Infant Mental Health Journal

The idea that the growth and maturation of males is affected more adversely by early environmental stress than females has a long history in the biological, medical, and anthropological literatures (e.g., Greulich, Crimson, & Turner, 1953; Tanner, 1978). The more modern concept of “boys at risk” clearly suggests the importance of gender in order to understand both the psychology and biology of human beings, especially early developing human beings. The term “at risk” implicitly implies a vulnerability not only in early development but also at some later stage of the life span, and explicitly connotes that a certain group of “high risk” male children will, as they enter adolescence, be highly susceptible to a number of psychiatric disorders whose diagnostic symptomatology first appears in that period of human development. It also suggests a vulnerability of specifically developing boys and not girls to certain psychiatric disorders, and thus psychological difficulties that are more associated with the male versus the female gender.

The study of the differences (and similarities) between the sexes has long been a major focus of scientific research in both psychology and biology. Indeed, for most of the last century, there was a substantial divide between the psychological and biological sciences, and thus gender has a long history of controversy. This is in part due to the fact that psychology's studies into the problem of gender have been substantially influenced by the theoretical model that is dominant at different points in its development as a discipline. In recent writings, I have described three paradigm shifts: beginning in the 1960s with behavioral psychology, to the 1980s with cognitive psychology, to the current 2000s and a shift into an emotional psychology (A.N. Schore, 2012). These disciplinary developmental transitions were manifest in changes in research and clinical focus from behavior to cognition to bodily based emotion. They paralleled transformations in biology and neuroscience from the voluntary motor and language functions of the left brain to the emotional functions of the right brain. Each of these three psychological theoretical perspectives has dictated the research orientation and methodologies of gender studies: sexual differences in behavior, sexual differences in cognition, and gender differences between the sexes in terms of the emotional and social functions of a male or female bodily based self.

Over this same time period, neurobiology, influenced by psychology also began to study similarities and differences between the male and female brain. Earlier biological research focused on developing psychological gender differences in behavior and language, and were paralleled by sex differences in the functional properties of the developing verbal left hemisphere. For the most part, this psychological research paid little attention to the very earliest stages of human development. Frequently, investigations were disconnected from studies that documented differences in emotional and social functions of developing male and female infants, from developmental neurobiological research on differences in early brain development between the genders, and from a substantial body of research documenting sex differences in psychiatric disorders. Indeed, gender studies in developmental psychology remained divorced from and frequently antithetical to biology. Due to the almost‐exclusive focus on late infancy and early childhood cognitive and behavioral differences, emotional differences were not measured or were ignored. Indeed, gender differences in early infancy were generally thought by developmental psychologists to be nonexistent, and not viewed as a relevant dimension of experimental research or clinical practice.

In contrast to earlier psychological studies which privileged social factors in generating sex differences in behavior and cognition (Maccoby & Jacklin, 1974; Money & Ehrhardt, 1972), my work has attempted to integrate the biological and social mechanisms that underlie the early origins of affective gender differences. In 1994, I cited extant 20th‐century studies of the developing brain to offer a model of gender development centered in early sex differences in the emotional right brain, which is dominant in human infancy. In later chapters of that volume, I described the critical role of gonadal steroids in the organization of right‐brain circuits, and proposed that the sexes differ in their experience‐dependent patterns of the wiring of the limbic system and cerebral cortex and thereby in the regulation of emotional behavior (A.N. Schore, 1994). Importantly, I cited classical neurological research which indicated that cerebral maturation as a whole is slower in males than in females, and therefore, developing boys were more at risk. In 2003, I was an author of the Commission on Children at Risk report Hardwired to Connect that concluded:

In recent decades, many adults have tended to withdraw from the task of assigning prosocial meaning to gender, especially in the case of boys… . But neglecting the gendered needs … can be dangerous. As the medical world has discovered, the risk of not attending to real differences that exist between males and females can have dangerous consequences. (pp. 24–25)

Two years later in an influential article “Sex and the Suffering Brain” in the journal Science, Holden (2005) asserted, “For many years we were not even allowed to say there were sex differences in the brain” (p. 1577). She observed that “It's easy to start a fight about whether there are gender differences when it comes to mental skills, but there's little debate that patterns of mental illness and disorders vary between the sexes” (p. 1574). On that point, she noted that although culture helps shape how the two sexes express mental problems, some differences persist across cultures and across time; specifically, women are more likely to get depressed while men are more severely afflicted by schizophrenia and exhibit more antisocial behavior, and most alcoholics and drug addicts are male. Holden cited Thomas Insel, the head of the National Institute of Mental Health, as saying “It's pretty difficult to find any single factor that's more predictive for some of these disorders than gender” (p. 1574).

If psychiatry had been ambivalent about gender studies, biology was less equivocal. In 2008, Sharpe offered a perspective on these gender differences in the extant biological literature:

The difference between becoming a male rather than a female is about as fundamental as you can get, as it will alter that individual's place in society, transform the shape of his body, reshape his inherent abilities, his thought processes and his behaviors … when compared with the “set‐up” program which would have led to a female, it is becomingly increasingly clear that “making a male” is a rather perilous process. (p. 1)

That same year, Zahn‐Waxler, Shirtcliff, and Marceau offered a forward‐looking “Disorders of Childhood and Adolescence: Gender and Psychopathology” in the psychological literature. Integrating psychiatry and developmental psychology, they concluded,

Even toddlers and preschool children can have serious externalizing problems, and sex differences are already present at this time. This suggests an even earlier onset that may need to be incorporated into developmental models. The delayed physical maturation and language development of boys, along with emotion regulation problems, may place young boys at greater risk than girls [italics added] (p. 282).

Referring to externalizing disorders in the ensuing stages of male development, Schneider et al. (2011) cited epidemiological studies indicating that “conduct disorders, characterized by a range of behaviors such as physical aggression, stealing, lying, and destruction of property, is most frequent in adolescent males” (p. 1848).

A central theme of this work dictates that this increased maturational risk of males is expressed at the earliest stages of the life span, from the male fetus to the male infant to the boy in childhood and teen in adolescence, when classical psychiatric disorders first appear. Furthermore, this normative maturational delay is principally involved in a male‐associated vulnerability to specific types of psychiatric disorders, especially to the externalizing psychopathologies and to deficits in the emotional and social functions of the early developing right brain. According to Holden (2005), “Men are more prone to expressing unhappiness through an “externalizing pathway” of physical behavior that includes drinking, drug abuse, and violence, whereas women are more likely to “internalize,” leading to depression and disorders such as anorexia” (p. 1576). She also reported that more males than females are diagnosed with schizophrenia and have earlier more severe symptoms, and intriguingly suggested that “these deficits all begin prenatally during the period of sexual differentiation of the brain” (p. 1577).

In agreement with this development model, Zahn‐Waxler et al. (2008) put forth the idea that the study of sex differences provides a means to identify the complex etiologies for different forms of emotional and behavioral problems, and that the origins of male and female dominant psychopathologies at later life are rooted in biological, physical, cognitive, and socioemotional differences in boys and girls that precede the expression of clinical problems. These psychiatric data also have become a focus of neuroendocrinology, where Kigar and Auger (2013) documented differences in the diagnostic ratios between genders of male‐dominant autism spectrum disorders (male/female = 80/20), early onset schizophrenia (80/20), and attention deficit hyperactivity disorder (ADHD) (58/42) versus female‐dominant major depressive disorders (33/67) and anorexia nervosa (7/93). In the neuroscience literature, it is now agreed that “in humans, males are more prone to neuropsychiatric disorders that appear developmentally, whereas females are more vulnerable to those that appear later” (Llorente et al., 2009, p. 240).

These male‐gender‐associated disorders have significantly increased recently. In the pediatrics literature, Boyle et al. (2011) reported that from 1997 to 2008, developmental disabilities rose dramatically, and that among this group, boys had a higher prevalence overall for a number of select disabilities, as compared to girls. This 17% increase in all developmental disabilities was caused in large part by shifts in the prevalence of ADHD and autism. Echoing this in the Annual Review of Public Health, Lanphear (2015) cited psychiatric epidemiological data to show that the prevalence of developmental disabilities has recently dramatically increased in U.S. children. He cited data from the Centers for Disease Control and Prevention (CDC) indicating a 123% increase from 2002 to 2010 in the prevalence of autism spectrum disorder among 8‐year‐old children, the age of peak prevalence, and stated:

ADHD, the most common brain disorder of childhood, affects about 1 in 10 children in the United States; boys are 2.5 times more likely criteria for ADHD than are girls … these data indicate that we are in the midst of an epidemic of brain‐based disorders. (p. 213)

Intriguingly, he links the sudden rise in developmental disabilities to the effects of environmental toxins on the developing brain.

Why are boys at risk? To address this question, I will use the perspective of regulation theory (A.N. Schore, 1994, 2003a, 2003b, 2012), an evidence‐based, interpersonal neurobiological model of development and psychopathogenesis to offer a model of the deeper psychoneurobiological mechanisms that underlie this vulnerability of the developing male. The central thesis of this work dictates that significant neurohormonally driven gender differences are seen between male and female social and emotional functions in the earliest stages of development, and that these result from not only differences in sex hormones and social experiences but also in rates of male and female brain maturation, specifically in the early developing right brain. I will suggest that the stress‐regulating circuits of the male brain mature more slowly than those of the female in the prenatal, perinatal, and postnatal critical periods, and that this is reflected in normal gender differences in right‐brain attachment functions.

I also will offer evidence to show that due to this maturational delay, developing males are more vulnerable over a longer period of time to stressors in in the social environment (attachment trauma) and toxins in the physical environment (endocrine disruptors) that negatively impact right brain development. These right‐lateralized structural alterations and deficits in social, emotional, and stress‐regulating functions—more so than later maturing left‐brain language and motor functions—underlie the etiology of documented gender differences in neural response to psychological stress seen in developmental disabilities and psychopathologies (J. Wang et al., 2007). In earlier work, I have offered a large body of research and clinical data to show that the predisposition to various psychiatric and personality disorders is rooted in postnatal attachment trauma that alters the experience‐dependent maturation of the early developing right brain (A.N. Schore, 1994, 2003a, 2003b, 2012), but I now expand that model to include the central role of gender. As I will soon describe, significant sex differences are operating early in the intrauterine period of development, and that in utero, male and female fetuses show differential rates of brain maturation and patterns of stress reactivity.

Thus, another major theme of this work is to move developmental etiological models even earlier in time to the period of “life before birth” (Nathanielsz, 1998). There is now widespread acceptance of the fetal programming hypothesis (Barker, 1998; Barker, Eiikkson, Forsen, & Osmond, 2002; Gluckman & Hanson, 2004), and here, I apply it to the problems of gender development and boys at risk. I will suggest that the developing male and female embryo/fetus undergoing rapid developmental changes are particularly vulnerable to organizing and disorganizing environmental influences during prenatal sensitive periods, and that these leave permanent imprints on later gender differences in both healthy emotional behavior and in susceptibility to certain psychiatric disorders.

Here, as in all my writings, I continue to use the device of citing verbatim the current voices of researchers across a number of disciplines to demonstrate an interdisciplinary convergence and agreement on the fundamental importance of gender, early brain maturation, neuroendocrinology, and socioemotional development in addressing the problem of why boys are at risk. In the following, I will offer a number of hypotheses derived from regulation theory (A.N. Schore, 1994, 2003a, 2003b, 2012) for experimental validation. In line with my ongoing work on the clinical applications of the theory, this work also addresses the fundamental question: How can we use the recent rapid advances in knowledge in the developmental sciences not only to generate more efficient models of diagnostic and treatment interventions of today's children and adults, but also prevention; that is, to improve the mental and physical health of subsequent generations?

