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The Neurobiology of Attachment

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 1 The Neurobiology of Attachment
2

3 Introduction
4 Understanding attachment from a biological perspective

5 Physiological homeostasis within the body is influenced by what occurs in the external environment.

6 Danger and distress, generated by the perception of the consequent outcomes of changes in the

7 external environment provoke psychological mechanisms that influence physiological systems

8 responsible for maintaining homeostasis. In his pioneering work on attachment theory Bowlby (1973)

9 was concerned with how psychological mechanisms affect psychobiological reactions and

10 physiological homeostasis. Bowlby suggested that a viable attachment behavioural system acts as a

11 buffer between the external stressors and an infant’s ability to maintain internal physiological

12 stability. He envisioned this as two concentric circles with the inner circle representing the body’s

13 internal regulatory mechanisms being surrounded by the outer circle representing the protective

14 attachment behaviour system resisting pressures from the external environment (John Bowlby, 1973).

15 His focus was on early psychological development and how the protective nature of attachment

16 relationships extend beyond functional physiological requirements (Goldberg, 2014). Giving a

17 salutary warning that an ineffective attachment behaviour system can overload homeostasis and

18 compromise survival (B. S. McEwen & Wingfield, 2003). An infant crying is a paradoxical graded

19 signal that changes with the level of distress (Riem, Voorthuis, Bakermans-Kranenburg, & van

20 Ijzendoorn, 2014). Crying evokes empathic emotional reactions that incite sensitive parental

21 behaviours that appease the infant and answer its needs. Crying also signals the infant’s need for the

22 caregiver’s physical presence that induces dynamically interactive cry-care thoughts and actions that

23 lead to attachment (Swain, Mayes, & Leckman, 2004) For example, an adult caregiver monitors an

24 infant using its appearance and behaviour as cues for action to regulate the child’s body temperature

25 by applying or removing appropriate layers of clothing. An infant’s fluid balance, nutrition and

26 toileting needs are controlled by similar processes.

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27 Rilling (2013) suggests that sensitive parenting is defined as contingent, reciprocating responses to

28 children, and associated with positive child outcomes, whereas insensitive parenting resulting from

29 neglect and abuse is associated with poor developmental outcomes (Rilling, 2013). Although mothers

30 are generally the primary caregiver, humans are an alloparental species, where the care of an infant is

31 often shared with other family members; who in turn form supplementary attachment behaviour

32 mechanisms that reinforce the buffer between the homeostatic mechanisms of the child and the

33 stressors of the external environment.

34 However, attachment behaviour extends beyond the provision of the basic physiological needs of an

35 infant. The primary function of attachment behaviour is provide comfort and caregiving to a person

36 who is frightened, fatigued or sick, which physiologically reduces the stress and anxiety that results

37 from external influences (J. Bowlby, 1982; Goldberg, 2014). The knowledge that an attachment figure

38 is available and responsive, provides a strong and pervasive feeling of security, which encourages the

39 person to value and continue the relationship (Bowlby 1982). Attachment is an integral part of human

40 nature that invokes feelings of support and protection, which may modify their perception of stress

41 and danger that attenuates the physiological response to their distress.

42 Affect regulation

43 Whereas Bowlby proposed that attachment theory encompasses the integration of psychological and

44 biological models of human development Schore and Schore (2008) argue that Bowlby’s core

45 principles of attachment have been expanded into a more complex and clinically relevant model (J. R.

46 Schore & Schore, 2008). Modern interest in affective physiological processes, interactive regulation,

47 early experience-dependent maturation of the brain, stress induced physiology and nonconscious

48 relational transactions have shifted attachment theory towards a regulation theory. Fonagy and Target

49 (2002) suggested that the establishment of early relationships equip individuals with an information

50 processing control system, a system that is the most important function of a child’s attachment to a

51 caregiver. They saw child development as the enhancement of self-regulation (Fonagy & Target,

52 2002).The shift in attachment theory towards affect and affect regulation has transformed

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53 developmental theory into a pragmatic framework for models of psychopathogenesis and the change

54 process in psychotherapy (Schore and Schore 2008).

55

56 The infantile development of attachment is linked to the neurobiology of optimal and pathological

57 emotional development and the genesis of adult personality disorders (Allan N Schore, 2000, 2001).

58 Figure 1 Structures of the brain associated with the neural and hormonal basis of attachment

59
A
60 B

61 C

D
62

63

64 E

F
65

66 G

67 H

68

69

70

71

72

A Medial prefrontal cortex E Hypothalamus

B Anterior cingulate F Amygdala,

C Orbitofrontal cortex G Pituitary gland

D Bed nucleus stria terminalis H Hippocampus

73

74 Emotions are described as consisting of physiological, behavioural and subjective-experiential

75 components (Stansbury & Gunnar, 1994). Emotional responses to external stimuli cause physiological

76 changes, processes that are associated with the behavioural expression and integral to the regulation of

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 77 emotion. Emotion and the consequent behaviours are initiated, organised and regulated by the brain

78 and other components of the nervous system (Goldberg 2014). In attachment theory the brain of both

79 individuals exchange information and influence one another. In infant/mother interactions the brain of

80 the infant is developing rapidly and will reflect social interactions. The effects of traumatic

81 experiences occurring during brain development may endure, lead to emotional and cognitive deficits

82 that manifest as psychiatric disorders in later life (Sullivan, 2012). Atypical emotional development

83 may lead to problems dealing with stress that lead to behaviour regulatory difficulties, interpersonal

84 problems, and engagement in high-risk antisocial activities (Bick & Nelson, 2016)

85 Sensitive periods

86 Brain development in time sensitive periods has been suggested to follow two distinct environmental

87 influences experience-expectant and experience-dependent processes (Bick & Nelson, 2016;

88 Greenough, Black, & Wallace, 1987). Such sensitive periods of development are advantageous by

89 guiding brain development and neurobiological adaptations from ubiquitous environmental signals.

