Pedunculopontine arousal system physiology – Implications for insomnia

Abstract

We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia.

Transdermal electrical neuromodulation of the trigeminal sensory nuclear complex improves sleep quality and mood

“…The ascending reticular activating system (RAS) represents a collection of brain stem nuclei and neuromodulatory projections, such as noradrenergic radiations from the locus coeruleus (LC) and cholinergic axons from the pedunculopontine nucleus (PPN) to higher brain circuits including the thalamus, hippocampus, amygdala, and vast regions of cortex. These ascending networks are known to provide strong neurophysiological control of consciousness, sleep/wake cycles, attention, alertness, other aspects of cognition including behavioral flexibility [1,15,28,[56][57][58][59][60]. Starting from the periphery, primary trigeminal and cervical afferent inputs to the trigeminal sensory nuclear complex (TSNC) from sensory and proprioceptive fibers located on the sides and front of the face, oral cavity, and anterior and posterior cervical regions of the neck provide robust disynaptic and polysynaptic regulation of LC and PPN neuron activity.…”

“…Based on these findings, we hypothesized that repeated daily dampening of psychophysiological and biochemical arousal might improve mood if used nightly to increase the quality, duration or efficiency of sleep. Supportive of this hypothesis there are numerous lines of evidence that suggest insomnia is a "waking" disorder (hyper-arousal) of RAS networks rather than a sleep disorder per se [1,41]. Viewed as such, we more specifically hypothesized that decreasing neurobehavioral and psychophysiological arousal by perturbing trigeminal LC/RAS networks prior to sleep onset for repetitive nights can enhance the restorative qualities of sleep on mood and mental health.…”

“…The ascending reticular activating system (RAS) is a collection of nuclei and circuits that sort, filter, integrate, and transmit incoming sensory information from the brain stem to the cortex to regulate sleep/wake cycles, arousal/alertness, attention, and sensorimotor behaviors [1][2][3][4][5][6][7][8]. The endogenous neuromodulatory actions of the RAS on consciousness and attention are orchestrated by at least three distinct sets of brain stem nuclei that include cholinergic neurons of the pedunculopontine nucleus (PPN), noradrenergic neurons of the locus coeruleus (LC), and serotonergic neurons of raphe nuclei [1]. Through a cytoarchitectural meshwork of interconnected brain stem nuclei in the pons and midbrain, sensory inputs first act upon the brain to engage ascending RAS networks, which generate global arousal ("waking"), alerting, and orienting cues as parsed sensory information projects through thalamic pathways onto the cortex for additional processing and integration.…”

“…More specifically the local and distal synaptic circuits formed by axons of neuromodulatory RAS networks (including neurons of the LC, PPN, RN) gate information flow from the sensory environment to the cortex and, in an activity-dependent manner, are capable of rapidly triggering neurobehavioral transitions across different states of behavioral awareness and consciousness [7,[9][10][11]. Depending on their firing rates for example, neurons of the PPN can differentially mediate REM sleep states [1,12] and neurons of the LC can trigger sleep/wake transitions [13,14]. Disrupted activity of ascending RAS networks underlies several neuropsychiatric conditions and disorders, such as insomnia, anxiety, depression, posttraumatic stress disorder (PTSD), and attention deficit hyperactivity disorder (ADHD) [1,[15][16][17].…”

“…Depending on their firing rates for example, neurons of the PPN can differentially mediate REM sleep states [1,12] and neurons of the LC can trigger sleep/wake transitions [13,14]. Disrupted activity of ascending RAS networks underlies several neuropsychiatric conditions and disorders, such as insomnia, anxiety, depression, posttraumatic stress disorder (PTSD), and attention deficit hyperactivity disorder (ADHD) [1,[15][16][17]. Therefore, a neural interface capable of dynamically and electrically modulating RAS networks should be able to provide a chemical-free approach to restoring poor daily function attributable to sleep loss or attention and mood disorders.…”