5

Personal Ties

The preceding discussions of predisease pathways, positive health, and environmentally induced gene expression emphasize the importance of proximate social interactions. Understanding the mediating and moderating effects of personal ties on mental and physical functioning is necessary to elucidate fully the mechanisms underlying health and disease. Social factors, for instance, are capable of activating aspects of innate or natural immunity that are the earliest responses to infectious or inflammatory responses (Maier and Watkins, 1998), and social influences on gene expression have been demonstrated (Gottlieb, 1998; Wu et al., 1999).

THE CENTRALITY OF PERSONAL TIES

Personal ties are a ubiquitous part of life, serving important social, psychological, and behavioral functions across the life span (see Cacioppo et al., in press a). People form personal ties with others from the moment they are born. The survival of newborns depends on their attachment to and nurturance by others over an extended period of time (Baumeister and Leary, 1995). The human brain has evolved to recognize faces holistically (Farah et al., 1998). Distress vocalization, a signaling mechanism designed to solicit and sustain parental caring, is one of the most primitive forms of audiovocal communication. Language, the bedrock of complex social interaction, is universal in humans. Even in the rare instances in which human language is not modeled or taught, a language system develops



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New Horizons in Health: An Integrative Approach 5 Personal Ties The preceding discussions of predisease pathways, positive health, and environmentally induced gene expression emphasize the importance of proximate social interactions. Understanding the mediating and moderating effects of personal ties on mental and physical functioning is necessary to elucidate fully the mechanisms underlying health and disease. Social factors, for instance, are capable of activating aspects of innate or natural immunity that are the earliest responses to infectious or inflammatory responses (Maier and Watkins, 1998), and social influences on gene expression have been demonstrated (Gottlieb, 1998; Wu et al., 1999). THE CENTRALITY OF PERSONAL TIES Personal ties are a ubiquitous part of life, serving important social, psychological, and behavioral functions across the life span (see Cacioppo et al., in press a). People form personal ties with others from the moment they are born. The survival of newborns depends on their attachment to and nurturance by others over an extended period of time (Baumeister and Leary, 1995). The human brain has evolved to recognize faces holistically (Farah et al., 1998). Distress vocalization, a signaling mechanism designed to solicit and sustain parental caring, is one of the most primitive forms of audiovocal communication. Language, the bedrock of complex social interaction, is universal in humans. Even in the rare instances in which human language is not modeled or taught, a language system develops

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New Horizons in Health: An Integrative Approach nevertheless (Goldin-Meadow and Mylander, 1983). Evolution, it appears, has sculpted the human genome to be sensitive to and succoring of contact and relationships with others. The need to belong does not stop at infancy; rather affiliation and nurturant social relationships are essential for physical and psychological well-being across the life span (Gardner et al., 2000; Seeman, 1996; Cohen and Syme, 1985). Affirmative social interactions—those satisfying needs for autonomy, competence, and relatedness—are related to feeling understood and appreciated (Reis, in press), and emotional disclosure improves affect and physical functioning among rheumatoid arthritis patients (Kelley et al., 1997). Disruptions of personal ties, whether through ridicule, discrimination, separation, divorce, or bereavement, are among the most stressful events people must endure (Gardner et al., 2000). Models of mental illness suggest that biological events (e.g., genetic heritage, in utero insult) produce a susceptibility to severe mental illness, but it is this vulnerability combined with the stress of life events, especially social events, that produces mood disorders, psychotic symptoms, or social apathy in late adolescence or early adulthood. Cognitive and interpersonal deficits in childhood and adolescence can further impair individuals from learning social and instrumental skills that help them avoid life stressors and achieve age-appropriate social roles. In sum, inadequate and restricted social connection during infancy and childhood has dramatic effects on psychopathology across the life span. Relationships in adult life have been studied for their contributions to intimacy (Berscheid and Reis, 1998) and well-being (Myers and Diener, 1995; Ryff and Singer, 2000; Sternberg and Hojaat, 1997) as well as the adverse consequences of divorce and bereavement (Kiecolt-Glaser et al., 1998), deficits in belongingness (Baumeister and Leary, 1995), and dispositional and cognitive factors contributing to loneliness and depression (Cacioppo et al., in press b; Marangoni and Ickes, 1989). Studies show that marital dysfunction and conflict have significant physiological consequences. A study of older adults and long-term marriages showed that 30 minutes of conflict discussion was associated with increases in cortisol, adrenocorticotropic hormone, and norepinephrine in women but not in men (Kiecolt-Glaser et al., 1997). Other studies have linked marital conflict with high blood pressure (Ewart et al., 1991), elevated plasma catecholamine levels (Malarkey et al., 1994), and autonomic activation (Levenson et al., 1993). Family life can also contribute to stress and dysfunctional coping with consequences for detrimental health behaviors (e.g., smoking, sedentary lifestyles, poor eating habits, type A behavior patterns). Characteristics of the family environment that may undermine the health of children and adolescents include a social climate that is conflictual and angry or even

