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How can we begin to design interventions to promote resilience, study their relative effectiveness, and implement them accordingly?
To Recognize the role epigenetics in resilience after trauma, in both individuals who experience trauma and their descendants.
After participating in this activity, you should be better prepared to:
1. Understand how various mechanisms of epigenetics can potentially contribute to transgenerational transmission of resilience.
2. Discuss the various interpretations of the American Psychiatric Association’s definition of resilience.
3. Review the different treatment modalities that could prevent transmission of trauma.
4. Understand the potential variables that either strengthen or weaken an individual’s resilience and positive health outcomes.
This continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.
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Traumatic events are quite common; the lifetime prevalence is 71% among the general population.1 The fear, grief, social isolation, and loss associated with COVID-19 are all potentially traumatic. The ongoing pandemic makes the study of resilience mechanisms after catastrophic experience all the more timely, since what is true for the pandemic experience may be true for any traumatic experience that causes long-term isolation and helplessness. Based on the epigenetic mechanisms that promote transgenerational transmission of resilience, a growing body of research points the way to promising clinical and public health interventions. By applying what we are learning about the potential biopsychosocial mechanisms for transgenerational resilience, we can begin to design interventions to promote resilience, study their relative effectiveness, and implement them accordingly.
According to a study by Benjet et al, approximately 70% of people worldwide will experience at least 1 traumatic event during their lifetimes, with 30.5% reporting more than 4 incidents.2 However, only 6% develop posttraumatic stress disorder (PTSD) or other trauma- and stressor-related disorders.3 Traumatic events such as threats to one’s life, natural disasters (including the current pandemic), exposure to war and conflict, torture, discrimination, and decimation of communities serve as brutal reminders of our past. However, a clear resilience to such stressors enables the individual to thrive in spite of hardship and social isolation, as well as to endure the memories of these ordeals. The offspring of such survivors have been shown to thrive and they are often better adapted and more resilient than the previous generation.4-8 Awareness of potential epigenetic mechanisms may help to guide clinical and public mental health interventions to ensure that future generations are better equipped to avoid trauma- or stressor-related disorders.
Epigenetics is the study of heritable changes that occur without directly altering the nucleotide sequence of a genome. Various epigenetic processes function to determine an individual’s phenotype and control the expression of various proteins and their corresponding functional pathways. Epigenetic mechanisms of transmission include CpG islands (sites in the genome containing large numbers of CpG dinucleotide repeats), histones, and noncoding RNA. Methylation, the process of adding or removing a methyl group (–CH3), can occur at CpG islands and on histone proteins. In addition, histones can be altered in a variety of other ways, including acetylation, ubiquitination, phosphorylation, and the addition or removal of various sugars. These modifications alter the capacity for further transcription factors to express a gene.
Exposure to traumatic events can produce long-term epigenetic changes in consistent regions of the genome. Epigenetic modifications during episodes of trauma have long-term effects on glucocorticoid receptors, adipose tissue, the hypothalamic–pituitary–adrenal (HPA) axis, hippocampus, and amygdala.9 A combination of these factors may influence not only an individual’s own phenotype, but also how that individual and their offspring will respond to further stressors in life.10-15
Epigenetic Changes in Plants and Animals
The ability to transmit epigenetic changes caused by trauma has been seen within both plant and animal models.16 Studies by Suter et al showed that plants such as Arabidopsis thaliana can pass on epigenetic changes such as DNA methylation induced by life-threatening heat stress over 3 consecutive generations.17 Migicovsky et al found that when the first-generation (F1) progeny of Arabidopsis thaliana were exposed to the same heat-induced stress as the parental generation, there was a significant decrease in the amount of global DNA methylation. The F1 progeny generation developed larger leaves than the control group but became more resistant to further methylation, despite exposure to the same external stressor as the parental generation.18 Other studies have shown that various sites of DNA methylation within Arabidopsis thaliana remain highly stable across multiple generations.19,20
