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Excerpted from Mind-Brain-Gene: Toward Psychotherapy Integration by John B. Arden. The following is from Chapter 4, “The Body-Mind and Health.” Used with the permission of the publisher, W. W. Norton & Company.

“Think with your whole body.” —Taisen Deshimaru

Anna and Michael had been married for seventeen years when both began to complain that the other no longer focused on the rest of the family. They spent an inordinate amount of time ruminating resentments about each other. Meanwhile, their two children were entering the first few years of high school and presenting new challenges for their parents. Both Anna and Michael felt they didn’t have the energy to keep up with the constant attention needed to maintain clear limits and expectations for the kids. Though they did not want to admit it, they felt relieved when their kids began to spend more time on their computers, playing video games and on social media. This meant less monitoring was necessary because the kids left the house less, and they began to match their parents in obesity, fatigue, and dysphoric moods.

Perplexed by everyone’s loss of energy, Anna asked their physician whether the entire family had contracted Lyme disease. They felt ill and did not know why. He ordered blood tests for each of the family members. Though there was no evidence of Lyme disease, he expressed concern that they all had become significantly overweight. He also reported that both Anna and Michael had high levels of C-reactive protein (a measure of inflammation), blood glucose, and LDL (bad) cholesterol. Anna had developed type 2 diabetes, and Michael had metabolic syndrome (a cluster of conditions—increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels that includes that occur together, increasing the risk of heart disease, stroke and diabetes). Anna responded by saying, “We were already very depressed! Now you are telling us we have bad genes? That makes me even feel worse.” Michael agreed. In response, their physician prescribed Prozac for both of them. With this medication Band-Aid their physician missed the opportunity to offer comprehensive health care and refer them to therapists to avert disastrous long-term mental and physical health. Though he started the consultation constructively by warning the entire family about their weight and both parents of their looming illnesses, the integrative approach they needed was compromised by the quick fix of “mismanaged” care.

What role should psychotherapy play in helping this family? Psychotherapy in the twenty-first century could be renamed “behavioral health,” because self- care behaviors have major effects on the immune system, the brain, and the body in general. These interactions have a profound effect on mental health. It is this relationship that is explored in this chapter.

Behavioral Health

Anna and Michael’s family has become the new norm. There are now overwhelming numbers of people like them throughout the developed world. Plagued with health problems brought on by poor physical and emotional self-care, they suffer bidirectional causal pathways between acquired physical and psychological impairments.

The Centers for Disease Control estimates that health behaviors account for 50 percent of adverse health outcomes in the United States— as much as genetics (20 percent), the environment (20 percent), and access to health care (10 percent) combined. These statistics suggest that half of all health conditions are preventable by changes in self-care behavior. Research has found that 40 percent of medical patients have a comorbid psychological disorder, while 75 percent of patients with a psychological disorder also suffer with a comorbid physical disorder. Essentially, health behaviors represent the interwoven natures of physical and mental health.

The number of Americans suffering at least one physical illness is predicted to increase to 157 million by the year 2020. This is a mental health crisis that can no longer be overlooked. Though these statistics are ominous, integrated health care providers, including psychotherapists, can work to avert disaster to the health of millions of people through a better understanding of the bidirectional causal interactions among the mind, brain, and the immune system found in the field of psychoneuroimmunology, and providing approaches consistent with it. Since its emergence as a rigorous field of research, psychoneuroimmunology has identified many interrelated mental and physical health dysregulations. Not so coincidentally, this field of inquiry the emerged with the surge in numbers of people, like Anna and Michael, with chronic and acquired illnesses that dysregulate the immune system who also suffer from psychological disorders.

Because over half the population of the United States unknowingly suffers from self-inflicted immune system dysregulation, psychotherapy in the twenty-first century must promote lifestyle and behavioral health changes. Not doing so is like building a house on a sandbar by a hurricane-swept beach.

The Immune System

To get a better idea how chronic health conditions develop and cause psychological disorders, it is useful to put the immune system in perspective. Just as we are optimally endowed with a stress response system to deal with external danger, such as fighting off or fleeing from a predator, our bodies are protected from pathogens by a dynamic immune system. Whether the threat is from foreign bacteria, a contagious virus, or simply a cut on the finger, your body marshals internal resources to protect its cells and maintain homeostasis. Like the police, fire, and ambulance services combined, the immune system protects the body from external and internal threat. When working optimally it can save your life. When activated inappropriately it can cripple your life.

