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.

Facilitation of somatosensory average-evoked potentials in hysterical anesthesia and pain.

Psychophysiological inhibition theories of hysterical anesthesia were not supported in a study of habituation of scalp somatosensory average-evoked responses. Facilitation, rather than habituation, was found in responses contralaterial to the affected side with strong tactile stimuli in patients with hysterical heminesthesia or hemihypoesthesia, regional pain, and weakness. We suggest that the increase in response amplitude is related to the unusual congnitive set in these patients. Corticufugal influences on tactile sensory input might be mediated through increasing-excitation in a spinal-gating system.

The heterogeneity of anorexia nervosa. Bulimia as a distinct subgroup.

Bulimia is a poor prognostic sign in anorexia nervosa. This raised the question of whether bulimia represented an "end stage" of chronic anorexia nervosa or whether bulimic patients were a distinct subgroup. All subjects seen by us personally from 1970 to 1978 were included in this study provided they met modified criteria of Feighner et al (1972). Of this group, 68 experienced bulimia and 73 did not (restricters). Bulimic patients had a history of weighing more and were more commonly premorbidly obese. Bulimic patients were those who vomited and misused laxatives. The bulimic group displayed a variety of impulsive behaviors, including use of alcohol and street drugs, stealing, suicide attempts, and self-mutilation. With regard to family history, the high frequency of obesity in the mothers of bulimic patients was noteworthy. The two groups share features common to patients with primary anorexia nervosa. However, these results suggest a different group of women are predisposed to have anorexia nervosa develop with bulimia.

Hypothalamic-pituitary function in anorexia nervosa.

We studied nine patients with anorexia nervosa: five were "undernourished" and four were "well-nourished". The undernourished patients had significantly higher plasma growth hormone (GH) levels in a fasting state and higher GH rebounds following glucose administration. In four of these patients, GH levels decreased to normal after weight restoration. Decreased urinary follicle stimulating hormone (FSH) in three and plasma luteinizing hormone in six patients were not related to nutritional status; however, positive correlation was found between duration of illness and urinary FSH. Other results included decreased plasma testosterone in the one male, elevated plasma cortisol in five, and decreased 17-ketosteroid excretion in five patients. The results support elevated GH as secondary to starvation of anorexia nervosa and not an independent hypothalamic-pituitary disturbance. Other endocrine findings indicate hypothalamic-pituitary malfunction is not confined to GH.

Withdrawal from long-term high-dose desipramine therapy. Clinical and biological changes.

Investigation was undertaken on a patient whose long-term intake of desipramine hydrochloride was amongst the highest reported. Desipramine treatment instituted at a daily dosage of 75 mg for depressive equivalents of head, chest, and abdominal pain was increased to 1,000 mg daily over a 12-year interval with minimal side effects. Plasma desipramine level dropped immediately on withdrawal, and urinary metabolite values dropped over the subsequent five days. The electrocardiographic abnormalities of first-degree atrioventricular block and incomplete left bundle branch block rapidly disappeared on cessation of medication. Electroencephalographic changes with symmetrical generalized irregular 5- to 7-cps theta activity and 18- to 28-cps beta activity also improved. Longitudinal polygraphic sleep studies showed prolonged rapid eye movement rebound and increased delta sleep coincident with withdrawal. It took ten days after cessation of desipramine for urinary 3-methoxy-4-hydroxyphenylglycol concentration to increase substantially. Although catecholamines are involved in growth hormone (GH) and cortisol regulation, no abnormalities were found in GH or cortisol levels.

EEG frequency patterns associated with hallucinations in schizophrenia and "creativity" in normals.

This study attempts to define EEG power spectral patterns associated with hallucinatory behaviors in schizophrenia. Six unmedicated schizophrenics with Schneiderian criteria were interviewed and their tongue potentials were monitored and recorded on FM tape. Eye movements and tongue potentials were monitored and segments with artifacts were not used. Consecutive 4-sec intervals of EEG were analyzed in the frequency domain using fast Fourier transorm methods and serial power spectra plots obtained. The intrusiveness of the hallucinatory experience may be similar to the sudden internal experience of perceptual resolution in a creative task. Six normal controls were similarly monitored and analyzed while responding to tests of "creativity." In the 4-sec interval prior to reports of hallucinatory experiences, a frequency pattern of predominatly delta and theta power was found in 71.7% of the EEG segments. In the control group, 78.1% of the EEG segments preceding a creative response demonstrated a similar low frequency pattern which also differed significantly from the base line EEG frequency pattern.

Dopamine D2 receptors quantified in vivo in human narcolepsy.

Assays in brain tissues from humans suffering from narcolepsy, and from genetically narcoleptic dogs have suggested that dopamine function may be disturbed in this condition. We have used the specific D2 receptor ligand N-(3-[18F]fluoropropyl)-spiperone and positron tomography to study a group of 6 well-characterized medication-free, HLA-DR2 DRW15 DW6-positive narcoleptic patients and a group of age- and sex-matched control individuals during life. We found no difference in striatal D2 receptor binding between these two groups. These results suggest that narcolepsy is not associated with alterations in D2 receptor density and affinity.

