CHAMBERS NEUROBIOLOGY OF ATTACHMENT The Neurobiology of Attachment: From Infancy to Clinical Outcomes Joanna Chambers Abstract: Attachment theory was developed by John Bowlby in the 1950s. He defined attachment as a specific neurobiological system that resulted in the infant connecting to the primary caretaker in such a way to create an inner working model of relationships that continues throughout life and affects the future mental health and physical health of the infant. Given the significance of this inner working model, there has been a tremendous amount of research done in animals as well as humans to better understand the neurobiology. In this article the neurobiology of early development will be outlined with respect to the formation of attachment. This article will review what we have begun to understand as the neurobiology of attachment and will describe how the relationship with the primary caretaker affects the infant in a way leading to neurobiological changes that later in life affect emotional responses, reward, and perception difficulties that we recognize as psychiatric illness and medical morbidity. Keywords: attachment theory, neurodevelopment, oxytocin, hypothalamic-pituitary-adrenal axis ATTACHMENT THEORY: A BRIEF HISTORY The parent–infant bond has arguably been the most important process for human survival. While the importance of the mother–infant attachment has been understood for centuries, it was not studied until John Bowlby developed attachment theory in the 1950s. In order to put attachment theory in proper context, one must begin with a reminder of Sigmund Freud’s drive theory. According to drive theory, we attached to our mothers because they fed us and gratified our oral yearnJoanna Chambers, M.D., Associate Professor of Clinical Psychiatry, Indiana University School of Medicine; Chair of Scientific Programs, American Academy of Psychoanalysis and Dynamic Psychiatry. Psychodynamic Psychiatry, 45(4) 542–563, 2017 © 2017 The American Academy of Psychoanalysis and Dynamic Psychiatry NEUROBIOLOGY OF ATTACHMENT 543 ings (Freud, 1923). In other words, our attachments were derived from our libidinal drives and did not exist independently. Drive theory was largely a one-person psychology focusing on the drives and conflicts of the individual; our mother was simply an instigator who either gratified or displeased our internal drives and wishes. Melanie Klein led us to a two-person psychology where the other person was more than an instigator of drives and wishes. The mother, in particular, shaped the psychology of the infant through representations of the good and the bad breast, the merger of the two, and the hope for reparation that allows us to stay attached to our mothers. Klein introduced the idea that we need to feel hope for reparation to stay connected to our loved ones in spite of our own aggressive drives (Kristeva, 2001). For the first time, the object had relevance in our psychology, though Klein believed that the emotional problems of children still came largely from the fantasies generated by internal conflict related to the object. John Bowlby was a supervisee of Melanie Klein and was influenced by her, however he argued that children’s emotional problems do not stem from their own internal conflicts based on a fantasy of the caretaker, but rather their emotional problems stem from actual experiences with their caretakers (Bretherton, 1992). Furthermore, Bowlby suggested that the need for social bonds is independent of feeding and sexual needs but equal in significance (Bowlby, 1977). Attachment theory suggests that through the earliest relationship with one’s parents, one develops an internal working model of relationships, which affects the capacity for relationships later in life. These difficulties in the earliest relationships can lead to marital difficulties, difficulties relating to one’s children, neuroses, and personality disorders (Bowlby, 1977). Since then, insecure attachment has also been shown to lead to difficulties with other psychiatric illnesses, including depression, anxiety disorders, substance abuse disorders, and several medical illnesses (Davies, Macfarlane, McBeth, Morriss, & Dickens, 2009; McWilliams & Bailey, 2010; Puig, Englund, Simpson, & Collins, 2013). THE IMPORTANCE OF ATTACHMENT Since Bowlby developed attachment theory in the 1950s, significant work has been done to investigate the importance of maternal attachment in mammals, including humans. Harry Harlow, a psychologist at the University of Wisconsin, was intrigued by John Bowlby’s work on attachment theory and carried out the first scientific study of at- 544 CHAMBERS tachment theory. In an effort to better understand the implications of mother–infant attachment, Harlow isolated neonatal monkeys from their mothers shortly after birth (Suomi, Harlow, & McKinney, 1972). These monkeys developed severe psychopathology with locomotive, exploratory, and social problems later on, demonstrating the neurovegetative and social effects that occur when infants are removed from their mothers. As adults, these “motherless monkeys” were unable to appropriately mother their young, demonstrating neglectful and abusive behaviors toward their young (Rupenthal, Arling, Harlow, Sackett, & Suomi, 1976). While this seems intuitive to us in the 21st century, in the 1970s when these experiments were carried out, this was revolutionary and validating of Bowlby’s attachment theory. The origins of attachment were still in question: was attachment dependent on libidinal drives or was it a separate process? To evaluate this question, Harlow’s isolated monkeys were given two surrogate “mothers” to choose from: one surrogate mother was covered in terry cloth with large eyes and the other surrogate mother was made of wire with no soft covering, with small eyes, and held a bottle of food for the monkeys. If attachment was indeed derived from libidinal drives, the monkeys would show attachment behaviors toward the wire mother with food. The monkeys showed a significant preference for the soft mother while they would only go to the wire mother to eat. This demonstrated that attachment was indeed its own process, independent of libidinal drives (Suomi, Harlow, & McKinney, 1972). Attachment to early childhood caretakers provided an inner working model for all relationships later in life. In an effort to better understand these inner working models, Mary Ainsworth, John Bowlby’s collaborator, went on to define three distinct and measurable levels of attachment: secure attachment, anxious attachment, and avoidant attachment (Ainsworth & Bell, 1970). Mary Main added a fourth level, namely disorganized attachment (Main & Solomon, 1990). Anxious, avoidant, and disorganized attachment were all classified as insecure attachments. These attachment patterns could be evaluated at 12 months of age and remain consistent over the time. Secure attachment was defined as the ability to carry a representational model of attachment figures as being available, responsive, and helpful. Insecure attachment was defined as not seeking out the attachment figure when distressed or having difficulty moving away from the attachment figure, likely due to having an unresponsive, rejecting, inconsistent, or insensitive caretaker (Ainsworth & Bell, 1970). NEUROBIOLOGY OF ATTACHMENT 545 THE DEVELOPMENT OF ATTACHMENT In humans, similar to Harlow’s “motherless monkeys,” attachment security is mostly intergenerational. In fact, the mother’s attachment security can predict the security of attachment of the infant with up to 75% certainty (Fonagy, Steele, & Steele, 1991). We understand this intergenerational process to be at least in part a psychological phenomenon through the interaction between the mother and her infant (Fonagy, Steele, & Steele, 1991). Watching a mother interact with her infant can be compared to a very sensitive and nuanced dance where each partner responds to the other in a complex and sometimes subtle way. This dance involves touch, eye contact, facial expression, and verbal expression in both partners. When these interactions happen synchronously, all goes well and the infant becomes securely attached. When these interactions are disjointed and cues are misunderstood, the infant’s attachment to his mother becomes conflicted and he later develops insecure attachment as a result. The attunement of the mother to her infant’s cues is often an unconscious process and is a significant predictor of her ability to exist in synchrony with her infant. Through this process, the infant internalizes the experiences with his mother. During the early process of attachment, as the mother responds to her infant’s needs in a sensitive way, she is teaching the infant about empathy. Through her empathy, she can essentially predict what needs the infant is conveying, be it the need for soothing, feeding, diaper changing, etc. As the mother meets the needs of the infant, he feels understood by her in a unique way. As the mother soothes her infant, he learns that his emotions can be regulated. As the mother takes pleasure in her infant, he is instilled with a sense of power as he realizes his capability to create pleasure in another person. These experiences by the infant involve significant neurobiological events that have implications for mental and medical health later in life. These experiences by the infant are also integral in forming the psychological internal working model (his mother) that is projected on to all future relationships. There are several risk factors that can lead to interference in the mother–infant relationship and the attachment process. These include mental illness including prenatal depression and postpartum depression, insecure attachment in the mother, parental insensitivity, disrupted affective communication between parent and infant, child abuse, and child neglect (Hayes, Goodman, & Carlson, 2013). Fortunately, there is evidence to suggest that the attachment process is malleable through preschool-aged children, especially if the mother undergoes attachment-focused treatment (Hoffman, Marvin, Cooper, & Powell, 546 CHAMBERS 2006). Hence, there seems to be a window of opportunity for intervention and treatment for insecurely attached infants. As we better understand the neurodevelopmental process involved in attachment, there has been a shift in increased importance of the prenatal period to be included in the sensitive period of development. This is particularly interesting as the psychological interaction between mother and infant has not yet developed at this time, yet it is clear that the infant is born with a preference for his mother’s smell, his mother’s milk, and his mother’s voice (Vaglio, 2009). Furthermore, there is a significant correlation between mothers with antenatal depression and infants with disorganized attachment styles at 12 months (Hayes, Goodman, & Carlson, 2013). Fortunately, it has been shown that higher quality parenting in the first three months can ameliorate the risk of disorganized attachment due to antenatal depression (Hayes, Goodman, & Carlson, 2013). This leads to the conclusion that there is an interplay between the fetal period and the first three months of life that is critical for the attachment process. Understanding the neurobiology of