Neurologic implications in sleep abnormalities
Thursday, December 13 2007 | Comments
The origin of many sleep abnormalities, such as narcolepsy and REM sleep behavior disorder, continue to puzzle neurologists, although recent developments in the study of the switch-like mechanisms of sleep-wake pathways are aiding in the understanding of this neural circuitry, according to Dr. Clifford Saper, chair of the department of neurology at Beth Israel Deaconess Medical Center
Dr. Saper explained that the waking state is maintained by 2 ascending arousal pathways originating from the brainstem. A cholinergic pathway sends signals to the thalamus, which opens up thalamocortical transmission, while a monoaminergic pathway sends sensory information directly to the cerebral cortex.
When both pathways are active, wakefulness results. REM sleep is characterized by full activity of the cholinergic system while the monoaminergic system is inactive. Non-REM sleep is characterized by decreased activity in the monoaminergic system and no activity in the cholinergic pathway.
In 1996, researchers identified a cell group in the hypothalamus called the ventrolateral preoptic nucleus (VLPO), Dr. Saper said. VLPO neurons, containing gamma-aminobutyric acid (GABA) and galanin inhibitory neurotransmitters, send inhibitory outputs to the ascending arousal pathways. The VLPO is active predominantly during sleep states and allows for the transition from waking to sleep states.
During wakefulness, the arousal pathways inhibit activity of the VLPO. This mutual inhibition is called a "flip-flop switch" because as inhibition of either system progresses, it results rapidly in an end state of either sleep or wakefulness. Ideally, these circuits function so that an individual falls asleep and wakes up quickly, rather than drifting back and forth between the two states.
What happens when these sleep switch mechanisms do not function properly? Dr. Saper cited a 1989 study by Hofman and Swaab that showed humans lose approximately 10% to 15% of cells in the preoptic nucleus during the course of a lifetime. In addition, a study by Lu et al. illustrated that rats with VLPO lesions experience sleep fragmentation and loss of slow wave sleep. Dr. Saper speculated that loss of cells in the VLPO and the subsequent decrease in its inhibitory effects on the ascending arousal system may result in the types of sleep disruption often seen in older adults, such as an increase in sleep latency, a decrease in stages 3 and 4 sleep, frequent wakening, and early awakening.
The excitatory neuropeptide orexin plays a key stabilizing role in the sleep-switch mechanism. Orexin neurons activate the entire ascending arousal system and also the cerebral cortex.
"It acts like a finger pushing the flip-flop switch to keep it in the 'on' position," Dr. Saper stated.
The VLPO is like an 'off" switch for the arousal systems of the brain and also turns off the orexin neurons, allowing for sleep. Research has demonstrated that animals develop a condition similar to human narcolepsy if orexin neurons are destroyed or if there are genetic mutations to the orexin gene. In addition, researchers have demonstrated that human patients with narcolepsy have selective loss of orexin neurons that is nongenetic in origin.
Dr. Saper and his colleagues predicted that the outputs of orexin neurons and the VLPO neurons should intersect in some area of the brain that inhibits REM sleep. In animal experiments, researchers found an area in the pons at the level of the dorsal raphe nucleus. The neurons in this area are GABAminergic and inhibit REM sleep. Neurons in the adjacent sublaterodorsal nucleus (SLD) are REM-on neurons and inhibit the REM-off population.
"What we found was a double inhibitory switch. When lesions are made on either side of this area, the switch is disinhibited and flip-flops back and forth between both REM-on and REM-off sleep," Dr. Saper said.
The wake-sleep switch and REM-on/REM-off switch also interact, with orexin being a key player in both functions, according to Dr. Saper. The wake position on the switch normally prevents REM sleep. Moreover, orexin neurons potentiate not only wakefulness but also the REM-off state.
If orexin neurons are destroyed, a patient might not only fall asleep at the wrong time, but he or she might also experience REM phenomena, such as cataplexy or dreaming, while fully awake. The relationship of orexin to the REM-off/REM-on switch and the wake-sleep switch may account for a number of puzzling symptoms present in REM behavior disorder.
This hypothesized pathophysiology may also explain why approximately 38% of patients with idiopathic REM behavior disorder develop a parkinsonian disorder within 3 to 10 years of onset, Dr. Saper said.
The SLD is adjacent to the locus coeruleus, which is one of the first areas to show degeneration in patients with Parkinson's disease. Many patients with idiopathic REM behavior disorder may actually be exhibiting an early clinical manifestation of an neurodegenerative disorder, he concluded.
By Katherine Kahn