ArticleLiterature Review

Contributions of the Pedunculopontine Region to Normal and Altered REM Sleep

October 1997
Sleep 20(9):757-88

October 1997
20(9):757-88

DOI:10.1093/sleep/20.9.757

Source
PubMed

Authors:

David Rye

Emory University

The pedunculopontine (PPN) region of the upper brainstem is recognized as a critical modulator of activated behavioral states such as wakefulness and rapid eye movement (REM) sleep. The expression of REM sleep-related physiology (e.g. thalamocortical arousal, ponto-geniculate-occipital (PGO) waves, and atonia) depends upon a subpopulation of PPN neurons that release acetylcholine (ACh) to act upon muscarinic receptors (mAChRs). Serotonin's potent hyperpolarization of cholinergic PPN neurons is central to present working models of REM sleep control. A growing body of experimental evidence and clinical experience suggests that the responsiveness of the PPN region, and thereby modulation of REM sleep, involves closely adjacent glutamatergic neurons and alternate afferent neurotransmitters. Although many of these afferents are yet to be defined, dopamine-sensitive GABAergic pathways exiting the main output nuclei of the basal ganglia and adjacent forebrain nuclei appear to be the most conspicuous and the most likely to be clinically relevant. These GABAergic pathways are ideally sited to modulate the physiologic hallmarks of REM sleep differentially (e.g. atonia versus cortical activation), because each originates from a functionally unique forebrain circuit and terminates in a unique pattern upon brain stem neurons with unique membrane characteristics. Evidence is reviewed that changes in the quality, timing, and quantity of REM sleep that characterize narcolepsy, REM sleep behavior disorder, and neurodegenerative and affective disorders (depression and schizophrenia) reflect 1) changes in responsiveness of cells in the PPN region governed by these afferents; 2) increase or decrease in PPN cell number; or 3) mAChRs mediating increased responsiveness to ACh derived from the PPN. Auditory evoked potentials and acoustic startle responses provide means independent from recording sleep to assess pathophysiologies affecting the PPN and its connections and thereby complement investigations of their role in affecting daytime functions (e.g. arousal and attention).

Pedunculopontine-Induced Cortical Decoupling as the Neurophysiological Locus of Dissociation

Article

Full-text available

Jan 2022

Mounting evidence suggests an association between aberrant sleep phenomena and dissociative experiences. However, no wake-sleep boundary theory provides a compelling explanation of dissociation or specifies its physiological substrates. We present a theoretical account of dissociation that integrates theories and empirical results from multiple lines of research concerning the domain of dissociation and the regulation of rapid eye movement (REM) sleep. This theory posits that individual differences in the circuitry governing the REM sleep promoting Pedunculopontine Nucleus and Laterodorsal Tegmental Nucleus determine the degree of similarity in the cortical connectivity profiles of wakefulness and REM sleep. We propose that a latent trait characterized by elevated dissociative experiences emerges from the decoupling of frontal executive regions due to a REM sleep-like aminergic/cholinergic balance. The Pedunculopontine-Induced Cortical Decoupling Account of Dissociation (PICDAD) suggests multiple fruitful lines of inquiry and provides novel insights. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Novel utilization of deep brain stimulation in the pedunculopontine nucleus with globus pallidus internus for treatment of childhood-onset dystonia

Article

Full-text available

Oct 2023
FRONT HUM NEUROSCI

Introduction Deep brain stimulation (DBS) is a well-documented therapy for dystonia utilized in many adult and pediatric movement disorders. Pedunculopontine nucleus (PPN) has been investigated as a DBS target primarily in adult patients with dystonia or dyskinesias from Parkinson’s disease, showing improvement in postural instability and gait dysfunction. Due to the difficulty in targeting PPN using standard techniques, it is not commonly chosen as a target for adult or pediatric pathology. There is no current literature describing the targeting of PPN in DBS for childhood-onset dystonia. Methods Two pediatric and one young adult patient with childhood-onset dystonia who underwent DBS implantation at our institution were identified. Patient 1 has Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration (MEPAN) syndrome. Patient 2 has Glutaric Aciduria Type 1 (GA1). Patient 3 has atypical pantothenate kinase-associated neurodegeneration (PKAN). PPN was identified as a potential target for these patients due to axial or orofacial dystonia. Pre- and post-operative videos taken as part of routine clinical assessments were evaluated and scored on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS). All patients had permanent electrodes placed bilaterally in PPN and globus pallidus internus (GPi). A Likert scale on quality of life was also obtained from the patient/parents as applicable. Results Significant programming was necessary over the first 3–12 months to optimize patients’ response to stimulation. All patients experienced at least a 34% improvement in the BFMDRS score. Patients 2 and 3 also experienced an over 30% improvement in BADS score. All patients/parents appreciated improvement in quality of life postoperatively. Discussion Deep brain stimulation in PPN was safely and successfully used in two pediatric patients and one young adult patient with childhood-onset dystonia. These patients showed clinically significant improvements in BFMDRS scoring post operatively. This represents the first reported DBS targeting of PPN in pediatric patients, and suggests that PPN is a possible target for pediatric-onset dystonia with axial and orofacial symptoms that may be refractory to traditional pallidal stimulation alone.

Focus on the Pedunculopontine Nucleus. Consensus review from the May 2018 Brainstem Society meeting in Washington, DC, USA

Article

Jun 2019
CLIN NEUROPHYSIOL

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.

Association between clinically probable REM sleep behavior disorder and tetanus in dogs

Article

Full-text available

Oct 2018

Background: Abnormal sleep behavior has been reported in 5 dogs during recovery from tetanus. Hypothesis: REM sleep behavior disorder (RBD) is a more common consequence of tetanus than previously reported in veterinary literature and easily confused for epileptic seizures. Animals: Sixty-one client-owned dogs diagnosed with tetanus at 2 UK referral centers. Methods: A retrospective review of medical records was combined with a questionnaire sent to owners of surviving dogs, to identify cases that developed clinically probable RBD and determine its clinical progression and effect on quality of life of affected dogs and their owners. Descriptive statistical evaluation was performed. Results: Eleven dogs (18%) died or were euthanized before discharge. At least 46% surviving dogs developed abnormal "dream enactment" clinically consistent with RBD. Twitching, running, and vocalization were new sleep behaviors in 53, 80, and 60% of affected dogs. Clinically probable RBD was described as violent or "nightmare"-like in 36% affected dogs, and like an epileptic seizure in 40% affected dogs. When trialed, antiepileptic medications were ineffective. Onset occurred before discharge in 25% cases. For dogs that developed clinically probable RBD postdischarge, onset occurred within 2 weeks of discharge in 77% dogs. Clinically probable RBD did not worsen in severity or frequency in any dog, and spontaneously resolved within 6 months in 43% cases. Conclusions and clinical importance: Clinically probable RBD is a common sequel to canine tetanus with many clinical similarities to epileptic seizure activity. Owners should be made aware of its potential development and care taken to avoid misdiagnosis with epileptic seizure activity.

A Review of the Pedunculopontine Nucleus in Parkinson's Disease

Article

Full-text available

Apr 2018

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

Induction of Active (REM) Sleep and Motor Inhibition by Hypocretin in the Nucleus Pontis Oralis of the Cat

Article

Full-text available

Jun 2002

Hypocretin (orexin)-containing neurons in the hypothalamus, which have been implicated in the pathology of narcolepsy, project to nuclei in the brain stem reticular formation that are involved in the control of the behavioral states of sleep and wakefulness. Among these nuclei is the nucleus pontis oralis (NPO). Consequently, the present study was undertaken to determine if the hypocretinergic system provides regulatory input to neurons in the NPO with respect to the generation of the states of sleep and wakefulness. Accordingly, polygraphic recordings and behavioral observations were obtained before and after hypocretin-1 and -2 were microinjected into the NPO in chronic, unanesthetized cats. Microinjections of either hypocretin-1 or -2 elicited, with a short latency, a state of active [rapid eye movement (REM)] sleep that appeared identical to naturally occurring active sleep. The percentage of time spent in active sleep was significantly increased. Dissociated states, which are characterized by the presence of muscle atonia without one or more of the electrophysiological correlates of active sleep, also arose following the injection. The effect of juxtacellular application of hypocretin-1 on the electrical activity of intracellularly recorded NPO neurons was then examined in the anesthetized cat. In this preparation, the application of hypocretin-1 resulted in the depolarization of NPO neurons, an increase in the frequency of their discharge and an increase in their excitability. These latter data represent the first description of the in vivo action of hypocretin on intracellularly recorded neuronal activity and provide evidence that the active sleep-inducing effects of hypocretin are due to a direct excitatory action on NPO neurons. Therefore we suggest that hypocretinergic processes in the NPO may play a role in the generation of active sleep, particularly muscle atonia and therefore are likely to be involved in the pathology of narcolepsy.

Rapid eye movement sleep and epilepsy: exploring interactions and therapeutic prospects

Article

Full-text available

Jun 2024
J SLEEP RES

While research interest in the relationship between sleep and epilepsy is growing, it primarily centres on the effects of non-rapid eye movement (NREM) sleep in favouring seizures. Nonetheless, a noteworthy aspect is the observation that, in the lives of patients with epilepsy, REM sleep represents the moment with the least epileptic activity and the lowest probability of having a seizure. Studies demonstrate a sup-pressive effect of phasic REM sleep on interictal epileptiform discharges, potentially offering insights into epilepsy localisation and management. Furthermore, epilepsy impacts REM sleep, with successful treatment correlating with improved REM sleep quality. Novel therapeutic strategies aim to harness REM's anti-epileptic effects, including pharmacological approaches targeting orexinergic systems and neuromodu-lation techniques promoting cortical desynchronisation. These findings underscore the intricate relationship between REM sleep and epilepsy, highlighting avenues for further research and therapeutic innovation in epilepsy management.

Research Progress on Neural Circuit Mechanisms of Depression

Article

Full-text available

May 2023

Wenxuan Gong

Depression is one of the most prevailing neurological and psychotic disorders with a high rate of mental disability. The depression is closely related to the abnormality of neural circuits in brain. As a result, it is of great significance to make a profound study of the neural circuit of depression for revealing new clinical therapies of depression. Currently, neural circuits about depression have not been fully understood and there are still many difficulties puzzling researchers. While with the processing effort of neuroscientists and the development of electrophysiology, epigenetics or neuroimmunology, great progresses have been made in studies about neuronal circuits in depression to some extent. In this paper, we discuss various brain areas those are related to depression including the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal raphe nucleus (DRN), and then put emphasis on their local function with different neurotransmitters and abnormality of neural circuits of depression by reviewing previous studies. In a way, figuring out the mechanism of depression can improve the cure rate, and reduce the economic loss due to depression around the world.

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Article

Full-text available

Oct 2022

Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a “dystonia circuit” that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not always correlated, it is hypothesized that common pathways may nevertheless be disrupted. In particular, circadian dysfunction and disordered sleep are common non-motor patient complaints in dystonia. Given recent evidence suggesting that the cerebellum contains a circadian oscillator, displays sleep-stage-specific neuronal activity, and sends robust long-range projections to several subcortical regions involved in circadian rhythm regulation, disordered sleep in dystonia may result from cerebellum-mediated dysfunction of the dystonia circuit. Here, we review the evidence linking dystonia, cerebellar network dysfunction, and cerebellar involvement in sleep. Together, these ideas may form the basis for the development of improved pharmacological and surgical interventions that could take advantage of cerebellar circuitry to restore normal motor function as well as non-motor (sleep) behaviors in dystonia.

Detection of Motor Dysfunction With Wearable Sensors in Patients With Idiopathic Rapid Eye Movement Disorder

Article

Full-text available

Apr 2021

Patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for conversion to synucleinopathy and Parkinson disease (PD). This can potentially be monitored by measuring gait characteristics of iRBD patients, although quantitative data are scarce and previous studies have reported inconsistent findings. This study investigated subclinical gait changes in polysomnography-proven iRBD patients compared to healthy controls (HCs) during 3 different walking conditions using wearable motor sensors in order to determine whether gait changes can be detected in iRBD patients that could reflect early symptoms of movement disorder. A total 31 iRBD patients and 20 HCs were asked to walk in a 10-m corridor at their usual pace, their fastest pace, and a normal pace while performing an arithmetic operation (dual-task condition) for 1 min each while using a wearable gait analysis system. General gait measurements including stride length, stride velocity, stride time, gait length asymmetry, and gait variability did not differ between iRBD patients and HCs; however, the patients showed decreases in range of motion (P = 0.004) and peak angular velocity of the trunk (P = 0.001) that were significant in all 3 walking conditions. iRBD patients also had a longer step time before turning compared to HCs (P = 0.035), and the difference between groups remained significant after adjusting for age, sex, and height. The decreased trunk motion while walking and increased step time before turning observed in iRBD may be early manifestations of body rigidity and freezing of gait and are possible prodromal symptoms of PD.

Pedunculopontine Nucleus Degeneration Contributes to Both Motor and Non-Motor Symptoms of Parkinson’s Disease

Article

Full-text available

Jan 2020

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.

Microinjection of Urotensin II into the Pedunculopontine Tegmentum Leads to an Increase in the Consumption of Sweet Tastants

Article

Dec 2019

The pedunculopontine tegmentum (PPTg) plays a role in processing multiple sensory inputs and innervates brain regions associated with reward-related behaviors. The urotensin II receptor, activated by the urotensin II peptide (UII), is selectively expressed by the cholinergic neurons of the PPTg. Although the exact function of cholinergic neurons of the PPTg is unknown, they are thought to contribute to the perception of reward magnitude or salience detection. We hypothesized that the activation of PPTg cholinergic neurons would alter sensory processing across multiple modalities (ex. taste and hearing). Here we had three aims: first, determine if cholinergic activation is involved in consumption behavior of palatable solutions (sucrose). Second, if so, distinguish the impact of the caloric value by using saccharin, a zero calorie sweetener. Lastly, we tested the UII-mediated effects on perception of acoustic stimuli by measuring acoustic startle reflex (ASR). Male Sprague-Dawley rats were bilaterally cannulated into the PPTg, then placed under food restriction lasting the entire consumption experiment (water ad lib.). Treatment consisted of a microinjection of either 1 μL of aCSF or 1 μL of 10 μM UII into the PPTg, and the rats were immediately given access to either sucrose or saccharin. For the remaining five days, rats were allowed one hour access per day to the same sweet solution without any further treatments. During the saccharin experiment rats were tested in a contact lickometer which recorded each individual lick to give insight into the microstructure of the consumption behavior. ASR testing consisted of a baseline (no treatment), treatment day, and two additional days (no treatment). Immediately following the microinjection of UII, consumption of both saccharin and sucrose increased compared to controls. This significant increase persisted for days after the single administration of UII, but there was no generalized arousal or increase in water consumption between testing sessions. The effects on ASR were not significant. Activating cholinergic PPTg neurons may lead to a miscalculation of the salience of external stimuli, implicating the importance of cholinergic input in modulating a variety of behaviors. The long-lasting effects seen after UII treatment support further research into the role of sensory processing on reward related-behaviors at the level of the PPTg cholinergic neurons.

Visual Hallucinations and Impaired Conscious Visual Perception in Parkinson Disease

Article

Dec 2019

Visual hallucinations (VHs) are common in patients with Parkinson disease (PD), especially those with dementia, whereas auditory hallucinations are quite rare. Recent studies have revealed the involvement of several regions along the visual information-processing system that contribute to the pathophysiological mechanism of VHs: the eyes and retina, retinofugal projection, lateral geniculate nucleus, striate cortex, ventral pathways in the temporal cortices, and frontal and parietal cortices. In addition, the concurrent involvement of other systems in the brainstem and basal forebrain further modify VHs in PD. In this review, we discuss the pathophysiological association between the regional involvement of these areas and VHs.

Long-term effects of bilateral subthalamic nucleus stimulation on sleep in patients with Parkinson’s disease

Article

Full-text available

Aug 2019
PLOS ONE

Objectives: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to have a positive effect on sleep-wake disturbance in Parkinson's disease (PD). We aimed to investigate the long-term effects of STN DBS on sleep in patients with PD. Methods: Sixty-one patients with PD who had undergone bilateral STN DBS were followed for 3 years with assessments including the Parkinson's disease sleep scale (PDSS), Epworth sleepiness scale (ESS), total sleep hours per day, Unified PD Rating Scale part I-III, Hoehn & Yahr stage, levodopa equivalent dose, quality of life measure, and depression scale measured preoperatively and at 6 months after postoperatively, and annually thereafter. Results: Among the 61 patients at baseline, 46 patients completed the last follow-up assessment. The total PDSS score significantly improved after STN DBS from baseline up to 3 years after STN DBS (79.0±30, 100.0±23.3, 98.8±23.0, 97.1±29.6, and 93.3±28.0 at baseline, 6, 12, 24, and 36 months, respectively, p = 0.006 for the change over time). Among the eight PDSS domains, the domains for overall quality of a night's sleep, sleep onset and maintenance insomnia, and nocturnal motor symptoms showed significant improvement after STN DBS (p = 0.036, 0.029, and < 0.001, respectively, for the change over time). The total sleep hours per day were increased, but the total ESS score did not show significant change after STN DBS (p = 0.001 and 0.055, respectively, for the change over time). Changes in the total PDSS were associated with changes in the depression and motivation items in the Unified PD Rating Scale part I, depression scale, and quality of life measure, but those variables at baseline were not predictive of changes in the total PDSS after STN DBS. Conclusion: In the largest systematic long-term follow-up study, the improvement in subjective sleep quality after bilateral STN DBS was sustained in PD patients. Improved nocturnal sleep and nocturnal motor symptoms were correlated with an improved mood and quality of life. However, STN DBS did not reduce excessive daytime sleepiness despite reductions in antiparkinsonian medications.

A Stage-Based Approach to Therapy in Parkinson’s Disease

Article

Full-text available

Aug 2019

Parkinson’s disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor. Nevertheless, some non-motor symptoms, including depression, REM sleep behavior disorder, and olfactive impairment, are even earlier features of PD. At later stages, apathy, impulse control disorder, neuropsychiatric disturbances, and cognitive impairment can present, and they often become a heavy burden for both patients and caregivers. Indeed, PD increasingly compromises activities of daily life, even though a high variability in clinical presentation can be observed among people affected. Nowadays, symptomatic drugs and non-pharmaceutical treatments represent the best therapeutic options to improve quality of life in PD patients. The aim of the present review is to provide a practical, stage-based guide to pharmacological management of both motor and non-motor symptoms of PD. Furthermore, warning about drug side effects, contraindications, as well as dosage and methods of administration, are highlighted here, to help the physician in yielding the best therapeutic strategies for each symptom and condition in patients with PD.

Impulse Control Disorders in REM Sleep Behavior Disorder

Article

Full-text available

Apr 2019

Purpose of review This paper reviews clinical and pathophysiological features of both impulse control disorders (ICDs) and REM sleep behavior disorder (RBD) in Parkinson’s disease (PD), as well as current evidences of their association. Then, we suggest recommendations to manage PD patients with RBD in order to prevent this potentially devastating psychiatric complication. Recent findings ICDs are psychiatric complications occurring in patients with Parkinson’s disease (PD) treated with dopaminergic replacement therapies (DRT). Besides DRT, risk factors for ICDs are poorly known. We recently showed an association between ICDs and RBD in PD. Summary Detecting RBD in PD may provide clinician the opportunity to identify patients at higher risk to develop ICDs. In PD patients with either a video-polysomnographic (v-PSG) diagnosis of RBD or a typical history of RBD when v-PSG is not available, dopamine agonists should be avoided whenever possible, or be prescribed at the lowest effective dose. Furthermore, gradual tapering of dopamine agonist would be recommended, due to the potential increased risk of dopamine withdrawal syndrome in these patients. Increased surveillance, implying patients and caregiver education to recognize early changes in behavior and in mood possibly related to a hyperdopaminergic status, should be part of the preventive strategies.

Sleep Complaints, Sleep and Breathing Disorders in Myotonic Dystrophy Type 2

Article

Full-text available

Feb 2019
CURR NEUROL NEUROSCI

Purpose of Review To update the current knowledge concerning sleep complaints and breathing disorders in myotonic dystrophy type 2 (DM2) and to better understand if sleep and breathing symptoms may add a further clinical definition of DM2. Recent Findings Although DM2 has been poorly evaluated, the most relevant sleep disorders are sleep-disordered breathing (SDB) (37.5–66.7%) and restless legs syndrome (RLS) (50–60%). Excessive daytime somnolence (EDS) is not consistent with SDB, and a large percentage of patients with sleep complaints (58–69%) report pain. In addition, respiratory dysfunctions are reported in 6 to 15% of DM2 patients, albeit few data are available regarding pulmonary restriction, hypoventilation, and non-invasive ventilation (NIV). Summary SDB, RLS, and pain may contribute to sleep fragmentation and EDS in DM2. In addition, few studies report hypoventilation and pulmonary restriction, although there are no studies at all on NIV, except for limited clinical experiences. These findings suggest performing a careful pulmonary examination and NIV when required. Furthermore, sleep studies and respiratory evaluation should be recommended if OSA or respiratory muscle dysfunctions are suspected. A large polysomnographic study should be performed to clarify the link between sleep disorders, pain, and sleep disruption in DM2.

Comparative Sleep Disturbances in Myotonic Dystrophy Types 1 and 2

Article

Full-text available

Oct 2018
CURR NEUROL NEUROSCI

Purpose of Review To update current knowledge regarding sleep disturbances and myotonic dystrophies so as to better understand if sleep symptoms may help in the early recognition of the two genetic subtypes: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Recent Findings Sleep-disordered breathing (SDB), restless legs syndrome, periodic limb movements in sleep, hypersomnia, and REM sleep dysregulation are frequently described in DM1 patients. SDB does not always explain hypersomnia, but a central dysregulation of sleep–wake modulation is reported mainly in DM1. Sleep apnea, restless legs syndrome, and REM sleep without atonia have been reported in single case reports and small case series of DM2. Summary DM2 is less prevalent and more recently described than DM1, with a milder phenotype than DM1. The most frequent sleep disorders in DM1 are hypersomnia, SDB, periodic limb movements, and a narcoleptic-like phenotype, whereas restless legs syndrome, SDB, and REM sleep without atonia seem to be the most frequent sleep disorders in DM2. Comparative sleep studies are strongly required to delineate the sleep phenotype of myotonic dystrophies.

Parkinsonism with excessive daytime sleepiness

Article

Feb 2005

Background : Parkinsonian patients with excessive daytime sleepiness (EDS), hallucinations, REM sleep behavior disorder (RBD), short mean sleep latencies, and sleep-onset REM periods (SOREMP) on multiple sleep latency tests (MSLT) have been reported. In these patients a narcolepsy-like pathophysiology of sleep-wake disturbances has been suggested. Patients and methods : We studied 14 consecutive patients with Parkinsonism and EDS. Standard studies included assessment of duration and severity of Parkinsonism (Hoehn & Yahr score), Epworth sleepiness score (ESS), history of "REM-symptoms” (RBD/hallucinations/sleep paralysis/cataplexy-like episodes), polysomnography (PSG),MSLT, and measurement of cerebrospinal fluid (CSF) levels of hypocretin-1 (orexin A). Results : There were 12 men and 2 women (mean age 69 years; range 54-82). The mean duration and the Hoehn & Yahr score were 6.3 years and 2.2, respectively. Diagnoses included idiopathic Parkinson's disease (IPD, n=10), dementia with diffuse Lewy bodies (n=3), and multisystem atrophy (n=1). The ESS was ≥10 in all patients (mean 12; range 10-18). "REM-symptoms” were reported by all but two patients (hallucinations: n=9; RBD: n=9).None of the patients reported cataplexy-like symptoms or sleep paralysis. On PSG sleep apnea (apnea hypopnea index > 10/h, n=7), periodic limb movements during sleep (PLMS-index > 10/h, n=6), and features of RBD (n=5) were found. On MSLT mean sleep latency was < 5 minutes in 10 patients, and SOREMP were found in two patients. When compared with controls (n=20, mean 497 pg/ml; range 350-603), CSF hypocretin-1 levels were normal in 8 patients and low in 2 patients (221 and 307 pg/ml, respectively). Conclusion : These findings do not support the hypothesis of a "final common pathway” in the pathophysiology of narcolepsy and Parkinsonism with EDS. Sleep apnea and PLMS may play a so-far underestimated role in the pathogenesis of EDS in Parkinsonian patients

Alterations of the brain network in idiopathic rapid eye movement sleep behavior disorder: structural connectivity analysis

Article

Full-text available

Jun 2019
SLEEP BREATH

Purpose To evaluate and compare structural connectivity using graph theoretical analysis in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy subjects. Methods Ten consecutive patients with iRBD were recruited from a single tertiary hospital. All patients had normal brain magnetic resonance imaging results on visual inspection. They did not have any other neurological disorder. Control subjects were also enrolled. All subjects underwent three-dimensional volumetric T1-weighted imaging. Absolute structural volumes were calculated using FreeSurfer image analysis software. Structural volume and connectivity analyses were performed with Brain Analysis using Graph Theory. Results Compared to healthy controls, patients with iRBD showed significant alterations in cortical and subcortical volumes, showing increased volumes of frontal cortex, thalamus, and caudate nucleus. In addition, patients with iRBD exhibited significantly different structural connectivity compared to healthy controls. In measures of global network, average degree, global efficiency, and local efficiency were decreased whereas characteristic path length was increased in iRBD patients. In measures of local network, there was significant hub reorganization in patients with iRBD. Betweenness centrality of caudate nucleus and frontal cortex was increased in patients with iRBD. Conclusions This is the first study to report that structural volume and connectivity in patients with iRBD are significantly different from those in healthy controls. iRBD patients exhibited disrupted topological disorganization of the global brain network and hub reorganization. These alterations are implicated in the pathogenesis of iRBD. They might be potential biomarkers of iRBD.

Neuroimaging of Sleep Disturbances in Movement Disorders

Article

Full-text available

Sep 2018

Sleep dysfunction is recognized as a distinct clinical manifestation in movement disorders, often reported early on in the disease course. Excessive daytime sleepiness, rapid eye movement sleep behavior disorder and restless leg syndrome, amidst several others, are common sleep disturbances that often result in significant morbidity. In this article, we review the spectrum of sleep abnormalities across atypical Parkinsonian disorders including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), as well as Parkinson's disease (PD) and Huntington's disease (HD). We also explore the current concepts on the neurobiological underpinnings of sleep disorders, including the role of dopaminergic and non-dopaminergic pathways, by evaluating the molecular, structural and functional neuroimaging evidence based on several novel techniques including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Based on the current state of research, we suggest that neuroimaging is an invaluable tool for assessing structural and functional correlates of sleep disturbances, harboring the ability to shed light on the sleep problems attached to the limited treatment options available today. As our understanding of the pathophysiology of sleep and wake disruption heightens, novel therapeutic approaches are certain to transpire.

Pharmacological treatment for REM sleep behavior disorder in Parkinson disease and related conditions: A scoping review

Article

Aug 2018

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the presence of a complex of signals resulting from the loss of REM sleep atony and manifested by vigorous and sometimes violent motor jerks and nocturnal vocalizations associated with dream enactment. RBD might be a clinical predictor of severity for Parkinson's disease (PD) and one of its most important non-motor manifestations, preceding the emergence of synucleinopathy by several years or even decades. The detection of RBD may represent a therapeutic window for research regarding the development of new neuroprotective therapies with the potential to modify the natural course of synucleinopathies, such as PD. We performed a scoping review of studies indexed in MEDLINE and LILACS focusing on pharmacological interventions for RBD associated with PD. Fourteen articles were selected. Study designs comprised randomized and non-randomized clinical trials (n = 153 participants) and observational studies (retrospective cohorts and case series, n = 248 participants). Melatonin and clonazepam appear to be useful for treating RBD in PD, but these findings are mostly supported by observational studies and a few controlled studies with a small number of participants. New pharmacological agents, such as melatoninergic agonists and phytocannabinoids, appear to be promising therapies. The findings from studies focusing on anticholinesterases and new dopaminergic agents are still deemed inconclusive.

Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation

Article

Full-text available

Oct 2018
CELL MOL LIFE SCI

Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.

Therapeutic Symptomatic Strategies in the Parasomnias

Article

Full-text available

Jun 2018

Purpose of review: The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias. Recent findings: Recent pathophysiological findings about sleep structure in parasomnias helped understanding several drug mechanisms of action. Serotoninergic theory accounts for the effect of serotoninergic drugs. Study about spectral analysis of sleep showed the effect of clonazepam on spectral bands. Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders. A series of therapeutic strategies were analyzed and compared. Benzodiazepines, antidepressant drugs, and L-5-hydroxytryptophan may be beneficial in DOA. SSRI and topiramate are effective in SRED. RBD responds to clonazepam, melatonin, and to a lesser extent to dopaminergic and anticholinergic agents. Prazosin and cannabinoids are effective in nightmare disorder. Sleep paralysis may respond to antidepressant agents. Tricyclic antidepressant may be effective in sleep-related hallucinations and exploding head syndrome. Sleep enuresis may be successfully treated with desmopressin, anticholinergic drugs, and imipramine.

The REM sleep circuit and how its impairment leads to REM sleep behavior disorder

Article

Full-text available

Jul 2018
CELL TISSUE RES

Alex Iranzo

REM sleep is characterized by rapid eye movements, desynchronized electroencephalographic activity, dreams and muscle paralysis that preclude the individual from acting out the action of dreams. REM sleep is generated and modulated by a complex and still poorly understood, neuronal network that involves multiple nuclei and neurotransmission systems. The key structures that generate REM sleep muscle paralysis are the subcoeruleus nucleus in the mesopontine tegmentum and the reticular formation of the ventral medial medulla. Using glutamatergic, GABAergic and glycinergic inputs, direct and indirect projections from these two areas inhibit the motoneurons of the spinal cord resulting in skeletal paralysis in REM sleep. Experimental studies in cats and rodents where the subcoeruleus nucleus and ventral medial medulla were impaired by electrolytic, pharmacological and genetic manipulations have repeatedly produced increased electromyography activity during REM sleep associated with abnormal motor behaviors (e.g., prominent twitching, attack-like behaviors). These animal models represent the pathophysiological substrate of REM sleep behavior disorder, a parasomnia in humans characterized by nightmares and abnormal vigorous behaviors (e.g., prominent jerking, shouting, kicking) linked to excessive phasic and/or tonic electromyographic activity in REM sleep. The extraordinary observation that a sleep disorder is often the first manifestation of a devastating neurodegenerative disease such as Parkinson disease carries important diagnostic implications and opens a window for neuroprotection. This review addresses the neuronal substrates of REM sleep generation and modulation and how its impairment may lead to REM sleep behavior disorder.

Neuroanatomical Structure of the MCH System

Chapter

Apr 2018

The mammalian melanin-concentrating hormone (MCH) system has been studied for almost 30 years as of the writing of this chapter. The understanding of any neural system starts with its structure, as the anatomical organization of its peptides and receptors provides important clues about its physiological activity. With that in mind, the MCH system will be reviewed as a whole in the first segment of this chapter, including the genes and proteins that comprise this system. In the following segment, a description of the morphological and neurochemical characteristics of MCH neurons will be provided, including the areas in the central nervous system where these neurons are found and their projection pathways and targets. In the last segment, the receptors for MCH will be briefly discussed, and the available anatomical information about these receptors will be presented to the reader. By the end of this chapter, the reader should be able to identify the sites of MCH synthesis, the major targets of MCH action, and the areas responsive to MCH owing to the presence of its receptor.

Effects of Pedunculopontine Nucleus (PPN) Stimulation on Caudal Pontine Reticular Formation (PnC) Neurons In Vitro

Article

Full-text available

Jun 2002

Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states. Previously, PPN stimulation was reported to induce prolonged responses (PRs) in extracellularly recorded PnC neurons in the decerebrate cat. The present study used intracellular recordings in semihorizontal slices from rat brain stem ( postnatal days 12–21) to determine responses in PnC neurons following PPN stimulation. Two-thirds (65%) of PnC neurons showed PRs after PPN stimulation. PnC neurons with PRs had higher amplitude afterhyperpolarizations (AHP) than non-PR (NPR) neurons. Both PR and NPR neurons were of mixed cell types characterized by “A” and/or “LTS,” or neither of these types of currents. PnC cells showed decreased AHP duration with age, due mostly to decreased AHP duration in NPR cells. The longest mean duration PRs were induced by stimulation at 60 and 90 Hz compared with 10 or 30 Hz. Maximal firing rates in PnC cells during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. BaCl 2 superfusion blocked PPN stimulation-induced PRs, suggesting that PRs may be mediated by blockade of potassium channels, in keeping with increased input resistance observed during PRs. Depolarizing pulses failed to elicit, and hyperpolarizing pulses failed to reset, PPN stimulation-induced PRs, suggesting that PRs may not be plateau potentials. Pharmacological testing revealed that nifedipine superfusion failed to block PPN stimulation-induced PRs; i.e., PRs may not be calcium channel-dependent. The muscarinic cholinergic agonist carbachol induced depolarization in most PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked PPN stimulation-induced PRs in some PnC neurons, suggesting that some PRs may be due to muscarinic receptor activation. The nonspecific ionotropic glutamate receptor antagonist kynurenic acid failed to block PPN stimulation-induced PRs, as did the metabotropic glutamate receptor antagonist (R, S)-αmethyl-4-carboxyphenylglycine, suggesting that PRs may not be mediated by glutamate receptors. These findings suggest that PPN stimulation-induced PRs may be due to increased excitability following closing of muscarinic receptor-sensitive potassium channels, allowing PnC neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs using parameters known best to induce locomotion. This mechanism may be related to switching from one state to another (e.g., locomotion vs. standing or sitting, waking vs. non-REM sleep or REM sleep).

The pedunculopontine tegmentum controls renal sympathetic nerve activity and cardiorespiratory activities in nembutal-anesthetized rats

Article

Full-text available

Nov 2017
PLOS ONE

Elevated renal sympathetic nerve activity (RSNA) accompanies a variety of complex disorders, including obstructive sleep apnea, heart failure, and chronic kidney disease. Understanding pathophysiologic renal mechanisms is important for determining why hypertension is both a common sequelae and a predisposing factor of these disorders. The role of the brainstem in regulating RSNA remains incompletely understood. The pedunculopontine tegmentum (PPT) is known for regulating behaviors including alertness, locomotion, and rapid eye movement sleep. Activation of PPT neurons in anesthetized rats was previously found to increase splanchnic sympathetic nerve activity and blood pressure, in addition to altering breathing. The present study is the first investigation of the PPT and its potential role in regulating RSNA. Microinjections of DL-homocysteic acid (DLH) were used to probe the PPT in 100-μm increments in Nembutal-anesthetized rats to identify effective sites, defined as locations where changes in RSNA could be evoked. A total of 239 DLH microinjections were made in 18 rats, which identified 20 effective sites (each confirmed by the ability to evoke a repeatable sympathoexcitatory response). Peak increases in RSNA occurred within 10–20 seconds of PPT activation, with RSNA increasing by 104.5 ± 68.4% (mean ± standard deviation) from baseline. Mean arterial pressure remained significantly elevated for 30 seconds, increasing from 101.6 ± 18.6 mmHg to 135.9 ± 36.4 mmHg. DLH microinjections also increased respiratory rate and minute ventilation. The effective sites were found throughout the rostal-caudal extent of the PPT with most located in the dorsal regions of the nucleus. The majority of PPT locations tested with DLH microinjections did not alter RSNA (179 sites), suggesting that the neurons that confer renal sympathoexcitatory functions comprise a small component of the PPT. The study also underscores the importance of further investigation to determine whether sympathoexcitatory PPT neurons contribute to adverse renal and cardiovascular consequences of diseases such as obstructive sleep apnea and heart failure.

Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson's disease cholinopathy

Article

Full-text available

Jul 2017

Rhythmic oscillations of neuronal populations, generated by different mechanisms, are present at several levels of the central nervous system and serve many important physiological or reflect pathological functions. Understanding the role of brain oscillations as possible biomarkers of brain function and plasticity is still a challenge, and despite extensive research, their role is still not well established. We recently demonstrated that the hallmarks of earlier aging onset during impaired thalamo-cortical cholinergic innervation (in a rat model of Parkinson’s disease cholinopathy) were consistently expressed, from 3 and one half to 5 and one half months of age, through increased electroencephalographic (EEG) sigma activity amplitude during rapid eye movement (REM) sleep, as a unique aging induced REM sleep phenomenon. In addition, there was altered motor cortical drive during non-rapid-eye-movement (NREM) and REM sleep. In order to explain this new aging-induced REM sleep phenomenon, we analyzed possible differences between control REM sleep spindle activity and REM sleep spindle activity at the onset of REM sleep “enriched“ with sigma activity (at 4 and one half months of age), following bilateral pedunculopontine tegmental nucleus (PPT) cholinergic neuronal loss in the rat. We analzyed differences in spindle density, duration, and frequency. We demonstrated in young adult Wistar rats with the severely impaired PPT cholinergic innervation the alterations in sleep spindle dynamics and pattern during REM sleep in the motor cortex as the earliest biomarkers for the onset of their altered aging processes.

Cardiovascular effects of nitrergic system of the pedunculopontine tegmental nucleus in anesthetized rats

Article

Full-text available

Jul 2017

Objectives: Nitric oxide (NO) is an important neurotransmitter in central nervous system involved in central cardiovascular regulation. The presence of NO in the pedunculopontine tegmental (PPT) nucleus has been shown, but its cardiovascular effect has not been determined. In the present study, the cardiovascular effect of NO in the PPT nucleus was evaluated. Materials and methods: After induction of anesthesia, a polyethylene catheter (PE-50) filled with heparinized saline inserted into the femoral artery, and the blood pressure (BP) and heart rate (HR) were continuously recorded. Animals were then placed in a stereotaxic apparatus and maximum changes of mean arterial pressure (∆MAP) and heart rate (∆HR) after microinjection of two doses of N(G)-nitro-L-arginine methyl ester (L-NAME, 30 and 90 nmol), L-arginine (L-Arg 10 and 50 nmol) and sodium nitroprusside (SNP, 9 and 27 nmol) into the PPT were provided and compared with control group (One-way ANOVA). Results: Both doses of L-NAME significantly increased ∆MAP compared to control (P<0.05 and P<0.01, respectively). ∆HR only in higher dose (90 nmol) significantly increased compared to control (P<0.05). Two doses of L-Arg (10 and 50 nmol/150 nl) had no significant effect on ∆MAP or ∆HR. Higher dose of SNP (27 nmol) significantly decreased ∆MAP (P<0.05) and its both doses significantly decreased ∆HR compared to control (P<0.05 and P<0.001, respectively). Effect of higher dose on ∆HR was significantly higher than the lower dose (P<0.05). Conclusion: Our results show an inhibitory effect of the nitrergic system of the PPT on central cardiovascular system.

The Impact of Subthalamic Deep Brain Stimulation on Sleep-Wake Behavior: A Prospective Electrophysiological Study in 50 Parkinson Patients

Article

Mar 2017

Study Objectives This prospective observational study was designed to systematically examine the effect of subthalamic deep brain stimulation (DBS) on subjective and objective sleep-wake parameters in Parkinson patients. Methods In 50 consecutive Parkinson patients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus, subjective sleep-wake parameters, two-week actigraphy, video-polysomnography studies and sleep EEG frequency and dynamics analyses before and 6 months after surgery. Results Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents, but also enhanced subjective sleep quality and reduced sleepiness (ESS: -2.1±3.8, P<0.001). Actigraphy recordings revealed longer bedtimes (+1:06±0:51 hours, P<0.001) without shifting of circadian timing. Upon polysomnography, we observed an increase of sleep efficiency (+5.2±17.6%, P=0.005) and deep sleep (+11.2±32.2 min, P=0.017), and increased accumulation of slow-wave activity over the night (+41.0±80.0%, P=0.005). REM sleep features were refractory to subthalamic DBS and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep efficiency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinson patients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the subthalamic nucleus directly contributes to changes in sleep-wake behavior, but dorsal positioning of electrodes within the subthalamic nucleus is linked to improved sleep-wake outcomes.

Schlafstörungen beim idiopathischen Parkinson-Syndrom

Article

Feb 2017

Viele Patienten mit idiopathischem Parkinson-Syndrom leiden unter nicht motorischen Symptomen wie Schlafstörungen, die zu Einschränkungen der Lebensqualität führen. Gehäuft treten Insomnien, eine erhöhte Tagesschläfrigkeit und die REM-Schlaf-Verhaltensstörung auf. Zudem leiden auch Parkinson-Patienten unter primären Schlafstörungen wie schlafbezogenen Atmungsstörungen und dem Restless-Legs-Syndrom. Zur Therapie der Schlafstörungen sollten zunächst eine Optimierung der Behandlung der Grunderkrankung sowie spezielle nicht medikamentöse und medikamentöse Verfahren angewendet werden

Pedunculopontine network dysfunction in Parkinson's disease with postural control and sleep disorders: Functional connectivity of PPN circuits in PD

Article

Feb 2017

Background: The objective of this study was to investigate pedunculopontine nucleus network dysfunctions that mediate impaired postural control and sleep disorder in Parkinson's disease. Methods: We examined (1) Parkinson's disease patients with impaired postural control and rapid eye movement sleep behavior disorder (further abbreviated as sleep disorder), (2) Parkinson's disease patients with sleep disorder only, (3) Parkinson's disease patients with neither impaired postural control nor sleep disorder, and (4) healthy volunteers. We assessed postural control with clinical scores and biomechanical recordings during gait initiation. Participants had video polysomnography, daytime sleepiness self-evaluation, and resting-state functional MRIs. Results: Patients with impaired postural control and sleep disorder had longer duration of anticipatory postural adjustments during gait initiation and decreased functional connectivity between the pedunculopontine nucleus and the supplementary motor area in the locomotor network that correlated negatively with the duration of anticipatory postural adjustments. Both groups of patients with sleep disorder had decreased functional connectivity between the pedunculopontine nucleus and the anterior cingulate cortex in the arousal network that correlated with daytime sleepiness. The degree of dysfunction in the arousal network was related to the degree of connectivity in the locomotor network in all patients with sleep disorder, but not in patients without sleep disorder or healthy volunteers. Conclusions: These results shed light on the functional neuroanatomy of pedunculopontine nucleus networks supporting the clinical manifestation and the interdependence between sleep and postural control impairments in Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.

Neurobiology of Dreaming

Chapter

Dec 2017

Role of the pedunculopontine nucleus in controlling gait and sleep in normal and parkinsonian monkeys

Article

Full-text available

Mar 2018
J NEURAL TRANSM

Patients with Parkinson’s disease (PD) develop cardinal motor symptoms, including akinesia, rigidity, and tremor, that are alleviated by dopaminergic medication and/or subthalamic deep brain stimulation. Over the time course of the disease, gait and balance disorders worsen and become resistant to pharmacological and surgical treatments. These disorders generate debilitating motor symptoms leading to increased dependency, morbidity, and mortality. PD patients also experience sleep disturbance that raise the question of a common physiological basis. An extensive experimental and clinical body of work has highlighted the crucial role of the pedunculopontine nucleus (PPN) in the control of gait and sleep, and its potential major role in PD. Here, we summarise our investigations in the monkey PPN in the normal and parkinsonian states. We first examined the anatomy and connectivity of the PPN and the cuneiform nucleus which both belong to the mesencephalic locomotor region. Second, we conducted experiments to demonstrate the specific effects of PPN cholinergic lesions on locomotion in the normal and parkinsonian monkey. Third, we aimed to understand how PPN cholinergic lesions impair sleep in parkinsonian monkeys. Our final goal was to develop a novel model of advanced PD with gait and sleep disorders. We believe that this monkey model, even if it does not attempt to reproduce the exact human disease with all its complexities, represents a good biomedical model to characterise locomotion and sleep in the context of PD.

Etude préclinique de l'effet de la stimulation cérébrale profonde de l'axe hypothalamo-pedonculopontin sur le comportement de veille/sommeil normal et en condition de déplétion en dopamine

Thesis

Full-text available

Feb 2022

Aurélie Davin

Moins connus que les symptômes moteurs et psychiatriques, les troubles du comportement de veille/sommeil affectent sérieusement la qualité de vie, l'autonomie et la sécurité des patients atteints de la maladie de Parkinson (MP). Il a été montré que certains de ces troubles peuvent apparaitre dès les stades précoces de la maladie mais la cinétique d’apparition et la nature de ces troubles ne sont pas encore complètement décrites. Ainsi, dans la première partie de ces travaux, nous nous sommes attachés à reproduire et caractériser ces signes cliniques dans un modèle progressif de la MP, chez le primate non-humain (PNH) traité au MPTP, qui présente une déplétion en dopamine similaire aux patients parkinsoniens, afin de mieux comprendre la physiopathologie sous-jacente et permettre d’identifier des biomarqueurs de la maladie (voir Etude1). La présente étude suggère que les somnolences excessives diurnes (SED), caractérisées, entre autres, par une diminution du délai d’apparition du premier épisode de sommeil le matin et une diminution des périodes d’éveil ininterrompu, ainsi qu’une désorganisation du sommeil nocturne, caractérisée par une augmentation du sommeil lent profond au détriment des autres stades de sommeil lent, apparaissent précocement chez le PNH traité au MPTP. Ainsi, ces signes cliniques pourraient être utilisés comme biomarqueurs pour une identification précoce des patients à risque de développer la MP. De plus, il a été montré que ces troubles, en particulier les SED sont corrélées et même aggravées par les traitements actuels de la MP. Aussi, il est important de développer de nouvelles thérapies pour traiter ce symptôme non-moteur. L’objectif de cette deuxième partie de l'étude a été d'évaluer l'effet de la stimulation cérébrale profonde, à basse et haute fréquence, de deux centres de l’éveil, le noyau pédonculopontin (PPN) (voir Etude2) et l'hypothalamus latéral (LH) (voir Etude3), sur le comportement de veille/sommeil des PNHs sains puis traités au MPTP selon le protocole précité. Ces expériences ont montré que la stimulation à basse fréquence, du PPN et du LH, est plus efficace pour potentialiser l’éveil pendant les périodes physiologiques, c’est-à-dire pendant la journée, et particulièrement en condition de déplétion en dopamine. Cet effet éveillant, observé dans notre étude, apparaît comme un résultat encourageant qui offre de nouvelles perspectives pour traiter les troubles de veille/sommeil dans la MP, et qui sont également observés dans d’autres maladies neurodégénératives.

New Paradigm in the Management of REM Sleep Behavior Disorder

Article

Full-text available

Feb 2023

Purpose of Review Rapid eye movement (REM) behavior disorder (RBD) is a complex parasomnia, with growing evidence showing that it represents a prodromal marker for the development of alpha-synuclein neurodegenerative disease. The treatment of RBD previously lacked strong evidence until now. In this paper, we aim to review the current and newly emerging options for the treatment of RBD. Recent Findings The best current evidence in the pharmacologic therapies for RBD is based on small clinical trials and case studies. Clonazepam and melatonin remain the initial standard of treatment and are used as an off-label for RBD. Additional pharmacologic agents have shown potential promise for controlling RBD symptoms, but more research is needed. Currently, large international initiatives such as the IRBDSG, the NAPS consortium, and the PPMI 2.0 are actually recruiting RBD patients into registries to better understand the pathophysiology of RBD, potential biomarkers that indicate phenoconversion to alpha-synuclein states, and to promote further research in neuroprotective trials for disease prevention. Summary The current literature highlights the exciting opportunities to conduct appropriately designed, large-scale, randomized, controlled trials to advance the management of RBD.

Parkinsons Disease: Recent Advancement and Future Aspects

Article

Oct 2022

A prevalent neurodegenerative condition known as Parkinson's disease (PD) is characterized by a movement disorder with bradykinesia, rest tremor, rigidity, and postural instability. The majority of contemporary PD treatments are predicated on restoring dopaminergic tone in the striatum; however, there are few effective choices available. These, however, do not change the course of the disease and do not address the dopamine-independent symptoms of PD, such as freezing gait, cognitive impairment, and other non-motor aspects of the condition, which frequently have the biggest effects on quality of life. Novel therapy approaches are developing as our understanding of Parkinson's disease pathophysiology increases. These include therapies that target PD symptoms while avoiding the unfavorable side effects associated with currently available therapies, as well as therapies that halt pathology, minimize neuronal loss, and moderate disease progression. This article discusses some promising approaches that are currently being researched in the laboratories or are in the clinical trial phase such as cell based therapies, gene therapy, neuronal therapy, infusion therapy, neuron regeneration and novel drug approaches, which can pose as the future for the treatment of Parkinson’s disease

Basal Ganglia Circuitry and Synaptic Connectivity

Chapter

Jan 2003

The basal ganglia are several synaptically interconnected subcortical structures that play important roles in regulating various aspects of psychomotor behaviors, and are central to the pathophysiology of common human movement disorders such as Parkinson’s and Huntington’s diseases (PD/HD). These structures classically include: 1) the striatum, which comprises the caudate nucleus (CD), putamen (PUT), and nucleus accumbens (Acc); 2) the globus pallidus, which includes the external (GPe; globus pallidus in nonprimates) and internal (GPi; entopeduncular nucleus [EPN] in nonprimates) segments; 3) the subthalamic nucleus (STN); and 4) the substantia nigra, which comprises the pars compacta (SNc) and pars reticulata (SNr) (Fig. 1).

Effects of Deep Brain Stimulation on Sleep-Wake Disturbances in Patients with Parkinson's Disease: A Narrative Review

Article

Full-text available

Feb 2021

Sleep-wake disturbances (SWD) are one of the most common non-motor symptoms in Parkinson's disease (PD) and can appear in the early stage even before the onset of motor symptoms. Deep brain stimulation (DBS) is an established treatment for the motor symptoms in patients with advanced PD. However, the effect of DBS on SWD and its specific mechanisms are not widely understood and remain controversial. In addition to the circuit-mediated direct effect, DBS may improve SWD by an indirect effect such as the resolution of nocturnal motor complications and a reduction of dopaminergic medication. Here, the authors review the recent literatures regarding the impact of DBS on SWD in patients with PD. Furthermore, the selection of the DBS targets and the specific effects of applying DBS to each target on SWD in PD are also discussed.

Étude des mécanismes de coordination des activités rythmiques locomotrices et sympathiques au sein d’un réseau spinal activé par l’acétylcholine chez le rat nouveau-né

Thesis

Full-text available

Dec 2017

Mélissa Sourioux

La locomotion, comme toute autre forme d'activité physique, mobilise le système nerveux autonome pour faire face à la demande physiologique croissante. Ces réponses autonomes impliquent un couplage entre les activités motrices sympathiques et somatiques. De manière intéressante, à la fois les réseaux locomoteurs spinaux, ainsi que les neurones préganglionnaires sympathiques intermédiolatéraux (IMLs) sont les cibles d’une modulation par le système cholinergique propriospinal. Dans ce contexte, le but de mon travail doctoral a été d'étudier le rôle du système cholinergique propriospinal dans la coordination entre ces deux systèmes. En utilisant une préparation de moelle épinière de rat nouveau-né isolée in vitro, nous avons montré que l’acétylcholine pourrait permettre un couplage entre les réseaux locomoteurs et sympathiques via l’activation de récepteurs muscariniques. En effet, l'oxotrémorine, un agoniste non-sélectif de ces récepteurs, induit une activité rythmique lente bloquée par des antagonistes des récepteurs muscariniques M1, M2, M3 et M4. De plus, l’oxotrémorine permet de révéler des capacités rythmogènes endogènes de la moelle épinière thoracique. Nous avons observé que les motoneurones thoraciques étaient rythmiquement actifs à la fois durant des épisodes de locomotion fictive et lors de l’application d'oxotrémorine. A l’inverse, les IMLs présentaient une activité rythmique uniquement en présence d'oxotrémorine. Cette étude fournit ainsi de nouveaux éléments concernant les processus neuronaux à l'origine du couplage entre les systèmes somatiques et sympathiques. Nous proposons ici que ces mécanismes de synchronisation sont réalisés en partie via un réseau intraspinal pouvant être activé conditionnellement par le système cholinergique propriospinal.

REM sleep behavior disorder in patients with Parkinson’s disease: clinical and polysomnographic characteristics

Article

Oct 2018

The objectives of this study were to describe the characteristics of RBD in a group of PD patients and verify the accuracy of the clinical interview in this group, determine the causes of failure of the interview, as well as to verify the clinical and polysomnographic differences between the groups of PD patients with and without RBD. So, a cross-sectional study was conducted in 88 consecutive PD patients from the outpatient clinic, during a period of 21 months. Participants underwent a clinical interview, assessment based on standardized scales (Epworth Sleepiness Scale, Parkinson’s disease Questionnaire, Pittsburgh Sleep Quality Index), and video polysomnography. Out of the 88 participants, 55 underwent vPSG which confirmed a diagnosis of RBD. The clinical interview had a high sensitivity (87.5%) but a low specificity (42.1%) for RBD diagnosis and thus the clinical interview alone may miss those without episodes of dream-enacting behavior. We note in this group a higher proportion of men (54.5%) and an average age of 60.4 years ± 10.6. In 54% of patients, RBD preceded motor symptoms of PD. In addition, patients with PD and RBD had lower Apnea–Hypopnea Index in REM sleep and a higher equivalent dose of levodopa than PD patients without RBD. RBD is a prevalent condition in patients with PD, requiring polysomnography for diagnostic confirmation, and is associated with certain particularities in PD.

Pedunculopontine nucleus: An integrative view with implications on Deep Brain Stimulation

Article

Sep 2018

The pedunculopontine nucleus (PPN) is a reticular nucleus located in the mesencephalic and upper pontine tegmentum. Initially, characterized by its predominant cholinergic projection neurons, it was associated with the "mesencephalic locomotor region" and "reticular activating system". Furthermore, based on histopathological studies, the PPN was hypothesized to play a role in the manifestation of symptoms in movement disorders such as Parkinson's disease (PD). Since axial symptoms represent unmet needs of PD treatments, a series of pioneering experiments in Parkinsonian monkeys promoted the idea of a potential new target for deep brain stimulation (DBS) and much clinical interest was generated in the following years leading to a number of trials analysing the role of PPN for gait disorders. This review summarizes the historical background and more recent findings about the anatomy and function of the PPN and its implications in the basal ganglia network of the normal as well as diseased brain. Classical views on PPN function shall be challenged by more recent findings. Additionally, the current role and future perspectives of PPN DBS in PD patients shall be outlined.

Update on the clinical application of deep brain stimulation in sleep dysfunction of Parkinson’s disease

Article

Jul 2018

Sleep dysfunctions, including rapid eye movement sleep behavior disorder, sleep fragmentation, excessive daytime sleepiness and various other dysfunctions, can seriously affect quality of life in patients with Parkinson's disease (PD). Emerging evidence suggests that deep brain stimulation (DBS) exerts a substantial effect when used to treat sleep dysfunctions, which are common nonmotor symptoms experienced by patients with PD. However, far less is known about the specific mechanisms underlying the effects of DBS on sleep processes and the factors that potentially influence these effects. These issues therefore need to be further clarified. Intriguingly, a number of recent studies have evaluated the effects of applying DBS to various brain targets on sleep in patients with PD. Deeper research into the efficacy of applying DBS to each brain target may help determine which region should be targeted during surgery in PD patients. Furthermore, compared with pharmacological therapy, DBS had more beneficial effects on sleep symptoms, and appropriate management involving the joint application of dopamine replacement therapy and DBS might accelerate the effects of treatment. Here, we review the potential roles DBS may play and provide clinical guidance for the use of DBS in treating sleep dysfunctions in PD patients.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder

Article

Mar 2018

Background: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. Methods: We studied twenty-one polysomnography-confirmed iRBD patients with18F-DOPA and11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 918F-DOPA and n = 2011C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. Results: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in11C-PK11195 binding were observed. Other regions sampled showed no18F-DOPA or11C-PK11195 PET differences between groups. Voxel-level interrogation of11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. Conclusion: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features

Article

Jun 2017
CEREB CORTEX

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. Anatomical gray matter abnormalities in the motor cortico-subcortical loop areas remain under studied in iRBD patients. We acquired T1-weighted images and administrated quantitative motor tasks in 41 patients with polysomnography-confirmed iRBD and 41 healthy subjects. Cortical thickness and voxel-based morphometry (VBM) analyses were performed to investigate local cortical thickness and gray matter volume changes, vertex-based shape analysis to investigate shape of subcortical structures, and structure-based volumetric analyses to investigate volumes of subcortical and brainstem structures. Cortical thickness analysis revealed thinning in iRBD patients in bilateral medial superior frontal, orbitofrontal, anterior cingulate cortices, and the right dorsolateral primary motor cortex. VBM results showed lower gray matter volume in iRBD patients in the frontal lobes, anterior cingulate gyri, and caudate nucleus. Shape analysis revealed extensive surface contraction in the external and internal segments of the left pallidum. Clinical and motor impaired features in iRBD were associated with anomalies of the motor cortico-subcortical loop. In summary, iRBD patients showed numerous gray matter structural abnormalities in the motor cortico-subcortical loop, which are associated with lower motor performance and clinical manifestations of iRBD.

Motor Control and Dyscontrol in Sleep

Chapter

May 2017

This chapter deals with motor functions and dysfunctions in sleep. A variety of motor disorders may appear during sleep interfering with sleep. After a brief summary of motor control in wakefulness the chapter addresses how this control changes during different stages of sleep and how its dyscontrol may arise and affect an individual. We classify motor disorders in sleep into two broad categories: Diurnal movement disorders persisting in sleep and those occurring exclusively in sleep. Following a brief description of these entities we conclude the chapter by addressing approach to these motor disorders in sleep and outlining principles of treatment.

Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology

Article

Full-text available

Oct 2016
STEREOT FUNCT NEUROS

Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.

Neural Control of the Upper Airway: Respiratory and State-Dependent Mechanisms

Chapter

Sep 2016

Leszek Kubin

Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA. © 2016 American Physiological Society. Compr Physiol 6:1801-1850, 2016.

A Review of Sleep and Its Disorders in Patients with Parkinson's Disease in Relation to Various Brain Structures

Article

Full-text available

May 2016

Sleep is an indispensable normal physiology of the human body fundamental for healthy functioning. It has been observed that Parkinson’s disease (PD) not only exhibits motor symptoms, but also non-motor symptoms such as metabolic irregularities, altered olfaction, cardiovascular dysfunction, gastrointestinal complications and especially sleep disorders which is the focus of this review. A good understanding and knowledge of the different brain structures involved and how they function in the development of sleep disorders should be well comprehended in order to treat and alleviate these symptoms and enhance quality of life for PD patients. Therefore it is vital that the normal functioning of the body in relation to sleep is well understood before proceeding on to the pathophysiology of PD correlating to its symptoms. Suitable treatment can then be administered towards enhancing the quality of life of these patients, perhaps even discovering the cause for this disease.

Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves

Article

Full-text available

Aug 1990

The only mesopontine neurons previously described as involved in the transfer of ponto-geniculo-occipital (PGO) waves from the brain stem to the thalamus were termed PGO-on bursting cells. We have studied, in chronically implanted cats, neuronal activities in brain-stem peribrachial (PB) and laterodorsal tegmental (LDT) cholinergic nuclei in relation to PGO waves recorded from the lateral geniculate (LG) thalamic nucleus during rapid-eye-movement (REM) sleep. We constructed peri-PGO histograms of PB/LDT cells' discharges and analyzed the interspike interval distribution during the period of increased neuronal activity related to PGO waves. Six categories of PGO-related PB/LDT neurons with identified thalamic projections were found: 4 classes of PGO-on cells: PGO-off but REM-on cells: and post-PGO cells. The physiological characteristics of a given cell class were stable even during prolonged recordings. One of these cell classes (1) represents the previously described PGO-on bursting neurons, while the other five (2–6) are newly discovered neuronal types. (1) Some neurons (16% of PGO-related cells) discharged stereotyped low-frequency (120– 180 Hz) spike bursts preceding the negative peak of the LG-PGO waves by 20–40 msec. These neurons had low firing rates (0.5–3.5 Hz) during all states. (2) A distinct cell class (22% of PGO-related neurons) fired high-frequency spike bursts (greater than 500 Hz) about 20–40 msec prior to the thalamic PGO wave. These bursts were preceded by a period (150–200 msec) of discharge acceleration on a background of tonically increased activity during REM sleep. (3) PGO-on tonic neurons (20% of PGO-related neurons) discharged trains of repetitive single spikes preceding the thalamic PGO waves by 100–150 msec, but never fired high- frequency spike bursts. (4) Other PGO-on neurons (10% of PGO-related neurons) discharged single spikes preceding thalamic PGO waves by 15–30 msec. On the basis of parallel intracellular recordings in acutely prepared, reserpine-treated animals, we concluded that the PGO-on single spikes arise from conventional excitatory postsynaptic potentials and do not reflect tiny postinhibitory rebounds. (5) A peculiar cellular class, termed PGO-off elements (8% of PGO-related neurons), consisted of neurons with tonic, high discharge rates (greater than 30 Hz) during REM sleep. These neurons stopped firing 100– 200 msec before and during the thalamic PGO waves. (6) Finally, other neurons discharged spike bursts or tonic spike trains 100–300 msec after the initially negative peak of the thalamic PGO field potential (post-PGO elements, 23% of PGO-related neurons).(ABSTRACT TRUNCATED AT 400 WORDS)

A primary acoustic startle circuit: lesion and stimulation studies

Article

Full-text available

Jun 1982

The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, "startle" cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.

Antagonist binding profiles of five cloned human muscarinic receptor subtypes

Article

Full-text available

Mar 2012

A variety of muscarinic antagonists are currently used as tools to pharmacologically subclassify muscarinic receptors into M1, M2 and M3 subtypes. In the present study, we have determined the affinity profiles of several of these antagonists at five cloned human muscarinic receptors (m1-m5) stably expressed in Chinese hamster ovary cells (CHO-K1). At all five receptors, the (R)-enantiomers of trihexyphenidyl and hexbutinol displayed considerably higher affinities (up to 525-fold) than their corresponding (S)-isomers. The stereoselectivity ratios [inhibition constant(S)/inhibition constant(R)] for both pairs of enantiomers were lowest at m2 receptors, suggesting that less stringent configurational demands are made by this receptor subtype. The "M1-selective" antagonist (R)-trihexyphenidyl displayed high affinities for m1 and m4 receptors. The "M2-selective" antagonists himbacine, (+-)-5,11-dihydro-11- ([(2-[(dipropylamino)methyl]-1- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one (AF-DX 384), 11-[4-[4-(diethylamino)butyl]-1-piperidinyl)acetyl)-5,11- dihydro-6H-pyrido(2,3-b) (1,4)benzodiazepine-6-one (AQ-RA 741) and (+)-(11-[2-[(diethylamino) methyl]-1-piperidinyl)acetyl)-5,11-di-hydro-6H-pyrido(2,3-b)(1,4) benzodiazepine-6-one [AF-DX 250; the (+)-enantiomer of AF-DX 116] exhibited high affinities for m2 and m4, intermediate affinities for m1 and m3 and low affinities for m5 receptors. This selectivity profile was most prominent for AQ-RA 741, which displayed 195- and 129-fold higher affinities for m2 and m4 receptors than for m5 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors

Article

Full-text available

Dec 1987

To investigate the molecular basis for the diversity in muscarinic cholinergic function, we have isolated the genes encoding the human M1 and M2 muscarinic receptors (mAChR) as well as two previously undiscovered mAChR subtypes, designated HM3 and HM4. The amino acid sequence of each subtype reflects a structure consisting of seven, highly conserved transmembrane segments and a large intracellular region unique to each subtype, which may constitute the ligand-binding and effector-coupling domains respectively. Significant differences in affinity for muscarinic ligands were detected in individual mAChR subtypes produced by transfection of mammalian cells. Each subtype exhibited multiple affinity states for agonists; differences among subtypes in the affinities and proportions of such sites suggest the capacity of mAChR subtypes to interact differentially with the cellular effector-coupling apparatus. Subtype-specific mRNA expression was observed in the heart, pancreas and a neuronal cell line, indicating that the regulation of mAChR gene expression contributes to the differentiation of cholinergic activity.

Organization of cortical, basal forebrain, and hypothalamic afferents to the parabrachial nucleus in the rat

Article

Full-text available

May 1990
J COMP NEUROL

In a previous study (Herbert et al., J. Comp. Neurol. [1990];293:540-580), we demonstrated that the ascending afferent projections from the medulla to the parabrachial nucleus (PB) mark out functionally specific terminal domains within the PB. In this study, we examine the organization of the forebrain afferents to the PB. The PB was found to recive afferents from the infralimbic, the lateral prefrontal, and the insular cortical areas; the dorsomedial, the ventromedial, the median preoptic, and the paraventricualr hypothalamic nuclei; the dorsal, the retrochiasmatic, and the lateral hypothalamic areas; the central nucleus of the amygdala; the substantia innominata; and the bed nucleus of the stria terminalis. In general, forebrain areas tend to innervate the same PB subnuclei from which they receive their input. Three major patterns of afferent termination were noted in the PB; these corresponded to the three primary sources of forebrain input to the PB: the cerebral cortex, the hypothalamus, and the basal forebrain. Hypothalamic afferents innervate predominantly rostral portions of the PB, particularly the central lateral and dorsal lateral subnuclei. The basal forebrain projection to the PB ends densely in the external lateral and waist subnuclei. Cortical afferents terminate most heavily in the caudal half of the PB, particularly in the ventral lateral and medial subnuclei. In addition, considerable topography organization was found within the individual projections. For example, tuberal lateral hypothalamic neurons project heavily to the central lateral subnucleus and lightly to the waist area; in contrast, caudal lateral hypothalamic neurons send a moderately heavy projection to both the central lateral and waist subnuclei. Our results show that the forebrain afferents of the PB are topographically organized. These topographical differences may provide a substrate for the diversity of visceral functions associated with the PB.

Anatomical and Physiological Substrates of Arousal

Chapter

Apr 2003

Arnold B. Scheibel

Consciousness is at the very core of the human condition. Yet only in recent decades has it become a major focus in the brain and behavioral sciences. Scientists now know that consciousness involves many levels of brain functioning, from brainstem to cortex. The almost seventy articles in this book reflect the breadth and depth of this burgeoning field. The many topics covered include consciousness in vision and inner speech, immediate memory and attention, waking, dreaming, coma, the effects of brain damage, fringe consciousness, hypnosis, and dissociation. Underlying all the selections are the questions, What difference does consciousness make? What are its properties? What role does it play in the nervous system? How do conscious brain functions differ from unconscious ones? The focus of the book is on scientific evidence and theory. The editors have also chosen introductory articles by leading scientists to allow a wide variety of new readers to gain insight into the field. Bradford Books imprint

Effects of monoamines and opiates on peduncolopontine neurones.

Chapter

Jan 1990

Nocturnal sleep of narcoleptics

Article

Jan 1963
Electroencephalogr Clin Neurophysiol

Movement disorders specific to sleep and the nocturnal manifestations of waking movement disorders

Article

Jan 1997

Evidence for the existence of monoamine-containing neurons in the central nervous system: I. Demonstration of monoamine in the cell bodies of brainstem neurons

Article

Jan 1964
Acta Physiol Scand Suppl

The rat brain in stereotaxic coordinates, Compact

Article

Jan 1997

Thalamocortical oscillations in the sleeping and aroused brain

Article

Sep 1993

Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations

The Isodendritic Core of the Brain Stem

Chapter

Jan 1993

According to their degree of morphological specialization, the cell populations of the brain stem may be classified into three groups: isodendritic, allo-dendritic and idiodendritic. The isodendritic neurons, or generalized neurons, are the most frequently encountered. If one discards those isodendritic centers that by common definition are sensory or motor, an isodendritic core is left which displays very little histological variation throughout the whole extent of the brain stem. This core corresponds, with certain restrictions, to the regions that are usually regarded as reticular formation. It constitutes a continuum of overlapping dendritic fields that extends from the spinal cord to the diencephalon. In view of the similarities that exist between the histology of the isodendritic core and the relatively disorganized nervous system of the lower vertebrates, it is postulated that it represents a pool of pluri-potential neurons which in the course of phylogeny have remained relatively undifferentiated and in charge of processing afferent signals of very heterogeneous origin. By contrast, the allodendritic and idiodendritic centers can be regarded as relatively specialized centers from the point of view of their dendritic morphology, connections and functions. Attention is paid to the fact that the diffuse characteristics of the isodendritic core do not necessarily entail ill-defined physiological properties.

Projections of the Lentiform Nucleus in the Monkey

Chapter

Jan 1993

The fiber projections of the corpus striatum have been the subject of intensive study and controversy for almost a century. This is particularly true of the major efferent connections represented by the ansa lenticularis. To early neurological explorers, this striking fiber system, sweeping across main subdivisions of the dienceph-alon in tortuous and recurrent trajectories, presented anatomical complexities that confounded even such distinguished investigators as Meynert, von Monakow, and von Bechterew. Although these early explorers set the stage for all subsequent studies by providing a definition and nomenclature of some of the major fiber systems related to the corpus striatum, their observations in normal human brains could furnish no reliable information concerning the origin of the ansa lenticularis, and only gross and conflicting evidence concerning its distribution. To this extent it is possible to agree with the Ransons’ indictment62 of the literature on the corpus striatum as ‘.... voluminous and full of contradictions and misinformation’.

Quisqualic acid lesions of the ventromedial medullary reticular formation: effects upon sleep-wakefulness states

Article

Jan 1988

Anatomical Investigations of the Pallidotegmental Pathway in Monkey and Man

Chapter

Jan 1996

The targets of internal pallidal efferents have attracted considerable attention given the central role proposed for the internal segment of the globus pallidus (GPi) in models of normal and pathological movement.1–3 The previous emphasis of these models on basal ganglia-thalamocortical circuitry, has left pathways between the GPi and the midbrain tegmentum largely unexplored. In the primate, the size and functional import of pallidofugal projections upon the mesopontine tegmentum are nonetheless likely to be significant. A majority of neurons in the primate GPi contribute to this pathway via collateralization from pallidothalamic fibers,4–6 and its terminl zone has been described as “extensive”7. Experimental and pathophysiological observations implicate the mesopontine tegmental region in receipt of basal ganglia output as important in modulating normal and pathological movement. Electrical stimulation and micro infusions of substance-P or NMDA8 into the mesopontine tegmentum in decerebrate subprimate preparations elicit treadmill locomotion, while GABAergic pathways play an inhibitory role8, 9 (i. e. the “mesencephalic locomotor region” (MLR).10–12 In awake behaving subprimates, cytotoxic lesions including, but not restricted to, midbrain tegmental/basal ganglia circuitry produce incomplete hindlimb extension, bradykinesia and dyscoordination.13 Depending on the locus and the electrical or pharamacological stimulus parameters applied, motor effects ranging from decreased “postural support” to increased spontaneous motor activity have also been reported.14–21 Enhanced utilization of 2-deoxyglucose in the mesopontine tegmentum in primate models of Parkinsons disease (PD)22 suggests that excessive pallidotegmental inhibition might contribute to hypokinesia, while decreased utilization in a model of hemiballismus23 suggests that disinhibition of the mesopontine tegmentum might contribute to hyperkinetic disorders.

Subcortical Structures and Neuropsychiatric Illness

Article

Jan 1996

Subcortical structures play an important role in modulating mood, drive, memory, executive functions, and cognitive timing. Subcortical structures are intimately linked with the frontal lobe and limbic system. Key subcortical structures regulating behavior include the caudate nucleus, the ventral striatum, the ventral pallidum, and the dorsomedial and reticular nuclei of the thalamus. Some degenerative diseases affect subcortical nuclear and white matter structures, causing involuntary movements and abnormal behavior. Primary psychiatric illnesses, such as obsessive-compulsive disorder, have been proposed to arise from dysfunction in the frontostriatal-thalamic circuits. The neuroanatomical and neurochemical organization of these subcortical systems mediating complex behaviors and the interactions between behavioral and motor systems are increasingly well understood. Undoubtedly, our newer understanding of subcortical systems will help us to unravel the pathophysiology of some neuropsychiatric disorders.

Cortico-striatal substrates of cognitive, motor and sensory gating: Speculations and implications for psychological function and dysfunction

Article

Jan 1996
Recent Adv Biol Psychiatr

N.R. Swerdlow

Cholinergic Pontine Mechanisms Causing State-Dependent Respiratory Depression

Article

Oct 1992

Microinjecting cholinergic agonists into the pontine reticular formation causes a rapid-eye-movement (REM) sleeplike state. The ability to cause this state pharmacologically has encouraged causal hypothesis testing. This pharmacological model has shown that cholinergic pontine mechanism known to regulate REM sleep can also cause state-dependent respiratory depression.

Marked Increase in REM Sleep Produced by a New Antipsychotic Compound

Article

Apr 1973

Polygraphic sleep recordings (EEG, EOG, EMG) were carried out on five patients (4 neurotic, 1 psychotic disorder) treated with W. 1854, which in addition to its good antipsychotic effect is distinguished by the development of slight to moderate temperature increases in the first two weeks of treatment. At the beginning of the drug induced temperature increase, the duration of the REM sleep increased to more than 85% of total sleeping time. Paradoxical sleep began immediately after going to sleep without deeper stages of sleep first being reached and was characterized by repeated and abrupt beginnings of short episodes of deeper sleep of 2-10 secs. duration during the first hours. Muscle action potentials of short duration were observed during these episodes. The high percentage of REM sleep during the total sleeping period leads to a levelling off of the sleep pattern which demonstrated a longer phase of deeper sleep in some patients toward morning.

The brain stem reticular formation in schizophrenia

Article

May 1991
PSYCHIAT RES

C KARSON

Some anatomical and physiological properties of ponto-mesencephalic tegmental neurons with special reference to the PGO waves and postural atonia during paradoxical sleep in the cat

Article

Jan 1980

K. Sakai

Mood disorders. Principles and practice of sleep medicine

Article

Ruth M Benca

Pirenzepine discriminates among ionic responses to acetylcholine in guinea-pig cerebral cortex and reticular nucleus of thalamus

Article

Jan 1986
TRENDS PHARMACOL SCI

Principles and Practice of Sleep Medicine

Article

Jan 2000

Transition Areas of the Striatopallidal System with the Extended Amygdala in the Rat and Primate: Observations from Histochemistry and Experiments with Mono- and Transsynaptic Tracer

Chapter

Jan 1994

In several papers we have extensively reviewed the concepts of the ventral striatopallidal system and the extended amygdala (de Olmos et al., 1985; Heimer et al., 1985; Alheid and Heimer, 1988; Alheid et al., 1990; Heimer and Alheid, 1991; Heimer et al., 1991a, 1993), and these topics are only briefly recapitulated here. In some of these (e.g. Alheid and Heimer, 1988; Heimer and Alheid, 1991; Heimer et al., 1993) we have pointed out areas where these two structures are difficult to distinguish; these are the problem areas that we wish to confront in this chapter. In some instances, it is clear that the extended amygdala occupies portions of the forebrain normally considered part of the basal ganglia and more speculatively, we believe that some unusual features in other areas of the basal ganglia might reflect some ectopic elements of the extended amygdala.

ADENOSINE INHIBITION OF MESOPONTINE CHOLINERGIC NEURONS - IMPLICATIONS FOR EEG AROUSAL (VOL 263, PG 689, 1994)

Article

Jul 1994

Donald Gordon Rainnie

The Sleep of Patients With Obsessive-Compulsive Disorder

Article

Dec 1982
ARCH GEN PSYCHIAT

Thomas R. Insel

• Fourteen patients with obsessive-compulsive disorder (OCD) were studied with all-night sleep EEG recordings. Nine of these patients reported abnormal sleep patterns before the polygraphic study. Analysis of the sleep records disclosed significantly decreased total sleep time with more awakenings, less stage 4 sleep, decreased rapid-eye-movement (REM) efficiency, and shortened REM latency compared with those of a group of age-and sex-matched normal subjects. These abnormalities generally resembled those of an age-matched group of depressed patients, although significant differences remained. These findings suggest that such sleep abnormalities as shortened REM latency may not be entirely specific for primary affective illness. They also point to a possible biological link between OCD and affective illness.

Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine

Article

Jan 1996
BRAIN RES

M Reid

Patterns of neuromodulation and nitric oxide signaling pathway in mesopontine cholinergic neurons

Article

Oct 1995
Semin Neurosci

Considerable evidence links the activity of mesopontine cholinergic neurons to the induction and maintenance of arousal and REM sleep through their projections to the thalamus and medial pontine reticular formation. In addition to acetylcholine, these cells synthesize neuropeptides and express high levels of the enzyme nitric oxide synthase suggesting they transmit complex chemical signals to their targets. This article reviews the physiological properties of these cells and the patterns of modulation by some putative transmitters. We also present new data which suggests that nitric oxide synthesis may be stimulated at the soma during repetitive firing and that nitric oxide plays a role in regulating the strength of excitatory synaptic input to these cells.

D and D dopamine receptor regulation of striatonigral and striatopallidal neurons

Article

Apr 1992
Semin Neurosci

Charles R Gerfen

Dopamine modulates the response of striatal projection neurons to excitatory cortical and thalamic input. The two major dopamine-receptor subtypes, the D1 and D2 receptors, are selectively localized on striatonigral and striatopallidal output neurons, respectively. Activation of these receptors has opposite effects on these striatal neurons and consequently dopamine functions to modulate the relative activity of the striatonigral and striatopallidal pathways. Thus, striatal circuitry converts excitatory cortical and thalamic inputs into antagonistic inputs to the output neurons of the basal ganglia, which are the GABA neurons of the entopeduncular and substantia nigra nuclei. The behavioural relevance of these antagonistic mechanisms is evident in Parkinson's disease, in which the degeneration of dopamine input to the striatum results in an imbalance in the striatal output pathways, which has been directly related to the clinical akinesia of this disease.

The effects of apomorphine and L-dopa challenge on prepulse inhibition in patients with Parkinson's disease

Article

Apr 1995
SCHIZOPHR RES

Brain Stem Control of Wakefulness and Sleep

Book

Jan 2005

A monograph communicating the current realities and future possibilities of unifying basic studies on anatomy and cellular physiology with investigations of the behavioral and physiological events of waking and sleep. Steriade established the Laboratory of Neurophysiology at Laval U., Quebec; McCarl

Ascending cholinergic pathways in the rat brain

Article

Jan 1990

Dahlstrom A, Fuxe K. Evidence for existence of monoamine-containing neurons in central nervous system. I. Demonstration of monoamines in cell bodies of brain stem neurons. Acta Physiol Scand 232(Suppl): 1-55

Article

Nov 1963
Acta Physiol Scand Suppl

Dependence on REM sleep of overnight improvment of a perceptual skill

Article

Jan 1994

Article

Apr 1996
Neuropsychiatry Neuropsychol Behav Neurol

Describes the cases of 2 females (aged 42 and 46 yrs), initially diagnosed with chronic, treatment-resistant schizophrenia, whose symptoms improved when they were rediagnosed and treated for narcolepsy. Narcolepsy may be confused with schizophrenia due to the hypnagogic hallucinations caused by REM intrusion into wakefulness. Narcolepsy should be considered as a possible diagnosis in patients diagnosed with schizophrenia who have no family history of psychosis, are refractory to psychotics, and have hallucinations and a history of sleep dysfunctions. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Structural substrates for integrative patterns in the brain stem reticular core

Article

Jan 1958

Using Golgi methods almost exclusively the brain stems of over "4000 cats, dogs, mice and rats, and a few young macaques" were studied in an attempt to construct a "total image" of the core of the brain stem. Collateral fibers from the long ascending systems, such as the spinal lemniscus, were found to penetrate the reticular formation and the resulting dendritic arbors running parallel to the afferents of the reticular system synapse with them during this parallel course. The authors see little possibility of maintained specificity of input, although some kind of segmental structure is apparently maintained. Typical reticular axons, regardless of position, appear to have frequent collaterals emitted over their entire course, the length of these collaterals varying greatly. 34 refs. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

The origins of cholinergic and other subcortical afferents to the thalamus in the rat

Article

Aug 1987
J COMP NEUROL

The origins of the cholinergic and other afferents of several thalamic nuclei were investigated in the rat by using the retrograde transport of wheat germ agglutinin conjugated‐horseradish peroxidase in combination with the immunohistochemical localization of choline acetyltransferase immunoreactivity. Small injections placed into the reticular, ventral, laterodorsal, lateroposterior, posterior, mediodorsal, geniculate, and intralaminar nuclei resulted in several distinct patterns of retrograde labelling. As expected, the appropriate specific sensory and motor‐related subcortical structures were retrogradely labelled after injections into the principal thalamic nuclei. In addition, other basal forebrain and brainstem structures were also labelled, with their distribution dependent on the site of injection. A large percentage of these latter projections was cholinergic. In the brainstem, the cholinergic pedunculopontine tegmental nucleus was retrogradely labelled after all thalamic injections, suggesting that it provides a widespread innervation to the thalamus. Neurons of the cholinergic laterodorsal tegmental nucleus were retrogradely labelled after injections into the anterior, laterodorsal, central medial, and mediodorsal nuclei, suggesting that it provides a projection to limbic components of the thalamus. Significant basal forebrain labelling occurred only with injections into the reticular and mediodorsal nuclei. Only injections into the reticular nucleus resulted in retrograde labelling of the cholinergic neurons in the nucleus basalis of Meynert. The results provide evidence for an organized system of thalamic afferents arising from cholinergic and noncholinergic structures in the brainstem and basal forebrain. The brainstem structures, especially the cholinergic pedunculopontine tegmental nucleus, appear to project directly to principal thalamic nuclei, thereby providing a possible anatomical substrate for mediating the well‐known facilitory effects of brainstem stimulation upon thalamocortical transmission.

Diffuse Cortical Projection Systems: Anatomical Organization and Role in Cortical Function

Chapter

Jan 2011

Clifford B. Saper

The sections in this article are:

Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: A tracing and immunohistochemical study in the cat

Article

Mar 1984
J COMP NEUROL

The efferent connections of the nucleus accumbens in the cat were studied with the aid of anterograde and retrograde tracing techniques. The description of the topography of these projections to pallidal, hypothalamic, and mesencephalic areas is preceded by a redefinition of the borders of the pallidal regions in the cat, using immunohistochemical criteria. In agreement with previous studies in rat and monkey substance-P-like and enkephalinlike immunoreactivity in the pallidum of the cat appears to be present in so-called “woolly fibers.” Substance-P- and enkephalin-positive woolly fibers are differentially distributed in the internal and external segments of the globus pallidus, as traditionally defined, but are both present in the rostral part of the substantia innominata, here called the “ventral pallidum.” Woolly fibers are also found in a number of other basal telencephalic structures and in the rostral part of the lateral hypothalamic area. Fibers from the medial part of the nucleus accumbens distribute to the ventral pallidum and to the just-mentioned area in the rostral part of the lateral hypothalamus, which most probably represents part of the internal segment of the globus pallidus. The medial nucleus accumbens projects in addition to the lateral septum, the bed nucleus of the stria terminalis, the medial preoptic and hypothalamic areas, the ventral tegmental area, the retrorubral nucleus, the central superior nucleus, the nucleus tegmenti pedunculopontinus, and the central gray. The lateral part of the nucleus accumbens projects to the ventral pallidum, the subcommissural part of the globus pallidus, the entopeduncular nucleus, the substantia nigra, and the retrorubral nucleus.

REM Sleep without Muscle Atonia (Stage 1‐REM) and Its Relation to Delirious Behavior during Sleep in Patients with Degenerative Diseases Involving the Brain Stem

Article

Dec 1990
PSYCHIAT CLIN NEUROS

Nocturnal sleep was examined in 12 patients with degenerative diseases involving the brain stem and in 2 patients with late cerebellar cortical atrophy (LCCA). A peculiar sleep state, characterized by the concomitant appearance of a low-voltage mixed frequency EEG, rapid eye movements (REMs) and tonic EMG in mental muscles, repeatedly appeared during nocturnal sleep in all of the 12 patients with degenerative diseases involving the brain stem and it was called stage 1-REM after Tachibana et al.32 In 8 of the 12 patients, delirious or oneiric behavior appeared during, or soon after, the episodes of stage 1-REM. Inner experiences reported by one of the subjects well corresponded to his behavior during the episode of stage 1-REM. Stage 1-REM was not observed during nocturnal sleep of the patients with LCCA. These results indicate that a degenerative lesion in the brain stem induced stage 1-REM and delirious behavior during nocturnal sleep through abolishing muscle atonia of REM sleep and causing dissociation of the functional components characterizing REM sleep.

Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus

Article

Sep 1992
J COMP NEUROL

The anatomical organization of cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase‐immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of cholinergic varicosities. The next highest density of cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30 :143–152). Although the vast majority of striatal cholinergic innervation was NGFr‐negative and, therefore, intrinsic, the striatum also contained NGFr‐positive axons, indicating the existence of an additional cholinergic input from the basal forebrain. This basal forebrain cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr‐positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia. © 1992 Wiley‐Liss, Inc.

The brainstem projection to the lateral geniculate nucleus in the cat: Identification of cholinergic and monoaminergic elements

Article

May 1987
J COMP NEUROL

The pontomesencephalic projection to the dorsal lateral geniculate nucleus (dLGN) of the cat was analyzed by combining retrograde transport of rhodamine-labeled latex spheres and immunohistochemistry. After injections of latex beads into the dLGN, sections of the brainstem were treated immunohistochemically for choline acetyltransferase (ChAT), serotonin (Ser), tyrosine hydroxylase (TH), and dopamine-beta-hydroxylase (DBH). Essentially, six regions in the brainstem contained retrogradely labeled cells: the superior colliculus, the parabigeminal nucleus, the dorsal raphe nuclei, the parabrachial area of the central tegmental field, the marginal nucleus of the brachium conjunctivum, and the nucleus coeruleus. Furthermore, isolated retrogradely labeled cells were present in the central nucleus of the raphe, in the cuneiform nucleus, and in the periaqueductal gray. Most serotoninergic double-labeled cells were found in the medial and lateral divisions of the dorsal raphe nuclei, but a few were also present in the central nucleus of the raphe. In the sections immunostained for ChAT, double-labeled cells were located in the central tegmental field, in the marginal nucleus of the brachium conjunctivum, and in the nucleus coeruleus. In the sections treated for TH and DBH, double-labeled cells showed a similar distribution, and like the ChAT(+) cells, they were located mainly in the central tegmental field, in the marginal nucleus of the brachium conjunctivum, and in the nucleus coeruleus. In these regions the cholinergic and noradrenergic cells that projected to the lateral geniculate nucleus were intermingled, the former predominating rostrally and the latter caudally. The majority of retrogradely labeled cells were located in the region of the central tegmental field in the vicinity of the brachium conjunctivum, and most of these cells were also ChAT-immunoreactive. We, therefore, conclude that the cholinergic projection is the most important of the central core projections ascending to the dLGN.

Sleep in Parkinson's disease

Article

Mar 1993
ACTA NEUROL SCAND

Jean Askenasy

Two major sources of dissatisfaction with the quality of life among Parkinsonian patients are the “locomotor disability” and the “nature of their sleep”. The main focus of research was directed towards the locomotor disability, but in the last two decades some progress has been made towards the understanding of sleep in PD patients. Sleep in Parkinson's disease is light and fragmented due to an increased skeletal muscle activity, disturbed breathing, impaired biological rhythm and REM-nonREM variations of the dopaminergic receptor sensitivity.

The brain stem reticular formation in schizophrenia

Article

Jun 1991
PSYCHIAT RES

Post-mortem brain tissue was obtained from four patients with schizophrenia and five controls to study cell groups in the brain stem reticular formation. Cholinergic neurons in the pedunculopontine nucleus (PPN) and lateral dorsal tegmental nucleus (LDT) were labeled using nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase histochemistry, while catecholaminergic neurons of the locus ceruleus (LC) were labeled immunocytochemically using an antibody to tyrosine hydroxylase. In schizophrenic patients, there were increased numbers of neurons in the PPN labeled by NADPH-diaphorase and reduced cell size in the LC. These results implicate the reticular formation as a possible pathophysiological site for at least some patients with schizophrenia. This also suggests that some of the deficits observed may be based on faulty neurodevelopment.

Dopamine attenuates the effects of GABA on single unit activity in the Globus pallidus

Article

Oct 1984
BRAIN RES

Studies were conducted to assess whether stimulation of dopamine receptors located in the globus pallidus might play a role in mediating the enhanced pallidal activity seen after systemic administration of dopamine agonists ord-amphetamine. Dopamine, applied iontophoretically, had modest effects on the activity of pallidal neurons; the baseline firing rates of 32% of cells recorded increased by an average of23 ± 2%, 18% decreased in rate and the remaining cells showed no significant rate change. More significantly, dopamine consistently attenuated the inhibitory actions of gamma-aminobutyric acid (GABA) in the globus pallidus. When dopamine was simultaneously iontophoresed with GABA, GABA's effectiveness at inhibiting pallidal activity was reduced by an average of 50%. Norepinephrine or acetylcholine, applied iontophoretically at equimolar concentrations and ejected at the same current as dopamine, caused no consistent attenuation of pallidal responses to GABA's rate effects.To determine whether the attenuation of GABA's inhibitory action by iontophoresed dopamine could be mimicked by systemic drug administration, apomorphine, 80 μ/kg, ord-amphetamine, 0.8 mg/kg, was given i.v. while GABA was iontophorosed. Apomorphine markedly decreased pallidal responses to the inhibitory effects of GABA in 75% of the cells by an average of 50%; haloperidol reversed this effect. Modulatory interactions between GABA andd-amphetamine were also observed in 5 of the 11 pallidal cells tested; GABA's inhibitory effect on pallidal cell activity was reduced by an average of 66% on these neurons. These results suggest that one way in which dopamine and dopamine agonists may effect basal ganglia function is by modulating GABAergic transmission in the globus pallidus.

Midlatency auditory evoked responses: Differential effects of sleep in the human

Article

Sep 1986

Middle latency responses (MLRs) in the 10-100 msec latency range, evoked by click stimuli, were studied in 14 adult volunteer subjects during sleep-wakefulness to determine whether such changes in state were reflected by any MLR component. Evoked potentials were collected in 500 trial averages during continuos presentation of 1/sec clicks during initial awake recordings and thereafter during a 2 h afternoon nap or all-night sleep session. Continuously recorded EEG, EOG and EMG were scored for wakefulness, stages 2-4 of slow wave sleep (SWS), and rapid eye movement (REM) sleep during each evoked potential epoch. The major components included in this study and their latency ranges, as determined by peak latency measurements from the awake records, were: ABR V, 5-8 msec, Pa, 30-40 msec, Nb, 45-55 msec, and P1, 55-80 msec. In agreement with previous reports, ABR V and Pa showed no amplitude changes from wakefulness to either SWS or REM. Not previously reported, however, was the dramatic decrease and disappearance of P1 during SWS and its reappearance during REM to an amplitude similar to that during wakefulness. This unique linkage between a particular evoked potential component and sleep-wakefulness indicates that its generator system must be functionally related to states of arousal. Relevant data from the cat model suggest that the generator substrate for P1 may be within the ascending reticular activating system.

Electroencephalographic sleep findings in depressed outpatients

Article

Mar 1982
PSYCHIAT RES

We compared the electroencephalographic (EEG) sleep characteristics of 20 outpatients with those of 20 age-matched inpatients with major primary depressive disorders. Both groups showed similar patterns of sleep disturbance: reduced rapid eye movement (REM) sleep latencies, sleep efficiencies, and slow wave sleep. While the inpatients had greater REM activity in the first REM period than did the outpatients, both groups showed evidence of greater REM sleep time and REM activity during the first half of the night than do normals. The outpatients demonstrated a level of adaptation in that more REM sleep time and activity were present on night 2 than on night 1.

Neuropeptides and NADPH-Diaphorase activity in the ascending cholinergic reticular system of the rat

Article

Feb 1986
NEUROSCIENCE

A major group of cholinergic neurons is present in the midbrain and pontine tegmentum. These cells could be selectively stained using either monoclonal antibodies to choline acetyltransferase, the pharmacohistochemical acetylcholinesterase procedure, or reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Using these three techniques, the precise distribution of this cell group was determined. By combining these techniques with immunohistochemical staining for various neuropeptides, examples of peptide-cholinergic coexistence could be demonstrated in this cell group. Approximately 30% of these cholinergic neurons displayed substance P immunoreactivity. Most of these cells also showed corticotropin-releasing factor immunoreactivity and bombesin/gastrin-releasing peptide immunoreactivity. These results therefore provide evidence for the coexistence of various neuropeptides together with NADPH-diaphorase activity in the ascending cholinergic reticular system.

Contributions of the Pedunculopontine Region to Normal and Altered REM Sleep

Abstract

No full-text available

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