Adenosine: a mediator of interleukin-1beta-induced hippocampal synaptic inhibition.

Interleukin-1 (IL-1) is a pleotrophic cytokine implicated in a variety of central activities, including fever, sleep, ischemic injury, and neuromodulatory responses, such as neuroimmune, and neuroendocrine interactions. Although accumulating evidence is available regarding the expression pattern of this cytokine, its receptors in the CNS, and its mechanistic profile under pathological levels, it is unclear whether this substance modulates central neurons under physiological concentrations. Further, in light of the functional and spatial overlap between the adenosine and IL-1 systems, it is not known whether these two systems are coupled. We report here that, in rat brain slices, brief application of sub-femtomolar IL-1beta causes a profound decrease of glutamate transmission, but not GABAergic inhibition, in hippocampal CA1 pyramidal neurons. This decrease by IL-1beta is prevented by pharmacological blockade of adenosine A1 receptors. In addition, we show that IL-1beta failed to suppress glutamate transmission at room temperature. Because the production and release of adenosine in the CNS is thought to be metabolically dependent, this observation suggests that one of the functions of IL-1beta is to increase the endogenous production of adenosine. Together, these data suggest for the first time that sub-femtomolar levels of IL-1 can effectively modulate glutamate excitation in hippocampal neurons via an adenosine-dependent mechanism.

Periodic movements in sleep and sleep-wake complaint.

Periodic movements during sleep (PMS) are frequent, involuntary movements, usually of the lower extremities, that disrupt sleep. Twelve patients (nine men and three women, mean age 53.9 years) with a complaint of persistent insomnia (DIMS) were compared with 11 patients (eight men and three women, mean age 53.0 years) complaining of excessive daytime sleepiness (DOES). DIMS patients had more PMS (both absolute and relative), a longer delay to sleep onset and to REM onset, more wakefulness after sleep onset, and less total sleep time. Although the fragmentation of physiological sleep was more severe in the DIMS patients, those individuals with DOES reported cognitive intrusions during their sleep. While DOES patients may be regarded as "sleeping through" the brief arousals associated with leg activity during sleep, there appears to be sufficient cognitive awareness of the nocturnal interruption to precipitate a complaint of daytime sleepiness. Insomnia patients, however, appear to experience longer and more frequent awakenings, which are proportional to increased fragmentation of sleep.

Sleep-related violence.

We hypothesized that sleep-related violent behavior associated with parasomnias occurs as the result of a diathesis and is precipitated by stressors and mediated by disturbed nonrapid eye movement (NREM) sleep physiology. Sixty-four consecutive adult patients (mean age 30 years) who were investigated for sleepwalking or sleep terrors were categorized according to clinical history into three groups: serious violence during sleep to other people or to property or self (n = 26); harmful, but not destructive behavior (n = 12); and nonviolent behavior (n = 26). Log linear analysis showed that a diathesis (childhood parasomnia and/or family history of parasomnia) and a stressor (psychologic distress, substance abuse and sleep schedule disorder) predicted the presence of sleepwalking or night terror. Serious violent acts were more likely to occur with males (p < 0.004) who showed sleep schedule disorder (p < 0.03). Both harmful and serious violent sleep behavior occurred with drug abuse (p < 0.009). In comparison to all other groups, those who were violent to other people were males who experienced more stressors (p < 0.02), drank excessive caffeinated beverages, abused drugs (p < 0.03) and showed less stage 4 sleep (p < 0.02) and less alpha (7.5-11 Hz) electroencephalogram NREM sleep (p < 0.02) on polysomnography. Being male and having < 2% stage 4 sleep provided 89% sensitivity, 80% specificity and 81% diagnostic accuracy for individuals who were violent to others. The forensic implications of these findings are discussed.

The relationship of lymphocytes in blood and in lymph to sleep/wake states in sheep.

Based on evidence of a role for immune-associated cytokines in sleep induction, we investigated the possibility that lymphocyte distribution between blood and lymphatics could be altered as a function of sleep/wakefulness. Blood and lymph sample were obtained from 5 sheep during periods of slow-wave sleep and wake. Blood and lymph lymphocytes were phenotyped using monoclonal antibodies against CD4, CD8, gd T-cell receptors and a surface marker on ovine B cells. Lymph flow rates and efferent lymph cell output were measured. Lymph flow and prescapular efferent lymphocyte output were reduced during sleep compared to wakefulness (p<0.0005). There were no differences in lymphocyte subsets in the blood and in the lymph during sleep/wake brain states. These data indicate that migration of cells in the peripheral lymphatic system is altered during sleep compared to wakefulness.

