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The pedunculopontine nucleus (PPN) is located in the mesopontine tegmentum and is best delimited by a group of large cholinergic neurons adjacent to the decussation of the superior cerebellar peduncle. This part of the brain, populated by many other neuronal groups, is a crossroads for many important functions. Good evidence relates the PPN to control of reflex reactions, sleep-wake cycles, posture and gait. However, the precise role of the PPN in all these functions has been controversial and there still are uncertainties in the functional anatomy and physiology of the nucleus. It is difficult to grasp the extent of the influence of the PPN, not only because of its varied functions and projections, but also because of the controversies arising from them. One controversy is its relationship to the mesencephalic locomotor region (MLR). In this regard, the PPN has become a new target for deep brain stimulation (DBS) for the treatment of parkinsonian gait disorders, including freezing of gait. This review is intended to indicate what is currently known, shed some light on the controversies that have arisen, and to provide a framework for future research., (Copyright © 2019. Published by Elsevier B.V.)

Most central disorders of hypersomnolence are conditions with poorly understood pathophysiologies, making their identification, treatment, and management challenging for sleep clinicians. The most challenging to diagnose and treat is idiopathic hypersomnia. There are no FDA-approved treatments, and off-label usage of narcolepsy treatments seldom provide benefit. Patients are largely left on their own to alleviate the compound effects of this disorder on their quality of life. This review covers the major points regarding clinical features and diagnosis of idiopathic hypersomnia, reviews current evidence supporting the available treatment options, and discusses the psychosocial impact and effects of idiopathic hypersomnia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Restless legs syndrome (RLS) is a common sensorimotor trait defined by symptoms that interfere with sleep onset and maintenance in a clinically meaningful way. Nonvolitional myoclonus while awake and asleep is a sign of the disorder and an informative endophenotype. The genetic contributions to RLS/periodic leg movements are substantial, are among the most robust defined to date for a common disease, and account for much of the variance in disease expressivity. The disorder is polygenic, as revealed by recent genome-wide association studies. Experimental studies are revealing mechanistic details of how these common variants might influence RLS expressivity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP⩽5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Phasic electromyographic (EMG) activity during sleep is characterized by brief muscle twitches (duration 100-500ms, amplitude four times background activity). High rates of such activity may have clinical relevance. This paper presents wavelet (WT) analyses to detect phasic EMG, examining both Symlet and Daubechies approaches. Feature extraction included 1s epoch processing with 24 WT-based features and dimensionality reduction involved comparing two techniques: principal component analysis and a feature/variable selection algorithm. Classification was conducted using a linear classifier. Valid automated detection was obtained in comparison to expert human judgment with high (>90%) classification performance for 11/12 datasets., (Published by Elsevier Ltd.)

