Running on Empty: Of Hypopinealism and Human Seasonality.

The pineal hormone melatonin is the natural transducer of the environmental light-dark signal to the body. Although the responsiveness to photoperiod is well-conserved in humans, only about 25 percent of the human population experiences seasonal changes in behavior. As a consequence, humans seem to have adapted-at least partly-to the seasonal changes in day length. The aim of the study was to demonstrate that the individual melatonin deficit marker DOC (degree of pineal calcification) is related to variation of seasonal phenomena in humans. Out of 3,011 patients in which cranial computer tomography (cCT) was performed for diagnostic reasons, 97 consecutive "healthy" subjects (43 female, 54 male; age 18-68 yrs, mean ± SD: 35.0 ± 13.1) were included. Exclusion criteria were pathological finding in cCT, acute/chronic illness including alcohol/drug abuse, shift work, and medication, which are known to influence melatonin excretion. The degree of pineal calcification (DOC) was semiquantitatively determined using the previously validated method. The Seasonal Pattern Assessment Questionnaire (SPAQ) was performed in a telephone interview. Twenty-six subjects fulfilled the criteria for seasonal affective disorder (SAD) or subsyndromal (S) SAD. Seasonality was more pronounced in women than in men (SPAQ seasonality score: 7.8 ± 4.0 vs. 4.9 ± 4.5; p = 0.001) and negatively and significantly associated with age (r = -0.178; p = 0.04). The subjective sleep length significantly varied between seasons (one-way repeated measures ANOVA: F = 45.75; p < 0.0001), with sleep during winter being 53 min (±70 min) longer than during summer. Controlling for age, the total seasonality score was negatively and significantly associated with DOC (r94 = -0.214; p = 0.036). Data confirm earlier studies with respect to distribution of seasonality with sex and age. The survival of seasonality in the sleep length of people living in an urban environment underlines functionality of the circadian timing system in modern societies. Moreover, data confirm for the first time that diminished experience of seasonality in behavior is associated with a reduced individual capacity to produce melatonin.

[Sleep Disturbances in the Elderly]. / Schlafstörungen im Alter.

Sleep disturbances are common in the elderly. Endogen regulation mechanisms are often unstable. Light treatment and melatonin are proved chronobiological interventions. Cataract surgery is effective to enhance the sleep-wake-rhythm.Mandibular advancement devices are a reliable alternative to continuous positive air pressure (CPAP) in obstructive sleep apnea syndrome (OSAS).

Decreased Verbal Learning but not Recognition Performance in Alcohol-dependent Individuals During Early Abstinence.

OBJECTIVE: Alcoholism ultimately leads to impairment of memory and other cognitive functions. This can interfere with treatment, if cognitively impaired alcohol-dependent individuals have difficulties recalling and implementing skills acquired during therapy. We investigate if alcohol-dependent individuals without clinically apparent withdrawal symptoms may still be impaired in higher-order cognitive functions. METHODS: Thirty-four alcohol-dependent patients and 20 matched healthy controls were tested with the Verbal Learning and Memory Test which includes seven measurement points. The test comprises free recall, free recall after distraction and after 30 minute delay, and a word recognition task. Testing was performed between day seven and day 10 after the beginning of abstinence, when clinical withdrawal symptoms had ceased. RESULTS: Compared to healthy controls, alcohol-dependent patients performed worse in free recall after delay, but not in word recognition. Healthy controls showed a more linear progression of improvement in verbal memory performance. Overall, alcohol-dependent individuals showed reduced verbal learning efficiency. The extent of impaired recall after distraction was positively associated (one-tailed test) with history of delirium (r=0.34, p=0.04), seizures (r=0.46, p=0.01), and years since diagnosis for alcohol dependency (r=0.39, p=0.01). CONCLUSIONS: Our results provide evidence that unmedicated alcohol-dependent patients without obvious withdrawal symptoms had impaired verbal recall, but normal recognition performance, at seven to 10 days after onset of abstinence. This deficit may deteriorate treatment outcomes due to poorer implementation of skills newly-learned during this time period.

Low effective organizational strategies in visual memory performance of unmedicated alcoholics during early abstinence.