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New Horizons in Health: An Integrative Approach violent and abusive; parent-child relationships that are unresponsive and lacking in cohesiveness, warmth, and emotional support; and parenting styles that are either overly controlling and dominating or involved with little imposition of rules and structure (Taylor et al., 1997). Empirical evidence suggests that long-term exposure to such conditions contributes to deficits in emotional understanding, difficulties with appropriate expression of emotion, increased emotional reactivity to conflict, and maladaptive coping strategies for managing stressful events more generally (Repetti et al., in press). Apart from family life, the social world also involves comparisons and standards that may be consequential for health. In the traditional culture of Fiji, the ideal body is robust, but satellite TV brought shows to Fijians that featured svelte women. In a 1995-1998 survey, teen Fijian girls who watched TV at least three nights per week were 50 percent more likely than others to report feeling too big or fat and were 30 percent more likely to diet even though the more frequent TV watchers were not more overweight. Fifteen percent said they had vomited to control their weight, up from 3 percent in 1995, and the proportion who scored high on risk for disordered eating was 29 percent in 1998, in contrast to 13 percent in 1995 (Becker, 1999). At the population level of analysis, epidemiological studies have shown that social isolation is a major risk factor for morbidity and mortality from widely varying causes (Berkman and Syme, 1979; Berkman and Breslow, 1983; House et al., 1988; Seeman et al., 1993). This relationship is evident even after statistically controlling for known biological risk factors, social status, and baseline measures of health. Astonishingly, the strength of social isolation as a risk factor is comparable to high blood pressure, obesity, sedentary lifestyles, and possibly even smoking (House et al., 1988). Increased survival has been associated with high quantity or quality of social relationships in several prospective studies (Funch and Marshall, 1983; Joffres et al., 1985; Rodin, 1986; Goodwin et al., 1987; Ganster and Victor, 1988; Kennedy et al., 1988; House et al., 1994). Women not socially isolated were at substantially lower risk for dying of cancer (Reynolds and Kaplan, 1990), and married cancer patients survived longer than unmarried persons (Goodwin et al., 1987). Emotional support is associated with longer survival following breast, colorectal, or lung cancer (Ell et al., 1992). Being part of a social network, however, can have detrimental as well as salubrious effects. Membership in networks, for example, provides access to domestic, economic, and informational resources (Uehara, 1990). The value to the individual of such ties, however, depends on the character of the network. If one's ties are limited to a tightly knit group, the resources available through that group, especially informational resources, are likely