attachment can help us uncover this interaction and possible ways to intervene. In addition to the interpersonal and relationship problems that Bowlby identified as resulting from insecure attachment, there has been a significant link of insecure attachment to psychiatric illnesses such as depression, anxiety, and substance abuse (Heim & Nemeroff, 2001). The developing knowledge of the neurobiology of attachment allows for a greater understanding of how attachment insecurity may lead to these afflictions. The hypothalamic-pitutiary-adrenal (HPA) axis and the reward neurocircuitry are likely to have very significant roles in the attachment process as well as in psychiatric illnesses and medical morbidity later in life. In order to understand these connections better, we must first explore the neurobiology of attachment. THE NEUROBIOLOGICAL DEVELOPMENT OF THE INFANT The Hypothalamus at Birth The hypothalamus is developing in the fetus and is affected by the maternal HPA axis (Giesbrecht et al., 2017), and at birth, the hypothalamus is already fully developed. The hypothalamus functions through the HPA axis to produce cortisol by the adrenal glands. Cortisol has a bipartite effect on the rest of the developing brain, where in high doses, cortisol is largely neurotoxic and inhibits neuronal connections, while lower levels of cortisol induces neuronal development and growth NEUROBIOLOGY OF ATTACHMENT 547 through neuroplasticity (Vela, 2014). Therefore, modulation of cortisol during this sensitive period of neural development is imperative for future function. Oxytocin and social interaction have been shown to decrease cortisol levels, demonstrating that even at this early stage, physical connection between a mother and her infant has an important effect on brain development and neuroplasticity (Heinrichs, Baumgartner, Kirschbaum, & Ehlert, 2003). Furthermore, adults with insecure attachment show a hyper-reactive HPA axis and cortisol response to acute stress, demonstrating that these effects are long lasting (Quirin, Pruessner, & Kuhl, 2008). In very young rat pups, it has been shown that the HPA axis is nonfunctional during postnatal days 4–14 (Rincon-Cortes et al., 2015). This lack of cortisol inhibits any fear response, allowing the rat pups to attach to their mothers during this developmental phase. In a study to better understand how child abuse affects the attachment process, rat pups at days 4–14 were repeatedly exposed to an odor paired with a foot shock in the presence of the mother. Later, when the abused rats became adults, the odor actually had a positive and antidepressant effect on the rats during stress. While the study was done in rats, it has significant clinical implications in humans. This study demonstrates the very powerful and non-discriminatory attachment process. This remarkable repetitive response in the rat explains, from a neurobiological perspective, how other mammals, including humans, who are abused in their youth still attach to their abusive parents with the same vigor as the non-abused child. If a child is exposed to a sensory experience, even a traumatic one, during this sensitive time period when the neurobiology is primed for attachment, they will seek out those traumatic experiences time and again. Hence, they repeatedly seek out abusive relationships because abuse was part of the attachment process in early childhood and the abuse became rewarding. This also explains, in part, why humans with histories of abuse in childhood will seek out and attach to abusive partners as adults. In this way, we begin to see that the early attachment process is interconnected with the reward system. The Hippocampus Develops It is clear from the previous section that the first three months of life are important with respect to the attachment process through modulation of the HPA axis. This is also the time when the hippocampus fully matures. The hippocampus is a part of the limbic system and is involved in spatial and emotional memory. It is instrumental in consoli- 548 CHAMBERS dating declarative or explicit memories, which are facts or events, and it provides the ability to consciously recall events or facts from longterm memory (Campbell & MacQueen, 2004). As the hippocampus develops, the infant is able to recognize and remember his mother, smile at her, begin to feel a sense of pleasure with her, and begin to actively engage with her. This is an extremely crucial time with respect to the development of the mother–infant bond and by four months of age, the relationship patterns between a mother and her infant can predict the attachment security of the infant at 12 months (Beebe et al., 2012; Koulomzin et al., 2002). The hippocampus has a large number of glucocorticoid receptors, causing significant sensitivity to stress and cortisol production through the HPA axis. When the infant is stressed, high doses of cortisol are produced, causing neurotoxicity to the hippocampus. Furthermore, the hippocampus is known to provide negative feedback to the HPA axis, decreasing cortisol production (Sapolsky, Krey, & McEwen, 1986). Hence, when the hippocampus suffers from neurotoxicity, cortisol production is further enhanced. Therefore, neglect or abuse at this stage can significantly impair the development of the hippocampus. Rat pups who were separated from their mothers during early development (a model of neglect) have been shown to have smaller hippocampi (Huot, Plotsky, Lenox, & McNamara, 2002). In humans, hippocampal glucocorticoid receptors have been shown to be affected by child abuse as well (McGowan et al., 2009). These first few months of life are vital in terms of