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder.

BACKGROUND: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Lecithin in the treatment of Gilles de la Tourette's syndrome.

Five patients with Tourette's syndrome were administered a mean dose of 512 mg/kg per day of oral lecithin. None of the patients exhibited sustained clinical improvement in symptom severity. No significant changes in serum prolactin or growth hormone were observed during lecithin administration.

A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette's syndrome.

In a double-blind placebo-controlled study, both pimozide and haloperidol significantly decreased tic frequency in nine patients with Gilles de la Tourette's syndrome. These findings are consistent with the catecholamine hypothesis of tic generation. Pimozide was associated with significantly fewer complaints of lethargy. Follow-up 4-20 months later showed that six of seven patients receiving pimozide and one of two receiving haloperidol had had greater than 75% improvement in symptoms.

Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy.

Seventy-five patients meeting international diagnostic criteria for narcolepsy enrolled in a 6-week, three-period, randomized, crossover, placebo-controlled trial. Patients received placebo, modafinil 200 mg, or modafinil 400 mg in divided doses (morning and noon). Evaluations occurred at baseline and at the end of each 2-week period. Compared with placebo, modafinil 200 and 400 mg significantly increased the mean sleep latency on the Maintenance of Wakefulness Test by 40% and 54%, with no significant difference between the two doses. Modafinil, 200 and 400 mg, also reduced the combined number of daytime sleep episodes and periods of severe sleepiness noted in sleep logs. The likelihood of falling asleep as measured by the Epworth Sleepiness Scale was equally reduced by both modafinil dose levels. There were no effects on nocturnal sleep initiation, maintenance, or architecture, nor were there any effects on sleep apnea or periodic leg movements. Neither dose interfered with the patients' ability to nap voluntarily during the day nor with their quantity or quality of nocturnal sleep. Modafinil produced no changes in blood pressure or heart rate in either normotensive or hypertensive patients. The only significant adverse effects were seen at the 400-mg dose, which was associated with more nausea and more nervousness than either placebo or the 200-mg dose. As little as a 200-mg daily dose of modafinil is therefore an effective and well-tolerated treatment of excessive daytime somnolence in narcoleptic persons.

The clinical course of musculoskeletal pain in empirically derived groupings of injured workers.

The purpose of this paper is to examine the clinical course of musculoskeletal, soft tissue, work-related injury. An analysis of empirically derived sub-groupings of workers based on prognostically important pain and disability variables assessed on enrollment into the study is described. Multidimensional time-dependent profiles are used to characterize stages in the development of pain, impairment, disability and handicap. The clinical course over the 18 months of study of the three subgroups is examined. The conceptual model, used to examine the workers' changing responses over time, is based on the World Health Organization Classification of Impairments, Disabilities and Handicaps (1980). Methodologically, the study employed a prospective longitudinal design. A randomly selected cohort of workers who had not returned to work by 3 months post-injury were identified from the files of the Workers' Compensation Board of Ontario. The workers were interviewed and examined on enrollment into the study at 3 months and subsequently at 9 months, 15 months and 21 months after injury. The outcomes were return to work or continued work disability. The results are based on those 104 workers who attended all four assessment periods. K means clustering was used to identify homogenous subgroups of workers. Repeated measures ANOVAs were used to characterize the stages of development of pain, impairment, disability and handicap. Duncan's multiple range test was used to compare pairs of means at each assessment period. Cluster groupings, based on three prognostically important clinical variables, number of pain sites, pain behavior and functional disability, obtained at the initial assessment were valid predictors of the number of days to return to work and total number of days on work disability. Prognostic stratification can enhance confidence in predictive decisions of clinical practice and improve clinical trials of therapy.

Sleep and musculoskeletal pain.

Chronic musculoskeletal pain and fatigue of "fibrositis syndrome" are associated with a physiologic arousal disorder within sleep, the alpha (7.5 to 11 Hz) electroencephalographic, non-rapid-eye-movement sleep anomaly. In this nonrestorative sleep disorder, pain and mood symptoms may be mediated by psychologic distress (e.g., following a nonphysically injurious industrial or automobile accident), noxious environmental stimuli (e.g., noise), physiologic disturbance (e.g., sleep-related myoclonus, painful inflamed joints, i.e., rheumatoid arthritis), and altered central nervous system metabolism (e.g., disordered brain serotoninergic functions). Because such heterogeneous agents influence this hitherto poorly understood nonarticular rheumatic syndrome, the descriptive term "rheumatic pain modulation disorder" is suggested.

Regional differences in technetium-99m-ECD clearance on brain SPECT in healthy subjects.