As a diffuse sense organ scattered throughout the body, the immune system communicates to the brain by both neural (fast) and hormone (slower) subsystems, influencing mood, cognition, and behavior. It comprises two main components: specialized cells that carry out protective functions and chemical messengers that allow those cells to communicate with one another and the rest of the body. The cells and the chemical messengers interact to mediate the location and intensity of inflammatory responses to protect the body from harm.

Chronic stress combined with poor self-care, such as inadequate sleep, impoverished diet, lack of exercise, and extra weight, inappropriately activates the immune system, with damaging effects. Anna and Michael, like millions of other people, acquired chronic conditions that turned their dysregulated immune systems into threats. Their immune systems switched from protectors to overactive enemies triggering autoimmune disorders and a downward spiral of significantly compromised physical and emotional health. Whether in response to adverse childhood experiences or chronic stress, or simply because of poor self-care, autoimmune disorders result in a variety psychological disorders, which then further exacerbate existing autoimmune disorders. To understand how this occurs and how psychotherapists can intervene, it is useful to highlight the multiple feedback systems that make up the immune system.

Specialized cells that carry out protective functions include the lymphocytes, which come in a wide variety of cell types, including B and T cells, produced in the bone marrow and thymus gland, respectively. Macrophages are the general foot soldiers that gobble up threatening bacteria, memory B cells are the snipers trained to attack specific targets, and helper T cells are communication officers, alerting other troops to an invasion. To maintain homeostasis in the body, these cells work together in a precise and coordinated dance choreographed by chemokines and cytokines, chemical messengers that allow those cells to communicate with one another and the rest of the body.

After lymphocytes are born they are tested in the bone marrow and thymus to be exposed to molecules of your body so that they will not attack the body. The ones that bind strongly to “self” molecules are killed off or undergo “editing” in the genes that give rise to receptors. Autoimmune disorders develop when this process fails. Facilitated through cytokines, pathogens are killed while avoiding harm to the body.

When harmful substances enter our body, cells in our immune system called macrophages (big eaters) serve as an immediate defense. These Pac-Men of the immune system detect, destroy, and clear foreign substances from the body. This first response system also includes neutrophils (40–75 percent of white blood cells), which aid the macrophages in killing foreign substances while initiating the inflammatory response. The term inflammation comes from a Latin term meaning “set on fire”; inflammation serves as a protective mechanism so that the healing processes of tissue repair can begin. For local responses, like a bruise on the knee, inflammation also produces a physical barrier that prevents the spread of infection into the blood stream.

Chronic Inflammation

While short-term inflammation that responds to injury or illness rep-resents a healthy process, chronic inflammation is not. Chronic inflammation represents a common factor among many psychological disorders and poor health. Because it is such a dominant feature, a better under-standing of chronic inflammation will help our efforts to put it under control. In other words, to understand how a healthy system becomes unhealthy so that we can shift it back to healthy again, we need to understand how chronic inflammation gets turned on and off.

Normally, as part of the inflammatory response, infected or damaged cells send out alarm signals via chemical messengers called cytokines that attract and guide specific immune cells to the site of infection or damage. Cytokines (cyto means “cell” in Greek, and kinos means “movement between cells”) are communication substances, proteins released by immune cells that act on target cells to regulate immunity. Cytokines include the interleukins (meaning “between the white blood cells”) and tumor necrosis factor alpha. There are pro-inflammatory and anti-inflammatory cytokines. The pro-inflammatory cytokines (PICs) coordinate inflammatory responses. Anti-inflammatory cytokines, as their name implies, work to dampen the inflammatory response. With chronic inflammation the PICs dominate. Inadequate diet, poor-quality sleep, and lack of exercise as well as stress, depression, autoimmune disorders, and obesity, are associated with excess release of PICs, and thus chronic inflammation. As a common marker of inflammation, a fluid produced by the liver called C-reactive protein (CRP) can be measured in a standard blood panel. One of the findings from Anna’s and Michael’s blood panels was moderately high levels of CRP. While very high levels of CRP are caused by infections, moderately high levels are associated with autoimmune diseases, obesity, and depression. Chronic inflammation represents one of the common factors associated with autoimmune disorders, such as rheumatoid arthritis, lupus, type 2 diabetes, Addison’s disease, Crohn’s disease, and ulcerative colitis. Chronic inflammation is also associated with neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease, and with psychological disorders.

