ISSUE #010 - Jan 09, 2019

In Pursuit of Resilience

Bruce S. McEwen

Stress, Epigenetics, and Brain Plasticity

Abstract

The brain is the central organ for adaptation to experiences, including those we call “stressors,” that are capable of changing brain architecture as well as altering systemic function via the neuroendocrine, autonomic, immune and metabolic systems. Because the brain is the master regulator of these systems, as well as of behavior, alterations in brain function by chronic stress can have direct and indirect effects on cumulative allostatic overload, a term referring to the cost of adaptation. There is much new knowledge regarding neural control of systemic physiology and the feedback actions of physiologic mediators on brain regions regulating higher cognitive function, emotional regulation and self-regulation. The healthy brain has a considerable capacity for resilience, based upon its ability to respond to interventions designed to open “windows of plasticity” and redirect its function towards better health. As a result, plasticity-facilitating treatments should be given within the framework of a positive behavioral intervention; negative experiences during the window may even make matters worse.  Indeed, there are no “magic bullets” and drugs cannot substitute for targeted interventions that help an individual become resilient, of which mindfulness based stress reduction (MBSR) and meditation are emerging as useful tools.

 

Introduction

The word “stress”, so commonly used in daily discourse, refers to experiences that cause feelings of anxiety and frustration because they threaten our security or push us beyond our ability to successfully cope: “There is so much to do and so little time!”  Besides time pressures and daily hassles at work and home, there are stressors related to economic insecurity, poor health, dangerous, toxic and noisy neighborhoods, and interpersonal conflict.  Much less frequently, there are situations that are life-threatening – accidents, natural disasters, violence – and these evoke the classical “fight or flight” response.  In contrast to daily hassles, these stressors are acute and yet they also usually lead to chronic stress, and may also cause post-traumatic stress disorder (PTSD), in the aftermath of the tragic event.

The most common “stressors” are therefore life experiences that cause us to behave in certain ways.  For example, being “stressed out” may cause us to be anxious and or depressed, to lose sleep at night, to eat comfort foods and take in more calories than our bodies need, and to smoke or drink alcohol excessively.  Being “stressed out” may also cause us to neglect seeing friends, or neglect to take time off to engage in regular physical activity as we, for example, sit at a computer and try to get out from under the burden of “too much to do in so little time.”  Often we are tempted to take medications – anxiolytics, sleep-promoting agents – to help us cope, and, with time, our bodies may increase in weight and develop metabolic syndrome and heart disease.

The brain is the organ that decides what is stressful and determines the behavioral and physiological responses, whether they are health promoting or health damaging.  And the brain is a biological organ that changes under acute and chronic stress and directs many systems of the body – neuroendocrine, autonomic, metabolic, cardiovascular, immune – that are involved in the short- and long-term consequences of daily experiences of living.  What do these experiences do to the body and brain, whether or not we call them “stress”?  This chapter is directed towards promoting resilience to adverse events, defined as “achieving a positive outcome in the face of adversity.”  This article emphasizes how the stress-related hormones can play both protective and damaging roles in the brain and the body, depending on how tightly their release is regulated, and it discusses some of the approaches for dealing with stress in our complex world by discussing interventions to set the body and brain on a health trajectory.  Among these interventions are meditation and mindfulness-based stress reduction that engage the brain-body interconnection while opening “windows of plasticity” that allow the brain to change itself.  But before discussing interventions we shall first consider how the body and brain adapt to their daily experiences.

 

Definition of allostasis and allostatic load and overload

The word “stress,” is ambiguous and has connotations that make it less useful in understanding how the body handles the events in daily life. To understand the balance between adaptation and maladaptation, we introduced a biologically oriented alternative that provides insight into the processes by which the body adapts to daily life.  This, in turn, can lead to a better understanding of how best to intervene, a topic that will be discussed at the end of this article.  There are two sides to this story: on the one hand, the body responds to almost any event or challenge by acutely releasing chemical mediators – e.g. catecholamines that increase heart rate and blood pressure – that help us cope with the situation; on the other hand, chronic elevation of these same mediators – e.g. chronically increased heart rate and blood pressure – produce a chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as strokes and heart attacks.  For this reason, the term “allostasis” was introduced by Sterling and Eyer in 19881 to refer to the active process by which the body responds to daily events and maintains homeostasis (NOTE: allostasis literally means “achieving stability through change”).    Because sustained  or inadequate  allostasis can lead to disease, we introduced the term “allostatic load or overload”2 to refer to the wear and tear that results from either too much stress or from inefficient management of allostasis, e.g., not turning off the response when it is no longer needed.  Other forms of allostatic load involve not turning on an adequate, e.g., cortisol, response in the first place, to which other systems, e.g., inflammation, over-reacts;  habituating or not habituating to the recurrence of the same stressor and thus dampening the allostatic response, leading to more “wear and tear” on brain and body3, 4.

