Friday, November 20, 2015

Conquering concussions: Optimizing recovery following traumatic brain injury

Concussion due to traumatic brain injury(TBI) is a relatively common occurrence that mostly happens to young men and children due to falls, motor vehicle accidents, or contact sports.  They are also common in battle exposed military personnel.  A concussion is defined as a traumatic brain injury that alters the way the brain functions.  One of the major problems with concussions is that they can have acute and long-term effects.  While the vast majority of concussions tend to be mild and people fully recover within 1 to 6 weeks, around 15% may experience persistent, long term effects on brain function.  These long term effects include headaches, mood and anxiety disorders, dizziness and motor problems, problems with memory, and more.  When someone experiences these symptoms for longer than six weeks, they are said to have post-concussion syndrome.  It is estimated that 5.3 million Americans are living with disability due to traumatic brain injury(1).

Persistent symptoms following a concussion are likely due to an impaired ability to heal the damage from the traumatic incident.  This can be due to the severity of the trauma as well as inter-individual variability in the ability to heal the damage.  Within the inter-individual variability aspect, we have genetic as well as environmental influences.  Since we have no control over genetic differences, it becomes important to look at environmental factors and how we can manipulate them. When we dig in to some of the physiological effects of traumatic brain injury, a few lifestyle factors stick out as potential environmental influences that can be manipulated successfully.

Traumatic brain injury and blood brain/intestinal barrier integrity

Within a few hours after a traumatic brain injury, integrity of the blood brain barrier is lost depending on multiple factors including the severity of the injury(2, 3, 4).  While this disruption is typically resolved within days to weeks, it can sometimes remain disrupted for months or even years after the injury(4).  The blood brain barrier functions to separate the circulation within the central nervous system from the general circulation.  Certain substances within the general circulation are necessary for optimal brain function while others are neurotoxic and must be kept out of the central nervous system.  The blood brain barrier functions to prevent neurotoxic substances from crossing in to the central nervous system and causing destruction of brain tissue.  Obviously a disrupted blood brain barrier is less than ideal when healing from traumatic brain injury, particularly if it remains disrupted for a long period of time.

While the damage related to traumatic brain injury is typically thought of as occurring solely in the brain, TBI also causes dysfunction of the gastrointestinal tract including intestinal barrier dysfunction and disturbed motility(5, 6).  This is likely due to the local effects of the traumatic brain injury causing autonomic dysregulation, potentially through the vagus nerve.  The vagus nerve links the brain and gut by providing a conduit through which the 2 organs can communicate.  Damage to the brain may derail this communication system and cause gastrointestinal dysfunction.  A study looking at the vagus nerve in mice found that vagus nerve stimulation attenuated the increase in intestinal permeability caused by traumatic brain injury(7).  

Adding another layer of complexity to the situation is that research has shown that bacteria found in the digestive tract that help regulate the permeability of the intestinal barrier also appear to regulate the blood brain barrier(8).  This suggests that one environmental influence that may dictate the ability to recover from TBI is the composition of bacteria in the gut.  This may not only have to do with regulating intestinal barrier integrity, it may have just as much to do with regulating blood brain barrier integrity through the vagus nerve.

Immunoexitotoxicity and recovery from traumatic brain injury

Intestinal barrier dysfunction may not seem like a big issue in recovering from traumatic brain injury, but it is probably the most important thing that needs to be addressed aside from avoiding a recurrent injury before the damage is repaired.  Intestinal permeability can prolong and even prevent recovery from traumatic brain injury as it causes an over-activation of the brain’s immune system that, when chronically active, is responsible for causing more damage than the actual injury itself, a process termed immunoexcitotoxicity(9).  If this process is allowed to continue, complete recovery is unlikely. 

The primary issue with intestinal permeability is that lipopolysaccharide(LPS), a component of the cell wall of gram-negative bacteria found in the digestive tract, is harmless in the digestive tract but toxic in the blood circulation.  If the intestinal barrier is compromised, LPS can leak from the digestive tract in to the circulation.  Furthermore, LPS can hitch a ride in to the lymphatic system on chylomicrons, the extent of which is determined by the amount and types of fat in the diet.  LPS causes excessive immune system activation throughout the body.  Compounding the issue is that TBI also causes permeability of the blood brain barrier, which should separate the circulation in the brain from that of the rest of the body.  This allows LPS and inflammatory cytokines that are in the general circulation to enter the central nervous system where they are neurotoxic. 