90 Experience-expectant processes are responsible for overproducing synaptic connections between

91 neurones that are subsequently reduced by a process in which, aspects of sensory experience

92 repeatedly utilized determine the pattern of connections that remain (Greenough 1987). Experience-

93 dependent information storage refers to the generation of new synaptic connections in response to

94 environmental information that are idiosyncratic to the individual, e.g., learning about a specific

95 physical environment or vocabulary (Goldberg 2014; Greenough 1987). Experience-dependent events

96 cannot be predicted and so the brain reacts to these situations as they occur, only events that are

97 important and repeated are encoded in the neural networks that remain. As these developmental

98 processes may occur concurrently, such categories offer a view more in accord with neural

99 mechanisms than terms such as "critical" or "sensitive period" (Goldberg 2014). The human brain

100 develops within a set of specific parameters through both genetic and environmental factors and their

101 complex interactions over time. The absence of expected input during sensitive periods of brain

102 development endangers the brain’s ability to achieve its genetic potential.

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103 Whereas Bowlby described attachment developing from danger with fear and distress being the

104 emotions Schore (1996) postulates that neurobiological development and specifically the

105 neurobiology of emotions and emotion regulation primarily develops through periods of mutual

106 delight, of interacting face-to-face in games involving eye contact, smiling and laughter (A. N.

107 Schore, 1996). However, Goldberg (2014) argues that although such a model is useful it is unlikely to

108 be the “fundamental context for normal emotional or neurobiological development,” because face-to-

109 face encounters, during the sensitive times of brain development vary considerably across a variety of

110 cultures.

111 In this chapter we will examine neurobiology of attachment systems, the neurochemical responses to

112 stress and its reduction that are attributable to three types of attachment behaviour infant-parent,

113 parent-infant and intraspecific attachment (with a partner). To understand the psychobiology of

114 attachment requires an understanding of the neural systems involved in social recognition, motivated

115 behaviours, reward, long term memory and disinhibition.

116 Neural and hormonal bases of adult attachment

117 This seems to be a larger section – might be useful to break it down for each aspect discussed? It is

118 dense and the students unlikely will have so much detailed pre-knowledge; however it is excellent to

119 offer it to them here, but we also need to make sure that we bring it together at the end into so why is

120 this relevant?

121 Oxytocin (OT) has long been recognised for its role in parturition and lactation (Kim, Fonagy, Koos,

122 Dorsett, & Strathearn, 2014), however, in mammals OT is also key to many homeostatic processes

123 that include; thermoregulation (Kasahara et al., 2013), nutrition (Maejima et al., 2014) and sexual

124 behaviours (Bale, Davis, Auger, Dorsa, & McCarthy, 2001; Gil, Bhatt, Picotte, & Hull, 2011). More

125 recently OT has been implicated in the regulation of maternal caregiving (L. Strathearn, Fonagy,

126 Amico, & Montague, 2009); social behaviours including pair bonding (Schneiderman, Zagoory-

127 Sharon, Leckman, & Feldman, 2012); interpersonal trust (Van IJzendoorn & Bakermans-Kranenburg,

128 2012); recognition of emotion (Perry et al., 2013) and empathy (Hurlemann et al., 2010). As early as

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129 1992 Insel described OT as the neuropeptide of affiliation and to date it is understood to play a vital

130 role in mother-infant interaction (Insel, 1992). Carter (2014) suggests that OT and the genetically and

131 structurally related neuropeptide vasopressin, and their receptors are “at the centre of physiological

132 and genetic systems that permitted the evolution of the human nervous system and allowed the

133 expression of contemporary human sociality” (Carter, 2014).

134 OT, a nonopeptide, contains a loop of 6 amino acids and a tail of the remaining 3 amino acids. Its

135 bonding properties to OT receptors are due in part to the sulphur bonds across the loop. OT is not a

136 classic neurotransmitter limited to local actions across a synapse but more a neuromodulator flowing

137 through neural tissue to regulate diverse populations of neurons (Carter, 2014). OT is synthesised by

138 neurons present in the paraventricular and supraoptic nuclei (PVN and SON) of the hypothalamus

139 with axons that reach the posterior pituitary. OT neurons also project into other regions of the brain

140 including the hippocampus, striatum and amygdala (Acevedo-Rodriguez, Mani, & Handa, 2015;

141 Knobloch et al., 2012). OT also has a role in the regulation of stress, being co-localized within

142 neurons of the PVN with major stress hormones, such as corticotropin-releasing hormone (CRH) that

143 regulates the hypothalamic–pituitary–adrenal axis (HPA). In humans plasma OT levels are higher in

144 pregnant and parturient women than those not pregnant and although plasma concentrations vary

145 between women they are particularly stable throughout the course of a pregnancy and early

146 motherhood (Feldman, Weller, Zagoory-Sharon, & Levine, 2007b; Gordon, Zagoory-Sharon,

147 Leckman, & Feldman, 2010) that may be a trait-like characteristic in the expression of maternal

148 behaviour (Kim 2014). High plasma OT concentrations during pregnancy and early motherhood are

149 positively associated with increased maternal behaviour in the postpartum months and with

150 predictable differences in the quality of maternal care (Feldman, Gordon, Schneiderman, Weisman, &

151 Zagoory-Sharon, 2010a; Feldman, Gordon, & Zagoory-Sharon, 2010b). The quality of maternal care,

152 sensitivity and responsiveness, have direct bearings on a child’s capacity for social adaptation and

153 stress regulation (Kim et al., 2014).

