve the general cognitive function of brain-injured patients. We outline neurophysiological foundations for novel neuromodulation strategies to address these goals. Emphasis is placed on developing a rationale for targeting the intralaminar and related nuclei of the human thalamus for electrical stimulation. Recent anatomical and physiological studies are compared with original neurophysiological recordings obtained in an alert non-human primate. In this context we consider neuronal mechanisms that may underlie both clinical observations and cognitive rehabilitation maneuvers that provide theoretical support for open and closed-loop strategies to remediate acquired cognitive disability (ACD).

Intrathalamic oscillations related to sleep and epilepsy depend on interactions between synaptic mechanisms and intrinsic membrane excitability. One intrinsic conductance implicated in the genesis of thalamic oscillations is the H-current – a cationic current activated by membrane hyperpolarization. Activation of H-current promotes rebound excitation of thalamic relay neurons and can thus enhance recurrent network activity.

We examined the effects of H-current modulation on bicuculline-enhanced network oscillations (2–4 Hz) in rat thalamic slices. The adrenergic agonist norepinephrine, a known regulator of H-current, caused an alteration of the internal structure of the oscillations – they were enhanced and accelerated as the interval between bursts was shortened. The acceleration was blocked by the β-adrenergic antagonist propranolol. The β-agonist isoproterenol mimicked the effect of norepinephrine on oscillation frequency and truncated the responses suggesting that a β-adrenergic up-regulation of H-current modifies the internal structure (frequency) of thalamic oscillations. Consistent with this, we found that H-channel blockade by Cs+ or ZD7288 could decelerate the oscillations and produce more robust (longer lasting) responses. High concentrations of either Cs+ or ZD7288 blocked the oscillations.

These results indicate that a critical amount of H-current is necessary for optimal intrathalamic oscillations in the delta frequency range. Up- or down-regulation of H-current alter not only the oscillation frequency but also retard or promote the development of thalamic synchronous oscillations. This conclusion has important implications regarding the development of epilepsy in thalamocortical circuits.

This study examines the temporal properties of geniculocortical and corticogeniculate (CG) pathways that link the lateral geniculate nucleus (LGN) and primary visual cortex in the ferret. Using electrical stimulation in the LGN to evoke action potentials in geniculocortical and CG axons, results show that conduction latencies are significantly faster in geniculocortical neurons than in CG neurons. Within each pathway, axonal latency and visual physiology support the view of sub-classes of neurons. By examining the timing of visual responses and the latency of CG feedback, estimates indicate that visual information can reach the cortex and return to the LGN as early as 60 msec following the onset of a visual stimulus. These findings place constraints on the functional role of corticogeniculate feedback for visual processing.

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.

Subthalamic nucleus (STN) neurons have a pivotal role in basal ganglia, as a result of their intrinsic membrane properties, connections within the circuit and glutamatergic nature. Their innate pacemaker activity, consisting of a single-spike tonic mode of discharge, is abolished in the case of hemiballism, profoundly disrupted in the Parkinsonian state and replaced by a regular bursting mode under treatment (high-frequency stimulation, HFS). We propose that control STN activity represents a clock, an internal measure of time allowing the correct automatic execution of learned movements and, in particular, the automatic switch from one movement to the next in a sequential motor pattern. STN neuronal activity would be able to reset the frequency of oscillations of motor thalamo-cortical loops, notably in the γ band.

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.