Nitrazepam for periodic movements in sleep (sleep-related myoclonus).

In a follow-up study (mean, approximately six months), nitrazepam was helpful in suppressing periodic movements in sleep (sleep-related myoclonus) and improving disturbed sleep physiology and daytime symptoms of 13 patients (mean age - 53 yr).

The relationship of alpha and delta EEG frequencies to pain and mood in 'fibrositis' patients treated with chlorpromazine and L-tryptophan.

Aspects of sleep stage evaluation and analysis of alpha and delta EEG frequencies in sleep were shown to be related to musculo-skeletal pain and mood disturbance in patients with 'fibrositis syndrome'. Patients were treated at bedtime for 3 weeks with either chlorpromazine, 100 mg (8 patients), or L-tryptophan, 5 g (7 patients). Chlorpromazine, but not L-tryptophan, was associated with increased slow wave sleep and amelioration of pain and mood symptoms. Mean percent time/min or mean percent power/min of alpha frequency during NREM and REM sleep corrlated with overnight increase in pain measures, hostility, and decrease in energy. On the other hand, mean percent time/min of delta in NREM sleep was related to overnight decrease in pain and mean percent delta power/min was associated with decreased anxiety and hostility, and increased energy.

Growth hormone and cortisol secretion in relation to sleep and wakefulness.

The study investigated secretory patterns of growth hormone (GH) and cortisol in relation to sleep and wakefulness. Plasma hormone levels were monitored in 10 young men during baseline waking and sleeping, during 40 hours of wakefulness, and during sleep following deprivation. The normal nocturnal GH surge disappeared with sleep deprivation, and was intensified following sleep deprivation. Mean GH levels were higher during slow wave sleep (SWS) compared with other sleep stages. During sleep after deprivation, GH secretion was prolonged, and second GH peaks occurred in three subjects which were not associated with SWS. Average 24-hour cortisol levels were not altered by sleep deprivation or sleep following deprivation, but the nocturnal cortisol rise occurred approximately one hour earlier with sleep deprivation and one hour later with resumed sleep, compared to baseline. This effect on the timing of the rise is consistent with an initial inhibitory influence of sleep on cortisol secretion. The results demonstrate that: the nocturnal growth hormone surge is largely sleep-dependent; temporal associations between GH and SWS are not reliable after sleep deprivation; although the cortisol rhythm is not sleep-dependent, the timing of the cortisol rise may be influenced by sudden changes in the sleep-wake schedule.

Sleep and morning pain in primary osteoarthritis.

Sleep physiology, pain and mood symptoms of 8 patients with idiopathic osteoarthritis of the hands who complained of morning symptoms were compared to 7 age and sex matched subjects with similar joint pathology, but who did not complain of morning symptoms. The "AM Symptoms" group had sleep related (nocturnal) myoclonus, associated with increased morning peripheral joint tenderness and decreased grip strength, whereas the "No Complaint" group had improved mood in the morning.

Sleep and posttraumatic rheumatic pain modulation disorder (fibrositis syndrome).

The clinical features and sleep physiology of 11 female patients with "fibrositis syndrome" or rheumatic pain modulation disorder (RPMD) were compared with 11 female postaccident pain (PAP) patients who complained of widespread musculoskeletal pain, fatigue, and nonrestorative sleep following a nonphysically injurious motor vehicle or work-related accident. Both groups had similar musculoskeletal pain, fatigue, sleepiness and an alpha (7.5-11 Hz) EEG non-rapid eye movement (NREM) sleep anomaly. A psychophysiologic arousal mechanism during NREM sleep induced by the emotional stress of the accident may mediate the subsequent nonrestorative sleep, musculoskeletal pain, and fatigue symptoms in the posttraumatic pain disorder.

Sleep related myoclonus in rheumatic pain modulation disorder (fibrositis syndrome).

