Reticular Activating System Research Articles

S106 Polysomnographic ascertainment of sleep-related alterations of breathing control and pattern

Under healthy condition, when awake, the breathing process is built up of regular, constant and repeated sequences of inhalation and exhalation. The volume and frequency of breathing is under control of a negative feedback system that keeps the partial pressure of arterial oxygen and carbon dioxide at constant level. In awake man, breathing is dependent on 3 different control systems. The behavioral control is intentional and arises from the cortex of the forebrain and corticospinal tract. The metabolic (autonom) control of breathing originates from the medulla oblongata as well as from the ventrolateral spinal tract. The metabolic control maintains the acid-base balance and O2-homeostasis. The third control level is the wakefulness stimulus, which affects breathing during wakefulness through the reticular activating system, independent of human intention. During sleep, these control systems undergo substantial alterations. The mechanism of alveolar ventilation/hypoventilation is complex, in which the changes of the central control of breathing play a prominent role. In this process, the outfall of the intentional influence of breathing through diminished vigilance level, furthermore, the inhibition of the reticular activating system during transitional sleep lead to disappearance of the cortical control mechanisms and to reduced mechanical and metabolic control of breathing. All these changes are the physiological background for the characteristic breathing pattern and also for the development of pathological breathing forms during sleep that can be visualised during polysomnography.

Injury of ascending reticular activating system associated with delayed post-hypoxic leukoencephalopathy: a case report

BackgroundDelayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by neurological relapse after an initial recovery from hypoxic brain injury. We describe a patient with impaired consciousness following DPHL, concurrent with injury of the ascending reticular activating system (ARAS) shown using diffusion tensor tractography (DTT).Case presentationA 50-year-old male patient was in a drowsy mental state after exposure to carbon monoxide (CO) for about ten hours. About a day after the CO exposure, his mental state recovered to an alert condition. However, his consciousness deteriorated to drowsy 24 days after the exposure and worsened to a semi-coma state at 26 days after onset. When he started rehabilitation six weeks after the CO exposure, he had impaired consciousness, with a Glasgow Coma Scale score of 8 and a Coma Recovery Scale-Revised score of 8. On 6-week DTT, decreased neural connectivity of the upper ARAS between the intralaminar thalamic nucleus and the cerebral cortex was observed in both frontal cortices, basal forebrains, basal ganglia and thalami. The lower dorsal ARAS was not reconstructed on the right side, and was thin on the left side. The lower ventral ARAS was not reconstructed on either side.ConclusionsUsing DTT, we demonstrated injury of the ARAS in a patient with impaired consciousness following DPHL. Our result suggests that injury of the ARAS is a plausible pathogenetic mechanism of impaired consciousness in patients with DPHL.

The Upper Ascending Reticular Activating System between Intralaminar Thalamic Nuclei and Cerebral Cortex in the Human Brain

Purpose: The ascending reticular activating system (ARAS) is responsible for regulation of consciousness. In this study, using diffusion tensor imaging (DTI), we attempted to reconstruct the thalamocortical projections between the intralaminar thalamic nuclei and the frontoparietal cortex in normal subjects. Methods: DTI data were acquired in 24 healthy subjects and eight kinds of thalamocortical projections were reconstructed: the seed re gion of interest (ROI) - the intralaminar thalamic nuclei and the eight target ROIs - the medial prefrontal cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, premotor cortex, primary motor cortex, primary somatosensory cortex, and posterior parietal cortex. Results: The eight thalamocortical projections were reconstructed in each hemisphere and the pathways were visualized: projections to the prefrontal cortex ascended through the anterior limb and genu of the internal capsule and anterior corona radiata. Projections to the premotor cortex passed through the genu and posterior limb of the internal capsule and middle corona radiata; in contrast, projections to the primary motor cortex, primary somatosensory cortex, and posterior parietal cortex ascended through the posterior limb of the in ternal capsule. No significant difference in fractional anisotropy, mean diffusivity, and fiber volume of all reconstructed thalamocortical projections was observed between the right and left hemispheres (p>0.05). Conclusion: We reconstructed the thalamocortical projections between the intralaminar thalamic nuclei and the frontoparietal cortex in normal subjects. We believe that our findings would be useful to clinicians involved in the care of patients with impaired consciousness and for researchers in studies of the ARAS.

