Restless Legs Syndrome (RLS), Insomnia and Brain Chemistry

Johns Hopkins researchers believe they may have discovered an explanation for the sleepless nights associated with Restless Legs Syndrome (RLS), a symptom that persists even when the disruptive, overwhelming nocturnal urge to move the legs is treated successfully with medication.

Neurologists have long believed RLS is related to a dysfunction in the way the brain uses the neurotransmitter dopamine, a chemical used by brain cells to communicate and produce smooth, purposeful muscle activity and movement.

Disruption of these neurochemical signals, characteristic of Parkinson's disease, frequently results in involuntary movements.

Drugs that increase dopamine levels are mainstay treatments for RLS, but studies have shown they don't significantly improve sleep. An estimated 5 percent of the U.S. population has RLS.

Richard P. Allen

The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate—a neurotransmitter involved in arousal—in abnormally high levels in people with RLS.

The more glutamate the researchers found in the brains of those with RLS, the worse their sleep. The findings are published in the May issue of the journal Neurology.

"We may have solved the mystery of why getting rid of patients' urge to move their legs doesn't improve their sleep," Allen says.

"We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS."

For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness.

They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.

The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting.

In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got.

They found no such association in the control group without RLS. Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness.

Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal, day or night.

If confirmed, the study's results may change the way RLS is treated, Allen says, potentially erasing the sleepless nights that are the worst side effect of the condition.

Dopamine-related drugs currently used in RLS do work, but many patients eventually lose the drug benefit and require ever higher doses.

When the doses get too high, the medication actually can make the symptoms much worse than before treatment.

Scientists don't fully understand why drugs that increase the amount of dopamine in the brain would work to calm the uncontrollable leg movement of RLS.

Allen says there are already drugs on the market, such as the anticonvulsive gabapentin enacarbil, that can reduce glutamate levels in the brain, but they have not been given as a first-line treatment for RLS patients.

RLS wreaks havoc on sleep because lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep.

Only getting up and moving around typically relieves the discomfort. The sensations range in severity from uncomfortable, to irritating, to downright painful.

"It's exciting to see something totally new in the field—something that really makes sense for the biology of arousal and sleep," Allen says.

As more is understood about this neurobiology, the findings may not only apply to RLS, he says, but also to some forms of insomnia.

PTSD: Anti-anxiety Drug Calms Fears by Altering Brain Chemistry

An advance in understanding the brain’s fear circuitry has been revealed by a research team. They say it may hold particular promise for people at risk for anxiety disorders, including those suffering post-traumatic stress disorder (PTSD). Findings are reported in the journal Molecular Psychiatry.

“What is most compelling is our ability to translate first from mice to human neurobiology and then all the way out to human behaviour,” says Ahmad Hariri, a neurobiologist at Duke University. “That kind of translation is going to define the future of psychiatry and neuroscience.”

Read the original study DOI: 10.1038/mp.2012.72

 

The common thread in their studies is a gene encoding an enzyme called fatty acid amide hydrolase, or FAAH.

The enzyme breaks down a natural endo-cannabinoid chemical in the brain that acts in essentially the same way that Cannabis, aka marijuana, does (hence the name endo-cannabinoid).

Earlier studies had suggested that blocking the FAAH enzyme could decrease fear and anxiety by increasing endo-cannabinoids, which is consistent with the decreased anxiety some experience after smoking marijuana.

In 2009, Hariri’s lab found that a common variant in the human FAAH gene leads to decreased enzyme function with affects on the brain’s circuitry for processing fear and anxiety.

In the new study, Andrew Holmes’ group at the National Institute on Alcoholism and Alcohol Abuse tested the effects of a drug that blocks FAAH activity in fear-prone mice that had also been trained to be fearful through experiences in which they were delivered foot shocks.

Tests for the ability of those mice to get over their bad experiences found that the drug allowed a faster recovery from fear thanks to higher brain endo-cannabinoid levels.

More specifically, the researchers showed that those drug effects traced to the amygdala, a small area of the brain that serves as a critical hub for fear processing and learning.

To test for the human relevance of the findings, Hariri’s group went back to the genetic variant they had studied earlier in a group of middle-aged adults.

They showed study participants a series of pictures depicting threatening faces while they monitored the activity of their amygdalas using functional magnetic resonance imaging (fMRI) scans. They then looked for how the genetic variant affected this activity.

While the activity of the amygdala in all participants decreased over repeated exposures to the pictures. But people who carried the version of the FAAH gene associated with lower enzyme function and higher endo-cannabinoid levels showed a greater decrease in activity.

Hariri says that suggests that those individuals may be better able to control and regulate their fear response.

Further confirmation came from an analysis led by Duke’s Avshalom Caspi and Terrie Moffitt of 1,000 individuals in the Dunedin Study, who have been under careful observation since their birth in the 1970s in New Zealand.

Consistent with the mouse and brain imaging studies, those New Zealanders carrying the lower-expressing version of the FAAH gene were found to be more likely to keep their cool under stress.

“This study in mice reveals how a drug that boosts one of the brain’s naturally occurring endo-cannaboids enables fear extinction, a process that forms the basis of exposure therapy for PTSD,” Holmes says.

“It also shows how human gene variation in the same chemical pathways modulates the amygdala’s processing of threats and predicts how well people cope with stress.”

Studies are now needed to further explore both the connections between FAAH variation and PTSD risk as well as the potential of FAAH inhibition as a novel therapy for fear-related disorders, the researchers say.

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