35 years of light treatment for mental disorders in the Netherlands.

BACKGROUND: Light therapy (LT) for Seasonal Affective Disorders (SAD) has been a well-known and effective treatment for 40 years. The psychiatric university clinic of Groningen, the Netherlands was an early adopter and started research and treatment of SAD in 1987. Research projects on mechanisms, the role of the circadian system, treatment optimization, and investigating new areas for the effects of light treatment have been carried out ever since, leading to a widespread interest across the country. OBJECTIVE: To provide an overview and description of the historical development of LT for mental disorders in the Netherlands. METHODS: A non-systematic, review of research on light treatment for mental problems in the Netherlands, published since 1987 was conducted. RESULTS: The fields of LT and chronotherapy are strongly based in the scientific interests of both chrono-biologists and therapists in the Netherlands. LT has shown effectiveness in treating mood disorders. Likewise, results for other mental disorders have shown some promise, but so far, the outcomes are not always unequivocal and have not always been based on robust data. Ongoing research is discussed. CONCLUSIONS: LT, and in addition exposure to the right light at the right time is an important issue in mental health. Over the past 3 decades research on light and LT in the Netherlands has become well established and is still growing.

Bright Light During Wakefulness Improves Sleep Quality in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (III).

Under real-life conditions, increased light exposure during wakefulness seems associated with improved sleep quality, quantified as reduced time awake during bed time, increased time spent in non-rapid eye movement (NREM) sleep, or increased power of the electroencephalogram delta band (0.5-4 Hz). The causality of these important relationships and their dependency on circadian phase and/or time awake has not been studied in depth. To disentangle possible circadian and homeostatic interactions, we employed a forced desynchrony protocol under dim light (6 lux) and under bright light (1300 lux) during wakefulness. Our protocol consisted of a fast cycling sleep-wake schedule (13 h wakefulness-5 h sleep; 4 cycles), followed by 3 h recovery sleep in a within-subject cross-over design. Individuals (8 men) were equipped with 10 polysomnography electrodes. Subjective sleep quality was measured immediately after wakening with a questionnaire. Results indicated that circadian variation in delta power was only detected under dim light. Circadian variation in time in rapid eye movement (REM) sleep and wakefulness were uninfluenced by light. Prior light exposure increased accumulation of delta power and time in NREM sleep, while it decreased wakefulness, especially during the circadian wake phase (biological day). Subjective sleep quality scores showed that participants rated their sleep quality better after bright light exposure while sleeping when the circadian system promoted wakefulness. These results suggest that high environmental light intensity either increases sleep pressure buildup during wakefulness or prevents the occurrence of micro-sleep, leading to improved quality of subsequent sleep.

Fatigue in children: reliability and validity of the Dutch PedsQL™ Multidimensional Fatigue Scale.

PURPOSE: The aim of the study is to report on the feasibility, reliability, validity, and the norm-references of the Dutch version of the PedsQL™ Multidimensional Fatigue Scale. METHODS: The study participants are four hundred and ninety-seven parents of children aged 2-18 years and 366 children aged 5-18 years from various day care facilities, elementary schools, and a high school who completed the Dutch version of the PedsQL™ Multidimensional Fatigue Scale. RESULTS: The number of missing items was minimal. All scales showed satisfactory internal consistency reliability, with Cronbach's coefficient alpha exceeding 0.70. Test-retest reliability was good to excellent (ICCs 0.68-0.84) and inter-observer reliability varied from moderate to excellent (ICCs 0.56-0.93) for total scores. Parent/child concordance for total scores was poor to good (ICCs 0.25-0.68). The PedsQL™ Multidimensional Fatigue Scale was able to distinguish between healthy children and children with an impaired health condition. CONCLUSIONS: The Dutch version of the PedsQL™ Multidimensional Fatigue Scale demonstrates an adequate feasibility, reliability, and validity in another sociocultural context. With the obtained norm-references, it can be utilized as a tool in the evaluation of fatigue in healthy and chronically ill children aged 2-18 years.