the future relationship between attachment, stress, and object relations of the infant. The Reward System The young infant clearly experiences pleasure in her interactions with her mother. The social smile, which usually begins between six to eight weeks of age, is evidence for this. It is also evidence for the presence of the reward neurocircuitry. The reward system is a complex neurocircuitry which has been described as a dichotomy of two systems: the novelty seeking system and the familiarity system (Tops, Koole, IJzerman, & Buisman-Pijlman, 2014). The ventral striatal pathway is involved in novelty seeking as a reward. The dorsal striatal pathway is involved in reward related to familiarity, comfort, and satiety. Early in development, the novelty-seeking ventral striatal system is thought to be more active. During the first three months, the mother’s face is novel and the infant is driven in part by the reward circuitry to look at NEUROBIOLOGY OF ATTACHMENT 549 her. As the infant is able to respond to her by smiling, body language, and eye contact, and if the mother is responsive, there is a shift to dorsal striatal activity where the familiarity of mother and the connection with her becomes rewarding. If there is neglect or abuse during this developmental phase, the development of the ventral novelty seeking system relative to the dorsal familiarity system is affected. This process has significant potential for the interaction of poor attachment with later substance abuse problems, as the reward of familiarity and comfort in relationships may not protect against the reward of substances and impulsivity (novelty). Indeed, there is evidence that both animal models and humans with poor attachments are more likely to develop substance abuse problems (Moffett et al., 2007). Furthermore, attachment style has been found to directly impact the recovery of patients hospitalized for the treatment of addictions, where insecure (avoidant) attachment leads to poor treatment outcomes (Caspers, Yucuis, Troutman, & Spinks, 2006; Fowler, Groat, & Ulanday, 2013). If the dorsal striatal reward network is not fully developed during the sensitive attachment period, one cannot develop a preference for familiarity, comfort, and satiety over the rewarding sensation of novelty brought on by substances of abuse. Strathearn (2011) found that there is an increase in activation in the ventral striatum when securely attached mothers see their infant’s happy face, while there is a decrease in activation in the ventral striatum when insecurely attached mothers see their infants. Interestingly, the ventral striatum has been shown to mount a diminished response to reward in neuroimaging of individuals with a history of early childhood abuse (Teicher, Samson, Anderson, & Ohashi, 2016). This is a particularly interesting finding as it demonstrates an altered reward system in insecurely attached mothers, while also helping us better understand how insecure attachment or a history of child abuse in the mother can lead to psychiatric illnesses such as postpartum depression, where interactions with the infant is not inherently rewarding. The Amygdala Even before birth, the fetal amygdala is affected by his mother’s affect (Qiu et al., 2015). Specifically, both depression and cortisol spikes in the mother during pregnancy have been shown to decrease the size of the amygdala later in the infant (Qiu et al., 2015). The amygdala matures at six to seven months of age (Vela, 2014). With this development, we also see the beginnings of fear and salience, two important functions of the 550 CHAMBERS amygdala. The infant at this age will show stranger anxiety and protest separation from his mother. Youths who have been institutionalized and suffer emotional deprivation, who are later adopted by families in the U.S., show a difference in amygdala response when compared to youths who had been raised by their biological parents without emotional deprivation. The youths, who were 4–17 years of age at the time of the imaging study, were shown pictures of their mothers (biological or adopted mothers in the case of the adopted youths; Olavsky et al., 2013). The youths who were raised by their mothers from birth showed significant amygdala responses to their mothers but not to strangers. The youths who had been institutionalized prior to adoption demonstrated a significant amygdala response to both their mothers and the strangers. The lack of differentiation became more significant with increased age of the youth at the time of adoption. In other words, the older the child’s age at adoption, the less likely their amygdala was to discriminate between the mother and the stranger. This study demonstrates that while the amygdala is important for a fear response, it is also important for the determination of salience. The study also validates the notion that there is a sensitive period of attachment development that has life-long consequences. This leads to the question: “What happens if we remove the amygdala?” Bauman, Lavener, Mason, Capitanio, and Amaral (2004) answered that exact question in a study with macaque monkeys. The macaques’ amygdalae were lesioned at two weeks of age and some interesting results were found. The monkeys without their amygdala spent more time with their mothers in the first six months. They were separated from their mothers at six months of age and placed in a holding box with equal proximity to their mothers and to a familiar female who was not their mother. In this box, the control (non-lesioned) monkeys spent all their time in proximity to their mother. The lesioned monkeys spent an equal amount of time