SEX DIFFERENCES IN BRAIN MATURATION, EARLY APPEARANCE OF SOCIOEMOTIONAL FUNCTIONS, AND THE NEUROENDOCRINE ORIGINS OF GENDER

Almost 50 years ago, D.C. Taylor (1969) published “Differential Rates of Maturation Between Sexes and Between Hemispheres” in The Lancet, thus initiating neuroscience's interest in the early emergence of gender differences in brain development. Based on clinical data regarding cerebral maturation, he concluded, “This process proceeds more rapidly in girls than in boys [italics added], a fact that is supported by general evidence of their physical, and behavioural development” (p. 141). This neurobiological mechanism of slower functional maturation of developing male to female brains is expressed immediately after birth.

Thirty years later in the developmental psychological literature, M. Weinberg, Tronick, Cohn, and Olson (1999) offered “Gender Differences in Emotional Expressivity and Self‐Regulation During Early Infancy.” Surveying the field, they cited research demonstrating that male newborns are less responsive to auditory and social stimuli and less able to maintain eye contact than are female newborns, and that they experience greater difficulties in maintaining affective regulation than do female newborns (Hittelman & Dickes, 1979). Male infants smile less than female infants and display more irritability, crying, facial grimacing, and lability of emotional states (Call, 1978; Feldman, Brody, & Miller, 1980; S. Phillips, King, & DuBois, 1978). Male as opposed to female neonates show a more rapid buildup of arousal and a quicker peak of excitement (Osofsky & O'Connell, 1977) and engage in less self‐comforting, a behavior that functions to regulate arousal, tension, excitement, or distress (Brazelton, Koslowski, & Main, 1974; Korner, 1974). On overviewing these studies, M. Weinberg et al. (1999) observed that girls seemed “less vulnerable to interactive stresses,” [italics added] and therefore these gender differences in emotional expressivity and self‐regulation differentially affected the regulatory demands of mothers and sons and mothers and daughters.

In more recent work, Tronick (2007) reported:

In 6‐month‐old infants … boys were more emotionally reactive than were girls during face‐to‐face social interactions with their mothers. Boys were more likely than were girls to show facial expressions and anger, to fuss and to cry, to want to be picked up, and to attempt to get away or distance themselves from their mothers by arching their backs and turning or twisting in their infant seats. (p. 340)

Interpreting these data, he suggested the following:

These gender differences focused on differences in boys’ and girls’ self‐regulation of affect. Boys greater emotional reactivity suggested that boys have greater difficulty self‐regulating their affective states and that they need to rely more on maternal regulatory input than do girls [italics added]. (p. 340)

Tronick concluded that “Boys … are more demanding social partners, have more difficult times regulating their affective states, and may need more of their mothers support to help them regulate affect. This increased demandingness would affect the infant boys’ interactive partner” (p. 345).

Other research has confirmed the continuity of these gender differences from the neonate to the toddler. Nagy, Kompagne, Orvos, and Pat (2007), in a study of neonatal imitation in 1‐ to 3‐day‐old infants, revealed that newborn girls are better at imitating fine motor extensions than are newborn boys. These authors concluded that newborn girls, with their faster and more accurate abilities, may create a more responsive and interactive social environment which in turn leads to differences in socioemotional development at later stages of development. At 12 months, female toddlers show a greater preference for dyadic interactions (Benenson, 1993), make more eye contact (Lutchmaya, Baron‐Cohen, & Raggart, 2002), spend more time watching a film of a face than a car (Lutchmaya & Baron‐Cohen, 2002), and show more affective empathy and prosocial behavior (Volbrecht, Lemery‐Chafant, Askan, Zahn‐Waxler, & Goldsmith, 2007) than do age‐related males.

In terms of interpersonal neurobiology, from the beginning and throughout infancy, boys show functional expressions of prolonged structural cerebral immaturity in affect and stress regulation, adaptive functions of the early developing right brain. Zahn‐Waxler et al. (2008) noted “The curve of development of the frontal cortex, caudate, and temporal lobes in girls is considerably faster than in boys” [italics added] (p. 279). Integrating this with D.C. Taylor's (1969) and Tronick's (2007) work, the longer period of development of social responsiveness and regulating affect in male infants reflects the slower maturation rate of the male brain during the brain growth spurt, from the last trimester through the end of the second postnatal year (Dobbing & Sands, 1973).

Not only the regulation but also the processing and expression of affect shows this gender difference. McClure (2000) documented “significant female advantages for facial expressing processing in infants and in children and adolescents” (p. 444). She asserted that this face‐processing system may not be fully mature at birth, that it continues to develop throughout the first 6 months of life, and that the brain regions that respond to faces “may develop more rapidly and earlier in females than in males” [italics added] (p. 428). McClure proposed,

Early developments in facial emotional processing depend heavily on maturational changes in a neurological subsystem specialized for recognition of complex patterns such as faces and selected facial features, including expressions … Studies have implicated a variety of structures as participants in this subsystem. The bulk of research, however, has focused on the temporal cortex and the amygdala, as well as a variety of structures seated in the right cerebral hemisphere [italics added]. (p. 426)

Over the last three decades, my work has documented the structure–function relationships of the early developing right hemisphere (Chi, Dooling, & Giles, 1977; Crowell, Jones, Kapuniai, & Nakagawa, 1973; Geschwind & Galaburda, 1987; Gupta et al., 2005; Mento, Suppiej, Altoe, & Bisiacchi, 2010; Sun et al., 2005), which is dominant in human infancy (Chiron et al., 1997; A.N. Schore, 1994). The nonverbal right hemisphere is in a growth spurt in the first year while the verbal left hemisphere is not until the second year (Thatcher, 1994). Expanding my studies on early emotional development, I suggest that the right hemisphere, which is dominant for the processing, expression, communication, and regulation of emotion, develops more slowly in male than in female infants. The infant right brain becomes dominant for the processing of visual–facial (de Heering & Rossion, 2015), auditory–prosodic (Grossmann, Oberecker, Koch, & Friederici, 2010), and tactile–gestural information (Montirosso, Borgatti, & Tronick, 2010), and although both sexes show the same sequence of posterior cortical to anterior cortical development, they do this at different maturational rates. In his classic study, D.C. Taylor (1969) concluded, “Cerebral maturation would be more rapid in girls, as are physical and psychological development, so that boys would be at risk for a longer time” [italics added] (p. 140). This means that there is a more protracted period of vulnerability in the boy's slower maturing right hemisphere, and that the male compared to the female infant's prolonged immaturity is manifest in a less efficient processing and regulating of stressful negative affects, a dominant function of the right hemisphere (A.N. Schore, 1994, 2003a, 2012).

In my 1994 book on the neurobiology of emotional development, I cited Taylor's (1994) developmental neurobiological principle in a chapter entitled “The Origins of Infantile Sexuality and Psychological Gender” (A.N. Schore, 1994). Integrating psychology and biology, I reviewed extant 20th‐century studies of the neuroendocrinology of the developing brain to describe the critical role of gonadal steroids in the organization of right‐brain circuits, and proposed that the sexes differ in their experience‐dependent patterns of the wiring of the limbic system (A.N. Schore, 1994). I also reported a sexual dimorphism and feminized versus masculinized wiring patterns in the emotion‐processing limbic system as well as gender differences in the regulation of the male and female infant's emotional and social functions. Over the course of the following two decades, a massive body of research now unequivocally has demonstrated that in prenatal and postnatal periods, the sex‐specific gonadal steroids androgen (testosterone) and estrogen (estradiol) produced by the hypothalamic–pituitary–gonadal (HPG) axis play an essential organizing role in brain development and in the early evolution of gender‐specific differences.

Both androgens and estrogens (which are derived from the aromatization of testosterone) are produced by the bodies of both sexes, although in different amounts. The action of sex steroids on the nervous system is classically described by two mechanisms. Organizational (programming) effects refer to the ability of gonadal steroids to permanently sculpt the nervous system during critical periods of development, thereby giving rise to male and female physiology and behavior in adulthood while activational effects of sex hormones are mediated through the acute and transitory actions on the fully developed nervous system, especially in social contexts. The focus of this work on boys at risk will be on the androgen testosterone, which causes male and female brains to develop differently in prenatal periods, infancy, childhood, adolescence, and adulthood (De Bellis et al., 2001; Hutchinson, 1997).

In current writings on early androgen exposure and human gender development, Hines, Constantinescu, and Spencer (2015) noted that literally thousands of studies have documented the organizational effects of early androgen influences on developing brain circuits, and thereby on enduring sex differences. In both the fetal and postnatal stages of early brain maturation, the gonadal steroid testosterone promotes neurite outgrowth, facilitates synaptogenesis and inhibits synapse elimination, regulates apoptotic developmental cell death and induces cell survival, and influences developing neurotransmitter systems. Hines et al. noted that testosterone is significantly higher in males than in females during two specific periods of early human development: a prenatal surge from Weeks 8 to 24 of gestation with maximal sex differences at 12 and 18 weeks, and a neonatal surge during the first months after birth, with the largest sex difference occurring in the first through the third postnatal month, a period also known as “mini puberty.” Hines et al. concluded, “These, therefore are the times when testosterone is likely to influence human gender development” (p. 3).

This enduring influence is not only on later sexual behavior but also on social, emotional, and stress‐regulating differences between the genders. Fetal testosterone affects the developmental anatomy of the hypothalamus and thereby the stress‐regulating hypothalamic–pituitary–adrenal (HPA) axis (Cunningham, Lumia, & McGinnis, 2012) as well as the limbic system (De Vries & Simerly, 2002). Interestingly, Sholl and Kim (1990) reported that androgens, which facilitate fetal synaptogenesis and inhibit synapse elimination, are highest in the right over left frontal primate fetal cortex, and higher in male than in female fetuses. Zahn‐Waxler et al. (2008) asserted that prenatal exposure to testosterone accounts for the slower biological and physical maturation as well as greater disinhibition in boys than in girls, and that gender differences in social and emotional functions and in psychopathology “derive from sexual dimorphisms of the brain and body that begin in utero” (p. 278). Indeed, researchers studying sex differences in the developing human fetal brain also have reported that “male brains develop more slowly than their female counterparts” (de Lacoste et al., 1991, p. 844).

This clearly suggests that males are extremely susceptible to alterations or disruptions in testosterone levels during the prenatal and perinatal critical periods. Such alterations have not only detrimental short‐term effects but also long‐term ones on the development of specific emotion and stress‐regulating functions, and thereby on the origins of a predisposition to male‐gender‐related psychiatric disorders. In a recent article on the early etiology of sex differences in mental health, Kigar and Auger (2013) observed that the developing brain is exquisitely sensitive to the effects of circulating steroid hormones during sensitive periods of perinatal development, and that hormonal surges occurring during discrete windows of time can have long‐term effects on an organism's behavior and physiology. They concluded, “Although neuronal sex differences are present at birth as a result of both genetic and hormonal organization, chemical and morphological changes continue to occur postnatally and into adulthood” (p. 1141). In upcoming sections, I will discuss the detrimental effects of antiandrogenic environmental toxins that specifically disrupt the testosterone surges, and link them with Lanphear's (2015) proposal that the current rise in developmental disabilities is associated with environmental toxins on the developing brain.