OBJECTIVE: Alcohol-dependent patients in early abstinence show an impairment of cognitive functions which can be seen in poor implementation of newly learned skills for avoiding relapse. Executive dysfunction may persist during abstinence in alcohol-dependent persons, thus mitigating long-term abstinence. This study assessed visual memory function and choice of organizational strategies in alcoholics, as these are major factors necessary to implement ongoing behavior changes which are required for maintaining abstinence. METHODS: We investigated 25 severely alcohol-dependent male patients between days 7 to 10 of abstinence, immediately after clinical withdrawal symptoms have ceased, compared to 15 healthy age, sex, and education matched controls. Pharmacological therapy had been terminated at least four half-lifes before inclusion into the study. Visual perceptual learning and organizational strategies were assessed with the Rey-Osterrieth Complex Figure Test (R-OCF). RESULTS: There were no group differences in copying or recalling the figure, but time differences occurred. Alcoholics and healthy controls performed worse in recalling than in copying. But, alcoholics used less effective organizational strategies. CONCLUSIONS: There was a deficit in choice of organizational strategy in newly abstinent and unmedicated alcohol-dependent patients. Due to the imperfect organizational strategies, alcoholics might need auxiliary therapeutic care to strengthen their cognitive ability.

A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder.

Rapid eye movement (REM) sleep behaviour disorder (RBD) has been suggested to predict the development of neurodegenerative disorders. Patients with RBD are acting out dream behaviour associated with loss of normal muscle atonia of REM sleep. The aim of the present study was to confirm that exogenous melatonin improves RBD. Eight consecutively recruited males (mean age 54 years) with a polysomnographically (PSG) confirmed diagnosis of RBD were included in a two-part, randomized, double-blind, placebo-controlled cross-over study. Patients received placebo and 3 mg of melatonin daily in a cross-over design, administered between 22:00 h and 23:00 h over a period of 4 weeks. PSG recordings were performed in all patients at baseline, at the end of Part I of the trial and at the end of Part II of the trial. Compared to baseline, melatonin significantly reduced the number of 30-s REM sleep epochs without muscle atonia (39% versus 27%; P = 0.012), and led to a significant improvement in clinical global impression (CGI: 6.1 versus 4.6; P = 0.024). Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (-16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment). The data suggest that melatonin might be a second useful agent besides clonazepam in the treatment of RBD.

Degree of pineal calcification (DOC) is associated with polysomnographic sleep measures in primary insomnia patients.

OBJECTIVE: Melatonin plays a key role in the proper functioning of the circadian timing system (CTS), and exogenous melatonin has been shown to be beneficial in cases of CTS and sleep disturbances. Nevertheless, the concept of "melatonin deficit" has yet to be defined. The aim of our study was, therefore, to determine the relationship between the degree of pineal calcification (DOC) and a range of sleep parameters measured objectively using polysomnography (PSG). METHODS: A total of 31 outpatients (17 women, 14 men, mean age 45.9 years; SD 14.4) with primary insomnia were included in our study. Following an adaptation night, a PSG recording night was performed in the sleep laboratory. Urine samples were collected at predefined intervals over a 32-h period that included both PSG nights. The measurement of 6-sulphatoxymelatonin (aMT6s) levels was determined using ELISA. DOC and volume of calcified pineal tissue (CPT) and uncalcified pineal tissue (UPT) were estimated by means of cranial computed tomography. RESULTS: UPT was positively associated with 24-h aMT6s excretion (r=0.569; P=0.002), but CPT was not. After controlling for age, aMT6s parameters, CPT, and UPT did not correlate with any of the PSG parameters evaluated. In contrast, DOC was negatively associated with REM sleep percentage (r=-0.567, P=0.001), total sleep time (r=-0.463, P=0.010), and sleep efficiency (r=-0.422, P=0.020). CONCLUSION: DOC appears to be a superior indicator of melatonin deficit compared to the absolute amount of melatonin in the circulation. High DOC values indicate changes predominantly in the PSG parameters governed by the circadian timing system. DOC may thus serve as a marker of CTS instability.

Age effects on trail making test during acute depressive and manic episode.

Impairment of executive functions and attention has been found in patients with acute depressive episodes but has rarely been investigated in manic patients to date. At the same time, executive functions decline with age. Thus, it is currently a matter of debate how to best measure decreased executive performance in elderly patients with affective disorders. In our study, we examined 30 depressed patients, 28 manic patients, and 30 healthy subjects of all age groups, using the Trail Making Test (TMT). Both depressed and manic patients needed twice as long as healthy subjects to perform the TMT Part A. In addition to this reduced performance due to affective disorders, we were also able to detect a decline in performance due to age. One could thus postulate that age and affective disorders each influence a different neuropsychological function, age affecting executive performance and affective disorders affecting attention, as measured in both cases by the TMT.

Evaluation of time memory in acutely depressed patients, manic patients, and healthy controls using a time reproduction task.