154 Mammalian parental behaviour across multiple species is varied and complex. However, lesion

155 studies in rodents, patterns of immediate-early gene expression, the use of neuropeptide knockout

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156 mice and pharmacological manipulation have revealed much of the brain structure involved in

157 parental attachment (Insel and Young 2001). Whereas parturition, vaginal-cervical stimulation (VCS),

158 lactation, nipple stimulation and cohabitation with rat pups may facilitate parental attachment, stimuli

159 such as copulation, mild stress and cohabitation facilitate the development of intraspecific attachments

160 between males and females. Coria-Avila et al., (2014) argues this must occur via two separate neural

161 pathways as both forms of attachment can occur simultaneously (Coria-Avila et al., 2014). Oestrogen

162 and prolactin, hormones related to pregnancy, act together with the medial preoptic area (MPOA) of

163 the hypothalamus, to enable natural maternal instinct at parturition (Rilling, 2013). OT released at

164 parturition is induced by oestrogen and facilitates maternal behaviour together with the release of

165 dopamine in the nucleus accumbens (NA), which augments the reward value of the offspring (Rilling,

166 2013). High licking and grooming mothers have more OT receptors in the MPOA. Rat pups born to

167 high licking and grooming mothers are less fearful and better able to deal with stress than pups born

168 of low licking and grooming mothers (Gunnar & Quevedo, 2007). Epigenetic studies (see later

169 section; Adverse childhood experiences and age related disease, for the importance of epigenetics)

170 have shown that licking and grooming reduce the methylation of the oestrogen receptor-α gene

171 promoter that would otherwise silence these genes and inhibit the development of the OT system (L.

172 Strathearn, 2011). Stress and maternal anxiety during pregnancy may reduce OT receptor binding in

173 key areas of the brain and consequently in the offspring. Such stress related effects may therefore lead

174 to defects in the oxytocinergic system of offspring in later life (L. Strathearn, 2011). Gunnar (2007)

175 suggests such epigenetic effects may be irreversible and are a powerful example of how stress

176 neurobiology is programmed by social experiences during sensitive periods of development. It is

177 unsurprising therefore, that in humans, the offspring of mothers with a history of inadequate

178 childhood attachment may result in the impaired development of secure attachment in their own

179 infants (Shah, Fonagy, & Strathearn, 2010).

180 Very few mammalian species are bi-parental, as males do not have the benefit of pregnancy related

181 hormones. In some rodent species prolactin is associated with male parental behaviour. Testosterone

182 may inhibit paternal behaviour or support it if the steroid hormone is converted to oestradiol by the

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183 catalytic effect of aromatase. Arginine vasopressin (AVP) can motivate male prairie voles to exhibit

184 paternal licking and grooming as injections of the hormone into the lateral septum of virgin males

185 stimulates paternal behaviour (Rilling, 2013).

186 In primates there is little evidence that oestrogen correlates to maternal behaviour post-partum.

187 However, there is evidence to support the positive correlation of OT with maternal care behaviour. In

188 addition maternal rejection is positively correlated to increased levels of plasma cortisol an

189 established marker of psychosocial stress generated by the HPA axis. Paternal care behaviour in

190 marmoset monkeys is associated with prolactin and mediated by physical contact. In Cotton-Top

191 Tamarins prolactin levels are positively correlated with the number of previous births the male has

192 experienced as a father. In addition, prolactin levels in cooperatively breeding species are also

193 elevated in non-reproductive alloparents who assist in infant care. (Rilling, 2013; Ziegler, Wegner, &

194 Snowdon, 1996).

195 Many studies have demonstrated that adult attachment predicts maternal behaviour patterns which in

196 turn influences infant social/emotional development and attachment (L. Strathearn, 2011). Strathearn

197 hypothesises that the intergenerational transmission of attachment is mediated by differences in the

198 maternal neuroendocrine responses to infant cues (Lane Strathearn, 2007; L. Strathearn et al., 2009);

199 which may then shape the infant’s neuroendocrine development and behaviour (L. Strathearn, 2011).

200 Figure 2 illustrates the intergenerational cycle of maternal caregiving and neuroendocrine

201 development from the mother through to the infant and hence the next generation.

202

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203 Figure 2 The cycle of maternal caregiving and neuroendocrine development across a lifetime

Maternal
caregiving
Adulthood (Pre- and post- Infancy
natal)

Maternal brain Neuroendocrine

and endocrine development of
response infant

Genetic variation and

epigenetic adaptation

Adult Infant
attachment attachment
strategy behavior

Ongoing
environmental
influences
204
205 Adapted from Strathearn 2011

206

207 Epigenetic changes caused by the caregiving environment, such as the methylation of the oestrogen

208 receptor-α, may influence the development of biological systems and behavioural phenotypes that

209 result from changes in the regulation of gene expression (L. Strathearn, 2011). Weaver (2004)

210 reported that increased pup licking and grooming and arched-back nursing by rat mothers altered the

211 epigenome of the pups through differences in DNA methylation, demonstrating that an epigenomic

212 state of a gene can be established through behavioural programming (Weaver et al., 2004).