EARLY MALE BRAIN DEVELOPMENT AND SEX DIFFERENCES IN STRESS REACTIVITY AND REGULATION

At present, there is intense interest across disciplines in the problem of specifically how genetic, hormonal, environmental, and social factors influence brain development, and how these act in the causal pathways that link early development with a predisposition to later psychopathologies and disease. All fields are now converging on the centrality of epigenetic mechanisms, heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic DNA methylation determines gene expression and silencing during both the prenatal and postnatal periods. Sex steroids are known to influence the onset and offset of gene expression, and are essential candidates for exerting epigenetic effects on the sexually dimorphic developing brain (McCarthy et al., 2009). This mechanism has been implicated in the etiology of both sex differences in the brain and in mental health risk and resilience. Writing in the field of neuroendocrinology, Kigar and Auger (2013) asserted, “There is … growing support for the culpability of hormones and the rearing environment [italics added] as organisers of an epigenetic [italics added] framework that determines risk and resilience to disease between the sexes” (p. 1147).

The epigenetic construct is now being used to understand not only the mechanism by which environmental neurotoxins in the physical environment that alter levels of gonadal steroids permanently influence brain development but also how variations in the quality of maternal care in the social environment indelibly organize brain development. Indeed, there is now agreement that

The enduring impact of early maternal care and the role of epigenetic modifications of the genome during critical periods in early brain development in health and disease is likely to be one of the most important discoveries in all of science that have major implications for our field [italics added] (Leckman & March, 2011, p. 334)

It has been established that postnatal changes in epigenetic programming of the infant's brain are directly linked to maternal behavior (Weaver et al., 2004), and that stress from the social environment embedded within the maternal–infant relationship activates epigenetic modifications (Gudsnik & Champagne, 2012). Over the course of my own writings, I have described how the unfolding of epigenetic programs that guide early brain development over the perinatal and postnatal stages of human infancy occur within mother–infant attachment transactions.

Epigenetic modifications also describe how regulated and dysregulated stressors in the social/maternal rearing environment and the attachment relationship differentially impact the developing male and female brain. Furthermore, an epigenetic perspective can be utilized to specify which particular neural circuits are hormonally activated and imprinted in specific critical periods. In my 1994 volume on the developmental neurobiology of emotional development, I suggested that in postnatal critical periods optimal levels of gonadal steroids in the developing male and female brains epigenetically influence the maturational rates of limbic–autonomic neural circuits involved in regulating emotional stress (A.N. Schore, 1994). I also proposed the existence of early gender differences in the regulation of emotional behavior, and that this sexual dimorphism of emotional function reflects a sexual dimorphism of the limbic structures responsible for such function. Thus, the sexes differ in the experience‐dependent patterns of the wiring of the emotion‐processing limbic system.

Even more specifically, I cited classic studies demonstrating sexual dimorphism in the medial and central amygdala, the core of the limbic system, and the orbitofrontal cortex, the hierarchical apex of the limbic system (Nishizuka & Arai, 1983; Van Eden, Uylings, & Van Pelt, 1984). Reflecting the maturational differences between the genders in brain development, I further suggested that the right orbitofrontal cortex, the attachment control system, functionally matures according to different timetables in females and males and that differentiation and growth stabilizes earlier in females than in males. This interpersonal neurobiological system is responsive to early relational stress via the right orbitofrontal regulation of the right amygdala (A.N. Schore, 1994). In other words, the developmental rate of the emotion‐processing and stress‐regulating attachment system is faster in female infants and slower in male infants. Such epigenetic hormonally influenced gender differences in limbic function are responsible for the earlier cited gender‐typical differences in socioemotional development and stress reactivity in the first year of life.

Confirming this model, Kunzler, Braun, & Bock (2015) reported basic developmental neurobiological research demonstrating that the “male and female brain display differential sensitivity towards early life stress” and that relational stress specifically impacts the maturation of prefrontal limbic regions. They observed, “Exposing newborn male … to separation stress causes an acute strong increase of cortisol and can therefore be regarded as a severe stressor” (p. 862). Repeated separation results in hyperactive behavior, and “changes … prefronto‐limbic pathways, i.e. regions that are dysfunctional in a variety of mental disorders” (p. 862). Furthermore, the long‐term outcome of these epigenetic stressors on the developing male brain are manifest in “impairments in behavioral flexibility, emotion processing and different aspects of executive control, which are mediated by the orbitofrontal and/or medial prefrontal cortex” (p. 866).

It is now well‐established that regulated levels of moderate stress facilitate normal brain development and account for the previously described normal gender differences in emotional and social development associated with delayed development of the male infant's right hemisphere (McClure, 2000). On the other hand, traumatic dysregulating levels of relational stress during the early stages of life exert an enduring detrimental epigenetic impact on the developing right brain, significantly altering the individual's emotional responsiveness and stress‐coping strategies later in life. Writing in the neuroscience literature, McCarthy et al. (2008) proclaimed, “Epigenetic changes in the nervous system are emerging as a critical component of enduring effects induced by early life experience, hormonal exposure, trauma and injury, or learning and memory” (p. 12815). They offered the important observation that stressful epigenetic changes are largely context‐dependent:

The context may be variables in the internal or external environment, such as steroid hormones or endocrine‐disrupting chemicals [italics added], respectively. Alternatively the context may be experiences as profound as early child abuse, or events as mild as context‐dependent learning [italics added]… the early social/maternal environment [italics added] can modify sex differences in behavior, and recent evidence suggests that it may do so in an epigenetic manner (p. 12816)

Epigenetic mechanisms are known to be activated in the perinatal programming of the stress‐regulating HPA axis (Meaney, Szyf, & Seckl, 2007). This neuroendocrine system is centrally involved in regulating responses to stress by direct influences and feedback interactions between the hypothalamus, pituitary, and adrenal glands. Upon activation of the HPA axis, the paraventricular nucleus of the hypothalamus and the pituitary secrete corticotropin‐releasing hormone and adrenocorticotropic hormone, respectively, which then act upon the adrenal gland to produce glucocorticoid hormones such as corticosterone and cortisol. Through a negative feedback cycle, glucocorticoids act on receptors in the hypothalamus and pituitary to suppress adrenocorticotropic hormone and corticotropin‐releasing hormone secretion.

In recent research, Bingham, Gray, Sun, and Viau (2011) demonstrated, “Manipulations that alter environmental variables, maternal—infant interactions, and the glucocorticoid and/or sex steroid hormone environment during the neonatal period permanently alter the magnitude of the hypothalamic‐pituitary‐adrenal axis response to stress” (p. 250). They demonstrated that during the prenatal and postnatal periods, testosterone surges exert significant changes in not only male brain morphology but also in the maturation of developing HPA function. Furthermore, they proposed that “the masculinization of the HPA axis, at least with respect to acute stress, is affected by testosterone and androgen receptors prior to parturition” [italics added] (p. 255). I would add that in addition to the earlier mentioned maturational differences between the postnatal male and female brains, in the prenatal period the primordial male HPA matures more slowly than does the female HPA, thus accounting for gender differences in stress regulation before birth.

A large body of studies has demonstrated that gender differences in stress reactivity and regulation are expressed in utero in the earliest stage of brain development, the prenatal period. Buss et al. (2009) reported that in response to a stressful, startling vibrotactile stimulus, the male fetus at 31 to 37 weeks’ gestation expresses a twofold higher heart rate as well as a slower neurodevelopmental trajectory, as compared to females. They concluded that fetuses present “different neurodevelopmental trajectories for males and females that result in sex‐specific developmental intervals of maximum susceptibility to environmental exposures” (p. 634), and that “there may be both optimal and detrimental endocrine influences on fetal behavior” (p. 637). Buss et al. concluded that the gender differences in the magnitude and the timing of the male and female fetal brains’ response to prenatal stress reflect “significant differences in the trajectory of maturation which may contribute to sex‐specific time windows when the developing fetus is vulnerable to programming influences” (p. 637), echoing the previously mentioned proposal by D.C. Taylor ’s that males’ slower brain maturation in the later stages of infancy and childhood “puts them at risk for a longer time” (1969, p. 140).

Indeed, boys are at risk in the womb. In fact, clinical and experimental research has indicated that male more than female fetuses are vulnerable if their nutrition is compromised (Pedersen 1980), and that the incidence of preterm birth, which involves the maternal and/or fetal HPA is higher in pregnancies carrying a male (Brettell, Yeh, & Impey, 2008; Challis, Newnham, Petraglia, Yeganegi, & Bocking, 2013). Weber, Harrison, and Steward (2012) elegantly applied my work to premature infants in neonatal intensive care units. I would now add that these high‐risk male preterms born in the early or mid third trimester may be even more vulnerable in the short‐ and long‐term than are females. Indeed, research has shown that the risk for preterm birth is increased in male fetuses (Zeitlin et al., 2002), that preterm males have a less effective stress response than do females (Greenough, Langercrantz, Pool, & Dahlin, 1987), and that prematurely born boys have significantly more neurological handicaps, subnormal development, and developmental disability than do girls (Hoffman & Bennett, 1990). In female preterms the surface of the right hemisphere is larger than the left whereas no difference is found in male (Dubois et al., 2008), suggesting less structural development. In light of the extreme immaturity of these preterm males at birth, their fragile socioemotional repertoire is much less developed, and therefore, they are not as well‐equipped to spontaneously enter into interactive dialogue with their primary caregiver, the maternal attachment object. That being the case, sensitive interactive regulation is essential to their further development.

Other studies have shown that during human fetal brain development, male brains develop more slowly than those of females (de Lacoste et al., 1991), that sex‐specific differences in the cortisol stress response are present before birth, with the output of cortisol being much greater in male than in female fetuses (Giussani, Fletcher, & Gardner, 2011), that full‐term males are more at risk for pregnancy outcome (Di Renzo, Rosati, Sarti, Cruciani, & Cutuli, 2007; Erickson, Kajantie, Osmond, Thornburg, & Barker, 2010), and that fetal distress during labor and low Apgar scores are more common in males (Bekedam, Engelsbel, Mol, Buitendijk, van der Pal‐de Bruin, 2002). In a study of sex differences in electrocortical activity in human neonates, Thordstein et al. (2006) documented an earlier maturation of cortical function in girls than in boys, indicating that at birth

[T]he CNS [central nervous system] of newborn full‐term girls is more mature than that of boys… . This may be part of the reason for the larger vulnerability of the CNS in boys than that of girls in the perinatal period manifested both in an increased tendency for brain damage and in higher mortality. Moreover, many neurodevelopmental disorders are overrepresented in boys (p. 1167).

Indeed, a large body of literature has indicated that newborn males are at risk, and that these increased risks continue during later development (see Elsmen, Steen, & Hellstrom‐Westas, 2004).

In support of this model of the continuity of gender differences in reactivity to stressors in the social and physical environment from the prenatal to the perinatal and postnatal periods, Davis and Emory (1995) showed that healthy, term male and female neonates respond differently to the mildly stressful behavioral assessment procedure, the Neonatal Behavior Assessment Scale (Brazelton, 1973). One‐day‐old males react with elevated cortisol levels, most marked at 10 to 15 min, while females do not show this elevation. Females exhibit a greater change in heart rate immediately following the assessment, returning to baseline within 10 min, while males show little change, a finding that reflects more immature regulation. Indeed, Davis and Emory proposed that the etiology of these gender differences reflects the effects of sex hormones, especially testosterone, which is known to be at higher levels in males than in females at birth (Hammond, Koivista, Kouvalainen, & Vihko, 1979).

