Parkinson’s disease (PD) is characterized by nigral degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. Rather than treating only the symptomatic aspects of Parkinson’s disease, one may also consider treatments designed to retard, arrest, or even reverse this degenerative process. Such strategies could include preventive or restorative treatments instead of purely palliative treatments. A recent hypothesis states that glutamate output from the subthalamic nucleus (STN) to the substantia nigra contributes to the neurotoxic process underlying dopaminergic cell death in Parkinson’s disease. Furthermore, high-frequency stimulation (HFS) of the STN inhibits neurons resulting in the suppression of their glutamate output. Experiments in both rats and monkeys provide preliminary data supporting this hypothesis. Kainic acid (KA) lesions of the STN prevent the loss of dopaminergic neurons in the substantia nigra after intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats, and after systemic administration of MPTP in monkeys. In PD patients, the background level of their disease is evaluated in the off medication/off stimulation state (UPDRS III score), over a period of 5 years. Thirty percent of the patients are stabilized and 18% have persistent improvement of their disease-related impairment. Further experiments are needed, including controlled clinical trials utilizing functional imaging of the dopamine transporters and post-synaptic receptors.

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.

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.

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.

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.

Broad amplitude variability and skewed distributions are characteristic features of quantal synaptic currents (minis) at central synapses. The relative contributions of the various underlying sources are still debated. Through computational models of thalamocortical neurons, we separated intra- from extra-synaptic sources. Our simulations indicate that the external factors of local input resistance and dendritic filtering generate equally small amounts of negatively skewed synaptic variability. The ability of these two factors to reduce positive skew increased as their contribution to variability increased, which in control trials for morphological, biophysical, and experimental parameters never exceeded 10% of the range. With these dendritic factors ruled out, we tested multiple release models, which led to distributions with clearly non-physiological multiple peaks. We conclude that intra-synaptic organization is the primary determinant of synaptic variability in thalamocortical neurons and, due to extra-synaptic mechanisms, is more potent than the data suggested. Thalamortical neurons, especially in rodents, constitute a remarkably favorable system for molecular genetic studies of synaptic variability and its functional consequence.