Gold, silver or bronze: circadian variation strongly affects performance in Olympic athletes.

The circadian system affects physiological, psychological, and molecular mechanisms in the body, resulting in varying physical performance over the day. The timing and relative size of these effects are important for optimizing sport performance. In this study, Olympic swim times (from 2004 to 2016) were used to determine time-of-day and circadian effects under maximal motivational conditions. Data of athletes who made it to the finals (N = 144, 72 female) were included and normalized on individual levels based on the average swim times over race types (heat, semifinal, and final) per individual for each stroke, distance and Olympic venue. Normalized swim times were analyzed with a linear mixed model and a sine fitted model. Swim performance was better during finals as compared to semi-finals and heats. Performance was strongly affected by time-of-day, showing fastest swim times in the late afternoon around 17:12 h, indicating 0.32% improved performance relative to 08:00 h. This study reveals clear effects of time-of-day on physical performance in Olympic athletes. The time-of-day effect is large, and exceeds the time difference between gold and silver medal in 40%, silver and bronze medal in 64%, and bronze or no medal in 61% of the finals.

Examining courses of sleep quality and sleepiness in full 2 weeks on/2 weeks off offshore day shift rotations.

To better understand sleep quality and sleepiness problems offshore, we examined courses of sleep quality and sleepiness in full 2-weeks on/2-weeks off offshore day shift rotations by comparing pre-offshore (1 week), offshore (2 weeks) and post-offshore (1 week) work periods. A longitudinal observational study was conducted among N=42 offshore workers. Sleep quality was measured subjectively with two daily questions and objectively with actigraphy, measuring: time in bed (TIB), total sleep time (TST), sleep latency (SL) and sleep efficiency percentage (SE%). Sleepiness was measured twice a day (morning and evening) with the Karolinska Sleepiness Scale. Changes in sleep and sleepiness parameters during the pre/post and offshore work periods were investigated using (generalized) linear mixed models. In the pre-offshore work period, courses of SE% significantly decreased (p=.038). During offshore work periods, the courses of evening sleepiness scores significantly increased (p<.001) and significantly decreased during post-offshore work periods (p=.004). During offshore work periods, TIB (p<.001) and TST (p<.001) were significantly shorter, SE% was significantly higher (p=.002), perceived sleep quality was significantly lower (p<.001) and level of rest after wake was significantly worse (p<.001) than during the pre- and post-offshore work periods. Morning sleepiness was significantly higher during offshore work periods (p=.015) and evening sleepiness was significantly higher in the post-offshore work period (p=.005) compared to the other periods. No significant changes in SL were observed. Courses of sleep quality and sleepiness parameters significantly changed during full 2-weeks on/2-weeks off offshore day shift rotation periods. These changes should be considered in offshore fatigue risk management programmes.

Integration of color and intensity increases time signal stability for the human circadian system when sunlight is obscured by clouds.

The mammalian circadian system encodes both absolute levels of light intensity and color to phase-lock (entrain) its rhythm to the 24-h solar cycle. The evolutionary benefits of circadian color-coding over intensity-coding per se are yet far from understood. A detailed characterization of sunlight is crucial in understanding how and why circadian photoreception integrates color and intensity information. To this end, we continuously measured 100 days of sunlight spectra over the course of a year. Our analyses suggest that circadian color-coding may have evolved to cope with cloud-induced variation in light intensity. We proceed to show how an integration of intensity and spectral composition reduces day-to-day variability in the synchronizing signal (Zeitgeber). As a consequence, entrained phase angle of the circadian clock will be more stable, which will be beneficial for the organism. The presented characterization of sunlight dynamics may become important in designing lighting solutions aimed at minimizing the detrimental effects of light at night in modern societies.

Testing the hypothesis of a circadian phase disturbance underlying depressive mood in nonseasonal depression.

