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New research offers insight into pathophysiology of insomnia, potential targets for treatment

Wednesday, December 12 2007 | Comments
Evidence Grade 0 What's This?
Advances in preclinical and clinical research have expanded what is known about the pathophysiology of insomnia and potential targets for treatment, according to a panel of experts.

Dr. Clifford Saper, chairman of the department of neurology at Beth Israel Deaconess Medical Center, noted that there are 2 major pathways that help keep the brain awake: the cholinergic neurons in the upper part of the brainstem and monoamine subgroups of neurons (noradrenergic, serotonergic, dopaminergic, and histaminergic neurons).

At the same time, the ventrolateral preoptic nucleus (VLPO) within the hypothalamus acts as a master switch capable of turning off the arousal systems of the brain through the release of gamma-aminobutyric acid (GABA). The arousal systems and the VLPO are mutually inhibitory, Dr. Saper explained; this interaction is often referred to as a "flip-flop switch" that allows for relatively rapid transitions between sleep and wakefulness.

According to Dr. Saper, preclinical research suggests that problems with this switch may lead to symptoms of insomnia in both younger and older adults. Older adults, he explained, experience approximately a 50% loss of cells in the VLPO during a normal life span. A preclinical analogy to this cell loss may be found in research evaluating rats with lesions in the VLPO. Relative to other rats, those with lesions exhibited fragmented sleep and subsequent difficulty maintaining wakefulness.

To illustrate the potential roles that the arousal systems and the VLPO may play in the pathophysiology of insomnia among younger adults, Dr. Saper cited the research of Georgina Cano, who evaluated brain circuitry in an animal model of stress-induced insomnia. At the start of a sleep cycle, male rats were placed in a cage that had previously been occupied by another male rat. Given the territorial nature of these animals, the scent of the original occupant (and the threat of its return) is interpreted as a stressful stimulus.

After 2 hours of nearly normal sleep, rats placed in previously occupied cages began to wake up; they experienced sleep fragmentation, increased wake time, and suppression of NREM and REM sleep for the remainder of the sleep period. Examination of the brains of animals that were in the previously occupied cages 5 to 6 hours after initial placement in the cage revealed partial activation of the animals' arousal systems, particularly the histaminergic neurons in the locus coeruleus. Cano also observed activation of neurons in regions of the brain that play a role in anxiety and stress responses (the infralimbic cortex [part of the cingulate gyrus]) as well as in fear responses and emotionally conditioned responses (the central nucleus of the amygdala).

In addition, EEG data showed excess activity in the high frequency range (indicative of activity in the cerebral cortex and typical of wakefulness), but delta power typical of that observed during sleep.

This pattern, Dr. Saper noted, "is actually quite reminiscent of patients who have stress-induced insomnia."

To determine the origin of this excess activity, Cano placed lesions in areas of the rats' brains that were hyperactive during sleep. Lesions placed in the locus coeruleus or infralimbic cortex restored NREM sleep, but this effect did not seem to carry over into REM sleep. However, lesions placed in the amygdala restored both NREM and REM sleep.

Therefore, Dr. Saper suggested, "We think that this is the key site of the brain that turns everybody else on and makes it impossible to fall back asleep normally."

He added, "[O]ur hypothesis is that perhaps the best way to treat insomnia may not be to turn off downstream sites by giving them GABA agonists that replace the VLPO, but may be by giving something that relieves the anxiety back at this site."

As a result, a new direction for research in insomnia is the evaluation of drugs that target anxiety and the amygdala to facilitate sleep, which could potentially lead to the development of an insomnia agent without sedative effects, Dr. Saper noted.

James Walsh, executive director at the Sleep Medicine Research Center of St. John's Mercy and St. Luke's Hospitals in St. Louis, added that additional research regarding potential treatments for insomnia has focused on enhancing slow-wave sleep (SWS), with the underlying premise being that NREM sleep periods with more SWS may be periods of relatively heightened neurophysiologic restoration or recuperation.

He cited his own research in which study participants were randomized to tiagabine, a drug that has been shown to increase SWS, or placebo during 4 nights of sleep restriction. Tiagabine-treated patients had approximately 30 min more SWS per night than did placebo-treated patients. Treatment with tiagabine, Walsh noted, "essentially eliminated impairment seen with placebo in psychomotor vigilance tasks" after sleep deprivation. Assessments of executive function, as measured by the Wisconsin Card Sorting Test, and subjective reports of the restorative nature of sleep also favored tiagabine, but there were no between-group differences in Multiple Sleep Latency Test (MSLT) scores or Karolinska Sleepiness Scale (KSS) scores.

In a separate but similar study involving gaboxadol, individuals treated with the active drug experienced approximately 25 extra mins of SWS relative to placebo-treated patients. In this study, MSLT and KSS scores favored active treatment, as did scores for the vigor and fatigue items of the Profile of Mood States scale. In addition, in an analysis of all patients (gaboxadol- and placebo-treated), researchers observed a correlation between the change in SWS and MSLT scores.

Although he described these results as intriguing, Walsh conceded that drugs such as gaboxadol and tiagabine are not as effective as benzodiazepine receptor agonists with respect to traditional measures of hypnotic efficacy.

Regardless, he speculated that SWS-enhancing drugs might still have a role to play in the treatment of insomnia. He suggested that it is worth asking whether it is actually necessary to improve traditional measures of efficacy to effectively treat insomnia, as well as whether increasing total sleep time and decreasing sleep-onset latency are the only things a physician can do to treat a patient's insomnia.

Walsh added that many patients with insomnia complaints do not actually exhibit deficits in these measures of efficacy, and that SWS-enhancing drugs may be able to enhance the restorative quality of sleep in these patients, perhaps as an adjunctive therapy.

This information concerns uses that have not been approved by the Food and Drug Administration.

By Courtneay Parsons

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