Behavioral & Attachment Jonathan Baylin

The New Science of Trust and Mistrust

68 The Neuropsychotherapist issue 3 Oct-Dec 2013 “…the of safety is the turning point in the development of relationships…” Stephen Porges, 2011

“The reality of the functional genome does not admit to main effects of either or environment, but rather to a constant interaction between the DNA and its environment” Michael Meaney, 2010

ne of the hottest areas of is the study of how life experience affects patterns of gene expression in the brain, what some call behavioral epigenetics (Weaver, 2004; McEwen, 2012). Of great relevance to therapists interested in attachment, this fast growing body of research is revealing how early life experi- Oence can influence brain development towards either social engagement or self defense. Researchers are uncovering experience-dependent effects on the development of the brain during the sensitive period for attachment-based learning in , work that has now been extended to . Furthermore, epigenetic research is exploring the potential of reversing the effects of poor parental care by altering patterns of gene expression in the brain after the sensitive period for attachment has passed (Landers and Sullivan, 2012). Clearly, this research has huge implications for the whole field of .

Epigenetic Effects of Early Care On mone receptor, called the GR, is more highly the Child’s Systems expressed (or in technical terms, less meth- ylated) in the hippocampus than it is in the Ground breaking studies by Michael less licked rats. This means that the well Meaney and his colleagues (Kaffman and cared for pups acquire more GRs in their hip- Meaney, 2007); Meaney, 2010) laid the pocampus. These hippocampal GRs are an foundation for studying the effects of -dif essential component of the stress response ferences between the quality of early ma- system as they help turn off the stress- re ternal care and patterns of gene expression sponse after a stressful experience. In the in the brains of offspring. This seminal work low licked offspring, the stress response sys- showed that naturally occurring differences tem stays active longer, facilitating self de- in the quality of maternal care within the fense at the cost of growth and social con- first week of a rat pup’s life trigger different nectedness. patterns of gene expression in the regions Epigenetic research that began with ro- of the brain that support both self defense dent studies has since been extended to and social engagement. Young rats who are both non- primates and humans. licked often and nursed in a certain position Maternal licking in rats is a form of tactile show a different pattern of gene expression stimulation similar to grooming in in their hippocampus, prefrontal cortex, and primates and to all forms of “good touch” amygdala than pups who do not get as much in humans. Human studies show that cer- of this “enriched” stimulation. These differ- tain qualities of touch activate the insula, ences in gene expression enable well cared anterior cingulate cortex (ACC), and orbi- for rats to be more social, less fearful, and tol regions of the brain while calming the faster to approach and explore new things amygdala in ways that promote well be- than their less well cared for peers. ing, trust, and social engagement—very In the well licked babies, the gene re- much like licking does in Meaney’s rat pups. sponsible for the corticosterone stress hor-

OlgaLIS/Bigstock.com Nivens/Bigstock.com Sergey While studying gene expression patterns in

