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Bereavement: Reactions, Consequences, and Care (1984)

Chapter: Toward a Biology of Grieving

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Suggested Citation:"Toward a Biology of Grieving." Institute of Medicine. 1984. Bereavement: Reactions, Consequences, and Care. Washington, DC: The National Academies Press. doi: 10.17226/8.
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Toward a Biology of Grieving

. ::::::: .. :~: ~ - Throughout the ages, people have wondered about the relationship of the brain to emotions and to bodily functions. One of them was Andreas VesaL'us, who In 1543 produced the first "modern" concept of the brain, shown above. Although it now is known that the brain regulates many physiologic fuIlct~'ons that are connnonly disrupted by the stress of bereavement, such as hormones, hears rhythm, andimmune responses, the extent to which these disruptions may affect health has not yet been estab17'shedl.

CHAPTER 6 Toward a Biology of Grieving r ~ . his chapter reviews the available data on the biologic events that occur during the grieving process and proposes several kinds of pathways through which grief might increase vulnerability to physical illness. The degree to which this vulnerability occurs and results in illness is still open to question. Research to date has shown that, like many other stressors, grief fre- quently leads to changes in the endocrine, immune, autonomic ner- vous, and cardiovascular systems; all of these are fundamentally influ- enced by brain function and neurotransmitters. However, the significance of these changes is not well understood. They may be pri- marily adaptive physiologic responses that in some persons become maladaptive and physiologically deleterious. The notion of a normal adaptive response becoming harmful is not new, especially in the context of the immune system. For instance, there is evidence that chronic active hepatitis is a virally induced or drug-induced autoimmune disease. Craddocki6 suggested other ways This chapter is based on material prepared by committee members Jules Hirsch, M.D., Myron Hofer, M.D., and Jimmie Holland, M.D., in collaboration with Fredric Solomon, M.D. It draws upon a background paper by Leonard Rosenblum, Ph.D., Direc- tor, Primate Behavior Laboratory, Downstate Medical Center, Brooklyn, New York. Additional assistance and background materials were provided by Elizabeth Guilfoyle, medical student, New York University School of Medicine. 145

146 / Bereavement: Reactions, Consequences, and Care the body's natural defenses may cause disease: the appropriate response to endotoxemia is fever and leukocytosis, but if the response is in- creased it may result in shock, consumption coagulopathy, tissue ne- crosis, hemorrhage, and death. The complexing of soluble antigen with antibody is a part of the immune response, but deposition of too many immune complexes can lead to severe vascular disease. Likewise, lym- phatic hyperplasia is necessary to combat the Epstein-Barr virus, but in severe infectious mononucleosis it can cause serious tissue destruction. The hypothesis that a normal adaptation to grief can become unregu- lated and lead to illness is considered further in the section of this chap- ter on a "psychoneuroimmunoendocrine system." This view is consis- tent with contemporary stress theory,~7 in which it is postulated that a stressor {x) produces certain transient biological or psychosocial reac- tions (yJ that may {or may not) cumulatively lead to certain health con- sequences I. Reactions and consequences may be modified by a num- ber of factors, and the consequences may themselves activate other stressors. In simplified form, the stress model looks like this: FIGURE 1 Modifiers / Reactions \ x~ :z Stressor ~ ~ - Consequences SOURCE: Adapted from Elliott and Eisdorfer.~7 Epidemiologic studies linking the stress of bereavement with adverse consequences to physical and mental health have been reviewed in Chapter 2; these are x-z correlations, using this model. This chapter re- views the many studies of prompt biological reactions to the stress of bereavement (x-ye and presents conceptualizations and promising leads but not confirming data on the implications of these particular physiologic changes for enduring health consequences (x-y-z) in human beings.

Toward a Biology of Gneving / 147 ANIMAL MODELS Finding out more about the involvement of complex biological sys- tems in grief would be greatly facilitated if animal models were avail- able. The history of medical investigation is testimony to the impor- tance of animal research in understanding the pathophysiology of human disease. Animal models rarely provide precise replicas of human conditions because of species differences. But nature, in evolution, has been con- servative, and human beings share many physiological and psychologi- cal processes with other species. Thus, a number of the studies dis- cussed in this chapter are based on research with monkeys, dogs, or rats. Social attachments, for example, are widely represented in mammals . . . . . ~ ~ and in olros, particularly between tne young and their social compan- ions, parents, and siblings. Acute behavioral responses of infants to sep- aration from their mothers are quite similar across species, including rat, guinea pig, cat, dog, monkey, and human being. And the few chronic biological responses to early separation that have been studied show striking similarities between monkeys and rats: a similar reduc- tion in rapid eye movement {REM) steep with insomnia, a Towering of cardiac rate, a thermoregulatory disturbance with decrease of core tem- perature, and a {very recently) demonstrated decrease in immune com- petence. ~ 26 27 30 46 62 63 What do these findings indicate about the biology of human grief? Be- cause of the differences between immature and mature organisms, be- tween separation and permanent Toss, and between various mammalian species, they can only be suggestive. They confirm that the response to separation has deep evolutionary roots and some biological impact on systems controlling vital processes of steeping, circulation, thermoreg- ulation, and immune surveillance. These studies require constant inno- vation in developing methods to detect physiologic changes, methods that may one day be applicable to human beings. Most important, animal studies provide new conceptual models for approaching an understanding of human bereavement. Examples are given in the section on social relationships as biological regulators and in Chapter 7. In an additional example, a single aspect of grief can be isolated and studied in terms of its biological substrate, as in the work of Weiss83 84 on learned helplessness. The helplessness of human grief is surely different from the state induced in rats by inescapable shock. Yet an understanding of the simpler case should provide clues about what to measure and how to begin to study the much more complex interrela- tionship of affects and biological changes that occur in human grief.