 

Classifying “stress” helps reduce ambiguity

The ambiguity of the word “stress” can be reduced by using the following classifications of types of stress:  good stress, tolerable stress, and toxic stress.

See (http://developingchild.harvard.edu/library/reports_and_working_papers/policy_framework/) for paper related to toxic stress.

“Good stress” is a term used in popular language to refer to the experience of rising to a challenge, taking a risk and feeling rewarded by an often positive outcome. A related term is “eustress”. Good self-esteem and good impulse control and decision-making capability, all functions of a healthy architecture of the brain, are important here! Even adverse outcomes can be “growth experiences” for individuals with such positive, adaptive characteristics.

“Tolerable stress” refers to those situations where bad things happen, but the individual with healthy brain architecture is able to cope, often with the aid of family, friends, and other individuals who provide support.  Here, “distress” refers to the uncomfortable feeling related to the nature of the stressor and the degree to which the individual feels a lack of ability to influence or control the stressor5.

Finally, “toxic stress” refers to the situation in which bad things happen to an individual who has limited support and who may also have brain architecture that reflects effects of adverse early life events that have impaired the development of good impulse control and judgment and adequate self-esteem.  Here, the degree and/or duration of “distress” may be greater.  With toxic stress, the inability to cope is likely to have adverse effects on behavior and physiology, and this will result in a higher degree of allostatic overload.

 

Circadian disruption, allostasis, and allostatic load

The circadian system, which is an essential component of allostasis that maintains homeostasis, is also a source of allostatic load and overload when disrupted6.   Based in the suprachiasmatic nucleus (SCN) of the hypothalamus, the brain’s clock controls rhythms in the rest of the brain and body through both neural mechanisms and diffusible signals such as glucocorticoids.  Biological clocks at the molecular level are present in every cell of the body, and these clocks are synchronized by the SCN directly (by way of neural connections) or, in some organs such as the liver, indirectly through hormonal signals (e.g. cortisol, melatonin) or behavioral outputs (e.g. feeding).   The SCN also regulates the timing of sleep and activity, so that circadian systems regulate rest-activity cycles and keep an organism in synchrony with the external environment.  Indeed disruption of these key homeostatic systems could clearly contribute to allostatic overload.

Reduced sleep duration is associated with increased body mass and obesity in the NHANES study 6 and sleep restriction to 4h of sleep per night increases blood pressure, decreases parasympathetic tone, increases inflammatory cytokines, and elevates evening cortisol and insulin levels and promotes increased appetite, possibly through the elevation of ghrelin, a pro-appetitive hormone, along with decreased levels of leptin6.  Circadian disruption, as in shift work and jet lag, have often been overlooked as a separate yet related phenomenon to sleep deprivation but they have been reported to contribute to obesity as well as cognitive impairment6 7 8.

 

Epigenetics: two meanings that are both important for prevention and treatment

Epigenetics now refers to events “above the genome” that regulate expression of genetic information without altering the DNA sequence.  Besides the CpG methylation described above, other mechanisms include histone modifications that repress or activate chromatin unfolding9 and the actions of non-coding RNAs10, as well as transposons and retrotransposons11 and RNA editing12.   For prevention and treatment, in the spirit of integrative medicine,  it is important to let the “wisdom of the body” prevail and to focus upon strategies that center around the use of targeted behavioral therapies along with treatments, including pharmaceutical agents, that “open up windows of plasticity” in the brain and facilitate the efficacy of the behavioral interventions13.  This is because a major challenge throughout the life course is to find ways of redirecting future behavior and physiology in more positive and healthy directions14.  In keeping with the original definition of epigenetics15 as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage (e.g. think about a fertilized frog or human egg which look similar and what happens as each develop!),  we do not mean “reversibility” as in “rolling back the developmental clock” but rather “redirection”.  

