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Sebastiaan Overeem

Publications and source records attributed to Sebastiaan Overeem.

18 recordsLinked to original sources
PubMed2007

Expectancy induces dynamic modulation of corticospinal excitability.

Behavioral studies using motor preparation paradigms have revealed that increased expectancy of a response signal shortens reaction times (RTs). Neurophysiological data suggest that in such paradigms, not only RT but also neuronal activity in the motor structures involved is modulated by expectancy of behaviorally relevant events. Here, we directly tested whether expectancy of a response signal modulates excitability of the corticospinal system used in the subsequent movement. We combined single- and paired-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex with a simple RT task with variable preparatory delays. We found that, in line with typical behavioral observations, the subjects' RTs decreased with increasing response signal expectancy. TMS results revealed a modulation of corticospinal excitability in correspondence with response signal expectancy. Besides an increased excitability over the time-course of the preparatory delay, corticospinal excitability transiently increased whenever a response signal was expected. Paired-pulse TMS showed that this modulation is unlikely to be mediated by excitability changes in interneuronal inhibitory or facilitatory networks in the primary motor cortex. Changes in corticospinal synchronization or other mechanisms involving spinal circuits are candidates mediating the modulation of corticospinal excitability by expectancy.

Adult↗
PubMed2006

A case of neuromuscular mimicry.

Recognizing an ALS-mimic can be challenging. Here, we describe a patient with a slowly progressive dysarthria and dysphagia, with fasciculations of the tongue and general hyperreflexia, fulfilling the diagnostic criteria of 'clinical probable ALS'. Because of a non-conclusive EMG, a muscle biopsy was performed that surprisingly showed widespread nemaline rods. The clinical features and the histological findings were compatible with a sporadic late onset nemaline myopathy. Three years after initial presentation the patient died and post-mortem examination not only showed nemaline bodies in every muscle examined, but also revealed an unsuspected final diagnosis: sarcoid brainstem encephalitis. Nemaline rods can be found in various disorders, and neurosarcoidosis should be added to this list.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Possible confusion between primary hypersomnia and adult attention-deficit/hyperactivity disorder.

We explored the possibility of diagnostic confusion between hypersomnias of central origin (narcolepsy and idiopathic hypersomnia, IH) and the adult form of attention-deficit/hyperactivity disorder (ADHD). We included 67 patients with narcolepsy, 7 with IH and 61 with ADHD. All patients completed the Epworth Sleepiness Scale and the ADHD Rating Scale. We found that 18.9% of the hypersomnia patients fulfilled the self-reported criteria for ADHD in adulthood, compared with 77% of the ADHD patients. A score > or =12 on the Epworth Sleepiness Scale (usually regarded to indicate excessive daytime sleepiness) was found in 37.7% of the ADHD patients compared 95.9% of the hypersomnia patients. In ADHD patients, inattention scores correlated with the excessive daytime sleepiness score. We conclude that one should be aware of possible diagnostic confusion between narcolepsy or IH and adult ADHD when using self-report questionnaires. The high percentage of symptom overlap found in our study raises questions about possible misdiagnosing of both conditions, comorbidity with sleep problems in adult ADHD, and the validation of the used scales. It remains unclear whether our findings indicate pathophysiological overlap.

Adult↗
PubMed2006

Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy.

Most human patients with narcolepsy have no detectable hypocretin-1 in their cerebrospinal fluid. The cause of this hypocretin deficiency is unknown, but the prevailing hypothesis states that an autoimmune-mediated mechanism is responsible. We screened for the presence of autoantibodies against neurons in the lateral hypothalamus in 76 patients and 63 controls, using immunohistochemistry. Autoantibodies were present in two patients, but also in two controls. However, one of the patients had a clearly different staining pattern and nerve endings of immunolabeled cells were found to project onto hypocretin-producing neurons, suggesting a possible pathophysiological role. Humoral immune mechanisms appear not to play a role in the pathogenesis of narcolepsy, at least not in the clinically overt stage of the disease.

Adult↗
PubMed2006

Altered skin-temperature regulation in narcolepsy relates to sleep propensity.

STUDY OBJECTIVES: In healthy subjects, sleep propensity increases when the distal skin temperature increases relative to the proximal skin temperature. This increase results from increased blood flow in the skin of the extremities and is, among other factors, controlled by the hypothalamic circadian clock, as is sleep. Because narcolepsy is characterized by hypothalamic alterations, we studied skin temperature in narcoleptic patients in relation to their characteristically increased sleep propensity during the day. DESIGN: Distal and proximal skin temperature and their gradient (DPG) were measured during a Multiple Sleep Latency Test. This allowed temperature to be studied during wakefulness, at sleep onset and during sleep. SETTING: Tertiary narcolepsy referral center in a university hospital. PATIENTS: Fifteen unmedicated narcolepsy patients with cataplexy and 15 controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: In subjects in the waking state, DPG was higher in narcoleptics than in controls throughout the day (time by group interaction, p < .0001), due to increased distal skin temperature and decreased proximal skin temperature. The increase in DPG was related to a shorter subsequent sleep-onset latency (p = .02). Once asleep, narcoleptics maintained their elevated distal skin temperature and DPG (p < .0001), whereas proximal skin temperature increased to reach normal levels. CONCLUSIONS: This is the first demonstration of a dramatic alteration of daytime skin temperature control in narcolepsy. Even awake narcoleptic patients showed a DPG higher than that which healthy controls achieve when asleep. This observation suggests that hypocretin deficiency in narcolepsy affects skin-temperature regulation and invites further examination. Skin-temperature control might ultimately even have therapeutic implications for the alleviation of narcoleptic symptoms.

Adult↗
PubMed2004

Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men.

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. Injection of hypocretin-1 acutely suppresses TRH and TSH release in rats. In contrast, subchronic administration does not appear to affect the hypothalamo-pituitary-thyroid ensemble in animals. We explored (in 7 patients and 7 controls) whether hypocretin deficiency impacts circulating TSH levels and circadian timing of TSH release in narcoleptic humans. Plasma TSH concentration profiles (blood samples taken at 10-min intervals during 24 h) and TSH levels in response to TRH injection were analyzed by Cluster, robust regression, approximate entropy (ApEn), and deconvolution. Circulating TSH levels were lower in patients, which was primarily attributable to lower pulse amplitude and nadir concentrations. TSH secretion correlated positively with mean 24-h leptin levels (R2 = 0.46, P = 0.02) and negatively with amount of sleep (R2 = 0.29, P = 0.048). Pattern-synchrony between 24-h leptin and TSH concentrations was demonstrated by significant cross-correlation and cross-ApEn analyses with no differences between controls and patients. Sleep onset was closely associated with a fall in circulating TSH. Features of diurnal rhythmicity of circulating TSH fluctuations were similar in patients and controls, with the acrophase occurring shortly after midnight. Thyroxine and triiodothyronine concentrations were similar in patients and controls and did not display a diurnal rhythm. The response of plasma TSH levels to TRH was also similar in both groups. Sleep patterns in narcoleptics were significantly disorderly compared with controls, as measured by ApEn (P = 0.006). In summary, circulating TSH concentrations are low in hypocretin-deficient narcoleptic men, which could be attributable to their low plasma leptin levels and/or their abnormal sleep-wake cycle.

Adaptation, Physiological↗
PubMed2004

Corticospinal excitability during laughter: implications for cataplexy and the comparison with REM sleep atonia.

Cataplexy is usually seen as rapid eye movement (REM) sleep atonia occurring at an inopportune moment. REM sleep atonia is the result of postsynaptic inhibition, i.e. inhibition of alpha motor neurones. Although this may explain the suppression of H-reflexes during REM sleep, cataplexy and laughter, it is not the only explanation. Presynaptic inhibition, in which afferent impulses are prevented from reaching motor neurones, is an alternative. Testing H-reflexes and magnetic-evoked potentials (MEPs) helps to tell them apart: in postsynaptic inhibition MEPs and H-reflexes change in tandem, while H-reflexes may decrease independent of MEPs with other inhibition modes. We studied motor inhibition during laughter, the strongest trigger for cataplexy. H-reflexes were evoked every 2 s in the soleus muscle in 10 healthy subjects watching comical video fragments. MEPs were evoked when H-reflexes decreased during laughter, and, as a control, when subjects did not laugh. Pairs of MEPs and the immediately preceding H-reflexes were studied. Compared with the control condition, laughter caused mean MEP area to increase by 60% (P=0.006) and mean H-reflex amplitude to decrease by 33% (P=0.008). This pattern proves that postsynaptic inhibition cannot have been the sole influence. The findings do not prove which mechanisms are involved; one possibility is that the decrease in H-reflex amplitude was the result of presynaptic inhibition, and that cortical and/or spinal facilitation accounted for increased MEPs. Regardless, the pattern differs fundamentally from the reported mechanism of REM sleep atonia. Existing scanty data on cataplexy suggest a pattern of H-reflexes and MEPs similar to that during laughter, but this needs further study.

Arousal↗
PubMed2004

Is motor inhibition during laughter due to emotional or respiratory influences?

