As much as I would have liked to continue my engaging research on Parkinson's Disease and Alzheimer's (issues I hold very dear to my heart), during my preliminary research for the third paper I felt drawn to another, equally interesting, topic. As finals rapidly approach and the idea of graduation becomes more real by day, this new topic seemed to have more personal significance to my life. And so I began research on this topic with purely selfish motivations- to better understand the phenomenon of stress.
A relatively new concept involving brain and behavior, Hans Selye first proposed the idea of stress as a normal adaptive syndrome, a fight-or- flight situation, very similar to escape behavior (1). Stress is defined as "the set of all organic reactions to physical, psychic, infectious, or other, aggressions, which are capable to disturb homeostasis" (1). Stress lies at the intersection between personal, social, and economic factors and biology. Although stress is an important, integral part of our existence, there is a point at which it becomes overwhelming and our adaptive responses may break down (2). The breaking point varies from person to person, depending on past experiences, coping responses, and genetics (2). Clearly, socio-economics has a lot to do with the ability to cope with stress over time. We may know of some people that are inherently better able to deal with life's stressors. However, genetic bases for dealing and coping with stress are unknown at this time. Stress, usually used to describe a state of mind, illustrates the important connection between mind and body. Although stress is primarily a neuronal reaction, it's effects reach far past neurobiology. Stress is thought to adversely affect the immune response, among other somatic conditions. It is estimated that up to 75% of all doctors' visits are made by people with stress-related problems. Also, it is thought that 50-80% of all diseases are a result of excessive stress (4). In this paper, the neuronal, physiological, and behavioral dimensions of stress will be explored. It will be proven that the phenomenon of stress involves the dynamic interaction of the body and mind- brain and behavior, ideas that were previously thought to be mutually exclusive. Further, I will use Panic Disorder and Post-Traumatic Stress Disorder as illustrative examples of how stress, in its extreme forms, links the functionality and physiology of brain and the nervous system to behavior. Stress is a complex physical and emotional reaction based on perception of reality (3). Selye cited three steps to stress adaptation. A thought is processed in the brain to activate the nervous system. The nervous system then decides to fight or flee. Second, as the body acclimates itself, it adjusts and adapts to the presence of the stressor. Finally, the exhaustion stage occurs if the present stress is overwhelming and builds up over time. Illness and death are results of overwhelming and exhaustive effects of stress (3). The accumulation of stress can be visualized and conceptualized as the staircase effect: if we do not acknowledge or adapt to the stressor then we proceed to the next situation with residual feelings of stress (3). As we climb higher on the staircase, the pressure builds (3). The build-up of stress is thought to lead to an organic malfunction that could cause disease, or worsen existing conditions (1). The sources of stress are, understandably, diverse and varied. The causes are generically described as "any change in our daily lives, whether good or bad" (1). In some cases, the stress can be a lesion in the brain, or nervous system. Others include psychological trauma, as found in war veterans and survivors of sexual assault and rape. This is clinically described as Post-Traumatic Stress Disorder (PTSD), which is characterized by "acute and invalidating episodes of anxiety or mental anguish, when the victim is exposed to situations similar to that one which had installed the disease" (1). Re-living the traumatic experience as a flashback is one of the symptoms of PTSD (1).The instance and mechanisms PTSD will be elaborated on later in the discussion.
The functional basis of stress was first identified by Hans Selye. He noted that the awareness of a potentially dangerous or traumatic situation is determined by the cortex and the sympathetic nervous system. Then, the perception of stress is interpreted by a network of neurons. If determined important, the cortex stimulates a subcortical brain circuit in the limbic system, which controls emotion and the autonomous nervous system regulating the visceral systems (including the heart, blood vessels, eye pupils, stomach, intestines, etc...) (1). The activation of these structures, the amygdaloid bodies and hypothalamus, lead to many of the changes we automatically feel when we experience stress: dilation of the pupils, paleness of skin, acceleration of the heart beat, increase in heart contraction strength, increase in respiration, sweating, paralysis of the gastrointestinal track, and increase in the secretion of adrenaline and noradrenaline (epinephrine and norepinephrine) by the medullary part of the adrenal glands (1). Around the same time, the hypothalamus activates the pituitary gland which produces the adrenocorticotrophic hormone (ACTH), the "stress hormone" (1). Once ACTH is carried through the bloodstream, it will, in turn, increase the secretion of corticosteroids, other hormones, by the cortical part of the adrenal glands (1). The corticosteroids alter the metabolism of the somatic tissue it comes into contact with, in addition to altering the resistance to invaders to the immune system (1). The long-term effects of stress on the immune response has wide implications in research, particularly in cancer (2). We can measure the long-term effects and the degree of stress activation, via brain-pituitary-adrenocortical axis, by the amount of cortisol present, one of the inner corticosteroids. The evidence that there is a double discharge of hormones, adrenaline and corticoids, has lead scientists to believe that the pituitary and the adrenal glands are the main actors in the stress response (1).