Animal models using rodents have also shown consistent patterns of transmission across multiple generations. Dias and Ressler showed that rodents conditioned with a fear response to acetophenone gave birth to F1 and F2 (second-generation) offspring exhibiting similar fear behaviors. They determined that a persistent CpG hypomethylation of the Olfr151 gene was largely responsible for the transgenerational inheritance of these behaviors.21 Exposure to social stressors has led to impaired rodent maternal behaviors across several generations, leading to offspring that consistently produce abnormal amounts of cortisone, oxytocin, and prolactin.22 These findings are consistent with hormonal changes in human families who experienced similar adverse stressors.23
Resilience and Posttraumatic Growth
Resilience is often cited as a key factor in preventing adverse changes in personality or affect in reaction to stressors experienced in one’s life.7,24-26 The American Psychiatric Association (APA) defines resilience as the ability to adapt in the face of adversity, trauma, tragedy, threats, or significant stress.27 Various interpretations of the APA’s definition have included an absence of psychopathology, an ability to return to homeostasis unimpaired by the traumatic event, or adaptive responses after exposure to adversity.28-31
Some researchers have highlighted a combination of core, internal, and external resilience factors that can also contribute to how one succeeds in life.32 Core resilience is largely defined by one’s genome. Internal resilience, on the other hand, is distinguished by learned and shared behaviors that can be influenced by family, friends, and life experiences. These involve the development of healthy behaviors such as autonomy, self-control, hardiness, toughness, coping style, past experiences, resourcefulness, social competence, and grit. External resilience focuses primarily on socioecological factors, such as support from one’s community and access to social and health care services. Recognizing the different ways in which resilience can manifest and understanding these manifestations in multifactorial terms is the best method of combating and resisting traumatic adversity.32 Standardizing measures of resilience and change with respect to trauma has, however, proven to be difficult across disparate events, populations, and generations.
One measure of the impact of trauma on an individual is posttraumatic growth (PTG), which was defined in 1996 by Tedeschi and Calhoun to describe positive effects and transformations due to trauma.33,34 Key components of affect were divided into 5 categories to measure and compare positive change due to trauma in various populations (Table).
Dekel et al published findings measuring PTG in a longitudinal study of 200 Israeli prisoners of war during the 1973 Yom Kippur War. Forty-three male Israeli combat veterans were second-generation survivors of the Holocaust. Dekel measured changes in PTG among both groups of veterans, with data sets collected at 30 and 35 years after the end of the war. The study found that veterans who were offspring of Holocaust survivors scored lower on PTG and had a lower likelihood of developing PTSD than veterans in the control group. A lower score on PTG as well as PTSD symptoms may indicate resilience to change as a result of trauma, whereas the effects of trauma may have been more pronounced in the control group (who were not offspring of Holocaust survivors). Whether a genetic component was responsible was not clear, but the authors proposed it as an area of further study.35
Human Epigenetics and Trauma
Our genome and epigenetics may provide explanations of human resilience in the face of trauma. For example, the FK506-binding protein 51 (FKBP5) is a biomolecule that appears to modulate our reaction to stress and ability to exhibit resilience. The FKBP5 gene encodes a cochaperone for glucocorticoid receptors on chromosome 6 (6p21.31).9,36 Research has shown that behavioral responses to stress are modulated by these cochaperones—as is the HPA axis—and can be affected by factors such as exposure to trauma.37,38 In animal studies, mice with the gene for FKBP5 removed show a stronger resilience to stressors by exhibiting a lowered fear response.9
In another study of Holocaust survivors, Yehuda et al looked at the epigenetic mechanisms of transmission of the FKBP5 gene, focusing primarily on DNA methylation of the CpG sites located in and proximal to intron 7 of FKPB5.39 Methylation of bin 3/site 6 was found to be 10% higher in Holocaust survivors, but methylation of the same bin 3/site 6 was 7.7% lower in the offspring of Holocaust survivors than in the control groups. These findings were consistent when controlling for lifetime PTSD in the offspring and for possible childhood trauma. The 30-year age difference between the parents and their offspring could explain the differences in methylation; however, Yehuda et al noted that even a 1% to 2% difference in gene methylation can significantly alter gene expression.39 Furthermore, the study of Miller et al showed that methylation of specific CpG sites of FKBP5 was correlated with both PTSD severity and resilience.40 Greater methylation of the CpG site cg07485685 decreased PTSD symptom severity while increasing resiliency scores measured via the Brief Resilience Scale. A PTG inventory was also used to measure any positive changes as a result of trauma. Lower levels of PTG after trauma were associated with methylation of the same CpG site cg07485685 on FKBP5. These findings are consistent with the lower scores on PTG and lower levels of PTSD found in the study of Dekel et al in 2013.35,40