At 3 to 4 months, male infants with increased levels of postnatal testosterone display higher levels of negative affectivity, as reflected in their greater frustration tendency that is expressed in fussing or crying during caretaking activities, when failing to achieve a goal, or when placed in a confining position (Alexander & Saenz, 2011). At 6 months, male infants are less able than females to physiologically regulate frustration (Calkins, Dedmon, Gill, Lomax, & Johnson, 2002). These physiological data are consonant with the previously mentioned gender studies of neonates that describe male newborns showing greater difficulties in maintaining affect regulation (M. Weinberg et al., 1999). The fetal and perinatal gender differences in stress reactivity and regulation continue in the middle of the first year, as Tronick (2007) documented. At 12 months, boys are more likely than are girls to become stressed when placed in a context in which they cannot control the onset of a potentially frightening stimulus, suggesting that they have a greater readiness for negative emotional responding under fearful arousal conditions (Gunnar‐Vongnechten, 1978). This trend is seen in the second year, where Bergman, Glover, Sarkar, Abbott, and O'Connor (2010) reported a significant association between prenatal amniotic fluid testosterone, but not fetal cortisol and fear reactivity in 17‐month‐old boys and not girls. They proposed that fear reactivity in males may reflect a joint activity of cortisol and testosterone, and that this interaction may underlie the general predisposition to greater arousal and reactivity in boys. A body of basic research has demonstrated that throughout development, the HPA and hypothalamic–adrenal–gonadal axes interact and influence each other (Cunningham et al., 2012).

Furthermore, in the postnatal period, males are more sensitive than are females not only to environmental stressors but also to infectious agents and immune challenges. Exposure of male neonates to a low dose of a bacterial endotoxin during the perinatal period (after the testosterone spike) has long‐term effects on the neuroimmune system in adulthood while the same dose at the same time in females does not (Bilbo et al., 2005; Bilbo, Smith, & Schwartz, 2011). This endotoxin exposure in male neonates results in long‐term changes in HPA axis activity expressed in elevated corticosteroid levels and increased stress reactivity (Bilbo et al., 2005), inhibited social emotional behavior in dyadic contexts (Granger, Hood, Ikeda, Reed, & Block, 1996) as well as altered neuroimmune response in adulthood (Boisse, Moulhate, Ellis, & Pittmna, 2004). Schwarz and Bilbo (2012) cited research on sex differences in the regulation of immune functions being linked to gonadal steroid hormones, which shows that in general, testosterone depresses immunity and increases susceptibility to bacterial and viral infections while estrogen enhances immunity. They concluded that “males and females may have a fundamentally different response to neonatal activation of the immune system. Specifically, females may be resilient to the long‐term alterations in the immune system” (p. 248), and that males are more sensitive than are females to early life immune challenges.

These early appearing sex differences in immune function set the tone for all later stages of development. A large body of studies has demonstrated that sex differences in the rates and severity of many infections are greater in human adult males than in females (Klein, 2004; McMillen, 1979; Washburn, Medaris, & Childs, 1965) and that female adults exhibit an enhanced immune response and increased resistance to disease and infection than do males (McClelland & Smith, 2011; Schuurs & Verheul, 1990). There is now agreement that immune maturation in the pre‐ and perinatal periods sets individual trajectories toward health and disease susceptibility across the life span (Gollwitzer & Marsland, 2015).

Early Development Of The HPA Axis, Attachment Trauma, And The Emergence Of Psychiatric Externalizing Psychopathologies In Adolescence

In the pre‐ and postnatal periods, the male's slowly maturing stress‐regulating HPA axis is more susceptible than that of the female to both external environmental stressors as well as to internal significant and chronic hormonal alterations that accompany these social stressors. These include not only gonadal sex steroids but also stressful alterations in adrenal corticosteroids that accompany dysregulated and regulated maternal–infant interactions, and thereby both are etiologically involved in sex differences in later disorders of HPA dysfunction. Maternal emotional stress in the prenatal period releases high levels of corticosteroids into the mother's bloodstream, and substantial proportions of stress hormones cross the placenta. Intriguingly, very recent research has demonstrated gender differences in the placenta, a temporary organ that is designed for exchange of oxygen, nutrients, antibodies, and hormones between the mother and fetus, and that plays a key role in fetal growth and development. According to Di Renzo, Picchiassi, Coata, Clerici, & Brillo (2015),

Female and male placentas have different strategies to optimize health…. The male strategy for responding to an adverse maternal environment is a minimalist approach: few genes, proteins or functional changes are involved in the placenta… . This specific male response is associated with a greater risk of intrauterine growth restriction, preterm delivery or death in utero if another adverse event occurs during the pregnancy. The female placenta responds to an adverse maternal environment with multiple placental gene and protein changes… . Thus, female adjustments in placental function and growth ensure survival in the presence of another adverse event which may further compromise nutrient or oxygen supply. (p. 5–6)

Indeed, a large body of research has indicated that “male and female fetuses and neonates institute different mechanisms to cope with an adverse environment or event” (Saif et al., 2015, p. 724). The female placenta adjusts its glucocorticoid activity and inflammatory cytokine gene expression to high maternal glucocorticoid concentrations, as opposed to the male placenta which does not adaptively change (Clifton, 2010), suggesting a maturational advance in female over male regulatory systems. Elevated cortisol levels interfere and reduce the fetus’ production of testosterone (Kime, Vinson, Malor, & Kilpatrick, 1980; Ward & Weisz, 1984), especially during the prenatal testosterone surge. In the fetus, high plasma concentrations of corticosteroids are known to have deleterious effects on the nervous system (Sapolsky, 1996) via increased apoptosis and cell death (Gruver‐Yates & Cidlowski, 2013). Androgenic steroids regulate the “programming” of developmental cell death (Evans‐Storms & Cidlowski, 1995), and so reduced testosterone levels could alter cell survival in a critical period of fetal brain growth. Interestingly, maternal alcohol consumption suppresses both testosterone surges in the male fetus/neonate (Ward et al., 2003; J. Weinberg, Sliwowska, Lan, & Hellemans, 2008).

In the perinatal period, the time of the second testosterone surge, maternal stress is known to influence both the onset and duration of testosterone exposure and thereby permanently alter the organization of the androgen‐sensitive pathways to the HPA axis (Bingham et al., 2011; Williamson, Bingham, & Viau, 2005). Over the course of the first year in the postnatal period, the developing male infant's extreme sensitivity to both stressful perturbations in the external social environment and hormonal changes in the internal environment makes him more vulnerable to early child abuse and neglect, extreme maternal–infant developmental stressors that alter the early organization of prefronto‐limbic pathways into the HPA axis.

There is now widespread agreement that both prenatal and postnatal maternal–infant factors program the HPA axis, and that severe early life stress permanently impairs this stress‐regulating system over later stages of the life span, thereby jeopardizing the future mental and physical health of the individual (A.N. Schore, 2003a, 2003b; Weinstock, 2005; Welberg & Seckl, 2001). Some studies have suggested that neurodevelopmental disorders result from alterations of the set points of neuroendocrine systems and the HPA axis (de Kloet, Joëls, & Holsboer, 2005; Gunnar & Quevedo, 2007; D.J. Phillips, 2007). In light of the fact that sex hormones have “organizational” or “programming” effects on the development of the HPA axis generating enduring gender differences in HPA stress activity (McCormick, Furey, Child, Sawyer, & Donohue, 1998), this conception of psychopathogenesis needs to be updated in terms of the expression of gender differences in the expression of a dysfunctional HPA axis in a male and a female infant. Note that under stress, HPA dysregulation can take two forms: underregulation and overregulation, which in turn underlie the susceptibility of males to externalizing disorders and of females to internalizing disorders.

Recall that exposing a newborn male to a separation stress triggers an acute strong increase of cortisol (Kunzler et al., 2015), but in the case of severe attachment stressors such as abuse and neglect, the stressors are extreme and chronic, and the stress hormones are elevated for long periods of time during a critical period, physiologically altering the HPA set point. Indeed, infants with disorganized‐disoriented insecure attachment associated with abuse and neglect (and maternal alcohol consumption; O'Connor, Sigman, & Brill, 1987) exhibit the highest cortisol levels than all other attachment classifications (Hertsgaard, Gunnar, Erickson, & Nachimias, 1995). Such long, enduring high levels of postnatal cortisol may be a continuation of elevated prenatal cortisol, associated with previously described highly stressful in utero experiences. In very recent writings in this journal of a clinical case of a boy with a history of maltreatment and disorganized attachment, Ribaudo (2016) observed, “For some, even the womb is not a safe haven. In the United States alone, as many as 500,000 children each year are exposed to interpersonal violence in utero” (p. 91).

Earlier research has shown that high maternal cortisol in late pregnancy is associated with more difficult behavior at birth (De Weerth, van Hees, & Buitelaar, 2003). At Weeks 1 to 7 (the very time of the postnatal testosterone surge), these infants display more crying, fussing, and negative facial expressions, a description of what has been termed a difficult temperament. It is usually not appreciated that “the fact of birth has apparently no significance for the brain developmental sequence” (Dobbing, 1974, p. 3). This continuity of brain development between the prenatal and postnatal stages clearly suggests that the long‐held idea that fixed “inborn” temperament represents genetic factors that are first expressed at birth is incorrect. Rather, temperament at birth is a result of epigenetic mechanisms that have evolved prenatally, and continue to be epigenetically shaped or misshaped by the postnatal socioemotional environment. In studies on “prenatal predictors of infant temperament,” Werner, Myers, Fifer, Cheng, Fang, et al. (2007) concluded that “what has been termed ‘constitutional’ about temperament is emerging as identifiable in the prenatal period and may be, in part, the consequence of environmental influences before birth” (p. 475).

In previous writings on the origins of “difficult temperament” dominated by states of negative emotionality, I proposed that due to delayed rates of cerebral maturation in male infants, gender differences must be considered in developmental traumatology (A.N. Schore, 2003a). In early studies, Carlson, Cicchetti, Barnett, and Braunwald (1989) documented that disorganized attachment is more frequent among boys in low‐income, maltreated infants. Ten years later, Lyons‐Ruth, Bronfman, and Parsons (1999) found that infant boys displayed significantly more disorganized attachment behaviors, and concluded that gender plays a role in the manifestation of disorganized behavior pattern in high‐risk samples. More recently in studies of the early origins of disorganized attachment in 4‐month‐old infants, Beebe et al. (2012) reported, “Male infants were overrepresented in future disorganized infants… . Moreover, male infants are more emotionally reactive than female (M. Weinberg, Tronick, Cohn, & Olson, 1999), so that they may be more vulnerable to a disorganized form of insecurity” [italics added] (p. 359). In light of the consequent increased risk of the developing male brain, these intense postnatal social stressors represent a significant etiological scenario of a vulnerability to later male‐dominant externalizing psychopathologies in adolescence.