Functional connectivity disturbances of the ascending reticular activating system in temporal lobe epilepsy

ObjectiveSeizures in temporal lobe epilepsy (TLE) disturb brain networks and lead to connectivity disturbances. We previously hypothesised that recurrent seizures in TLE may lead to abnormal connections involving subcortical activating...

Bottom-up gamma and stages of waking

Gamma activity has been proposed to promote the feed forward or “bottom-up” flow of information from lower to higher regions of the brain during perception. The pedunculopontine nucleus (PPN) modulates waking and REM sleep, and is part of the reticular activating system (RAS). The properties of PPN cells are unique in that all PPN neurons fire maximally at gamma band frequency regardless of electrophysiological or transmitter type, thus proposed as one origin of “bottom-up” gamma. This property is based on the presence of intrinsic membrane oscillations subserved by high threshold, voltage-dependent calcium channels. Moreover, some PPN cells are electrically coupled. Assuming that the population of PPN neurons has the capacity to fire at ∼40Hz coherently, then the population as a whole can be expected to generate a stable gamma band signal. But what if not all the neurons are firing at the peaks of the oscillations? That means that some cells may fire only at the peaks of every second oscillation. Therefore, the population as a whole can be expected to be firing at a net ∼20Hz. If some cells are firing at the peaks of every fourth oscillation, then the PPN as a whole would be firing at ∼10Hz. Firing at rates below 10Hz would imply that the system is seldom firing at the peaks of any oscillation, basically asleep, in slow wave sleep, thus the activation of the RAS is insufficient to promote waking. This hypothesis carries certain implications, one of which is that we awaken in stages as more and more cells are recruited to fire at the peaks of more and more oscillations. For this system, it would imply that, as we awaken, we step from ∼10Hz to ∼20Hz to ∼30Hz to ∼40Hz, that is, in stages and presumably at different levels of awareness. A similar process can be expected to take place as we fall asleep. Awakening can then be considered to be stepwise, not linear. That is, the implication is that the process of waking is a stepwise event, not a gradual increase, suggesting that the brain can spend time at each of these different stages of arousal.

Interaction between neuronal calcium sensor protein 1 and lithium in pedunculopontine neurons.

Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Postmortem studies showed increased expression of neuronal calcium sensor protein 1 (NCS‐1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients. We previously showed that NCS‐1 at low levels increased, and at high levels decreased, gamma oscillations in RAS pedunculopontine neurons (PPN), and that Li+ decreased these oscillations. We previously described the effects of each agent on oscillations, G‐protein mechanisms, and Ca2+ currents. However, we designed the present experiments to determine the nature of the interaction of NCS‐1 and Li+ at physiological concentrations that would have an effect within minutes of application. As expected, Li+ decreased gamma oscillation amplitude, while NCS‐1 increased the amplitude of gamma oscillations. We identified NCS‐1 at 2 μmol/L as a concentration that increased gamma oscillations within 5–10 min, and Li+ at 10 μmol/L as a concentration that decreased gamma oscillations within 5 min. The combined application of NCS‐1 and Li+ at these concentrations showed that Li+ reduced the effects of NCS‐1 on oscillation amplitude within 5–10 min. These results demonstrate that at physiological levels, Li+ acts to reduce the effects of NCS‐1 so that, given over expression of NCS‐1, Li+ would have salutary effects.

Astrocyte-Dependent Slow Inward Currents (SICs) Participate in Neuromodulatory Mechanisms in the Pedunculopontine Nucleus (PPN).

Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms.

Domains of the brain which propofol acts on, an update

Background Propofol is one of the most common intravenous general anesthetics used in current clinical practices. The anesthetic mechanism of propofol, particularly the functional targets of propofol within the brain, has not yet been fully clarified. Objective To discuss which domains may be the target locations of propofol in the brain. Content To expound the possible correlation between the anesthetic mechanism of propofol and endogenous sleep hypothalamic pathway, ascending reticular activating system, thalamic cortical network or thalamic reticular nucleus. Trend To reveal the initial nuclei or related area in the brain of the anesthetic effect of propofol will possess important guiding significance for avoiding the adverse consequences of much deep or much light anesthesia, reducing the complications of anesthesia and developing more effective anesthetic drugs. Key words: Propofol; Anesthetic mechanism; Brain

