News and Publications

Sleep and Cytokine Research

D.F. Darko, A. Dawson, M. Erman, R. Hayduk, M.M. Mitler, J.S. Poceta

HIV AND NEUROCOGNITIVE IMPAIRMENT

HIV infects the brain, resulting in CNS impairment. The mechanisms of HIV-related impairment of cognitive and motor functions are still under investigation. Possibly, halting HIV replication or eliminating the virus would not prevent CNS damage. Because specific interventions do not normalize physiologic changes in the CNS and the neuromotor system associated with HIV infection, the effect of direct (but generalized) neurostimulation, such as that mediated by methamphetamine, on these systems is of interest. In addition, some patients with HIV infection use, abuse, or become dependent on methamphetamine as self-treatment for CNS and neuromotor dysfunction.

We used a randomized, parallel-groups, double-blind, placebo-controlled protocol to examine the effects of methamphetamine on brain, nervous system, and neuromotor control in subjects with a history of methamphetamine abuse who were seropositive for HIV. The specific measures of brain, nervous system, and neuromotor control used were chosen because of their relevance to sleep-deprived states and states of excessive daytime sleepiness. The data were examined for correction of changes similar to those caused by sleep deprivation or excessive daytime sleepiness. A total of 15 subjects were randomly assigned to 2 groups. One group was given methamphetamine; the other group was given a placebo. Each subject did 3 hours of training trials on a computer-based performance assessment battery.

The resistance of changes in cognitive and neuromotor function related to HIV infection to standard clinical doses of methamphetamine was remarkable. The only difference between the 2 groups was the score on the Psychomotor Vigilence Test, a hand-held test of reaction time. Subjects given methamphetamine had a more rapid response (shorter reaction time) at the end of the study than did the subjects given a placebo. None of the other 17 measures differed between the 2 groups before or after the experimental group was given methamphetamine.

The dose of methamphetamine used in this study was adequate to produce a functional change in CNS-relevant effects. The lack of effect in HIV-infected subjects reflects the profound effect of HIV infection on the nervous and neuromuscular systems. According to the literature on use of methamphetamine in humans, uninfected, healthy control subjects given the dose we used would be expected to have an improvement in the cognitive and motor measures used in our study.

The lack of a general CNS effect and the specific lessening of reaction time (faster neuromotor response) suggests that methamphetamine may have toxic and pharmacologic effects on the CNS, the peripheral nervous system, neuromuscular junctions, and muscle cell responses. Extensive preclinical and clinical evidence confirms that certain patterns of amphetamine administration result in significant immediate and long-term neuronal dysfunction.

In a separate study, we hypothesized that an aspect of coordination between secretion of human growth hormone (hGH) and slow-wave sleep, defined as the strength of the delta wave on an electroencephalogram, would be affected by HIV infection. Data were collected from 2 groups: 11 control subjects and 12 subjects infected with HIV. We obtained plasma samples from each subject every 15 minutes throughout the night while the electroencephalogram was recorded. Plasma levels of hGH, TNF-a, and IL-1ß were determined. Polysomnography was used to divide the data into 4 sleep cycles.

The results indicated that sleep cycles were not affected strongly by the degrees of HIV infection and that the 2 cytokines were not related to sleep cycling. We found (1) a similarity of delta activities across the 2 groups, (2) an orderly pattern of hGH peak plasma level in the first, second, and fourth sleep cycles of the night in the control group, and (3) a degradation of this orderly pattern of hGH peak plasma level in the group with HIV infection. The degradation suggests that nocturnal, sleep cycle--related protein anabolism or secretion may have been modified in the HIV-infected subjects.

NARCOLEPSY

Narcolepsy is a CNS disorder characterized by disabling dysregulation of sleep and wakefulness. Narcolepsy is not rare; it affects about 1 of every 1000--2000 North Americans. A 5-year research project funded by the National Institute of Neurological Disorders and Stroke on the human genetics of narcolepsy is under way. This multisite project involves work with M. Anne Spence, University of California, Irvine, and L. Field, University of Calgary, Alberta.

Although the inheritance of narcolepsy is not known, the disorder is strongly, but not always, associated with subtypes of the HLA region on chromosome 6: HLA-DR15(DRB1*1501) and HLA-DQ6(DQB1*0602). Thus, the presence of HLA-associated and non--HLA-associated forms indicates that narcolepsy is at least 2 disorders. Further, both the HLA-associated (H+) form and the non--HLA-associated (H-) form occur as sporadic isolated cases (F-) and in persons with a family history of narcolepsy (F+). Possibly, each of the 4 types, (H+F-), (H+F+), (H-F-), and (H-F+), represents a different etiology.

Baseline data collected for a large clinical trial involving 504 patients with narcolepsy were used to compare clinical and polysomnographic features of narcolepsy patients with and without HLA-DQB1*0602. Comparisons were adjusted for possible confounding factors, and linear regression modeling was used to extract the best predictors for DQB1*0602 positivity.