213 Dopamine (DA) is a second neuromodulator, produced in the NA of the ventral striatum. Dopamine

214 exerts widespread effects on the central nervous system that influence maternal caregiving behaviour.

215 Mesocorticolimbic and nigrostriatal dopamine pathways are responsible for the processing of infant-

216 related sensory cues that lead to a behavioural response (L. Strathearn, 2011). The dopaminergic

217 system is involved with reinforcement stimulus reward learning and associated with responsive

218 maternal caregiving behaviour in the rat, together with early developmental stimulation that imbues

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219 the infant with intuitive reinforcement and provides motivational drive to maternal behaviour (Atzil,

220 Hendler, & Feldman, 2011; L. Strathearn, 2011). Disruption in dopaminergic neurotransmission can

221 have profound effects on mood and behaviour (Baskerville & Douglas, 2010). OT is an important

222 neuromodulator that interacts with central dopamine systems. Postnatal stress, early parental neglect

223 and abuse can have far-reaching and long lasting changes to the emotional and motivational

224 development of an infant that consequently leads to abnormal attachment behaviours in adulthood

225 (Seso-Simic, Sedmak, Hof, & Simic, 2010).

226 In Figure 3 the three circles represent the neural areas that facilitate the formation, expression and

227 maintenance of intraspecific and parental attachments activated during social encounters; social

228 recognition, reward and motivation, and the inhibition of fear/anxiety. The arrows indicate the neural

229 projections and where the circles overlap represents areas of the brain that may participate in more

230 than one function. Sensory stimuli activate neural areas that facilitate social recognition and the

231 inhibition of fear/anxiety whereas the spinal cord inputs facilitate reward and motivation. Both OT

232 and DA interact to facilitate social recognition and reward motivation. D1-type receptors within the

233 nucleus accumbens (NAcc) facilitate parental attachment, while D2-type receptors facilitate

234 intraspecific attachment. Although a common neural system appears to underpin both parental and

235 intraspecific attachments the stimuli that trigger the neural cascades are different. Pregnancy,

236 parturition and lactation facilitate parental attachment, whereas copulation or sexual reward develop

237 intraspecific attachment (Coria-Avila et al., 2014). The anterior cingulate cortex (ACC) may

238 discriminate different stimuli and orchestrate the behavioural output directing the appropriate

239 responses to the infant or partner. Coria-Avila et al., (2014) point out that social recognition alone is

240 insufficient for successful intraspecific and parental attachments as reward and motivation must also

241 be activated, while those associated with the inhibition of fear must be inactivated.

242

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243

244 Figure 3. The neural pathways that mediate intraspecific and parental attachments.

245

246

247

248

249

250

251

252

253

254

255
256 Reproduced with permission from (Coria-Avila et al., 2014)

257 1. OT, oxytocin; 265 9. MPOA, medial preoptic area;

258 2. DA, dopamine; 266 10. NAcc, nucleus accumbens;

259 3. MeA, medial amygdala; 267 11. VTA, ventral tegmental area;

260 4. ACCv, anterior cingulated cortex ventral part; 268 12. VP, ventral pallidum;

261 5. AVP, arginine vasopressin; 269 13. PVN, paraventricular nucleus;

262 6. BLA, basolateral amygdala; 270 14. PAG, periaqueductal gray matter;

263 7. BNST, bed nucleus of the stria terminalis; 271 15. PFC, prefrontal cortex;

264 8. CoA, cortical amygdala; 272 16. NTS, nucleus tractus solitarius.

273

274
275 Consequent to these neural pathways, insecure mothers have infants who exhibit insecure attachment,

276 whereas secure mothers have offspring who exhibit secure attachment behaviours (Riem, Bakermans-

277 Kranenburg, van Ijzendoorn, Out, & Rombouts, 2012). In a 2006 study Leerkes & Siepak examined

278 attachment linked predictors of a mother’s emotional and cognitive responses to infant distress. They

279 found that, consistent with Bowlby’s attachment theory, the perception and response to infant cries

280 were different for insecure parents compared to secure parents. Parents whose emotional needs were

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281 not met in childhood or who have insecure traits as adults are more likely to make defensive,

282 negatively biased assumptions (e.g. the child is being difficult or has a difficult temperament), which

283 results in less empathy with the infant; results that are consistent with that of Dykas and Cassidy

284 (2011). Secure-autonomous adults are more likely to respond appropriately as firm parental

285 attachment moderates the association of postnatal parental rejection and their emotional and cognitive

286 responses to infant distress (Leerkes & Siepak, 2006). Interestingly these results varied with respect to

287 race and parent gender (Leerkes & Siepak, 2006). From magnetic resonance imaging Bos et al.,

288 (2012) reported that the perception of infant crying involves a complex neural network that Riem et

289 al., (2012) suggests involves the amygdala, the ACC and the orbitofrontal cortex (Bos, Panksepp,

290 Bluthe, & van Honk, 2012; Riem et al., 2012). In later research Riem and colleagues examined the

291 effects of nasally administered OT on neural responses to infant crying and reported that OT increased

292 empathic reactions to sick infants’ crying, and lowered the perceived urgency of an infant perceived

293 as being bored. OT enhanced insula, inferior frontal gyrus and amygdala responses to sick, high-

294 pitched infant crying compared to the cries of a bored infant. OT enhanced the perceived urgency of

295 responding to an infant in distress and lowered neural reactivity when the cries were perceived as

296 being non-urgent (Riem et al., 2014). Figure 4 represents the maternal brain responses to infant cues:

297 proposed dopaminergic and oxytocinergic pathways relating to adult attachment patterns (L.

