Nearly 1.7 million traumatic brain injuries (TBI) occur every year in the US, and they have a significant impact on the lives of patients and their families1. Headache is the most common complaint, and it can occur after mild, moderate or severe injury.
What is Post-Traumatic Headache?
Post-traumatic headache (PTH) is defined by the International Headache Society as: “a headache developing within seven days of the injury or after regaining consciousness.”2 Different types of headache have been described, but the most common headache resembles migraine (moderate to severe in intensity, pulsating, associated nausea/vomiting or light/sound sensitivity, worsened with routine activity), and tension-type headache (mild to moderate in intensity, non-pulsating headache with either light or sound sensitivity but no nausea or vomiting).3,4 PTH is commonly associated with many symptoms including dizziness, insomnia, poor concentration, memory problems, sensitivity to noise or bright lights, fatigue as well as mood and personality changes like depression and nervousness4,5.
Several studies show that the headache usually resolves within three months, however, in 18-65% of cases, it may last longer and is then referred to as persistent PTH1,3,4,5,6. A number of factors may increase the risk of persistent PTH including pre-existing headache, being female and family history of migraine. Severe head trauma does not necessarily cause prolonged headaches as patients with mild head trauma can suffer for months or years7.
What Causes PTH and How Do We Investigate It?
The cause of PTH is not well understood but could relate to the release of certain chemicals, swelling of important brain structures or even brain shrinkage. Most patients with mild PTH do not need extensive testing other than a good history and neurologic exam. With more severe injuries, a CT or an MRI scan might be done to rule out a brain bleed1,6.
How Do We Treat Post-Traumatic Headache?
Head-injured patients can experience difficulty performing daily activities, may miss school or work, and have a lower quality of life. An approach looking at all aspects of the patient’s symptoms is best. Medication is the most effective treatment for PTH and treatment will depend on the type of headache.7 Some medications, like anti-inflammatories or pain medicines, including those for migraine (triptans), are used in the first few weeks. However, if the headache persists and remains moderate to severe, adding in preventative medication should be considered—especially to avoid rebound headache (over-using pain medicines).6,7 The most commonly used preventives for PTH are antidepressants, blood pressure pills, and anti-seizure medicines.
Non-Drug Treatments of Post-Traumatic Headache
Other non-drug treatments include physical therapy, biofeedback/relaxation therapy, nerve stimulators, and cognitive behavioral therapies.6 Education about PTH is an important part of the management. Since psychological problems may trigger headache or persistent headaches may exacerbate emotional problems, providing psychological support is crucial.
Ana Marissa Lagman-Bartolome MD, Headache Medicine Fellow, Department of Pediatric Neurology, Hospital for Sick Children and Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada.
New Investigator and Trainee Section of the American Headache Society
Last updated November 4, 2013
Post-Traumatic Stress Disorder (PTSD) & Migraine
Definition & Epidemiology:
PTSD occurs as a result of trauma arousing feelings of intense fear, helplessness, and horror. The individual’s response involves emotionally re-experiencing the event, numbing of affect, avoidance of stimuli associated with the event, and increased arousal. The 12-month prevalence rate of PTSD is about 3.5%, and the lifetime prevalence rate 6.8%.1
PTSD prevalence rates have been shown to be increased in those with migraine in multiple cohorts.2,3 In one general population study, the 12-month PTSD prevalence rate in migraineurs was 14.3%, and the lifetime PTSD prevalence rate was 21.5% in migraineurs as compared to 2.1% (12-month) and 4.5% (lifetime) in those without headache disorders.3
Further, the 12-month and lifetime odds of PTSD in migraineurs was noted to be greater or comparable to the odds for either major depression or generalized anxiety in episodic migraineurs (Figure 1). Notably, PTSD symptoms preceded migraine symptoms in almost 70% of those with migraine and PTSD.3
Migraineurs report almost twice as many traumatic stressors than those without headache.2,3 The most common traumatic life events (TLE) reported in one headache survey included learning about a close family member or friend who was hurt or killed, sudden injury/auto accident, observing someone being hurt/killed, and violent attacks. These findings were supported by a second clinic study of almost 600 migraineurs, with the most common TLE including: natural disaster, sudden violent death, combat & transportation accidents.2
Potential Mechanism of PTSD & Migraine
There are several potential mechanisms for the association between PTSD and migraine. Potential mechanisms include dysfunction of the central monoaminergic system, and the hypothalamic-pituitary-adrenal (HPA) axis.2,3[/vc_column_text][vc_empty_space height=”40px”][vc_column_text]Screening for anxiety or depression is not sufficient for capturing PTSD. PTSD may be screened for with casual questions about continually reliving a past traumatic event, with affirmative replies meriting further evaluation. PTSD may also be screened for using the Life Event checklist with the validated questionnaire: the PTSD Checklist (PCL). Finally, a shorter screener, the Primary Care PTSD Screen (PC-PTSD) may be utilized. Positive screens on either the PCL or PC-PTSD warrant further evaluation.
Disability & Treatment for PTSD
PTSD has a negative impact on the disability of chronic pain patients, and migraineurs with PTSD have greater disability than migraineurs without PTSD.2
While the largest body of evidence for efficacy for PTSD (alone) exists for selective serotonin reuptake inhibitors (SSRIs), SSRIs provide no or less benefit for migraine. Two considerations for those with both PTSD and migraine are amitriptyline and venlafaxine.
Amitripyline has been shown to be of some benefit for PTSD in at least three small clinical trials and is often used with success for migraine.
Venlafaxine has also been demonstrated to be effective for PTSD and may likewise be of benefit for migraine prevention.
Finally, behavioral treatment alone can positively influence chronic pain and disability in those with PTSD. Thus, the use of cognitive/behavioral therapy, alone or in combination with pharmacological therapy, should also be considered in migraineurs with PTSD.2,4
Figure created from data from: Peterlin BL, Rosso AL, Sheftell FD, et al. Post-traumatic stress disorder, drug abuse and migraine: new finding from the national comorbidity survey replication (NCS-R). Cephalalgia. 2011;31(2):235-244
© B. Lee Peterlin, DO, 2014. All rights reserved.
Last updated October 15, 2014.
Epidemiololgy of Military Post-Traumatic Headache
Ann I. Scher, PhD
How Common is Headache or Migraine in the Active-Duty Population?