Glutamate, the most abundant neurotransmitter in the brain, has many important roles there.  However, it does not play well with LPS.  Too much glutamate can be toxic, but when subtoxic levels of glutamate are exposed to subtoxic levels of LPS or inflammatory cytokines, resident immune cells of the brain called microglia begin destroying neurons and secreting more glutamate causing a vicious cycle, the aforementioned immunoexcitotoxicity(9).  This process prevents optimal recovery from TBI, underscoring the importance of restoring intestinal barrier integrity.  Immunoexcitotoxicity is thought to underlie chronic traumatic encephalopathy, the degenerative neurological condition seen in retired NFL players as well as combat veterans and athletes.  It also plays a role in Alzheimer's disease which is why both CTE and Alzheimer's have essentially the same symptoms.

Neurogenesis and recovery from traumatic brain injury

During recovery from traumatic brain injury, and even throughout life, new neurons are created through a process known as neurogenesis.  This process promotes learning as well as healing from traumatic brain injury and is partially regulated by microglia.  When microglia are in their resting, ramified state they appear to be an integral player in promoting neurogenesis(10).  When microglia remain in a primed, activated state due to inflammation or LPS in the local environment, the research shows they inhibit neurogenesis and destroy healthy neurons(11, 12) while disrupting the blood brain barrier(13).  This same process occurs in the hippocampus during chronic intestinal inflammation(14) which both causes and is a consequence of a disrupted intestinal barrier.  This allows LPS to leak from a disrupted intestinal barrier in to the bloodstream and from the bloodstream across a disrupted blood brain barrier in to the central nervous system where it can interact with microglia.  The combination of impaired neurogenesis coupled with hyperactive microglia that destroy neurons is likely a significant factor in delayed healing from TBI.

The enteric nervous system

As mentioned above, stimulation of the vagus nerve can attenuate intestinal barrier dysfunction due to TBI.  Yoga, diaphragmatic breathing, meditation, and other relaxation techniques are all ways to stimulate the vagus nerve.  However, vagus nerve stimulation is not the only way to improve intestinal barrier function.  While the brain exerts a significant amount of influence on the function of the digestive tract, the digestive tract has its own nervous system, the enteric nervous system, which can function on its own without help from the brain.  Studies have shown that despite severing the vagus nerve, the enteric nervous system still functions via reflexive activity(15).  

The enteric nervous system appears to function as a back-up generator to the digestive system capable of holding intestinal barrier integrity while the brain heals from injury.  While the blunt force trauma that occurs during traumatic brain injury may disrupt the communication of the gut-brain axis, the enteric nervous system can maintain intestinal barrier integrity until the vagus nerve comes back online.  Unfortunately, the standard American diet is fairly devoid of the nutrients necessary to keep this generator going and an individual's diet prior to the traumatic brain injury is probably a significant factor in how likely that person is to fully recover from it.  This all comes back to the composition of bacteria in the gut which are, to a great degree, dictated by diet.  This does not mean all is lost as certain dietary, behavioral, and exercise interventions implemented after a traumatic brain injury can optimize recovery and potentially prevent chronic symptoms.

Functional goals in healing from traumatic brain in jury

The functional goals with diet after traumatic brain injury are to maintain intestinal barrier integrity to prevent LPS from entering the circulation and activating microglia while providing nutrients that give the brain what it needs to heal.  The great part about diet is that it is an intervention that can be implemented immediately.  In addition, relaxation methods such as yoga and meditation can be used to restore function of the vagus nerve and restore communication between the brain and gut.  Finally, and this may seem counterintuitive, but aerobic exercise can be initiated as symptoms allow.  While the standard of care for concussions has always been lots of bed rest, recent research is showing long term bed rest may not be optimal and is possibly destructive.

In healthy individuals, aerobic exercise has been shown to improve autonomic function(16, 17) and promote neurogenesis in the hippocampus(18).  A recent review of the literature cites ample evidence that aerobic exercise is a potent intervention for improving recovery from traumatic brain injury through improved autonomic function, enhanced neurogenesis, and both reduced inflammation and brain immunoexitotoxicity.  This means that we have direct control over improving intestinal barrier function and neurogenesis and, thus, may have significant control over recovery from TBI.  


In the initial stages of TBI, eating the proper diet will keep the back-up generator going while a combination of yoga or meditation and aerobic exercise, when tolerable, can help to expedite recovery by repairing the damage to the autonomic nervous and re-establishing the brain-gut connection by improving function of the vagus nerve.