Bottom-up gamma: the pedunculopontine nucleus and reticular activating system

Gamma rhythms have been proposed to promote the feed forward or "bottom-up" flow of information from lower to higher regions in the brain during perception. On the other hand, beta rhythms have been proposed to represent feed back or "top-down" influence from higher regions to lower. The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control and arousal, and is part of the reticular activating system (RAS). This review describes the properties of the cells in this nucleus. These properties are unique, and perhaps it is the particular characteristics of these cells that allow the PPN to be involved in a host of functions and disorders. The fact that all PPN neurons fire maximally at gamma band frequency regardless of electrophysiological or transmitter type, make this an unusual cell group. In other regions, for example in the cortex, cells with such a property represent only a sub-population. More importantly, the fact that this cell group's functions are related to the capacity to generate coherent activity at a preferred natural frequency, gamma band, speaks volumes about how the PPN functions. We propose that "bottom-up" gamma band influence arises in the RAS and contributes to the build-up of the background of activity necessary for preconscious awareness and gamma activity at cortical levels.

Multiple injuries of the ascending reticular activating system in a stroke patient: a diffusion tensor tractography study.

Multiple injuries of the ascending reticular activating system in a stroke patient: a diffusion tensor tractography study.

The effect of motion sickness on the sleep–wake cycle in rats exposed to prenatal hypoxia

This study is a continuation of our research of phenomenology and mechanisms of motion sickness (MS) and the relation of this phenomenon to features of sleep-wake cycle (SWC) changes. It presents data about the effect of MS on SWC in 30-day-old intact rats and rats exposed previously to prenatal hypoxia on days 13 and 19 of gestation. In all groups of animals MS was shown to reduce significantly the waking time and to increase the time of paradoxical sleep (PS). For the first time it became possible to reveal a connection between hypothalamic mechanisms controlling MS and SWC and to suggest the role of this connection in mechanisms of development of the sopite syndrome which may be the only manifestation of MS in some animals and man. The results obtained demonstrate that hypoxia on day 19 of gestation has a greater damaging effect on the thalamocortical sleep-regulating structures than hypoxia on day 13 when only hypothalamic-hippocampal systems controlling slow-wave sleep were found disturbed. Against this background MS substantially suppresses the activity of the brain excitatory systems which provide wake- fulness maintenance (it appears to be the ascending reticular activating system) and enhances the work of those activating systems that control PS. It is in rats exposed to preliminary hypoxia on day 19 of gesta- tion, where it was possible to show the role of the evolutionary young thalamocortical system in the control of PS.

Ascending Reticular Activating System of the Brain

There were two stages in the history of the studies on ascending reticular activating system of the brain (ARAS). The first stage began with the ARAS discovery by Magoun and Moruzzi and the following investigations using the methods of stimulation and lesion at that time mainly in acute cats. These studies led to the hypothesis of a “diffuse” and “unspecific” ARAS of the brain stem. The second stage was associated with using more precise neurophysiological and histochemical methods mainly in chronically operated free-moving cats and rats. By 2010, the idea of the ARAS as an organized hierarchy of the cerebral “waking centers” distributed along the entire cerebral axis and releasing all the known neuromediators of low molecular weight together with the most important neuropeptides was formulated. To date, the aforementioned hypothesis has been revised again. The glutamatergic activating system has been discovered and described in detail. Presumably, this system is responsible for the appearance of electroencephalogram (EEG) arousal reaction and maintenance of the neocortex in the state of tonic depolarization during wakefulness and rapid eye movement (REM) sleep. Its destruction results in a deep comatose-like state. At the same time, the activity of all other “waking centers” is probably the result of the cortical activation.

Comment: Coma-causing brainstem lesions.

Arousal, or wakefulness, is an integral component of consciousness and prerequisite for other brain functions, yet its neuroanatomy in humans is poorly understood. Classically, the brainstem “reticular formation” has been considered important for wakefulness.1 Experiments in rodents suggest this brainstem area can be subdivided into functionally discrete regions, and that injury to one region in the pontine tegmentum reliably disrupts arousal and produces coma.2 A homologous brainstem region is likely present in humans, based on analysis of coma-causing lesions.3 However, it remains unclear whether there is a human brainstem site significantly more associated with coma-causing lesions than with non–coma-causing lesions, and exactly where this site is located. Such a brainstem site would likely maintain arousal through ascending projections to other brain regions (originally termed the ascending reticular activating system, or ARAS),1,4 but this network of brain regions in humans is also unclear.

Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons.