298 Strathearn, 2011).

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299 Figure 4 A model of the maternal brain responses to infant cues: proposed dopaminergic and oxytocinergic pathways relating to adult attachment patterns
300 (secure and insecure/dismissing). Adapted from Strathearn 2011 [SON = supraoptic nucleus; PVN = paraventricular nucleus; MPOA = Medial preoptic area]
301
Mesocorticolimbic Nigrostriatal
302
dopamine pathway dopamine pathway
303 AFFECT COGNITION
304

305 Medial Dorsolateral

306 prefrontal cortex prefrontal cortex

(mPFC) (DLPFC)
307

308

309 Sensory Input Motor output

Ventral Striatum Dorsal striatum
310 e.g. infant face cues (e.g. Caregiving behaviour)
311
312 + + +
313 +
314 +/- +/-
315 Venteral tegmental Substantia nigra
316 Oxytocin pathway
317 + area (VTA) (SN)
318
319
320
321 Hypothalamus
322 Secure Insecure/dismissing
e.g. SON, PVN,
323 adult attachment adult attachment
324 MPOA/pituitary
325
326
Serum
Oxytocin
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327 Neural and hormonal bases of infant attachment

328 Goldberg (2014) cautions that the neurophysiology of animal models does not always translate into

329 similar human attachment behaviour. Animal studies are approximations of human infant behaviours

330 and it is risky to extrapolate from one to the other. In comparison to animal studies Goldberg suggests

331 that the differences observed in human attachment will be behaviourally and physiologically more

332 subtle. Goldberg suggests that attachment patterns in humans represent strategies for coping with

333 stressful events. It is anticipated that attachment strategies are traits that are learned in response to an

334 attachment figure’s reliability and effectiveness to attenuate stress by the provision of comfort and

335 assistance. Table 1 sets out the variation of an individual’s personality in response to the altered

336 competence of the attachment figure dealing with stressful events

337

338 Table 1 Personality characteristics of an individual learned from an attachment figure’s response to
339 stress.

Individual’s attachment
Learned traits in response to stress
character
Confidence in the attachment figure’s ability to provide
Secure/autonomous
comfort to reduce stress.
The attachment figures are unresponsive to their distress and
Avoidant/dismissing
are reliant upon self-regulation to reduce stress.
The attachment figure’s response to stress is unreliable and
Resistant/preoccupied make exaggerated bids for attention that are not always
effective in reducing stress.
Lack organised strategies to manage stressful events with an
Disorganised
attachment figure.
340 Adapted from Goldberg 2014

341

342 To understand stress responses and attachment it is necessary to determine the physiological changes

343 that occur when an individual is exposed to physical or psychological stressors. In mammals there are

344 two parallel systems that react to stress, the sympathetic-adrenomedullary (SAM) system and the

345 hypothalamic-pituitary-adrenocortical (HPA) system. SAM system releases epinephrine from the

346 medulla of the adrenal gland and is a component of the sympathetic nervous system. Epinephrine

347 facilitates the rapid mobilisation of metabolic resources that orchestrate the fight or flight response

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348 (Gunnar & Quevedo, 2007). In rats the HPA system produces corticosterone while in primates it

349 produces the steroid hormone cortisol (both being glucocorticoids). Figure 5 illustrates the

350 neurochemical cascade that leads to the release of glucocorticoids (GC) into the blood circulation.

351

352 Figure 5 The human hypothalamic-pituitary-adrenocortical system

353

354

355 Stress

356

357

358
Hypothalamus
359
CRH/AVP
360

361 Pituitary

362 ACTH
Negative feedback
363 Adrenal Cortex
364
Cortisol
365
Stress
366 Response
367
368 Abbreviations: CRH = Corticotropin releasing hormone; ACTH = Adrenocorticotropic hormone; AVP = Arginine
369 vasopressin.
370

371 In response to stress corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) are

372 released by cells in the paraventricular nucleus (PVN). Both AVP and CRH travel to the anterior

373 pituitary through small blood vesicles where they stimulate the release of adrenocorticotropic

374 hormone (ACTH). ACTH binds to receptors in the adrenal cortex and stimulates the release of GC

375 into the blood stream. Unlike the SAM system, in the HPA system the action of the GCs on target

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376 tissues involves gene transcription and as a result the HPA system reacts more slowly, although the

377 effect of the GCs are longer lasting (Gunnar & Quevedo, 2007).

378 Cortisol is essential for normal, non-stressed activity and the basal cortisol levels follow a circadian

379 rhythm where the levels are highest in the morning. These basal levels help sustain the available

380 energy for action and stimulate the appetite for carbohydrates (Stansbury & Gunnar, 1994). There are

381 two types of receptors; mineralocorticoid receptors (MCR) and glucocorticoid receptors (GCR) and

382 the effects of circulating GC’s is dependent upon which of the receptors the GC’s bind with.

383 Activation of the GCR’s through cortisol binding in the hypothalamus and pituitary initiates the

384 inhibition of further cortisol release, in a negative feedback system (Laryea, Muglia, Arnett, &

385 Muglia, 2015), that prevents the damaging effects of excessive or chronic activation (A. R. Tyrka,

386 Ridout, & Parade, 2016), conditions which may alter the function of the HPA axis (Doom, Cicchetti,

387 & Rogosch, 2014). Prolonged stress from severe adverse childhood experiences may result in HPA

388 axis dysregulation and blunted diurnal cortisol profiles, in addition to abnormal stress reactivity

389 (Andrea Gonzalez, 2013).