Patients with affective disorders have often been reported to experience subjective changes in how they perceive the flow of time. Time reproduction tasks provide information about the memory component of time perception and are thought to remain unaffected by pulse rate disturbances in the pacemaker of the internal clock. In our study, 30 patients with acute depression, 30 patients with acute mania, and 30 healthy subjects of all age groups were presented with a time reproduction task. Participants were asked to observe a stimulus presented on a computer screen for a certain length of time and, subsequently, to reproduce the stimulus for a similar length of time by pressing the space bar on the computer keyboard. Stimuli were presented to each subject for 1, 6, and 37s. On average, the time intervals reproduced by manic patients were shorter than those reproduced by depressed patients. Manic patients reproduced the short time interval (6s) correctly, but under-reproduced the long time interval (37s, P<0.001). Depressed patients correctly reproduced the long time interval, but over-reproduced the short time interval (P<0.001). Remembering time intervals as having been longer than they actually were may lead to a slowed experience of time, as has been described in depressed patients; precisely the converse seems to apply to manic patients.

Pineal calcification in Alzheimer's disease: an in vivo study using computed tomography.

Melatonin has been postulated to have diverse properties, acting as an antioxidant, a neuroprotector, or a stabilizer within the circadian timing system, and is thus thought to be involved in the aging process and Alzheimer's disease (AD). We used computed tomography to determine the degree of pineal calcification (DOC), an intra-individual melatonin deficit marker, as well as the size of uncalcified pineal tissue, in 279 consecutive memory clinic outpatients (AD: 155; other dementia: 25; mild cognitive impairment: 33; depression: 66) and 37 age-matched controls. The size of uncalcified pineal tissue in patients with AD (mean 0.15 cm(2) [S.D. 0.24]) was significantly smaller than in patients with other types of dementia (0.26 [0.34]; P=0.038), with depression (0.28 [0.34]; P=0.005), or in controls (0.25 [0.31]; P=0.027). Additionally, the DOC in patients with AD (mean 76.2% [S.D. 26.6]) was significantly higher than in patients with other types of dementia (63.7 [34.7]; P=0.042), with depression (60.5 [33.8]; P=0.001), or in controls (64.5 [30.6]; P=0.021). These two findings may reflect two different aspects of melatonin in AD. On the one hand, the absolute amount of melatonin excretion capability, as indicated by uncalcified pineal volume, refers to the antioxidant properties of melatonin. On the other hand, the relative reduction in melatonin production capability in the individual, as indicated by DOC, refers to the circadian properties of melatonin.

Melatonin excretion levels and polysomnographic sleep parameters in healthy subjects and patients with sleep-related disturbances.

BACKGROUND: The hormone melatonin plays a key role in the proper functioning of the circadian timing system (CTS). Exogenous melatonin has been shown to be beneficial in cases of CTS dysfunction and sleep disturbances. The aim of our study was to relate 24-h melatonin excretion to objective sleep measures. METHODS: A total of 67 individuals were included in the study: 29 healthy subjects (16 women, 13 men; mean age 62.4 y, range 24-86) and 38 outpatients with neuropsychiatric sleep-related disturbances (25 women, 13 men; mean age 46.5 y, range 21-69). Over two consecutive nights in the sleep laboratory, polysomnographic (PSG) recordings were made and urine samples were collected at predefined intervals. RESULTS: Our data failed to show any age-controlled partial correlation between 6-sulphatoxymelatonin (aMT6s) parameters and PSG parameters in either of the two groups. CONCLUSION: Measuring endogenous melatonin does not seem to be an adequate way to evaluate sleep quality. This could be due to the fact that the size of the pineal gland and the amount of melatonin produced vary 20-fold between individuals.

[Alterations of time judgement with age]. / Veränderungen der Zeitbeurteilung im Alter.

OBJECTIVE: Time perception can be divided into two processes: time experience and time judgement. Although there have been frequent reports of changes in these two processes with increasing age, none of these changes has been demonstrated using objective measures. METHODS: We evaluated time judgement by employing time estimation, time production, and time reproduction tasks in 33 healthy subjects of all age groups. In addition, we used the Trail-Making Test to measure attentional performance. RESULTS: For both time estimation and time reproduction, we found positive correlations between length of time interval and age (overestimation). After we calculated partial correlations controlling for the results of the Trail-Making Test, the age-related changes we initially observed in the time estimation task disappeared, but the age-related changes seen in the time reproduction task remained significant. CONCLUSIONS: Considering the Scalar Timing Theory and the Attentional Gate Theory, our findings indicated that age-related effects on time estimation may be due to attentional factors. In contrast, the age-related changes seen in the time reproduction task may be due to disturbances in working memory function.

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study.

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84.