One aspect of epigenetics,  defined as the regulation of gene expression, is assessing the impact of childhood abuse, where increased methylation of CpG residues in the glucocorticoid receptor (GR) promotor resulting in lower GR expression and thus reduced capacity for glucocorticoid-mediated allostasis16 .  Histone methylation has been studied as a mediator of stress-induced repression of genes and the activity of retrotransposons17 whereas acetylation of histones mediates gene activation, as in the action of new rapidly acting antidepressants candidates18.

Even in adulthood, gene expression in the brain continually changes with experience19 and there is loss of resilience of neural architecture with aging20 that can be redirected by exercise21 and possibly by pharmacological interventions22.  Even chronic anxiety, possibly resulting from adverse childhood experiences, can respond to a behavioral intervention in adulthood23.  Indeed, MBSR and meditation increases functional connectivity within the brain and benefit fluid intelligence as well as improving function in aging24, 25   and meaning and purpose in life also has benefits for overall health and cognitive function26, 27.   We shall return to this at the end.

 

The brain as a target of stress

The response of the brain to stressors is a complex process involving multiple interacting mediators that utilizes both epigenetic genomic and non-genomic mechanisms from the cell surface to the cytoskeleton to epigenetic regulation via the cell nucleus.  Resilience in the face of stress is a key aspect of a healthy brain, even though gene expression shows a brain that continually changes with experience28. Therefore recovery of stress-induced changes in neural architecture after stress is not a “reversal” but a form of neuro-plastic adaptation that is impaired in mood disorders and reduced with aging.   Resilience may be thought of as an active process that involves ongoing adaptive plasticity without external intervention29 .

On the other hand, resilience is decreased and vulnerability is increased by adverse childhood experiences (ACE) that lead to “biological embedding” of trajectories of response to stressful life events30  throughout the life course 14 which contribute disproportionately to allostatic overload in the form of physical and mental health disorders over the lifespan31. Evidence from CpG methylation of  DNA indicates the embedded influence of early adversity16.

 

Interventions that change the brain and improve health

Can the effects of stress and adverse early life experiences on the brain be treated and compensated even though there are no “magic bullets” like penicillin for stress-related disorders14?  Depression and anxiety disorders, including PTSD, need to be treated with targeted behavioral therapies, where  pharmaceutical agents are used to open up “windows of plasticity” in the brain and facilitate the efficacy of the behavioral interventions13, 32, 33.   Indeed the goal  for stress-related disorders Is to mobilize internal and external coping resources that can lead to growth, adaptation, and learning to promote resilience and improved mental as well as physical health34,29.

Brain-derived neurotrophic factor (BDNF) is a mediator of plasticity and, while it can facilitate beneficial plasticity (e.g. see35 ), it should be noted that BDNF also has the ability to promote pathophysiology, as in seizures36-38.   BDNF is one of an increasing number of mediators that work with glucocorticoids and excitatory amino acids to regulate plasticity39. Over-expression of BDNF creates a ceiling the prevents further stress induced change while under-expression of BDNF also creates a state of rigidity39-41.  With the limits of too much and not enough BDNF, glucocorticoid actions both facilitate BDNF actions and are facilitated by BDNF in a feed-forward loop that facilitates plasticity42.

 

How the brain gets “stuck”

Depression and anxiety disorders illustrate loss of resilience.  This means that changes in brain circuitry and function, caused by the stressors that precipitate the disorder, become “locked” in a particular state and thus need external intervention.  Indeed, prolonged depression is associated with shrinkage of the hippocampus43, 44 and prefrontal cortex45.  While there appears to be no neuronal loss, there is evidence for glial cell loss and smaller neuronal cell nuclei46, 47, which is consistent with a shrinking of the dendritic tree described above after chronic stress.  As far as reversal of these changes,  there are a few studies which indicate that pharmacological treatment reverses the decreased hippocampal volume in unipolar48 and bipolar49 depression, but the possible role of any concurrent cognitive-behavioral therapy  in these studies is unclear.

Aging is also an example of loss of resilience to the effects of chronic stress, based on studies of the rodent prefrontal cortex20.  What is not clear yet is whether this loss of resilience can be reversed or prevented, although pharmacological studies do indicate some retardation of age-related changes in morphology, neurochemical markers and cognitive function22, 50.   Although not directly addressing recovery of resilience, studies of the beneficial effects of physical activity on the aging brain are revealing the retention with age of the capacity for structural plasticity.