Inflammation and Associated Psychological Disorders

  • Depression
  • Bipolar disorder
  • Autism
  • Posttraumatic stress disorder
  • Cognitive decline

In addition, in children inflammation has been linked to:

  • Tourette’s syndrome
  • Obsessive compulsive disorder
  • Attention deficit hyperactivity disorder

Anna and Michael, along with their kids, were unknowingly stoking up the amount of PICs and offering themselves few opportunities to generate anti-inflammatory cytokines through lifestyle changes. As a result, they were all suffering from chronic inflammation, with its associated fatigue, cognitive deficits, and depression.

When Anna returned to her family doctor for follow-up, complaining that she felt too little improvement, she was referred to me. Initially, she was quite perturbed that I addressed her poor self-care behaviors and associated them with her depression. Her resistance to these factors began to dissipate when I noted that both of her children began developing some of the same symptoms when their self-care matched hers.

The Brain’s Immune System

Chronic inflammation can lead to depression, cognitive impairments, fatigue, and achiness. Brain systems are affected by inflammation that can also perpetuate inflammation. These systems directly affect energy levels, pain, coping responses, and sense of self. So when Anna and Michael complained about lethargy, difficulty generating positive thoughts, depression, and cognitive deficits, inflammation likely played a significant role.

The brain has specialized cells with immune-like functions. Chief among them are the glial cells. Initially glial cells were thought of as the substance that holds neurons together (glia means “glue”) and were erroneously thought to function only as support cells. Glial cells include microglia and astrocytes, which are considered part of the brain’s resident immune cells.

Microglia make up 6–12 percent of all the cells in the central nervous system, where they constantly monitor for potential immune problems. They have many of the same receptors as peripheral macrophages and so can recognize bacteria and viruses. When they detect danger microglia release PICs such as interleukin-1 (IL- 1). Chronic stress and compromised health “prime” microglia so that they make and release PICs more easily when they encounter danger again. In other words, once the immune cells in the brain have been activated, it is more likely that activation will occur in the future.

Astrocytes play a significant role in the immune system by providing a point of interaction between cytokines and neurons via genetic transcription and synaptic plasticity. Astrocytes exchange signals with neurons, detect and react to immune signals, and release PICs, which influence peripheral immune cells. Through this process of monitoring, reaction, and learning, astrocytes can play significant roles in the perpetuation of the inflammatory spiral.

Activation of the inflammatory pathways in the brain adversely affect memory and mood. The excessive release of PICs from microglia and astrocytes in the brain, as well as in the rest of the body, including from fat cells, causes wide-ranging detrimental psychological effects. Overexpressed PICs cause cognitive deficits that involve disturbances in synaptic strength. High concentrations of receptors for PICs are located in the prefrontal cortex and hippocampus, potentiating cognitive impairments, including poorer working memory, episodic memory, and executive functions. This is why Annie and Michael had an executive network “brownout.” For example, excessive IL-1 in the hippocampus has been shown to impair memory by interfering with brain- derived neurotrophic factor (BDNF), which is involved in neural plasticity, neurogenesis, memory, energy balance, and mood.

Because chronic inflammation deteriorates overall health and contributes to cognitive deficits and mood disorders, promoting lifestyle changes that lower inflammation should be a major goal of therapy. For example, given that extra fat cells contribute to chronic inflammation, weight loss should be a major goal—but this also represents a major challenge to building the therapeutic alliance!