148 / Bereavement: Reactions, Consequences, and Care BIOLOGIC STUDIES OF BEREAVED HUMAN BEINGS There have been very few studies employing biologic variables in actively grieving people. The first study of this sort was Lindemann's,48 in which he concentrated on what he termed the "syndrome" of acute grief. The data he collected from the relatives of victims of the "Coco- nut Grove" nightclub fire in Boston in the early 1940s, as amplified and extended in the work of Parkes59 in London in the late 1960s and more recently in studies by CIaytoni3 and others (e.g., Bartrop et a].5), give a picture of the behavioral and physiologic symptomatology of grief, as outlined in Table I. The symptoms described in Table ~ are present to a greater or lesser extent in most bereaved people for a period of weeks or months and in brief reactivation bouts, such as anniversaries, for years. They are the best evidence, thus far, that bereavement involves a physiologic distur- bance. Unfortunately, symptoms such as these are not infallible indica- tors of physiologic change, nor are most of them very specific indicators of which organ or system may be involved. More specific physiologic data have been collected in animal studies of mother-infant separation; and these are summarized in Table 2 {page 165~. In 1944, Lindemann described having made respiratory tracings by polygraph of bereaved people and discovered an unusual pattern that he indicated would be described in detail in a subsequent paper. That paper was never written, and the idea dropped from sight until 1980 when TABLE 1 Adult Grief Responses {Human Studies) Behavior Physiology Acute episodes: waves of distress, lasting minutes Agitation Crying .. . . . . . Alm ess actlvlty-mactlvlty Preoccupation with image of deceased Tears Sighing respiration Muscular weakness Chronic background disturbance: lasting weeks to months Social withdrawal Decreased concentration Decreased attention Restlessness, anxiety Decreased or increased food intake Postures and facial expressions of sadness Illusions or hallucinations Depressed mood Decreased or increased body weight Sleep disturbance Muscular weakness Cardiovascular changes Endocrine changes Immunologic changes

Toward a Biology of Grieving / 149 Schiffman and his colleagues,70 looking for a heritable respiratory defect in relatives of Sudden Infant Death Syndrome {SIDS) victims, found compromised ventilation in recently bereaved parents of children lost to SIDS, suggesting that the chemical regulation of their breathing might be defective. It is unclear from this study whether the alteration in the autonomic regulation of breathing is genetic or acquired, and if acquired whether it is related to the grief state. In order to understand this more fully, Shannon and his colleagues at the Massachusetts Gene- ral Hospital in Boston are conducting a study to determine the relation- ship between grieving, depression, and autonomic regulation of breath- ing and cardiovascular function in recently bereaved parents of SIDS victims, parents whose child died from other causes, depressed pa- tients, and nongrieving/nondepressed parents {D. Shannon, personal communication . The pituitary-adrenocortical system was studied in the parents of children with leukemia, both before the child's deaths and in the period of bereavement.33 34 The researchers found that the operation of psycho- ~og~ca' defenses played a major role in modifying the extent of activa- tion of this system during the threat of loss. A subject's level of cortiso! {a hormone secreted by the adrenal cortex in response to adrenocortico- trophic hormone [ACTH] from the pituitary) could be predicted on the oasis or an assessment of aerense effectiveness. In follow-up visits six months and two years after the child's death, however, parents no longer maintained the same rank order of cortisol levels as they had prior to the death; cortisoT levels varied directly with the extent of ac- t~ve grieving {at the six-month follow-up visit) as judged by an assess- ment procedure carried out without knowledge of the hormonal data. From these data, it might appear that grief is associated with adrenocor- tical activation, which continues as long as grief is an ongoing con- scious psychological process. However, in those who had been actively grieving at six months and whose grief appeared to have run its course by the two-year return visit, cortisol levels remained high and un- changed. This pioneering study raised as many questions as it answered and gave an early indication of the complications that may arise in this kind of research. Current psychoendocrine studies at Yale measure plasma levels of pi- tuitary prolactin and growth hormone, as well as cortisol, in recently bereaved subjects during interviews in which the loss experiences were reviewed. Those whose growth hormone output increased during the interview tended to be subjects whose distress had been worsening in the two months between the loss and the interview. Measures of dis- tress during the interview did not correlate in a simple way with pitui . . . . , . . . . . · . ~. ~. r ~. ~

150 / Bereavement: Reactions, Consequences, and Care tary hormone responses, but when one takes into account subtle as- pects of the interview situation and the subject's coping mechanisms, interesting correlations begin to emerge.35 39 4~ 52 The data suggest a spe- cificity between certain psychological variables and certain hormones; a selective organization of neurohumoral responsiveness seems to be in- volved in the independent regulation of prolactin, growth hormone, and ACTH. In the past few years, two studies have addressed the possibility that bereaved individuals have abnormal responses of their cell-mediated immune system. This research was stimulated by suggestions that ma- lignancies may originate more readily among the bereaved. Although, as discussed in Chapter 2, the association is not firmly established on epidemiologic grounds, the clinical observations are frequently intrigu- ing. Researchers in AustraTias and the United States7i have found that bereaved persons have an impaired function of T-lymphocytes, the agents of cell-mediated immunity. The lessened T-cell function was not a concomitant of changes in number of circulating T-celis, or of changes in adrenal or thyroid hormones in blood plasma. Neither of these stud- ies was designed to tell whether the reduced T-cell function posed a clinically significant vulnerability of the subjects to disease. These studies require follow-ups that will include investigations of the mounting of specific immune responses. Such research would permit consideration of the relationship of immune function to bereavement and the possible relevance to clinical vulnerability. PROMISING RESEARCH APPROACHES Much less is known about the physiology of human bereavement than, for example, about the physiology of exercise or pregnancy. Thus, the most important statement that can be made about the biology of grieving relates to the need for research in this area. There are at least four areas of knowledge that give useful clues about where to begin: the symptomatology of grief, the epidemiology of be- reavement, recent findings in the biology of depression and anxiety dis- orders, and current knowledge about neuroregulatory mechanisms. In these areas the autonomic, physiologic, biochemical, and endocrino- logic systems most likely to be affected by grief and the bereavement process can be identified regardless of whether the response is viewed as a subcategory of stress response, as a withdrawal of psychobiological regulators, as an adaptive response to a natural event, or as the activa- tion of a neurobiological substrate.

Toward a Biology of Grieving / 151 Changes in these systems over time should be studied to reveal the processes of recovery from bereavement as well as the form and dura- tion of the acute disruption. How do children and aging people differ in grief from young and middle-aged adults? What are the special features of the biological responses that are relevant for adverse consequences? In all these areas, the psychological and behavioral responses will have to be related to the biological changes, because there is powerful inter- play between these systems in determining the final outcome. clues from the SymptomatoJogy of Bereavement Research should take into account the natural division of symptoms into acute waves of distress, lasting minutes at a time, and chronic dis- turbance, which can last weeks and months. Acute waves of distress will be reasonably easy to study, because in many people they can be precipitated by an empathetic interviewer and their elicitation is often viewed as helpful to the subject. The symptoms of sighing respiration, dyspnea, substernal tightness, palpitation, weakness, and crying sug- gest that tests should be made of respiratory control and blood gases, autonomic function jparticulaxTy in the cardiovascular system), and en- ergy metabolism {including the rapidly responding hormone systems of the pituitary, thyroid, and adrenal glands). These measures will be most useful if evidence about the sub ject's inner affective and cognitive state is collected simultaneously and integrated with the physiologic data, so that a comprehensive view of the psychobiological organization of the acute distress "waves" will be obtained. This basic knowledge will be useful in planning clinical studies of pa- tients at risk because of preexisting disease such as asthma, pulmonary emphysema, coronary heart disease, or congestive heart failure. These conditions are most likely to be affected by the physiologic changes of acute distress waves. The chronic form of disturbance is characterized by symptoms in- volving a number of different biological systems that are regulated or powerfully influenced by the central nervous system through its auto- nomic, neuroendocrine, and muscuToskeletal outflow channels. Many of the symptoms may be related to the neural regulation of the sTeep- wake cycle and related biological rhythms, that is, to disturbance of chronobiological organization. The insomnia, chronic fatigue, restIess- ness, appetite disturbance, cognitive and perceptual disturbance, and even the illusions and depressive affect may be manifestations of altered integration or patterning of biological rhythms. If this is true, circadian