 

Opening windows with physical activity

Regular physical activity has effects not only on the cardiovascular and metabolic systems but also on the brain.   It improves prefrontal and parietal cortex blood flow and enhances executive function51.  Moreover, regular physical activity, consisting of walking an hour a day, 5 out of 7 days a week, increases hippocampal volume in previously sedentary elderly adults21 and this complements another study  showing that fit individuals have larger hippocampal volumes than sedentary adults of the same age-range52.  Regular physical activity is an effective antidepressant and protects against cardiovascular disease, diabetes, and dementia53, 54.  Moreover, intensive learning has also been shown to increase the volume of the human hippocampus, based on a study on medical students55.  See Table 1.

 

Redirecting biological embedding from early life experiences

Along with cardiovascular disease, obesity and substance abuse,  depression is more prevalent in individuals who have had adverse early life experiences (ACE)56.  Compensating for the biological embedding of ACE is  a huge challenge, and the reversal of amblyopia and other conditions by “releasing the brakes” that retard structural and functional plasticity 32 has provided some hope.  BDNF may be a key feature of the depressive state and elevation of BDNF by diverse treatments ranging from antidepressant drugs to regular physical activity may be a key feature of successful treatment57.  Yet, there are other potential applications, such as the recently reported ability of fluoxetine to enhance recovery from stroke58.   However, a key aspect of this new view 33 is that the drug is opening a “window of opportunity” that may be capitalized by a positive behavioral intervention, e.g., behavioral therapy in the case of depression or the intensive physiotherapy to promote neuroplasticity to counteract the effects of a stroke.

 

Potential of fluoxetine, caloric restriction and cortisol as regulators of neuroplasticity

“Opening a window of plasticity” is  consistent with studies in  animal models that shows that ocular dominance imbalance from early monocular deprivation can be reversed by patterned light exposure in adulthood that can be facilitated by fluoxetine, on the one hand,59 and caloric restriction, on the other hand,60 in which reducing inhibitory neuronal activity appears to play a key role.  Investigations of underlying mechanisms for the reestablishment of a new window of plasticity are focusing on the balance between excitatory and inhibitory transmission and removing molecules that put the “brakes” on such plasticity32.

The caloric restriction study also showed that putting cortisol in the drinking water instead of caloric restriction60 was able to open a window of plasticity and enable binocular visual stimulation to correct amblyopia. This may be explained, at least in part, by the key role of  physiologic levels of cortisol in promoting turnover of spine synapses and the important of circadian patterns of glucocorticoid elevation in spine formation and elimination in relation to motor learning and possibly other forms of learning61, 62.

 

Perception based therapy

A new therapeutic approach63 is based upon training older adults in visual perceptual discrimination using Gabor patches that had built-in animation for directed motion64.  Ten hours of training were found to improve on-task perception, and the training also benefitted working memory for a delayed-recognition motion direction task.  Moreover, electroencephalography (EEG) showed that training produced more efficient sensory encoding of the stimuli, which correlated with gains in working memory performance.  This finding fits with other evidence that perceptual training improves the ability to detect signal over noise and thus produces some generalized cognitive benefits.  The authors suggest that there are two fundamental design elements that drive neuroplasticity in this type of intervention, because they personalize training to the capacity of each person and allow abilities to improve over time.  To do so, the training incorporates continuous performance feedback to provide repeated cycles of reward to the subject.   Moreover, training is designed to adapt to the trainee’s on-going performance using psychophysical staircase functions that enhance the challenge in response to accurate performance and reduce it for inaccurate performance.

 

Other top-down therapies that change the brain

Social integration and support, and finding meaning and purpose in life are known to be protective against allostatic load65 and dementia,66 and programs such as the Experience Corps that promote these along with increased physical activity, have been shown to slow the decline of physical and mental health and to improve prefrontal cortical blood flow in a similar manner to regular physical activity26, 67. It should be noted that many of these interventions that are intended to promote plasticity and slow decline with age, such as physical activity and positive social interactions that give meaning and purpose, are also useful for promoting “positive health” and “eudamonia”68, 69 independently of any notable disorder and within the range of normal behavior and physiology.   See Table 1.