Although the hormone melatonin is a key factor for the proper functioning of the circadian timing system (CTS) and exogenous melatonin has been shown to be beneficial in cases of CTS disturbances, a deficit of melatonin has yet to be defined as a disorder. The aim of our study was to collect a normative data set on 24-h melatonin excretion in healthy human adults living in a natural environment. Urine samples were collected from 75 healthy subjects (45 women/30 men; mean age 47.2, SD 19.5, range 20-84) after five consecutive periods: 2300-0700, 0700-1100, 1100-1800, 1800-2300 and 2300-0700 h. 6-Sulfatoxymelatonin (aMT6s) concentrations were analyzed in duplicate by IBL (Hamburg) using a highly sensitive, competitive ELISA kit. Twenty-four hour-aMT6s total amount (rho=-0.68, p<0.001), aMT6s nighttime excretion (rho=-0.69, p<0.001), aMT6s morning excretion (rho=-0.66, p<0.001) and evening excretion (r=-0.26, p=0.023) were negatively associated with age, whereas daytime excretion (r=-0.17, p=0.15) was not. The intra-subject night-day ratio varied up to 10.5 (mean 6.0) in young subjects (aged 20-35) and up to 5.4 (mean 2.8) in older individuals (age>65). The total amount of 24 h-aMT6s (range 7.5-58 microg) as well as the amount of aMT6s excreted during the nighttime period (range 327-6.074 ng/h) varied as much as 20-fold between individuals. Our data show an age-related decline in melatonin excretion in healthy subjects living in a natural environment. The high inter-individual variability of excretion rates may explain why a normative data set is of no use in replacement strategies.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia.

RATIONALE: Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. OBJECTIVES: The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. METHODS: In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy. RESULTS: Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed. CONCLUSIONS: The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia.

Current treatments for Alzheimer's disease (AD) are only able to slow the progression of mental deterioration, making early and reliable diagnosis an essential part of any promising therapeutic strategy. In the initial stages of AD, the first neuropathological alterations occur in the perforant pathway (PP), a large neuronal fiber tract located at the entrance to the limbic system. However, to date, there is no sensitive diagnostic tool for performing in vivo assessments of this structure. In the present bimodal magnetic resonance imaging (MRI) study, we examined 10 elderly controls, 10 subjects suffering from mild cognitive impairment (MCI), and 10 AD patients in order to evaluate the sensitivity of diffusion tensor imaging (DTI), a new MRI technique, for detecting changes in the PP. Furthermore, the diagnostic explanatory power of DTI data of the PP should be compared to high-resolution MRI volumetry and intervoxel coherences (COH) of the hippocampus and the entorhinal cortex, two limbic regions also involved in the pathophysiology of early AD. DTI revealed a marked decrease in COH values in the PP region of MCI (right side: 26%, left side: 29%, as compared to controls) and AD patients (right side: 37%, left side: 43%, as compared to controls). Reductions in COH values of the PP region were significantly correlated with cognitive impairment. DTI data of the PP zone were the only parameter differing significantly between control subjects and MCI patients, while the volumetric measures and the COH values of the hippocampus and the entorhinal cortex did not. DTI of medial temporal brain regions is a promising non-invasive tool for the in vivo diagnosis of the early/preclinical stages of AD.

Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111).

Melatonin in patients with reduced REM sleep duration: two randomized controlled trials.

Recent data suggest that melatonin may influence human physiology, including the sleep-wake cycle, in a time-dependent manner via the body's internal clock. Rapid-eye-movement (REM) sleep expression is strongly circadian modulated, and the impact of REM sleep on primary brain functions, metabolic processes, and immune system function has become increasingly clear over the past decade. In our study, we evaluated the effects of exogenous melatonin on disturbed REM sleep in humans. Fourteen consecutive outpatients (five women, nine men; mean age, 50 yr) with unselected neuropsychiatric sleep disorders and reduced REM sleep duration (25% or more below age norm according to diagnostic polysomnography) were included in two consecutive, randomized, double-blind, placebo-controlled, parallel design clinical trials. Patients received 3 mg melatonin daily, administered between 2200 and 2300 h for 4 wk. The results of the study show that melatonin was significantly more effective than placebo: patients on melatonin experienced significant increases in REM sleep percentage (baseline/melatonin, 14.7/17.8 vs. baseline/placebo, 14.3/12.0) and improvements in subjective measures of daytime dysfunction as well as clinical global impression score. Melatonin did not shift circadian phase or suppress temperature but did increase REM sleep continuity and promote decline in rectal temperature during sleep. These results were confirmed in patients who received melatonin in the second study (REM sleep percentage baseline/placebo/melatonin, 14.3/12.0/17.9). In patients who received melatonin in the first study and placebo in the second, the above mentioned effects outlasted the period of melatonin administration and diminished only slowly over time (REM sleep percentage baseline/melatonin/placebo, 14.7/17.8/16.2). Our findings show that exogenous melatonin, when administered at the appropriate time, seems to normalize circadian variation in human physiology. It may, therefore, have a strong impact on general health, especially in the elderly and in shift workers.