Thirty-three patients with rheumatic pain modulation disorder (RPMD) were divided into 2 groups: RPMD with sleep related myoclonus (RPMD-SM) (n = 12) and RPMD only (n = 21). Both groups showed chronic nonarticular musculoskeletal pain, fatigue, tender points, and nonrestorative sleep with alpha (7.5-11 Hz) EEG sleep anomaly. RPMD-SM patients were older, had later onset of illness, showed disrupted sleep with periodic involuntary leg movements that were related to fatigue, and alpha EEG sleep related to fatigue and pain.

Sleep and symptoms in fibrositis syndrome after a febrile illness.

Sleep physiology and symptoms of 9 patients with fibrositis syndrome secondary to a febrile illness were compared to 9 patients with fibrositis syndrome who did not attribute their symptoms to a febrile illness and to 10 healthy controls. Both patient groups showed an alpha EEG (7.5 to 11 Hz) nonrapid eye movement sleep anomaly, had similar observed tender points, and self-ratings of musculoskeletal pain. These findings suggest that patients with postfebrile fibrositis have a nonrestorative sleep disorder characteristic of patients with fibrositis syndrome and share similar symptoms with patients who have a "chronic fatigue syndrome."

Litigation, sleep, symptoms and disabilities in postaccident pain (fibromyalgia)

Twenty-four patients with chronic postaccident pain were studied with self-rating symptom checklists, polysomnography and disability questionnaires. All except one had fibromyalgia. Eight had litigation resolved (R) while 16 had medicolegal claims still unresolved (UR). Patients from the R group were older, with a longer duration of symptoms and more occupation handicap compared to those from the UR group. There were no significant differences between the 2 groups in other demographic data, nature of accident, symptoms, polysomnographic findings and disability. Medicolegal claim status in these patients did not differentiate the outcome of their symptoms. Implications for litigation, treatment and further studies are discussed.

Alpha EEG sleep and morning symptoms in rheumatoid arthritis.

We studied the influence of disturbed sleep physiology on morning symptoms in 15 patients with classical rheumatoid arthritis (RA) who were experiencing an acute flare. All were found to have an alpha frequency (7 to 11.5 Hz) EEG sleep anomaly, an overnight increase in tenderness in their peripheral joints and in "fibrositic" regions, as well as increased weakness and diminished energy. One patient experienced remission in symptoms and improvement in sleep physiology. The morning symptoms may relate to a nonrestorative sleep disorder associated with the alpha EEG sleep anomaly.

The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia.

A double blind, placebo controlled, crossover design study examined overnight sleep physiology, pain, fatigue, and mood symptoms in 12 patients with fibromyalgia treated with cyclobenzaprine. Nine patients completed the study. Patients receiving cyclobenzaprine showed a decrease in evening fatigue (F = 4.7, p less than 0.05) and an increase in total sleep time (F = 4.4, p less than 0.05). Pain, including tender point count and dolorimetry, mood ratings, and alpha non-REM EEG sleep anomaly were unchanged by cyclobenzaprine.

Sleep physiology and psychological aspects of the fibrositis (fibromyalgia) syndrome.

Fibrositis (fibromyalgia) patients were compared with normal controls in terms of electrophysiology (EEG), self-report indicants of awakening, quality of sleep, behaviourally signalled awakenings, and Symptom Check List 90R (SCL-90R) scores. The results differentiated fibrositis patients from normal controls in terms of SCL-90R scores, with fibrositis patients showing significantly more psychopathology. Fibrositis patients had more alpha EEG sleep and less REM and Stage 1 sleep. They were better able to recall their behaviourally signalled awakenings the following morning and reported qualitatively less satisfying sleep than the normal controls. The alpha EEG sleep anomaly may reflect a vigilant arousal state during nocturnal sleep and result in the daytime experience of unrefreshing sleep, psychologic distress, that re-enforces the perpetuation of the sleep-related symptoms.

The relationship of interleukin-1 and immune functions to sleep in humans.