 

Mindfulness and meditation

Therapies addressing functional links between brain and body may be particularly effective in treating the range of symptoms associated with many chronic diseases70. Successful cognitive behavioral therapies, which are tailored to individual needs, can produce volumetric changes in both prefrontal cortex in the case of chronic fatigue71, and in amygdala, in the case of chronic anxiety 23 (see Table 1) and in brainstem area associated with well-being72.   Mindfulness-based stress-reduction (MBSR)  has been shown to increase regional brain gray matter density in hippocampus, cerebellum and prefrontal cortex, which are brain regions involved in in learning and memory processes, emotion regulation, self-referential processing, and perspective taking73.  Indeed, enhancing self-regulation of mood and emotion appears to be an important outcome25.  More studies showing brain changes after MBSR have been reviewed very recently74.

In relation to MBSR effects on amygdala volume that accompany anxiety reduction in generalized anxiety disorder (GAD)23, a follow-up  study of symptom improvements followed GAD patients who were randomized to an 8-week MBSR or a stress management education (SME) active control program.  In GAD patients, amygdala activation in response to neutral faces decreased following both interventions, whereas BOLD responses in ventrolateral prefrontal regions (VLPFC) showed greater increases in MBSR than in SME participants. Furthermore, functional connectivity between amygdala and PFC increased significantly pre- to post-intervention within the MBSR subjects, but did not do so in the SME group, at least not to a level that has clinical relevance, based on changes in Beck Anxiety Inventory (BAI) scores. Amygdala–prefrontal connectivity turned from negative coupling, as typically seen in down regulation of emotions, to positive coupling suggesting a unique mechanism of mindfulness involving other components of the complex prefrontal cortex.   These findings suggest that,  in GAD, MBSR training leads to changes in frontolimbic areas crucial for the regulation of emotion and may do so in ways unique to MBSR75.

Meditation is reported to enlarge volume of the hippocampus and to do so differently in men and women, suggesting to the authors that meditation practices and, most likely, MBSR,  operate differently in males and females76.   This suggestion is reminiscent of very recent work showing sex differences in rats differing in fear responses. During fear conditioning and extinction, the work revealed that, despite no overall sex differences in freezing behavior, the neural processes underlying successful or failed extinction maintenance are sex-specific77.  Given other work showing sex differences in stress-induced structural plasticity in prefrontal cortex projections to amygdala and other cortical areas,78 these findings are relevant not only to sex differences in fear conditioning and extinction but “also to exposure-based clinical therapies, which are similar in their premises to those of fear extinction and which are primarily used to treat disorders that are more common in women than in men.”77

Another domain where MBSR and mediation practices are reported to have positive effects on brain function is in age-related cognitive decline24.  Fluid intelligence declined slower in aging yoga practitioners and in aging MBSR practitioners then in controls25. Resting state functional networks of yoga practitioners and meditators were more integrated and more resilient to simulated damage than those of controls. Furthermore, the practice of meditation was found to be positively correlated with fluid intelligence, resilience, and global network efficiency25.  Moreover, gray matter volume is reported to be preserved in meditators versus age-matched controls79.

 

Conclusions

The brain is the central organ for perceiving and adapting to experiences that we often call “stressors” and it is a plastic and malleable organ that responds to interventions designed to redirect its function towards healthier behavior and physiology.  There has been considerable expansion of knowledge regarding neural control of systemic physiology and the feedback actions of physiologic mediators on the brain regions regulating higher cognitive function, emotional regulation and self-regulation.

The key is to use the wisdom of the body’s mechanisms of allostasis to “open a window for plasticity” of brain architecture and then use a targeted intervention to change the brain in a desired direction, with resulting improvement in brain-body interactions and health.

This new view reinforces two important messages: first, that plasticity-facilitating treatments should be given within the framework of a positive behavioral or physical therapy intervention; and, second, that negative experiences during the window may even make matters worse.  Indeed, there are no “magic bullets” and drugs cannot substitute for targeted interventions that help an individual become resilient. MBSR and meditation are among the new tools for promoting benefiting physical and mental health.  A major challenge is making this approach useful for individuals who have had adverse early life experiences that predispose them to an array of mental, cognitive and physical health problems.

 

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ISSUE #010

On the New Science of Spirit
Image: On the New Science of Spirit

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