In support of this model, it is now thought that adolescence represents a developmental stage in which, like the earlier periods of prenatal and postnatal testosterone surges, there is a steroid‐dependent organizational remodeling of the developing male brain, and thus it is a “vital junction during which carefully timed exposure to gonadal hormones permanently alter developmental trajectory to influence adult behavior” (Sisk & Zehr, 2005, p. 169). During puberty, a period of considerable biological and social change and sexual maturation, secretion of androgens significantly increases due to the maturation of the male gonads, leading to dramatic gender differences in testosterone. Adolescent boys and adult men produce far more testosterone than do adolescent girls and adult women. Boys’ testosterone levels increase at a more accelerated rate and are more variable during adolescence than girls’ levels (Shirtcliff, Granger, & Likos, 2002).

As a result, puberty, a time of intense neurostructural and endocrine changes, has been identified as a risk factor for both male‐ and female‐related psychopathologies (Hayward & Sanborn, 2002). During adolescence, conduct disorder—a prime example of externalizing behavior problems—increases in males (Moffit, 1993), as opposed to depression—one of the main internalizing disorders—which increases from mid‐puberty onward in females, but not males (Angold & Costello, 2006). The higher testosterone levels found in male, but not female, adolescents with externalizing aggressive behavior have been linked to a risk of psychopathology for later antisocial behaviors (Maras et al., 2003). Attachment experiences significantly influence the relationship between high circulating testosterone and antisocial behavior in adolescence (Fang et al., 2009; Updegraff, Booth, & Thayer, 2006). The transition into adolescence thus represents a period of risk for boys, especially those who have experienced fetal and/or postnatal testosterone dysregulation as a result of antiandrogenic environmental toxins, prenatal alcohol, or traumatic attachments, including early abuse and/or neglect.

As an example, histories of early abuse and neglect are common in severe conduct disorders and therefore in creating a predisposition to violence (A.N. Schore, 2003a). In a recent review article on life‐course persistent antisocial behavior, Yildirim and Derksen (2012) cited research showing that activational effects of high levels of testosterone and low HPA‐axis responsivity are associated with psychopathy. Not moderate, but elevated, levels of fetal testosterone are consistently found in this disorder, which is 10 to 14 times more likely in males than in females. They cited research indicating that heightened developmental testosterone is an essential biological determinant in the etiology of psychopathy, and that “fetal testosterone may inhibit the maturation of the right orbitofrontal cortex and circulating testosterone may subsequently dampen its responsivity to social cues resulting in lower empathy and higher aggressive behaviors, processes that increase the risk for chronic antisocial behavior” (p. 999). They noted that high fetal testosterone predicts less eye contact in infancy at 12 months (Lutchmaya & Baron‐Cohen, 2002), and this impaired attention to the eyes of attachment figures is later associated with reduced affective empathy and psychopathic development in adolescence (Dadds, Jambrak, Pasalich, Hawes, & Brennan, 2010). In this later stage of development, “cold‐blooded” instrumental aggression, strongly linked to psychopathy, is directly related to high testosterone levels in males (Van Bokhoven et al., 2006). A study of incarcerated late‐adolescent males reported that the testosterone–violence relationship is strongest at low cortisol levels (Dadds, Jurkovic, & Frady, 1991).

In other writings, Yildirim and Derksen (2013, p. 1261) proposed, “Since the life‐long functioning of the ventromedial prefrontal (orbitofrontal) cortex is programmed and fine‐tuned during the early years of life, traumatic and abusive experiences can permanently alter ventromedial cortex maturation and basal HPA‐axis throughout life (Schore, 2001),” and concluded that the interpersonal/affective facet of psychopathy arises from insecure/disorganized attachment in childhood, congruent with my own studies on early attachment trauma, right orbitofrontal dysfunction and the development of a predisposition to violence that leads to the clinical expression of severe conduct disorders in adolescence (A.N. Schore, 2003aa). In that work, I differentiated early histories of abuse and disorganized attachment associated with an elevated HPA set point of high resting arousal and elevated cortisol with impulsive aggression, versus neglect, disorganized attachment trauma and an HPA set point of low resting heart rate, reduced cortisol, and predatory, callous, fearless, instrumental aggression. I would now add that in these most severe conduct disorders, high testosterone when coupled with a hyperactive HPA, high fear‐reactivity, and hot‐blooded rage reflects the impulsive aggression while when coupled with low fear‐reactivity and cold‐blooded rage generates instrumental aggression. Recall that testosterone dampens the HPA‐axis reactivity to stressors and threats. Interestingly, increased testosterone in adolescent boys and not girls is associated with reduced amygdala–orbitofrontal connectivity, which in turn is associated with increased alcohol intake (Peters, Jolles, Van Duijvenvoorde, Crone, & Peper, 2015).

In a recent study on androgen signaling and cortical maturation in adolescence, Raznahan et al. (2010) showed “a focally accentuated delay of frontal maturation in males compared to females” [italics added] in the orbitofrontal and ventromedial cortices. Note that the delayed maturation of this emotion processing and regulating cortical system in males, earlier expressed in fetal development, infancy, and childhood, is still operating in adolescence. Citing studies documenting the rapid and disproportionately male increases in violent offenses and substance abuse with the onset and progression of puberty, Raznahan et al. observed that “protracted cortical maturation in males could also lead to a regionally specific broadening of the temporal windows through which detrimental genetic and environmental influences are accrued” [italics added] (p. 16991). They further observed that maleness is an especially potent risk for antisocial disorder and psychopathy in the next stage of development, adulthood, where these conditions manifest strong associations with aberrant structure and function in the orbitofrontal cortex. These authors specifically noted the work of Y. Yang and Raine (2009), who cited a number of studies showing functional impairments specifically in the right orbitofrontal cortex, the control center of attachment (A.N. Schore, 2000).

Integrating the information in this section, I propose that the fetal and neonatal developing male brain, especially its early emotion processing limbic circuits that regulate the HPA axis, functionally develop at a slower rate than the female limbic system. In addition to accounting for normal gender differences in social and emotional functions and stress regulation in male and female infants, this longer period of developmental neurobiological immaturity is expressed in an oversensitivity to and inefficiency in regulating more intense and chronic forms of interpersonal stress. The slower maturation exposes the developing male brain to stressful altered levels of testosterone and corticosteroids during critical periods of right‐brain development. Attachment trauma such as abuse and/or neglect interfere with or preclude optimal interactive stress regulation, and because they occur in critical periods of right‐brain development, they epigenetically generate enduring maturational failures in the limbic system and the HPA, structural deficits that are reactivated in adolescence, a time of substantial remodeling of cortical and limbic circuits. This model supports Zahn‐Waxler et al.’s (2008) assertion that “Gender intensification could result from earlier vulnerabilities such as insecure attachments” (p. 285).

BOYS AT RISK: ENDOCRINE DISRUPTORS IN FETAL AND POSTNATAL DEVELOPMENT AND MALE PSYCHOPATHOGENESIS

According to Kigar and Auger (2013), “Perinatal exposure to a chemical (e.g. testosterone, folic acid) or an environmental cue (e.g. nurturance, maternal depression) [all italics added] can create a lasting change in mental health risk or resilience” (p. 1147). It has been established that the androgenic hormone testosterone regulates and interacts with neurotransmitters and neuromodulators and thereby influences the structural and functional organization of the developing brain, that androgen receptor functions in prenatal and postnatal periods are essential to “brain masculinization” and to male‐typical behaviors in later stages, and that environmental “antiandrogens” interfere with androgen action by binding to and inhibiting androgen receptors and thereby contribute to abnormal development. There is currently intense interest across a large number of disciplines in “endocrine disruptors,” environmental toxins that directly interfere with the synthesis, function, storage, and/or metabolism of natural hormones, including androgens and estrogens. These substances undergo bio‐accumulation and at this point in time are so widespread in humans and animals that they are described as “ubiquitous” in the air, water, and earth.

A large body of research in endocrinology, the study of the mechanisms by which hormones coordinate and control the functions of multiple organ systems and processes throughout life, has indicated that endocrine disruptors alter their normal regulatory functions, especially during early critical periods of brain development. Both environmental androgenic disruptors that mimic natural male androgenic hormones susch as testosterone and estrogenic disruptors that mimic the female hormone estradiol have sex‐specific impacts, and they alter the normal balance between androgens and estrogens in the brain and body. Although developing male brains are vulnerable to both classes of environmental chemicals, in this work on “boys at risk,” I shall focus on the enduring detrimental effects of masculine androgen disruptors.

In an article in the Journal of Neurological Sciences entitled “Endocrine Disruptors as a Threat to Neurological Function,” B. Weiss (2011) noted that “Sex differences, taking root before birth, are planted by the actions of hormones. These actions can be modified during fetal life by exposure of the mother to environmental chemicals that mimic, inhibit, or otherwise distort normal hormonal function” (p. 13). In terms of neurodevelopmental implications, he concluded that morphological differences between male and female brains translate into behavioral differences, and environmental endocrine disruptors transform these differences in various ways. He also documented that androgen disruptors are found in specific herbicides, fungicides, insecticides, and plasticizers, and that “Human exposure is universal” (p. 15).

Because sex hormones such as androgens and estrogens have different effects at different times of the life cycle, the timing and duration of exposure to endocrine disruptors is essential (Zoeller et al., 2012). Critical periods of fetal, infant, and pubertal development are more sensitive to low doses of hormones than adult tissues, and thereby during these “critical windows of exposure” are more vulnerable to endocrine disruption (Selevan, Kimmel, & Mendola, 2000, p. 451). This fundamental biological principle applies to significant alterations in prenatal and postnatal androgen surges of the rapidly developing male brain, and it implies that endocrine‐disrupting chemicals during early critical periods represent a major etiological factor of “boys at risk” and an important contributor to the current significant increase in male‐gender‐related psychiatric disorders.

The association of endocrine disruptors, early brain development, and the link to later male‐dominant psychopathologies is now receiving a great deal of attention from a number of different scientific disciplines. Discussing the detrimental effects of these environmental toxins on developmental programming in the neuroendocrinology literature, Gore (2008) offered the important observation:

The developing fetus or infant is much more sensitive to endocrine‐disrupting compounds than the adult, moreover, effects early in life may not be manifested until adulthood [italics added]. Extremely low‐dose exposures may exert significant effects on a developing organism, particularly if the exposure occurs during critical developmental periods. (p. 363)

Gore (2008) also noted that exposure to these “ubiquitous” chemicals occurs in critical developmental times, including maternal–fetal transfer through the placenta in perinatal periods and breastfeeding via lactation in postnatal periods. Clinical studies have shown fivefold‐higher concentrations of endocrine disruptors in human amniotic fluid at 15 to 18 weeks’ gestation (Ikezuki, Tsutsumi, Takai, Kameei, & Taketani, 2002), and elevated concentrations in breast milk and lower testosterone level in 3‐month‐old male infants (Main et al., 2006). These and other studies clearly have suggested that developing males are more at risk than are females to exposures of environmental androgen disruptors, especially during the prenatal testosterone surge at 12 to 18 weeks in utero and the postnatal surge at 1 to 3 months. They also imply that when a prenatal alteration in testosterone is combined with a suppression of the neonatal testosterone surge, there will be even more severe consequence on the developing male brain.