in proximity to the familiar female as to their mother. Furthermore, the control monkeys screamed in protest at not being able to be held by their mother, while the amygdalalesioned monkeys showed no distress at having limited proximity to their mother. So while the lesioned monkeys were content with their mothers in the first six months of life, they had no ability to understand the salience of their mother when compared to a familiar female without their amygdala. In humans, amygdala lesions have been described in Urbach–Wiethe syndrome, an autosomal recessively inherited syndrome that causes bilateral calcifications of the amygdala in 50% of patients. In an interesting report, the psychoanalytic findings in a 38-year-old male patient NEUROBIOLOGY OF ATTACHMENT 551 with bilateral amygdala calcifications due to Urbach–Wiethe syndrome was described (Wiest & Brainin, 2010). This patient had sought treatment due to new onset panic attacks and depressive symptoms. While the patient was easily able to remember facts, he had more trouble with emotionally salient memory as he could not remember what he did while together with his friends. While he could remember if he liked a certain book or movie, he had trouble remembering what happened in the stories of the books or movies. He could only remember if a place was familiar or not, but could not recall how to get there. He was notably unable to free associate in the analytic sessions. The analyst described each session as feeling like a repetition without any connection to the previous session. He had a wide range of emotions and was able to recognize negative emotions such as anger and sadness. He was seemingly able to attach as he had a fulfilling relationship for nine years with the same woman and was able to develop a transference to his analyst. While this study is interesting, the implications for the neurobiological function of the amygdala in attachment are unclear since we do not know at what age the amygdala calcifications occurred. Given the sensitive period of development, there is likely a difference between having a functional amygdala in the first year of life which is impaired later on and being born without an amygdala. The report does validate the function of the amygdala in the appreciation for emotional salience however. The report also suggests that the amygdala may serve as an emotional compass, without which we feel lost, causing anxiety and depression over time. More studies have been done in the amygdala of parents in an effort to understand the role of the amygdala in parental attachment. Firsttime mothers, imaged with fMRI in the first postpartum month while listening to recordings of babies crying, including their own baby, demonstrate an activated neurocircuitry when hearing their own baby cry already in the first two weeks postpartum (Swain, 2008). When compared to brain responses to the control babies cries, the mothers’ activated neurocircuitry included the anterior cingulate gyrus and the amygdala. The fathers, who were also imaged, did not show activation in the amygdala, but instead showed other areas of activation including the anterior cingulate, the visual cortex, and the parahippocampal gyrus. This might be the result of mothers’ attachment neurocircuitry being “primed” earlier than that of fathers. This could be partially due to the effects of oxytocin elevations during the process of parturition and nursing. 552 CHAMBERS Oxytocin: Attachment and Synchronicity In pregnant mothers, there is evidence that an increase in maternal oxytocin levels during the first and second trimester of pregnancy predict mothering behavior in the postpartum (Levine, Zagoory-Sharon, Feldman, & Weller, 2007). In securely attached individuals, oxytocin levels are generally higher and increase during periods of stress, increase with play, and oxytocin and reward activation synchronize during interaction with one’s infant (Pierrehumbert, Torrisi, Ansermet, Borghini, & Halfon, 2012). Women with a history of child abuse have lower oxytocin levels in general as well as during pregnancy and the postpartum period (Heim et al., 2009). This is significant for the infant because in the postpartum period, there appears to be a synchronous relationship between oxytocin in the parents and oxytocin in the infant (Levine, Zagoory-Sharon, Feldman, & Weller, 2007). When the parent and child interact with each other, the oxytocin levels increase in both the parent and the infant. Oxytocin plays an important role in the attachment process of parents. An imaging study looking at mothers interacting with their 4–6-month-old infants showed a clear distinction in neurocircuitry between mothers described as either synchronous or intrusive with their infants (Atzil, Hendler, & Feldman, 2011). In the synchronous mothers, the right nucleus accumbens (ventral striatum) was active and showed an organized response with the prefrontal cortex (PFC). In addition, the oxytocin levels seem to increase and correlate with the neurocircuitry response. In the intrusive mothers, the left amygdala was active and showed a disorganized response with the PFC while the oxytocin levels did not correlate with the neurocircuitry response. In a separate study by Gordon, Zagoory-Sharon, Leckman, and Feldman (2010), plasma oxytocin levels in mothers correlated with the amount of time the mother spent in affectionate behavior with her infant. Furthermore, salivary oxytocin levels in both mothers and fathers increase when playing with their infants and correlate directly to infant oxytocin levels (Feldman, 2010). When fathers were given intranasal oxytocin and then interacted