152 / Bereavement: Reactions, Consequences, and Care rhythms of body temperature, physical activity, cardiac rate, urinary Output, an] other vital functions should be examined for evidence of free running {non-24-hour rhythmicityJ or internal desynchronization (lack of consistent relationship between physiologic systems). Clues from the Epidemiology of Bereavement As documented in Chapter 2, a number of studies suggest that be- reavement may enhance vulnerability to neoplastic disease, infection, cardiovascular disease, substance abuse, or depression. The existence of hormone-sensitive cancers raises the possibility that alterations in hormonal milieu following bereavement may have clini- cal importance. Estrogen-dependent breast cancers and testosterone- dependent prostatic cancers are some of the best known examples of this sort. Studies are needed of ovarian, testicular, and adrenal hormo- nal regulation in bereavement, and of the hypothalamic-pituitary stim- ulating hormones that control these target glands. The potential in- volvement of the immune system in the recognition and suppression of neoplasia makes it an obvious subject of study during grief. Important interactions are already known among adrenal cortical hormones, auto- nomic nervous system neurotransmitters, and the immune system. Susceptibility to bacterial and viral infections has been linked to be- reavement in some studies (Chapter 2~. This, too, suggests a need for a combined endocrine and immune system investigation. Resistance to infectious agents is known to depend critically on hormonal milieu and on humoral and cell-mediated immune mechanisms. The incidence of pneumonia as a terminal event in the bereaved might also indicate dis- turbed respiratory regulation during grieving. The link between disease and bereavement is strongest for the cardio- vascular system. Sudden cardiac death, cardiac arrhythmias, myocar- dial infarction, and congestive heart failure are the most frequently mentioned conditions of that system associated with grief.72 This presents us with the clue that disturbances in autonomic cardiovascular regulation and in circulating catecholamines may be present in bereave- ment and may be exaggerated in patients with preexisting cardiovascu- lar disease of the arteriosclerotic or hypertensive variety. Studies have shown that patients with congestive heart failures and with essential hypertensions and arrhythmias60 6i are particularly prone to exacerba- tion of their condition in response to threatened or actual loss of human relationships. Enough is known about the pathophysiology of these con- ditions to make quite specific hypotheses as to the probable autonomic

Toward a Biology of Grieving / 153 and neuronumorai mechanisms involved. In addition, methods to test such hypotheses are currently available. Vulnerability of the bereaved to substance abuse suggests that they are self-medicating themselves in an effort to alleviate their psychic pain and bodily discomfort. The possibility that sensory and pain thresholds are altered in the bereaved has not been systematically eval- uated by modem methods, nor have any of the newer approaches to the study of endogenous, opiate-like peptides and their receptors been em- ployed with this group. Alternatively, substance abuse may be related to depression, a possibility discussed in the next section. clues from the Endocrinology and Biochemistry of Depression and Anxiety States Two well-delineated mental disorders, major depression and panic disorder, may share a common neurobiological substrate with the re- sponse to loss in the bereaved. This hypothesis bears testing by looking for the characteristic biochemical, physiologic, and pharmacologic re- sponses of these two patient groups in adults following bereavement un- complicated by diagnosed psychiatric illness. Endocrine control during depressive illness and recovery still requires fuller study and documentation. Abnormalities of hypothalamic neuro- transmitter systems controlling the pituitary output of ACTH, luteiniz- ing hormone, and prolactin have been found in depressed patients; these findings may also reflect abnormalities in neurotransmitters in other areas of the brain that mediate mood and behavior. Are similar abnor- malities found in the bereaved? How are these related to peptide levels in plasma, to immune function, to psychological status? A characteristic change in sleep-wake state regulation {a shortened la- tency to the first REM period has been found in many depressed pa- tients, and reverts to normal with easing of the illness. Might a similar abnormality be found in disturbed steep following bereavement? Patients with panic disorder show two biological abnormalities that may have some relevance to the psychobiology of acute grief. They have abnormally wide fluctuations in certain autonomic variables {particu- larly skin resistance!, especially in the prodromal period before a panic attack.45 And they are extremely susceptible to precipitation of a panic attack by intravenous lactate infusion.37 This susceptibility appears to be blocked by the tricyclic antidepressant drug, imipramine. The waves of distress, a hallmark of acute grief, bear some resemblance to acute

154 / Bereavement: Reactions, Consequences, and Care panic attacks; can they be precipitated by lactate infusion and are they heralded by similar patterns of autonomic instability? The complexity of interactions between the psychologic and the physiologic has been illustrated in a study by Kraemer and McKinney.42 They used drugs to alter the function of two neurotransmitters that have been implicated in the genesis of depression. With drug doses that failed to produce any detectable effects in juvenile monkeys while they were in their home-peer groups {thus obviating any spurious side ef- fects), increases or decreases in behavior patterns of despair could be produced following peer separation. Thus, only when beset by the sig- nificant psychological stress imposed by Toss of their peers were these animals responsive to the drug regimen. This complex interaction, in which events at the psychological level affect physiologic processes and where the physiology in turn alters psychological functioning, is a ubiquitous quality of primate psychobiology. Two neurochemical changes have been found in rhesus monkey in- fants separated from their mothers and placed in isolation: increases in catecholamine-synthesizing enzymes and in hypothalamic levels of the neurotransmitter serotonin.8 Suomi and his colleagues77 subsequently studied rhesus infants raised in peer groups without their mothers until 90 days and then subjected to repetitive peer separations; the tricyclic antidepressant, imipramine, decreased excessive self-clasping and pre- vented reduction in play behavior characteristically found after such ex- periences. However, social contact also was reduced and locomotor be- havior increased by the drug. Although neurochemical changes clearly occur in infant monkeys separated from social companions, the neuro- chemical basis for the behavioral changes and the mechanism of their modification by psychoactive drugs are not yet clear. Clues from Current Knowledge of Neuroregu~atory Mechanisms The neuroregulatory pathways that are known to mediate the conver- sion of life experiences into changes of bodily function provide many insights into the biology of grief. Whether some or all of these actually are involved in human grief is an empirical question that has received little study. Research on stress physiology has identified many neural and endocrine control systems that are at least a good place to begin investigation. These involve the autonomic neural system, endocrine events, and immune changes related to endocrine and direct neural in- fluences. i7 Autonomic Neural Effects. Since the time of W. B. Cannon,9 it has been known that emotional states of rage and fear affect such biological

Toward a Biology of Grieving / 155

156 / Bereavement: Reactions, Consequences, and Care seconds, when the heart is particularly vulnerable to developing multi- ple beats and even ventricular fibrillation in response to a weak electri- cal current. Verrier,8° working with Lown, then studied the threshold for this "ventricular vulnerable period" as it might be influenced by the emotional state of the experimental animal and by brief episodes of cor- onary narrowing and reperfusion {as might occur with coronary artery spasm). They discovered that unfamiliarity with the testing chamber and expectation of receiving mild punishment reduced the threshold by 41 percent. They were then able to analyze this effect in terms of the contribution of sympathetic and parasympathetic autonomic influ- ences. Using pharmacologic blocking agents, measurement of plasma norepinephrine and epinephrine, and surgical excision of the stelIate ganglia, they found that the reduced threshold was the result of in- creased sympathetic influences-both along neural pathways and through increased circulating levels of norepinephrine and epinephrine. These experimental findings do not bear directly on the question of how grief may contribute to cardiac arrhythmias, for they involved a different emotional setting and a different species. But they do suggest how growing knowledge about autonomic mechanisms may help direct the search for biological mechanisms in grief that may predispose indi- viduals to health risks. Endocnne Events. Psychological events cause many changes in the internal hormonal milieu, principally via the hypothalamic-pituitary axis. The response of the hypothalamic-pituitary-adrenocortical axis to stress has been well documented. Increased urinary and plasma levels of 17-hydroxycorticosteroids (17-OHCSJ have been demonstrated in re- sponse to movies of emotionally charged material,2i the stress of army basic "raining, 66 test-taking, aircraft flight, preoperative period novel situations,22 hospital admission,53 athletic events, 78 and other stressful situations. Secretion of other hormones also is altered by stressful situations. Testosterone decreases during stress.43 Sowers and colleagues74 found that physical and psychological stress related to diagnostic procedures and surgery was associated with decreased thyrotropin and thyroxine and with increased prolactin, growth hormone, cortisol, and luteinizing hormone, with no evident effect on follicle stimulating hormone. Stress increases prolactin in the morning when the level is low, and suppresses it in the afternoon when levels are high.23 Masonsi found that in mon- keys performing a reamed avoidance task, there was an increase in cata- bolic hormones and growth hormone and a decrease in anabolic hor- mones.

Toward a Biology of Grieving / 157 Different emotional responses to stress are reflected in hormonal pat- terns. Von Euler et al.2i measured urinary catecholamines in young men shown films of murders, fights, tortures, executions, and cruelty to ani- mals and found that those who were the most emotionally distressed by the films had the most significant endocrine reaction. Psychiatric inter- views, field observations, and measurements of 17-OHCS excretion in army recruits showed that Tow excretors had better defense mecha- nisms and that high excretors were less successful in dealing with the stress of basic training.66 Animal studies have shown that stress, especially uncontrolIable or inescapable shock, causes many changes in norepinephrine, epineph- rine, and dopamine concentrations in peripheral blood and in different parts of the brainstem, hypothalamus, and limbic system.68 Although the link between these neuroendocrine substances and the hypothal- amic-pituitary axis has not been completely elucidated, a relationship certainly exists. The "helpless-hopeless syndrome" seen in animal studies of inescapable shock situations appears to have special effects on endocrine activity that may have some potential relevance for stud- ies of human stress, including bereavement. In patients entering the psychiatric ward of a general hospital, most of whom had recently suf- fered a very difficult interpersonal event, Board et al.7 found that those diagnosed as the most distressed had the highest levels of 17-OHCS and that they tended to be sad, hopeless, and "retarded" rather than agi- tated. In animal studies, investigators have found that stress-induced Increases In plasma ano urinary 17-OHCS are highest in situations in which long-established rules have changed and previously effective be- havior no longer works to alleviate the stress. Research on the response of the endocrine system to disruption of at- tachments has been conducted by Levine and his associates in both the squirrel monkey and the rhesus macaque.~547 These studies generally have involved relatively brief and often repeated separation experiences, usually lasting for periods of hours or a few days. This work has shown quite consistently in both species that the sudden loss of the partner causes rapid and often dramatic increases in adrenal function with marked cortiso] secretion evident even 30 minutes after separation. In general, the period of highest cortiso] concentration is found during the first 24 hours following separation, with a decline thereafter. This pe- riod coincides with the initial phase of "protest" in response to loss. In squirrel monkeys, at least, both the mother and infant show these rapid cortiso] increases; the mother's return to baseline levels is more rapid than her infant's.~4 The diminution of response after the first day not O

158 / Bereavement: Reactions, Consequences, and Care withstanding, recent research by this group reveals that increased adre- nal activity may be detected as long as two weeks after the separation.85 Further research illustrates another significant fact that has emerged in physiologic research the potential for discontinuity be- tween the behavioral and physiologic measures of the loss response. Consider the following: infant monkeys can develop strong attachment bonds toward inanimate surrogate mothers. When infant squirrel mon- keys are separated from their surrogate mothers, they show a very dra- matic behavioral response of the "protest" variety. If the infant, at sepa- ration, is removed to a novel pen, it shows a large increase in blood cortisol thus, the behavioral measures of stress used here, that is, screaming and agitated activity, are congruent with the physiologic measure. If the infant is left in its home cage and it is the surrogate that is removed, however, the infant still screeches, but its cortiso! level re- mains undisturbed. In rhesus monkeys separated from their biological mothers, elevated cortiso! coincided with the protest pattern of the first day, but cortisol levels returned to baseline after 24 hours while various aspects of the initial behavioral response continued for ~ ~ days after sep- aration. i5 Immune Changes Related to Endocrine Events. It is well known that adrenal cortical activity has the effect of reducing circulating lym- phocytes and increasing thymic involution, resulting in diminished im- mune function.55 58 Riley and others have conjectured that an increase in adrenal cortical activity induced by stressful manipulation of experi- mental animals was causally related to an enhanced susceptibility to the growth of malignant tumors.64 65 Thymic involution and fewer cir- culating lymphocytes implicate T-cell deficiency as a possible factor in tumor susceptibility; hence Riley and others have shown tumor en- hancement. But Newberry37 and others have found the opposite effect: that some stressors suppress tumor development, which suggests that timing, tumor model, and type of stressor all are factors to be consid- ered. Immune Changes Related to Psychological Events: Psychoneuroim- mune Reactions. Palmblad38 demonstrated that stress-induced im- munosuppression occurs independent of endocrine function. Based on previous findings that the surgical stress of thoracotomy increased the number of lung metastases and tumor growth, Hattori and colleagues24 administered immunopotentiators jstreptococcal preparation and mito- gens) to animals with cancer and reduced the number of metastases af- ter thoracotomy, suggesting that tumor spread after surgery was due to 1mmunosuppresslon.