Indeed, writing in the journal Neurotoxicology, Miodovnik et al. (2011) asserted,

The prenatal [italics added] period is uniquely vulnerable to the effects of endocrine disruptors on maternal and fetal sex hormones in brain development (p. 266) … ongoing exposure to these endocrine disruptors in the postnatal [italics added] period may be independently associated or may act cumulatively with prenatal exposure to increase the risk of atypical behavior. (p. 267)

They noted that the effects of these endocrine disruptors are seen in later stages as “impaired reciprocal social behaviors” in male dominant autistic spectrum disorders, ADHD, and oppositional defiant disorder. These sobering warnings are echoed in an article on “Neurobehavioral Effects of Developmental Toxicity” in Lancet Neurologyby Grandjean and Landrigan (2014), who described a “pandemic of developmental neurotoxicity” (p. 330). They concluded,

Neurodevelopmental disabilities, including autism, attention‐deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence (p. 330).

The Centers for Disease Control and Prevention has estimated the current prevalence of developmental disorders at one in every six children (Boyle et al., 2011). In light of the fact that the prevalence of autism has dramatically escalated from 3 in 10,000 children in 1970 to 1 in 68 children in 2014, it is now thought that genetic factors alone cannot account for an epidemic that developed in the relatively short period of the past several decades, and that environmental toxicants are considered to be a strong contributor to the increased prevalence of autism (Berg, 2009; Deth, Muratore, Benzecry, Power‐Charnitsky, & Waly, 2008; Rossignol, Genuis, & Frye, 2014). Researchers have now linked perinatal exposure to androgenic (and ovarian estrogenic) endocrine disruptors to not only autism spectrum disorders (de Cock, Maas, & van de Bor, 2012) but also to ADHD (Zhou et al., 2011). These data are congruent with the idea that exposure of the developing male brain to environmental toxins that interfere with the functions of the endocrine system are associated with the current significant increase in a number of male‐dominant psychiatric disorders.

Because these endocrine disruptors are known to act on and interfere with the programming effects of gonadal steroids in the primordial stages of brain development, it follows that their association with extensive neurobiological and hormonal dysregulation will have a substantial detrimental effect on the emotional survival functions of the early developing right brain. In classic writings, Geschwind and Galaburda (1987) linked early appropriate levels of testosterone with right‐hemispheric growth. Following up on this early study, Toga and Thompson (2003) suggested that early testosterone levels favored structural and functional lateralization to the right hemisphere. More recently, Bourne and Gray (2009) showed that early prenatal and not later life testosterone exposure is specifically associated with later right‐brain‐dominant functions of processing positive and negative facial expressions. Thus, significantly altered levels of testosterone in pre‐ and postnatal periods by endocrine disruptors would contribute to psychopathogenesis by negatively impacting the maturational trajectory of the socioemotional right brain in males at later stages of life, especially during the later testosterone surge in puberty and adolescence.

BOYS AT RISK: VULNERABLE RIGHT‐BRAIN FUNCTIONS IN PERINATAL AND POSTNATAL CRITICAL PERIODS

An overarching model of the neurobiological mechanisms that underlie why and when boys are at risk for later gender‐related psychopathologies must address the fundamental question of specifically which brain circuits are shaped or misshaped by fetal and postnatal stressors, and how these systems show later deficits in social and emotional functions in adolescence and adulthood. The initial wiring of these circuits is influenced by regulated and dysregulated levels of organizational gonadal steroids and corticosteroids on the developing brain's evolving stress‐regulating systems, in first, dyadic fetal–maternal placental and then dyadic infant–maternal attachment transactions. In terms of the development of socioemotional deficits, subcortical and cortical circuits of the limbic–HPA system enter critical periods of maturation during the brain growth spurt, from the last trimester through the end of the second postnatal year, a period of maximal neuroplasticity. Indeed research now documents rapid initiation of neural growth in the third trimester of gestation (Doria, Beckmann, Arichit, Merchant, Groppo, et al., 2010; Yu, Ouyang, Chalak, Jeon, Chia, et al., 2016). These systems continue to evolve, especially in adolescence, the time of the appearance of Axis I psychiatric and Axis ll personality disorders. The brain growth spurt represents a stage of vulnerability in all humans (Dobbing, 1974); during this period, the slow maturation of the male brain makes it even more at risk during the period of maximal vulnerability. Recall that the CNS of both the male fetus and the male neonate is less mature than that of females. In other words, during developmental “windows of vulnerability,” males are more vulnerable than are females.

In terms of early intervention of boys at risk, the structure–function relationships of developing socioemotional systems, which are on line significantly before later evolving language functions, need to be assessed in their critical periods. This applies to perinatal and postnatal interventions, but in the case of early male development, clinical attachment evaluations need to be informed by the slower maturation and gender differences in the processing and regulation of social and emotional information in the developing male's interactions with the mother. With respect to the maturation of the male fetal and postnatal brain, the early developing right brain, which for the life span is dominant for socioemotional functions and stress regulation is more than the later developing left vulnerable to the previously described stress‐related alterations in testosterone and corticosteroids.

In 1996, Trevarthen proposed, “The right hemisphere is more advanced than the left in surface features from about the 25th (gestational) week and this advance persists until the left hemisphere shows a postnatal growth spurt starting in the second year” (p. 582). Supporting this, later studies by Schleussner et al. (2004) have reported “an earlier maturation of certain right than homologous left hemispheric brain areas during fetal brain development” (p. 133). Even more recently, Kasprian et al. (2011) documented that at 26 gestational weeks, the human fetal right superior temporal sulcus appears earlier and is deeper than that on the left and concluded, “Our structural data further support the findings of functional neuroimaging studies indicating an earlier maturity of right hemispheric function” (p. 1081).

This maturation of the early developing right brain continues after birth, in infancy, a time of right‐brain dominance (Chiron et al., 1997), when the mother–infant attachment mechanism is activated. Attachment transactions thus influence the “early life programming of hemispheric lateralization” and the initiation of adaptive stress‐regulating right‐brain functions (Stevenson, Halliday, Marsden, & Mason, 2008, p. 852). Over the last three decades, I have offered a large body of studies to show that in right‐brain to right‐brain attachment communications, the mother regulates (for better or worse) the infant's stressful states of emotional arousal, and thereby influences the maturation of the infant's developing right‐lateralized HPA axis (A.N. Schore, 1994, 2003a, 2003b, 2012). Research now has clearly shown that maternal care within the attachment relationship shapes the infant's stress‐regulating HPA axis (Gunnar, 2000); that specifically the right and not left prefrontal areas regulate the HPA axis (Sullivan & Gratton, 2002); and that for the rest of the life span, the right hemisphere regulates the HPA and thereby controls vital functions supporting survival and enabling organisms to cope with stresses and challenges (A.N. Schore, 1994; Wittling, 1997).

In an optimal developmental scenario, the evolutionary attachment mechanism, maturing during a period of right‐brain growth, thus allows epigenetic factors in the social environment to impact genomic and hormonal mechanisms at both the subcortical and then cortical brain levels. By the end of the first year and into the second, higher centers in the right orbitofrontal and ventromedial cortices begin to forge mutual synaptic connections with the lower subcortical centers, including the arousal systems in the midbrain and brain stem and the HPA axis, thereby allowing for more complex strategies of affect regulation, especially during moments of interpersonal stress. That said, as I noted in 1994, the right orbitofrontal cortex, the attachment control system, functionally matures according to different timetables in females and males, and thus, differentiation and growth stabilizes earlier in females than in males (A.N. Schore, 1994). In either case, optimal attachment scenarios allow for the development of a right‐lateralized system of efficient activation and feedback inhibition of the HPA axis and autonomic arousal, essential components for optimal coping abilities.

In marked contrast to this growth‐facilitating attachment scenario, in a relational growth‐inhibiting postnatal environment, less than optimal maternal sensitivity, responsiveness, and regulation are associated with insecure attachments. In the most detrimental growth‐inhibiting relational context of maltreatment and attachment trauma (abuse and/or neglect), the primary caregiver of an insecure disorganized–disoriented infant induces traumatic states of enduring negative affect in the child (A.N. Schore, 2001b, 2003b). As a result, dysregulated allostatic processes produce excessive wear and tear on the developing brain, severe apoptotic parcellation of subcortical–cortical stress circuits, and long‐term detrimental health consequences (McEwen & Gianaros, 2011). Relational trauma in early critical periods of brain development thus imprints a permanent physiological reactivity of the right brain, alters the corticolimbic connectivity into the HPA, and generates a susceptibility to later disorders of affect regulation expressed in a deficit in coping with future socioemotional stressors. Earlier, I described that slow‐maturing male brains are particularly vulnerable to this most dysregulated attachment typology, which is expressed in severe deficits in social and emotional functions.

Based on behavioral observations (“the Strange Situation;” Ainsworth, Blehar, Waters, & Wall, 1978), it is now commonly assumed that there are no gender differences between male and female attachment in the first 2 years of life. As opposed to classical attachment theory, neurobiologically informed, emotionally focused, modern attachment theory asserts that this is incorrect (J.R. Schore & Schore, 2008). In both secure and insecure attachment scenarios, the male infant's right brain takes longer to mature and is less able to regulate stress than is the female infant. Such epigenetic hormonally influenced gender differences in limbic function are responsible for the earlier cited gender‐typical differences in socioemotional development and stress reactivity at birth and through the first year of life. Thus, it takes longer for males to functionally express the efficient stress‐regulating coping strategies of a secure attachment. Mature self‐regulatory systems in secure infants utilize two complementary modes of action: interactive regulation and autoregulation. Over the life span, females under stress initially interactively regulate and males autoregulate, a normal gender difference in affect regulation. This regulatory bias is shown in early development.

As I have indicated, the male fetus and the male infant exhibit androgenic‐influenced gender differences in brain structural and functional systems that are responsive to stress. Insecure attachments, which are defined by dysregulated stress‐regulating systems, show enduring altered patterns of inefficient right‐brain connectivity, which lead to a vulnerability to later psychopathologies (A.N. Schore, 1994). Over the course of the life span, the right and not the left lateralized prefrontal regions and their subcortical connections are responsible for the most complex regulation of emotion and stress (Cerqueira, Almeida, & Sousa, 2008; Czeh, Perez‐Cruz, Fuchs, & Flugge, 2008; A.N. Schore, 1994, 2003a, 2003b, 2012; Wang et al., 2005), and it is these circuits that are developmentally impaired in their earliest critical period of growth.

To understand a particular individual's right‐brain emotional response to the relational stressors of later developmental stages such as adolescence, it is necessary to take into consideration the preexisting right‐brain prenatal and postnatal attachment history as well as gender. This includes the male infant's attachment transactions with the father in the second year, when he is critically involved in not only androgen‐controlled rough‐and‐tumble play (Meaney, Stewart, Poulin, & McEwen, 1983) but in facilitating the male (and female) toddler's aggression regulation (as opposed to the mother's earlier role in fear regulation). This same period (18–24 months) involves the initiation of a critical period of growth in the left hemisphere (Thatcher 1994), and so the “paternal attachment system” of father–son interactions would presumably forge an androgenic imprint in the toddler's evolving left‐brain circuits, including the left dorsolateral prefrontal cortex (see A.N. Schore, 1994), allowing for his regulation of the male toddler's testosterone‐induced aggression (“terrible twos”) and rough‐and‐tumble play. However, in light of the male infant's slower brain maturation, the secure mother's attachment‐regulating function as a sensitively responsive, interactive affect regulator of his immature right brain in the first year is essential to optimal male socioemotional development. The misattuned insecure mother, on the other hand, is a source of considerable relational stress, especially when the immature male toddler is expressing high levels of dysregulated aggression or fear. That said, research has documented that boys more so than girls raised in single‐mother families show twice the rate of behavioral problems than do boys in two‐parent families (Bertrand & Pan, 2013), and that in the first 3 years, single mothers spend less time with their sons than their daughters of the same age (U.S. Department of Labor Bureau's of Labor Statistics, 2014).