Synaptic efferents from the PPN are known to modulate the neuronal activity of several intralaminar thalamic regions (e.g., the centrolateral/parafascicular; Cl/Pf nucleus). The activation of either the PPN or Cl/Pf nuclei in vivo has been described to induce the arousal of the animal and an increment in gamma band activity in the cortical electroencephalogram (EEG). The cellular mechanisms for the generation of gamma band oscillations in Reticular Activating System (RAS) neurons are the same as those found to generate gamma band oscillations in other brains nuclei. During current-clamp recordings of PPN neurons (from parasagittal slices from 9 - 25 day-old rats), the use of depolarizing square steps rapidly activated voltage-dependent potassium channels that prevented PPN neurons from being depolarized beyond -25 mV. Injecting 1 - 2 sec long depolarizing current ramps gradually depolarized PPN membrane potential resting values towards 0 mV. However, injecting depolarizing square pulses generated gamma-band oscillations of membrane potential that showed to be smaller in amplitude compared to the oscillations generated by ramps. All experiments were performed in the presence of voltage-gated sodium channels and fast synaptic receptors blockers. It has been shown that the activation of high-threshold voltage-dependent calcium channels underlie gamma-band oscillatory activity in PPN neurons. Specific methodological and pharmacological interventions are described here, providing the necessary tools to induce and sustain PPN subthreshold gamma band oscillation in vitro.

Brainstem Monitoring in the Neurocritical Care Unit: A Rationale for Real-Time, Automated Neurophysiological Monitoring.

Patients with severe traumatic brain injury or large intracranial space-occupying lesions (spontaneous cerebral hemorrhage, infarction, or tumor) commonly present to the neurocritical care unit with an altered mental status. Many experience progressive stupor and coma from mass effects and transtentorial brain herniation compromising the ascending arousal (reticular activating) system. Yet, little progress has been made in the practicality of bedside, noninvasive, real-time, automated, neurophysiological brainstem, or cerebral hemispheric monitoring. In this critical review, we discuss the ascending arousal system, brain herniation, and shortcomings of our current management including the neurological exam, intracranial pressure monitoring, and neuroimaging. We present a rationale for the development of nurse-friendly-continuous, automated, and alarmed-evoked potential monitoring, based upon the clinical and experimental literature, advances in the prognostication of cerebral anoxia, and intraoperative neurophysiological monitoring.

Intracellular mechanisms modulating gamma band activity in the pedunculopontine nucleus (PPN).

The pedunculopontine nucleus is a part of the reticular activating system, and is active during waking and REM sleep. Previous results showed that all PPN cells tested fired maximally at gamma frequencies when depolarized. This intrinsic membrane property was shown to be mediated by high‐threshold N‐ and P/Q‐type Ca2+ channels. Recent studies show that the PPN contains three independent populations of neurons which can generate gamma band oscillations through only N‐type channels, only P/Q‐type channels, or both N‐ and P/Q‐type channels. This study investigated the intracellular mechanisms modulating gamma band activity in each population of neurons. We performed in vitro patch‐clamp recordings of PPN neurons from Sprague–Dawley rat pups, and applied 1‐sec ramps to induce intrinsic membrane oscillations. Our results show that there are two pathways modulating gamma band activity in PPN neurons. We describe populations of neurons mediating gamma band activity through only N‐type channels and the cAMP/PKA pathway (presumed “REM‐on” neurons), through only P/Q‐type channels and the CaMKII pathway (presumed “Wake‐on” neurons), and a third population which can mediate gamma activity through both N‐type channels and cAMP/PK and P/Q‐type channels and CaMKII (presumed “Wake/REM‐on” neurons). These novel results suggest that PPN gamma oscillations are modulated by two independent pathways related to different Ca2+ channel types.

Direct presynaptic and indirect astrocyte-mediated mechanisms both contribute to endocannabinoid signaling in the pedunculopontine nucleus of mice.