Toward a Biology of Grieving / 159 Coe et al. is report that squirrel monkeys separated from their mothers for seven days showed immunosuppression as well as "a marked reduc- tion in their antibody response" when challenged with a benign bacte- riophage. However, in keeping with the importance of the environment in affecting response to loss, infants left in their home cage during sepa- ration showed less immunologic deficit than those moved to novel set- tings. In support of hypotheses regarding the role of genetic factors, par- allel studies in the rhesus macaque have suggested rather different results. Despite their typically pronounced behavioral response to sepa- ration, but perhaps related to their lower adrenal response profiles, the rhesus failed to show immunosuppression after seven days of separa- tion. The development of virally induced neoplasms in animals and infec- tious diseases in human beings and animals may be enhanced or dimin- ished depending on the tvDe of stre.~f,~1 .cit',~tic~n 2-4,17 Ctr-~e has Lear' ,, -~ . v ~^ ~ .A-C, Labs ~ shown to attect humoral and cell-mediated immuni~v End m~r.rn ~ ~ _ .. . . . puages, warn acute stress Increasing the immune response and chronic stress decreasing it.~75 Stress such as steep deprivation has caused ini- tial immunosuppression, followed by enhancement of the immune re- sponse.s~ In reviewing the positive and negative effects of stress on immune function in animals, Ader3 concluded that "in general. high strew ~1e ~ ~ 1~: _ _ ~ _ _ 1_ ~ ~U1~b ~Ulil~lIl~U won a presumed unsuccessful coping response were correlated with depressed immunologic defenses." The impact of stress on disease depends on "the quality and quantity of stressful stimula- tion, the quality and quantity of immunogenic stimulation the mvri~1 1~. Len 1 - 1 'cur` Or upon wn~cn stress and immunogenesis are supenmposed, the temporal relationship between stress and immunologic stimula- tion, procedural factors such as the nature of the dependent variable and sampling procedures, and the interaction between any or all of the above. " Human beings also respond to stress with immunologic changes, which probably are determined by a combination of the same variables. Among psychiatry trainees facing their final exam for fellowships, those who were highly stressed psychologically displayed transient increases in T- and B-celIs but decreases in plaque formation and response to mi- togens prior to the exam. These values returned to normal later. Palmblads~ cites studies of bereavement and other life changes that have shown depression of both humoral and cell-mediated immunity, corre- lating most highly with the amount of subjectively perceived stress. SchIeifer and his colleagues7~ studied immune function in a group of 15 widowers and found that in vitro lymphocyte response to stimulation

160 / Bereavement: Reactions, Consequences, and Care by common mitogens was significantly lower in the two months fol- Towing the deaths of their wives, compared with prebereavement levels. The total numbers of B- and T-celIs were unaltered, suggesting altera- tions in subpopulation ratios or defects in responsivity. After two months, some responses improved but others did not. Bartrop and oth- ersS also found that T-cell function was significantly decreased after be- reavement, without a change in T-cell number. There was no change in B-cell function, nor in adrenocortical, adrenomedulIary, or thyroid hor- mones. Further evidence of psychoneurologic influence over the immune sys- tem is provided by the many studies of behavioral conditioning of im- mune function.4 Ader2 has written a historical account of conditioned immunobiologic responses, in which he notes that studies of such re- sponses originally done in Russia early in this century were based on the belief that immunologic mechanisms were basically physiologic phe- nomena under complete control of the brain. Repeated experiments have shown that so-called "natural" defense mechanisms (cell-medi- ated immunity, phagocytosis, etc.J were readily conditionable, with less evidence being provided for conditionability of humoral immunity. Ader points out the variability of results, depending on the antigen used, the conditioned stimulus, and other factors, and states that it is too early to determine the mechanism by which conditioned immunosup- pression occurs. There is also evidence that immunosuppression can be hypnotically induced in human beings.6 73 75 These findings indicate that immune systems are influenced directly by the central nervous system as well as by hormonal factors. The pre- cise mechanisms are as yet unclear, but it appears that stress of many kinds affects both the endocrine and immune systems and that grieving, considered as a type of stress, would be expected to do so as well. A cautionary note about interpreting measurements of immune func- tion must be added, however, along with an argument for clinically rele- vant research involving human subjects. Assessment of T-cell or B-cell functions in vitro is of uncertain meaning in regard to actual vulnerabil- ity to infection. When these measures are done in a clinical setting, ex- treme values generally do indicate immune incompetence. Further evi- dence is required to demonstrate that the association of grieving with lesser immune changes actually bears a relationship to health. Studies of bereavement and immune function have primarily investi- gated mitogen-induced lymphocyte stimulation, which is an in vitro correlate of immunity and provides a general measure of the lympho- cyte's ability to synthesize deoxyribonucleic acid and ultimately divide.

Toward a Biology of Grieving / 161 Mitogen activation is a useful probe, but it does not involve processes associated with the induction of an immune response. The ability to mount an immune response to an antigen is a primary and specific func- tion of the immune system requiring both antigen recognition and ef- fector processes. One approach, which has yet to be applied systemati- cally, is the direct measure of immune functions in human beings in viva. For example, by skin testing two agents to which nearly everyone is sensitive {"allergic" J. such as candida or trichophyton, it seems pos- sible to establish the nature and intensity of the skin response as a func- tion of psychological state, changing over time. Alterations in measure- ments of antibodies to cytomegalovirus or herpes virus might also be considered. Another potentially helpful advance would be development of reliable techniques for assessing the incidence of minor cutaneous infections, head colds, and other infections during the grieving process. There are not only urgent needs but also promising opportunities for the direct study of the clinically relevant biology of grieving, including im- munity, in the human being. GRIEF AS AN ADAPTATION IN A " PSYCHONEUROIMMUNOENDOCRINE SYSTEM" There are abundant data on the effect of psychological events on the endocrine and immune systems and a growing body of information on the endocrine-immune interaction. Probably these interactions are not a one-way street. Thus, a "psychoneuroimmunoendocrine system" can be envisioned. Grief may be viewed as a series of events or reactions in an activated "psychoneuroimmunoendocrine" system that may come to a favorable or at least neutral outcome for health or to less favor- able and maladaptive consequences. As shown in Figure 2, the system in simplified form is composed of elements that fluctuate in terms of blood level or activity level. Implicit in the diagram is the existence of effecter arms linking each system to another, and also feedback arms. The description in previous sections has already dealt extensively with many of the effecters. There are pos- sibilities for connections with other mechanisms and systems. This system is hypothesized to be a basic, coordinated mechanism for the response of the organism to stress or arousal and to more chronic events such as loss and bereavement. The activated hypothalamus se- cretes corticotropin releasing factor, which triggers release of a large peptide synthesized in the pituitary. This peptide, pro-opio-melano- cortin {POMC) contains ACTH, d-endorphin, and other peptides with

162 / Bereavement: Reactions, Consequences, and Care FIGURE 2 The Psychoneuroimmunoendocrine System. EXTERNAL STIMULUS CENTRAL NERVOUS SYSTEM ENDOCRINE 7~ He's SYSTEM less well understood functions. Some of these peptides or some smaller peptides derived from them are believed to play a role in affective and . . , cognitive function. in, . ..... . . ~ nere Is tne poss~ty that the secretion of one or more products of POMC leads to the activation of various portions of a psychoneuroim- munoendocrine system with separate and important functions. Thus, the effect of adrenal stimulation may be of consequence in the meta- bolic "preparation" for threat of injury. The catabolic state induced by adrenal activation may provide the organism with an important sub- strate for energy metabolism. The simultaneous secretion of substances that suppress immune function may serve as a protection by transiently halting the immune response to a flood of antigens appearing from en- dogenous {proteolysis) or exogenous {injury) effects. The presence of 3- endorphin and other brain-related peptides may provide the transient alla',, u' ~vct' Hi aier~ness required to focus on tne extema threat and deal with it in the most appropriate way possible. This integrated system may also be utilized in dealing with chronic arousal such as grief. In this circumstance, the presence of neurohor- mones that may assist in denial and may therefore permit the metering of recognition of external events in a slow and staged way may be called upon with each new flood of arousing stimuli. The immune or other effects of the system may become increasingly "maladaptive" in the chronic situation. The adverse biological consequences of continued, "inappropriate" need for activation of the system are evident. Perhaps certain genetic characteristics, the use of culturally learned practices, the intervention of key figures in the social network, or other such fac- tors can reduce a person's "need" to utilize this system in the solution of the problem of grief. The approach outlined above has the merit of suggesting how im- munosuppression, for example, might come about as a maladaptive use of a system, functioning on behalf of the need for unusually prolonged _ . ~ . . . .

Toward a Biology of Grieving / 163 or excessive autopalliation in the face of grief that is particularly diffi- cult to resolve. Such a unified approach, which ties together psychologi- cal, endocrine, and immune events, is most attractive but will require validation by much clinical, cross-disciplinary, Tong-term observation. CONCEPTUAL FRAMEWORKS In the absence of good data, theories abound. And theoretical posi- tions determine what questions are asked and what data are collected as well as how studies are interpreted. Thus, it is important to have some insight into the main theoretical outlooks with which clinicians and investigators approach the subject of the biological nature of grief. The remainder of this chapter summarizes three current theoretical frame- works. It should be noted that they are not mutually exclusive and may even be integrated eventually as data are obtained. Bexcavement as a Stressor As mentioned previously, the current information available on stress and health has been summarized in an Institute of Medicine report.~7 The physiologic responses to a range of external events viewed as stress- fu] have identifiable effects on biological systems. The stress imposed on the bereaved person derives from the internal disequilibrium created both by Toss and the attempt to regain homeostasis and by the external disruption of the environment following loss of someone close. Grief could be considered a reaction to stress that is unusual in at least two respects its chronicity {the Toss of the loved object is forever) and the absence of an effective repertoire of behaviors to undo the stressor The love object cannot be brought back without hallucinations or a denial of reality). Rose and his colleagues66 pointed out that successful mechanisms for managing stress are not always equivalent to adaptive coping mecha- nisms. In bereavement, the common immediate response to loss is de- nial. As discussed in Chapters 3 and i;, this response is not adaptive over time, but it allows the bereaved to function immediately after the loss. The Tonger-term goal is to recognize and accept the loss and to return to normal functioning. The active, goal-directed behavior so commonly used successfully in adapting to other stressful situations is useless. The central task for the bereaved, therefore, is to reconcile them- selves to a situation that cannot be changed and over which they have no control. Studies on both human beings and animals indicate that the sense of control is an important variable in the psychological and physi

164 / Bereavement: Reactions, Consequences, and Care ologic consequences of stress. Uncontrollable shock in animals has been demonstrated to be more effective than controllable shock in the promotion of gastric uIcerations,83 immunosuppression, jj tumor growth,36 74 and a depression-like syndrome.84 In animals given uncon- trolIable shock, Weiss et al.84 observed similar behavior to the criteria for major depression as defined in the American Psychiatric Associa- tion's Diagnostic and Statistical Manual. Neuroendocrine changes were also correlated with both. In observing the development of gastric uicer- ation in rats subjected to inescapable shock, Angelo proposed that to be without the information and/or the psychological behavioral resources tO cope effectively with a particular life circumstance appears to be a highly significant vari- able. Under such conditions, the organism typically alternates between activity and inactivity, the first reflecting efforts to maintain or reestablish control, the second waiting or giving up. If its efforts succeed, or If circumstances change soon enough, illness may be averted. But the longer such cycles of stn~ggling and inactivity go on, the greater the risk of morbidity. Several human studies indicate that it is the subjec- tive experience, rather than the external situation, which is the best predictor of a person's reaction, be it emotional or physical. There is physiologic evidence indicating that responses to the stresses of bereavement are not the same for all people and that individual re- sponses are situation-specific. In comparing psychological and endo- crinologic data on parents before and after Toss of their children, Hofer et al.33 emphasized that the "chronic stress mean" of a person anticipating loss applied only to that situation and could not be annlier1 to other ~ ~ _~1 ~.~ : A_ _ ~ ~ ~ 1 _ · ~ . · .. · . . .. Bout ;. o`;nlelrer el al.~1 arrived at tne same conclll~ion in studying lymphocyte activity before and alter death of a spouse. Ma ~ ~ ~ . - 1 ~ ~ ~ ~ ~. _ , ~, ~ ~^ ~ v v ~ ~4~) OUt1-- 11~1~ ~l'QWll tUHt Hormonal response patterns vary, depending on the stimulus. He described several situations of "stress" isuch as acute avoidance, sleep deprivation, and fasting in which the patterns of corti- sol, norepinephrine, and epinephrine are different. Kuhn and his colleagues44 also observed different physiologic re- sponses, as measured by omithine decarboxylase activity, in response to maternal separation and other types of stress in rats. Both Engeli9 and Ader and Cohen4 noted that the relationship between "stress" and dis- ease in animals depended on both the type of stress and the nature of the disease. Thus, it cannot be assumed that because one physiologic pat- tem is present in response to one type of stress, it is the prototype for all stress responses. The use of inescapable or uncontrollable punishment in animal studies appears to result in a type of stress similar to the hope- lessness-helplessness syndrome described by Engel and SchmaTe.20 These studies may be helpful in providing a conceptual framework from which to investigate the biology of grieving, in particular the response to unavoidable stress.

