Post Traumatic Stress Disorder: Part II

Pathophysiology and Neurobiology of Post Traumatic Stress Disorder

There is abundant evidence that emotional stress structurally affects the body. Post Traumatic Stress Disorder (PTSD) produces substantial changes in the nervous system and our understanding of this is rapidly advancing as technology allows. Multiple neurological and endocrinological systems are affected by psychological trauma. This is a complex topic, there is a vast literature that covers it, this is a brief summary of some findings.

A primary area of pathological activity occurs in the limbic system, and amygdala in particular, which mediates emotional, learning, and memory functions. Essentially, this is where the brain stores information concerning emotional experiences of critical survival value. Dr. R. A. Mory at Duke University/Durham VAMC, found that soldiers with PTSD reacted to combat photos with elevated activation of emotion processing centers of the brain, amygdala, fusiform gyrus and ventrolateral prefrontal cortex compared to soldiers without PTSD.¹⁵ Stored traumatic memories are then activated by emotional excitation, hyper-arousal or cues reminiscent of circumstances surrounding the traumatic event. Specific neuropathways affected are those related to glutamate, excitatory, and the N-Methyl-D-Aspartate (NMDA) receptors which mediate learning and memory. The hippocampus plays a central role in the mediation of psychological trauma and is central to memory formation, fear conditioning, and neuroendocrinological response to stress.

Other involved brain structures include:

1. Medial prefrontal cortex involved in extinction of fear-based conditioning;

2. Orbito-frontal cortex which is involved in social cue recognition; and

3. Anterior cingulate which inhibits inappropriate or irrelevant thoughts, emotions, and the regulation of autonomic functions such as pulse/blood pressure.¹⁶

PTSD also affects the prefrontal cortex structures and correlates with the pattern of symptom expression in the disorder. The dorsal medial prefrontal cortex shows increased activity in PTSD patients. This area is associated with an individual’s sense of self and may account for the disruption to “self ” related psychological structures. The dorsal lateral prefrontal cortex is associated with focus and concentration. Disruptions in these cognitive functions, particularly after trauma-cue triggered hyper-arousal symptoms, are common. Morey found that soldiers with PTSD showed reduced activity and memory performance after shown images of combat, he observed that “People with PTSD often misinterpret things in the environment, reacting to nontraumatic events as it they were an imminent threat. Hypervigilance often leads to difficulty in focusing.”¹⁷

The stress response system is over-taxed in PTSD patients due to chronic sympathetic over-activation. Primary biomarkers are corticosteroids (e.g., cortisol), GABA and platelet serotonin. Work done by Su TP et al found that p11 mRNA levels in peripheral blood cells (PBMC), were lower in PTSD patients than control and that levels for bipolar disorder (BP), major depression (MDD) and schizophrenia (SCZ) were higher, that work suggested that PBMC p11 may serve as a potential biomarker to distinguish PTSD from BP, MDD, SCZ.¹⁸

Work by Zhang L et al, based on experiments, inescapable tail shock in rats, found increased prefrontal cortical p11 and cortisol. Elevated p11 was observed in the postmortem prefrontal cortex of PTSD patients, these findings suggested that traumatic stress, affects expression of p11 by elevated stress-related glucocorticoid hormones. HPA-axis dysregulation appears integral to this process.¹⁹

This dysfunction also appears transmittable to offspring. For example, male children of mothers who were exposed to trauma as children and have a history of PTSD “showed a hyper-reactive cortisol response to stress” that put them at high risk for episodes of major depression.²⁰

This over-stimulation damages many of these brain centers, apparently due to the influx of calcium and glutamate released which may trigger cell death. This neurotoxicity cycle may explain the overlap of symptoms in Depression, PTSD and mild Traumatic Brain Injury, particularly among returning OIF/OEF veterans. These neuropathological changes have been extensively documented by imaging studies that showed structural brain changes, such as lower hippocampal volumes.

PTSD also affects other body systems as evidenced by recent studies demonstrating correlations between active PTSD symptoms and cardiovascular pathology.²¹ Common correlational findings among combat veterans with PTSD include coronary artery disease, myocardial infarctions, hypertension and other cardiovascular symptom.

Developmental Factors

There are multiple associated pre-morbid factors for PTSD: these include a prior trauma history, personality disorders, and a family history of mental illness. However, the factor most predictive of developing PTSD are those associated with the trauma exposure itself; that is, the nature, duration, magnitude, and other criterion A stressor-related factors:

1. The person has experienced, witnessed, or been confronted with an event or events that involve actual or threatened death or serious injury, or a threat to the physical integrity of oneself or others.

2. The person’s response involved intense fear, helplessness, or horror. Note: in children, it may be expressed instead by disorganized or agitated behavior.²²

Animal research has shown that stress induced in newborn rodents can negatively affect their future behavior through the process of epigenetic methylation patterns with the AVP (Arginine vasopressin) gene.²³ This groundbreaking work also demonstrated that a molecular change associated with a persistent hyper-aroused state in an adult animal was induced by behavioral neglect. Discoveries such as these laid the foundation for studying the alteration of molecular mechanisms produced by early trauma that affect later life behavior.

In early life, we are vulnerable to stressful experiences because of the rapid neural development and accompanying bio-circuitry changes which produces alterations in the central nervous system in general and the dynamics of cortisol and neurotransmitters, in particular. This also renders us vulnerable to traumatic injury; PTSD has been diagnosed in children under age six.²⁴

Weber et al found that “high stress load in childhood and before puberty, but no in adulthood, was related to negative effects …depressive and posttraumatic symptoms…” They concluded that their findings supported the hypothesis of “stress sensitive periods during development” this may interact with other vulnerability factors. This supported the idea of childhood as a critical period. Some explanations are offered: “Stress-related enhancement of CRF secretions during sensitive periods of brain plasticity in childhood and adolescence may prompt hippocampal volume loss, or sensitize and alter feedback properties of the HPA axis.” And states that “stress induced hyperactivity operates by way of combined effects of CRF and glucocorticoids, to drive plastic changes in amygdala, hippocampus and the mesocorticolimbic system.” ²⁵

While the pace of neuro-cognitive development slows by the time most reach military age, the late adolescent continues to navigate critical psycho-developmental challenges including critical choices in the development of an adult identity. Trauma at this stage can produce profound alterations on one’s world view, interpersonal functioning, and sense of self. Central to the concept of traumatic injury is the overwhelming nature of the stressor, the helplessness and loss of control it engenders, and the aggregate impact on the stress response system. This chain of events triggers the neuro-chemical cascade which defines acute stress disorder (ASD), the precursor of the post traumatic stress disorder. In most combat actions, individuals are exposed to multiple extreme stressors over a sustained period of time. Multiple exposures and the particularly psychological toxicity of combat environments account for the high rates of PTSD and related stress reactions among combat troops.

The very symptoms identified as pathological in PTSD clinics are often adaptive in the combat environment. Intrusive re-experiencing may represent the mind’s attempt to process and integrate overwhelming events. Avoidance symptoms such as distancing from of painful stimuli, truncation of emotional range, psychological numbing, and the destruction of time (i.e., foreshortened future) all serve to conserve precious mental resources during times of stress. Finally, hyper-arousal symptoms, such as hyper-vigilance and reduced sleep, may keep one acutely attuned and ready to respond to external threats.

Many of the reactions that we label as ‘symptoms’ of PTSD when soldiers come home are, in fact, adaptive skills necessary in combat that soldiers must turn on again when they return for their next deployment.²⁶ There is increasing attention on the protective factors in combat and emotional resilience in the face of trauma. Whereas soldiers of the past had little involvement or understanding of their role in the broader context of combat, the current focus is on understanding of the units objectives, the vital importance of the soldier’s individual role, and unified commitment to the overall mission. This engenders a greater sense of control and lends meaning to the combatant’s service.

To promote these protective factors among its troops, in 2008, the US Army launched the “Comprehensive Soldier Fitness Program.” This is a structured, long-term assessment and development program to built the resilience and enhance the performance of every soldier, family member and DA civilian. This systematizes emotional resilience training for combat troops.

Brigadier General Rhonda Cornum is the new Director of Comprehensive Soldier Fitness. According to the program, soldiers have to work on the “Five Dimensions of Strength.”

1. Physical

Performing and excelling in physical activities that require aerobic fitness, endurance, strength, healthy body composition and flexibility derived through exercise, nutrition and training.