The Mental Health Consequences of Excessive Fat Cells

According to the World Health Organization approximately 2 billion people are overweight. Approximately 68 percent of the population of the United States is overweight. As of 2016, 35 percent of men, 40 percent of women, and 17 percent of children and adolescents were obese—the United States leads the world with this pandemic. Obesity contributes to many other chronic health conditions strongly associated with psychological disorders. On average, obese people over 40 will die 6 to 7 years earlier than non-obese people. And those fewer years are marked by cognitive deficits and emotional dysregulation. Obesity shortens telomeres more than smoking.

Being overweight or obese causes a systemic feedforward breakdown in multiple homeostatic pathways, including a condition referred to as leptin resistance, further fueling obesity and rising cortisol levels (New-comber et al., 1998). Obesity also causes inflammation, which in turn increases the risk of illnesses like autoimmune disorders, coronary heart disease, stroke, hypertension, sleep apnea, and type 2 diabetes. These physical illnesses are all associated with depression, anxiety, and cognitive impairments.

The Centers for Disease Control and Prevention defines obesity as a body mass index (BMI) over 30. Independent of age, BMI is inversely associated with a range of cognitive impairments and temporal lobe and global brain atrophy, cognitive decline, and incidence of dementia. A meta- analysis showed that people who are obese during midlife harbor a 1.35-fold increase risk for dementia late in life. A large study spanning thirty-six years found that those who were obese in midlife were three times more likely to develop Alzheimer’s disease than those who were not obese. The higher the BMI, the greater the circulating IL-1. And where the fat cells were located is critically significant. Central adiposity (belly fat) predicts dementia independent of BMI. In fact, people with normal weight who nonetheless had central adiposity were 89 percent more likely to develop dementia than people without it. In other words, the larger the belly, the greater the risk of dementia. These findings have led to the concept that an apple-shaped body places you at a greater risk than a pear shape. Because Michael carried an abnormally large belly, he was at greater risk for cognitive, mood problems, and dementia.

Obesity blocks BDNF, which is one of the many ways it contributes to dementia and depression. With the increase in PICs associated with obesity, there is a corresponding decrease in BDNF. Obesity also results in the dysregulation of energy intake and expenditure. Because BDNF plays an important role in energy balance, it can reduce inappropriate feeding while increasing energy output. Obesity increases feeding and decreases energy.

With the pandemic of overweight and obesity in the United States, the number of people with type 2 diabetes (90–95 percent of all those with diabetes) is currently over 28 million. By far the most significant risk factor of type 2 diabetes is obesity, and especially fat above the hips. This makes excessive belly fat diagnostic of not only health problems but also cognitive and mood problems.

To understand the relationship between obesity and immune system dysregulation, it is useful to consider that obesity is regarded as a chronic subclinical inflammatory condition. Not only do adipose tissues (fat cells) swell up, but the dead cells are not cleared out efficiently in obese individuals, setting in motion inflammatory cells and macrophages to cluster around dead and degenerated cells to engulf and digest them. Like a stagnant pond with muck building up because there are no streams coming in or out, in fatty tissues fat cells decay without any clearing or nourishment. Chronic inflammation present in obese people is distinct from acute inflammation—it is no longer involved in tissue repair. Fat cells leach out PICs, producing 10–35 percent more circulating PICs, such as IL-6, than in non-obese people. This makes these cells function as agents of mood instability and cognitive impairment.

In addition to contributing to depression and cognitive deficits, IL-6 is associated with coronary heart disease and insulin resistance and is increased in people who are obese. The higher the IL-6, the greater the risk of developing the type 2 diabetes. In fact, some neurologists are calling Alzheimer’s disease “diabetes type 3.”

Autoimmune and Psychological Disorders

Inflammation represents the common denominator for metabolic syndrome, obesity, and depression. These conditions break down many of the homeostatic processes important to maintain general health and mental health. Though the periodic inflammatory response is critical for tissue repair and homeostasis, chronic inflammation dysregulates the immune system feedback loops, leading to a variety of pathological conditions, such as autoimmune disorders.

Like Michael, one in five Americans likely have metabolic syndrome. The percentage of people increases with age, reaching more than 40 per-cent among people in their sixties and seventies. Metabolic syndrome is marked by insulin resistance, dyslipidemia (abnormally elevated cholesterol fats in the blood), and elevated blood pressure. All these factors are strongly predictive of cardiovascular disease and accelerated neurocognitive deficits.