As previously reported, cataplexy was the best clinical predictor for DQB1*0602 positivity. According to the polysomnographic data, subjects with DQB1*0602 had a significantly more disrupted nocturnal sleep, a much shorter nocturnal rapid eye movement (REM) sleep latency, and more abnormalities in multiple sleep latency tests (increased number of sleep-onset REM periods and decreased mean sleep latency) than did subjects without DQB1*0602. Subjects with DQB1*0602 also had a much higher prevalence of periodic limb movements during sleep, confirming the notion that this sign is genuinely associated with the narcolepsy phenotype. These results support the notion that narcolepsy patients with HLA-DQB1*0602 are more etiologically homogeneous than are narcolepsy patients without HLA-DQB1*0602.

SLEEP AND BREATHING

In a project funded by the state of California Tobacco-Related Disease Research Program, we are using both established and new methods to assess upper airway resistance, hypoxic drive, and hypercapnic drive during wakefulness and sleep. We are studying young male smokers before and after smoking cessation to test the following hypotheses: (1) Nicotine, through its respiratory stimulant effect, will increase hypercapnic and hypoxic respiratory responses. (2) The irritants contained in cigarette smoke will increase upper airway resistance. (3) The combination of increased inspiratory drive and increased upper airway resistance due to tobacco smoke containing nicotine will cause instability of the upper part of the airway and will lead to more snoring and more obstructive respiratory events (sleep apnea) during sleep.

The data collection phase of 18 months is nearing the end. We have collected data on 15 subjects in 3 overnight sleep studies in the TSRI General Clinical Research Center. Each subject was studied 3 times, under 3 conditions: (1) after having their usual number of cigarettes and wearing a 21-mg transdermal nicotine patch, (2) after 30 days of no smoking and continued use of nicotine patches, and (3) after 7 days of abstinence from smoking and nicotine patches. We anticipate enrolling 1 or 2 more subjects as we analyze data and prepare our findings.

The change in total upper airway resistance has been variable from subject to subject and also between nights. Total upper airway resistance has tended to be lower during the 2 nicotine nights (conditions 1 and 2), but no obvious increase in total upper airway resistance has occurred during the smoking night (condition 1). The effect of nicotine appears to be small. Our previous finding that total upper airway resistance is higher during sleep stages 2 and 3/4 than during wakefulness has been confirmed. In addition, we found that total upper airway resistance in REM sleep is similar to upper airway resistance during waking. We do not see an effect of nicotine on this finding.

After we altered our method for measuring nasal resistance, an important component of upper airway resistance, we obtained good data on nasal resistance during all stages of sleep, and although the data are variable, the hypothesis of increased nasal resistance during smoking appears to be confirmed, but must await statistical analysis. We have collected measurements of nasal resistance during all stages of sleep. The hypoxic and hypercapnic drive studies have been hindered because of marked arousability of the patients during the nicotine nights, a situation that leads to variable breath-to-breath tidal volumes and makes calculations difficult. We cannot make a statement about the effect of nicotine on these measures of respiratory drive.

PUBLICATIONS

Hong, S.C., Hayduk, R., Lim, J., Mignot, E. Clinical and polysomnographic features in DQB1*0602 positive and negative narcolepsy patients: Results from the modafinil clinical trial. Sleep Med. 1:33, 2000.

Mitler, E.A., Mitler M.M. 101 Questions About Sleep and Dreams, 6W ed. Wakefulness-Sleep Education and Research Foundation, Solana Beach, CA, 2000. Available at: http://www.sleepmedservices.com/.

Mitler M.M. Nonselective and selective benzodiazepine receptor agonists: Where are we today? Sleep 23(Suppl. 1):S39, 2000.

Mitler, M.M., Aldrich, M.A. Stimulants: Efficacy and adverse effects. In: Principles and Practice of Sleep Medicine. Kryger, M.H., Roth, T., Dement, W.C. (Eds.). Saunders, Philadelphia, 2000, p. 429.

Mitler, M.M., Carskadon, M.A., Hirshkowitz, M. Evaluating sleepiness. In: Principles and Practice of Sleep Medicine. Kryger, M.H., Roth, T., Dement, W.C. (Eds.). Saunders, Philadelphia, 2000, p. 1251.

Mitler, M.M., Dement, W.C., Dinges, D.F. Sleep medicine, public policy and public health. In: Principles and Practice of Sleep Medicine. Kryger, M.H., Roth, T., Dement, W.C. (Eds.). Saunders, Philadelphia, 2000, p. 580.

Mitler, M.M., Harsh, J., Hirshkowitz, M., Guilleminault, C., for the US Modafinil in Narcolepsy Multicenter Study Group. Long-term efficacy and safety of modafinil (PROVIGIL) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med. 1:231, 2000.

Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Neurology 54:1166, 2000.

Sangal, R.B., Mitler, M.M., Sangal, J.M. Subjective sleepiness ratings (Epworth Sleepiness Scale) do not reflect the same parameter of sleepiness as objective sleepiness (Maintenance of Wakefulness Test) in patients with narcolepsy. Clin. Neurophysiol. 110:2131, 1999.