2. Emotional

Approaching life’s challenges in a positive, optimistic way by demonstrating self-control, stamina and good character with your choices and actions.

3. Social

Developing and maintaining trusted, valued relationships and friendships that are personally fulfilling and foster good communication including a comfortable exchange of ideas, views, and experiences.

4. Family

Being part of a family unit that is safe, supportive and loving, and provides the resources needed for all members to live in a healthy and secure environment.

5. Spiritual

Strengthening a set of beliefs, principles or values that sustain a person beyond family, institutional, and societal sources of strength. More information can be found at: http://www.army.mil/csf/resources.html

These efforts, in conjunction with the concepts of “post traumatic growth” described by R.G Tedeschi and L. Calhoun (1996)²⁶ and the “salutogenic” effects of stress described by Antonovsky ²⁷ have marked the frontier in promoting successful adaptation to combat stress. These factors were observed and promoted decades earlier when Viktor Frankl ²⁸ observed in concentration camps that a person can grow, mature, and become more competent in response to trauma. Indeed, the US military promotes resilience and the expectation of successful post combat-adaptation with its “Battlemind” training module. In this way, contemporary combat psychiatry is seeking to minimize the psychiatric casualty rates.

Prognosis

Though some in the field conceptualize PTSD as a stalling of the natural recovery process, our experience has shown that combat related PTSD tends to be a chronic condition, with resulting ebbs and flows of symptoms and accompanying impairments. However, with successful treatment, the majority improve to the point that they are able to function with varying limitations in social and vocational activities. Of the remaining sufferers, some members of this group do completely recover and a minority tends to get worse to the point that co-morbidities of substance abuse, depression, and suicide are common.

Axel and colleagues studied the natural course of PTSD in a prospective sample of adolescents and young adults where 48% (N=2,548) respondents did not remit after 34–50 months, they were more likely to have higher symptoms at baseline and likely to suffer subsequent traumatic events.²⁹ They concluded that PTSD is often a persistent and chronic disorder, that specific symptoms, especially avoidance, might be associated with the chronic course, and that the occurrence of subsequent traumatic events differentiate cases with a chronic course from those with remission.

Ardelt, Landes and Vaillant³⁰ followed WWII veterans into their 80s, they were exposed to heavy combat at a young age, they found that the exposure had a detrimental effect on physical health and well being in about half of the studied, half showed signs of stress-related growth at midlife leading to greater wisdom and well being. They experienced ‘generativity’ in middle age, a concept of Erik Erikson. They were able to live their lives with purpose. They suffered less depression and anxiety, and did not abuse alcohol as the other half or even the sample that was not exposed to combat. They chose to open themselves and developed compassion for the suffering of others. The authors stressed the need to treat the group negatively affected to prevent complications: depression, anxiety alcohol abuse, etc., later in life.

Zakoyriashin studied those with favorable and unfavorable outcomes at the acute and chronic stage. Prognostic factors associated with poor outcomes were affective tension, impulsivity, high personal anxiety and depressive tendencies. They used these variables to predict longer term outcomes (two-four years) reliably in 85% for favorable and 79% for “protracted” types. ³¹

In our clinic, which treats all veterans from Gulf War I back to WWII, the delayed onset subtype of PTSD is common. We typically see a patient for the first time around retirement age. The modal dynamic involves the cessation of the structure and distraction of working life which supplanted reflection on the war and suppressed the manifestation of symptoms. This often coincides with additional stressors (loss, medical illness, and developmental adjustments) which may prompt symptomatic expression.

Similar observations were made by one of the authors during a visit to Veterans in Holland. Retirement and “the life review process of old age can also increase vulnerability to the development of PTSD for the first time, exacerbation of an existing condition, or relapse.”³² See Figure 1.

Figure 1.