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New Horizons in Health: An Integrative Approach to be limited, whereas ties to others who are otherwise unconnected expands the potential resource base (Pescosolido, 1986, 1991; Uehara, 1990). A final realm of relevant research pertains to the experimental literature in animals, where possible confounds can be better controlled. Here the absence or impairment of personal ties has been associated with altered physiological responses. In a series of studies in cynomolgus monkeys, experimentally induced social disruptions and instability were found to promote coronary atherogenesis (Manuck et al., 1995; Skantze et al., 1998). Animals exhibiting a heightened cardiac reactivity to stress developed the most extensive coronary lesions. Disruptions of personal ties were further shown to increase the formation of endothelial lesions even in the absence of an atherosclerosis-inducing diet (Skantze et al., 1998). On the positive side, animal studies also clarify the neurobiology of affiliation and attachment (Panksepp, 1998). A review of caregiver-infant and adult-adult (heterosexual) pair bonds showed recurrent associations between high levels of activity in the hypothalamic-pituitary-adrenal (HPA) axis and subsequent expression of social behaviors and attachments (Carter, 1998). Central neuropeptides, especially oxytocin and vasopressin, are implicated in social bonding and central control of the HPA axis. Moreover, in both male and female rats, oxytocin exerts potent antistress effects, such as decreases in blood pressure, heart rate, and cortisol levels, with effects lasting from one to several weeks (Uvnäs-Moberg, 1997, 1998; Petersson et al., 1996). Together, these human and animal studies provide extensive evidence of linkages between the social relational realm and health. Some focus on proximal social ties and their implications for health behaviors, while others examine the neurobiology of interpersonal conflict or relational intimacy. Still other inquiries document, via large epidemiological samples, links between social integration or isolation and unfolding profiles of morbidity and mortality. How the social world is structured by community environments (see Chapter 6) and macro-level influences (see Chapter 8) is also a key target for future inquiries. A major message is that all such levels of analysis are necessary to fully explicate how personal ties impact health. The mechanisms underlying these effects cannot be fully explicated by biological, behavioral, or social approaches alone but rather require multi-level integrative analyses. The following sections describe areas of particular importance in advancing this broad agenda. Key future directions pertain to studies of how personal ties influence genetic expression as well as brain structure and function and neuroimmunological activity. The links between social factors and infectious disease are also considered. A final section underscores the need to connect the extensive epidemiological literature on social support and health to the mechanisms (behavioral, neurobiological) through which these effects occur.

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New Horizons in Health: An Integrative Approach PERSONAL TIES AND GENE EXPRESSION As described in Chapter 4, extended disruption of personal ties, such as that experienced by people caring for their spouses with Alzheimer's disease, results in significant suppression of lymphocyte growth hormone (LGH; Wu et al., 1999). It is likely that this suppression is due to the effects of stress hormones and catecholamines on gene expression (Malarkey et al., 1996) and may compromise immune function. The social influence on gene expressions is also illustrated in recent research on early nurturance. Rhesus monkeys characterized by high hypothalamic-pituitary-adrenal (HPA) reactivity have a lower threshold for stress reactions and show larger responses to stressors than their genetically less reactive counterparts. The mothers of low-and high-reactive monkeys also differ in their attention to and nurturance of their infants, with the mothers of high-reactive monkeys being less attentive and nurturant. Cross-fostering, however, influences the phenotypic expression of these genotypes: High-reactive infants raised by low-reactive mothers produce adults who are low in stress reactivity. Thus, HPA reactivity is a genetically inherited trait, but high reactivity can be controlled by modifying personal ties during development (Suomi, 1999; see Chapter 2). Research further shows that early tactile deprivation reduces the number of glucocorticoid receptor binding sites in the hippocampus and frontal cortex via an action on gene expression (Meaney et al., 1985). Studies of rat pups show that transient early life stress (e.g., brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, whereas more severe early life stressors (e.g., protracted separation from the dam) accentuate responses to these stressors in adulthood (Anisman et al., 1998). These early life experiences particularly affect HPA functioning, which can modify the responses to subsequent stressors. These effects again appear to be mediated by variations in maternal care. Cross-fostering with mothers who exhibited more licking and grooming and nurturance of pups during the first 10 days of life revealed reduced adrenocorticotropic hormone and corticosterone responses to acute stress. As mothers these rats also tended to lick and groom their pups (Liu et al., 1997; see Chapter 4). Collectively, these studies illustrate the reciprocal influences between the social and biological factors in health and, in so doing, reframe the guiding questions as fundamentally about the roles of nature and nurture. PERSONAL TIES AND BRAIN FUNCTION AND STRUCTURE Personal ties constitute a major influence on the emotions of an individual, which are increasingly recognized to be important for fundamental