Both a symptom and cause of major health problems and psychological disorders, autoimmune diseases represent bidirectional causal interactions with psychological disorders. For example, it is now well documented not only that people who develop type 2 diabetes are prone to depression. Once the inflammatory spiral begins, it is difficult to put on the brakes. Anna would have been best served had their family physician recommended significant lifestyle changes to pull out of the self-perpetuating nose dive into inflammation, diabetes, depression, and cognitive deficits.

People with type 2 diabetes are twice as likely to experience depression as their counterparts who do not suffer from diabetes. Large meta-analytic studies have shown that there is a bidirectional causal relationship between type 2 diabetes and depression across diverse populations. In other words, type 2 diabetes increases the likelihood of becoming depressed, and depression increases the likelihood of developing type 2 diabetes.

The Stress-Inflammation Connection

Michael complained that when he began to feel overwhelmed with stress he seemed to pick up any virus going around. Eventually, he transitioned into a phase of feeling like he had the mild case of the flu all the time: achy and tired, with a queasy stomach, but never breaking out into a full-blown flu with a fever and its associated symptoms.

It has long been the folklore of psychology that stress dampens the immune system. Short-term stress, in fact, has been shown to suppress T cell formation and natural killer cell function and to decrease the ability to repair broken DNA. But stress can enhance inflammation, too. Stress can activate PICs, including within the glial cells in the brain.

Michael’s chronic stress felt like an odd mix of feeling nervous and fatigued at the same time. Chronic stress can cause epigenetic changes in the expression of PIC genes in immune cells. With more peripheral inflammation Michael experienced, the more neuroinflammation he had. With mood and cognition compromised, his self-care deteriorated. He joined Anna in eating more and moving less. With significant weight gain, he also joined her in malaise and obesity.

Addressing Anna’s poor self-care, associated health problems, and depression was only the beginning of therapy. There was a backstory that Anna did not tell her physician: she had experienced increasing stress during the previous few years. Her boss demoted her after her job performance had begun to suffer because of low energy, and her new position required that she work swing shifts. Because her employer did not provide adequate parking, finding her car on a dark street at midnight presented a daily stressful challenge. Because her neighborhood was crime infested, she asked that the security guards provide an escort to her car. After her boss told the security department not to allow any of the guards to leave company property, one night she was physically assaulted and robbed. In response to a union grievance, her boss relented and allowed a security guard to escort to her car, but the residual symptoms of the trauma persisted. She found little support at home during the year before visiting her primary care physician. The only semblance of comfort she found was “vegging out” on the couch watching movies with Michael.

Anna’s chronic stress, exacerbated by trauma and poor self-care, combined to trigger an autoimmune disorder. Multiple physiological pathways contributed to her increased inflammation and decreased stress tolerance. The chronic and acute stress disrupted the insulin balance in her body and led to insulin resistance, which paved the way for type 2 diabetes through a series of metabolic changes. When stressed, her body assumed that more fuel was needed, and to accommodate, genes activated in cells to increase glucose uptake. During and following the assault, her body released surges of norepinephrine, adrenaline, and cortisol, which also increased blood glucose. The increases in cortisol triggered the break-down of protein and its conversion in her liver to glucose. The excessive cortisol resulted in too much glucose floating around, which increased risk of insulin resistance. It was in the year prior to visiting her primary care physician that she developed type 2 diabetes.

We see the same dysregulating spiral with illnesses like arthritis, chronic pain, fibromyalgia, and chronic fatigue syndrome. As people become more depressed, their physical illness increases, which leads to greater depression. Decreased stress tolerance, increased anxiety, and depression associated with these chronic diseases combine to potentiate all of them together.

It is difficult to calculate how many people are depressed, suffer from cognitive deficits, and do not know that they are afflicted with spiraling dysregulations of their immune system, but it could be in the many millions. PICs tend to rise when physical health is compromised by autoimmune disorders, excess weight, and increases in response to stress. Stress and poor health feedback on multiple systems to create a spiral of decompensation within all levels of the mind-brain-gene feedback loops. The nonlinear interactions of all these factors put the person at greater risk for more serious physical and psychological disorders.