Normal responses to stress are important for an organism's survival in any situation, whether in danger or diseased (1). Stress becomes problematic when the process becomes chronic. Chronic activation of the autonomic nervous system stresses the heart and coronary arteries, causing them to be continuously dilated and contracted, while also increasing blood pressure (1). Genetics comes in to play when examining a person who has lesions already in their coronary walls which leads to the decreased availability of oxygen in the heart muscle tissue. Once the diameter of the coronaries is narrowed, there is an increase chance of myocardial ischema, along with heart angina (pain). Ultimately, when the level of oxygen reaches an all-time low, the heart muscles begin to die out, causing a heart attack (heart infarction) (1).
Stress can also cause other minor changes in the body, called neurovegetative symptoms. These include: weakness and fatigue, increased tension in the muscles, myofibralgia (painful knots in the muscles), headaches, migraines, back pains, increase in blood pressure (hypertension), bowel disease, and pains in the urinary system (1). We can also examine blood chemistry to shed light on the stress level. For example, the increase in blood concentration and density, amount of platelets (involved in clotting), alteration in the cortisol, alterations in the hormone levels, and increase in sugar and cholesterol levels in the blood can all be measured to quantify stress (1). Long term stress may also have detrimental effects on brain structure and function. It was found that too much stress hormone over time can weaken the all-important blood-brain barrier that normally protects toxic substances from entering the brain (5). Researchers in Israel showed that mice exposed to a stress and then injected with a drug (that usually does not pass through the blood-brain barrier) were 100 times more permeable to the drug than were non-stressed mice (5). Also, long-term effects of stress hormones, especially cortisol, may shrink cells in the hippocampus region of the brain (5) (6). In a study recently published in Science, patients with an abnormally high level of glucocorticoids, as in Cushing's Syndrome, Post-Traumatic Stress Disorder, and severe depression, had a correlated reduction in the hippocampus. The longer the exposure to high levels of stress hormone, the more dramatic the reduction in the hippocampi (5). This study illustrates how excessive stress hormone can be damaging. It also has implications in the approaches of drug therapies in the treatment of stress (6).
From personal experience, too much stress can take its toll on you, biologically and psychologically. Stress and feelings of anxiety are among the most universal emotions. In its extreme forms, though, stress can have deleterious effects, leading to such conditions as Panic Disorder (PD) and Post-Traumatic Stress Disorder (PTSD). Both disorders involve an abnormality where stress interferes with day-to-day activity. While realizing the benefits of a healthy dose of anxiety, how it can push you through the end of the exam period, stress can get out of control in the cases of PD and PTSD. By understanding the etiology of these conditions, not only do we have a better grasp of the biological mechanisms of neurobiology , we have a new appreciation of the balance of the nervous system and behavior.
Normally, as predicted by the general adaptive syndrome proposed by Selye, when faced with stress or anxiety, we react with either a fight or flight response. This reaction is biologically characterized by the peripheral secretion of catecholamines, especially epinephrine and norepinephrine and glucocorticoids, causing the dilation of the coronary blood vessels and increase in heart beat. Involving a complex and varied response, possibly including hypertension, increased body temperature, and sensitivity to light, Panic Disorder is thought to illicit an emergency response when there is no emergency (7). People who suffer from Panic Disorder seem to be always on guard, ready to react to anything potentially threatening. Panic is thought to be a heightened state of fear and anxiousness occurring in a positive feedback loop. In this way, Panic Disorder, is an example of bi-directional causation (10). For example, if you have a panic attack that you are not going to graduate because every computer you've worked on has crashed, you will be much more weary and careful working with computers at least until you graduate. Hence, the output affects the input which affects subsequent outputs.
Panic disorders, and related conditions, can be increasingly characterized in terms of physiology and biochemistry, lending credence to the theory that brain=behavior. By exploring the intricacies of brain structure and function, we can better understand the behavior of what we know as Panic Disorder. For example, it is known that most aspects of Panic Disorder can be explained in terms of biochemical imbalances. One study links levels of monoamine neurotransmitters in the central nervous system to anxiety. It is thought that those with Panic Disorder may produce lower levels of the neurotransmitter, serotonin, that causes alarming and anxious behavior (11). It is also hypothesized that GABA (gamma amino butyric acid) is implicated in Panic Disorder since it is found in 80% of nerve cell connections in the brain that are associated with anxiety producing behaviors (11).