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New Horizons in Health: An Integrative Approach tasks of survival and adaptation (Damasio, 1994; Pinker, 1997; Ekman and Davidson, 1994). In addition, plasticity in the neural circuitry underlying emotion plays an important role in the influence of early environmental factors on later behaviors and psychopathological susceptibility (Meaney et al., 1996). Research demonstrates a number of ways that emotions affect brain functioning. For example, positive affective states induced by viewing film clips increases left-side prefrontal and anterior temporal activation, whereas induced negative affect elicits an opposite pattern of asymmetric activation (Davidson et al., 1990). The right inferior region and the right medial orbital region of the prefrontal cortex have been found to be activated more strongly among individuals exhibiting anxiety disorders than among controls not exhibiting psychopathology (Rauch et al., 1997). Studies of patients with selective bilateral destruction in the amygdala suggest the importance of this brain region for specific tasks involving emotional processing (Davidson et al., 2000). From a developmental perspective, brain electrical measures of baseline prefrontal activation asymmetry show little stability between the ages of 3 and 11 (Davidson and Rickman, 1999), a period during which the central circuitry of emotion, particularly in the prefrontal cortex, is still undergoing development (Huttenlocher, 1990). Emotions also can affect the development of specific brain regions. As already discussed, the early interactions between rat pups and their mothers —frequency of maternal licking/grooming and arched-backed nursing—and the resulting biological changes affect the pups' response to stress stimuli as adults. In addition, these offspring show increased central benzodiazepine receptor densities in parts of the amygdala and in the locus coeruleus (LC), increased density of corticosteriod receptors in the LC, and decreased corticotropin-releasing hormone receptor density in the LC (Caldji et al., 1998). They also show increased concentrations of receptors for glucocorticoids in both the hippocampus and the prefrontal cortex (Liu et al., 1997; Meaney et al., 1996). Rhesus monkeys exposed to a human intruder who appears in profile (i.e., makes no eye contact) freeze more frequently and for longer duration than do animals at which the intruder stares (Kalin et al., 1998). A few animals, however, display levels of freezing during the stare condition that are indistinguishable from their freezing during the no-eye-contact condition. These animals show more extreme patterns of prefrontal cortex activation asymmetry and cortisol levels than their counterparts. Behavioral differences that help account for some of the variance in base levels of prefrontal activation asymmetry and cortisol levels were revealed only when behavior under exceptional conditions was assessed (Kalin et al., 2000). Individuals who habitually fail to regulate their affective responses in a

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New Horizons in Health: An Integrative Approach context-sensitive situation may have functional impairment of the hippocampus and/or stria terminalis (Davidson et al., 2000). Collectively, such findings highlight the plasticity of certain regions of the brain and raise the possibility that social and behavioral interventions, even those occurring during adulthood, can not only affect neural function but also influence neurogenesis. Critical for future research are inquiries working at the nexus of social interaction, emotion, and brain activity. The growing field of affective neuroscience (Davidson, 1998; Panksepp, 1998) is well poised to make major contributions to such integrative initiatives. PERSONAL TIES AND NEUROIMMUNOLOGICAL ACTIVITY Empirical observations of social influences on autonomic activity date back more than 2,000 years (Mesulam and Perry, 1972). Until recently, however, immune functions were thought to reflect specific and nonspecific physiological responses to pathogens or tissue damage. It is now clear that the immune system is tightly regulated and integrated with the nervous and endocrine systems and that social events influence immune function through these systems. A bidirectional communication network comprised of soluble ligands and cellular receptors links both afferent and efferent functions of the immune system to the nervous and endocrine systems. Thus, a stimulus within the nervous system that activates the sympathetic adrenomedullary and HPA axis results in peripheral release of catecholamines and adrenal steroids, respectively, that have immunoregulatory potential. Similarly, a challenge within host tissue that induces an inflammatory response (e.g., an infection or a wound) results in the release of cytokines that stimulate peripheral and central circuits of the nervous system. This communication provides an important link through which the neuroendocrine response modulates the development of an inflammatory response at a site of challenge (Kusnecov et al., 1999; Maier and Watkins, 1998). Personal ties are capable of activating aspects of innate or natural immunity that lead to the expression of illness behaviors (e.g., fever, reduced food and water intake, reduced social and sexual activity, depressed mood). These behaviors are some of the earliest responses to infectious or inflammatory challenges (Maier and Watkins, 1998). Natural immunity also encodes a number of protein molecules that provide initial resistance to the replication and spread of microbial pathogens and set the microenvironmental stage for the subsequent development of specific immune responses necessary to eliminate the pathogen (Bonneau et al., 1991). Among the protein molecules induced during challenge are the proinflammatory cytokines (e.g., IL-1, TNF, and IL-6). These cytokine responses represent peripheral signals that are conveyed through the blood-brain barrier to the