390 Outside the brain GC’s predominantly bind to the MCR’s and this provides the basal level responses

391 that fluctuate during the circadian rhythm. GCs bind with GCR’s at the height of the daily fluctuations

392 or when stress stimulates their production of GC’s above the basal levels.

393 Whereas MCR mediated effects allow appropriate fight or flight responses via the secretion of the

394 catecholamines, epinephrine (Epi) and also some norepinephrine (NEpi), from the adrenal medulla

395 GCR mediated effects may antagonistically oppose this (Gunnar & Quevedo, 2007). Why GCR plays

396 such a suppressive role in stress management has not been determined, however, one explanation may

397 be that the GCR response may facilitate the reestablishment of cellular homeostasis (Sapolsky,

398 Romero, & Munck, 2000).

399 Three stimulants result in the release of cortisol; internal biochemical processes, e.g., the circadian

400 rhythm, physical stressors e.g., pain and hunger, and psychological stressors e.g., the perception of

401 aversive experiences (Goldberg, 2000) Two psychological factors that are responsible for the increase

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402 in cortisol output are negative events that are unpredictable and those that are uncontrollable

403 (Goldberg, 2000). Although it is unethical to subject human infants to high levels of stress, salivary

404 cortisol levels, which correlate to unbound plasma cortisol, have been determined during; mild

405 restraint, vaccinations and maternal separations (Cacioppo, Cacioppo, Capitanio, & Cole, 2015;

406 Goldberg, 2000). Indeed Blair et al., (Clancy Blair et al., 2011a; C. Blair & Raver, 2016) have shown

407 that salivary cortisol is elevated in children in poverty (Clancy Blair, Raver, Granger, Mills-Koonce,

408 & Hibel, 2011b) and the effects of socioeconomic and early psychosocial disadvantage affect the

409 development of executive function in childhood.

410 Developmental changes in the reaction to stressful events that occur during infancy are

411 contemporaneous with the quality of caregiving behaviour. The magnitude of cortisol release in

412 response to stress attenuates as an infant’s experience of negative events and is tempered by

413 predictable control and security offered by attachment to the caregiver.

414 Mammalian mothers shape the socio-emotional development of their infants by serving as essential

415 external regulators of an infant’s physiology, neurodevelopment, behaviour, and emotion regulation

416 (Drury, Sanchez, & Gonzalez, 2016). An infant’s neurobiology during stressful events can be shaped

417 by the external social environment and key to this is a mother’s behaviour. Buss et al., (2012) reported

418 that, after accounting for potential confounding pre- and postnatal factors, higher maternal cortisol

419 levels in early human gestation was associated with affective problems in girls, and this association

420 was mediated, in part, by an increase in right amygdala volume (Buss et al., 2012). The amygdala is

421 known to regulate many emotions, including fear, depression, and anxiety. The amygdala has an

422 important role in emotional memory processing and the HPA axis reactivity to stress (Buss et al.,

423 2012). They concluded that their results suggest that neurological development may result from foetal

424 exposure to high levels of cortisol, which may result in psychopathologic disorders in later life.

425 How adults react to stress can be permanently imprinted by patterns of caregiving early in an infant’s

426 development, however, alterations influenced by negative caregiving may be reversed by improved

427 caregiving later (Drury et al., 2016). Methylation of DNA, histone modification, non-coding RNA’s

17 | P a g e
428 and telomere erosion are thought to be the mechanisms by which genetic information can be re-

429 programmed by negative caregiving behaviour (Shonkoff & Garner, 2012). The methylation of

430 serotonin transporter gene (5-HTT) is thought to be one example of how epigenetic regulation may

431 signal the link between infant stress and lifetime health trajectories (Kinnally, 2014). Classically DNA

432 coding was thought to be immutable, however, recent studies have shown that the structure of DNA

433 can be reprogrammed by a range of factors that include; stress, trauma, sleep, nutrition,

434 pharmacologic agents, and abnormal caregiving behaviour. (Anderson, Sant, & Dolinoy, 2012;

435 Massart et al., 2014; Numata et al., 2012). Numata et al., (2012) investigated the epigenetics of the

436 developing pre-frontal cortex, one of the last brain regions to develop. They examined DNA

437 methylation in ~14500 genes and 27000 CpG loci on 5´promoter regions of 108 human subjects aged

438 between foetal to the elderly. Their results indicated that promoter DNA methylation in the human

439 pre-frontal cortex is a highly dynamic process that progressively increases from demethylation

440 prenatally to methylation postnatally (Numata et al., 2012). The environmental reprogramming

441 suggests a mechanism by which social stimulation can impact on an infant’s reaction to stress and the

442 molecular process by which DNA can be reprogrammed. (Gunnar & Quevedo, 2007). Interestingly,

443 Bos et al., (2012) have found that, in line with animal studies, OT attenuates the cortisol responses to

444 stress and most effectively with social support (Bos et al., 2012).

445 In stressful situations infants use selective coping strategies to minimise the effect of the stressor that

446 may involve a secure attachment figure’s comforting behaviour. If such a strategy has been reliable in

447 minimising stress, the physiological response will be reduced. However, if these strategies have not

448 been reliable the uncertainty of gaining comfort or the expectation of failure to gain comfort will elicit

449 a physiological response such as an increase in plasma cortisol. Goldberg (2000) suggests that it is the

450 perception of the effectiveness of previous coping strategies to stressful events not the event itself that

451 is intrinsically associated with physiological stress. In adults Ditzen et al., (2008) suggests that

452 although attachment and social support may play an important protective role in the attenuation of

453 psychological stress it may not directly moderate cortisol responses to acute stress (Ditzen et al.,

454 2008).

