Inspiration
“Well, she was born early at 24 weeks. She spent about three and a half months in the NICU. They tell me she can’t remember any of it, but I’m not so sure…” These are the words of the mother of a six-year-old, generally healthy female brought to the pediatric pulmonology clinic for asthma follow up. Her asthma is well controlled by medications and from a respiratory standpoint she is doing quite well. However, even a simple, seemingly benign visit to the doctor’s office evoked an intense emotional response in this little girl. Her mom shared that the patient had been dragging her feet on the way into the hospital where the clinic is located, kicking and screaming that she wanted to go home. She was inconsolable during pulmonary function testing, to the point that she was not able to complete the tests during either of her attempts. She clung to her mother’s arms throughout the visit, insisting that she and her mother stay on one side of the exam room while any medical professional stay as far away as possible in the opposite corner. Needless to say, she did not tolerate the physical exam well at all – she buried her head in her mother’s chest and screamed at the top of her lungs as soon as anyone approached her, much less laid a stethoscope over her chest. Upon asking the mother if her daughter experienced this type of distress outside of a medical setting, the mother said no, sharing that her daughter is a very happy-go-lucky child until it comes to medical environments – it is there that she is transformed into being “this way.” Upon asking the mother if the patient has had any other significant interactions with the medical community apart from her prolonged hospitalization at the time of her birth, she said, “No. But I’m telling you, she remembers that one.” This begged the question – do prolonged, repeated, or particularly traumatic hospitalizations have more of a lasting impact on a child than we realize?
What We Know
In the last several decades, the impact of adverse childhood experiences (ACEs) on the long-term health of an individual has begun to be recognized and explored. A landmark study in this field was the 1998 Kaiser ACEs study. This study explored the adult respondents’ exposure to ACEs during the first 18 years of life; examined ACEs included psychological abuse, physical abuse, sexual abuse, and household dysfunction (substance abuse in the home, mental illness in the home, violence toward the mother in the home, and criminal behavior in the home). More than half (52%) of respondents reported having experienced one or more ACE(s) during their childhood and adolescence. The researchers then examined the prevalence and risk of negative health and well-being outcomes later in life: smoking, severe obesity, physical inactivity, depressed mood, suicide attempts, alcoholism, use of illicit drugs, injection of illicit drugs, ≥50 intercourse partners, and history of sexually transmitted disease. Not only did the authors find a relationship between ACEs and negative health and well-being outcomes later in life, but they found that this relationship was in fact a graded, dose-response (1).
One framework that is useful for categorizing stress experiences is provided by the National Scientific Council on the Developing Child. Based on the physiological expression of the stress response system, this classification system breaks stress experiences into three categories: positive stress, tolerable stress, and toxic stress. Positive stresses are those that cause moderate, short-lived responses of the sympathetic nervous system (increases in heart rate, blood pressure, and stress hormone levels). Examples include receiving an injected vaccine or dealing with frustration. The defining characteristic of these stresses is that they are experienced in the context of stable and supportive relationships; this is crucial to facilitation of adaptive responses, which, in turn, restore the stress response system to baseline. These experiences are considered to be important aspects of healthy development. Tolerable stresses represent a physiological state that could potentially disrupt brain architecture. This can occur through neuronal death in the hippocampus or cortisol-induced disruption of neural circuits. However, these experiences are buffered by supportive relationships, which, in turn, allow the individual to practice adaptive coping. A key feature of these stresses is that they occur within a time-limited period; during this time, protective, supportive relationships enable the body’s stress response system to return to baseline. This gives the individual’s brain an opportunity to recover from effects that may otherwise cause long-term damage. Examples of tolerable stress include homelessness, a natural disaster, or the death or serious illness of a loved one. Finally, toxic stresses are strong, frequent, and/or prolonged activation of the body’s stress response system without the protective buffering of supportive relationships. By definition, these stresses disrupt brain architecture, affect other organ systems, and lead to stress response systems that are less equipped to manage stressful situations throughout life; this can manifest as stress-related disease and cognitive impairment (such as limitations in learning and memory) throughout adulthood (2).