Genes that are responsible for regulation of the HPA axis may also confer resilience to trauma. For example, multiple studies have found that childhood trauma and mistreatment are a risk factor for methylation of the human glucocorticoid receptor (NR3C1) gene and changes to the HPA axis.41-43 The amount of methylation of NR3C1 in newborn infants has been linked to prenatal exposure to stress.44 For instance, Perroud and colleagues examined the epigenetic changes in pregnant Tutsi survivors of the Rwandan genocide and their offspring. The mothers and their offspring were found to have higher methylation of NR3C1 exon 1F compared with controls.45
Variations in single-nucleotide polymorphisms (SNPs), specifically rs10482672, were also found to increase the risk of psychopathology. Albert et al found that children who were identified as having this genotype were more vulnerable to developing substance abuse and antisocial behavior under adverse conditions, but at the same time were more likely to benefit from advantageous conditions.46 Children were placed in a fast-track program, which fostered the development of emotional regulation, self-control, and other treatments to minimize the effects of harsh parenting and violent environment. Those who received early intervention to reduce risks of developing psychopathology had a significantly decreased risk of external psychopathology via substance abuse or antisocial behavior later in life. Those in the control group, who had SNP rs10482672 but did not receive early treatment, had a higher likelihood of external psychopathology by the time they reached 25 years of age.46 In 2020, Miller et al also found methylation of 5 CpG sites in the NR3C1 gene that were significantly linked with resilience.40 Three CpG sites were correlated with an increased score (indicating higher resilience) on the Brief Resilience Scale, whereas 2 CpG sites were correlated with decreased resilience. Authors in all studies noted the need for larger sample sizes as well as additional longitudinal studies.
Reducing Risks, and Building Resilience
What can be done to prevent transmission of past trauma to future generations? Studies have shown that nonpharmacological treatment of trauma- and stressor-related disorders can induce epigenetic changes in the genome responsible for the HPA axis.23,36 Roberts et al examined the methylation of FKBP5 before and after exposure-based cognitive behavioral therapy (CBT) in patients previously diagnosed with agoraphobia. Those who reported benefits from CBT after completing treatment were found to have lower levels of methylation at a CpG island at intron 7 of FKBP5. The severity of symptoms was reduced by an average of 69.5% in those who received exposure-based CBT, which correlated with the decrease in methylation. Individuals who reported little change from CBT were found to have either no significant changes or even increases in methylation of CpG islands at intron 7 of FKBP5. The authors believed that FKBP5 may play a part in susceptibility to various environmental stressors.47,48
Bishop et al found similar results in patients with PTSD who received mindfulness-based stress reduction interventions. These patients showed levels of methylation of intron 7 of FKBP5 significantly different after intervention compared with initial levels. Those who responded to treatment, as indicated by a 10-point drop in PTSD severity via a PTSD checklist, had significantly decreased levels of methylation, whereas those who did not respond to treatment showed higher levels of methylation in a different site at bin 2 of FKPB5.49 Mindfulness and techniques that encourage thought and understanding, such as CBT and storytelling, might enhance resilience to trauma for the benefit of future generations (Figure 1).50
Family and community play a strong role in enhancing an individual’s resilience. Fundamental building blocks for resilience include a secure foundation and promotion of self-esteem and self-efficacy.51 Strong bonds with caregivers and shared values and religious beliefs that find meaning in suffering are protective against adverse effects of trauma in children. Longitudinal studies of the effects of social relationships have found that support from family, friends, colleagues, and community leaders leads to a reduction in psychological distress, as well as a more rapid recovery from the effects of trauma.52,53