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New Horizons in Health: An Integrative Approach central nervous system to induce illness/sickness behaviors (Fleshner et al., 1997). Stress mediators associated with personal ties can be protective and adaptive as well as damaging. For example, significantly larger numbers of leukocytes were found in the skin of stressed animals both before and after experimental introduction of antigen (Dhabhar and McEwen, 1999), suggesting that stress prepared the immune system to respond to challenges such as infection. The bidirectional effects of stress on skin immunity are mediated by the adrenal hormones corticosterone and epinephrine. However, while acute stress is immunoenhancing, chronic stress is immunosuppressive (Dhabhar and McEwen, 1997; Dhabhar et al., 1995). The chronic stress of caring for a relative with dementia was linked with elevated SAM and HPA activation and diminished immune function, such as reduced proliferative responses of peripheral blood leukocytes (Kiecolt-Glaser et al., 1991), lower natural killer cell response (Esterling et al., 1994), and impaired antibody response to influenza virus vaccine (Kiecolt-Glaser et al., 1996). Similar results have emerged from studies of the effects of psychosocial stress on vaccine responses. Using the stress of taking a university examination (Glaser et al., 1992) or the chronic stress of being a caregiver (Kiecolt-Glaser et al., 1996; Glaser et al., 1998), the response to vaccination was examined during the stressful period. In both cases, vaccine responses were attenuated in the stressed groups. Caregivers of relatives with progressive dementia have also shown impaired wound healing relative to controls matched for age and family income (Kiecolt-Glaser et al., 1995, 1998). Alteration of immune function has been observed among persons in marital conflict (Kiecolt-Glaser et al., 1987). Specifically, negative or hostile behaviors during a marital conflict produce greater and/or more persistent alterations in autonomic activation and circulating stress hormones. Couples characterized by high, relative to low, negative behaviors during a marital conflict also show greater decrements over the 24 hours of study on natural killer cell lysis, the blastogenic response to two mitogens, and the proliferative response to a monoclonal antibody to the T3 receptor (Kiecolt-Glaser et al., 1994). PERSONAL TIES AND INFECTIOUS DISEASE In an experimental study of stress and infectious illness, healthy volunteers reported their level of stress and were exposed to saline or one of several strains of respiratory virus (Cohen et al., 1991). Following inoculation, subjects were quarantined and monitored for the development of respiratory illness. After seven days of quarantine, each participant was classified as not infected, infected but not ill, or infected and ill. No

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New Horizons in Health: An Integrative Approach participant exposed to saline became ill, and about a third of the participants exposed to the cold viruses became ill. Results revealed that three measures of stress were related to disease onset: (1) a stressful life event scale to measure the cumulative event load, (2) a perceived-stress scale to assess perceptions of overload-induced stress, (3) and a measure of negative affect. For all three measures, participants who reported high stress were more likely to develop an infection than those who reported low stress (Cohen et al., 1991). Subsequent research has determined that risk of infection was increased most by stressors lasting over a month, especially those involving disruptions in personal ties (i.e., social conflicts, unemployment, and underemployment; Cohen et al., 1998; Glaser et al., 1999). Social influences on infectious disease processes have also been linked with gene expression. In an experimental model of pyschosocial stress, the stress of social disruption caused by reorganizing established murine hierarchies during a respiratory viral infection significantly increased mortality compared to the stress of physical restraint in home cage control animals (Padgett and Sheridan, 1999). The increased severity of the infection leading to mortality was associated with hyper-inflammatory responses due to overexpression of key cytokine genes. Enhanced gene expression led to increased cell trafficking and accumulation in the lungs of infected animals, which in turn led to tissue consolidation and compromised lung function. These results contrasted with animals undergoing the stress of physical restraint, which is devoid of social interactions, but nonetheless activates the HPA axis in a similar fashion to the psychosocial stressor. However, hypo-inflammatory responses during respiratory viral infection were observed in these animals, due to suppression of cytokine responses by glucocorticoid hormones. Under these conditions, no increase in mortality was observed. Such findings underscore the unique significance of social interactional stressors in activating overexpression of cytokine genes implicated in increased mortality risks. The specific nature of the personal ties, particularly their hierarchical features, also plays a major role in the individual response to stress and susceptibility to infectious disease. For example, in the social disruption paradigm described above, dominant male mice, when latently infected in the trigeminal ganglia with herpes simplex virus (HSV, a model for recurrent herpes labialis in humans), were twice as likely as subordinate animals to reactivate and shed infectious virus when their social environment was disrupted by reorganization (Padgett et al., 1998). The psychosocial nature of the stressor was also important in this model, simply stressing latently infected mice by restraint did not cause reactivation. Again, it is social interactional stress that activates physiological signals modulating the expression of individual host/pathogen genes. In the model of latent HSV infection, the inactive viral genome represents an environmental (or for-

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New Horizons in Health: An Integrative Approach eign) gene that has parasitized the host. It resides in the neurons of the trigeminal ganglia and remains latent or inactive until an appropriate set of physiological signals is received. Importantly, it is psychosocial, not general, stress that provides the appropriate signals for reactivation of the viral genes leading to recurrent infection and the shedding of infectious virus. SOCIAL RELATIONAL ROUTES TO HEALTH A recent review of epidemiological research shows that, in each study examined, mortality was significantly lower among persons who were more socially integrated (Berkman, 1995). Such studies are, however, limited in their ability to address questions of causality between social relationships and health (Berscheid and Reis, 1998) because a large number of factors (sociodemographic, geographic, occupational, personality) covary with measures of social integration. Initial assessments of social isolation (or integration) emphasized objective features of social support such as the size or density of one's social network and frequency of contact with relatives and friends. Subsequent studies elaborated more subjective and/or functional aspects, such as the perception of emotional and instrumental support and assistance provided by others (Cohen, 1988; Cohen and Wills, 1985; Vaux, 1988). The social support field has been increasingly differentiated into specific substantive areas, such as the role of social support in stress and coping (Thoits, 1995), social support in family relationships (Pierce et al., 1996), social support and personality (Pierce et al., 1997), and social support in differential survival from various health challenges, such as myocardial infarction (e.g., Ruberman et al., 1984) or cancer (e.g., Spiegel et al., 1981). The latter work illustrates the “buffering model” of social support (Cohen, 1988; Cohen and Willis, 1985), which is also illustrated by research on medical students undergoing the stress of exams. Findings showed stress-induced decrements in immune functioning, but the decline was particularly pronounced for those lacking social buffers (i.e., medical students who reported being lonely; Kiecolt-Glaser et al., 1984; Glaser et al., 1992). Other research examines possible mechanisms through which social support impacts health through behavioral routes, such as the extent to which “significant others” promote and encourage positive health practices (Berkman, 1995; Spiegel and Kimerling, in press; Taylor et al., 1997). Feeling socially embedded may enhance the salubrious effects of restorative behaviors such as sleep (Cacioppo et al., in press b). Sleep is a quintessential act of restoration that is performed without immediate social contact, indeed without much explicit awareness at all. Although lonely individuals slept as many hours per day as normal and socially embedded individuals, responses to the Pittsburgh Sleep Quality Index (PSQI) revealed that lonely