Wounded tended in the field. Chancellorsville, May 2, 1863

Source: National Archives

Treatment

Though there is no single superior treatment for PTSD, a combination of pharmacological and psychological modalities are used with fairly good results.³³ There are also promising surgical advances, such as Stellate Ganglion Block (SGB). According to Lipov, SGB reverses changes in nerve growth factor that augments the production of norepinephrine which is related to the expression of PTSD symptoms. ³⁴ Early reports suggest that results are immediate and can be expected to last from three to seven months. ³⁵

Overview of Contemporary Psychological PTSD Treatments

Most PTSD treatment models are individually designed therapies, though group formats are being developed and tested. In addition to these newer therapies, most trauma treatment programs rely heavily on group therapy applications. While a gold standard group therapy has yet to be identified, the literature consistently demonstrates favorable outcomes in group psychotherapies for PTSD, regardless of treatment type. ^{36, 37, 38} In general, groups function more effectively when applied to homogenous traumas (e.g., rape, combat, etc.).

PTSD symptoms generally result from a failure to inhibit trauma-related fear structures and the consequent alterations in world view following traumatic experiences. These symptoms most often abate over time, though in a proportion of trauma victims, the distress morphs into a constellation of symptoms resulting in the disorder of PTSD. Though there are many effective approaches to treating PTSD, the literature has decisively concluded that exposure-based models produce superior outcomes relative to other trauma treatments. While there are many variants of therapies based partially or entirely on exposure principles, the fundamental process and desired outcomes are similar. In short, exposure therapies work on the principle of “facing one’s fears” in order to promote extinction, habituation, and integration. However, this occurs in a systematic and controlled manner which promotes desensitization to the feared memories/stimuli, reduces fear-based avoidance, and addresses the cognitive and perceptual alterations in world view and subjective meaning of the experience. Specifically, this process aims to extinguish the fear and subsequent avoidance associated with internal (e.g., intrusive re-experiencing) and external (e.g., environmental triggers) traumatic cues. While this distress often takes the form of anxiety, other affective responses are commonplace and require clinical attention. Examples include associated reactions such as anger and grief, or a disconnection from one’s emotional experience (i.e., psychological numbing or dissociation). When these treatment elements are effectively executed, the trauma is re-processed and individuals are better able to reduce their distress and avoidance, find meaning in their experience, and integrate the trauma. The goal is to help a person live more effectively with their trauma and in the optimal outcomes, show post-traumatic growth.

The two exposure-based therapies currently receiving the strongest empirical support are Prolonged Exposure (PE)³⁹ and Cognitive Processing Therapy (CPT).⁴⁰ The centerpiece of both therapies is imaginal exposure to the individual’s traumatic experience, though PE also adds an in-vivo component to assist in reducing behavioral avoidance. While PE’s primary goal is desensitization of trauma-induced mental fear network, CPT includes a significant cognitive therapy component to address the manner in which the individual construes and attempts to cope with the trauma. More recent evidence suggest that the cognitive restricting component may be the most potent therapeutic agent in the treatment. Despite significant differences in PE and CPT, in general, both models strive for mastery via symptom reduction based on internal control strategies.

Following the Cognitive-Behavioral/Exposure models of the 1980–90s, the so-called “Third Wave” treatments are a leading edge in evidenced-based care for PTSD. A distinguishing feature of the third wave therapies is reconsideration of the role of avoidance and interventions targeting cognitive control. Borrowing from eastern views on human psychology and mindfulness practices, these therapies view attempts to control our inner experience with respect to PTSD symptoms as part of the problem rather than the solution. This paved the way for mindfulness-based or acceptance-based therapies such as Acceptance and Commitment Therapy or ACT among others. The core treatment strategy of acceptance-based therapy is the recognition and acceptance of internal experience (e.g., thoughts and feelings), relating differently to that experience, the study of what’s important to that individual, and how to re-invest one’s mental efforts from avoidance towards engagement with life. In contrast to traditional CBT approaches which emphasize increased control as the mechanism of action, the objective here is to relinquish control and embrace acceptance. The goal of treatment is to reduce distress by neutralizing avoidance-based control strategies and committing oneself to value-based action in order to promote change.