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455

456 Adverse childhood experiences and age related disease

457 Whereas homeostasis is the maintenance of systems that are essential for life, allostasis is the

458 maintenance of these systems when the environment and life history changes, such as social

459 interactions, weather, disease, pollution or stress (B. S. McEwen & Wingfield, 2003). Allostasis

460 involves the nervous, the endocrine and the immune systems that interact together to activate

461 specialized adaptive responses to maintain physiological stability.

462 Figure 6. A conceptual model of the influence and consequence of ACE’s in the

463 development of risk factors for disease, and premature death throughout the lifespan

Premature

death
Disease, Disability
& Social problems

Adoption of Health Risk

Behaviours

Social, Emotional & Cognitive

Impairment

Disruption of Neurodevelopment

Adverse Childhood Experiences

464
465 Adapted from Felitti et al. (1998) and the CDC-Kaiser ACE study (Centers for Disease Control and Prevention,
466 2016)

467

468 Childhood maltreatment, all too frequent in western societies, has an estimated prevalence of 10-15%

469 and that over 30% of adult psychopathology is directly related to childhood maltreatment (Lutz,

470 Almeida, Fiori, & Turecki, 2015). Adverse childhood experiences (ACE,), defined as physical,

19 | P a g e
471 sexual, and psychological abuse, parental neglect, household dysfunction and poverty remain risk

472 factors for disease in adulthood Figure 6 (Felitti et al., 1998; Su, Jimenez, Roberts, & Loucks, 2015).

473 ACE’s result in diminished maladaptive childhood attachment. In response to chronic adverse

474 psychosocial stressors key areas of the brain (e.g., the thalamus, the sensory cortex, and the amygdala)

475 which detect such stressors, may develop abnormally. Such abnormalities in the nervous system may

476 affect the volumes of the prefrontal cortex (PFC) and hippocampus and the shortening of dendrites in

477 the PFC. In the endocrine system chronic exposure to stress results in increased CRH levels and

478 greater activation of the HPA axis, flattening the circadian rhythm of plasma cortisol. In the immune

479 system, stress results in the elevation of inflammatory compounds e.g., cytokines (Danese &

480 McEwen, 2012). Chronic, repeated exposure to psychosocial stress in childhood is associated with

481 enduring changes in the function of the allostatic mediators (allostatic overload) that may result in

482 long term, age related disease in adulthood such as cardiovascular disease, type 2 diabetes and

483 metabolic syndrome; diseases which are involved in socioeconomic inequalities in healthcare (Figure

484 7). Both maltreated children and maltreated adults show remarkable similarities in structural and

485 functional abnormalities in the PFC that can be linked with behavioural disorders, depression and

486 post-traumatic stress disorder (A. Gonzalez, 2013).

487 Figure 7 The physiological outcomes of childhood maltreatment

488
Physiological
489 Functioning
HPA
Activity
490 Cardiovascular disease
Asthma
Child Maltreatment and
Arthritis
491 Socioeconomic Disadvantage Diabetes
Chronic pain
Immune Cognitive problems
492 Epigenetics
Function Behavioural problems
Obesity
493 Psychiatric disorders

494 Effectiveness of interventions

495

496 Adapted from (A. Gonzalez, 2013)

497 Such similarities Danese and McEwen (2007) suggest are remarkable because they persist regardless

498 of subsequent changes in their environment; such that years after the cessation of maltreatment adults

20 | P a g e
499 with a history adverse childhood experience still exhibit significant abnormalities in allostatic

500 mediation (Danese & McEwen, 2012; Danese, Pariante, Caspi, Taylor, & Poulton, 2007).

501 Bellis and Zisk (2014) warn that ACE’s are a serious psychosocial, medical, and public policy

502 problem that has serious consequences for its sufferers and for its burden on society (De Bellis &

503 Zisk, 2014). Adversity in childhood, from parental maltreatment and socioeconomic disadvantage can

504 alter physiological functioning in the stress related pathways that will lead to long-lasting abnormal

505 responses in adulthood (Su et al., 2015). The victims of ACE’s may struggle to reduce anxiety or

506 stress and utilise avoidant, self-medicating (e.g., smoking or alcohol abuse), compulsive (e.g.,

507 overeating), and/or self-injurious behaviours (Maguire et al., 2015; Su et al., 2015). These behavioural

508 modifications have the potential to impact complex, multifactorial disease e.g., cardiovascular disease

509 and type 1 diabetes (Saban, Mathews, DeVon, & Janusek, 2014).

510

511 Current research would suggest that ACE’s mediate irrevocable physiological changes that may

512 ultimately lead to chronic diseases such as CVD, and that interventions in adolescence and adulthood

513 will not alter the risk associated with these diseases (Centers for Disease Control and Prevention,

514 2016). Sustained ACE’s impact a physiologic stress response and hyperactivity of the HPA axis. The

515 hippocampus, amygdala, and prefrontal cortex have a high density of glucocorticoid receptors (GR’s)

516 and prolonged exposure to stress (e.g., ACE’s) or excess glucocorticoids, alter neural structures in

517 these regions and change brain circuitry critical to stress responses (Figure 5) (Bruce S. McEwen,

518 Nasca, & Gray, 2016). The most likely mechanisms through which early childhood ACE’s can cause

519 irrevocable pathophysiological changes are epigenetic changes to DNA. Epigenetic modifications

520 refer to chemical and physical alterations in the genome that turn on or switch off gene activity and

521 expression in a time- and cell-dependent manner (Lutz et al., 2015).