How It Works
As the primary organ of sensation and adaptation, the brain processes, consolidates, and generates responses to all types of stressors; significant adversity can affect both the structure and function of the brain. In an effort to study and understand the intricate interfaces between human experiences and biology, animal studies have contributed significantly to current understanding of how stressful events affect physiology. For example, studies have shown that stress-related changes in brain circuitry incurred early in life can persist into adult life. They can, in turn, alter emotions, bodily process related to emotional instability, substance abuse, aggression, obesity, and stress related disorders, and the ability to make decisions (3, 4). The hippocampus, amygdala, and prefrontal cortex have been shown to be especially responsive to stress, largely in response to stress hormones (5). Human studies have revealed similar patterns. For example, one study demonstrated an association between prolonged perceived stress and reduced hippocampal volume (6). Others have revealed a link between decreased hippocampal volume with diagnoses including diabetes, major depressive disorder, Cushing’s disease, and posttraumatic stress disorder (7, 8). Conversely, physical activity and fitness in elderly individuals has been correlated with increased hippocampal volume and superior memory function (9). Furthermore, increased activation of the amygdala has been correlated with the development of atherosclerosis (10), which in turn increases risk for both morbidity and mortality secondary to cardiovascular disease and stroke. Finally, the volume of the prefrontal cortex has been shown to be reduced in people suffering from major depression and to be transiently impaired by increased levels of perceived stress (11, 12).
Another mechanism by which stressors affect physiology is epigenetics. Brain autopsies of individuals who experienced abuse during childhood revealed changes in DNA methylation patters related to the glucocorticoid receptor. These methylation patters are similar to the changes observed in the brains of rodents that experienced inadequate maternal care (13). DNA methylation patterns are often transmitted to the second and third generations of offspring, thus predisposing that person’s progeny to consequences of the stress experienced by their ancestors (14, 15). It is conceivable that these molecular markers of stress could accumulate over generations as well.
Why It Matters
The human brain, especially during infancy and childhood, is extremely malleable. However, with this flexibility comes vulnerability. Prolonged or excessive activation of stress response systems in the body and the brain can derail healthy development. For example, one study revealed that of individuals reporting significant childhood emotional abuse, 61% developed major depression during adulthood (16). Persistent release of cortisol, one of the body’s principle stress hormones, can have last effects such as immune system suppression, poor memory function, and increased risk of loss of muscle mass and bone mineral, as well as metabolic disorders, such as obesity and diabetes (17).
In fact, environmental stressors have been demonstrated to affect physiology as early as during fetal development. For example, female rodents experiencing high levels of stress during pregnancy have been shown to produce offspring that are more reactive to stress and more fearful of their environment. Furthermore, these animals were observed to have impaired memory and learning abilities; they also suffered from increased burdens of memory and cognitive decline related to aging throughout adulthood (18). While the effect of poor post-natal maternal care on offspring wellbeing has revealed similar trends, studies have also demonstrated that positive experiences in young animals can have a “rescue effect,” and to some degree can compensate for the negative consequences of prenatal and/or postnatal stress/neglect. Positive experiences include social play and environments that promote exploration and discovery; exposure to these influences has been shown to result in adaptive changes in not only the chemistry, but also the architecture of the developing brain. These changes can result, for example, in the reversal of the effects of mild hardship on stress hormone release. Of course, the plasticity of the brain has limits. For example, the reduced number of glucocorticoid receptors in the hippocampus that has been observed to result from persistent stress has proven to be resistant to reversal over time, thus having the potential to adversely affect the individual throughout his or her lifetime (19). Furthermore, due to the epigenetic mechanisms discussed above, these effects can have consequences on generations to come (14, 15).
So, What About Hospitalizations?
In 2012, nearly one out of six United States hospital discharges was for a child of age 17 or younger. That year, for this age group, there were a stunning 5.9 million pediatric hospital stays; 3.9 million of these stays were for newborn infants. These hospitalizations averaged 3.9 days in length (20).