Researchers found how brain injury can lead to post-traumatic stress disorder

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Post-traumatic stress disorder in U.S. military members frequently follows a concussion-like brain injury.

Until now, it has been unclear why. A UCLA team of psychologists and neurologists reports that a traumatic brain injury causes changes in a brain region called the amygdala; and the brain processes fear differently after such an injury.

“Is one causing the other, and how does that occur?” asked senior author Michael Fanselow, who holds the Staglin Family Chair in Psychology at UCLA and is the director of UCLA’s Staglin Music Festival Center for Brain and Behavioral Health. “We’re learning.”

Two groups of rats were studied. Through surgery, a concussion-like brain injury was produced in 19 of the rats. Sixteen other rats — a control group — also had the surgery, but did not sustain a brain injury.

All of the rats were then exposed to a low level of noise, followed by a series of moderate, brief foot shocks.

The foot shocks were frightening to the rats, but not very painful, Fanselow said. Because the rats learned to associate the noise with the shock, they became afraid of the noise.

Rats tend to stand still when they experience fear. When they recall a frightening memory, they freeze.

Their heart rate and blood pressure go up — and the stronger the memory, the more they freeze, Fanselow said.

On the experiment’s third day, the researchers again exposed the rats to the same place where they had been shocked, but did not give them any additional shocks, and studied their reactions.

The rats in the control group did freeze, but the rats that received the brain injury froze for a much longer time.

The researchers discovered that even without receiving a foot shock, the rats that had a brain injury showed a fear response to the noise.

“Sensitivity to noise is a common symptom after concussion, which suggested to us that this might partly explain why fear reactions to certain stimuli are increased after brain injury,” said Ann Hoffman, a UCLA researcher in psychology and lead author of the research, which is published in the journal Scientific Reports.

“It’s almost as if the white noise acted like the shock,” Fanselow said.

“The noise itself became scary to them, even though it wasn’t much noise. They treated it almost like a shock.”

The researchers studied the amygdala, which is known to be crucial in learning fear. People with anxiety disorders have increased activity in the amygdala, and PTSD has been linked to increased activity in the amygdala.

The amygdala is made up of neurons, and a rat’s amygdala has about 60,000.

The researchers discovered that five times as many neurons in the amygdala were active during the white noise in the rats with the brain injury than in the control group, Hoffman said.

The amygdala listens to other brain areas that provide it with information.

“The amygdala makes a decision whether a situation is frightening, and when it decides a situation is frightening, it generates a fear response,” Fanselow said.

Another new discovery the researchers report is that after the traumatic brain injury, the brain processes sounds from a more primitive part of the brain — the thalamus — than from a more sophisticated, highly evolved area of the brain — the auditory cortex.

The thalamus provides a more simplistic, crude representation of sound than the auditory cortex.

About four times as many neurons were active in a network from the thalamus to the amygdala in the rats with the injury than in the control group rats, Hoffman said.

The researchers studied the amygdala, which is known to be crucial in learning fear. People with anxiety disorders have increased activity in the amygdala, and PTSD has been linked to increased activity in the amygdala.

The study raises the question of whether it is possible to get the brain’s amygdala back to normal following a concussion-like injury, perhaps through behavioral therapy or a pharmaceutical.

If so, that could benefit members of the military, as well as civilians who have had serious brain injuries, Fanselow said. He and his team will continue their research in an effort to answer this question.

If so, that could benefit members of the military, as well as civilians who have had serious brain injuries, Fanselow said.

He and his team will continue their research in an effort to answer this question.

Co-authors are David Hovda, a professor of neurosurgery at the David Geffen School of Medicine at UCLA and director of UCLA’s Brain Injury Research Center; Christopher Giza, director of the UCLA Steve Tisch BrainSPORT program and professor of neurosurgery and pediatrics at the Geffen School of Medicine; and Jamie Lam, a UCLA psychology undergraduate.

Funding: The research was funded by the National Institute of Mental Health, a UCLA Depression Grand Challenge Fellowship Fund, Staglin Center for Brain and Behavioral Health, and UCLA Brain Injury Research Center.


Traumatic Brain Injury (TBI) may result from anywhere between a simple blow to the head to a penetrating injury to the brain. In the United States, around 1.7 million people suffer TBI with older adolescents (ages 15 to 19 years) and older adults (ages 65 years and older) among the most likely to sustain a TBI. 

Frontal and temporal areas of the brain are the main areas involved. Mild TBI (mTBI), also known as brain concussion, initially considered as a benign event, has galvanized tremendous attention for some of its adverse neuropsychological outcomes in civilians (e.g., athletes who play contact sports) as well as military personnel.

Moderate to severe TBI is a primary cause of injury-induced death and disability. In the United States, It has an annual incidence of approximately 500 in 100,000. However, around 80% of all TBI cases are categorized as mild head injuries.[1][2][3][4]

Etiology

Mild TBI or brain concussion usually results from closed brain injuries, the incident when the head is being struck by an object, such as a bat or a fist during a fight or when the head is affected by a nearby blast or explosion. Such injuries have shown to affect the structural integrity of the neurons.

Epidemiology

Male to female ratio is 2:1. A private study of 1084 individuals with traumatic brain injuries revealed that TBI was a high-risk factor not only for post-traumatic stress disorder (PTSD) but also for other psychiatric disorders. Statistically, the Center for Disease Control and Prevention (CDC) has estimated that annually, about 1.5 million Americans survive a traumatic brain injury (TBI).

Among these, approximately 230,000 are hospitalized. In 2000, there were 10,958 TBI diagnoses. In 2015, this number jumped to 344,030. Mortality across all TBI severities is approximately 3%, yet morbidity is more difficult to estimate.

Pathophysiology

Diffuse axonal injury (DAI) underlying mild to moderate TBI potentially results from any shearing, stretching, or twisting injuries to the neuronal axons. This phenomenon is mainly seen at the junction of the gray and white matter where neuronal axons are entering a more dense, fatty (myelinated), and less fluid-filled white matter.

Such shearing forces cause the neuronal axon to be stretched, and the subsequent damage to cytoskeleton may lead to axonal swelling, increased permeability, calcium influx, detachment, and axonal death. Diffuse laminar necrosis is typically seen on autopsy. [5]

Histopathology

The events of posttraumatic accumulation of fluid, (cerebral edema), the disruption of the blood-brain barrier (BBB), and histopathological changes were studied in a mice model studies. Researchers have discovered significant neuronal cell death in some areas of the left hippocampus following a closed-head injury.

An immunohistochemistry using multiple antibodies to the amyloid precursor protein and/or amyloid precursor protein-like proteins showed a novel axonal degeneration in the striatum, corpus callosum, and injured cortex. Histological evaluation of injured brains illustrated an expansion of the cortical cavity, enlargement of the lateral ventricles, deformation of the hippocampus, and thalamic calcifications.

Toxicokinetics

In addition to the biomarkers released secondary to the neuronal injury (proteins that leak from astrocytes and neuron when are damaged), researchers have studied the role of cJun N-terminal kinase (JNK) that mediates neuronal death in response to stress and injury in the CNS and peripheral nervous system.

Some of the other variables in settings of TBI include interleukin-1beta concentration, aspartate, glutamate in the CSF, and microdialysate lactate, glucose, pyruvate, and glycerol, along with brain tissue partial oxygen pressure and intracranial pressure. Most of these were measured while studying different modalities of therapy like hyperbaric oxygen treatment and hypothermia in TBI.

History and Physical

Unfortunately, many incidents of mild-moderate traumatic brain injuries in our everyday life do not even present to the emergency room or other healthcare settings, especially when they are associated with sports-related or recreation-related settings. Per the Journal of Pediatrics, cases of TBI in children of age 18 and under were believed to be caused mainly by sports and recreation-related concussions. However, the vast majority of service members and veterans experience a TBI in a non-deployed setting (diagnosed in up to 80%) due to the nature of their training or participation in sports and leisure activities.[6][7][8][9]

The American Journal of Psychiatry published a study in 2015 that showed the prevalence of comorbidity of disorders among soldiers classified at T2 (3 months post-deployment) as experiencing major depressive episode, PTSD, generalized anxiety disorder, or suicidality in the past 30 days went up from 12.9% to 16.8% at T3 (9 months post-deployment).

Apart from the obvious physical complaints, neuropsychiatric symptoms noticeably vary out of proportion with the severity of the correspondent TBI. The patients who experience a post-concussion syndrome may have somatic complaints like a headache, dizziness, cognitive impairment, and neuropsychiatric symptoms like anxiety, irritability, depression, and sleep disorders. They may have frontal lobe syndrome with behaviors like labile affect, poor social judgment, and lewd behavior with loss of social graces, aggressiveness, and perseveration. These are common in up to 23% of adult patients with TBI.

Working memory is largely affected among patients with mTBI. They may also abuse drugs and experience PTSD symptoms more than the general population (up to 18% and 22%, respectively).

Psychotic disorder following traumatic brain injury (PDFTBI) occurs in 0.7% to 8.9% of persons who sustain TBI. Psychosis following TBI causes patients to have deficits: brain-injured (primarily executive), and psychotic (executive and semantic).

Although infrequent, auditory hallucinations are a debilitating complication of TBI that can manifest itself 4 to 5 years after the occurrence of the TBI.

The latency between traumatic brain injury (TBI) and the onset of psychotic symptoms is highly variable but typically characterized by paranoid delusions and auditory hallucinations, with visual hallucinations and negative symptoms being less common. Studies showed that PDFTBI has an additive effect on executive dysfunction among TBI patients. Significant executive dysfunction was evident in patients with PFTBI on all measures.

Evaluation

Level of consciousness (LOC), altered mental status (AMS), post-traumatic amnesia (PTA), and Glasgow coma scale (GCS) are used in the evaluation of the severity of the TBI (see table 1).

Moreover, recent studies recommend implementation of the portable cognitive assessment tools at the time of the incidence of the TBI as a potential indicator for the long-term effects. One of the scales used in measuring the severity of deficit in cognitive functioning is Ranchos Los Amigos Scale, as below:

  • Level I = No response
  • Level II = Generalized response
  • Level III = Localized response
  • Level IV = Confused-agitated
  • Level V = Confused-inappropriate
  • Level VI = Confused-appropriate
  • Level VII = Automatic-appropriate
  • Level VIII = Purposeful-appropriate

 Comprehensive evaluation should include the utilization of the following tools:

  • Clinical history/presentation with thorough neurological  and psychiatric evaluation including cognitive assessment
  • Labs: Serum levels of two biomarkers: Glial fibrillary acidic protein (GFAP) and Ubiquitin C-terminal hydrolase (UCH-L1) correlated with the degree of brain injury, with GFAP being the more reliable of the two up to 7 days after impact. They are proteins that leak from astrocytes and neuron when are damaged.
  • Neuroimaging

CT head and MRI are used to measure changes in anatomical or physiological parameters of TBI. These include hemorrhage, edema, vascular injury, and intracranial pressure. However, for most cases of mild TBI, CT and MRI often show no abnormalities.

Diffusion tensor imaging (DTI) is used to detect axonal injury for mild to moderate TBI.

Functional MRI (fMRI) is often used to differentiate TBI from control groups and has been used to study activation patterns in patients with TBI.

Brain Perfusion Single Photon Emission Computed Tomography (SPECT) is used to measure cerebral blood flow and activity patterns. It is indicated for the evaluation of TBI in the absence of anatomical findings.

Some authors suggest that SPECT should be part of a clinical evaluation in the diagnosis and management of TBI. A recent meta-analysis showed that PTSD patients have significant activation of the mid-line retrosplenial cortex and precuneus when presented with trauma-related stimuli.

The preliminary data suggest it has a potential role in distinguishing PTSD from TBI. When compared to subjects with TBI, relative increases in perfusion were observed in PTSD in the limbic regions, cingulum, basal ganglia, insula, thalamus, prefrontal cortex, and temporal lobes.

These results suggest that TBI is associated with hypoperfusion while PTSD is associated with regional hyperperfusion, providing important insights regarding pathophysiological differences between these disorders. Recent studies are also highly promising in differentiating PTSD from TBI using both region of interest (ROI) and visual readings (VR) analysis (The study was published on July 1, 2015, in PLOS One).

  • Sleep studies: Some power-spectral analyses revealed patients in the mTBI group showed lower delta power and higher alpha power in the first NREM period and higher beta power in the first and second NREM period. REM-period findings included lower beta in the third REM period and higher delta in the first REM period. Recent data suggested that sleep tests may be a sensitive measure of brain injury after mTBI and, theoretically, could be used to determine the anatomy of brain injury.

Treatment / Management

Treatment of psychiatric symptoms following concussion/mTBI should be based on individual factors and the nature and severity of symptom presentation. It may include physiotherapy, psychotherapeutic, and pharmacological treatment modalities.[10][11][12]

Physical Rehabilitation

TBI may result in a decrease in short and long-term global health (physical and behavioral) and put them at an elevated risk for disability, pain, and handicap (i.e., difficulty with a return to work, maintaining peer networks.) Rehabilitation therapies like physical therapy, occupational therapy, speech-language therapy, and assistive devices and technologies may help to strengthen patients to perform their activities of daily living.

Psychotherapy

  • Initial education, long-term support groups (symptom-focused and process groups), family education, and social issues like financial, legal and transportation.
  • Virtual reality and videogaming-based therapy in treating balance, coordination, and cognitive issues like attention and concentration data are under larger scale clinical trials to prove efficacy.

Medications

  • Depakote, NSAIDs, and triptans: May be considered for headaches which are the single most common symptom associated with concussion/mTBI
  • SSRIs: Citalopram 10 mg daily for 1 week, then 20 mg daily if tolerated (up to 80 mg daily if needed). Sertraline 25 mg daily increasing weekly in 25 mg increments to a maximum dose of 200 mg/day for depression
  • Anticonvulsants: mood stabilization and seizure prevention
  • Atypical antipsychotics: for agitation and irritability with beta-blockers in severe cases
  • Dopaminergic agents: for concentration and focus
  • Cholinesterase inhibitors/cognitive enhancers for memory
  • Atypical agents: Buspar for emotional stabilization and Modafinil for focus.

General Guidelines for Using Medications:

  • Start low, go slow, whenever medications are required
  • Rule out social factors first, such as abuse, neglect, caregiver conflict, and environmental issues
  • No large quantities of lethal medications, high suicide rate due to disinhibition
  • Full therapeutic trials, since under treatment is common
  • Minimize benzodiazepines (impairs cognition), anticholinergics (induces sedation), seizure-inducing (impedes neuronal recovery), and antidopaminergic agents
  • No caffeine (due to agitation and insomnia), no diet, herbal, or energy drinks (may precipitate aggression).

Other Considerations in Treating PTSD in Patients with mTBI

  • Present information at a slower rate
  • Use structured intervention approach with agenda, outline, or handouts
  • In groups, ask “PTSD” to respond first, then ask others to respond
  • Allow free contribution, use refocus/redirection with a clear transition between topics
  • The therapist should avoid frustrating the mTBI patients by forcing them to recall incidents that are only partially encoded.

Management of Sleep Dysfunction

Immediately following TBI, the difficulty in falling asleep and frequent waking is common; whereas, after several years excessive somnolence is more typical.

  1. Acute Phase less than 3 months: Provide education about concussion about changes in sleep quality and duration sometimes associated with concussion. Provide information on good sleep habits with specific suggestions to improve the quality and duration of sleep (regularly scheduled bedtime). Sleep medications may be helpful in the short-term. Zolpidem 5 mg at night, if poor results after 3 nights of therapy, increase to 10 mg nightly. Also, prazosin, with 1 mg at bedtime for 3 days, may increase to 2 mg at bedtime through day 7.
  2. Chronic phase: more than 3 months: Review current medications and other current health conditions for factors which might contribute to chronic sleep disturbances, including chronic pain or co-morbid psychiatric conditions. Consider sleep study to provide objective evidence of sleep disturbance and to rule out coexisting sleep apnea or other sleep disorders. Consider a course of cognitive behavioral therapy (CBT) focused on sleep.

Hyperbaric Oxygen Therapy (HBO2)

Some researchers discussed the role of oxygen delivered at supraphysiological amounts in the treatment of TBI. A study published in 2010 included closed-head trauma victims with GCS scores of 3 to 8 after resuscitation, without effects from paralytics, sedation, alcohol, and/or street drugs. HBO2 treatment began within 24 hrs post injury admission to hospital with a mild or moderate TBI compared the effect of HBO2 to normobaric oxygen. They found a significant post-treatment effect of HBO2 on cerebral oxidative metabolism due to its ability to produce a brain tissue PO2 greater than or equal to 200 mmHg (higher cerebral blood flow lead to higher PO2, lower levels of lactate by 13% compared to control group, and lower intracranial pressure). However, in severe TBI, it is not an all or nothing phenomenon but represents a graduated effect. Some controversy still surrounds the use of HBO2 due to the limitations of studies such as the lack of blinding to the intervention, cost, time-consuming practice, and the validity of the actual diagnoses of the patients with reported TBI and PTSD who had a subsequent improvement.

Hypothermia

Studies have shown some controversy in the practicality of this practice depending on the patient’s characteristics (age, the initial GCS, the presence or absence of pupillary abnormalities, and CT-based classification of the severity of the injury). In general, there has been an increased belief that cooling the body to systemic temperatures around 34 C to 35 C, helps reduce secondary injury and improve behavioral outcomes. Studies have suggested that this occurs because of the ability of hypothermia to suppress post-traumatic inflammatory response, in turn, preserving the blood-brain barrier and reducing the number of cytokines released as well as glutamate.


Source:
UCLA
Media Contacts:
Stuart Wolpert – UCLA
Image Source:
The image is in the public domain.

Original Research: Open access
“Sensory sensitivity as a link between concussive traumatic brain injury and PTSD”. Ann N. Hoffman, Jamie Lam, David A. Hovda, Christopher C. Giza & Michael S. Fanselow.
Scientific Reports doi:10.1038/s41598-019-50312-y.

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