We compared the effects of laughter and several respiratory movements on spinal motor excitability to unravel their respective influences. We measured H-reflexes in 13 healthy volunteers during 10 different tasks (including laughter, simulated laughter, and various respiratory movements). We compared the percentage that remained of the initial H-reflex during each task with that during a neutral task. H-reflex percentage differed between the neutral task (79.4 +/- 16.1%), true laughter (43.7 +/- 17.9%), and simulated laughter (66.6 +/- 24.3%), and between the two latter tasks. Coughing also resulted in H-reflex suppression, but not as deeply as true laughter. During the other respiratory maneuvers, the H-reflex increased compared to the neutral task. Our finding that true laughter evoked more H-reflex depression than simulated laughter suggests that mirth on its own depresses the H-reflex. This mechanism may also be involved in the pathophysiology of cataplexy, the main symptom of narcolepsy.

Adolescent↗
PubMed2003

Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy.

Narcolepsy is a sleep disorder caused by defective hypocretin (orexin) neurotransmission. It is thought to result from an autoimmune destruction of hypocretin producing neurons. Recently, low hypocretin levels were found in patients with Guillain-Barré syndrome, a post-infectious immune-mediated disorder in which a variety of circulating antibodies against neuronal gangliosides are found. We therefore considered gangliosides to be candidate antigens in narcolepsy as well, and screened for the presence of a panel of serum anti-ganglioside antibodies in a group of 28 well-characterized narcoleptic patients. We did not find a correlation between increased titers of anti-ganglioside antibodies and hypocretin-deficient narcolepsy. This study does not support the hypothesis that an autoimmune response is involved in narcolepsy. However, as an autoimmune attack may be selective and/or transient, future studies are needed to ultimately refute or confirm the autoimmune hypothesis.

Adolescent↗
PubMed2003

Voxel-based morphometry in hypocretin-deficient narcolepsy.

STUDY OBJECTIVES: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy. DESIGN: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes. SETTING: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London. PARTICIPANTS: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects. MEASUREMENTS AND RESULTS: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls. CONCLUSIONS: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

Adult↗
PubMed2003

Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity.

OBJECTIVE: To determine the prevalence of obesity among patients with narcolepsy, to estimate associated long-term health risks on the basis of waist circumference, and to distinguish the impact of hypocretin deficiency from that of increased daytime sleepiness (i.e., reduced physical activity) on these anthropometric measures. RESEARCH METHODS AND PROCEDURES: A cross-sectional, case-control study was conducted. Patients with narcolepsy (n = 138) or idiopathic hypersomnia (IH) (n = 33) were included. Age-matched, healthy members of the Dutch population (Monitoring Project on Risk Factors for Chronic Diseases and Doetinchem Project; n = 10,526) were used as controls. BMI and waist circumference were determined. RESULTS: Obesity (BMI > or = 30 kg/m(2)) and overweight (BMI 25 to 30 kg/m(2)) occurred more often among narcolepsy patients [prevalence: 33% (narcoleptics) vs. 12.5% (controls) and 43% (narcoleptics) vs. 36% (controls), respectively; both p < 0.05]. Narcoleptics had a larger waist circumference (mean difference 5 +/- 1.4 cm, p < 0.001). The BMI of patients with IH was significantly lower than that of narcolepsy patients (25.6 +/- 3.6 vs. 28.5 +/- 5.4 kg/m(2); p = 0.004). DISCUSSION: Overweight and obesity occur frequently in patients with narcolepsy. Moreover, these patients have an increased waist circumference, indicating excess fat storage in abdominal depots. The fact that patients with IH had a lower BMI than narcoleptics supports the notion that excessive daytime sleepiness (i.e., inactivity) cannot account for excess body fat in narcoleptic patients.

Abdomen↗
PubMed2003

Pharmacological management of narcolepsy.

Narcolepsy is a disabling disorder characterised by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Traditionally, a wide variety of substances are used in the symptomatic pharmacological treatment of narcolepsy. Several generally more-tolerated substances have been added to the therapeutic repertoire after extensive testing in large patient populations during recent years. This review addresses the state-of-the-art knowledge about the pharmacological treatment of narcolepsy along with the personal view of the authors. The recent discovery that narcolepsy is caused by deficient hypocretin (orexin) transmission opens a perspective on causal therapy.

Antidepressive Agents, Tricyclic↗
PubMed2002

Somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH-secretory events.

Narcolepsy is a sleep disorder caused by impaired hypocretin (orexin) neurotransmission. Growth hormone (GH) secretion may be altered in narcolepsy for various reasons. Slow-wave sleep episodes, which are closely associated with GH-secretory events, are more randomly dispersed over 24 h in narcoleptics. Furthermore, hypocretins may inhibit pituitary GH release. We assessed the function of the somatotropic axis in narcolepsy by deconvolving 24-h (10-min sampling interval) plasma GH concentration profiles in seven hypocretin-deficient narcoleptic patients and in seven healthy controls matched for age, sex, and body weight. Both basal and pulsatile GH secretion rate and secretagogue-induced GH release were similar in patients and controls. However, narcoleptics secreted approximately 50% of their total production during the daytime, whereas controls secreted only 25% during the day. Also, the GH output pattern of narcoleptics was significantly less regular. We propose that hypocretin deficiency disrupts the circadian distribution of hypothalamic GH-releasing hormone release in narcoleptic patients to simultaneously cause daytime GH release and promote their propensity to fall asleep during the day.

Adult↗
PubMed2002

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

CONTEXT: Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. OBJECTIVES: To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. DESIGN: Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. SETTING: Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. PARTICIPANTS: There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). INTERVENTION: Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. MAIN OUTCOME MEASURES: Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. RESULTS: HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. CONCLUSIONS: Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

Adult↗
PubMed2002

Cataplexy: 'tonic immobility' rather than 'REM-sleep atonia'?

BACKGROUND: Cataplexy, a sudden loss of muscle tone in response to strong emotions, is the most specific symptom of narcolepsy. It is currently thought to be due to disturbed rapid eye movement (REM) sleep regulation, and portrayed as REM sleep atonia occurring at the wrong time. However, there are several arguments against including cataplexy in the 'state boundary control' hypothesis. It does not explain why cataplexy is triggered by emotions, and recent studies in narcoleptic dogs showed that REM sleep regulatory mechanisms were in fact intact in these animals. METHODS: We review the literature on the REM sleep dissociation theory, discuss the merits and demerits of the theory, and propose an alternative hypothesis explaining cataplexy. RESULTS: Cataplexy may represent an atavism (recurrence of an ancestral characteristic) of tonic immobility. Tonic immobility (TI) denotes a condition in which an animal is rendered immobile when faced with danger. Arguments in favor of the TI hypotheses are that it explains the emotional triggering. Furthermore, centers regulating narcolepsy and TI are both located in the lateral hypothalamic area. Finally, several drugs known for their ameliorating effect on cataplexy reduce the frequency and duration of TI in animals. CONCLUSION: Cataplexy may be due to a mechanism different from the other clinical symptoms of narcolepsy.

Journal Article↗
PubMed2002

The hypothalamus in episodic brain disorders.

Episodic brain disorders (EBD) form an intriguing group of neurological diseases in which at least some of the symptoms occur in attacks. The hypothalamus integrates many brain functions, including endocrine and autonomic control, and governs various body rhythms. It seems a likely site in which the initiation of attacks of EBD can be modulated. Indeed, the hypothalamus has a crucial role in EBD such as narcolepsy and cluster headache. The same may be true for migraine and depression. Here we summarise the evidence supporting an important role for the hypothalamus in the initiation of disease episodes in various EBD. Study of the various pathophysiological concepts of EBD within the context of the hypothalamus may prove a fruitful example of cross-fertilisation between various research areas.

Animals↗
PubMed2002

Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy.

PURPOSE OF REVIEW: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The discovery that the majority of human patients lack the hypothalamic neuropeptide hypocretin-1 has initiated a large body of new research. RECENT FINDINGS: Several studies on cerebrospinal fluid hypocretin-1 levels in narcolepsy and in various other sleep disorders have shown that hypocretin deficiency is both highly sensitive and specific for narcolepsy/cataplexy. Importantly, 15% of narcoleptic patients show low hypocretin levels, despite a negative multiple sleep latency test. Besides regulating sleep, the hypocretin system is involved in the regulation of energy balance, autonomic function and several neuroendocrine ensembles. Consequently, up to one-third of patients are obese (body mass index > 30). Furthermore, serum leptin levels are decreased in both nonoverweight and obese patients. The new rodent models for narcolepsy may aid in the further characterization of these endocrinological abnormalities. Finally, there is increasing insight into the physiological role of the hypocretin system in the regulation of sleep and wakefulness. SUMMARY: Hypocretin measurements may now be applied as a new diagnostic tool, providing the results are interpreted within the clinical context. In the clinical care of narcoleptic patients, attention should be paid to the obesity that frequently accompanies the disorder. In the future, hypocretin agonists may become available. Further characterization of animal models for narcolepsy will undoubtedly increase our insight into the pathophysiology of the disorder.

Animals↗