522

523 One mechanism thought to be involved is the addition of small methyl groups to regions of the DNA

524 where a cytosine nucleotide (via a phosphate group) is adjacent to a guanine nucleotide (CpG), sites

525 involved in transcription initiation, may act as shut-down signals (Deaton & Bird, 2011; Mukherjee,

21 | P a g e
526 2016). Methylation of CpG islands are thought to alter the chromatin architecture by the recruitment

527 of methyl-CpG binding proteins or the inhibition of transcription factor binding to gene promoter

528 regions, resulting in diminished gene expression by transcriptional repression (A. R. Tyrka et al.,

529 2016). One example of epigenetic changes is the methylation of CpG islands in the NR3C1 gene.

530 Stressful stimuli such as ACE’s trigger the HPA axis and the release of cortisol from the adrenal

531 cortex, the cortisol binds to intracellular GR’s in the body and brain and initiates changes to

532 ameliorate the acute stress (Kadmiel & Cidlowski, 2013). Intranuclear GR’s induce the expression of

533 many genes depending on the type of stress (Bruce S. McEwen et al., 2015; Bruce S. McEwen et al.,

534 2016). There is compelling evidence that NR3C1 methylation in humans is responsive to stress in pre-

535 and postnatal periods (A. R. Tyrka et al., 2016; L. J. van der Knaap et al., 2014; Lisette J. van der

536 Knaap, van Oort, Verhulst, Oldehinkel, & Riese, 2015).

537

538 Tyrka and colleagues (2015) demonstrated in a study of 184 impoverished maltreated and

539 nonmaltreated preschool children that increased methylation of salivary DNA NR3C1 was positively

540 associated with past month and lifetime contextual stress as well as being a composite measure of

541 adversity exposure. They also demonstrated that methylation of NR3C1 was associated with the

542 development of internalizing behaviour problems, a finding which is concordant with those of Parade

543 et al., (2016) who found that such methylation mediated the effects of early adversity on internalizing

544 behaviour problems. In a similar study van der Knaap and colleagues (2015) found that NR3C1

545 methylation in teenagers (16 years of age) was positively associated with the probability of a lifetime

546 pathophysiology of internalizing disorders, in addition to internalizing symptom scores three years

547 later. NR3C1 methylation they found was positively associated with an increased risk of anxiety and

548 depression.

549

550 In a genome-wide study by Labonté and colleagues (2012) identified 362 differentially methylated

551 sites in victims of suicide with a history of ACE’s in comparison to normal controls. Of the 362

552 identified 248 were hypermethylated and 114 hypomethylated sites, these sites were distributed in a

553 non-random pattern and clustered around specific genomic regions. The authors demonstrated that

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554 ACE’s are associated with epigenetic alterations in several gene promoters in hippocampal neurons

555 (Labonté et al., 2012). To date studies of epigenetic methylation (Labonté et al., 2012; Suderman et

556 al., 2014; A. R. Tyrka et al., 2016) support the hypothesis that ACE’s lead to functionally relevant,

557 genome-wide and cell-type specific reprogramming of the epigenome that affect stress regulation, (the

558 HPA axis) neural plasticity and neurodevelopment that mediate lifelong consequences both

559 physiologically and psychologically (Lutz et al., 2015).

560

561 To avoid adult pathophysiologies early preventative interventions are paramount (Figure 6). The

562 dysregulation of biological systems such as the HPA axis in the childhood victims of maltreatment

563 and socioeconomic disadvantage may be modified by improving the sensitivity and responsiveness of

564 caregivers, or through placements in alternative environments that foster warm, healthy and positive

565 relationships (A. Gonzalez, 2013).

566

567

568 Summary

569 There is little doubt that Bowlby’s theoretical viewpoint that attachments act as a buffer between

570 external stressors and the internal regulatory systems have been substantiated. This viewpoint has

571 been corroborated by the studies of neurobiological hormones and neuropeptides that modulate

572 physiological responses to stress and fear. Humans are social animals and pro-social behaviour is

573 important for the well-being of an individual (IsHak, Kahloon, & Fakhry, 2011). In the uterine

574 environment and in early infancy neurophysiology is key to how we will relate to others in adulthood.

575 Behavioural inhibition in social relationships affects an individual’s quality of life and may lead to

576 future psychopathies. When social experience becomes a source of anxiety rather than comfort we

577 become behaviourally inhibited (Heinrichs & Domes, 2008). Emotional regulation is the mechanism

578 by which humans deal with novel situations without fear and limiting stress. We deploy behavioural

579 strategies to regulate our emotional states. Physiological and psychological homeostasis is maintained

23 | P a g e
580 by the neurobiological hormones and neuropeptides released when we perceive changes in our

581 environment. Modern interest in affective physiological processes, interactive regulation, early

582 experience-dependent maturation of the brain, stress induced physiology and nonconscious relational

583 transactions have shifted attachment theory towards a regulation theory (J. R. Schore & Schore,

584 2008). A protective attachment behaviour system resists pressures from the external environment by

585 internal neurophysiological regulatory mechanisms that modulate emotion generated by the

586 perception of stress and danger. Such mechanisms attenuate the physiological response to their

587 distress. Emotions are powerful dynamic processes that can modify physiological processes and be

588 modified (Cole, Martin, & Dennis, 2004). Attachment behavioural systems help attenuate the

589 emotions and the physiological responses to external stressors, thus acting as a buffer between the

590 external environment and the internal regulatory systems of self.

591 References

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