with their infants, the infants showed a similar increase in oxytocin during the interaction (Naber, van IJzendoorn, Deschamps, van Engeland, & Bakermans-Kranenburg, 2010; Weisman, ZagoorySharon, & Feldman, 2012). Securely attached mothers have an increase in oxytocin when playing with their infants while insecurely attached mothers’ oxytocin levels actually decrease with play (Strathearn, Fonagy, Amico, & Montague, 2009). Furthermore, secure attachment was correlated with higher oxytocin levels and decreased subjective stress NEUROBIOLOGY OF ATTACHMENT 553 during an acutely stressful situation (Pierrehumbert, Torrisi, Ansermet, Borghini, & Halfon, 2012). Hence, it appears that oxytocin and secure attachment may regulate the stress system. The Maturing PreFrontal Cortex (PFC) The prefrontal cortex (PFC) begins development in the early neonatal stage and continues to evolve through pruning until the middle of the third decade of life (Kolb et al., 2012). While the role of the immature PFC in infants and children is unclear, the mature PFC has been shown to be important in the process of attachment in adults. In a rat model of social interaction, two adult rats who are introduced under stressful conditions lessen each other’s anxiety levels during a stressful challenge. If the rats are first introduced in a non-stressful situation, they will not have the same ability to modulate each others’ anxiety levels: they must be introduced during a stressful event to have an anxiolytic effect on each other. This effect is directly modulated by the medial PFC (Lungwitz et al., 2014). Of course, we see this on a regular basis in human situations. For example, military veterans will tell us that their closest attachments are the other veterans who served with them. There may be a similar effect in psychotherapy, where therapists engage their patients in some of their most stressful memories, cognitions, and affects, which may, in part, contribute to the patient’s attachment to the therapist. It is clear that the PFC plays an important role in the attachment process, especially later in development. In rat pups exposed to an abusive caretaker early in development, brain-derived neurotrophic factor (BDNF) gene expression has been shown to be decreased in the PFC as adults (Roth, Lubin, Funk, & Sweatt, 2009). This may have implications for later developments of depression as BDNF has been shown to be decreased in depression and increases with treatment (Duman, 2004) It is also likely that the proper development of the PFC depends on the functionality of earlier neurobiological developments. However, while the exact role of the PFC in the attachment process early in development remains unclear, it is clear that the PFC has an important role in modulating anxiety and depression, which may rely on a healthy neurobiological environment during early development. Summary of the Neurobiology The attachment neurobiology develops early, beginning in utero and continues through preschool age. It appears to be partially set by 554 CHAMBERS pruning around 24 months (Vela, 2014). This is a complex process that involves the development of HPA axis and reward system early on, followed by the development of the amygdala, followed by PFC development into adulthood. As we have a better understanding of the attachment neurocircuitry, we can see how this sensitive period of development leads to neurobiological changes later in life affecting emotional response, reward, and perception difficulties. Our understanding of neurobiology is finally catching up and validating what psychoanalytic theory has always assumed: the importance of early development and the necessary process of each stage of development, building on earlier stages and experiences. Clinical Implications of Insecure Attachment In a 30-year prospective study by Fan et al. (2014), infants who experienced poor attachment behaviors from their mothers at eight months of age were at higher risk for mental illness 30 years later. Depression, anxiety, and substance use disorders have all been linked to insecure attachment (Heim & Nemeroff, 2001). Medical morbidities, such as chronic pain, cardiovascular disease, and inflammation-based illnesses have also been linked to poor attachment (Davies, Macfarlane, McBeth, Morriss, & Dickens, 2009; McWilliams & Bailey, 2010; Puig, Englung, Simpson, & Collins, 2013). Adverse childhood events (ACE) have also been shown to correlate to physical illness in adulthood (Felitti et al., 1998). Epidemiological studies have shown that a lack of social relationships has similar consequences on physical health as smoking, obesity, and inactivity (Puig, Englung, Simpson, & Collins, 2013). The quality of close relationships, especially marriage partners, had a significant effect on the immune system, the neuroendocrine system, and resiliency to stress (Puig, Englung, Simpson, & Collins, 2013). Perhaps, this could be in part mediated through early attachment developments. Avoidant attachment has been correlated to chronic back pain and neck problems, frequent and severe headaches, chronic pain, and ulcers (McWilliams & Bailey, 2010). Anxious attachment has been correlated to chronic back and neck problems, frequent and severe headaches, chronic pain, as well as strokes, myocardial infarction, hypertension, and ulcers (McWilliams & Bailey, 2010). Insecurely attached individuals perceived pain as more threatening, had a negative perception of social support, demonstrated decreased support seeking, experienced increased depression, anxiety, stress, were more inclined to catastrophize, and showed decreased adaptive coping (Meredith, Ownsworth, & NEUROBIOLOGY OF ATTACHMENT 555 Strong, 2008). Insecure attachment correlated to increased number of pain sites in people with chronic widespread pain (CWP), had twice the prevalence of CWP, and demonstrated an increase in pain-related disability (Davies, Macfarlane, McBeth, Morriss, & Dickens, 2009). Insecurely attached individuals also had four times greater chance of physical illness, four times greater chance of inflammatory related illness, and were three times more likely to have nonspecific physical symptoms (Puig, Englund, Simpson, & Collins, 2013). It is clear from these studies that attachment security affects medical and psychological wellbeing later in life. Understanding the neurobiological underpinnings of the attachment process allows us to better identify how these morbidities may be linked to insecure attachment. Attachment insecurity may lead to these psychiatric and medical changes later in life through several neurobiological mechanisms, including stress response, inflammatory responses, neurocircuitry changes, and epigenetics. These mechanisms are also likely to interact causing a cumulative effect. THE STRESS RESPONSE The role of the HPA axis and cortisol is complicated and likely of great importance in the relationship between attachment security and medical and psychiatric comorbidity. Individuals with insecure attachment show a greater perception of stress when compared to securely attached individuals (Kidd, Hamer, & Steptoe, 2011). In general, cortisol levels are known to be altered in patients with depression, anxiety, posttraumatic stress disorder, as well as in insecure attachment (Kidd, Hamer, & Steptoe, 2010; Quirin, Pruessner, & Kuhl, 2008). It is therefore reasonable to assume that modulation of the hypothalamus early in development has significant effects on the individual later in life. Interpersonal stress is increased in insecurely attached individuals and this has several neurobiological causes. In interpersonal stress, the prefrontal cortex is downregulated and its inhibitory control of the amygdala decreases (Gold, 2015). In addition, the HPA axis is activated during interpersonal stress through increased activation of the amygdala, as well as through the lack of inhibition by the PFC, leading to increased cortisol production. Cortisol further increases amygdala activation. In addition, corticotropin releasing hormone (CRH) is increased by interpersonal stress, further increasing fear and anxiety through its effect on the sympathetic nervous system and the amygdala (Gold, 2015). While the hippocampus generally has an inhibitory effect the HPA stress response (Radley & Sawchenko, 2011), if the hippocampus 556 CHAMBERS has been negatively affected by elevated cortisol in infancy, the inhibitory effect of the hippocampus on the HPA axis is also likely to be compromised. One quickly begins to see that there is little inhibition in this process once it gets started and the system behaves largely in a feed forward manner, where stress increases amygdala activity, HPA activity, cortisol, CRH, and the sympathetic nervous system with minimal inhibition. Oxytocin has many functions, including lowering HPA activity and cortisol. Cortisol increases plasma oxytocin levels, hence this serves as a negative feedback system where stress increases cortisol, which then increases oxytocin, which then decreases cortisol. In individuals who are securely attached, oxytocin levels increase in response to stress (Pierrehumbert, Torrisi, Ansermet, Borghini, & Halfon, 2012). Given that women with a history of child abuse have lower oxytocin levels in general (Heim et al., 2009), it is possible that insecurely attached individuals do not have this inhibitory process in place, allowing the stress response to escalate to higher levels. Furthermore, insecurely attached individuals are less likely to reach out to their loved ones in times of stress, may have a lower oxytocin response to interaction with loved ones, both which contribute to lower oxytocin levels (Pierrehumbert, Torrisi, Ansermet, Borghini, & Halfon, 2012; Strathearn, Fonagy, Amico, & Montague, 2009). THE INFLAMMATORY RESPONSE Inflammatory responses may also be a culprit in the connection between insecure attachment and psychiatric and medical morbidity. During stress, an increase in CRH causes acute stage inflammatory responses, including interleukin-6 and cytokines (Gold, 2015). While acute increases in cortisol deactivate the inflammatory system, both chronic elevations and chronic hypoactivity in cortisol levels lead to a hyperactive inflammatory system. Insulin, which also increases in response to acute stress, increases the inflammatory response and contributes to activating the sympathetic nervous system (Gold, 2015). These inflammatory responses are noteworthy as they contribute to a variety of medical complications, including: auto immune disorders; cardiovascular disease, such as hypertension, myocardial infarctions, and stroke; pain; gastric and duodenal ulcers; and cancer (Puig, Englund, Simpson, & Collins, 2013). An increase in cytokines has been shown to lead to depression, as cytokines in the brain have an effect on the production, release, and metabolism of neurotransmitters. Therefore, it may be that insecure attachment leads to early changes in CRH/ NEUROBIOLOGY OF ATTACHMENT 557 HPA axis, which then leads to increases in cytokines, which contribute to the development of depression later in life. Insecure attachment may also lead to cardiovascular events through inflammatory changes (Gold, 2015). NEUROCIRCUITRY The effects that abuse and neglect have on the developing brain as