E.J.W. van Someren

Correlating the alpha rhythm to BOLD using simultaneous EEG/fMRI: Inter-subject variability

Simultaneous recording of electroencephalogram/functional magnetic resonance images (EEG/fMRI) was applied to identify blood oxygenation level-dependent (BOLD) changes associated with spontaneous variations of the alpha rhythm, which is considered the hallmark of the brain resting state. The analysis was focused on inter-subject variability associated with the resting state. Data from 7 normal subjects are presented. Confirming earlier findings, three subjects showed a negative correlation between the BOLD signal and the average power time series within the alpha band (8--12 Hz) in extensive areas of the occipital, parietal and frontal lobes. In small thalamic areas, the BOLD signal was positively correlated with the alpha power. For subjects 3 and 4, who displayed two different states during the data acquisition time, it was shown that the corresponding correlation patterns were different, thus demonstrating the state dependency of the results. In subject 5, the changes in BOLD were observed mainly in the frontal and temporal lobes. Subject 6 only showed positive correlations, thus contradicting the negative BOLD alpha power cortical correlations that were found in most subjects. Results suggest that the resting state varies over subjects and, sometimes, even within one subject. As the resting state plays an important role in many fMRI experiments, the inter-subject variability of this state should be addressed when comparing fMRI results from different subjects.

Circadian and age-related modulation of thermoreception and temperature regulation: mechanisms and functional implications

At older ages, the circadian rhythm of body temperature shows a decreased amplitude, an advanced phase, and decreased stability. The present review evaluates to what extent these changes may result from age-related deficiencies at several levels of the thermoregulatory system, including thermoreception, thermogenesis and conservation, heat loss, and central regulation. Whereas some changes are related to the aging process per se, others appear to be secondary to other factors, for which the risk increases with aging, notably a decreased level of fitness and physical activity. Moreover, functional implications of the body temperature rhythm are discussed. For example, the relation between circadian rhythm and thermoregulation has hardly been investigated, while evidence showed that sleep quality is dependent on both aspects. It is proposed that the circadian rhythm in temperature in homeotherms should not be regarded as a leftover of ectothermy in early evolution, but appears to be of functional significance for physiology from the level of molecules to cognition. A new view on the functional significance of the circadian rhythm in peripheral vasodilation and the consequent out-of-phase rhythms in skin and core temperature is presented. It is unlikely that the strong, daily occurring, peripheral vasodilation primarily represents heat loss in response to a lowering of set point, since behavioral measures are simultaneously taken in order to prevent heat loss. Several indications rather point towards a supportive role in immunological host defense mechanisms. Given the functional significance of the temperature rhythm, research should focus on the feasibility and effectiveness of methods that can in principle be applied in order to enhance the weakened circadian temperature rhythm in the elderly.

Skin deep: enhanced sleep depth by cutaneous temperature manipulation

With ageing, an increasingly disturbed sleep is reported as a significant complaint affecting the health and well-being of many people. The available treatments for sleep disturbance have their limitations, so we have adopted a different approach to the improvement of sleep. Since in animal and human studies skin warming has been found to increase neuronal activity in brain areas that are critically involved in sleep regulation, we investigated whether subtle skin temperature manipulations could improve human sleep. By employing a thermosuit to control skin temperature during nocturnal sleep, we demonstrate that induction of a mere 0.4 degrees C increase in skin temperature, whilst not altering core temperature, suppresses nocturnal wakefulness (P<0.001) and shifts sleep to deeper stages (P<0.001) in young and, especially, in elderly healthy and insomniac participants. Elderly subjects showed such a pronounced sensitivity, that the induced 0.4 degrees C increase in skin temperature was sufficient to almost double the proportion of nocturnal slow wave sleep and to decrease the probability of early morning awakening from 0.58 to 0.04. Therefore, skin warming strongly improved the two most typical age-related sleep problems; a decreased slow wave sleep and an increased risk of early morning awakening. EEG frequency spectra showed enhancement of low-frequency cortical oscillations. The results indicate that subtle feedback control of in-bed temperature through very mild manipulations could have strong clinical relevance in the management of disturbed sleep especially in the elderly, who have an attenuated behavioural response to suboptimal environmental temperature, which may hamper them from taking appropriate action to optimize their bed temperature.

Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: Chronobiological perspectives

Numerous studies indicate a deterioration of nighttime sleep and daytime cognitive performance in elderly people and Alzheimer patients. As a result of the increasing number of elderly people and Alzheimer patients in the western society, attention for these problems has grown. However, so far, the major research effort has been concentrating on the development of pharmacological therapies for an isolated age-related problem. In the present review it is argued that several age-related problems with sleep and wakefulness may reflect a dampening of circadian rhythm amplitudes. Non-pharmacological manipulation of circadian rhythms by means of various external stimuli appears to be effective in improving sleep and cognitive functioning in elderly people and Alzheimer patients.

Fatigue, sleep disturbances and circadian rhythm in multiple sclerosis

The aim of this study was to investigate whether fatigue and sleep disturbances in multiple sclerosis (MS) patients might be due to disrupted circadian sleep wake regulation. Actigraphy and a multiple sleep latency test (MSLT) were performed in 16 MS patients with both prominent sleep complaints and fatigue. Actigraphy scores did not differ from control values, whereas sleep onset latency values were altered in subgroups of MS patients. No evidence was found for a generalized circadian disturbance in MS patients.

Reduced neuronal activity and reactivation in Alzheimer's disease.

Publisher Summary Alzheimers disease (AD) is a multifactorial disease in which APOE-ɛ4 and age are important risk factors. In addition, various mutations and even viral infections, such as herpex simplex may play a role. AD is characterized histopathologically by the presence of large numbers of neuritic plaques (NPs) and cytoskeletal changes that are present as pretangles after staining— that is, by Alz-50 or AT8, or as neurofibrillary tangles (NFT) after silver staining. NFT are present in the cell bodies of affected neurons, while the same cytoskeletal changes are called neuropil threads when present outside neuritic plaques or dystrophic neurites when they are the neuritic components of neuritic plaques (NPs). Dystrophic neurites or neuropil threads are short, thickened, curly, coiled, or sometimes hooked fibres. To a lesser degree, NPs and cytoskeletal changes can also be observed in aged, nondemented control subjects. This chapter provides evidence in favor of the hypotheses that (1) the neuropathological Alzheimer changes cannot all be explained by a cascade starting with amyloid (β/A4) deposits as suggested example by Selkoe, but that (2) the neuropathological hallmarks of Alzheimers disease are basically independent phenomena, and that (3) cell death in Alzheimers disease is not a major generally occurring phenomenon, but is restricted to a few brain areas. A long struggle has been going on about the question what is more important for the development of dementia: cytoskeletal changes or amyloid. The answer is probably neither. As it is argued in this chapter, (4) reduced neuronal activity is most probably one of the major characteristics of AD and may underlie the clinical symptoms of dementia. Experiments are discussed that indicate that it is attractive to direct therapeutic strategies towards restimulation of neuronal metabolism and repair mechanisms in order to improve cognitive and behavioral symptoms of AD.

Transcutaneous electrical nerve stimulation (TENS) improves circadian rhythm disturbances in alzheimer disease

In patients with Alzheimer disease (AD), an irregular day-night rhythm with behavioral restlessness during the night makes a strong demand on caregivers and is among the most important reasons for institutionalization. A dysfunctioning circadian timing system is supposed to underlie the disturbance or at least to contribute to it. The disturbance improves with increased environmental light, which, through the retinohypothalamic tract, activates the suprachiasmatic nucleus (SCN), the biological clock of the brain. Because recent studies have indicated both direct and indirect spinal projections to the SCN, we investigated whether excitation of spinal neurons by means of transcutaneous electrical nerve stimulation (TENS) could also improve circadian rhythm disturbances in AD patients. The actigraphically obtained rest-activity rhythm of 14 AD patients showed an improvement in its coupling to Zeitgeber after TENS treatment but not after placebo treatment.

Actigraphic monitoring of movement and rest-activity rhythms in aging, Alzheimer's disease, and Parkinson's disease