The Armed Forces Health Surveillance Center (AFHSC) recently reported on the number of visits for headache or migraine. During the years 2001 through 2007, 2.5% of male and 9.5% of female active duty service members had at least one medical visit yearly for headache or migraine. This agrees with about 50,000 individuals (30,000 men, 20,000 women) and 100,000 visits yearly.
These are likely low numbers. This report did not include medical visits during deployment or at non-military facilities. By contrast, migraine affects about 7% of men and 17% of women in adult US civilians. About half seek medical care. For a variety of reasons, military and civilian groups are difficult to directly compare. It appears that headache or migraine is an important health problem in both military and civilian groups.
How Many Service Members With TBI Have Headaches?
The AFHSC reports a generally increasing rate of TBI in the U.S. Armed Forces, notably in the Army. See Figure 1. Headache is a key symptom of TBI. Therefore, headache or migraine is likely to continue as an important problem in the military healthcare system in the near future. Even in the absence of head injury, headache disorders may be especially common following deployment. For example, a recent Theeler study reported on headache symptoms in 2,726 US Army soldiers returning from combat duties during 2005. Surprisingly, 19% of the soldiers had symptoms consistent with migraine. Almost all were men. Only one in four had received a medical diagnosis.
New onset migraine is even more likely in service members who sustained a head injury (Figure 2). For women, new migraine following deployment was about twice as common with a deployment-related concussion (21%) than without (8%). The increase in new migraine was particularly notable in men. Ten percent (10%) of men with a concussion have new migraine compared to 2% of men without a concussion. These numbers are likely an underestimate. They are based on diagnosed migraine rather than total migraine. Diagnosed means from medical records rather than interviews of all subjects whether or not they have sought care.
What is the Outlook or Prognosis of Military PTH or Post-Deployment Headache?
The short and long-term outlook of headache following deployment or injury is not well known, as more studies are needed. In the Theeler study mentioned earlier, 36% of the soldiers with post-deployment migraine had trouble due to headache at a three-month follow-up visit. A small but very interesting Walker study followed the outlook of PTH. Study subjects were veterans or persons who receive military benefits, mostly men, who sustained a moderate to severe head injury. Whether soldiers sustained injuries during deployment is not clear. Thirty-eight percent (38%) reported acute headache right after the injury. Most of these individuals reported daily headache. Just over half (54%) of those with acute headaches still reported headaches six months following the injury.
Do Post-Traumatic Headaches Differ From “Regular” Headaches?
The International Classification of Headache Disorders (ICHD) includes diagnostic criteria for post-traumatic headache. According to ICHD, post-traumatic headaches are of “no typical characteristics.” They must also occur within seven days of injury or regaining consciousness after injury. Acute headaches last less than three months. Headaches that persist for three months or more are chronic. The rule that headaches must occur within one week of injury may not reflect reality. Some individuals appear to develop PTH in a delayed manner. In the study by Walker about one quarter of the patients without headaches immediately after TBI had “delayed onset” headaches at six months. Currently, the evidence for how the symptoms and outlook of PTH differ from regular headaches is scarce. This is an area of active research.
Figure 1: Incidence rates of “TBI” as ascertained by the DoD surveillance case definition, by Service, active component, U.S. Armed Forces, July 1999-June 2009
Source: Reprinted from Medical Surveillance Monthly Report, Vol 16, No 12, December 2009
No migraine before deployment
Migraine before deployment
Figure 2: Percent of OEF/OIF deployers with at least one diagnosis of migraine after deployment, by history of migraine before deployment, active component, U.S. Armed Forces
Source: Reprinted from Medical Surveillance Monthly Report, Vol 16, No 12, December 2009
Ann I. Scher, PhD, Associate Professor of Epidemiology, Preventive Medicine Biometrics, Uniformed Services University, Bethesda, MD
Abuse, Post-Traumatic Stress Disorder, and Migraine
Gretchen E. Tietjen, MD and Dawn C. Buse, PhD
Childhood Maltreatment and Migraine
Sadly, abuse is common. Abuse can happen to someone of any age, gender, and race, by someone of any age, gender, and race. Child abuse is especially heartbreaking. In 2009 alone, the U.S. Health And Human Services—Child Protective Services received more than 2 million reports of suspected child abuse. This number is likely lower than what actually occurs. It is believed that the majority of cases are not reported. In that same year, it was estimated that 1,760 children died in the US due to child abuse or neglect. The Federal Child Abuse Prevention and Treatment Act (CAPTA) of 2003 defines child abuse and neglect. It states: “Any recent act or failure to act on the part of a parent or caretaker which results in death, serious physical or emotional harm, sexual abuse or exploitation; or an act or failure to act which presents an imminent risk of serious harm.” The US Department of Health and Human Services- Child Welfare Information Gateway calls these events “Childhood aversive experiences.” These include:[/vc_column_text][vc_column_text]See https://www.childwelfare.gov/ for more information.
Childhood maltreatment or abuse predicts many other possible problems. These occur both during childhood and adulthood. Problems include medical and psychological conditions. They sometimes include harm to others (called “revictimization” or inflicting abuse upon others). They sometimes include harm to oneself, such as cutting or burning oneself, or suicide attempts. These behaviors can last well into adulthood. Many persist throughout life if not treated. Several studies demonstrate that childhood injury or abuse makes it more likely to develop migraine later in life. The more severe the abuse, the stronger the link grows. These headaches are also more likely to be frequent and disabling. Severe abuse is also linked to other conditions, including chronic pain, fibromyalgia, and irritable bowel disease.
Chronic maltreatment early in life alters the brain’s response to stress. This may make it more likely to have migraine. A study of inflammatory blood tests suggests a mechanism for the link. In this study, adults showed higher levels of biomarkers in the bloodstream when exposed to abuse in childhood. Genes are also important in this process. Genes are responsible for how a person and their body respond to early stressful experiences. It is also possible that early stressful experiences may become hard-coded into DNA. This creates a memory of events that leads to impaired health at a later date.
Post Traumatic Stress Disorder and Migraine
Childhood maltreatment, abuse, or violence may lead to post-traumatic stress disorder (PTSD) at a later age. PTSD is a condition that results from exposure to an event that caused feelings of intense fear, helplessness, or horror. Many traumatic stressors exist. These include natural disasters and transportation accidents. Others are physical and sexual assault, such as rape and exposure to war or combat. Finding out about a traumatic event or about the violent death of a loved one may also lead to PTSD. The main symptoms of PTSD include: 1) re-experiencing the traumatic event through flashbacks or nightmares; 2) avoiding reminders of the trauma; 3) increased anxiety and emotional arousal such as feeling irritable, jumpy, or being easily startled; and 4) feeling detached from others or emotionally “numb.” Other symptoms may include feeling angry, guilty, hopeless, and experiencing physical aches and pains, including headache.
Studies show a connection between PTSD and migraine. PTSD occurs in about 10% of the general population. It is present in about 25% of patients in a headache clinic. About 50% of combat veteran clinic patients have headache. In one study of PTSD and migraine, nearly 60% reported physical or sexual abuse as the cause. Not unexpectedly, the presence of PTSD complicates migraine. In persons with migraine, headache frequency and headache-related disability are greater than in those without PTSD. Interestingly, in a study of the PTSD-migraine link, men with migraine were three times more likely to have PTSD than women with migraine.
The process that links migraine and PTSD is not known. PTSD may affect the autonomic (or “automatic”) nervous system. This part of the nervous system controls the “fight or flight” response. This is the body’s natural response to danger. It is controlled by the hypothalamus, pituitary and adrenal glands. Relaxation therapies can counter-act the “fight or flight” response. They engage the parasympathetic branch of the nervous system that controls the “relaxation response.” The relaxation response can often be started through deep breathing or focusing on a pleasant image or memory. PTSD also affects the brain’s corpus callosum: a bundle of nerve fibers that connect the right and left sides of the brain. In PTSD, the corpus callosum shrinks.
Cognitive behavioral therapies (CBT) have the best evidence for treating the effects of PTSD and abuse. CBT can be helpful both during and immediately following a traumatic experience, or years later to help one cope with the after effects. CBT can be used in adults, children, elderly or disabled persons.
There are several subtypes of CBT with scientific data supporting their use for PTSD. Cognitive therapy involves identifying and managing distressing trauma-related thoughts and abnormal patterns of thinking. Exposure therapy involves reducing the fear associated with traumatic experiences. This occurs through repeated confrontation combined with relaxation. This can be for feared places, situations, memories, thoughts, and feelings. Stress inoculation therapy involves developing skills for managing stress and anxiety.
Types of skills include deep breathing, muscle relaxation, assertiveness training, role playing, thought stopping, and positive thinking. In eye movement desensitization and resensitization (EMDR) therapy, a person focuses on emotionally disturbing material. At the same time they focus on an external stimulus. This is usually eye movements, hand tapping, or sounds.
For people who struggle with self-harm behaviors, dialectic behavior therapy (DBT) is especially helpful. Behaviors include self-cutting, or suicidal thoughts or actions. DBT is also useful for those making dangerous or unhealthy life choices. DBT combines the basic principles of CBT with relaxation training, mindfulness mediation, and other proven interventions.
For help finding a mental health provider who uses these therapies, see the recommendations below. Everyone can benefit from learning and practicing relaxation techniques such as deep breathing, meditation and visual imagery. There are many tools such as workbooks and self-guided audio resources available.
The role of medication for the treatment of PTSD is less firmly proven. Selective Serotonin Reuptake Inhibitors (SSRIs) are a group of antidepressant medications. They are often prescribed for PTSD, but there is debate over the benefit. Studies in animals suggest that treatment with SSRIs may actually reverse some of the effects of maltreatment on the stress response. Other medications which are currently being investigated for the treatment of PTSD include beta-blockers (e.g. propranolol), Prazocin, and Ketamine. It is not recommended to take benzodiazepines, such as Valium, Ativan or Xanax, because they are not effective in treating PTSD and can be addictive.
Gretchen E. Tietjen, MD, Professor and Chairman of Neurology, University of Toledo, Toledo OH; and Dawn C. Buse, PhD, Assistant Professor, Albert Einstein College of Medicine, Director of Behavioral Medicine, Montefiore Headache Center, Bronx, NY.
Military Post-Traumatic Headache: A Hidden Injury of War
Alan Finkel, MD
Mild TBI and Post-traumatic Headache: What, where, when, how and why
They were horse soldiers and foot soldiers and soldiers blown up and shot down. They were jumping from planes and breaching buildings. They were driving their cars or fighting in bars. They were men and women in the prime of life.
His first war related injury was in Iraq, February 2007. He was walking outside of his vehicle when a 40 lb land mine exploded. It ripped off his helmet cover, breaking off a piece. He didn’t remember anything after the “flash.”
He awoke in the helicopter with dizziness, headache, and gagging. He was hospitalized for three days, and went back to the fighting 10 days later. For a month, he had terrible headaches. In March, he sustained three injuries in 36 hours. In the first, an IED exploded beneath the humvee he was driving. He lurched forward, smashing his helmeted head on the steering wheel. During the blast, he first experienced a “vacuum” feeling and then a “crisp smack” in the face, chest and stomach followed by “energy passing through” like a “ghost inside.” Some others were mortally wounded. One hour later, his vehicle was hit with mortar and his headache and left ear ringing worsened.
The following day, an anti-tank mine went off below his humvee that was thrown and rolled. He immediately had sharp, shooting neck pain, dizziness, vomiting and dramatic worsening of the headache from the day before. May 2007, another humvee and another IED flipped the truck on its side. June and July brought two more blasts and with the last he was medically evacuated to his American base. His headaches, initially extreme and continuous, eventually became exactly like a left sided cluster headache. He took Topamax and triptans and improved, and eventually was medically discharged.
Traumatic brain injury (TBI) in civilians accounts for over 1.3 million emergency room visits, 275,000 hospitalizations and 52,000 deaths per year. Most of these are car wrecks or falls and accidents. Post-traumatic Stress Disorder (PTSD) in civilians is most often after assault, rape or accident.
In the military at war, other things happen, including bullets. Massive explosions sending people, and shrapnel and multi-ton vehicles flying into the air happen. These were the daily norms in the early to middle days of the Global Wars on Terrorism in Iraq and Afghanistan. Advances in armor helped to deflect blasts away from vehicles; scientifically designed helmets absorbed more and more of the forces that otherwise would have killed. Concussions without something hard smacking the head became another daily norm—and still our soldiers survived. They returned with invisible injuries. They were not understood by their friends or their families, and their doctors and other medical personnel often didn’t know what was wrong or how to fix it.