Additional contemporary therapies utilizing an exposure platform include Eye Movement Reprocessing and Desensitization (EMDR) ⁴¹ and more recently developed Virtual Reality Exposure (VRE) which uses virtual reality technology in an attempt to improve upon typical imaginal exposure techniques. This technique offers a close to in-vivo experience as can be safely and ethically possible. These methods offer some unique approaches to both accessing and processing traumatic material. While EMDR is deemed efficacious, questions remain concerning the role of the eye movements in treatment response. Early VRE studies show some promise though remain in development.⁴²

For PTSD patient populations, group therapies offer advantages to leverage recovery and change. These include therapeutic multipliers such as social cohesion, support, hope, empathy and social modeling. Some popular group formats include Existential Models⁴³, Milieu Models^44, Motivation Enhancement which incorporates stages of change and motivational interviewing theory⁴⁵, and adaptations of CBT-based individual therapies (e.g., CPT) to group settings.

Increasingly, research is revealing similarities in the underlying nature of PTSD which is bridging schools of thought regarding treatment. These trans-diagnostic system are distilling evidenced based practice models to identify common intervention principles which can then be flexibly applied to meet the treatment needs of the individual ^46,47 The tremendous political and scientific interest in PTSD promises continued rapid development of our knowledge base and therapies.

Pharmacological Therapies

We continue to explore pharmacological approaches to PTSD treatment. The primary role in treatment is alleviating the disorder’s most problematic primary symptoms (e.g., anger, insomnia, anxiety, etc.) and co-morbidities (e.g., depression). However, there is no universally effective treatment regimen in PTSD care and treatment must be individualized. This requires flexibility and patience from the doctor and patient. SSRIs show superior evidence for efficacy and tolerability and as such, are considered first line agents. Zoloft and Paxil are the only two FDA-approved SSRIs for PTSD, though virtually all of the SSRIs are used off-label with side effect profiles guiding treatment planning. Other classes are employed specifically for their secondary effects. For example, the leading complaints among PTSD veterans are anger and sleep disturbance. Sleep impairment in PTSD is multifaceted and may be due to nightmares, conditioned sleep aversion, psycho-physiological insomnia (e.g., secondary to anxiety/hyperarousal), or as a symptom of depression. Accordingly, some antidepressants with sedating side effect profiles, such mirtazepine (Remeron) and trazodone (Desyrel), may be used to good effect as soporifics. However, with trazodone, the potential for priapism must be considered. Newer prescribing trends recommend beginning treatment with two concurrent antidepressants; for example, combinations of mirtazepine and bupropion, mirtazepine and fluoxetine, or mirtazepine and venlafaxine have been more effective treating depression than when used alone. Ongoing research will determine if these combined therapies will prove efficacious in PTSD treatment.

Standard hypnotics are also used to address sleep disturbances though tolerance-based reduced effectiveness with chronic use may limit their effectiveness in regimens for those with chronic PTSD. Others use Prazosin, an alpha1-adrenergic blocker, to treat nightmares and hyperarousal, with doses ranging from 2 mg to 15 mg nightly. Cognitive behavioral treatment for Insomnia and Imagery Rehearsal therapy (IRT) for nightmares has been used with good results. Sleep apnea presents as a significant co-morbidity in many of our patients and effective CPAP or similar treatment has improved sleep quality and associated symptoms (nightmares, depression, etc.) in this sub-population.

Minor tranquilizers, such as clonazepam (Klonopin) and diazepam (Valium) may be employed to address anxiety, agitation, anger/irritability, insomnia and other sympathetic arousal dysfunction. Though some believe that are not indicated for this population, in practice, many patients cannot function without them.

This topic is addressed by Roth.⁴⁸ recommends that the guidelines be based in a wider research base and “to give more weight to the experience of the significant minority of clinicians who continue to prescribe this medication.” Major tranquilizers such as risperidone (Risperidal), quetiapine (Seroquel), and olanzapine (Zyprexa) are also frequently employed to treat persistent/ intense anger or high violence potential, agitation, and insomnia. Some of our patients have also reported nightmare suppression with some of these agents.

A review of the literature on valproic acid use in PTSD by Adamou et al⁴⁹ found that the limited evidence base suggests that valproate can be effective as a monotherapy for the treatment of both PTSD and mood symptoms. However, mood stabilizers were not found to be effective in children and adolescents.⁵⁰ Regarding the use of anticonvulsants, Ravindran and Stein⁵¹ in their review, concluded: “What is striking about the results of trials using anticonvulsants in PTSD is the lack of consistent results.” They cited as contributing elements the lack of controlled studies, they excepted work done by Davison on tiagabine. At present no statements can be made supporting or denying the efficacy of this medications given the limited sample sizes.

In terms of prescribing patterns, using VA data from 2004, Somaia et al⁵² found that older veterans with PTSD received 83% antidepressants, 61.2 % anxiolytics-sedative/hypnotics, and 32.9% antipsychotics. They reported prescriptions tended to decrease with age and thus observed older veterans in particular tended to receive conservative cautious treatment to the point that this may reflect some degree of under treatment. Patients whose injuries were treated with Morphine during trauma had a reduced risk of developing PTSD, suggesting that peri-traumatic morphine may have a protective effect.⁵³ Others are studying propranolol, neuropeptide Y, or interleukin-6 in hopes of finding similarly trauma-protective agent.

Studies with large samples, double blind, in homogenous populations are required to evaluate with reliability and confidence drugs that can be used safely to treat this illness.

Memory reconsolidation research provides a possible powerful tool to deal with the traumatic memories that are at the core of PTSD. Medina described the work of Schiller et. al. where blocking fearful memories by “updating” them with positive information, helps to deal with “toxic emotional memories.”⁵⁴

Conclusions

Encompassing all treatment approaches is the existential reality that all humans face, which is nothing short of the meaning of life and death. Trauma punctures our emotional defenses and transforms the manner in which we fundamentally perceive and relate to our inner and outer worlds. Having faced and seen the horror of war and the face of death, many of our veterans with PTSD present as affectively hollowed, apathetic, socially alienated and often, self-destructive. Consequently, patients frequently report feeling empty, alienated from themselves and others, having no purpose in life, and a sense of existential angst that transcends typical depths of common depressive conditions. These patients cannot be reduced to syndromes that can simply be ameliorated with pills or simple behavioral therapies. As human beings they need to heal their emotional injuries, regain a sense of meaning, and find their place in the world by reconnecting with their families, communities, and country.

We have observed numerous times how their condition improves when they recognize and accept their responsibilities in life and devote themselves to their fellow human beings. Patients’ greatest strides in recovery often follow their rediscovery of love by accepting the challenge of caring for others.⁵⁵ Indeed, we are well acquainted with these patients’ narratives suggesting that the only reason many of them have for living is the care of others. Viktor Frankl observed similar phenomena in concentration camps during WWII, in that older prisoners who devoted themselves to help others survived while younger and stronger prisoners that were only concerned on their own well-being did not. ⁵⁶

Work by Wheeler et al⁵⁷ confirmed research indicating a significant relationship between well-being and life goal orientation. “Recognition of a framework of purpose,a perspective of progress and a sense of commitment significantly differentiated between people who scored high and low in well being.” Regarding stress buffers, Wheeler⁵⁸ found four “true” buffers among 22 variables. They were: sense of competence, exercise pattern, sense of purpose and leisure activity. The variables Coherence, Sense of Purpose and Effectence contributed most to Total Well Being and Happiness scales.

Life-Esteem reflects the view that a person has of a major goal that provides a sense of purpose, this is an extension of Frankl’s concept of noogenic meaning. In a study of college students, Wheeler⁵⁹ found that the life goal component of “quality and the value placed on individual goals was significantly different: high performers rated hedonistically oriented goals lower and giving (service, religion, benevolence) type goals higher than low performers”

Not all patients, even with good treatment, can be free from the destructive effects of PTSD. However, we believe that irrespective of therapeutic methods, the practitioner should always remember that we are treating not just syndromes but human beings who should not be denied the opportunity to assume responsibility for their lives, discovering the meaning of the suffering caused by their traumatic experiences and as a consequence, finding purpose and peace in their lives.

“Adapt yourself to the things among which your lot has been cast and love sincerely the fellow mortals with whom destiny has ordained that you shall live.”

-Marcus Aurelius, Meditations, Book VI, 39

Biography

Juan C. Corvalan, MD, Col USAFR, (Ret), MSMA member since 1976, is a psychiatrist at the St. Louis VA Medical Center, an Emeritus Assistant Professor at Washington University School of Medicine, and serves on the Missouri Medicine Editorial Board. This is the second in a two-part series. Part I and the first 14 references appeared in the July/August 2011 edition of Missouri Medicine.

Contact: Juan.Corvalan@va.gov