Dietary amino acids improve sleep problems in mice with traumatic brain injury

Scientists have discovered how to fix sleep disturbances in mice with traumatic brain injuries — a discovery that could lead to help for hundreds of thousands of people who have long-term and debilitating sleep and wakefulness issues after they suffer concussions.

What scientists found helpful was giving the mice something all humans produce from foods in their normal diets — something called branched chain amino acids.

“If further research confirms what this study suggests, we could develop a dietary supplement of these amino acids that could be a viable therapy to help people after a concussion,” said Miranda Lim, M.D., Ph.D., a neurologist and sleep medicine specialist at the Portland VA Medical Center and an assistant professor of pulmonary and critical care medicine, neurology and behavioral neuroscience at Oregon Health & Science University. Lim is the first author of the study, published online today in Science Translational Medicine.

Lim performed this research during her sleep medicine fellowship at the University of Pennsylvania. Senior authors on the study are Akiva S. Cohen, Ph.D., a neuroscientist at The Children's Hospital of Philadelphia and Allan I. Pack, M.D., Ph.D., director of the Center for Sleep and Circadian Neurobiology in the Perelman School of Medicine at the University of Pennsylvania.

Nearly 2 million people a year in the United States suffer a traumatic brain injury, including concussion, which is considered a mild traumatic brain injury. Sleep disturbances are common in those with TBI; some studies show up to 72 percent of TBI patients — including those who’ve suffered concussions — have sleep problems.

Sleep problems impair attention and memory formation in TBI patients, who have a higher rate of functional disability and a higher cost of rehabilitation.

“Sleep disturbances, such as excessive daytime sleepiness and nighttime insomnia, disrupt quality of life and can delay cognitive recovery in patients with TBI,” Lim said. Although physicians can relieve the dangerous swelling that occurs after a severe TBI, there are no existing treatments to address the underlying brain damage associated with problems such as impaired memory, learning and sleep patterns.

In their study, the scientists compared mice with mild TBI to uninjured mice. They found that injured mice were much less able to stay awake for sustained periods of time. The scientists also found that the orexin neurons in the brains of injured mice were much less active than the same neurons in uninjured mice. Orexin neurons help to maintain wakefulness, in mice and in humans. Human studies have shown decreased orexin levels in the spinal fluid of people who have suffered a traumatic brain injury.

Based on prior research, the scientists gave the injured mice a dietary therapy of branched chain amino acids — which humans get most often through foods high in protein, including red meat, poultry and eggs. Branched chain amino acids are the building blocks of neurotransmitters, the chemicals released by neurons in the brain. Like the oil in a car engine, branched chain amino acids keep neurons running smoothly and boost neuron excitability. The branched chain amino acids restored the orexin neurons in the injured mice to a normal activity level, and improved wakefulness.

“These results in an animal model provide a proof-of-principle for investigating this dietary intervention as a treatment for TBI patients,” said Cohen. “If a dietary supplement can improve sleeping and waking patterns as well as cognitive problems, it could help brain-injured patients regain crucial functions.”

The scientists note that human patients with a variety of disorders have been treated with branched chain amino acid therapy for up to two years without adverse effects, so with further study it may prove to be a viable therapy for sleep problems in TBI patients. Cohen cautioned, however, that current evidence does not support TBI patients medicating themselves with commercially available amino acid supplements.

The National Institutes of Health (grants HL007713, HL111725-01A1, NS069629 and HD059288) supported the study, as well as the University of Pennsylvania Department of Medicine/Measey Research Fellowship. Cohen and the Children’s Hospital of Philadelphia hold a provisional U.S. patent for the use of branched chain amino acids as a therapy for traumatic brain injury.

About the OHSU Brain Institute

The Oregon Health & Science University Brain Institute is a national neuroscience leader in patient care, research and education. With more than 1,000 brain scientists and specialists, OHSU is home to one of the largest communities of brain and central nervous system experts in the nation. OHSU Brain Institute scientists have won national recognition for breaking new ground in understanding Alzheimer’s disease and for discoveries that have led to new treatments for Parkinson’s disease, multiple sclerosis, stroke and other brain disorders and diseases.

About OHSU

Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.