described in this article are significant. Understanding how poor attachment leads to changes in neurocircuitry later in life is still in progress. For instance, in individuals with a history of child abuse, the amygdala is hyper-responsive to angry faces (Teicher, Samson, Anderson, & Ohashi, 2016). This hyper-responsivity may be due partly to a failure to develop appropriate inhibitory mechanisms during the first year of life. If the amygdala is faced with an aggressive, abusive, or unpredictable attachment figure in the first year of life, without appropriate modulation through oxytocin and other neural connections, hyperactivity may be the result. The reward neurocircuitry also appears to be affected by attachment, which may have implications for psychopathology later in life. For example, in depression the nucleus accumbens is less active which is largely responsible for the sense of anhedonia in depression (Satterthwaite et al., 2015). It is possible that the altered function of the nucleus accumbens developed in the early stages of life as a response to poor attachment increases the risk for anhedonia and depression. An altered reward neurocircuitry may also lead to a vulnerability to addictions. Decreased function in the PFC, which may be caused by attachment insecurity, also has a negative effect on the reward process by decreasing activity in the nucleus accumbens (Gold 2015). Given that the striatum and PFC are both involved in the development of attachment, it seems possible that insecure attachment may lead to a dysfunction in these neurocircuits, leading to later development of psychopathology. EPIGENETICS Gene expression is the underlying mechanism for all neuroscience and behavior. It has become increasingly clear that early environment affects gene expression. This is done through a process of methylation to various sections of the DNA, causing a difference in the expression pattern of the DNA. These methylation changes can be reversible or permanent and can be heritable by offspring (Monk, Spicer, & Cham- 558 CHAMBERS pagne, 2012). More recently, in utero and postpartum environments are thought to have a significant effect on the genetic expression of the offspring, which are evident early in the infant’s life and are sustained throughout their lives (Fish et al., 2004). These alterations in genetic expression seem to be affected significantly by the mother’s affective state in pregnancy (Monk, Spicer, & Champagne, 2012), as well as the mother’s behaviors toward the offspring in the postpartum (Fish et al., 2004). These genetic changes are implicated in many important neuropsychiatric processes, including but not limited to BDNF synthesis, neurotransmitter receptor levels and responsivity, and synaptogenesis in the offspring (Fish et al., 2004). Epigenetics have been studied in humans as well as in other mammals. For example, rat pups exposed to various levels of licking and grooming and nursing postures showed different levels of glucocorticoid receptor gene promotors in the hippocampus, which has implications for cortisol effects on the hippocampus. These genetic alterations were found as early as the first week of life and the changes were reversible when cross-fostered (Weaver et al. 2004). In humans, McGowan et al. (2009) found that adult suicide victims with a history of child abuse had altered hippocampal glucocorticoid receptor genes, demonstrating that an abusive environment in childhood had a sustained epigenetic effect on cortisol receptors in the hippocampus. Rat pups exposed to a stressed and hence neglectful or abusive caretaker in the first week of life demonstrated altered BDNF gene expression, which lasted into adulthood (Roth et al., 2009). While these epigenetic changes appear to be relatively stable throughout life, there is some evidence that they are potentially reversible in adulthood (Weaver, Meaney, & Szyf, 2006). The suggestion that these epigenetic changes are both heritable and reversible may have significant implications for treatment in mothers who are pregnant and postpartum. If a mother has already passed epigenetic changes to her child, it may be that secure attachment behaviors may reverse these changes in the infant early on, giving the infant the opportunity to change the intergenerational pattern. SUMMARY While much work has been done to increase the understanding of the neurobiology of attachment, we are left with many unanswered questions that require more research. For instance, can we affect attachment style later in life? Can insecure attachment be treated? If so, how? In addition, can psychotherapy be enhanced with direct neurobiological modification, such as oxytocin or cortisol modulation? It might be in- NEUROBIOLOGY OF ATTACHMENT 559 teresting to check both cortisol and oxytocin levels in patients who are undergoing psychoanalysis or psychodynamic psychotherapy. Would attachment treatment be a part of the overall treatment to improve other psychiatric and medical morbidities? Given that we already have evidence that attachment treatment to postpartum mothers improves postpartum depression (Hoffman, Marvin, Cooper, & Powell, 2006), it may be worth considering for other illnesses as well. Given what we know about the role of oxytocin and cortisol specifically, are pregnancy and the postpartum periods a natural time to intervene in mothers with poor attachment? Knowing the importance of mother’s attachment process for the success of secure attachment in the infant, it may be that nature has provided us with an additional sensitive period in the attachment neurocircuitry. 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