How can we clinically and experimentally access these immature, dysregulated states that will become the painful emotional core of male‐gender‐related psychopathologies? Currently, there is much interest in the psychological and biological literatures in the formation of early phenotypes for specific neurodevelopmental psychiatric disorders. These phenotypes depict the range of regulatory failures of early developing systems, later expressed in affective “regressions” to highly dysregulated immature states. How can we observe changes in brain activity associated with dysregulated states, especially right‐brain circuits that are hyperaroused in high levels of fear, and of aggression? Note that these are hyperactivated limbic circuits and that they are therefore experienced by the developing feeling organism as a subjectively painful state. How would a dysregulated allostatic overload, both neurobiologically as well as hormonally, of the earliest evolving components of the emotion‐processing limbic system be observed in terms of an individual's emerging predisposition for psychopathology? How does a clinician or researcher observe and take part in an array of right‐brain stress‐regulating attachment emotional communications? At the most fundamental level, how can we access and study the adaptive and maladaptive attachment functions of the right‐brain limbic system as they operate in real time?

DEVELOPMENTAL NEUROBIOLOGY OF THE AMYGDALA COMPLEX, THE CORE OF THE RIGHT‐LATERALIZED LIMBIC SYSTEM

The mental health field is now urgently calling for programs of early prevention. The scientific–clinical discipline of infant mental health can make important and valuable contributions in this effort because the stages of human development that it studies are occurring in critical periods of brain maturation. In my earlier contributions in this journal, I linked infant mental health to adult mental health (A.N. Schore, 2001a, 2001b). Here, I apply regulation theory's developmental model to the earliest prenatal stage of human development and suggest that infant mental health rests upon preceding fetal health. In terms of brain development, this primordial stage represents the most rapid genesis of neurons. Indeed, neural proliferation before birth is estimated at 250,000 per minute (Cowan, 1979). This primordial stage of human development, described as “life before birth” (Nathanielsz, 1998), has been largely overlooked both in neuroscience and in developmental psychology. As recently as 2009, Buss et al. proclaimed, “Despite acknowledgement of the critical role the prenatal period plays for an individual's health outcome, little effort has been invested in studying human fetal behavior and its consequences” (p. 633), and that “the study of fetal behavior has not progressed because it has been judged as insignificant” (p. 637).

The greatly enhanced rate of neuronal development continues in the perinatal period. From birth to 3 months, the total number of cortical neurons increases by 23 to 30% (Shankle, Rafii, Landing, & Fallon, 1999). The earliest of human beginnings, the prenatal and postnatal stages of human development, are ones in which the fetus and then infant is evolving through a succession of critical periods in both the in utero and then extrauterine environments, experience‐dependent stages of brain growth that can both support or inhibit the development of more complex brain structure and function. Since the brain evolves caudally to rostrally, subcortically to cortically, the question becomes: What early evolving regions of the brain are in critical periods in the fetal and postnatal stages of development? There is now agreement that “the ontogenetic neural timetable might have consequences for the timing of early intervention” (de Graaf‐Peters & Hadders‐Algra, 2006, p. 262). These authors suggested that the best opportunities for intervention occur between 28 weeks’ postmenstrual age and 15 months, the period of the brain growth spurt and right‐brain dominance.

Indeed, this information is useful in terms of generating evidence‐based assessments that can tap into subcortical systems of the developing brain that are in critical periods in utero. The earliest evolving subcortical systems, including noradrenergic, dopaminergic, and serotonergic neuromodulatory bioaminergic systems that are essential to neurotransmission and the development of neuronal circuits in the embryo and later in generating emotional arousal in the neonate, evolve very early in utero, at 8 to 10 weeks’ gestational age (de Graaf‐Peters & Hadders‐Algra, 2006), the time of the first testosterone surge. Brainstem catecholamine neurons are known to be target sites for androgenic and estrogenic hormones (Heritage, Stumpf, Sar, & Grant, 1980). These neuromodulators are susceptible to fetal stress that can result in long‐term changes in the structure and function of the organism (Herlenius & Lagercrantz, 2001). At birth, there is a surge of the catecholamines noradrenaline and dopamine, which is important to neonatal adaptation. These subcortical arousal‐generating systems continue to evolve in postnatal periods when they send axon collaterals up the neuraxis, thereby exerting trophic and regulatory roles on the development of the limbic system and cerebral cortex (Lambe, Krimer, & Goldman‐Rakic, 2000; A.N. Schore, 1994). The volume of the subcortical area, including the brainstem, increases by 130% in the first year (Knickmeyer et al., 2008), and it is influenced by the attachment relationship.

In addition to the energy‐regulating bioamines, what other subcortical regulatory systems are known to evolve in the fetal brain? For some time, I have used regulation theory to model the developmental progression of postnatal limbic–autonomic regulatory centers (A.N. Schore, 1994, 2003a, 2003b), but I now extend this model to prenatal regulatory systems. The insula, which begins its maturation at 13 to 18 gestational weeks (the time of the first testosterone surge) and shows earlier development in the right fetal hemisphere, becomes involved in stress‐responsive visceroautonomic functions (Afif, Bouvier, Buenerd, Trouillas, & Mertens, 2007). At 22 weeks’ gestation, the human fetal adrenal gland develops and now produces cortisol in appreciable quantities (Mesiano & Jaffe, 1997). In the last trimester, the paraventricular areas of the hypothalamus that produce the stress‐intensifying neuropeptide corticotropin releasing factor, and the sexually dimorphic androgen‐imprinted ventromedial hypothalamus, later associated with aggression in males (Choate, Slayden, & Resko, 1998; C.F. Yang et al., 2013), are functional. But perhaps most important, the amygdala complex, especially the central and medial nuclei that develop before the basolateral nucleus, is structurally mature (Humphrey, 1968), suggesting that at this point the fetus’ right limbic–autonomic HPA axis is capable of processing negative and positive proto‐emotional states.

During the last gestational trimester, while the aforementioned systems are in a critical period of maturation and the brain growth spurt commences, plasticity and pruning of the developing brain is at its highest, with almost 50% of neurons in the fetal brain experiencing apoptotic programmed cell death (Volpe, 2000). Apoptosis is regulated by the organizational function of gonadal steroids (Evans‐Storms & Cidlowski, 1995) that allows for the preservation of developing sexually dimorphic nuclei and imprinting of gender‐related limbic circuits. Circulating levels of androgens and tissue levels of estrogens are higher in males than in females in the late prenatal/early postnatal periods (Weisz & Ward, 1980). This is the exact time of the beginning of the second testosterone surge (Hines et al., 2015) and therefore the amygdala, which is known to contain many androgen receptors and is larger in males than in females (Nishizuka & Arai, 1981), is vulnerable to stress or endocrine disruptors that could amplify cell death in this critical period.

At the end of the fetal period, the medial and central amygdala, with their connections into bioaminergic arousal centers in the midbrain and brainstem, the sympathetic and parasympathetic components of the autonomic nervous system, and the insula, represent the hierarchical apex of the fetal regulatory system. The maturity/immaturity of this amygdala stress‐regulating system is expressed at birth. In the normal developmental scenario, this system is less mature in the more slowly developing male fetus and neonate. In assessments of the earliest appearing gender‐specific socioemotional functions that I described at the beginning of this work, attention needs to be paid to the amygdala, which in optimal contexts is known to reach a high degree of maturity in the Month 8 of gestation (Ulfig, Setzer, & Bohl, 2003) and is therefore operational at birth, the very onset of the perinatal period. The more slowly evolving male right amygdala thus regulates the previously described social and emotional behaviors of the male neonate.

As opposed to optimal fetal development, a chronically stressful and thereby growth‐inhibiting intrauterine context produces an immature amygdala–HPA regulatory system with poor capacities for not only autoregulation of dysregulated states but also difficulty in entering into states of dyadic interactive regulation with the mother. Immediately after emerging from the womb, the infant is exposed to the novel stimulation of the outside world, especially the face (eyes), smell, and touch of the mother. The amygdala and subcortical sensory areas are involved in all of these functions. In high‐risk infants, an immature and inefficient right amygdala is poor at eye gaze, an essential point of contact with another human being. In light of the extreme immaturity of these preterm males, their socioemotional repertoire is much less developed; therefore, they are not well‐equipped to enter into normal interactive dialogues with their caregivers. That being the case, interactive regulation is essential to their further development.

The amygdala system that first emerges in the prenatal period continues to rapidly evolve in the perinatal and postnatal periods. In recent writings (A.N. Schore, 2012, 2013, 2104), I suggested that the later developing basolateral nucleus, with its extensive cortical connections, begins a critical period at about 2 to 3 months when the infant is able to enter into more complex socioemotional interactions with the mother (see A.N. Schore, 1994). Recall McClure's (2000) finding that the function of the infant's amygdala in right‐hemispheric face processing develops faster in females than in males. This clearly suggests that the slowly developing male basolateral amygdala would be more vulnerable to certain perinatal stressors, especially neglect, which deprives him form receiving sufficient amounts of maternal interactive regulation (maternal postpartum depression).

Since this is the period of the second testosterone surge, the male basolateral amygdala also is more at risk for androgenic endocrine disruptors at this time. Indeed, research has indicated that perinatal exposure of the male brain to an endocrine disruptor is specifically associated with abnormal synaptic plasticity in the developing basolateral amygdala, especially in alterations in dopamine and GABA circuits (Zhou et al., 2011). This structural defect is accompanied by functional deficits, hyperactivity and attention deficit, leading Zhou et al. (2011) to suggest that this developmental mechanism is involved in the neuropathogenesis of ADHD. Other research has demonstrated that in adults with ADHD, more hyperactivity and less inattention are associated with smaller right amygdala volumes (Frodi et al., 2010). Endocrine disruptors also have been implicated in schizophrenia pathogenesis (Brown, 2009). In an overview of abnormal amygdala structure and function in autism and schizophrenia, Schumann, Bauman, and Amaral (2011) concluded, “The amygdala, perhaps more than any other brain region, has been implicated in numerous neuropsychiatric and neurodevelopmental disorders. It is part of a system initially evolved to detect dangers in the environment and modulate subsequent responses” (p. 745). This adaptive function is altered by early chronic exposure to endocrine disruptors.

Diagnostic evaluations of early socioemotional development would thus need to assess the early socioemotional and regulatory functions of the right amygdala. It is now thought that in human infancy, the right amygdala is more greatly affected by early rearing experiences than is the left (Joseph, 1992; A.N. Schore, 1994). A prime example of the enduring impact of severe early adverse experiences on brain development is seen in studies of infants who had experienced institutional deprivation in Romania. As children, these individuals show greater activity in the right than in the left amygdala and decreased eye contact during a live dyadic interaction (Tottenham et al., 2011). In adolescence, Romanian orphans with histories of severe early deprivation and neglect show “reduced probability of connection to the frontal pole in the right hemisphere … associated with increased externalizing behavioral problems” (Behen et al., 2009, p. 295). Another study of this population has revealed “greater amygdala volumes, especially on the right” (M.A. Mehta et al., 2009, p. 943).