UNLABELLED: The aim of this study was to evaluate the in vivo stability of ECD brain SPECT. METHODS: Twenty normal volunteers (35.4 +/- 9.1 yr) each had six ECD scans at 30, 60, 120, 240, 360 and 480 min postinjection. Each scan was acquired for 24 min using a triple-head SPECT system. Average counts per pixel were measured from frontal, temporal, parietal, occipital, cerebellum, basal ganglia, thalamus and white matter regions. ECD clearance rates were calculated by fitting regional time activity data to a monoexponential equation. Regional gray-to-white matter (G/W) and gray-to-cerebellum (G/C) ratios were calculated for each scan. Analysis of variance was used to compare regional ECD clearance and ratio measurements. RESULTS: The average ECD clearance was 4.3%/hr. There was a significant regional variation in the ECD clearance, being higher for occipital (6.34%/hr) but lower for both white matter (2.39%/hr) and thalamus (2.45%/hr). Both G/W and G/C ratios showed a significant regional variation with time. The overall G/W ratio was 2.13 at 30 min and became progressively lower after 2 hr, reaching 1.78 at 8 hr. All regional G/W ratios declined with time except for thalamus where it remained constant at 2.15. The overall G/C ratio was 0.984 at 30 min but it declined after 4 hr, reaching 0.955 at 8 hr. All regional G/C ratios declined with time except for thalamus where it increased progressively from 0.955 to 1.120 at 8 hr. CONCLUSION: ECD clears from normal brain slowly and shows a significant regional variation. As a result, G/W contrast begins to decrease after 2 hr and the gray-matter activity pattern becomes significantly different after 4 hr. Therefore, the optimal imaging time may be between 30-120 min. However, images obtained up to 4 hr still maintain the initial gray-matter activity pattern.

Insomnia and health problems in Canadians.

STUDY OBJECTIVES: The objective of this study was to determine the prevalence of, and to identify the relative contribution of selected factors associated with insomnia in the Canadian population age 15 and older. DESIGN: Weighted analysis of cross-sectional data from the Canadian General Social Survey, Cycle 6, 1991. Prevalence estimates were calculated for the total and age-specific Canadian population age 15 and older. Multiple logistic regression techniques were employed to study the contribution of an array of sociodemographic, lifestyle, stress, and physical health factors to the experience of insomnia. SETTING: N/A. PARTICIPANTS: A representative sample of the Canadian household population age 15+ (n=11,924). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Twenty-four percent of the Canadian population age 15+ report insomnia. The following factors were associated with insomnia in multivariate logistic regression: female gender, being widowed or single, low education, low income, not being in the labor force, ever having smoked, life stress, specific chronic physical health problems (circulatory, digestive and respiratory disease, migraine, allergy and rheumatic disorders), pain, activity limitation and health dissatisfaction. Age was not significantly associated with insomnia. CONCLUSIONS: Insomnia was highly prevalent among the non-institutionalized Canadian population age 15 and older. A very stressful life, severe pain and dissatisfaction with one's health demonstrated the highest odds ratios associated with insomnia. Increasing age per se and lifestyle factors were not significantly associated with insomnia.

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.

Periodic K-alpha sleep EEG activity and periodic limb movements during sleep: comparisons of clinical features and sleep parameters.

The K-alpha sleep electroencephalographic (EEG) phenomenon is characterized by periodic (approximately 20-40 seconds) K-complexes, immediately followed by alpha-EEG activity (7.5-11 Hz) of 0.5- to 5.0-second duration. A group of 14 subjects with the periodic K-alpha anomaly was found to have a similar distribution pattern of interevent intervals as compared with previously published data for sleep-related periodic limb movements during sleep (PLMS). Sleep parameters and somatic symptoms of 30 patients with K-alpha were compared with 30 patients with PLMS. The periodic K-alpha group was predominantly female, younger, exhibiting more slow-wave sleep, gastrointestinal symptoms and muscular complaints and fewer movement arousals on overnight polysomnography. The K-alpha group presented uniformly with complaints of unrefreshing sleep, often associated with fibromyalgia and chronic fatigue syndrome. The PLMS group was predominantly male, showed greater sleep disruption and presented with a variety of sleep-related symptoms.

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.

Actigraphy and parental ratings of sleep in children with attention-deficit/hyperactivity disorder (ADHD).

STUDY OBJECTIVES: To assess various sleep parameters in latency-aged children with ADHD and their normally developing peers through the use of multiple sleep measures. DESIGN: Six sleep parameters were evaluated for two groups of children, ADHD and normal comparison. Each group consisted of 25 children (20 males, 5 females) who ranged in age from 7 to 11 years. All children underwent rigorous diagnostic procedures and the ADHD subjects were selected only if they displayed pervasiveness in their symptomatology and were medication naive. Parents completed a retrospective questionnaire which evaluated sleep problems over the past six months. Additionally, each child wore an actigraph for seven consecutive nights, and the child's parents completed a sleep diary during this time period. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. RESULTS: Based on the findings from the questionnaire, parents of children with ADHD reported significantly more sleep problems than parents of normally developing children. However, the majority of these sleep differences were not verified through actigraphy or sleep diary data, with the exception of longer sleep duration for children with ADHD and parent reports that describe increased bedtime resistence. It was also found that child-parent interactions during bedtime routines were more challenging in the ADHD group. CONCLUSIONS: Despite the possibility of intrinsic sleep problems such as longer sleep duration, results indicate that many of the sleep problems of children with ADHD may be due to challenging behaviours during bedtime routines. The reason for discrepancies among sleep studies employing objective measures as well as between retrospective and prospective measures are discussed.