The pedunculopontine nucleus (PPN), a cholinergic nucleus of the reticular activating system, is known to be involved in the regulation of sleep and wakefulness. Endogenous and exogenous cannabinoids, by systemic or local administration to the pedunculopontine nucleus, can both influence sleep. We previously demonstrated that activation of astrocytes by cannabinoid type 1 (CB1) receptor agonists was able to modulate the membrane potential of PPN neurons, even in the presence of blockers of fast synaptic neurotransmission. In the present work, we provide evidence that synaptic inputs of PPN neurons are also affected by activation of presynaptic and astrocytic CB1 receptors. Using slice electrophysiology combined with calcium imaging, optogenetics and immunohistochemistry, we revealed a direct presynaptic inhibitory action on inhibitory postsynaptic currents, along with a mild increase of excitatory postsynaptic currents during CB1 receptor stimulation. Besides inhibition of excitatory and inhibitory neurotransmission through stimulation of presynaptic CB1 receptors, astrocyte- and mGluR-dependent tonic inhibition and excitation also developed. The mild stimulatory action of CB1 receptor activation on excitatory neurotransmission is the combination of astrocyte-dependent tonic excitation on excitatory neurons and the canonical presynaptic CB1 receptor activation and consequential inhibition of excitatory synaptic neurotransmission, whereas the astrocyte-dependent stimulatory action was not observed in inhibitory neurotransmission within the PPN. Our findings demonstrate that endocannabinoids act in the PPN via a dual pathway, consisting of a direct presynaptic and an indirect, astrocyte-mediated component, regulating synaptic strength and neuronal activity via independent mechanisms.

Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives

Wake-Promoting Agents (WPAs) such as amphetamine-like stimulants or modafinil, armodafinil, methyl phenidate, caffeine and nicotine reinforce the level of vigilance through an stimulated release of neurotransmitters implicated in the arousal threshold maintenance, hence shift the drive from the sleep-promoting to wake-promoting system. The modulatory effects of WPAs on cortical activation pathways give rise to enhanced vigilance. For example, cholinergic neurons of the basal forebrain and the adenosine receptors on these neurons are agonized and antagonized by nicotine and caffeine, respectively. Caffeine similarly antagonizes adenosine receptors on the GABAergic neurons and intensifies the inhibitory drive in preoptic/anterior hypothalamus which involve in sleep induction. Modafinil however exerts its wake-promoting effects through stimulating the tuberomammillary nucleus and the hypocretinergic neurons which activate the ascending reticular activating system. Although many neutransmitter systems such as dopamine are thought to be involved upon the effects of WPAs, the empirical evidence to explain the exact mechanisms need to gain strength.

Structural and functional considerations of the cholinergic brainstem.

Cholinergic neurons of the brainstem have traditionally been associated with a role in wakefulness as part of the reticular activating system, but their function cannot be explained solely on the basis of their modulation of the brain state. Recent findings about their connectivity and functional heterogeneity suggest a wider role in behavior, where basal ganglia is at the center of their influence. This review focuses on recent findings that suggest an intrinsic functional organization of the cholinergic brainstem that is closely correlated with its connectivity with midbrain and forebrain circuits. Furthermore, recent evidence on the temporal structure of the activation of brainstem cholinergic neurons reveals fundamental aspects about the nature of cholinergic signaling. Consideration of the cholinergic brainstem complex in the context of wider brain circuits is critical to understand its contribution to normal behavior.

Lithium decreases the effects of neuronal calcium sensor protein 1 in pedunculopontine neurons.

Human postmortem studies reported increased expression of neuronal calcium sensor protein 1 (NCS‐1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients and was proposed to act by inhibiting the interaction between NCS‐1 and inositol 1,4,5‐triphosphate receptor protein (InsP3R). NCS‐1 is known to enhance the activity of InsP3R, and of Ca2+‐mediated gamma oscillatory activity in the pedunculopontine nucleus (PPN), part of the RAS. This study aimed to determine the nature of some of the intracellular mechanisms of Li+ on rat PPN cells and to identify the interaction between Li+ and NCS‐1. Since Li+ has been shown to act by inhibiting the enhancing effects of NCS‐1, we tested the hypothesis that Li+ would reduced the effects of overexpression of NCS‐1 and prevent the downregulation of gamma band activity. Li+ decreased gamma oscillation frequency and amplitude by downregulating Ca2+ channel activity, whereas NCS‐1 reduced the effect of Li+ on Ca2+ currents. These effects were mediated by a G‐protein overinhibition of Ca2+ currents. These results suggest that Li+ affected intracellular pathways involving the activation of voltage‐gated Ca2+ channels mediated by an intracellular mechanism involving voltage‐dependent activation of G proteins, thereby normalizing gamma band oscillations mediated by P/Q‐type calcium channels modulated by NCS‐1.