Background: Restless legs syndrome (RLS) is a common sleep disorder in which urges to move the legs are felt during rest, are felt at night, and are improved by leg movement. RLS has been implicated in the development of cardiovascular disease. Periodic leg movements (PLMs) may be a mediator of this relationship. We evaluated systemic inflammation and PLMs in RLS patients to further assess cardiovascular risk., Methods: 137 RLS patients had PLM measurements taken while unmedicated for RLS. Banked plasma was assayed for high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)., Results: Mean (SD) PLM index was 19.3 (22.0). PLMs were unrelated to TNF-a and IL-6, but were modestly correlated with logCRP (r(129)=0.19, p=0.03). Those patients with at least 45PLMs/h had an odds ratio of 3.56 (95% CI 1.26-10.03, p=0.02, df=1) for having elevated CRP compared to those with fewer than 45PLMs/h. After adjustment for age, race, gender, diabetes, hypertension, hyperlipidemia, inflammatory disorders, CRP-lowering medications, and body mass index, the OR for those with ≥ 45PLMs/h was 8.60 (95% CI 1.23 to 60.17, p=0.03, df=10)., Conclusions: PLMs are associated with increased inflammation, such that those RLS patients with at least 45PLMs/h had more than triple the odds of elevated CRP than those with fewer PLMs. Further investigation into PLMs and inflammation is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Restless legs syndrome (RLS) is characterized by a compelling, often insatiable, need to move the legs, accompanied by unpleasant sensations located mainly in the ankles and calves. Because symptoms are brought on by inactivity, distress intrudes upon everyday, sedentary activities such as plane travel, car rides, and attending school, meetings, or the theatre. Symptoms show a diurnal preference for the evening and night, so disruption of sleep onset or maintenance is particularly common. RLS is associated with both lower ratings of quality of life and higher rates of cardiovascular disease. Four common genetic loci associating to RLS have recently been identified, but the molecular pathways by which they increase risk for RLS have yet to be determined. Both sensory (RLS) and motor (periodic limb movements of sleep) symptoms are responsive to dopaminergic medications, yet clear delineation of dopaminergic pathology has not emerged. Brain iron is reduced in many, but not all, patients with RLS. First-line treatment for RLS includes agents acting at D(2) and D(3) dopamine receptors., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Consequences of chronic exposure to cytokines of the innate immune system on sleep in humans and the association of cytokine-induced sleep alterations with behavior, motor performance, and cortisol secretion are unknown., Methods: Thirty-one patients with hepatitis C without pre-existing sleep disorders underwent nighttime polysomnography, daytime multiple sleep latency testing, behavioral assessments, neuropsychological testing, and serial blood sampling at baseline and after ∼12 weeks of either treatment with the innate immune cytokine interferon (IFN)-alpha (n = 19) or no treatment (n = 12). Fatigue and sleepiness were assessed using the Multidimensional Fatigue Inventory and Epworth Sleepiness Scale., Results: Interferon-alpha administration led to significant increases in wake after sleep onset and significant decreases in stage 3/4 sleep and sleep efficiency. Rapid eye movement latency and stage 2 sleep were significantly increased during IFN-alpha treatment. Decreases in stage 3/4 sleep and increases in rapid eye movement latency were associated with increases in fatigue, whereas decreases in sleep efficiency were associated with reduced motor speed. Increased wake after sleep onset was associated with increased evening plasma cortisol. Despite IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase. In fact, IFN-alpha-treated patients exhibited decreased propensity to fall asleep during daytime nap opportunities., Conclusions: Chronic exposure to an innate immune cytokine reduced sleep continuity and depth and induced a sleep pattern consistent with insomnia and hyperarousal. These data suggest that innate immune cytokines may provide a mechanistic link between disorders associated with chronic inflammation, including medical and/or psychiatric illnesses and insomnia, which, in turn, is associated with fatigue, motor slowing, and altered cortisol., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cocaine- and amphetamine-regulated transcript (CART) peptides modulate anxiety, food intake, endocrine function, and mesolimbic dopamine related reward and reinforcement. Each of these disparate behaviors takes place during the state of wakefulness. Here, we identify a potential wake promoting role of CART by characterizing its effects upon sleep/wake architecture in rats. Dose-dependent increases in wake were documented following intracerebroventricular CART 55-102 administered at the beginning of the rat's major sleep period. Sustained wake was observed for up to 4h following delivery of 2.0 microg of CART peptide. The wake promoting effect was specific to active CART 55-102 because no effect on sleep/wake was observed with the inactive form of the peptide. Increased wake was followed by robust rebound in NREM and REM sleep that extended well into the subsequent lights-off, or typical wake period, of the rat. These findings point to a potential novel role for CART in regulating wakefulness., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Cocaine- and amphetamine-regulated transcript (CART) peptides are neurotransmitters found throughout the nervous system and in the periphery. CART has an important role in the regulation of food intake, anxiety, endocrine function, and in mesolimbic-mediated reward and reinforcement. This short report casts light upon previous descriptions of presumed behavioral seizure and tremor activity following administration of CART into the central nervous system. By employing electroencephalographic (EEG) recordings, we document the state of cerebrocortical activity. We find that intracerebroventricular (icv) administration of 5 microg of CART 55-102 readily produces an abnormal EEG characterized initially by high amplitude hypersynchronous alpha in the 8-10 Hz range during behavioral wakefulness as manifest in both cortical and hippocampal theta EEG channels. This reliably progressed in three of three animals tested to unequivocal epileptiform activity accompanied by tremors and assumption of a rigid, tonic body posture. The neural substrates underlying this finding are unclear. This novel description of the epileptogenic quality of CART should lend caution to interpretations of the behaviors attributed to CART in other experimental paradigms.

Unlabelled: Autonomic nervous system (ANS) dysfunction has been suggested in patients with chronic fatigue syndrome (CFS). In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR, and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect, and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders. Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] (p<0.0004, each), and reduced low frequency (LF), very low frequency (VLF), and total power (TP) of HRV (p<0.02, all). CFS cases had significantly lower plasma aldosterone (p<0.05), and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine (r=0.23, p=0.05) and moderately with vitality and fatigue scores (r=-0.49 and 0.46, respectively, p<0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p=0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders case-control differences in HR and TP remained significant (p<0.05)., Conclusion: the presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed.