REM Sleep Abnormalities Research Articles

B26 Sleep and EEG abnormalities in Huntington's disease mice

There is good evidence to suggest that Huntington9s disease (HD) patients have sleep disturbances that may deleteriously affect their cognitive performance, affective behaviour, and general well-being. Although sleep studies in HD patents were originally carried out more than 20 years ago, a comprehensive description of the progression of sleep and EEG changes in HD has been never conducted. Here we analysed the sleep and EEG changes in a transgenic mouse model of HD. We used R6/2 mice that carry a fragment of the HTT gene including a moderately long (250) CAG repeat. These mice show a progressive neurological phenotype including cognitive abnormalities and circadian disruption. R6/2 mice and their wild-type littermates were instrumented with EEG/EMG electrodes, and 24 h recordings were made using Neurologgers at a late stage of the disease (17–18 weeks of age). The signals were digitally filtered and scored in 10-s epochs as Wake, non-REM sleep, or REM sleep using SleepSign (Kissei Comtec CO., LTD., Japan). We then visually inspected all scoring and made corrections when appropriate. In addition to the standard scoring, we performed a spectral analysis of the sleep EEG by means of fast Fourier transformation as this procedure allows a much more sensitive and detailed description of EEG changes than the conventional staging. Our preliminary data show that sleep and EEG are significantly disrupted in R6/2 mice by 18 weeks of age. We found that R6/2 mice have fragmented sleep during the lights-on period as well as severe REM sleep abnormalities. R6/2 mice showed twice as much REM sleep as WT mice and a slower but highly synchronised theta activity during REM sleep. Defining the abnormalities of sleep that exist in HD and understanding their influence on other disease-related features is important for enabling clinicians to initiate appropriate investigations and to instigate treatments that could dramatically improve quality of life in HD patients.

Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.

Significance of REM Sleep in Depression: Effects on Neurogenesis

Significance of REM Sleep in Depression: Effects on Neurogenesis

Comparison of polysomnographic variables and their relationship to cognitive impairment in patients with Alzheimer's disease and frontotemporal dementia

Abstract Polysomnograhic (PSG) studies in Alzheimer’s disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD

A Missense Mutation in Myelin Oligodendrocyte Glycoprotein as a Cause of Familial Narcolepsy with Cataplexy

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Comparison of polysomnographic variables and their relationship to cognitive impairment in patients with Alzheimer’s disease and frontotemporal dementia

Polysomnograhic (PSG) studies in Alzheimer’s disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD < FTD) were considered as covariates. Polysomnography revealed a trend towards increased REM latency and reduced REM sleep in AD, as well as a decrease of stage 2 sleep, however, at least partly due to effects of age. Declarative memory was more impaired in AD than in FTD, but this difference disappeared when adjusted for covariates. While no relationship was found between REM sleep and CERAD-NB parameters, strong positive correlations between stage 2 sleep and declarative memory measures were observed, which were also detectable when analyzing both groups separately. Based on these results we conclude that REM sleep alterations may be specific for AD, distinguishable from other dementia diagnoses, whereas NonREM stage 2 sleep may be related to declarative memory formation in dementia independent of subtype.

Recent Advances in the Treatment of Narcolepsy

A diagnosis of narcolepsy requires pharmacologic treatment in more than 90% of patients. Wake-promoting compounds are used to treat excessive daytime sleepiness (EDS), and anticataplectics are used for cataplexy. The treatment of EDS includes the use of amphetamine-like CNS stimulants (such as dextroamphetamine and methylphenidate), modafinil, and its R-enantiomer, armodafinil. Because of its high safety and low side-effect profiles, modafinil has become the first-line treatment of choice for EDS associated with narcolepsy. However, wake-promoting compounds do not improve cataplexy and dissociated manifestation of REM sleep, and so antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Tricyclic antidepressants potently reduce REM sleep and thus have been used for the treatment of cataplexy and REM sleep abnormalities, but these have recently been replaced by more selective serotonin and/or noradrenaline uptake inhibitors with better side-effect profiles. As sodium oxybate (the approved formula of γ-hydroxybutyrate in the United States), given at night, improves both EDS and cataplexy, the number of US patients treated with sodium oxybate is increasing, while much progress has been made in understanding the modes of action of amphetamine-like CNS stimulants.

Abnormally Low Serum Acylcarnitine Levels in Narcolepsy Patients

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and REM sleep abnormalities. A genome-wide association study identified a novel narcolepsy-related single nucleotide polymorphism (SNP), rs5770917, which is located adjacent to CPT1B (carnitine palmitoyltransferase 1B). In this study, we analyzed the CPT1B expression level and measured the carnitine fractions in blood samples obtained from narcolepsy patients and control subjects to test the hypothesis that fatty acid β-oxidation is altered in narcolepsy. We measured CPT1B mRNA expression in white blood cells of 38 narcolepsy patients and 56 healthy control subjects. The serum carnitine fractions (total carnitine, free carnitine, and acylcarnitine) were measured in the 38 narcolepsy patients and in 30 of 56 control subjects. Stepwise multiple regression analysis revealed that the risk allele (C) for SNP rs5770917 was significantly associated with decreased CPT1B mRNA expression (P = 1.0 × 10(-9)), and the CPT1B expression was higher in the narcolepsy patients than in the controls (P = 0.005). The acylcarnitine levels were abnormally low in 21% of the narcolepsy patients while those of all the controls were within the normal range. Stepwise multiple regression analysis using the dichotomous variable for acylcarnitine (normal or abnormal) as an objective variable revealed that the diagnosis of narcolepsy but not CPT1B expression level and BMI was associated with abnormally low acylcarnitine levels (P = 0.006). Our results indicate that multiple factors are involved in the regulation of serum acylcarnitine levels. Abnormally low levels of acylcarnitine observed in narcolepsy suggest dysfunctional fatty acid β-oxidation pathway.

Pseudocataplexy and Transient Functional Paralysis: A Spectrum of Psychogenic Motor Disorder

Pseudocataplexy and Transient Functional Paralysis: A Spectrum of Psychogenic Motor Disorder

Decrease in acetylcholinergic neurons in the pedunculopontine tegmental nucleus in a patient with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is caused by the absence of paternally contributed genes in chromosome 15, and is characterized by hypotonia, feeding difficulty, mental retardation, growth failure, hypogonadism and severe obesity. To elucidate the pathogenesis of neurological disorders, we immunohistochemically examined the γ-aminobutyric acid (GABA)ergic interneurons (GABAis) in the cerebral cortex and acetylcholine neurons (AchNs) in the nucleus basalis of Meynert (MyN) and pedunculopontine tegmental nucleus pars compacta (PPNc) in an autopsy case of one PWS patient with a deletion in the 15q11-q12 region and three control patients. The GABAis in the cerebral cortex and AchNs in the MyN were well preserved in the PWS patient. The AchNs in the PPNc in the PWS patient were severely reduced in comparison with those in controls, whereas catecholaminergic neurons and GABAis were preserved. The selective loss of AchNs in the PPNc may be involved in hypotonia and/or REM sleep abnormalities in PWS patients.

Sleep in Genetically Confirmed Pantothenate Kinase-Associated Neurodegeneration: A Video-Polysomnographic Study

Pantothenate kinase-associated neurodegeneration (PKAN) is a familial or sporadic disease characterized by extrapyramidal and corticospinal signs with dementia. Patients show iron accumulation in the basal ganglia, with neuronal loss and gliosis. A mutation of pantothenate kinase (PANK2) gene localized on chromosome 20p13 has been described in familiar forms, as well as in sporadic patients. We sought to assess sleep characteristics, including muscle activity during REM sleep, in three patients with PANK2 gene mutation-confirmed diagnosis of PKAN. Sleep architecture was altered in all patients with reduced total time of sleep in two and lack of SWS in one. No significant apnea/hypopnea were detected, and mild PLMS were observed in one patient (PLMS index:10.7/h). In contrast with other neurodegenerative diseases, no REM sleep abnormalities, especially REM sleep behavior disorder, were observed in PKAN patients, and percentage of both REM sleep atonia and phasic EMG activity were within normal ranges. Sleep studies may phenotypically differentiate PKAN from other neurodegenerative disorders.

Interaction between sleep and growth hormone

The relation between nightly growth hormone (GH) secretion and sleep is poorly understood. To examine whether disturbances in GH secretion are reflected in abnormal sleep patterns 8 subjects with isolated GH deficiency and 9 subjects with excess of GH (acromegalics) underwent all night sleep studies, polysomnography. Moreover, the effect of correcting GH concentration on sleep patterns were examined in the same subjects. The results showed that all subjects with GH disturbances had abnormal REM and delta sleep and normalization of GH concentration was followed by correction of the sleep stages. By power spectrum analysis of the sleep EEG it was showed that during low GH concentration the sleep energy was low, and high GH concentration was associated with high sleep energy, and correction of abnormal plasma GH levels resulted in normalization of REM and delta sleep energy per time unit.

REM sleep disorders and parkinsonism

REM sleep abnormalities are frequently encountered in disorders with alpha-synuclein pathology including Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Symptoms of REM sleep behavior disorder (RBD) may precede the onset of motor and cognitive symptoms in these underlying neurological disorders. Clinical and neuroimaging studies suggest that there may be reductions in dopaminergic mechanisms centrally in primary RBD. Anatomic studies in animals suggest dysfunction of brainstem nuclei. The treatment of RBD has not been adequately evaluated with controlled studies. Clonazepam and melatonin might be effective.

REM Sleep Characteristics in Narcolepsy and REM Sleep Behavior Disorder

To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) in narcolepsy; and to quantify REM sleep parameters in patients with narcolepsy, in patients with "idiopathic" RBD, and in normal controls. Sleep laboratory study Sixteen patients with narcolepsy and cataplexy matched for age and sex with 16 patients with "idiopathic" RBD and with 16 normal controls were studied. Higher percentages of REM sleep without atonia, phasic electromyographic (EMG) activity, and REM density were found in patients with narcolepsy than normal controls. In contrast, RBD patients had a higher percentage of REM sleep without atonia but a lower REM density than patients with narcolepsy and normal controls. Based on a threshold of 80% for percentage of REM sleep with atonia, 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity. No significant behavioral manifestation in REM sleep was noted in either narcoleptics or controls. We also found a higher frequency of periodic leg movements during wake (PLMW) and during sleep (PLMS) in narcoleptic patients compared to controls. The present study demonstrates abnormalities in REM sleep motor regulation with an increased frequency of REM sleep without atonia, phasic EMG events and PLMS in narcoleptic patients when compared to controls. These abnormalities were seen more prominently in patients with RBD than in narcoleptics, with the exception of the PLMS index. We proposed that dysfunctions in hypocretin/dopaminergic system may lead to motor dyscontrol in REM sleep that results in dissociated sleep/wake states.

REM Sleep Behavior Disorder and Narcoleptic Features in Anti—Ma2-associated Encephalitis

A 69-year-old man with anti-Ma2 paraneoplastic encephalitis presented with subacute onset of severe hypersomnia, memory loss, parkinsonism, and gaze palsy. A brain magnetic resonance imaging study showed bilateral damage in the dorsolateral midbrain, amygdala, and paramedian thalami. Videopolysomnography disclosed rapid eye movement (REM) sleep behavior disorder, and a Multiple Sleep Latency Test showed a mean sleep latency of 7 minutes and 4 sleep-onset REM periods. The level of hypocretin-1 in the cerebrospinal fluid was low (49 pg/mL). This observation illustrates that REM sleep behavior disorder and narcoleptic features are 2 REM-sleep abnormalities that (1) may share the same autoimmune-mediated origin affecting the brainstem, limbic, and diencephalic structures and (2) may occur in the setting of the paraneoplastic anti-Ma2-associated encephalitis.

Restoration of normal motor control in Parkinson's disease during REM sleep

Although normal subjects do not move during REM sleep, patients with Parkinson's disease may experience REM sleep behaviour disorder (RBD). The characteristics of the abnormal REM sleep movements in RBD have, however, not been studied. We interviewed one hundred consecutive non-demented patients with Parkinson's disease and their bed partners using a structured questionnaire assessing the presence of RBD. They rated the quality of movements, voice and facial expression during RBD as being better, equal or worse than in awake ON levodopa condition. Night-time sleep and movements were video-monitored during polysomnography in 51 patients to evaluate the presence of bradykinesia, tremor and hypophonia during REM sleep. Fifty-nine patients had clinical RBD with 53/59 bed partners able to evaluate them. All 53 (100%) reported an improvement of at least one component of motor control during RBD. By history, movements were improved in 87% patients (faster, 87%; stronger, 87%; smoother, 51%), speech was better in 77% patients (more intelligible, 77%; louder, 38%; better articulated, 57%) and facial expression was normalized in 47% patients. Thirty-eight per cent of bed partners reported that movements were 'much better', even in the most disabled patients. The video-monitored purposeful movements in REM sleep were also surprisingly fast, ample, coordinated and symmetrical, without obvious sign of parkinsonism. The movements were, however, jerky, violent and often repetitive. While all patients had asymmetrical parkinsonism when awake, most of the time they used the more disabled arm, hand and leg during the RBD (P = 0.04). Movements involved six times as often the upper limbs and the face as the lower limbs (OR: 5.9, P = 0.004). The percentage of time containing tremor EMG activity decreased with sleep stages from 34.9 +/- 15.5% during wakefulness, to 3.6 +/- 5.7% during non-REM sleep stages 1-2, 1.4 +/- 3.0% during non-REM sleep stages 3-4, and 0.06 +/- 0.2% during REM sleep (in this last case, it was subclinical tremor). The restored motor control during REM sleep suggests a transient 'levodopa-like' reestablishment of the basal ganglia loop. Alternatively, parkinsonism may disappear by REM sleep-related disjunction between pyramidal and extrapyramidal systems. We suggest the following model: the movements during the RBD would be generated by the motor cortex and would follow the pyramidal tract bypassing the extrapyramidal system. These movements would eventually be transmitted to lower motor neurons because of brainstem lesions interrupting the pontomedullary pathways which mediate the REM sleep atonia.

Sleep in obsessive compulsive disorder

Several lines of evidence suggest that brain serotonergic systems may be disturbed in obsessive compulsive disorder (OCD). The serotonergic system strongly affects sleep and characteristic abnormalities of sleep are documented in depression. This study, therefore, aimed to investigate sleep structure of OCD patients in order to evaluate whether similar changes as in depression are present. Up to now, this issue has been addressed only in few studies with small numbers of patients. Sleep patterns of 62 unmedicated patients with primary OCD and 62 age- and sex-matched healthy controls were investigated by polysomnography. Additionally, the impact of tryptophan depletion on sleep was studied in a subgroup of 12 OCD patients and 12 controls. The OCD patients exhibited moderate, but significant disturbances of sleep continuity measures but no abnormalities of slow wave sleep or REM sleep, except a significant elevation of 1st REM density. Tryptophan depletion induced a worsening of sleep continuity, but no changes of REM sleep or slow wave sleep. Assuming that changes of sleep architecture indicate underlying neurobiological abnormalities, this study indicates that neurobiological disturbances are different in primary OCD as compared with primary depression.

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

Increased delta power and discrepancies in objective and subjective sleep measurements in borderline personality disorder

Background Previous studies have shown depression-like sleep abnormalities in borderline personality disorder (BPD). However, findings in BPD are not unequivocal for REM dysregulation, as well as for a decrement of slow wave sleep and sleep continuity disturbances. Earlier findings in sleep EEG abnormalities in BPD may have been confounded by concomitant depressive symptoms. Methods Twenty unmedicated female BPD patients without current comorbid major depression and 20 sex- and age-matched control subjects entered the study. Conventional polysomnographic parameters and for the first time sleep EEG spectral power analysis was performed on two sleep laboratory nights. Subjective sleep parameters were collected by sleep questionnaires in order to assess the relationship between objective and subjective sleep measurements. Results BPD patients showed a tendency for shortened REM latency and significantly decreased NonREM sleep (stage 2). Spectral EEG analysis showed increased delta power in total NREM sleep as well as in REM sleep in BPD patients. Subjective ratings documented drastically impaired sleep quality in BPD patients for the two weeks before the study and during the two laboratory nights. Conclusion Not-depressed BPD patients only showed tendencies for depression-like REM sleep abnormalities. Surprisingly, BPD patients displayed higher levels of delta power in the sleep EEG in NREM sleep than healthy control subjects. There was a marked discrepancy between objective and subjective sleep measurements, which indicates an altered perception of sleep in BPD. The underlying psychological and neurobiological mechanisms of these alterations are still unclear and need to be clarified in future studies including interventions on a pharmacological and cognitive-behavioral level.

Hallucinations and sleep disturbances in Parkinson’s disease

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD.