Post-Traumatic Stress Disorder Following TBI and the Neurologic-Psychiatric Borderland

Over the last three years in my cognitive neurology practice, I have had the unique opportunity to evaluate over a 100 veterans who have been exposed to blast injuries. The injuries range from automobile accidents to military training. Recreational sporting events like basketball, soccer, or football may also be the cause for such injuries. The veterans represent numerous wars, including Vietnam, the Gulf war, and the ongoing wars in the Middle East.

My requirement was to spend an hour with each patient and focus predominantly on their TBI history (its immediate and prolonged effects) and perform a cognitive exam using the Montreal Cognitive Assessment Test (MOCA) and general neurological exam. I also reviewed all of their TBI records and suggested any further management. Almost every veteran had a diagnosis of PTSD and was taking one or more anti-depressant/anti-anxiety medication. Almost all had subjective symptoms of memory loss, slow thinking, depression, and anxiety, along with recurrent headaches and trouble sleeping. This was the case in those who had a normal MOCA scores (which we know is not a definitive cognitive test), normal MRI of the brain, and standard and nutritional blood work testing.

Characterizing Trauma

As neurologists, when we hear the diagnosis of PTSD we usually immediately relate this to a series of psychiatric symptoms secondary to some stressful/traumatic emotional event, a common entity in the military. The Diagnostic and Statistical Manual (DSM), fifth edition has criteria categories for PTSD from A-H, with five choices for each (I will only include the five choices for criteria A):

Criteria A: The person was exposed to death, threatened death, actual or threatened serious injury or sexual violence in the following way: 1.) direct exposure; 2.) witness the harm; 3.) learning relative was exposed to trauma; 4.) Indirect exposure; 5.) first responder.

Criteria B: The traumatic event is consistently experienced.

Criteria C: Avoidance of trauma-related stimulation after the trauma.

Criteria D: Frequent thoughts or feelings that began or worsened after the trauma.

Criteria E: Trauma related arousal and reactivity that began or worsened after the trauma.

Criteria F: Symptoms last greater than one month.

Criteria G: Creates distress or functional impairment.

Criteria H: Symptoms not due to medications, drug abuse, or medical illnesses.

Experiences include: Depersonalization (outside observers believe the person is in a dream) and Derealization (things they feel are not real).

As a neurologist seeing many of these veterans, I began to wonder: What is the real pathology: Is it primarily psychiatric, neurologic, or both? Neurologists in general do not treat primary psychiatric disorders. However, we often work with psychiatrists to treat dementia cases that frequently have psychiatric symptoms, such as hallucinations, delusions, and severe depression. These cases may require combinations of anti-anxiety medications, anti-depressants, and occasional antipsychotic medications along with psychiatric consultation and counselling.

High explosive exposure in combat troops make up 60 percent of casualties, and 60 percent of these troops report more than five incidences of blast exposure. PTSD and TBI did not come to widespread medical attention until more recent reports from the US military in Afghanistan (Operation Enduring Freedom) and Iraq (Operation Iraqi Freedom.) This relative inattention to TBI-PTSD comorbidity may reflect the fact that PTSD has been the province of mental health professionals, whereas TBI has been primarily the interest of neurologists, neurosurgeons, neuropsychologists, and physical medicine and rehab specialists. Moreover, the different disciplines approach and understand trauma in fundamentally different ways. Mental health professionals generally understand trauma to mean threat of harm or loss of life associated with extreme fear or horror, whereas neurologists, neurosurgeons, physiatrists, and neuropsychologists understand trauma to mean the result of destructive biomechanical forces acting on the brain and other body parts. Despite these differences, it is critical that mental health and cognitive and physical medicine experts work together in diagnosis and treatment. Ahead I will review several studies demonstrating the overlap between neurological and psychiatric elements in these cases.

Anatomy of a Blast

A recent article in The Lancet Neurology examined brain autopsy specimens from three tissue banks, including five cases from remote chronic blast exposures who died more than six months after injury.¹ All five cases had a diagnosis of PTSD with additional symptoms of headache, insomnia, memory loss, and anxiety; three cases with acute blast exposure who died between four and 60 days after injury; five cases with chronic remote TBI (nonmilitary) without any blast exposure; five cases with overuse of opiates with no TBI; and three control cases with no known neurological disorder. All cases were men with a mean age of 35 years. The reason why cases with overuse of opioids were used was that a few of the blast-exposed military members had died of opioid overuse.

In the five cases with chronic blast TBI, prominent astroglial scarring was identified by a marker of glial fibrillary acidic protein (GFAP) immunoreactivity with astrocytic processes. This scarring was uniquely seen and previously undescribed in tissue adjacent to the CSF (subpial regions), boundaries between gray and white matter, and penetrating cortical blood vessels. One case showed extensive astrogliosis in the hippocampus, and tissue lining the lateral ventricle including the fimbria, thalamus, corpus callosum, fornix and amygdala, as well as cortical regions of dorsolateral prefrontal, anterior and posterior cingulate, entorhinal, parietal and calcarine regions. There was no evidence of amyloid beta using an antibody in any areas of the brain regions studied. The three acute blast exposure cases also showed reactive astrocytes in the subpial glial plate and at the gray/white junction in all cortical samples. GFAP immunoreactivity was also seen in perivascular macrophages in the leptomeninges. Focal axonal damage was noted in all these areas. Two cases with chronic blast exposure and one case of chronic non-blast TBI showed tau tangles and tau immunoreactivity in the entorhinal cortex suggestive of chronic traumatic encephalopathy (CTE) disorder. In the remaining four civilian cases with chronic non-blast related TBI, no astrogliosis pattern similar to the blast exposed individuals was present, nor was any evidence of beta amyloid or tau pathology was evident.

The authors speculate that damage to the pia and penetrating cortical vessels might explain altered CSF flow and headaches. Damage to the U fibres at the gray matter junction at many areas might explain cognitive impairment. Damage to the structures lining the ventricles, which are part of the limbic system and hypothalamus, may account for sleep disorders and memory impairment. Astroglial scarring in the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, anterior insular cortex, amygdala, and hippocampi have been areas reported to be associated with PTSD.

Since blast injuries cause brain damage different from basic TBI, many questions about the mechanisms of the blasts themselves have been raised. At the time of a blast, a conversion of liquids and solids into gas with release of high energy, pressure, and temperature takes place. The rapidly expanding gases compress the surrounding air to form a blast wave that moves outward radially from the explosive core at speeds greater than the speed of sound. The whole body and brain come under intense pressure.^2-4 Following the blast wave, a blast wind reaching hurricane speed hurls objects into its path. This causes a penetrating trauma with further acceleration of the head, causing it to impact against another solid object. These pressure waves disrupt structures with different densities such as borders between parenchyma and blood in the brain and borders between gray and white matter.⁵ The human brain, when structural boundaries are disturbed, responds with astrogliosis resulting in astroglial scarring with structural and functional change. A case control study showed that the number of combat-re;ated mild TBI due to blast exposure correlates with PTSD severity, neurodeficits, and cognitive impairment.¹¹ Roughly 90 percent of combat veterans with greater than five episodes of blast exposure with loss of consciousness reported these medical complaints.

Neuroimaging in PTSD cases without a detailed description of the event such as physical assault or blast injury often show identical abnormalities, but the scientific literature lacks detailed neuropathological information such as cellular and molecular changes in the postmortem brains of PTSD. Neuropath studies of human chronic blast TBI have focused mostly on Tau pathology associated with CTE. In five cases of CTE with blast exposer, three had a strong history of impact TBI.^6-8 Blast waves in animals also cause axonal damage.^9,10 It is not clear how CTE develops, but the type of injury and susceptibility likely play a role.

Until the Lancet study,¹ blast TBI has been termed the “invisible wound.” The reason is that the majority of military members present with impaired neuropsychiatric symptoms but with no established clinical biomarkers. Numerous blastexposed veterans and increasing civilians exposed to blasts are trying to re-integrate into society with a DX of PTSD. Also, when I reviewed the medical records of some veterans who said they were exposed to blasts, many were never recorded in the medical records. This is because many of the blasts occur during or preparing for battle. When the blast occurs, many of the veterans develop transient symptoms and then continue in battle without ever seeing the medics. Also, veterans frequently are exposed to other sources of injury, including sports and motor vehicle accidents often not noted in medical records. Thus, clinical biomarkers are desperately needed to verify brain lesions in these individuals with or without PTSD, to help to strengthen the diagnosis and find a treatment.

In 2012, a team of researchers conducted a case control study to determine if neurological deficits and PTSD in combat veterans are related to episodes of mild TBI.¹¹ The team compared 126 veterans who sustained a mild TBI with one or more episodes of LOC in combat to 21 combat veterans who had mild TBI without LOC. These were then compared to 21 veterans who sustained a mild TBI with LOC as civilians (not in combat). In the combat veterans group with mild TBI, 52 percent had neurological deficits (mostly smell loss), 66 percent had PTSD, and 50 percent had neurological deficit and PTSD. Neurological deficits and PTSD correlated with the number of mild TBI exposures with LOC. The prevalence of neurological deficits or PTSD was greater than 90 percent for more than five episodes of LOC. There was no difference in neurological deficits or PTSD in the combat veterans or civilians with mild TBI with one episode of LOC. Montreal cognitive assessment testing (MOCA) scores were also utilized in this study. Veterans with reduced scores were more likely with TBI and LOC. The study concluded that olfaction was the most frequently recognized neurological deficit along with mild unsteadiness. PTSD was common, the more likely with repeated mild TBI. The study’s limitations are worth noting, because veterans who do not have health issues may not seek care from the VA. The study was also relatively small.

Neurochemical Clinical Data in repetitive TBI: What We Know

In a study published several months ago in JAMA Neurology, researchers studied cerebral spinal fluid biomarkers in Post-Concussion Syndrome (PCS).¹² PCS is defined as symptoms that last greater than three months post-TBI. These include memory loss, headaches, dizziness, anxiety etc. This is the first study to investigate these CSF biomarkers. The researchers elected to study CSF markers such as Neurogranin (NG) which reflects synaptic degeneration and loss^13,14: increased CSF Neurofilament plus Light Protein (NF-L), reflecting injury to large calibrated axons in the white matter.^15,16 PCS has been associated with axonal injury and astrogliosis. Amyloid burden using AB42 and tau burden measuring P-tau was also recorded.

These biomarkers were studied in sixteen male professional hockey players with PCS greater than three months and fifteen normal individuals. Nine of the 16 players had PCS greater than one year and stopped playing hockey. Seven out of sixteen returned to play one year after injury. Time between concussion and LP was four months. Neuropsychological assessments were done at study inclusion and study completion. The study found that the marker NF-L was increased only in players with PCS greater than one year. Total tau and GFAP were equal in all players and controls. AB42 was lower in PCS group but even lower in the PCS group after more than one year. No changes were noted in P-tau or NG markers.

The study concluded that in PCS, increased CSF NF-L and decreased AB42 suggests axonal injury and amyloid deposition in the brain. Measurement of these biomarkers may be an objective tool to access the degree of brain injury in PCS, correlate this with those who develop PTSD and who are at risk for future CTE and neurodegenerative disorders like AD. This information can further help in recommending early retirement or future disease treatment, which can be initiated early.

In another study, researchers studied PTSD and age and their relation to outcome in military blast concussion.¹⁷ This was the first study to provide a longitudinal assessment in acute and chronic stages of military TBI. They compared US military with blast-related TBI (38 cases) to non-blast or TBI military controls (34 cases). All participants returned to duty and did not require evacuation. Participants were evaluated acutely zero to seven days after injury in Afghanistan and again six to 12 months at follow-up in the US. The acute assessment showed heightened post concussive, posttraumatic stress and depressive symptoms along with worse cognitive performance in the TBI cases. At six to 12-month follow-up, 63 percent of participants with TBI and 20 percent of controls had moderate overall disability. The individuals with TBI showed more severe neurobehavioral, PTSD, and depression symptoms, along with more impaired cognitive performance. The study noted that regardless of the measures tested, poor global outcome was driven largely by psychological health measures, TBI status, and age.

This study also had a small sample size and was limited by some mismatch in age and education, and no information regarding treatment during the interval following injury. Nevertheless, the information yielded adds to the growing body of literature underscoring the very high risk of disability in patients with both psychological health impairments and TBI in the military.^18,19 An alternative explanation given by the authors is that the TBI status acts as a surrogate marker for greater combat stress, which is hard to measure in the acute phase following injury, and that it is the combat stress which is the primary driver of adverse outcomes. Previous work in civilian studies has shown vulnerability to poor outcome following TBI in older patients and those with preinjury psychiatric history.^20,21 In absence of direct measures of combat stress and structural brain injury, these possible explanations cannot be resolved.

In 2014, one study examined neuroimaging as well as behavioral and psychological sequelae of repetitive combined blast/impact TBI injury in Iraq and Afghanistan war veterans.²² The researchers studied 34 veterans with and 18 veterans without one or more combined blast /impact related TBI. They used MRI of Fractional Anisotropy (diffusion Tensor Imaging), Macromolecular proton fraction (MPF) to assess brain white matter integrity, FDG PET imaging of cerebral glucose metabolism, and structured clinical assessments of blast exposure to ascertain psychiatric diagnosis, PTSD symptoms, neurologic evaluations, self-report scales of Post Concussion Syndrome, combat exposure, depression, sleep quality, and alcohol use. They also compared these parameters between blast/TBI veterans with and without a diagnosis of PTSD. There were 34 male blast/TBI veterans studied with a median age of 31 years, 13 years of education, and experience in at least one war zone blast or combined blast/impact exposure that resulted in acute TBI. They also looked at 18 non-blast exposure male veterans median age 32 years who reported no lifetime TBI. Notably, no veterans had a history of loss of consciousness greater than 30 minutes, penetrating head wound, seizure disorder, insulin dependent diabetes, diagnosis of schizophrenia or bipolar disorder, other psychotic disorders, dementia, or alcohol abuse. Ferromagnetic medical impacts, shrapnel retention, etc., which excluded MR imaging and seen on CT scan were eliminated from the study.

Compared to non-blast exposure veterans, blast exposure veterans had lower fractional anisotropy (FA) in the genu of the corpus callosum, producing diffuse axonal injury. This structure is commonly affected in impact head trauma. The blast exposure vets also endured more frequent and severe PCS, more severe combat exposure, much higher PTSD symptoms score, higher depression scores, and greater sleep impairment. No focal neuro deficits or smell impairment occurred in either group. MPF values (which measures white matter integrity) was lower in the blast/TBI group and included brain areas such as: internal and external capsules, right superior longitudinal fasciculus, frontal and parietal sub-gyri regions including multiple cortical gray matter regions. Also, the FDG PET showed glucose reduction in the right and left parietal cortices, left somatosensory cortex and visual cortex. This was even worse in veterans with higher exposure to blast injuries with also para-hippocampal involvement. In the blast/TBI group, these different parameters of analysis showed no significant associations. Importantly, the findings did not show any difference in the presence of PTSD in either group using these measuring parameters. This conclusion also eliminates the concept that PTSD is responsible for any of the abnormal parameters measured in this study. The study, however, did suggest that the severity of PTSD was greater in the blast/TBI group.

Similar results were also noted in other studies,^23,24 but other studies did not.²⁵ Possible difference in outcomes has been suggested to be one of the following options:

• Difference in subject characteristics and imaging protocols.
• Time of imaging after blast exposure averages 14 days to nine years.
• The accuracy of FA measurements are known to be sensitive to artifacts in diffusion tensor imaging and statistical analysis.

This study is notable because it represents the first evaluation blast/TBI exposure on brain structures by means of brain mapping. When evaluated against the first postmortem analysis of blast vs TBI and controls,¹ this study is much more reliable.

To make this overall subject even more confusing, a recent study evaluated Microglia activity (resident immune cells of the CNS) white matter integrity in the brain of active and recently retired NFL football players and controls.²⁶ The investigators measured translocator protein 18kDa (TSPO), a marker of activated glial cell response. The players included four active and 10 former NFL participant from across the US and 16 controls matched for age, education, BMI, and sex. The study measured PET TSPO, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural MRI and neuropsychological performance. The mean age of the NFL participants and controls were 31.3 years and 27.6 years. Players reported a mean of seven years since last reported concussion. The PET TSO study showed higher total distribution volume in eight of 12 brain regions examined (increased microglial activity) and increased diffusion tensor imaging (impaired white matter) in 13 players compared with control participants. Regional cerebral volume overall and neuropsychological performance were identical in both groups. This study suggests that brain injury and repair indicated by higher TSPO signal and white matter changes is associated with head trauma from NFL play. Whether these changes are related to future neuropsychiatric symptoms is unclear. Activated microglia has been shown to influence synaptic remodeling and white matter recovery after TBI²⁷ and showing increased activation close to the time of NFL play may demonstrate a relationship between microglial response, tissue structural organization, and symptoms. This suggests a promising basis for PET based imaging methods to measure brain injury and repair.^28,29

What Does All of This Mean for the Neurologist?

The information presented in these recent studies should change the way we think when we see patients with TBI (especially blast or even non-blast related) in the civilian or military world and who carry a diagnosis of PTSD post-injury. As neurologists, we need to suspect structural brain changes to account for cognitive and psychiatric symptoms and not consider PTSD only as a primary psychiatric disorder without anatomical pathology. This is not a condition that psychiatrists alone should manage. This will require a very detailed history from the patient, family members, medical and psychiatric records, including psychiatric history (pre and post injury). Patients who have had TBI and clearly show structural brain damage such as contusions, hematomas etc., with or without focal neurological deficits should be strongly considered to have PTSD as part of the structural brain injury. More common cases in practice are TBIs with normal or minimal neurological findings and relatively normal CT or MRI of the brain. Patients with recurrent TBI with LOC should be even more suspect, as these individuals could have “silent structural brain changes,” with or without the presence of a blast injury.

It’s worth pointing out that a number of biological markers that have been described in this article in various studies are not ready for “prime time,” so to speak. Diffusion Tensor Imaging (which measures axon integrity), PET TSPO (which measures microglial activity), Neurogranin levels in CSF (which measures synaptic integrity), and Neurofilament plus Light Protein in CSF (which reflects injury to large myelinated axons) can all be done, but much more information on these tests in many more TBI patients is needed. In the mean time, we should all keep a high suspicion of these patients with close follow-up, neuropsychological testing as needed, and close collaboration with our psychiatric colleagues. All of this information likely ties in to other future degenerative disorders such as CTE, Alzheimer’s disease, and Parkinson’s disease.

The borderland between neurology and psychiatry is getting closer in TBI with or without blast injuries. We need a large government-sponsored study on TBI to include the military, NFL, and high school football players, and the general public that measures multiple parameters of CSF biomarkers, brain mapping, and continued longitudinal monitoring for as long as it takes to get good feedback. Included, of course, would be neurological, psychological, and neuropsychological evaluations.

Unless this kind of study is undertaken, we won’t be able to determine early-on who is likely to develop PTSD, progressive cognitive impairment, and any one of the neurodegenerative disorders such as CTE, Alzheimer’s disease, or Parkinson’s disease, all of which would likely respond better to early or prevention treatment when available.

Ronald Devere, MD is Director Alzheimer’s Disease And Memory Disorders Center Austin, Texas.

1. Sharon B Shively et al. Characterisation of Interface Astroglial Scarring in the Human brain after blast exposure: a postmortem case series. Lancet Neurology Aug 2016 vol 15 pp 944-953

1. Bass CR et al. Brain Injuries from blast. Ann Biomed Eng 2012. 40: 185-202.

3. Rosenfeld JV. et al Blast related traumatic brain injury Lancet Neurology 2013 12: 882-91

4. Bauman RA et al, An introductory characterization of a combat casualty care relevant swine model of closed head injury resulting from exposure to explosive blast. J. Neurotrauma 2009 vol 26: 841 to 60.

5. Cernak I et al, Traumatic brain injury : an overview of pathology with emphasis on military populations: J Cerebral blood flow and metabolism; 2010; vol 30; 255-66.

6. Omalu B. et al Chronic Traumatic Encephalopathy in an Iraqui war veteran with PTSD who committed suicide. Neurosurg Focus; 2011; 31: E3

7. Goldstein LA. Et al, Chronic Traumatic Encephalopathy in Blast exposed military veterans and a blast neurotrauma mouse model. Science Transl Med. 2012 ; 4: 134 ra60.

8. Mckee AC. Et al. Military related traumatic brain injury and neurodegeneration. Alzheimers Dementia 2014; 10; s242-53.

9. De Lanerolle NC et al, Characteristics of an explosive blast induced brain injury in an experimental model. J Neuropath Exp Neurol 2011; 70; 1046-57.

10. Koliatsos VE et al. A mouse model of blast injury to the brain; initial pathological, neuropathological and behavior characterization. J Neuropath Exp Neurol 2011; 70; 1046-57.

11. Ruff RL et al, A case control study examining whether neurological deficits and PTSD in in combat veterans are related to mild TBI. BMJ Open 2012; 2; e000312.

12. Shahim P. et al. Neurochemical aftermath of repetitive mild TBI. Jama Neurology 2016: 73 (11): 1308-1315.

13. Kvartsberg H, et al Cerebral spinal fluid levels of the synaptic protein Neurogranin correlates with cognitive decline in prodromal AD. Alzheimer,s Dement. 2015: 11(10): 1180-1190.

14. Portelius E. et al Alzheimers disease neuroimaging initiative. Cerebralspinal fluid neurogranin; relation to cognition and neurodegeneration In AD Brain, 2015 ;138(pt11) 3373-3385

15. Zetterberg H. et al. AD neuroimaging initiative. Association of cerebral spinal fluid neurofilament light concentration with AD progression. Jama Neurology 2016; 73(1): 60-67.

16. Skillback T. et al, CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival Neurology 2014;83(21): 1945-1953.

17. Mac Donald C.L. et al, Acute Post-traumatic stress symptoms and age predict outcome in military blast concussion. Brain 2015: 138; 1314-1326

18. Verfaellie M et al, Chronic post-concussion symptoms and functional outcomes in OEF/OIF veterans with self- report of blast exposure. J. of International Neuropsych society. 2013; 19: 1-10.

19. Yurgil K.A. et al. Assn between TBI and risk of post-traumatic stress disorder in active duty marines. Jama Psychiatry 2014; 71: 149-57.

20. Spitz G. et al, The relations among cognitive impairment, coping style and emotional adjustment following TBI. J Head Trauma and rehabilitation. 2013; 28: 116-25.

21. Senathi-Raja D. et al, Impact of age on long term cognitive function one year after TBI. Neuropsychology 2010; 24: 336-44.

22. Petrie E.C. et al, Neuroimaging, Behavioral and Psychological sequelae of repetitive combined blast/Impact mild TBI in Iraq and Afghanistan war veterans. Journal of Neurotrauma 2014 31: 425-436.

23. Macdonald C.L. et al, Detection of blast related TBI in US military Personnel. NEJM 2011; 364; 2091-2100.

24. Morey R.A. et al, Effects of chronic mild TBI on white matter integrity in Iraq and Afghanistan war veterans. Human Brain Mapp. 34; 2986-2999.

25. Smith S.M. et al Tract-based spatial statistics; voxelwise analysis of multi-subject diffusion data. Neuroimaging 2006 31: 1487-1505.

26. Coughlin J.M. et al, Imaging of glial cell activation and white matter integrity in brains of active and recently retired NFL football league players. Jama Neurology Jan 2017: 74;(1); 67-74.

27. Hu X. et al, Microglial and macrophage polarization: new prospects for brain repair. Nat Rev Neurol. 2015;11(1):56-64

28. Ching AS. Et al, Current Paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuro-inflammation and neurodegenerative diseases. Insights Imaging 2012; 3(1):111-119.

29. Venneti S. et al, Molecular imaging of microglia/macrophages in the brain. Glia 2013;61(1):10-23.