Serial sampling of peripheral blood from six healthy adult male volunteers was performed during daytime waking and nighttime sleeping. In addition, sleep physiology was assessed in all subjects (Ss) and sleep stages scored blind by standard criteria. Samples of plasma were analyzed for cortisol (Co) levels, functional interleukin-1 (IL-1), and interleukin-2 (IL-2) activity. Peripheral blood monocytes (PBM) were assayed to evaluate natural killer (NK) activity and mitogen responsiveness. Dramatic increase in IL-1 activity along with changes in other immune functions occurred during sleep and were related to onset of slow wave sleep.

Sleep and cerebrospinal fluid interleukin-1-like activity in the cat.

Exogenous interleukin-1 (IL-1), applied intraventricularly, has been reported to enhance slow wave sleep. Here, we demonstrate that endogenous interleukin-1-like activity and IL-1 beta of the cat CSF increases during sleep in comparison to wake.

The effect of zolpidem in patients with fibromyalgia: a dose ranging, double blind, placebo controlled, modified crossover study.

OBJECTIVE: This dose ranging, double blind, placebo controlled, modified crossover study examined whether zolpidem would improve the disturbed sleep, fatigue, mood and pain symptoms in patients with fibromyalgia (FM). METHODS: All symptoms were rated over 4 nights and 4 conditions for 16 consecutive nights during which 19 patients (mean age 42 years) randomly received placebo or zolpidem 5 mg, 10 mg, or 15 mg at bedtime. RESULTS: The 16 patients who completed the study reported no significant differences in ratings of pain, number of tender points, mood, sleep quality, morning fatigue, morning sleepiness or ability to concentrate. Compared to the placebo group, patients treated with zolpidem recorded significantly reduced time to fall asleep, increased sleep time, reduced awakenings, overall improvement in sleep and daytime energy, but a lower rating for evening energy. Zolpidem at the 10 mg dose was rated most acceptable for sleep. Adverse incidence rates were highest in the placebo group and lowest in the zolpidem 10 mg group. One person withdrew because of migraine while taking zolpidem 10 mg. CONCLUSION: Short term treatment with zolpidem (5 to 15 mg) does not affect the pain of FM, but is useful for sleep and daytime energy in this patient population.

Intracerebroventricular injection of TNF-alpha promotes sleep and is recovered in cervical lymph.

Recent studies have shown that the central nervous system (CNS) communicates with the periphery by the drainage of cerebrospinal fluid and brain interstitial fluid into blood and lymph. We hypothesized that tumor necrosis factor (TNF)-alpha would not only influence the CNS by promoting sleep but also would be directly transmitted into the peripheral immune system. Five hundred nanograms of 125I-labeled TNF-alpha were injected into the lateral ventricles of the brain of six sheep and sampled in venous blood and cervical and prescapular lymph every 30 min for 6 h. 125I-TNF-alpha was measured in lymph nodes and control fat, skin, and muscle tissues 6 h postinjection. 125I-TNF-alpha was detected in the cervical lymphatics within the first 30 min and peaked within 2-3 h. 125I-TNF-alpha counts were elevated in the nodes of the head and neck region. Polysomnographic recordings of four animals showed that TNF-alpha induced a significant increase in slow-wave sleep at postinjection hours 4 and 5. CNS TNF-alpha and its direct drainage into the lymphatic system may influence both the sleeping/waking brain and peripheral immune functions.

Sleep-related myoclonus in rheumatic pain modulation disorder (fibrositis syndrome) and in excessive daytime somnolence.

We describe a new syndrome, Rheumatic Pain Modulation Disorder (RPMD) ("fibrositis syndrome") with sleep-related myoclonus (involuntary periodic leg movements). Measures of sleepiness, fatigue and pain, before and after sleep, and aspects of sleep of nine subjects (Ss) with RPMD and sleep-related myoclonus were compared to nine subjects with excessive daytime somnolence and sleep-related myoclonus. In eight of the RPMD with sleep-related myoclonus and three of those with daytime sleepiness, an alpha (7.5-11 Hz) EEG Non-Rapid Eye Movement sleep disorder was demonstrated. The RPMD with sleep-related myoclonus group contained a greater number of women, more pain, morning fatigue, and disturbances in sleep (more stage changes and alpha EEG sleep prior to leg myoclonus); but in comparison to the sleep-related myoclonus, daytime somnolent group, there were no differences in evening and morning sleepiness, number of limb movements, movement arousals, awakenings after sleep onset, sleep duration, and percent sleep stages.