Actigraphy, the long-term assessment of wrist movements, is used in several research fields, among which are included sleep and circadian rhythms. Actigraphs record movements using accelerometers. The present paper addresses some basic problems and their solutions in the actigraphic assessment of movement, motor symptoms, circadian rest-activity rhythms, and nocturnal agitation in healthy elderly and elderly suffering from a neurodegenerative disease (i.e., Parkinsons disease or Alzheimers disease) and summarizes the results of previous and ongoing research. First, the author has investigated how to filter the accelerometer signal in order to minimize the contribution of accelerations induced by positional changes in the gravitational field-a strong source of artefacts. A bandpass filter from 0.5 to 11 Hz appropriately assesses movement induced accelerations while minimizing gravitational artefact. The application of a bandpass filter from 0.25 to 2 or 3 Hz, as is used in some of the commercially available actigraphs, results in artefacts and moreover biases the slower part of the movement spectrum. It is therefore far from optimal for research on aging, which is associated with a generalized motor slowing. Second, the author has proposed an alternative to traditional methods of signal processing in actigraphy, in order to assess both the duration and intensity of movements, and in order to distinguish Parkinsonian tremor. Based on this algorithm, new types of actigraphs have been designed. Third, the author has proposed sensitive variables in order to quantify rest-activity rhythm disturbances in healthy elderly subjects and Alzheimer patients, who often present with symptoms of nocturnal restlessness. Since, in these subjects, research protocols applying enforced phase shifts or time-free environments are unfeasible and not justifiable from an ethical point of view, the variables were specifically designed to assess the functionality of the circadian timing system from actigraphic recordings made in the natural environment of subjects. Examples of the application of actigraphy are given, including studies on symptom fluctuations and medication responses in Parkinson patients, and studies on circadian rhythm disturbances and possible remedies in elderly and Alzheimer patients.

Chronic Insomnia: Clinical and Research Challenges – An Agenda

Chronic insomnia afflicts up to 10% of the population in Western industrialized countries. It is characterized by delayed sleep onset, problems in maintaining sleep, early morning awakening or the feeling of non-restorative sleep coupled with significant daytime impairments on an emotional, social or professional level. It can occur as a co-morbid condition in any other medical or mental disorder, but also as a primary condition. Within the last decade new diagnostic and differential diagnostic approaches have been suggested that enhance diagnostic precision. Epidemiological data and data relating to the health care and cost situation of chronic insomnia suggest a huge burden for society. Chronic insomnia leads to a clear-cut increased risk for psychopathology (i. e., affective disorders) and probably also for cardiovascular and metabolic dysfunction. The pathophysiology of the condition is still poorly understood and will profit from integrating modern neuroscientific approaches (animal studies, molecular biology, neuroimaging, neurophysiology, etc.). Current treatment strategies are mainly based on cognitive behavioural interventions (CBT-I) and hypnotic treatment with benzodiazepine receptor agonists and sedating antidepressants. Although the effectiveness of these treatments has been clearly demonstrated, a substantial proportion of patients proves to be treatment-resistant or profits only poorly. The question of long-term pharmaceutical treatment of chronic insomnia, at least in Europe, is unresolved and urgently needs answers. Novel rational treatment avenues require clues on causes and mechanisms from integrated neuroscientific approaches. The important issues concerning insomnia treatment in the future especially in Europe will be reviewed and discussed critically.

Biological rhythms in the human life cycle and their relationship to functional changes in the suprachiasmatic nucleus

Biological rhythms play a prominent role in the human life cycle. The endogenous rhythms are entrained by the environment and have an astronomical counterpart which is obvious for daily, monthly, and yearly rhythms, and may possibly also be present in weekly rhythms. Circadian rhythms are present in, e.g. testosterone levels, spontaneous birth, strokes, and death from cardiovascular causes. Circaseptan rhythms are present in, e.g. spontaneous birth, 17-ketosteroid levels, myocardial infarctions, and strokes. The relationship of these rhythms with the suprachiasmatic nucleus (SCN) has not yet been established. Circatrigintan rhythms, such as the menstrual cycle, have so far not been associated with the SCN. Circannual rhythms are present in, e.g. mood, suicides, reproduction, birth weight, sleep and season of birth of psychiatric patients. The human SCN shows strong circadian and circannual fluctuations in the number of neurons expressing vasopressin. The vasopressin and VIP cell population of the SCN develop late, i.e. for a major part postnatally. After the age of 50 the amplitudes of circadian and circannual fluctuations of the vasopressin cell numbers are reduced whereas the number of vasopressin expressing neurons decreases after the age of 80 and do so even more and earlier in Alzheimers disease. Sex differences are present in the shape of the vasopressin subnucleus of the SCN and in the vasoactive intestinal polypeptide (VIP) cell number. The sex differences in the SCN, the doubling of the number of vasopressin neurons in the SCN of homosexual men, and a variety of animal experimental observations indicate that the SCN is involved in sexual behavior and reproduction. The exact role of the SCN in these processes is subject to current research.