Rolf Fronczek

Evaluation of wireless determination of skin temperature using iButtons

Measurements of skin temperatures are often complicated because of the use of wired sensors. This is so in field studies, but also holds for many laboratory conditions. This article describes a wireless temperature system for human skin temperature measurements, i.e. the Thermochron iButton DS1291H. The study deals with validation of the iButton and its application on the human skin, and describes clinical and field measurements. The validation study shows that iButtons have a mean accuracy of -0.09 degrees C (-0.4 degrees C at most) with a precision of 0.05 degrees C (0.09 degrees C at most). These properties can be improved by using calibration. Due to the size of the device the response time is longer than that of conventional sensors, with a tau in water of 19 s. On the human skin under transient conditions the response time is significantly longer, revealing momentary deviations with a magnitude of 1 degrees C. The use of iButtons has been described in studies on circadian rhythms, sleep and cardiac surgery. With respect to circadian rhythm and sleep research, skin temperature assessment by iButtons is of significant value in laboratory, clinical and home situations. We demonstrate that differences in laboratory and field measurements add to our understanding of thermophysiology under natural living conditions. The advantage of iButtons in surgery research is that they are easy to sterilize and wireless so that they do not hinder the surgical procedure. In conclusion, the application of iButtons is advantageous for measuring skin temperatures in those situations in which wired instruments are unpractical and fast responses are not required.

Hypocretin (orexin) loss in Alzheimer's disease.

Sleep disturbances in Alzheimers disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels.

Hypocretin and Melanin-Concentrating Hormone in Patients with Huntington Disease

To evaluate whether hypocretin‐1 (orexin‐A) and melanin‐concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, hypocretin‐1 levels were determined in prefrontal cortical tissue and post‐mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of hypocretin‐1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of hypocretin‐1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH‐expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.

Hypocretin/orexin disturbances in neurological disorders.

The hypothalamic hypocretin (orexin) system plays a crucial role in the regulation of sleep and wakefulness. The strongest evidence for this is the fact that the primary sleep disorder narcolepsy is caused by disrupted hypocretin signaling in humans as well as various animal models. There is a growing interest in the role of hypocretin defects not only in the pathophysiology of other sleep disorders, but also in neurological diseases with associated sleep symptomatology. In this paper we first review the current methods to measure the integrity of the hypocretin system in human patients. The most widely used technique entails the measurement of hypocretin-1 in lumbar cerebrospinal fluid. In addition, hypocretin levels can be measured in ventricular cerebrospinal fluid and brain tissue extract. Finally, in post-mortem hypothalamic material, the number of hypocretin neurons can be precisely quantified. In the second part of this paper we describe the various neurological disorders in which hypocretin defects have been reported. These include neurodegenerative, neuromuscular and immune-mediated diseases, as well as traumatic brain injury. We conclude with a discussion of the functional relevance of partial hypocretin defects, and the various pathophysiological mechanisms that can lead to such defects.

Sleep, vigilance, and thermosensitivity

The regulation of sleep and wakefulness is well modeled with two underlying processes: a circadian and a homeostatic one. So far, the parameters and mechanisms of additional sleep-permissive and wake-promoting conditions have been largely overlooked. The present overview focuses on one of these conditions: the effect of skin temperature on the onset and maintenance of sleep, and alertness. Skin temperature is quite well suited to provide the brain with information on sleep-permissive and wake-promoting conditions because it changes with most if not all of them. Skin temperature changes with environmental heat and cold, but also with posture, environmental light, danger, nutritional status, pain, and stress. Its effect on the brain may thus moderate the efficacy by which the clock and homeostat manage to initiate or maintain sleep or wakefulness. The review provides a brief overview of the neuroanatomical pathways and physiological mechanisms by which skin temperature can affect the regulation of sleep and vigilance. In addition, current pitfalls and possibilities of practical applications for sleep enhancement are discussed, including the recent finding of impaired thermal comfort perception in insomniacs.

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.

Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy

Sirs: Narcolepsy with cataplexy is caused by a loss of hypocretin producing neurons in the lateral hypothalamus [6, 8]. The strong Human Leukocyte Antigen (HLA DQB1*0602) association supports an autoimmune aetiology [5]. Still, there is no direct evidence for antineuronal antibodies or T-cell mediated autoimmunity to support this hypothesis [1, 7]. Treatment with high-dose prednisone after acute onset of hypocretin-deficiency in an 8-year-old boy without cataplexy was not effective [3]. However, two studies suggested that treating narcoleptics with intravenous immunoglobulins (IVIg) shortly after disease onset may dramatically reduce the frequency and severity of cataplexy [2, 4]. We present a n = 1 study in a 55year-old female patient suffering from typical narcolepsy with cataplexy for 7 years, who was almost unresponsive to any regular treatment, but had a dramatic response on open label treatment with IVIg. Polysomnographic findings were typical of narcolepsy with cataplexy. She was HLADQB1*0602 positive, hypocretin deficient and used venlafaxine (75 mg/d) with limited effects. Cataplexy was frequent and disabling (according to her diary: mean ± standard deviation; 3.30 ± 0.15 complete attacks per day; range 3–4). Together with her severe excessive daytime sleepiness, the patient was invalided with profound impact on quality of life. She was almost homebound and evaded social activities to avoid a provocation of her complaints. After informed consent, we treated her with open label IVIg (1 g/kg/d over 2 days). After treatment she reported a clear reduction of cataplectic attacks and several days without any attacks. This effect lasted three weeks and disappeared gradually. Repeated treatment six months later showed a similar response. We started a double-blind placebocontrolled n = 1 trial to analyse this remarkable response [9]. This consisted of four successive treatment periods in which IVIg (1 g/kg/d over 2 days) or placebo was randomly administered [9]. The patient could request the ‘rescue’ medication for that period, if she did not experience significant clinical improvement within 10 days after treatment. This rescue medication was IVIg when the treatment period was started with placebo and placebo when the treatment period was started with IVIg. The next treatment period was started after the patient indicated that the treatment effect had disappeared, and at least 4 weeks after the previous treatment. During the entire study period the patient kept a diary in which she noted the number of complete cataplectic attacks. Venlafaxine was continued in an unchanged dose throughout the entire study. Differences between the placebo and the IVIg periods were analysed using ttests, corrected for the number of days within each period. LETTER TO THE EDITORS

Manipulation of skin temperature improves nocturnal sleep in narcolepsy

Objective: Besides excessive daytime sleepiness, disturbed nocturnal sleep is a major complaint of patients with narcolepsy. Previously, alterations in skin temperature regulation in narcoleptic patients have been shown to be related to increased sleepiness. This study tests the hypothesis that direct control of nocturnal skin temperature might be applied to improve the disturbed sleep of narcoleptic patients. Methods: Participants were eight patients (five males) diagnosed as having narcolepsy with cataplexy according to the ICSD-2 criteria, mean (SD) age 28.6 (6.4) years, range 18–35 years. During two nights, sleep was recorded polysomnographically while proximal and distal skin temperature were manipulated using a comfortable thermosuit that induced skin temperature to cycle slowly with an amplitude of only 0.4°C within the comfortable range normally observed during sleep. Logistic regression was used to evaluate the effect of skin temperature manipulation on the probability of occurrence of different sleep stages and nocturnal wakefulness. Results: Proximal skin warming significantly suppressed wakefulness and enhanced slow wave sleep (SWS). In contrast, distal skin warming enhanced wakefulness and stage 1 sleep at the cost of SWS and REM sleep. The optimal combination of proximal skin warming and distal skin cooling led to a 160% increase in SWS, a 50% increase in REM sleep and a 68% decrease in wakefulness, compared with the least beneficial combination of proximal skin cooling and distal skin warming. Interpretation: Subtle skin temperature manipulations under controlled conditions significantly improved the typical nocturnal sleep problems in narcolepsy.

Sustained attention to response task (SART) shows impaired vigilance in a spectrum of disorders of excessive daytime sleepiness

The sustained attention to response task comprises withholding key presses to one in nine of 225 target stimuli; it proved to be a sensitive measure of vigilance in a small group of narcoleptics. We studied sustained attention to response task results in 96 patients from a tertiary narcolepsy referral centre. Diagnoses according to ICSD‐2 criteria were narcolepsy with (n = 42) and without cataplexy (n = 5), idiopathic hypersomnia without long sleep time (n = 37), and obstructive sleep apnoea syndrome (n = 12). The sustained attention to response task was administered prior to each of five multiple sleep latency test sessions. Analysis concerned error rates, mean reaction time, reaction time variability and post‐error slowing, as well as the correlation of sustained attention to response task results with mean latency of the multiple sleep latency test and possible time of day influences. Median sustained attention to response task error scores ranged from 8.4 to 11.1, and mean reaction times from 332 to 366 ms. Sustained attention to response task error score and mean reaction time did not differ significantly between patient groups. Sustained attention to response task error score did not correlate with multiple sleep latency test sleep latency. Reaction time was more variable as the error score was higher. Sustained attention to response task error score was highest for the first session. We conclude that a high sustained attention to response task error rate reflects vigilance impairment in excessive daytime sleepiness irrespective of its cause. The sustained attention to response task and the multiple sleep latency test reflect different aspects of sleep/wakefulness and are complementary.

Reward-seeking behavior in human narcolepsy

STUDY OBJECTIVES The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk- and reward-seeking behaviors, including substance abuse. DESIGN Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). SETTING Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). PATIENTS Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. INTERVENTIONS None. MEASUREMENTS AND RESULTS There was no difference in risk-taking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. CONCLUSIONS We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety were higher in all narcoleptic subjects. However, using the current methods, no evidence could be found to support the hypothesis that hypocretin deficiency would affect reward-processing in humans.