In a crossover design, 8 nonseasonal depressed subjects, selected on the presence of diurnal mood variations, and 8 sex- and age-matched controls were exposed to dim light (< 10 lux) in the evening (18:00-21:00 h) and bright light (2500 lux) in the morning (ML, 6:00-9:00 h), to dim light in the morning and bright light in the evening (EL), or to dim light both in the evening and in the morning (DL) during 3 consecutive days in each of these conditions. There were no initial phase differences between depressed and healthy subjects in the timing of dim light melatonin onset, sleep termination, and body temperature. The phase shifts after EL and ML in both healthy and depressed subjects were as expected on the basis of a human phase response curve. On average, there was no therapeutic effect of the light exposure in the depressed patients. Two patients improved, but these effects do not seem to be related to shifts in the circadian system.

Prediction of the antidepressant response to total sleep deprivation of depressed patients: longitudinal versus single day assessment of diurnal mood variation.

The relationship between diurnal variation of mood and the clinical response to total sleep deprivation (TSD) was investigated in 43 depressed patients. The question asked was whether the propensity to produce diurnal variations of mood or the actual mood course on the day before TSD determines the clinical response to TSD. Patients rated their mood three times daily during an experimental period of 56 days. The frequency as well as the amplitude of daily mood changes were assessed during this period. For each patient six TSDs were scheduled: two after days with a positive mood course, two after a negative mood course, and two after days without a diurnal change of mood. This strategy allowed comparisons of TSD responses within patients. Moreover, longitudinally and retrospectively assessed diurnal variation were compared with each other. It was found that patients vary largely in the occurrence of diurnal variations of mood. The propensity to produce diurnal variations either in terms of frequency or amplitude was positively correlated with the response to TSD. Within patients no differences were found in responses to TSDs applied after days with diurnal variations (positive or negative) or without diurnal variations. A second aim was to get more insight into the mechanism relating diurnal variations of mood and the TSD response. Therefore, the interrelatedness of various measures of diurnal variations, such as amplitudes and frequencies of positive or negative diurnal mood changes, was studied, as well as the relationships of these variables with TSD responses. On the basis of the strong interrelatedness it is suggested that they all reflect the same underlying mechanism, to be symbolized by an oscillator, producing positive daily fluctuations of mood.

Body temperature and mood variations during forced desynchronization in winter depression: a preliminary report.

BACKGROUND: It has been suggested that certain abnormalities (e.g., in phase or amplitude) of the circadian pacemaker underlie seasonal affective disorder. METHODS: One male seasonal affective disorder patient (blind to the study design) participated in two 120-hour forced desynchrony experiments and was subjected to six 20-hour days, once during a depressive episode and once after recovery. Core body temperature was continuously measured. During wakefulness, the Adjective Mood Scale was completed at 2-hour intervals. RESULTS: Sleep-wake as well as pacemaker-related variations of mood were found, both when the subject was depressed and when he was euthymic. Compared with recovery, during the depressive episode the circadian temperature minimum and the circadian mood variation showed phase delays of approximately 1 and 2 hours, respectively. CONCLUSIONS: The data of this first seasonal affective disorder patient, participating in forced desynchrony experiments, may indicate a phase delay of the circadian pacemaker during a seasonal affective disorder episode.

Extraocular light therapy in winter depression: a double-blind placebo-controlled study.

BACKGROUND: It has been hypothesized that the circadian pacemaker is phase delayed in seasonal affective disorder, (SAD) winter type, and that the phase advance resulting from morning ocular light accounts for the efficacy of light therapy. Extraocular light has been reported to produce phase-shifts of the human circadian pacemaker. This allows a double-blind, placebo-controlled study of light therapy in SAD. METHODS: Twenty-nine SAD patients participated. Clinical state was measured on days 1, 8, and 15 of the protocol. From days 4 through 8, 15 patients (4 M, 11 F) received extraocular light by fiberoptic illumination, and 14 (4 M, 10 F) placebo (no light) in the popliteal fossae, from 8 AM to 11 AM. In the evenings of days 3 and 8, the salivary dim light melatonin onset (DLMO) was assessed. Patients completed daily self-ratings on mood, alertness, and sleep. RESULTS: Both conditions showed a progressive improvement of clinical state over time. Between conditions, no significant differences were observed in clinical scores, the self-ratings on mood and alertness, and in timing of the DLMO before and directly after treatment. CONCLUSIONS: The response to extraocular light therapy in SAD patients did not exceed its placebo effect. Extraocular light did not induce a phase shift of the circadian pacemaker.