Likewise, the World Health Organization has found that the arts have contributed to the improvement of public health. Music, art, dance, and communication through storytelling about past events at an early age not only reduce anxiety but also protect against cognitive decline later in life. Exposure to and involvement with the arts “trigger psychological, physiological, social, and behavioral responses” associated with positive health outcomes that may be linked to heritable epigenetic changes.54
Exercise has long been associated with various health benefits and has been documented to be valuable for regulating reactions to stress, sleep, and resilience to mood disorders.55-58 In animal models, exercise serves a protective role in lowering the rates of depressive and anxiety-related behaviors in socially isolated prairie voles.59 Mice who exercised via long-term wheel running had increased levels of galanin, a neuropeptide that has been linked to stress resilience as well as the regulation of norepinephrine and other products of the HPA axis.60 Long-term exercise in mice was also consistent with a significant increase in stress resilience, inducing methylation of NR3C1 and downregulating noncoding RNA such as microRNA-124 in areas such as the hippocampus.61 Epigenetic changes as a result of exercise improved cognition in the mice of the parental generation as well as subsequent offspring.62,63
Findings in mice have correlated with findings in human studies, as mothers who exercised regularly before and during pregnancy had offspring who achieved higher levels of academic performance, excelling in language and math and having higher overall grade point averages.64,65 Other factors, such as shared environments and positive parental influences, may have played a part in the success, but they do not account for epigenetic differences in DNA seen at birth. Regular moderate exercise seems to confer a protective effect that enables future generations to adapt to and thrive in their new world.
Patients diagnosed with trauma- and stressor-related disorders show evidence of dysregulation of their HPA axis, resulting in persistent personality changes.66-70 The diagnosis of Enduring Personality Change After Catastrophic Experience (EPCACE) is defined as an enduring personality change lasting at least 2 years that a patient experiences following a catastrophic stressor (ICD-10). Thus, the presence or absence of a diagnosis of EPCACE may serve as a predictive factor for resilience and vulnerability in the face of trauma.71 Long-lasting epigenetic changes may present themselves as enduring changes in personality.72 Those diagnosed with EPCACE often are socially isolated, fearing the stigma of their suffering. This may lead to a vicious cycle by which epigenetic effects are compounded and changes further solidified until a persistent and permanent change in personality has taken place (Figure 2).73-76
As the COVID-19 pandemic waxes and wanes and the fear, grief, and stress of the pandemic itself and preventive social isolation measures take their toll, it is paramount that we identify the most trauma-vulnerable patients and populations early on. Individuals diagnosed with PTSD and other trauma-related disorders are heritably linked to autoimmune diseases, dementia, schizophrenia, bipolar, and major depressive disorders.73,74 Chronic stress and isolation continue to be correlated with increased risks for anxiety and depression, leading to higher rates of infection and early mortality.75
Fortunately, those who are most vulnerable to isolation and demoralization are often most likely to benefit from preventive intervention,46 the need for which is all too evident in our current circumstances. At the same time, there is a lack of transgenerational studies of, and a dearth of instruments to reliably study, the effectiveness of interventions to promote resilience in communities.
With the COVID-19 pandemic coming to an end, it is time to apply what we know about potential biopsychosocial mechanisms for transgenerational resilience in order to design alternative interventions to promote such resilience. We can then study the relative effectiveness of such interventions and support those that are most effective, in keeping with considerations of social justice and equity. Otherwise, even as we win the battle to defeat COVID-19, we may lose the transgenerational war to preserve healthy postpandemic resilience.76
Mr Tang is a second-year medical student at Pacific Northwest University Health Sciences. Dr Tanaka is an assistant professor of psychiatry in the Oregon Health & Science University (OHSU) School of Medicine. Dr Bursztajn is the cofounder of the Program in Psychiatry and the Law at Harvard Medical School and President of the American Unit of the UNESCO Bioethics Chair (Haifa). He is the coauthor of Medical Choices, Medical Chances: How Patients, Families, and Physicians Can Cope with Uncertainty (1981/1990). He practices clinical and forensic psychiatry and risk management in Cambridge, Massachusetts.
The authors thank Raquelle Mesholam-Gately, PhD, and Anthony Cunningham, PhD, for their thoughtful reading of an earlier draft.
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