Interestingly DBS in the medial or intralaminar thalamus

Interestingly, DBS in the medial or intralaminar thalamus is being used with great success for the treatment of Tourette׳s syndrome [82,83]. One side effect of intralaminar thalamus DBS for Tourette׳s syndrome is profound fatigue. The parameters of stimulation typically include 24h stimulation at high frequencies (>100Hz). This side effect may respond to decreased frequency of stimulation (e.g. 40–60Hz) and for 20/24h schedules (Visser-Vandewalle, personal communication). That is, stimulation at frequencies and schedules closer to those used for PPN DBS may help prevent the fatigue manifested.
Conclusion While the use of PPN DBS is becoming more common, there is still much testing to be performed before it can become clinical routine. However, the foregoing should make it evident that optimal outcomes may ensue from using stimulation parameters that take advantage of novel information on the physiology of PPN cells. That is, stimulation at the natural frequency of PPN pgc-1α inhibitor (20–60Hz) is likely to recruit beta/gamma band intrinsic membrane oscillations that are maintained by the continuous application of PPN DBS. Both ascending arousal and descending motor control projections from the PPN are thus optimally activated to normalize PPN outputs. In the implementation of PPN DBS, we should determine its effects on wake/sleep cycles by performing sleep studies before and after implantation. One study performed sleep measures and found that PPN DBS improved not only nighttime sleep, but also daytime sleepiness [84]. If PPN DBS can normalize wake/sleep characteristics, then the technique can be determined to have a positive outcome on wake/sleep dysregulation in this disorder. In PD patients followed longitudinally, delta and theta power increased while higher frequencies, including gamma, decreased, and these changes correlated with cognitive decline [85]. Determining the effects of PPN DBS on gamma band power, but especially on gamma band maintenance, would be very important for assessing the beneficial effects of PPN stimulation on higher functions. A number of neurological and psychiatric disorders are also characterized by interrupted or decreased gamma band activity [39,44]. There is some information that PPN DBS may improve cognitive function [86], and that low frequency stimulation (5–30Hz) may improve executive and higher functions [73], but this issue needs further elucidation. Lesions of the PPN disturb attention, executive function and working memory [87], therefore, it should be expected that PPN DBS may beneficially affect higher functions using the appropriate parameters of stimulation. In addition, the PPN has been proposed to participate in the process of preconscious awareness, the mechanism that allows us to evaluate the world around us on a continuous basis [44]. This process is embedded in the formulation of our perceptions and actions, and modulates higher-level beta/gamma processing through its projections to the intralaminar thalamus, basal ganglia, hypothalamus, and basal forebrain. That is why it affects functions as disparate as waking and REM sleep, mood and perception, and homeostatic regulation. The effects of PPN DBS also need to be studied for potential modulation of this essential survival mechanism, preconscious awareness.
Wake–sleep control by the Reticular Activating System and its influence on substance abuse Substance abuse and the perception of withdrawal/relapse are mediated by neurobiological processes that occur when we are awake, but not when we are asleep. Furthermore, sleep disturbances (i.e., sleep deprivation) have been considered a risk for psychotimulant abuse. The Reticular Activating System (RAS) plays a central role controlling sleep homeostasis, modulating oscillatory rhythms between the thalamus and cortex that are distinguishable in the EEG during wake–sleep states [1]. The interactions between the pedunculopontine nucleus (PPN) and the thalamus are critical to its function of wake–sleep control, exerting a push–pull effect on two centers. That is, the PPN inhibits the reticular thalamic nucleus (RTN) (which decreases slow waves during sleep), and excites specific thalamic relay nuclei (which increases tonic firing during the awake state) (Fig. 1) [2,3]. Thalamic relay neurons (which by definition send glutamatergic projections to the cortex) also receive RTN (GABAergic) afferents whose axons remain within the boundaries of the dorsal thalamic nucleus where the somata are located [4]. Thalamic relay neurons are bushy and, depending on the size of the soma, project to different layers of the cortex [5,6]. RTN neurons, on the other hand, have axons that collateralize within the nucleus and also project to dorsal thalamic nuclei, but not to the cortex; they have long dendrites, whose secondary and tertiary branches possess vesicle-containing appendages that form synapses on the dendrites of other reticular neurons [7]. The cells of the RTN are electrically coupled via gap junctions, providing a coherent recurrent inhibitory signal to thalamic relay cells, causing activation of T-type calcium channels responsible for slow waves during sleep [8]. Therefore, cholinergic afferents from the PPN to the RTN are inhibitory (pull away from slow wave sleep) [9], but excitatory to thalamic relay neurons (push towards waking). This prevents the bursting mediated by the activation of T-type calcium channels by RTN inhibition [10], and tonically depolarizes thalamic relay neurons, thus inducing a global disinhibition of thalamocortical activity. That is, when the PPN is activated, slow wave sleep is reduced and arousal is increased.