There are several cognitive theories accounting for Panic Disorder. One theory contends that in Panic Disorder a person has the fight or flight reaction without the real presence of a stressor (7). Another theory maintains that individuals with PD over-interpret and are over-sensitive to normal physical sensations (9). For example, a minor heart palpitation would be interpreted as a heart attack (9). Also, it is thought that those with PD pay too much attention to their somatic sensations making it more likely that they would overreact to common interoceptive stimuli (9). Because of the diverse symptomization of Panic Disorder, it is thought that it must involve many different areas of the brain. Consistent with the findings previously cited implicating stress hormones with decreased permeability of the blood-brain barrier, it has been found that Panic Disorder is also associated with alterations in the blood-brain barrier. This barrier is directly regulated in part by the afferents originating in the locus ceruleus (7). The locus ceruleus produces much of the norepinephrine in the central nervous system and seems to be involved in the sleep-wake cycle, arousal, anxiety and fear (7). A particularly important structure related to anxiety is the amygdala, located in the limbic system of primates. The classic limbic system model includes the amygdala, hippocampus, and a few other small structures which process inputs from the outside: smell, sight, touch, and taste. The limbic system attaches emotion to these inputs and experiences. The amygdala, a small almond shaped tissue found near the center of the brain, is important in "interpreting emotions and rendering emotional events into highly memorable forms" (8). The ability to respond and learn about an outside stressor is channeled through neurons which send information to the amygdala. The amygdala receives projections from the frontal cortex, association cortex, temporal lobe, olfactory system, and other parts of the limbic system. It directs its afferents to frontal and prefrontal cortex, orbitofrontal cortex, hypothalamus, hippocampus, and brain stem nuclei (7). The amygdala is also crucial to communication between different brain regions, including those that control breathing, motor function, autonomic responses, hormone release, and processing interoceptive and external information (7). Since it is thought that the amygdala holds most of the memories of fear, it also has the capability for misinterpreting normal signals, which might be occurring in the case of Panic Disorder. Another cognitive theory of the causes of Panic Disorder proposed by Beck et al. takes into account predisposing and precipitating factors including heredity, past experience, certain physical conditions, ineffective coping skills, or trauma (9). How the experience of major trauma can disrupt normal responses to anxiety is also related to this idea. Similar panic-related symptoms are observed in cases with a history of extreme trauma and suffering, most often involving victimization (12). This condition, Post-Traumatic Stress Disorder, is characterized by recurrent re-experiencing of the trauma, avoidance of stimuli that are reminiscent of the trauma, psychogenic amnesia, numbing responsiveness, distress, irritability, and hypersensitivity (13). Commonly observed in victims of sexual assault and rape, PTSD is gaining importance as a major medical and public health concern. Although not an example of bi-directional causation, PTSD is an example of how fear and extreme stress is registered and processed in the brain, and how that, in turn, permanently modifies particular behaviors. People with PTSD have an increased physiological response to not only traumatic reminders but also to any stress, such as loud noises (14). Many studies with PTSD have been conducted using veterans; for example, it was found that combat veterans with PTSD have a higher than average resting heart rate and blood pressure (14). This constant state of alarm is due to stimulation of norepinephrine and epinephrine. It is hypothesized that those with PTSD have problems with the storage, release, and disposal of catecholamines (14). Also important, as mentioned in Panic Disorder, is the locus ceruleus, where catecholamines are produced. In a study in which animals are repeatedly shocked and cannot escape, catecholamine activity and the locus ceruleus are hypersensitive and the animals develop PTSD-like symptoms (14). In addition, the release of dopamine in the cerebral cortex upon activation in the locus ceruleus is an important mechanism as it is thought to be involved in attention and vigilance (14).
Another parallel to Panic Disorder is the role of the amygdala and hippocampus, where any hyperactivation of these structures disrupts the process of memory for emotionally significant events. Since the amygdala stores memories and the hippocampus "supplies the narrative for emotionally important events", any interference with the mechanism causes memories to be preserved as nightmares, flashbacks, or displayed as physical problems or symptoms (14). It is also thought that the amygdala monitors the mechanisms that normally suppress reactions to fear. While this study started as a personal interest in exploration of the phenomenon of stress- it's paralyzing effects when faced with a daunting paper plus 3 exams- I have been amazed at how stress potentially touches all aspects of life. Further, similarities in the normal stress response and conditions such as PD and PTSD illuminates a common neurobiological pathway and causal connections between neurobiology and behavior. As in most neurobiological conditions, the ability to boil a disorder down to one or two hormones or a specific structure in the brain is an enormous feat. Making this connection, or jump, from the identification of a biochemical pathway, such as hormone release, to a pattern of behavior, is what makes the brain=behavior equation so challenging and yet, so essential. While it may be impossible for me to control the excessive release of norepinephrine on the day of an exam, realizing what's going on inside you and maintaining a behavioral balance can make a difference. On the other hand, you realize your limitedness in your abilities to control how you react to certain things- much of it is biology- pre-wired and out of your hands.
Bibliography:
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