The Defense and Veterans Brain Injury Centers (DVBIC) estimates that in the wars of the last 10 years, there have been more than 178 thousand mild traumatic brain injuries. To date, the Veteran’s Administration has screened over 426,000 soldiers where one in five claim some concussion and 7.5% had confirmed TBI. According to Defense data, in 2009 there were 22,684 active duty soldiers with mild TBI. Compared to the 3,690 moderate to severe injuries, soldiers with invisible injuries made up 75-80% of all TBI. In response to these statistics, agencies inside the military have been increasingly aggressive to make sure that command decisions do not put soldiers at greater risk. The most recent guideline for concussion forces the soldier to rest for 24 hours after first concussion.
A second concussion in the next 12 months results in limited duty. This includes the avoidance of contact sports until one week after symptom resolution and medical clearance. A third concussion will mandate a comprehensive evaluation and clearance by a neurologist or certified practitioner prior to return to full duty or contact sports. Sadly, the guidelines for how headache is assessed are vague; DVBIC and DOD require evidence, and for headache that evidence is just becoming available.
We don’t know exactly what happens to the brain when blows to the head occur. More mysterious, is the impact that being blasted by explosives has upon the brain, nerves, skin, muscles, and bones of the head. Whereas most think of concussion as the head hitting something or vice versa, blasts add new complications. The wave, called an overpressure, coming off some bombs is travelling at twice the speed of sound, smashing or compressing everything in its wake. Most of the injuries these cause are called mild because no bones are breached or tissue scraped or bloodied.
All the studies of returning soldiers detail how common headache really is. About a third of soldiers returning say they have migraine type pain in the first months after being home. Most of those get better, but only amongst those with significant injuries headaches abound. About 90% of those who were blasted by explosives have headaches lasting more than three months after injury. Those who have many injuries are more likely to have more headaches.
On the ground they say the headaches are constant and they may rage severe. They may be like migraine with vomiting, or like cluster with unbearable pain. They may want to disappear when the headaches are so severe; they say they want to beat their heads; they fear the pain and how it makes them feel. They say they are always there, or come at times like exercise or making love. They make their lives an unpredictable misery or a constant struggle to feel normal. Combining this with the other symptoms after concussion such as balance and hearing problems it becomes hard to think straight or feel safe and calm. Yet even with that, many choose to go back to duty and keep their families and love their service to country. Then, some are not so lucky or able to dedicate themselves, remaining in wounded warrior battalions.
Why do they get headaches? The simple answer is that we don’t exactly know, but there may be subtle brain damage after having your bell rung and head rocked. Damage to the parts of nerves called axons occurs because of twisting and shearing. This is not routinely seen on brain scans. Like a wire stripped of insulation, sparks may fly and “brown outs” of the brain are experienced as problems of memory or pain. Getting annoyed or even violent over usual stress can come from this “just missing.” Headaches may come from waves of “wrong messages” as the brain struggles to get the point of what is going on in life.
In order to understand particular headaches and their treatment, specialists will classify them with such names as migraine, or tension-type or cluster. Treatments are made to match this diagnosis or primary headache. This is now most evident in the established fact that triptans are effective in migraine but not necessarily in tension headache.
Post-traumatic headaches may “act like” these so called primary headaches, even if the causes may be different. Does this mean that TBI creates migraine or tension or cluster headache, or are they are a completely new and different type of headache?
What is happening to our warriors who have bad parachute landings, or who fall from high places, or who fly inside or outside the MRAP as an IED batters the armor and the persons it was created to protect? What of the death and destruction? Shouldn’t effective drugs or techniques that work for migraine work in headaches that are “migraine-like” even if they occur after being blasted? Sometimes they do, but many times they don’t.
The biggest controversy in the military literature right now is, simply stated, the difference between the emotional versus the physical damage to the brain, alternately called PTSD and TBI. The most prominent author on the subject, Charles Hoge, has published several reports that show that much of what the soldier’s suffer can be ascribed to the events that leave traces of impossible memories and psychological states which are experienced as physical symptoms such as dizziness, balance and sleep problems.
These are also well-known symptoms that can follow a concussion. Although these studies are not universally accepted, other studies opposing them are few. Amazingly, for all the work so far, headache has remained the singular symptom that has no adequate explanation, except for concussion and/or TBI.
There is a growing awareness that injured soldiers should be helped to return to service, or to the often chaotic life beyond deployment or discharge. Both of these paths demand all the efforts that one can muster. Government, industry, foundations, and individuals are examining everything from armor to personal protection. For those who suffer and for those who live with or care for the injured, the headaches are more than just a pain of the head. They make life hard. They make the promise of duty to comrades more difficult to keep. They add to the struggle to find a place to rest, work, or love.
Our hope is that through better understanding, the headaches after war will be knowable and treatable. For now, the challenges are great. The American Headache Society and its partners are dedicated to this challenge and we offer this special edition of the newsletter in hopes that the information and links will help all those involved.
Alan Finkel, MD Carolina Headache Institute, Chapel Hill, NC, TBI Center of Womack Army Medical Center, Fort Bragg, NC and Chair of the Post-Traumatic Headache Section of the American Headache Society
The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense.
Military Post-Traumatic Headache: The State of the Science and What is Being Done to Find More Answers
Andrew H. Ahn, MD, PhD
- Very little is known about how a knock to the head from a military explosion, called a concussion, leads to post-traumatic headache (PTH).
- Experts base what is known about concussion and headache on indirect evidence.
- How brain trauma affects structures and chemical signals in the brain is the focus of current research.
- Trying to understand blast-injury is a big challenge.
- Researchers will need more information from the affected soldiers to guide future animal and human studies.
The Problem of Post-Traumatic Headache
A large number of soldiers experience problems with sleep, concentration, and constant headaches who have served in Iraq and Afghanistan. These problems are due to the large number of hard knocks to the head suffered by the soldiers. Experts call these hard knocks concussions when they cause a brief sense of being dazed or a loss of consciousness. Current military duty related concussions result most often from the blast of improvised explosive devices (IED’s). Experts do not completely know how blast-related concussion causes constant headache and these other problems.
If concussions are so common, why do we know so little about them? Currently, no accepted way to test for concussion is the single most important reason. Like civilian sports and motor vehicle accidents, a blast-related concussion shows no visible brain injury on standard brain images. That is, an MRI of the brain that your doctor can order is usually normal.
Also, because concussions are not fatal, there are no autopsy studies of concussion or of PTH. Thus, no detailed brain facts exist to compare with the clinical problems. A major research priority is to measure the amount of injury from a concussion. When this research is successful, a “biomarker” will exist.
Researchers have proposed various brain changes in concussion. These ideas result from advanced brain imaging methods used in small groups of subjects. Experts hope that one day these facts will lead to a biomarker for concussion. These imaging changes in the brain relate to chemical signals, blood flow, and the relative size of certain brain areas. These tests are in their earliest stages. We need to regard the results as tentative. Many more subjects need testing.
Clues from Related Conditions
Let’s consider two related conditions. Traumatic brain injury (TBI) is the first. With this injury the trauma is severe enough to cause visible brain injury. Brain contusion is one type of such injury. This bruise is a small blood vessel leak. However, unlike a simple bruise under the skin, a brain contusion can lead to long-term changes in the normal function of that part of the brain. Shear injury is another kind of TBI. Diffuse-axonal injury is another name. Shear injury, in this case, refers to the sudden jarring of the brain. This causes layers of the brain to slide past each other. Shearing in the brain causes a break in axons, the parts of nerve cells that form connections with each other. The detection of even a small amount of this type of brain injury predicts the presence of severe problems like sleep, mood changes, attention difficulties and headaches.
The experience with brain imaging of TBI has identified a common pattern of injuries. Though the pattern is not a perfect predictor, it does provide clues as to the parts of the brain most likely affected in the mildest cases. This pattern includes brain contusions at the surface of the brain directly under the area hit.
In addition, there is sometimes an area of injury at the opposite side of the brain, called a contra coup injury. Bounce-back of the brain against the skull after the initial blow causes the contra coup.
Also, there is a vulnerable region of the brain, along the elongated lobes that sit alongside each side of the brain, called the temporal lobes. Their vulnerability is significant due to the importance of the temporal lobes in memory, emotions, and communication.
Blast-related concussion closely relates to sport-related concussion. Experts in the field of sports medicine accept that repeated concussions are bad. Sports that involve repetitive blows to the head, such as professional boxing, are proof of that.
These blows have long been known to greatly increase the risk of severe and progressive problems later in life. These problems include memory, attention span, problem solving, speech and physical movement abnormalities. All of these problems occur in the elderly with dementia. Abnormal findings in the brain at autopsy occur so often in boxers that experts call this dementia pugilistica. More recent studies confirm that other athletes receive repetitive head trauma. The sports of football, hockey, X-games, also place the athlete at high risk for brain injury. This injury goes by the term chronic traumatic encephalopathy, or CTE. The media has discussed CTE recently related to professional football and boxing. Among those with the clinical picture of CTE, the brain has strong similarities to the problems seen in Alzheimer’s and Parkinson’s disease. These changes include the abnormal build-up of proteins called beta-amyloid and tau, as well as another protein called TDP-43.
Animal Models of Concussion
In the laboratory, researchers have well-established experiments meant to copy the conditions of TBI in animals. However, because these tests produce a well-defined brain injury, they are for the most part not good tests for concussion.
The so-called cortical impact model involves a controlled blow of a weight onto an exposed brain surface. Because the researcher removes a portion of the skull this model is a very good way to produce a local region of brain injury. However, this test is a model of “open head injury” in which the force of the injury exposes the brain. By contrast, a concussion is by definition a “closed head injury.” The skull is still intact. The mechanism of how the energy of the injury is sent throughout the brain is very likely to be different. Another method, called fluid percussion, involves the spread of a fixed blow through a column of fluid. Researchers usually use an exposed brain; thus this is a form of “open head injury.”
There are a few animal models of “closed head injury.” One such model involves the controlled blow of a weight on an anesthetized animal held in a secured position. We all should regard these studies as preliminary. In any case, they remain only a gross likeness of the real-life conditions of a concussion.[/vc_column_text][vc_empty_space height=”40px”][vc_column_text]Towards new test models of concussion
The ability to copy the conditions of an explosive blast in the laboratory is a technical challenge. One unique aspect of an explosion is the “primary blast wave.” This refers to the energy of the blast explosion first carried through the air.
This blast wave is the rapid sequence of high pressure followed by a wave of very low pressure. The subsequent events, such as collisions with hard surfaces, the sudden deceleration with impact, etc., have similar injuries in the civilian setting. The understanding of the physics of blast injury on living tissues is poor at this time, but is the subject of intensive study.
There are still several basic questions that would go a long way towards understanding military PTH. For the time being, the most direct way to address these questions appears to be through further studies of the soldiers returning from combat (see article by Ann Scher). We all hope that these key insights will provide clearer direction on how to design laboratory models and how they lead to ongoing sleep, attention and headache and other symptoms.
Andrew H. Ahn, MD PhD, Assistant Professor of Neurology and Neuroscience, University of Florida College of Medicine, Gainesville, Florida[/vc_column_text][vc_empty_space height=”40px”][vc_column_text]Military Post-Traumatic Headache: Vicious Blasts and Vicious Cycles
Anne Calhoun, MD
- Migraine-like headaches frequently develop after combat related head injuries.
- Factors beyond the injury itself play a key role in the development and resolution of these headaches.
- Underlying factors in chronic headaches often include sleep problems, medication overuse, anxiety and posttraumatic stress disorder (PTSD).
Roughly 20% of US soldiers returning from Operation Iraqi Freedom/Enduring Freedom sustained a concussion during their deployment. Among those suffering a concussion, 37% had post-traumatic headache defined as headaches beginning within one week following the concussion.
Providers classified the majority of these post-traumatic headaches as migraine. These headaches have occurred more frequently than non-post-traumatic headaches.
To understand the migraine-like features of these headaches, one needs to know that the brain responds to trauma using pathways similar to those in migraine. Research reveals that migraine can be a consequence of mild traumatic brain injury (TBI). A link between migraine and TBI can be post-traumatic stress disorder (PTSD). This article looks at how these conditions can interact in a vicious cycle to produce chronic pain.
Traumatic Brain Injury Facts
Today, almost a third of the injuries from the battlefields of Iraq and Afghanistan are to the head and neck. This pattern is significantly higher—50% to 100% higher—than in World War II, Korea or Vietnam. Along with this, more of our wounded are surviving and returning home with their injuries, thanks to the rapid transport of casualties to definitive care stations.