A longitudinal study of diurnal mood variation in depression; characteristics and significance.

The course of 39 depressed in-patients' daily mood was recorded by means of frequent self-ratings during their entire stay (in total 3718 days). The frequency of diurnal variations largely varies between subjects without clear dichotomy in 'diurnal' and 'non-diurnal' subjects and the occurrence of diurnal variations is rather irregular. Mood variability measures rather than average daily mood improvement correlate with the response to sleep deprivation. These observations do not support theories of chronobiological rhythm disturbances in depression. It is argued that depressed subjects largely vary in susceptibility to stimuli. Signals generated by the biological clock or by processes related to the sleep-wake cycle are considered examples of such stimuli.

Gender-specific mechanisms associated with outcome of depression: perception of emotions, coping and interpersonal functioning.

We proposed that a negative bias in the perception of facial expressions would affect the way in which deficient coping and interpersonal functioning influenced the risk of persistent depression. Furthermore, we hypothesised that cognitions, coping strategies, and interpersonal functioning would be more likely to contribute to the prediction of outcome of depression among women than among men. At admission, 60 in-patients with major depression judged 12 schematic faces with respect to the emotions that they expressed (fear, happiness, anger, sadness, disgust, surprise, rejection and invitation). In addition, difficulty in assertiveness and social distress, and coping strategies for dealing with stressful events were measured with self-report questionnaires. At admission and 6 weeks later, the severity of depression was evaluated with the Beck Depression Inventory. Women who were inclined to perceive high levels of negative emotions from facial expressions and who reported high levels of social distress at admission were less likely to be improved after 6 weeks. Among women, these high levels of perception of negative emotions and high levels of social distress tended to predict the persistence of depression independently. A propensity to perceive negative facial expressions may underlie the unfavourable course of depression, especially among women.

The duration of light treatment and therapy outcome in seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is characterized by recurrent episodes of major depression with a seasonal pattern, treated with light therapy (LT). Duration of light therapy differs. This study investigates retrospectively whether a single week of LT is as effective as two weeks, whether males and females respond differently, and whether there is an effect of expectations as assessed before treatment. METHODS: 83 women, and 25 men received either one-week (n=42) or two weeks (n=66) of LT were included in three studies. Before LT, patients׳ expectations on therapy response were assessed. RESULTS: Depression severity was similar in both groups before treatment (F(1,106)=0.19ns) and decreased significantly during treatment (main effect "time" F(2,105)=176.7, p<0.001). The speed of therapy response differs significantly in treatment duration, in favor of 1 week (F(2,105)=3.2, p=0.046). A significant positive correlation between expectations and therapy response was found in women (ρ=0.243, p=0.027) and not in men (ρ=-0.154,ns). When expectation was added as a covariate in the repeated-measures analysis it shows a positive effect of the level of expectation on the speed of therapy response (F(2,104)=4.1, p=0.018). LIMITATIONS: A limitation is the retrospective design. CONCLUSIONS: There is no difference between 1 and 2 weeks of LT in overall therapy outcome, but the speed of therapy response differed between 1 week LT and 2 weeks LT. Together with the significant correlation between expectations and therapy response in women, we hypothesize that expectations play a role in the speed of therapy response.

The effects of blue-enriched light treatment compared to standard light treatment in Seasonal Affective Disorder.