Psychotherapy in the twenty-first century must address the pandemic of acquired inflammatory diseases that have a devastating effect on mood and cognition. Lifestyle changes such as diet, exercise, and sleep can affect the immune system. But before turning to those self-maintenance factors, we need to better understand a major part of the immune system, the gut.

Mind, Brain, and Gut

Michael, introduced at the beginning of this chapter, felt that he had a “nervous stomach.” The gut communicates with the brain through multiple channels. Microbes coat the razor-thin layer of mucus and cells of the inner lining of our intestines. This puts them in very close proximity to the gut’s immune cells and cellular sensors that encode our gut sensations. Many of the brain- gut interactions occur here, ensuring that signals generated by the microbes are received by the brain and, in turn, those sent back to the gut are influenced by our emotions. Gut feelings are bidirectional, linking cells in the brain with those in the gut.

Interactions among the mind, brain, and gut can occur through top-down or bottom-up pathways that are emotionally laden via both branches of the autonomic nervous system. However, Michael primed his sympathetic branch and his neuroendocrine system so that he responded to assumed threats that were benign. For example, stress primed his hypothalamus to release corticotropin-releasing hormone activity and dampen the activity of gamma-aminobutyric acid, the principle inhibiting neurotransmitter in the body. This means that his stress tolerance and his ability to self-sooth tended to be low. In addition to the heightened tendency to easily trigger the release of stress hormones, such as norepinephrine and cortisol, which increased his hypervigilance and anxiety, corticotropin-releasing hormone stimulated his pituitary to release adrenocorticotropic hormone, which traveled through his blood-stream to the adrenal glands, which in turn released adrenalin, more norepinephrine, and cortisol. Simultaneously, the stress induced a gut reaction that impacted the composition and activity of the gut micro-biota. He became prone to a wide range of sensations, including belly pain and gut contractions that resulted in frequent diarrhea. His stomach slowed down and even reversed itself, so he often felt like throwing up. Not only does the elevation in cortisol contribute to changes in the mix of gut bacteria, but it also increases the gut’s permeability and triggers the release of PICs, which further increases the gut’s permeability.

Early stress is also associated with alterations in microbiota and their metabolites, as well as with the stress circuits in the brain. The neurodevelopmental changes resulting from early stress occur through multiple pathways, including epigenetic modifications of the brain-gut axis and stress-induced changes in gut microbiota and their products, which can further impair the brain. These abnormalities can begin to develop in utero and soon after birth. Interference in the infant’s gut microbiome and a variety of challenges, including stress, nonvaginal delivery, unnecessary use of antibiotics, and unhealthy dietary habits during pre- and postnatal periods, can lay the groundwork for brain- gut disorders. The pathophysiological syndromes that result from early stress and deprivation include the elevation of pro-inflammatory processes, as measured by C-reactive protein levels, decades later in life.

Throughout life chronic stress can stimulate the growth of many pathogens in a person’s gut, making those pathogens more aggressive. Stress signals can also reduce the thickness of the mucus layer lining the colon, making it leakier, allowing microbes greater access to the gut’s immune system, circumventing many of the gut’s defensive mechanisms. Norepinephrine can stimulate the growth of bacterial pathogens that can cause serious stomach ulcers, gut infections, and sepsis. It can also activate genes in the pathogens that make them more aggressive and increase their odds of survival in the intestines. Certain gut microbes can modify norepinephrine into a more powerful form, intensifying its effect on other microbes (Mayer, 2016). Overall the combination of chronic stress, poor diet, and dysbiosis can increase the leakiness of the gut leading to greater metabolic toxemia.

In the epigraph to this chapter, Taisen Deshimaru’s quote, “Think with your whole body,” referred to being consciously present with every ounce of your being. Based on the concepts described in this chapter, we actually do think and feel with our whole body. The interactions between the immune system, including within our gut, and the brain are dynamic. Dysregulation at any level of the gene-immune system-mind continuum can have confusing and devastating effects on mood and cognition.

Psychotherapy by necessity must focus on the behavioral health of clients. This means that self- maintenance factors such as diet, exercise, and sleep need to be addressed as foundational factors to mental health.

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