A new study highlights how important uninterrupted sleep is to recovery after a traumatic brain injury, finding that fragmented sleep in injured mice is linked to a loss of rapid-eye-movement (REM) sleep and increased fatigue.
Specifically, the research shows that fragmented sleep worsens symptoms that a traumatic brain injury (TBI) alone produces - and that mice without a head injury can make up for some REM sleep loss brought on by interruptions to sleep, but injured mice do not.
REM sleep has a major role in helping the brain consolidate and process new information and is associated with better concentration and mood regulation. Loss of REM sleep can lower brain and cellular function.
"I think sleep has gone underappreciated as a key determinant of traumatic brain injury outcomes for a long time," said senior author Olga Kokiko-Cochran, an investigator in the Chronic Brain Injury Program and the Institute of Brain, Behavior, and Immunology (formerly the IBMR) at The Ohio State University and associate professor of neuroscience in the College of Medicine.
"A brain injury doesn't occur in isolation. We have to think about the recovery environment and acknowledge that there are effects of external stimuli," she said. "We set up the paper to think about recovery in a hospital, rehabilitation or even a home setting where there are lots of things in the environment that might influence someone's sleep - and oftentimes those may go unrecognized or unnoticed or even downplayed as to how important they could be in influencing recovery."
The research was published recently in the journal Experimental Neurology.
Injuries in this work were moderate in severity and resembled the type of TBI that could result from a fall - the most common cause of traumatic brain injury.
The experiments involved four groups of mice: those with a TBI (performed surgically under anesthesia) exposed to either sleep fragmentation or no sleep disturbance, and "sham" mice, which had surgery but no brain injury, that got either normal or fragmented sleep.
Select mice from each group were implanted with telemetry sensors to detect brain (EEG) and muscle (EMG) activity, body temperature and cage activity for 30 days after the surgery or injury - the equivalent of several months in a human.
Sleep was interrupted in the sleep fragmentation groups by a bar that swept across the floor of the mouse cage every two minutes during the first four hours of the animals' sleep phase - intended to mimic a period when sleep need is high, such as when a patient might have trouble falling asleep in a clinical setting.
Results showed that after about a week, mice with TBI were less active than uninjured mice, and their activity continued to decrease over weeks three and four. Sleep fragmentation alone also brought on fatigue - but interrupted sleep on top of the TBI significantly intensified the fatigue.
Analysis of data on the animals' biological rhythms showed there was more to the story of TBI coupled with interrupted sleep: changes to their rest-activity patterns over time.
"Just looking at the activity alone you can't differentiate that the fatigue is worse until you look at some more nuanced statistical tests," said Christopher Cotter, co-first author of the paper and a student in Ohio State's Neuroscience Graduate Program. "That's really important when we think about clinical populations - they might get sleep recordings that suggest nothing is wrong. One of the points of this analysis was to show that there are a lot of biological things happening that you may not be able to see with sleep analysis alone."
Sleep fragmentation affected both non-REM and REM sleep in all of the mice, which was not a surprise. The analysis of interrupted sleep on the REM phase focused on what recovery looked like in the mice after the fragmentation exposure stopped.
Findings show that mice with TBI and TBI with fragmented sleep displayed decreased REM sleep, while uninjured mice with sleep fragmentation made up for the sleep loss.
"So the sham mice are compensating for the loss, but all of the animals with TBI are not compensating for that loss and they continue not compensating for the loss over the four weeks. They just lose that REM sleep and they don't get it back," Cotter said. "We looked to see if they were sleeping more when they were not supposed to be, and the answer was no. So they just lost that sleep, and that was a really striking finding."
The EEG provided data on electricity released by different structures of the brain that are associated with specific biological functions. Results showed that injured mice with interrupted sleep had deficits not seen in uninjured mice: These animals had an increased need for non-REM sleep but didn't get more non-REM sleep, and their loss of REM sleep - especially in the acute recovery phase - could be linked to loss of cognitive function.
"Change in sleep quality really happens between one and 14 days, so that is a more vulnerable time for disruption after traumatic brain injury," Cotter said. "There is this sensitized injury response period."
Kokiko-Cochran said the collection of 30 days of continuous EEG and EMG data provided insights that will enhance future sleep-related TBI research in her lab.
"This model of brain injury and sleep fragmentation gives us an opportunity to study things like fatigue - something understudied in the space of traumatic brain injury that can be difficult to model," she said. "It's important because many survivors have an opportunity for extended lifespans. They're surviving sometimes decades after their brain injury, but there are still persistent symptoms.
"We are trying to be conscious of the fact that people are having lots of other experiences that could influence their recovery."
This work was supported by the National Institutes of Health.
Additional co-authors, all from Ohio State, included co-first author Zoe Tapp, Cindy Ren, Sam Houle, Jessica Mitsch, John Sheridan, Jonathan Godbout, Juan Peng and Ashley Ingiosi.