Toward a Biology of Grieving / 165 Social Relation ships as Biological Regulators Disruption of Biological Rhythms. As described earlier in this chap- ter and in several previous chapters, people typically have a number of symptomatic responses to bereavement. These include physiologic, be- havioral, cognitive, and perceptual disturbances as well as a disorgani- zation of ego functioning. Although the links between all these changes are not well understood, it has been hypothesized that social relation- ships may be an important regulator of these various responses. Reviewing animal studies and some human studies, Hofer32 summa- rized the behavioral and physiologic components of the infant separa- tion response and called attention to the similarities between it and the human adult response to bereavement {Table 2~. In studies on infant rats, there is a clear difference between the acute and chronic phases of the separation response; the phenomena of the slow phase remain even when the acute phase is prevented.27-3i 76 What TABLE 2 Infant Separation Responses Animal Studies) Phase Behavior Physiology Acute "Protest" phase last . . 1ng mmutes or hours Chronic . . Agltatlon Vocalization S earching-inactivity Increased heart rate Increased cortisol Increased catecholamines Slow developing Decreased social Decreased body weight "despair" phase interaction, Sleep disturbance lasting hours decreased play Decreased rapid eye move or days Mouthing, rocking ment Hypo- or hyper- Increased arousals responsiveness Metabolic: Decreased or decreased core increased food temperature intake decreased oxygen Postures and facial consumption expressions of Cardiovascular: sadness decreased cardiac rate decreased resistance increased ectopic beats Endocrine: decreased growth hormone Immune: decreased T-cell activity

166 / Bereavement: Reactions, Consequences, and Care Hofer has suggested is that the slow phase response is actually the sum of many responses to the loss of many separate aspects of the mother- infant interaction. He found that preservation of a single aspect of the mother-infant relationship could prevent a single physiologic change, without affecting any other of the physiologic responses to separation. From analytic studies on infant rats separated from their mothers, a number of "hidden regulators" have been discovered within the mother-infant relationship, which act to maintain the homeostasis of the developing child. There is evidence of biologically powerful sensorimotor regulators even within adult social relationships, such as the menstrual synchrony that develops in young women who live together, 04 and bereavement may constitute a Toss of these regulators as well as an emotional loss. The data {Table 3) from studies of sensory deprivation, jet lag, and work shift changes can be used to emphasize the importance of unseen regula- tors in human behavior and to illustrate the similarities in the physio- logic responses to these varied disturbances of internal equilibrium. There is an obvious similarity between these responses and the cogni- tive and perceptual disturbances seen in the chronic grief response, all TABLE 3 Responses to Disrupted Regulation of Homeostas~s Human StudiesJ Symptoms following sensory deprivation: Fluctuating concentration and attention Restlessness, anxiety Difficulty in ordering thoughts Decreased food intake Illusions and hallucinations Decreased body weight Sleep disturbance Muscular weakness Symptoms following jet travel across time zones: Decreased vigilance, decreased attention span Decreased appetite Sleep disturbance Malaise, fatigue Symptoms following work shift change: Decreased vigilance Cognitive impairment Insomnia Weakness, fatiguability Depression, hostility

Toward a Biology of Grieving / 167 of which contribute to the feeling of losing control. The similarities in physiologic disturbances resulting from bereavement, sensory denrivn- tion, jet lag, and work shift change have led Hofer32 to postulate that the regulators' function was to maintain the biological rhythms of the indi- vidual. The death of someone with whom a person has lived in close proximity involves the loss of social entraining stimuli for circadian systems, and may therefore disrupt normal biological timing. In fact, there is evidence that social interactions for human beings may be the cues regulating human biological rhythms, rather than light or tempera- ture as in other species. Hofer32 suggests that these somatosensory regulators may be the pre- cursors of psychological regulators that take over as the infant matures. He contends that disturbances of physiologic regulation may be in- vo~vea even In the loss ot someone who has been living far away, be- cause internal representations of the person may have served a regula- tory function; when these are altered in the psychological process of grieving, their regulatory function may be dissolved. Study of the regu- latory aspects of social relationships may eventually lead to some un- derst~nding of the mechanisms by which the presence or absence of so- cial support systems modifies physiologic responses to stress and vulnerability to disease. Rhythms in the Endocrine and Immune Systems. ~, . . ~, _ ~. , . It is well known that cortisol levels in plasma and urine are cyclical. There is evidence that many other hormones and biochemical systems also have cyclical patterns.56 Catecholamine excretion displays periodicity, for example, and growth hormone secretion, although not itself rhythmic, changes in response to other variables that are in turn rhythmic. The cycles of all hormones are influenced by many environmental variables, and it seems likely that social interactions and their sudden alteration after bereavement may exert major disruptive effects. The immune system also follows a daily rhythm. Tavadia and col- leagues79 found that the circadian rhythm followed by cortisol secretion is accompanied by changes in the number of lymphocytes and in mito- gen-stimulated lymphocyte transformation. Cortisol and lymphocyte transformation were directly correlated, but both varied inversely with absolute numbers of lymphocytes. Maestroni and Pierpaolis° suggest that the lymphopenia seen after pinealectomy may be due to the loss of rhythmicity previously regulated by the pineal body. Others38 have tounct circadian rhythms involved in immune competence, and Kort and Weijma38 recently demonstrated that the stress of a chronic light- dark cycle shift in rats resulted in decreased lymphocyte response to a , . . ..