www.neuropsychotherapist.com The Neuropsychotherapist 69 early life patterns of gene suppression as- sociated with separation, early abuse, and neglect. This research includes both environ- mental interventions (Environmental Enrich- ment) and pharmacological methods such as the administration of demethylating drugs to unblock methylated regions of in animals exposed to poor care ear- ly in life. Both types of interventions have shown some capacity to alter the effects of early life adversity on gene expression in brain regions such as the hippocampus. While epigenetic effects triggered by social experiences are strongest during the sensi- tive period for attachment-based learning, experience-dependent gene expression con- tinues throughout life (Weaver et al, 2004). Young rats who are licked often and nursed in This exciting line of research has strong im- a certain position show a different pattern of plications both for and psy- chopharmacology. gene expression in their hippocampus, prefron- tal cortex, and amygdala than pups who do not get as much of this “enriched” stimulation Gene Expression, Trust, and Mistrust The social engagement and social defense systems are developing early in life and both are affected by the nature of caregiving that of various mammalian species re- human brains is more difficult than it is with ceive. Epigenetic research is showing that rodents, where brain tissues from different differences in the quality of early care have regions can be readily examined, methods differential impact on the patterns of gene for behavioral epigenetic studies in humans expression in these two systems, channel- are being developed. ling brain structure and functioning along An intriguing study by Meaney’s group different trajectories. In effect, epigenetic (McGowen et al., 2009) used postmortem mechanisms, whereby the environment im- brain tissue to explore patterns of gene ex- pacts brain development, is nature’s way of pression associated with childhood abuse helping to ensure that the young adapt to the in a group of suicide victims (McGowan et specific kind of social world they are likely to al., 2009). The pattern of gene expression be living in. If this first “environment of care” seen in the brains of those individuals who is safe, the young brain will be sculpted or had experienced abuse in early childhood “programmed” for living in connection with matched the pattern of in the other people. If the early environment ex- rat studies, showing gene suppression in poses the young to harsh, insensitive treat- the equivalent promoter region of the GR ment by attachment figures, the young brain gene. In other words, the pattern of gene will be epigenetically sculpted for surviving expression was consistent with epigenetic (and reproducing) in a world in which it is programming of the by early vital to be hypervigilant, slow to trust, and life adversity. quick to deploy one’s defenses. While both In addition to showing that early life ex- of these developmental scenarios of “biolog- periences with attachment figures activate ical embedding of early experience” (Hertz- different patterns of gene expression (and man,2012 ) are initially adaptive, a wealth therefore, protein synthesis and brain struc- of research on attachment formation shows ture) during the initial period for attach- that early experiences with sensitive, nurtur- ment-based learning, epigenetic research ing caregivers promotes a pattern of brain

Life on White/Bigstock.com is also exploring the potential of reversing

70 The Neuropsychotherapist issue 3 Oct-Dec 2013 development supportive of emotional re- promoting chronic hyper-activation of the silience, empathy, and cognitive flexibility amygdala. (National Scientific Council on the Develop- This developmental scenario of chronic ing Child, 2008). stress is a common one for children exposed Children who are forced to adapt to high to abuse and neglect early in life. Having an levels of adversity very early in life when underdeveloped fronto-limbic system bias- the brain systems for social engagement es these children towards hyper-reactivity and self defense are under construction are to aspects of their environment that they at risk for developmental stress disorders, perceive as threatening. This includes a including depression, social anxiety, and strong tendency to perceive other people as PTSD (Heim and Nemeroff, 2002). In brain untrustworthy, based on prior learning that terms, this means that the development of has become the basis for habitual ways of the circuit that connects the prefrontal cor- responding to attachment figures. In com- tex to subcortical regions, especially to the mon parlance, these kids are more prone to amygdala, may be compromised by over “flipping their lids” and either blowing up or activation of the child’s stress response sys- freezing in fright when they detect signs of tem early in life. The development of the negative intentions or rejection, especially fronto-limbic system connecting the lower in other people’s facial expressions and regions of the prefrontal cortex, including voices. the orbitol region and the ventral ACC, to the amgydala forms the core neural sub- strate for self regulation throughout life. Appraising Safety and Threat: When the initial development of this circuit A Two Level System is suppressed for any reason, it is more diffi- The process of shifting between social cult later in life to regulate , behav- engagement and defensive states depends ior, , and . As a result heavily on the way we appraise the level of of these regulatory difficulties, it is harder safety or threat posed by other people in our for the individual to learn from new experi- environment (Porges, 2011). This appraisal ences and to change one’s mind about the process occurs on two basic levels: of old experiences. Children who 1) an unconscious, or implicit, ultra have to adopt an early life survival strategy rapid level based heavily on the function- of premature self reliance and defensive- ing of the amygdala and its ability to acti- ness are vulnerable later in life to all kinds vate approach and avoidance responses of health problems because of their chronic to other people and exposure to high levels of stress hormones. 2) a conscious, slower appraisal sys- In the brain, chronic activation of the stress tem based on prefrontal regions of the response systems can have toxic effects, brain that can modulate and inhibit the especially on the hippocampus and the implicit, fast acting “first pass” appraisal prefrontal cortex (McEwen, 2012), while system.

Children who are forced to adapt to high levels of adversity very early in life when the brain systems for social engagement and self defense are un- der construction are at risk for devel- opmental stress disorders, including depression, social anxiety, and PTSD soupstock/Bigstock.com www.neuropsychotherapist.com The Neuropsychotherapist 71 Porges calls the implicit, subcortical or social avoidance. The role of the amyg- appraisal of safety and threat “neurocep- dala as a switching mechanism between at- tion”. The ability of the prefrontal regions tachment learning and avoidance learning to modulate the neuroceptive process typi- is beautifully described by Landers and Sul- cally increases with age and brain matura- livan (2012) and there is a wealth of data that tion into adulthood; however, this process strongly indicates a similar process in hu- of developing a robust fronto-limbic system mans (Caldji et al., 2003). is also significantly affected by early life -ex The amygdala is a creature of proximity in periences with attachment figures, i.e., by the sense that the closer something comes epigenetic processes. to us, either in space or time, the stronger the potential reaction of the amygdala, es- Epigenetics and The Amygdala pecially to something perceived as threaten- ing or stressful. The amygdala appears to be The amygdala is functional very early part of the brain system that monitors “per- in life, providing infants with a rough and sonal space” at about an arm’s length from ready, implicit way of detecting threats in our bodies, basically treating this space as the social environment. However, nurtur- an extension of ourselves. This helps to un- ing, responsive parenting buffers the defen- derstand why mistrustful children are likely sive reactions from the amygdala, in part by to become more defensive the closer we try decreasing the release of stress hormones to get to them. Some children, with insecure such as cortisol and norepinephrine while attachment experiences, often respond dra- promoting the release of calming chemi- matically differently to strangers or people cals such as oxytocin in this region. Social who are more distant from them than to at- engagement involves eye contact, the abil- tachment figures who try to come very close. ity to read other people’s facial expressions, They are responding from a neurobiological the ability to extract emotional meaning in defensiveness. other people’s voices, and the ability to put If a caregiver is being neglectful or caus- into one’s own voice. Different ing , the child’s amygdala starts to react types of social stimuli all pass through the to the caregiver as, in part at least, a source amygdala early in the sequence of sensory of pain and fear, setting up the potential processing in the brain. How the amygda- for chronic conflict between approach and la responds to this information biases the avoidance tendencies. The amygdala is young child towards either social approach strongly connected to the stress response system, or hypothalamus-pituitary-adrenal (HPA) axis, that activates the endocrine cir- cuitry and ultimately engages the adrenal glands in producing stress hormones such as cortisol. It is also strongly connected to the brain’s vigilance system that operates through the release of norepinephrine (NE) from the locus coeruleus (LC). When the amygdala detects a potential threat, it trig- gers the release of NE from the LC, ramping up attention to the possible threatening ob- ject or person. Through back projections to all sensory processing regions, the amygdala can intensify sensory experiences if it detects something as emotionally relevant, ramping up attention to that thing or person. Through its connections with the stress/defense sys- tems—the HPA axis that produces stress hor- mones and the sympathetic and parasym- pathetic defense systems that support fight, TatyanaGI/Bigstock.com

72 The Neuropsychotherapist issue 3 Oct-Dec 2013 ...people with reduced GABA activity in the amygdala are more “amygdaloid” in their reactions to all kinds of stressors— they have difficulty regulating negative emotions, actions, & thoughts.

flight, and freeze reactions—the amygdala rats life, maternal care is associated with dif-

can orchestrate the process of keeping the ferences in GABAA receptor subunit expres- brain and body on high alert, promoting self sion and these differences are intriguingly defense over social engagement. related to fearful behavior throughout the A number of genes are now known to be life of these animals. According to this re- targets for epigenetic effects in the amyg- search, “the offspring of high licking- dala. These include GABA receptor genes, grooming mothers show significantly high-

the gene for the oxytocin receptor, genes er levels of GABAA/Benzodiazepine receptor that express proteins involved in the growth binding in the basolateral and central nuclei of connections between the amygdala and of the amygdala and the locus coeruleus. other brain regions, and genes for corti- These findings provide a mechanism for in- cotrophin-releasing hormone (CRH), the creased GABAergic inhibition of amygdala- chemical that triggers the neuroendocrine locus coeruleus activity” (Caldji et al., 2003, stress response system. Research has be- p.1957). gun to target the GABA system in the amyg- In poorly nurtured rats, suppression of

dala as an extremely important mechanism the gene for GABAA receptor subunits in the for epigenetic effects of early experience amygdala leads to less sensitive GABA re- on emotional resilience and vulnerability ceptors, which, in turn, makes the amygdala (Cadji, Diorio, & Meaney, 2003; Diorio and more highly reactive to perceived threats. Meaney, 2007). Also, because higher brain regions in the prefrontal cortex modulate the amygdala by activating GABA receptors in the amyg- The GABA Receptor in the A dala, the lower sensitivity of the GABA sys- Amygdala tem in the amygdala reduces the capacity of In the amygdala of well cared for rats, the the prefrontal regions to dampen amygdala reactivity. gene for the GABAA receptor shows different patterns of expression compared to the less This is a structural and functional design nurtured peers. This is important because to make someone more highly reactive to GABA is the main inhibitory chemical in the stress, but unfortunately, also more vulner- brain. The action of GABA in the amygdala able to stress-induced disorders of all kinds, makes it possible to modulate defensive re- including PTSD, depression, and social activity that otherwise can set off the fight, anxiety. In essence, people with reduced flight, or freeze responses within millisec- GABA activity in the amygdala are more onds of detecting a potential threat. The “amygdaloid” in their reactions to all kinds amygdala specializes in avoidance learning, of stressors—they have difficulty regulating orchestrating the process of learning to as- negative emotions, actions, and thoughts. sociate social stimuli with pain, danger, or These individuals are likely to have a nega-

distress. By having more sensitive GABAA tive reaction to novelty, being more at the receptors in their amygdala, the well licked mercy of their rapid appraisal system that is rats have more power to “veto” output from biased towards avoidance of new things in a the central region of the amygdala to the seemingly “better safe than sorry” approach stress/defense systems. to life. With less ability to inhibit the activ- ity of the amygdala, it is harder for these The GABAA receptor is composed of sev- eral different subunits and the genes for people to “get above” their quick reactions these subunits are targets for epigenetic to things and to other people. This makes it programming by maternal care (Caldji, Dio- harder for them to change their behavior in ri, and Meaney, 2003). In the first week of a the light of new experiences. www.neuropsychotherapist.com The Neuropsychotherapist 73 By activating the oxytocin system, sensitive par- enting helps to quiet the amygdala and facilitate bonding and trust.

The Oxytocin Receptor in the Kumsta et al., 2013). Amygdala The amygdala is a key region of the brain for oxytocin activity at OTRs. Considering Oxytocin (OT) plays several roles in hu- both and human studies, it is clear that mans and other mammals: there is an important process of environmen- 1) promotes social approach behavior tal tuning of the structure and functioning of 2) facilitates formation of social mem- the amygdala and the genetic expression of ories the OTR gene in this area. This research is ex- 3) enhances the ability to read other tremely interesting in terms of understand- people’s minds, facilitating empathy and ing how good care buffers the child’s stress “mindsight” and systems and promotes the development of 4) reduces stress reactivity and self secure attachments and pro-social behavior. defensiveness (Carter, 2007). By activating the oxytocin system, sensitive parenting helps to quiet the amygdala and All of these functions are made possible facilitate bonding and trust. by the presence of the oxytocin receptor (OTR) in a wide variety of brain regions that Based on this research, we can see how are involved in social and emotional aspects early experiences with attachment figures of functioning. The gene for the OTR is a can promote either secure attachment based known target for epigenetic effects, mean- on deep safety being close to an adult or in- ing that early life experiences affect the level secure attachment that depends upon a cer- of expression of the OTR gene in the brain. tain level of vigilance or at least ambivalence Furthermore, researchers have found a sig- about being close to others. For children nificant relationship between the density who are exposed early in life to abusive and/ of OTR receptors in key brain regions in the or neglectful attachment figures, it would limbic system, and individual differences in be maladaptive to have a high level of gene social affiliation, empathy, and “mind read- expression of the OTR gene in the amygdala

olly2/Bigstock.com ing” ability in humans (Andari et al., 2010; because this would promote pro-social be- havior and a tendency to approach unreliable

74 The Neuropsychotherapist issue 3 Oct-Dec 2013 attachment figures in a trusting, relaxed and the manner, a potentially dangerous behavior Re Opening of Attachment-based trait. It would be adaptive for these children Learning if their brains produced fewer OTRs and GABA receptors, making it easier neurobio- The key to helping mistrustful children logically to “play defense” around others. learn to trust is to somehow re-engage them in attachment learning when they have passed the sensitive period for this process. Targeting The Neuroceptive Sys- Environmental enrichment involves creat- tem: An Epigenetic Model of At- ing opportunities for novel social experi- tachment-based Intervention ences, which can “jiggle” the brain into a state of alertness, surprise and curiosity and Since the amygdala is a major switch- launch a process of renewed social learning ing station in the brain between the social that can alter old learning that is no longer engagement system and the self defense adaptive. This involves surprising a mis- system, it makes evolutionary sense that trusting child with openness rather than re- this region is a major target for epigenetic sponding in a predictably defensive way to effects of good and poor relationships. The mistrusting behavior. question for intervention then becomes “what kinds of relational processes have Re-engaging the child’s brain in new at- the power to alter early patterns of gene tachment-based learning requires that the expression in the amygdala so as to shift its child experience an immediate disparity or functioning towards social engagement and incongruity between the caregiver’s behav- away from reflexive defensiveness?” This ior in the moment and the kind of reactions shifting of the neuroceptive system can be predicted by the child in a “mindless” state seen as the key to helping defensive chil- of mistrustfulness. Novel experiences with dren (and ) shift from core defensive- caregivers can trigger the process of tag- ness and mistrust towards social engage- ging brain cells for further gene expression, ment and trust. a process involving what are called Immedi- ate Early Genes or IEGs. Brains are in the business of making sense of experiences by Reversal of Early Epigenetic Effects comparing new and old experiences, deter- The task for a model of therapeutic in- mining rapidly if there is “news of a differ- tervention is to determine what kind of new ence” and if so, starting a process of trying experiences, beyond the sensitive period for to resolve the disparity. So creating dispari- ty, surprising the brain, presenting the brain The key to helping mistrustful children learn to trust is to somehow re-engage them in attachment learning when they have passed the sensitive period for this process.

attachment formation, can alter the early patterns of gene activity that supported self with a mystery, would appear to be essen- defensive living. In animal research, there tial to altering patterns of gene expression is a line of recent research that is studying in a therapeutic direction. this very question, exploring the kinds of The neuroscience literature on sensitive later life experiences that can shift patterns periods and post sensitive period learning of gene expression in the direction of less shows that different brain processes are in- defensive, more pro-social behavior. This volved during these different periods. Dur- research deals with so called environmental ing a sensitive period, learning is highly ef- enrichment. ficient because the brain is in a state of high arousal and receptivity, making it easy to www.neuropsychotherapist.com The Neuropsychotherapist 75 learn simply from continued exposure to to be a formula for re-engaging the child’s recurring experiences with an attachment brain in attachment based learning, based figure. Sensitive periods are a time in brain on a growing body of evidence from attach- development when there are high levels ment-focused treatment around the world. of activity in the brain, From a brain based perspective, PACE can including high levels of , seroto- be seen as a formula for promoting the kinds nin and norepinephrine. This high level of of epigenetic changes in a child’s brain that arousal facilitates all kinds of learning. The could facilitate the shift from defensiveness sensitive period for attachment in humans to openness. Clearly, from the research de- is probably the time between birth and scribed earlier, the important brain targets around 18 to 24 months. Once this period for these changes would be selected genes has passed, attachment learning probably in the amygdala, the hippocampus, and the requires intensive, highly arousing, atten- prefrontal cortex (PFC). How might PACE tion-demanding experiences to re open the trigger changes in gene expression in these “gate” for engaging the brain in this kind key brain regions? of learning and for facilitating the unlearn- PACE has the potential to do two impor- ing of old patterns of relating to unreliable tant things that could promote epigenetic caregivers. The new attachment figure has changes in a child’s brain: to somehow co-create with the child experi- 1) dampen the reflexive defense sys- ences that are novel, surprising, beyond the tem by promoting oxytocin flow into the “same old, same old”, triggering unpredict- amygdala and able reactions in the child. While all kinds of learning are more difficult after a sensitive 2) turn on excitatory neurochemis- period for that type of learning has been try, especially dopamine, to support new closed, neuroscience suggests that post learning (engaging what Panksepp calls sensitive period learning is quite possible if the “seeking system”), and a state of cu- given the necessary experiences and stimu- riosity about the new attachment figure lation. that reopens the child’s mind to attach- ment-based learning.

PACE: A Formula for Epigenetic PACE and the Amygdala: Shifting Reprogramming of the Child’s From Self Defense to Openness Neuroceptive System A major goal of a brain based approach to PACE 1 (playfulness, acceptance, curi- helping defensive children form secure at- osity, empathy), (Hughes, 2009) appears tachments to trustworthy caregivers would omgimages/Bigstock.com

1. Dyadic developmental therapy, developed by Daniel Hughes, principally involves creating a “playful, accepting, curious, and empathic” (PACE) environment. The therapist “co-regulates” affect and “co-constructs” an alternative narratives with the child by being attuned to the child’s “subjective experiences”. Ed.

76 The Neuropsychotherapist issue 3 Oct-Dec 2013 be to alter the pattern of activity in the chil- the research on various kinds of epigenetic dren’s defensive brain circuitry. Since the processes, we begin to see an emergent amygdala plays a leading part in orches- integration of relational processes, intrap- trating this defensive way of relating, it is ersonal processes, and pharmacology that essential to target the amygdala for thera- could be the foundation for a more effective peutic modulation, for shifting the amyg- model of mental health interventions. With dala’s bias towards self defensive behavior a deeper understanding of how experience towards social engagement. By being play- becomes embedded in our brains and bod- ful, accepting, curious, and empathic, the ies, we can learn to target epigenetic chang- adult may be able to de-activate the child’s es that promote greater resilience and ca- defense system, at least transiently. This pacity for human connection. transient buffering of the child’s defense system would very likely activate the im- mediate early gene system to tag brain cells References and Resources for in the amygdala, alerting them, in a sense, Further Reading that there is “news of a difference”, that this Andari, E., Duhamel, J.-R., Zalla, T., Herbre- adult seems different from other adults who cht, E., Leboyer, M., & Sirigu, A. (2010). presented a threat in the past. This “news of Promoting social behavior with oxytocin a difference”, would, in turn, likely activate: in high-functioning autism spectrum dis- • the hippocampus to help compare orders. Proceedings of the National Acad- the present experience to the past; emy of Sciences of the United States of America, 107(9), 4389–4394. doi:10.1073/ • the lower region of the PFC; pnas.0910249107 • the orbitol region, which specializes Avishai-Eliner, S., Gilles, E. E., Eghal-Ahma- in learning and remembering social di, M., Bar-El, Y., and Baram, T. Z. (2001). contingencies and in “reversal learn- Altered regulation of gene and protein ing”; expression of hypothalamic-pituitary- • and the ACC that is vitally involved adrenal axis components in an immature in fear “extinction” and in resolving rat model of chronic stress. Journal of conflicts between old, habitual ways , 15, 114-119. of reacting and new ways of behav- Caldji, C., Diorio, J., and Meaney, M. J. ing. (2003). Variations in maternal care alter GABA receptor subunit expression in This sequence of brain activity would A very likely create a state of mind conducive brain regions associated with fear. Neu- ropsychopharmacology, 28, 1950-1959. to altering patterns of gene expression in Canli, T., Qui, M., Omura, K., Congdon, E., the fronto-limbic regions—the foundational Haas, B. W., Amin, Z. et al. (2006). Neu- system for social and emotional function- ral correlates of epigenesis. 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