Does Traumatic Brain Injury Cause Sleep Disruption?
By Alan Z. Segal, MD
Associate Professor of Clinical Neurology,
Weill Cornell Medical College
Dr. Segal reports no financial relationships relevant to this field of study.
Synopsis: In a well-designed animal model of traumatic brain injury, a sleep disorder was induced that resembles, in many ways, what is observed in spontaneous human narcolepsy.
Source: Skopin MD, et al. Chronic decrease in wakefulness and disruption of sleep-wake behavior after experimental traumatic brain injury. J Neurotrauma 2015;32:289-296.
Traumatic brain injury (TBI) commonly produces difficulties with memory and multiple other aspects of cognition. TBI is also associated with mood disorders such as depression and anxiety, along with insomnia and excessive daytime sleepiness. Even in the absence of TBI, poor sleep can produce memory loss, impaired concentration, and depression. Therefore, it is likely that TBI and sleep disorders have complementary and synergistic effects.
TBI has been shown to decrease the density of orexin (hypocretin) neurons in the hypothalamus, though these data are limited to autopsy studies involving only a handful of patients. Such changes mimic those typically associated with the loss of orexin neurons seen in patients with narcolepsy. Clinically, both disorders are characterized by excessive daytime sleepiness, with poor nocturnal sleep efficiency and architecture.
In the current report, the lateral fluid percussion (LFP) model of TBI is used. A craniotomy is performed, followed by indirect head trauma, generated by a pendulum striking a column of water. This is the most widely used TBI animal model and has been shown to correlate well with the behavioral and neuro-anatomic abnormalities observed in humans. LFP tends to create damage most prominently in the cortex, hippocampus, and corpus callosum. LFP in comparison to other models, such as direct cortical impact, is thought to most closely resemble the typical concussive injuries that occur, for example, during motor vehicle accidents or sports collisions.
In the current study, rats were subjected to LPF and compared with sham controls at intervals of 6, 19, and 29 days post-injury. Polysomnography was performed for 24-hour periods at each of these intervals with a dark phase from 8 p.m. to 8 a.m. and light phase from 8 a.m. to 8 p.m. Behavioral tests included those of spatial memory (using novel object recognition) as well as contextual and emotional memory (using a “fear-based” sequence of electric shocks and a water maze). These tests are thought to test both cortical as well as subcortical (limbic system) function and were all adversely affected among animals exposed to head trauma.
Results demonstrated that the overall sleep times (both rapid eye movement [REM] and non-REM) did not differ between the two groups, but TBI rats showed markedly disordered nocturnal sleep architecture with frequent bouts of awakening and showed increased intrusion of sleep into daytime alertness. This is a fairly typical pattern seen in narcoleptics. Sleep-onset REM, however, which is characteristic of narcolepsy, was not increased in the experimental animals.
Perhaps most importantly, brain-injured rats showed an approximately 50% reduction (P < 0.001) in orexin-positive neurons in the lateral hypothalamus when compared with controls. In prior human studies using transcranial magnetic stimulation, TBI has been shown to produce decreased cortical excitation. This is thought to be a direct result of impaired orexin-mediated subcortical input and is similarly seen in patients with narcolepsy.
These results confirm that traumatic brain injury, as demonstrated in a well-recognized animal model, produces both excessive daytime sleepiness and nocturnal sleep disruption. Therefore, difficulties in memory and concentration seen in patients with TBI can be the result of dual and likely synergistic causes. Superimposed on any direct destructive effects of TBI are the known cognitive difficulties associated with poor sleep. Perhaps more importantly, TBI may be associated with a loss of hypothalamic orexin neurons producing the same impairments in cortical activation commonly seen in patients with narcolepsy.
Given these results, therapy for narcolepsy possibly may be extrapolated to patients with TBI. In narcoleptics, sleepiness may be treated with stimulants such as modafinil to maintain daytime alertness. However, narcolepsy is as much a product of impaired nocturnal sleep as it is a disorder of daytime sleepiness. Gamma-hydroxybutyrate (GHB), also known as sodium oxybate (trade name Xyrem), is a prominent GABA-agonist that promotes slow wave sleep and is a crucial element in the pharmacological armamentarium for narcolepsy. Given the overlapping patterns observed here, GHB might similarly benefit patients with TBI and bears further investigation.
In a well-designed animal model of traumatic brain injury, a sleep disorder was induced that resembles, in many ways, what is observed in spontaneous human narcolepsy.
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