168 / Bereavement: Reactions, Consequences, and Care mitogen and decreased immune response as measured by popliteal lymph node assay, but not in a change in adrenocortical activity. Grief and Depression on a NeurobioJogica] Continuum As discussed in the section on promising research approaches, the phenomena of bereavement mirror to a considerable extent the symp- toms and signs of depressive illness and share some aspects of anxiety states. Because overt depressive illness and, to a lesser extent, severe anxiety states are often precipitated by major Tosses, it seems reasonable to look for connections between bereavement and these two common psychiatric disorders. Indeed, it is a plausible hypothesis that the three conditions share a common neurobiological substrate. Klein37 has made a strong case for this point of view, and his concep- tual basis for this involves the temporal contiguity of the protest and despair phases in infantile separation responses as early "AnIagen" of the adult conditions. Klein follows Bow~by's view that these two infan- tile responses are deeply embedded in phylogenetic history, and hypoth- esizes that some individuals, even when they are adults, have low thresholds for elicitation. In some, the system may even discharge spontaneously, resulting in classical panic attacks. As Klein points out, patients with panic attacks also have an increased incidence of depres- sive episodes. But it was the finding that the same drug, the tricyclic antidepressant, imipramine, prevented panic attacks as well as depres- sion that prompted Klein to develop his theory. He supposed that imip- ramine raised the threshold to both conditions by acting on a common neurochemical substrate. Other findings tend to link depressive illness with bereavement. Both conditions seem to imperil the resistance of an individual to major physical challenges and have been associated with increased incidence and severity of a number of medical conditions. Second, both condi- tions result in increased rates of suicide. In addition, there is some lim- ited evidence for similarity in neuroendocrine responses. Thus, in women undergoing psychotherapy for reactive depression, Sachar and his collaborators69 noted a peak in corticosteroids when patients con- fronted the fact of the precipitating loss during therapy. The bereave- ment is often considered more painful than the chronic depression after loss, which may be defensive and help the person to avoid experiencing the Toss. Abnormal endocrine patterns are present in major affective disorders such as depression. Abnormalities in growth hormone, insulin, and thy- roid-stimulating hormone are often observed in depression.67 Depressed

Toward a Biology of Grieving / 169 individuals tend to have high ACTH and cortiso! levels and fait to fol- low normal diurnal rhythmicity; many severely depressed people fail to depress cortiso! levels in response to an exogenous corticosteroid, dex- amethasone. However, a new study40 from Yale of the dexamethasone suppression test in bereaved individuals who met the criteria for a diag- nosis of major depression revealed the great majority as having normal adrenocortical responses-not those considered typical of depression.4" On this dimension, then, severe grief reactions would seem to occupy a place on a neurobiologic continuum that is distinct from the one occu- pied by major depression. This study notwithstanding, most of the evidence suggests that be- reavement may bear more than a superficial resemblance to depressive illness and that it would be appropriate to continue to search in the be- reaved for some of the biological phenomena that have been found in depressed patients and in those with panic disorders. CONCLUSIONS Very little is known about the biology of the varying states of grief. Clues about promising avenues for research in this field can be gleaned from the symptomatology and epidemiology of bereavement and from current knowledge about several of the body's regulatory systems. Ac- tive grieving produces a number of symptoms that suggest involvement of the respiratory, autonomic, and endocrine systems. The epidemiol- ogy of bereavement suggests that cardiovascular and immune function may be substantially altered by grief. And there are enough similarities between grief and depression to merit a comparison of neuroendocrine and other biological changes in the two conditions. Studies are needed on basic neurophysiologic parameters, including cardiovascular, thermal, and central nervous system regulation. In par- ticular, more information is needed on the long-term effects of bereave- ment: how do physiologic responses change during prolonged grief, both "spontaneously" and in response to specific stimuli and to other signif- icant life events? As more substantial baseline material is collected, possible genetic and experiential precursors should be sought to account for the variability in response encountered so often in studies of both animals and human beings. Considerable expansion of the knowledge of neurochemical changes accompanying the response to loss is required, including further investigation of neuroendocrine functions across a wider array of hormones as well as more studies of the neurotransmitter alterations that may underlie the dramatic and more subtle affective, motivational, and cognitive changes that emerge. In each of these areas,

170 / Bereavement: Reactions, Consequences, and Care further development of remote, miniaturized blood collection devices {which would permit study of free-moving subjects, as in neurophysio- logic research would provide substantial opportunities to gather signifi- cant new data. The preliminary data now available make it clear that traumatic loss experiences may have a long-term impact on the body's immune sys- tem. Expanding the data base on the disease susceptibility of bereaved subjects under controlled conditions and gaining further understanding of the basic immune processes that are affected will improve the chances that appropriate intervention models are developed. The relationship between the responses to loss and the patterns ob- served in response to other life stresses should be established more fully. Do the patterns during bereavement parallel those in other situa- tions in which "loss of control" is a prominent element? What types of physical and social environmental factors alter the intensity and time course of human physiologic responses? What is the meaning, in terms of basic processes and the possibilities for effective intervention and treatment strategies, of the fact that events at the behavioral and physi- ologic level are not always as congruent as might otherwise be expected? Research involving animal models plays a crucial role in generating new hypotheses and methods. But even more urgent is the need for prospec- tive human studies employing the most modern biological and psycho- Togical methods and concepts. REFERENCES 1. Ackerman, S.H., Keller, S.E., Schleifer, S.~., Shindledecker, R.D., Camerino, W.S., Hofer, M.A., Weiner, H., and Stein, M. Effect of premature weaning on lymphocyte stimulation in the rat. {Abstract.J Psychosomatic Medicine 45:75, 1983. 2. Ader, A. [Ed.J Psychoneuroimmunology. New York: Academic Press, 1981. 3. Ader, R. Stress and illness: immune processes. Paper prepared for the Institute of Medicine, Washington, I).C., 1981. 4. Ader R., and Cohen, N. Behaviorally conditioned immuno-suppression. Psychoso- matic Medicine 37:333-340, 1975. 5. Bartrop, R., Luckhurst, E., Lazarus, L., Kiloh, L.G., and Perry, R. Depressed lym- phocyte function after bereavement. Lancet 1:834-836, 1977. 6. Black, S., Humphrey, l.H., and Niven, I.S.F. Inhibition of mantoux reaction by di- rect suggestion under hypnosis. British Medical [oumal 5346:1649-1652, 1963. Board, F., Persky, H., and Hamburg, D.A. Psychological stress and endocrine func- tions: blood levels of adrenocortical and thyroid hormones in acutely disturbed pa- tients. Psychosomatic Medicine 18:324-333, 1956. 8. Breese, G.R., Smith, R.D., Mueller, R.A., Howard, J.L., Prangle, A.J., Lipton, M.A., Young, L.D., McKinney, W.T., and Lewis, J.K. Induction of adrenal catecho- lamine synthesizing enzymes following mother-infant separation. Nature New Bi- ology 246:94-96, 1973.

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"The book is well organized, well detailed, and well referenced; it is an invaluable sourcebook for researchers and clinicians working in the area of bereavement. For those with limited knowledge about bereavement, this volume provides an excellent introduction to the field and should be of use to students as well as to professionals," states Contemporary Psychology. The Lancet comments that this book "makes good and compelling reading....It was mandated to address three questions: what is known about the health consequences of bereavement; what further research would be important and promising; and whether there are preventive interventions that should either be widely adopted or further tested to evaluate their efficacy. The writers have fulfilled this mandate well."

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