It is well known that the signature injury of this war is the blast, accounting for almost 80% of injuries. In fact, the majority of our wounded suffer some degree of TBI. Mild TBIs—meaning that loss of consciousness was less than one hour—are the injuries most associated with chronic post-traumatic headache.
Paralleling this surge of blasts and TBIs is an epidemic of PTSD. Between 2003 and 2007, newly diagnosed cases grew almost nine-fold, with the burden of the disorder borne by the troops on the ground—the Army and the Marines.
Better reporting of PTSD following the introduction of the electronic medical records in 2004 and greater awareness of the condition likely explains the surge in cases. Unquestionably, there is also the key factor of increased combat exposure of our troops on the ground, due to multiple deployments and extended tour lengths.
What Post-Traumatic Headache Means
Before any meaningful discussion of “post-traumatic headache” (PTH), it is necessary to ask what “post-traumatic” means in this context. If post-traumatic is taken to imply causation—that the headache is due to the trauma—then we would have to focus on the physics of the blast and the mechanisms of tissue injury to understand or discuss PTH (and when dealing with an individual patient and his injuries, this can be appropriate). Howeve, there are problems with this approach when we consider PTH as a headache disorder.
First, each injury is unique. Second, although PTH develops in the vast majority of mild TBI cases, most studies show an inverse relationship between the severity of the injury and subsequent development of headache. These studies imply that there are factors at work beyond the physical injury, and that are at least partly responsible for the generation or maintenance of these headaches.
If post-traumatic is understood to describe a temporal relationship—that these headaches follow a brain injury—then instead, we must look for clues in the associated factors and evaluate their respective contributions to the overall clinical picture. With this definition, we can discuss important generalities that are common to the development of chronic PTH following combat trauma—even where individual injuries may be quite diverse.
Prevalence of Migraine in the Theatre
We do know that there is something about the battlefield that increases susceptibility to migraine. A brigade of soldiers—93% male, with an average age of 27—was screened with a validated headache questionnaire immediately following a one-year tour in Iraq. The screener asked detailed questions about headache symptoms during the last three months of their deployment. Researchers applied formalized criteria to the answers provided, and classified the headaches as migraine, probable migraine, or non-migraine headaches. Surprisingly, an astounding 19% of the troops were judged to have migraine; 17.5% had probable migraine and 11.4% had non-migraine headaches. Only 5% had been diagnosed with migraine prior to their deployment. This is much higher than would be predicted for a young, mostly male population. The reported general population prevalence of migraine in men is about 6% and 18% in women.
To explain this high prevalence of migraine in theatre, we know that these headaches have both a genetic predisposition and a threshold for expression. Certain factors appear to lower that threshold, making attacks more likely. These include chronic exposure to migraine triggers, such as lack of sleep, stress, heat, exertion, strong smells, hunger, weather fronts, and glare—factors that are prevalent on the battlefield. Our troops often rely on caffeine and sleeping pills as they work with heavy packs and body armor in the desert heat.
Progression from Episodic to Chronic Headache
To illustrate the process of transitioning from occasional or episodic headaches to chronic headaches, let’s look at a model for the chronification process. With migraine, there is a genetic component—an inherited susceptibility. The susceptible individual then encounters an occasional migraine trigger and experiences occasional, or episodic migraine. These individuals are typically able to manage attacks with effective, acute, migraine medications, however, when individuals get into trouble with increasing frequency of headaches, they enter into a vicious cycle of progression to chronicity. Chronic migraine is marked by some degree of headache discomfort on at least half the days of the month, and, if left untreated, eight or more of these would become migraines.
How one enters the vicious cycle likely differs to some degree from individual to individual, and is a matter of debate among headache specialists. This illustration shows entering the circle through non-restorative sleep, which can be attributed to any of a vast array of issues. Chronic, poor sleep is a risk factor for progression to more frequent headaches. Then, if drugs are taken for each attack, medication overuse or “rebound” headaches can ensue, perpetuating the headaches.
Medication overuse is present in 70% of patients with chronic migraine. This factor may then interact with anxiety—which is quite common in migraine sufferers. Anxiety is five times more likely with migraine and vice-versa. The migraineur may worry if enough pills are available to treat headaches, or be anxious over whether the pain will become worse. Anxiety, in turn, may interfere with sleep initiation or maintenance, continuing the vicious cycle. There are also brain pain processes that amplify the cycle. Side effects of the medications taken (for headache pain or prevention, anxiety or sleep) can, in turn, make the sleep worse. Consequences of poorer sleep include an increase in anxiety, depression, eating disorders, fatigue and stress. The worse the progression, the more likely the patient is to overuse medications and experience anxiety, depression and or PTSD.
Progression from Acute to Chronic PTH
Similar factors may be involved in the transformation of acute PTH to chronic PTH. Certainly, the reported inverse relationship between severity of injury and headache chronicity is intriguing and argues for other, equally important factors. The next illustration shows how mild TBI may lead into a vicious cycle of headache chronification.
The blast has two components: (1) the physical impact produces an acute PTH, experienced after about 80% of mild TBIs. This can lead to medication use—or overuse—particularly when the soldier is self-medicating without appropriate evaluation. Here, it is important to remember that caffeine is a drug that can readily perpetuate chronic headaches. There is also the psychological impact—what the soldier saw, what he heard, what he smelled, and what he imagined. This can fuel the anxiety component of the vicious cycle and lead to non-restorative sleep.
Most cases of PTH resolve within the first 6 to 12 months, but with protracted cases, research suggests psychological factors play a role in etiology and headache maintenance. Addressing psychological factors is necessary for eventual relief. Among cases that don’t resolve within the first year, there are two key factors. A study of veterans with TBI showed high association of persistent neurologic or neuropsychological abnormalities with PTSD and disturbed sleep: 90% of these persistent cases had PTSD; over 80% had disturbed sleep. Only 11% of those with normal neurologic or neuropsychological exams had either PTSD or disturbed sleep.
Post-Traumatic Stress Disorder
PTSD is a severe anxiety reaction to a traumatic event, in which individuals repeatedly relive that event, avoid stimuli associated with it, and experience symptoms such as difficulty sleeping and irritability. It is common in our combat veterans, particularly those who have sustained head injuries. After careful examination of a brigade of returning soldiers, a study reported PTSD in 44% of those who had experienced injuries with loss of consciousness, 27% of those with lesser concussions (no loss of consciousness), 16% of those with other (non-TBI) injuries, and 9% of those with no injury.
Solders with TBI were more likely than those with other injuries to report poor general health, missed workdays, medical visits and a host of physical symptoms. However, after adjustment for PTSD and depression, the head injury itself was no longer significantly associated with any of these outcomes, except for headache. In other words, headache appears related to the injury itself. PTSD and depression appear to explain the missed workdays, medical visits and host of other symptoms.
In the overall clinical picture, it can be hard to disentangle TBI and PTSD. Three factors appear to account for persistent symptoms following a mild TBI. These include the relative severity of the injury, multiple injury mechanisms and PTSD.
In turn, factors associated with development of PTSD include service in Iraq as opposed to Afghanistan, female gender, multiple injury mechanisms and a TBI. This is reflective of what military history has taught us. Records from the US Civil War showed that the dual factors of individual vulnerability and magnitude of exposure were key factors in development of a syndrome that was similar to what we know as PTSD. The youngest soldiers were the hardest hit, as were members of units that sustained the most extensive battlefield losses.
There are four basic patterns of functioning after trauma: (1) severe disruption in psychological function beginning immediately after the trauma and persisting for years, (2) initial disruption in function, but improvement over time and recovery, (3) initial adjustment to the trauma with deterioration over time, and (4) resilience.
Resilient patients recover after relatively mild short-term disruptions. One theory is that resilient individuals may be genetically different—among the quarter of the population with two long variants of the 5HT transporter gene. With poor psychological functioning comes increased likelihood of chronic headaches. Increased risk for poor psychological function can be related to traumatic events in earlier life, especially childhood. These events can then render an individual more vulnerable to later traumas including traumatic spectrum disorders, such as PTSD.
Treatment of Post-Traumatic Headache
Optimal treatment must address the issues involved. Typically, these include a minimum of headache, psychological dysfunction, medication use/overuse, sleep disturbances, inactivity, and dietary issues.
For the headaches, treatment typically follows established guidelines for preventive and acute therapy of the type of primary headache that the condition most closely resembles—usually chronic migraine. This includes avoidance or resolution of medication overuse headache, or caffeine-related headaches.
For the psychological component, especially PTSD, there is evidence supporting the effectiveness of several treatment modalities, including both individual and group trauma-focused cognitive behavioral therapy including somatic experiencing, guided imagery, stress management, and eye movement desensitization and reprocessing (EMDR). Two resources developed specifically for the military by Belleruth Naparstek can be found on healthjourneys.com entitled the Military Welcome Home Guided Imagery Pack and Healing Trauma (PTSD). James Gordon’s Center for Mind-Body Medicine is listed as a resource in the National Resource Directory (NRD), a federal government Web site for wounded, ill and injured Service Members, Veterans, their families, and those who support them. The Center for Mind Body Medicine also has a $400,000 research grant from the Defense Center of Excellence (DCOE) for Psychological Health to study the Center’s trauma healing model with veterans returning from Iraq & Afghanistan. Contact the NRD for specific military resources or the Center for more details.
Among treatment choices, there is evidence that trauma-focused treatment is more effective than non-trauma-focused. One example of individual trauma-focused somatic experiencing is “Virtual Iraq,” an immersion therapy that utilizes video gaming technology. These virtual reality experiences can be individualized to the setting of the trauma—for example, a roadside explosion, or an urban street-fight. Sights, sounds, tank rumbling and motion, and even smells have been used to reproduce the setting of the trauma.
The intent is for the soldier to revisit the trauma in progressively greater detail as he learns to “dial down” his response to it. “Dialing down” the emotional response seems to be a key component of resilience. Functional MRI studies in PTSD patients have shown that these techniques can be learned, with benefits demonstrated on brain scans.
Disrupted sleep specifically warrants targeted treatments. This may require an assessment of sleep apnea, but more likely use of classic sleep hygiene techniques is more important. Disturbed sleep seems to be a core feature of PTSD, not just a common symptom. In fact, early onset of sleep disturbances following the trauma is predictive of PTSD one year later. Persistent sleep problems that remained years after the injury were also associated with greater neurobehavioral impairment and with unemployment. Guided imagery with the Healthful Sleep CD by Belleruth Naparstek and Emotional Freedom Technique (EFT) at eftuniverse.com are excellent resources for PTSD sleep specific problems.
Any inactivity due to pain, sleep deprivation or PTSD needs reversal beginning with increased activity as soon as possible. This should advance gradually from non-exercise activity to some degree of cardiovascular exercise. If maintaining a level of exercise, assess capability for possible advancement. Dietary treatment consists mainly of avoiding known headache triggers including headache-promoting substances such as caffeine, artificial sweeteners, nitrates, tobacco and possibly alcohol.
Summary of Post-Traumatic Headache
Proper diagnosis of PTH is essential. This includes not only proper headache diagnosis, but evaluation for psychological dysfunctions including sleep disturbance and PTSD. Effective treatment of chronic PTH after combat-related mild TBI may resemble the treatment plan of chronic migraine. This requires appropriate preventive and acute medications, elimination of analgesic overuse and/or caffeine rebound, effective treatment of anxiety disorder/PTSD and depression and improved sleep hygiene to restore sleep.
Anne Calhoun, MD, CAPT/MC/USNR-Ret, Partner, Co-Founder, Carolina Headache Institute
Chapel Hill, NC
Military Post-Traumatic Headache: What are we doing about it: Government?
Teshamae Monteith, MD
- Congressionally Directed Medical Research Programs FY2010 exist for chronic migraine and posttraumatic headache, but still require funding.
- National Defense Authorization Act for 2010 to develop and implement a comprehensive policy on pain management by the Army Pain Management Task Force.
- Key components of the National Pain Care Policy Act included in the Patient Protection and Affordable Care Act.
I met a young veteran not too long ago whose personal stories remains vivid in my mind. He was exposed to an improvised explosive device that resulted in a traumatic blast injury and an early discharge. Now back at home, he is currently taking biology classes to become an army physician and help soldiers with TBI. Unfortunately, he has intrusive flashbacks, cognitive impairments and daily headaches that interfere with his performance. He now takes daily Vicodin, but this only dulls the pain.
Traumatic Brain Injury (TBI) is a serious public health concern afflicting our active duty soldiers and veterans alike. In fact, an estimated 15-20% of soldiers have sustained TBIs in Iraq and Afghanistan, making it the signature injury of our current conflicts. While TBI is the signature wound, headache has become the signature symptom. Post-traumatic headache is a serious problem, especially in military populations, as cultural barriers exist in pain reporting. Inadequately treated pain may cause mental anguish, exacerbate psychological or psychiatric disorders and may contribute to rising rates of suicide. Furthermore, acute pain may progress to chronic headache, medication overuse, and dependency on controlled prescriptions. All these elements may confound the disability associated with TBI and affect the quality of life and functional capacity of afflicted service-members. So we asked what is the government doing about it?
Congressionally Directed Medical Research Programs FY2010
In response to this growing public health problems associated with TBI, the fiscal year 2007 marked a dramatic increase in psychological health and traumatic brain injury research when the Congressionally Directed Medical Research Programs (CDMRP) was allocated an unprecedented $301million(M) to advance the military’s understanding of these disorders. $151M is for research on Posttraumatic Stress Disorder and $150M for research on TBI. Despite the large burden in headache prevalence of those afflicted with TBI, headache disorders have been under-investigated and there are large gaps in our knowledge base of service-connected migraine and posttraumatic headache.
Neurologists, headache specialists, patients, and veteran advocacy groups including members of the Alliance for Headache Disorders Advocacy contacted Congress in concern for returning troops suffering from posttraumatic headache. In response to advocacy initiatives for the health care needs of the Armed Forces, Congress fortunately added chronic migraine and post-traumatic headache to the list of topic areas for the Peer Reviewed Medical Research Programs (PRMRP) for the fiscal year 2010. The programs seek a wide spectrum of disciplines with the vision to identify and fund the best medical research to protect and support our servicemen. These programs currently remain unfunded, but the Office of the CDMRP expects to allot approximately $6.6M of the $50M FY10 PRMRP appropriation to fund approximately 2 clinical trial applications including headache.
Congressional Brain Injury Task Force
The Congressional Brain Injury Task Force or TBI Caucus held a congressional briefing in February 2010 with the American Academy of Neurology Palatucci Advocacy Leadership Forum and representatives from the American Headache Society (AHS)—including Past President Fred Sheftell, MD, immediate past co-chair of the AHS Posttraumatic Headache Section Ann Scher, Ph.D, National Director of the Neurology for the Veteran Affairs Health System (VHA), and Peter J. Goadsby, MD, PhD.
As a result, the TBI caucus sent out a Dear Colleague Letter in support of the Department of Defense (DoD) appropriations of $10M for migraine and post-traumatic headache research for FY2011. While the Department of Defense did not support the exact recommendations of the caucus, a greater awareness for the impact of posttraumatic headache in the military population arouse.
National Defense Authorization Act FY2010
Section 711 of the National Defense Authorization Act (NDAA) for fiscal year 2010 tasked the Secretary of Defense to develop and implement a comprehensive policy on pain management by the military health care system, no later than March 31, 2011. Hopefully, the military headache will be addressed along with other pain conditions as a part of this comprehensive and interdisciplinary pain management approach in compliance with Section 711 of the NDAA.
Army Pain Management Task Force
The Army Surgeon General LTG Eric B. Schoomaker chartered the Army Pain Management Task Force in August 2009 to provide a standardized DoD and VHA vision and approach to pain management to optimize the care for warriors and their families.
The Task Force members included a variety of medical specialist disciplines from the Army, and representatives from Navy, Air Force, TRICARE Management Activity, and Veterans Health Administration (VHA). In the May 2010 final report, 109 recommendations emphasized a holistic, multidisciplinary and multimodal approach. The recommendations depend on an education and communication plan that crosses DoD and VHA medical staff. The recommendations may be divided into four areas: to provide tools and infrastructure that support and encourage practice and research advancements, build a set of best practices, focus on the warrior and family, and to promote pain awareness, education, and proactive intervention. The task force emphasizes the need for prevention, prompt and appropriate treatment that relieves acute pain and eliminates progression. Over time, we look forward to see how these initiatives provide the groundwork necessary to reduce the pain and suffering associated with posttraumatic headache.
National Pain Care Policy Act into Law
The National Pain Care Policy Act (NPCPA) resulted from the diligent work of several advocacy groups including the Pain Care Coalition (PCC), the American Pain Foundation and others. The PCC was organized in 1989 by the American Pain Society, American Association of Pain Medicine and the AHS. These advocacy groups contributed to the inclusion of key components from the 2009 NPCPA into the Patient Protection and Affordable Care Act, the landmark healthcare reform bill.
The National Pain Care Policy Act of 2009 requires the Secretary of Health and Human Services seek to enter into an agreement with the Institute of Medicine to convene a Conference on pain, which may be major way forward in the road to providing better care for serviceman with posttraumatic headache. The purpose of the conference is to address key medical and policy issues of pain care.
Secondly, training programs will be necessary to improve health care skills of assessing and treating pain. Lastly, Sections in the NPCPA also requires that the Director of the National Institutes of Health (NIH) continue to expand research through the NIH Pain Consortium. The Consortium is lead by directors of the NIH Centers for Complementary and Alternative Medicine, and Institutes of Nursing Research, Neurological Disorders and Stroke, Dental and Craniofacial Research and Drug Abuse.
Through collaboration the NIH Pain Consortium could help us understand more about both the basic mechanisms and clinical challenges of posttraumatic headache. The Consortium is responsible for submitting recommendations to the Director of NIH with the goals of expanding the pain research agenda.
TBI and the sequelae of post-traumatic headache can be a disabling condition that interferes with assimilation and adjustment of our military servicemen back into society. In order to best manage posttraumatic headache, research efforts in the basic, translational and clinical sciences is greatly necessary to both fill gaps in knowledge and provide the best medicines.
Thanks to our government, pain management efforts across the DoD and VHA are underway to address these issues. In order to adequately address headache and prevent widespread disability, more work needs to be done in the interest of military headache sufferers. As secretary of the Posttraumatic Section of the American Headache Society, rest assured that we are committed to improving the quality of lives of our servicemen. You may then ask how can I help? Patient advocacy is a powerful way to move the government and ensure the best is being done for our brave soldier and veterans. You may help by writing to your representatives and ask them to support increased NIH funding for headache and pain research.
For more reading and ways to support:
- Defense and Veterans Brain Injury Center
- Pain Management Task Force
- Alliance for Headache Disorders Advocacy
Teshamae Monteith, MD, Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, CA