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New Horizons in Health: An Integrative Approach individuals reported poorer sleep quality, longer sleep latency, longer perceived sleep duration, and greater daytime dysfunction due to sleepiness than socially embedded individuals (Buysse et al., 1989). Other data confirmed that lonely individuals slept less efficiently, took slightly longer to fall asleep, evidenced longer REM latency, and had more frequent microawakenings during the night than embedded and normal individuals (Cacioppo et al., in press b). Thus, the restorative act of sleep was more efficient and effective in socially embedded than in lonely individuals. The most extensive research on how social ties influence health, however, pertains to the underlying physiological routes (e.g., Uchino et al., 1996; Seeman, 1996; Seeman and McEwen, 1996; Cohen and Herbert, 1996; Kang et al., 1998; Kiecolt-Glaser et al., 1994). Meta-analyses of the experimental literature support the hypothesis that perceived social isolation is associated with physiological adjustments, with the most reliable effects found for blood pressure, catecholamines, and aspects of both cellular and humoral immune function (Uchino et al., 1996; see also Seeman and McEwen, 1996). In a study of carotid atherosclerosis in middle-aged men, higher intima media thickness of the carotid artery was found in those living alone than in cohabitating counterparts even after controlling for age, health status, education level, saturated-fat consumption, and smoking (Helminen et al., 1995). Although individual differences in personality play a role, the biological effects of loneliness are evident even after controlling for common individual differences (e.g., extroversion, neuroticism) and in intervention studies designed to reduce social isolation and improve physiological functioning (Cacioppo et al., in press b; Uchino et al., 1996). People 's beliefs, attitudes, and values pertaining to others appear to be especially important, because subjective indices of social isolation have been found to be more powerful predictors of stress and health than objective indices (e.g., Seeman et al., 1997; Uchino et al., 1996). Social relationship researchers looking at attachments in early and later life and at close personal relationships, including marital and family ties, have described some features of deep, meaningful, loving human connections (Ryff and Singer, 2000). Numerous investigations have examined the nature of affect in intimate relationships, its developmental course over time, and related expressions of emotion during marital interaction (e.g., Carstensen et al., 1995, 1996; Gottman, 1994; Gottman and Levenson, 1992). Collectively, research on interpersonal flourishing gives greater attention to the emotional upside of significant social relationships and their consequences for improved health (see Ryff and Singer, 1998, 2000; Taylor et al., 2000). Of particular importance are studies that track the cumulative long-term features of social relational experience and its biological sequelae. Individuals on positive relationship pathways (positive ties with parents in childhood, intimate ties with spouse in adulthood) are

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New Horizons in Health: An Integrative Approach less likely to show high allostatic load compared to those on negative relationship pathways, and such relational strengths also appear to offer protection against cumulative economic adversity (Singer and Ryff, 1999). Such findings call for greater understanding of the neurobiological processes that underlie positive social relationships and their role in health protection and promotion. Across these diverse areas of inquiry, longitudinal studies are also needed to help disentangle causal directionality among psychosocial and physiological factors. RECOMMENDATIONS NIH studies of the links between the social world and health should focus on the underlying causal (including reciprocal) mechanisms in both animals and humans. The objective is to understand interrelationships between social interaction and correlative biological phenomena. This work should include: studies that explicate the links between social relationships and gene expression, brain structure and function, and neuroimmunological activity; investigations that identify pathways through which social ties and interacting biological systems influence health practices and behaviors; longitudinal studies that link cumulative social relational profiles with cumulative biological profiles (e.g., allostatic load); increased emphasis on the collection of biomarkers in epidemiological studies of social relationships and health; extensions of traditional laboratory studies to include experience sampling methodologies and corresponding ambulatory neurobiological assessments; multilevel integrative studies working at the interface of social interaction, emotion and brain activity, and downstream endocrinological and immunological processes. REFERENCES Anisman H , Zaharia MD , Meaney MJ , Merali Z. 1998 “Do early-life events permanently alter behavioral and hormonal responses to stressors?” International Journal of Developmental Neuroscience 16/3-4 : 149-164 . Baumeister RF , Leary MR. 1995 “The need to belong: Desire for interpersonal attachments as a fundamental human motivation” Psychological Bulletin 117/3 : 497-529 . Becker A. 1999 “Acculturation and Disordered Eating in Fiji” Paper presented at the annual meeting of the American Psychiatric Association, May 19, Washington DC. Berkman LF. 1995 “The role of social relations in health promotion” Psychosomatic Medicine 57/3 : 245-254 . Berkman LF , Breslow L. 1983 Health and Ways of Living ( New York : Oxford University Press ).

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