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Going Under

January 28, 2016

Graphic representation of a brain

By Whitney Heins

Anyone who has undergone an invasive surgery is familiar with the pre-op routine of trying to count backward from one hundred before slipping into unconsciousness. Unfortunately, many have also become acquainted with unwanted post-op side effects—headaches, nausea, and confusion—caused by anesthetics.

Neuroscientists Helen A. Baghdoyan and Ralph Lydic are determined to eliminate those unwanted consequences. But that’s a tall order considering that exactly what happens to our anesthetized brains is pretty much still unknown.

Anesthesia has been called one of the greatest medical advances in the past thousand years, even though it has been around only since 1846. “Everyone who has surgery wants it, but we still don’t know how it makes us unconscious and eliminates the perception of pain,” Lydic said.

Baghdoyan and Lydic are superstar sleep researchers who were recruited to build a nationally recognized neuroscience research program in the UT Graduate School of Medicine’s Department of Anesthesiology. They are leading the movement to bridge the gap between sleep and anesthesia-related research. By investigating various states of consciousness—wakefulness, sleep, sedation, pain, and anesthesia—Baghdoyan and Lydic want to improve drugs and help everyone sleep better.

Changing States

After an operation, most patients cannot recall what happened between counting backward and waking up. Although care providers tell patients they went to sleep, that’s not really accurate. “Clinicians know sleep is a metaphor,” Baghdoyan explained.

Helen A. Baghdoyan and Ralph Lydic

Neuroscientists Helen A. Baghdoyan and Ralph Lydic. Photo courtesy of UT Medical Center.

When we fall asleep, it takes more than just one switch to turn out the lights. Multiple regions of the brain are involved in making fundamental changes throughout the body: slowing the heart rate, reducing blood pressure, regulating temperature, and secreting hormones.

Under anesthesia, many of the same brain regions are preferentially involved—but not all. A sleeping brain and an anesthetized brain have similar traits but are in distinctly different states.

“Most of the advances in sleep neurobiology have occurred in the past sixty to seventy years,” Baghdoyan said. “Understanding the brain mechanisms that generate sleep remains one of the most exciting mysteries being addressed by neuroscience.”

Finding the Mechanisms

Baghdoyan and Lydic have assembled a team to find the switches—brain regions and neurochemical systems—responsible for regulating the specific traits that control breathing, muscle tone, electrical brain activity, and levels of brain chemicals. But it won’t be easy.

The human brain is by far the most complex system on the planet. About half its volume is composed of a hundred billion neurons, each capable of a thousand synaptic connections. The other half is made up of one trillion to five trillion glial cells, which release neurotransmitters and contribute to brain function.

To begin sifting through all the neurons and glia involved in the different states of consciousness, the pair has enlisted the help of UT Chemistry Professor Shawn Campagna and graduate student Allen Bourdon. The mission is to measure brain fluids collected from rats and mice—animals that have similar sleep patterns to people.

Sara Mihalko, Chelsea Angel, and Wateen Alami

Senior Sara Mihalko, lab manager Chelsea Angel, and senior Wateen Alami assist with a variety of NeuroNET experiments.

To obtain these samples, the rodents are anesthetized and a stainless steel probe is implanted into the brain region of interest. “The process is very humane,” Lydic said. “Because the brain has no pain receptors, the animals do not feel a thing. The permanently implanted rats and mice exhibit normal patterns of sleep, feeding, and grooming.”

The tip of the probe is covered with a semipermeable membrane that filters chemicals based on weight. A tiny sample of brain fluid is collected, then analyzed by specialized instruments in Campagna’s laboratory.

Previous studies indicate that a neurotransmitter known as acetylcholine plays a key role in regulating behavioral states such as sleep, anesthesia, and pain. But this is just the beginning.

“Before, we were only able to measure one chemical at a time,” Lydic said. “But now we can take small samples—just a few drops—and measure hundreds of chemicals.” The goal is to develop a map of chemicals or “chemical cartography” of the different behavioral states.

A map outlining the switches that regulate the specific traits and characterize states of consciousness will allow drug designers to develop better anesthetic molecules and sleep-enhancing drugs. “We would like to have a drug that has all the desired effects: rapid onset and rapid offset so you don’t feel groggy, a drug that is safe, doesn’t depress breathing, and doesn’t impair immune function and cognition,” Lydic added.

Secrets of Sleep

Drugs that would not inhibit brain and physical functions but enable us to sleep better and therefore heal faster could drastically cut down on hospital recovery time and get patients back to their lives sooner.

Woman asleep in bed“If you talk with anyone who has spent a few nights in the hospital, they commonly report that they can’t sleep through the night due to the many interruptions related to delivery of clinical care. There must be ways to improve conditions for sleep in the hospital and to promote the concept of sleep health as an essential component of medicine,” Baghdoyan said.

In fact, humans spend nearly a third of their lives asleep. The quality and amount of sleep play a direct role in how full, energetic, and successful the other two-thirds can be.

“Sleep is often the dividing line between being healthy and ill,” Baghdoyan said. “Normal sleep is important for maintaining immune function, promoting learning and memory, regulating mood and mental health, modulating pain—and it even influences our body weight.”

By better understanding what happens in our brains when we sleep, the researchers believe they can accelerate the development of anesthetics without side effects.

Strength in Numbers

Among their many partnerships, Baghdoyan and Lydic belong to a regional group known as the Neuroscience Network of East Tennessee (NeuroNET). Based at UT and directed by Rebecca Prosser, NeuroNET fosters interactions and shares knowledge among individuals engaged in various aspects of neuroscience research.

These collaborations have the potential to change lives by developing opiates that are less dangerous for obese people, finding causal links between sleep disruptions and mental illnesses, helping those suffering from disorders of consciousness like autism and schizophrenia, and allowing everyone to get a good night’s rest.

“All behavior is a product of brain chemistry. Understanding the link between states of consciousness and brain chemistry is essential for developing drugs to treat disorders such as anxiety, depression, addiction, or chronic pain,” Lydic said.

It’s just going to take some time to figure out the humblingly complex brain works. One hundred … ninety-nine … ninety-eight … ninety-seven….

For more information, visit the NeuroNET website.

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