BACKGROUND: One of the most frequently investigated hypotheses of the pathophysiology underlying Seasonal Affective Disorder (SAD) is a disturbance of circadian rhythms. Since the circadian system as well as other non-visual effects is especially sensitive to blue light, a new light therapy device with blue enriched polychromatic light was tested for its efficacy to treat SAD. METHODS: Within one winter 52 patients were treated in one of three conditions: 30 min full spectrum light (9000 lx, 5000 K), 30 min blue-enriched light (9000 lx, 17,000 K), or 20 min blue-enriched light. The study lasted 22 days with 10 days of morning-light treatment on weekdays during the first 2 weeks. RESULTS: Depressive symptoms (SIGH SAD) diminished over the 3-week period in all conditions, with no significant differences between conditions. The percentage responders were high, differing from 75%, 59% and 71% for the standard-LT, 30 min blue-enriched-LT, and 20 min blue-enriched-LT, respectively. CONCLUSION: The lack of superiority of high intensity blue-enriched light over standard bright light treatment does not clearly support nor rule out the possibility of an important role for the circadian system or the blue sensitive non-visual image forming system in general, in the pathophysiology of SAD. The lack of a difference between conditions may also be the result of a saturated response to the high light intensities used. Recent data indeed suggest that low intensity blue-enriched light may be as effective as standard bright light treatment. The possibility of improving light therapy for SAD patients by applying light of shorter duration or at lower light intensities is highly relevant for optimizing treatment and will help to clarify the role of the circadian system and/or the non-image forming photoreceptors in SAD pathophysiology. CLINICAL TRIAL: https://register.clinicaltrials.gov: NCT01048294.

[Two infants with bleeding caused by alpha-1-antitrypsin deficiency]. / Bloedingen bij twee zuigelingen met alpha1-antitrypsinedeficiëntie.

Alpha-1-antitrypsin deficiency (AATD) was diagnosed in a girl aged two months and a boy aged 18 days with neonatal cholestasis syndrome and vitamin K deficiency-induced bleeding, including intracerebral bleeding. The differential diagnosis of neonatal cholestasis syndrome takes time, and treatable causes should be recognised as soon as possible. AATD is the most common hereditary cause of neonatal cholestasis syndrome. This autosomal recessive disorder is also associated with adult pulmonary emphysema. Diagnosis is simply made by determining the proteinase inhibitor (PI) phenotype with isoelectric focusing. No effective treatment is available. For patients with persistent liver disease liver transplantation may be necessary.

Will light brighten the future of the depressed patient?

The present explosive growth of interest in the therapeutic possibilities of exposure to light was triggered by a patient, Herbert Kern. He suffered from episodic depressive and manic complaints and discovered, by registering these over the years, a seasonal pattern in their occurrence. Discussions with scientists of the NIMH resulted in his participation in a bright light-treatment experiment when he was depressed in the winter of 1980-1981. He recovered. Next, the same group of investigators defined the criteria for a new syndrome, Seasonal Affective Disorder (SAD): a history of major affective disorder (according to the Research Diagnostic Criteria), at least two consecutive years in which the depressions have occurred during fall or winter and remitted in the following spring or summer, and the absence of any clear-cut seasonally changing psychosocial variable, such as work, stress and so on.

Depressed patients' perceptions of facial emotions in depressed and remitted states are associated with relapse: a longitudinal study.

Within the framework of interpersonal and cognitive theories of depression, we investigated whether the perception of facial emotions was associated with subsequent relapse into depression. The 23 inpatients with major depression who remitted (65 admitted patients) were studied at admission (T0), at discharge (T1), and 6 months thereafter to assess relapse. They judged schematic faces with respect to the expression of positive and negative emotions. Six patients (26.1%) relapsed. High levels of perception of negative emotions in faces, either assessed at T0 or at T1, were associated with relapse. Moreover, subjects saw more negative emotions in depressed than in remitted state. Significant results were confined to ambiguous faces, i.e., faces expressing equal amounts of positive and negative emotions. Our data support the hypothesis that a bias toward the perception of others' facial emotions as negative is an enduring vulnerability factor to depression relapse and depressed mood amplifies this negative bias in perception.

Effects of light exposure and sleep displacement on dim light melatonin onset.

The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.