The early expression of a structurally impaired right amygdala also is seen in autism. Studying children as young as 18 months, Munson et al. (2006) reported an association between enlarged right (and not left) amygdala volume with poorer socialization and communication development as measured on the Autism Diagnostic Interview and Vineland Scale. They speculated that right amygdala enlargement may reflect “right‐sided amygdala activation in response to conditioned fear” (p. 690). Commenting on this amygdala enlargement in 18‐months‐old toddlers, Schumann, Barnes, Lord, and Courchesne (2009) stated,

The amygdala has long been a site of intense interest in the search for neuropathologic markers for autism, given its well‐established role in the production and recognition of emotions and modulatory role in social behavior. Initial signs of autism in toddlers include unusual affective behavior, reduced social interest, and poor eye contact, which are all suggestive of aberrant amygdalar function. (p. 942)

The problem of diminished attention to faces early on “may be the first in a cascade of problems that lead to later emotional and social impairments” (p. 947). Furthermore, they concluded that the autistic toddler's dysfunctional hyperaroused amygdala “suggests a heightened emotional, or even fearful, response when autistic individuals look at another person's eyes, regardless of whether they are familiar or a stranger” (p. 947). This early developing right basolateral amygdalar enlargement, associated with amygdalar hyperreactivity and abnormal fear conditioning, persists in 6‐ to 7‐year‐old children (J. Kim et al., 2010) and strongly suggests that a chronic, fear‐based subjectivity continues in the autistic infant's and child's mind.

Microstructural alterations of the right amygdala have been identified even earlier, in 6‐ to 14‐day‐old neonates of prenatally depressed mothers (Rifkin‐Graboi et al., 2013). I suggest that at this perinatal stage, the dysfunction is mainly in the early developing central and medial rather than the later maturing basolateral amygdala which initiates a critical period at 2 to 3 months (A.N. Schore, 2012, 2013). In discussing the functional expressions of this structural alteration, Rifkin‐Graboi et al. (2013) offered the important observation that amygdala dysregulation is expressed in increased negative emotionality, a state that also effects the quality of the interactions adults direct toward the infant. They proposed a prenatal transmission for a vulnerability to depression:

These findings suggest a cascade whereby maternal signals influence the in utero development of brain regions that regulate the emotional well‐being of the infant, which, in turn, affect parent‐infant interactions that reinforce negative emotionality and thus risk for mood disorders (p. 842).

They cited the work of Tronick and Reck (2009), who stated that these infants develop negative affective states that bias their interactions with others, which in turn exacerbates their affective problems, and that male infants are more vulnerable than are female infants to maternal depression. These data clearly have suggested that early attachment assessments of boys at risk need to involve not only the infant and the mother but also the intersubjective socioemotional interactions between them.

FURTHER IMPLICATIONS FOR EARLY ASSESSMENTS OF BOYS AT RISK

There is now agreement that at all stages of the life span, attachment security is mediated by the subcortical amygdala (Lemche et al., 2006; A.N. Schore, 1994, 2003a, 2003b, 2012), which is known to show sex differences (Hamann, 2005), and so very early attachment assessments of males in the perinatal and then postnatal critical periods are essential to early intervention. As an example, Beebe et al. (2012) offered a study of the origins of disorganized attachment in the microanalysis of dysregulated emotional interactions within the 4‐month mother–infant interaction. I suggest that these assessments must be more than behavioral; they also must include an interpersonal neurobiological perspective that can track the development or failure of development of the right‐brain emotion‐processing limbic system. In recent writings in the psychiatric literature, Schwartz et al. (2012) demonstrated that a phenotype of early infancy identified at 4 months predicts individual differences in reactivity of the right amygdala to faces almost two decades later in adults. The rapidly growing body of developmental neurobiological research has emphasized the important need for clinical assessment and early intervention for chronically misattuned caregiver–infant communications that are found in contexts of relational attachment trauma, especially for boys at risk.

In a pair of articles in the 2001 issue of this journal, I articulated a model of the pre‐ and postnatal ontogeny of the hierarchically organized limbic system, which suggests that a number of discrete limbic components come online and develop connectivity in a defined sequence in the first year (A.N. Schore, 2001a, 2001b). The model proposes that the neuroanatomy of the emotion‐processing limbic system is characterized as a series of hierarchically organized “control systems” or “hubs” in the right amygdala, right anterior cingulate, and right orbitofrontal cortex. In my most recent articulation of this model (A.N. Schore, 2012, 2013, 2014), I offered evidence showing that at 2 to 3 months, the right basolateral amygdala, which densely connects with higher cortical association areas, begins a critical period of growth, initiating the infant's burgeoning intersubjective functions. From 3 to 9 months, the anterior cingulate, a cortical–limbic structure associated with responsivity to social cues comes online, giving the infant even greater capacities for intersubjectivity and for receiving nonverbal communications of “good‐enough” caregiver interactive regulation. From 10 to 12 months of age, the regulatory center in the orbitofrontal cortex, the attachment executive control system, begins its developmental growth period, which spans until the end of the second year (A.N. Schore, 2000).

This ontogenetic progression of limbic–autonomic regulatory centers can serve as the foundation of an evidence‐based clinical model of longitudinal assessments of the same dyad across the stages of infancy and toddlerhood over the first 2 years, the time of the brain growth spurt. Assessments of right‐brain nonverbal socioemotional functions can be used to clinically formulate specifically tailored interventions during these critical periods of interpersonal neurobiological maturation, which are timed differently in male and female infants. The right hemisphere enters subsequent growth spurts, but exhibits maximal plasticity during the brain growth spurt, from the last trimester through the second year. Furthermore, in light of the precedence of later maturing left‐brain cognitive development by earlier right‐brain emotional development, the focus should move from higher verbal cortical executive functions to lower subcortical limbic–autonomic circuits that are imprinted in the attachment transactions of infancy and toddlerhood. Evidence‐based regulation theory formulates an assessment of attachment episodes of rapid, spontaneous, right‐brain visual–facial, auditory–prosodic, and tactile–gestural communications, in which the primary caregiver interactively regulates the infant's states of emotional arousal. In my most recent formulations of neurobiologically informed modern attachment theory, I concluded that attachment transactions influence the “early life programming of hemispheric lateralization” that, in turn, generates the dominance of the right hemisphere in the first year of life.

In support of this model, Michael Meaney and his colleagues offered neuroimaging research of neonates at the beginning of the first year and concluded, “In early life the right cerebral hemisphere could be better able to process … emotion (Schore, 2000; Wada and Davis, 1977) … These neural substrates function as hubs in the right hemisphere for emotion processes and mother and child interaction” (Ratnarajah et al., 2013, p. 193). Research from Tronick's lab on infants in the middle of the first year has demonstrated that under relational stress, 6‐month‐old infants use left‐sided gestures generated by the right hemisphere. They interpreted this data as being “consistent with Schore's (2005) hypotheses of hemispheric right‐sided activation of emotions and their regulation during infant–mother interactions” (Montirosso, Cozzi, Tronick, & Borgatti, 2012, p. 826). Using near‐infrared spectroscopy, Minagawa‐Kawai and her colleagues' fMRI study of infant–mother attachment at the end of the first year observed, “Our results are in agreement with that of Schore (2000) who addressed the importance of the right hemisphere in the attachment system” (2009, p. 289).

The evolving attachment system that is fundamentally expressed in right lateralized visual–facial, auditory–prosodic, and tactile–gestural nonverbal communication functions of “the human social brain” can be assessed over the pre‐ and postnatal stages of infancy to appraise the ongoing status of emotional and social development. Allman, Watson, Tetreault, and Hakeem (2005) articulated an organizing principle of developmental neuroscience: “The strong and consistent predominance for the right hemisphere emerges postnatally” (p. 367). In an overview of their research on the development of voice‐sensitive areas of the right hemisphere, Grossmann et al. (2010) proposed that in postnatal periods, “responses to voices and emotional prosody … might thus serve as one of potentially multiple markers that can help with an early identification of infants at risk for neurodevelopmental disorders” (p. 856). With an eye to diagnostic implications, Montirosso et al. (2010) called for future study of different gestures with simultaneous measurement of brain functions and suggested that “such studies would also be useful with samples of high risk infants whose behavior and brain organization may be compromised” (p. 109).

The growing body of research on the early developing right brain can serve as the foundation of an evidence‐based clinical model of early intervention and prevention. Toward that effort, in a number of recent publications, I used a large body of neurobiological studies to outline a model of clinical assessments of the mother's right brain, the infant's right brain, and their right‐brain to right‐brain expanding capacity for intersubjectivity. With respect to the mother, I suggested that the sensitive mother accesses not her left but her right brain in attachment communications (A.N. Schore, 1994, 2003a, 2012). Recent studies have indicated that “The right prefrontal cortex is involved in human maternal behavior concerning infant facial emotion discrimination” (Nishitani, Doi, Koyama, & Shinohara, 2011, p. 183). Killeen and Teti (2012) reported “greater relative right frontal activation in response to seeing one's own infant is related to maternal negative affect matching during times of infant distress, and greater perceived intensity of infant joy during times of joy” (p. 18). Note that these findings (as well as the body of my work) do not support the idea that the left hemisphere is dominant for positive emotions and the right only for negative emotions (see my critique of valence theory in A.N. Schore, 2015a). Maternal assessments thus should evaluate the mother's capacity to access her right brain for interpreting her infant's spontaneous nonverbal communications, facial expression, vocal tone, and body posture.

Regarding assessment of the infant's developing right brain, I refer the reader to my work on the ontogeny of infants’ increasing ability to process an expanding array of visual–facial, auditory–prosodic, and tactile–gestural attachment communications from birth through 18 months (A.N. Schore, 2012, 2013, 2014), thereby tracking the developmental progression to more complex sensory–affective functions. The future capacity to receive and express essential visual–facial social information is expressed in face‐to‐face communications, a central aspect of all later intimate relationships, and is dependent upon caregiver–infant eye contact and visual gazing during early critical periods. How often and in what contexts the mother and infant spontaneously look (and not look) directly at each other is of key importance to evaluating both an infant's development and the health of the dyadic relationship.

In addition, an assessment needs to be made of the infant's developmental progression to more complex auditory–prosodic attachment communications. The emotional quality of what infants hear in the early stages of infancy affects the development of voice‐processing areas of the right hemisphere, especially the temporal voice areas in the upper banks of the right superior temporal sulcus. This underscores the importance of evaluating the infant's emotional response to not the verbal content but the melody of the mother's voice, and whether she's using infant‐directed versus adult‐directed speech in her interactions with her child, especially in both arousal‐reducing calming‐soothing and arousal‐amplifying playful contexts. In addition, an assessment needs to be made of the infant's developmental progression to more complex tactile–gestural attachment communications (“affective touch”). This focuses not only on the quantity but also the quality and amount of sensitive interpersonal touch that the infant is receiving and expressing.

Furthermore, in addition to the dyadic right‐brain to right‐brain expression, reception, and communication of bodily based emotional information, an organizing principle of modern attachment theory dictates that the mother's attachment functions are expressed in her ability to interactively regulate various states of infant emotional arousal. Again, I refer the reader to my latest book The Science of the Art of Psychotherapy(for a model of mother–infant right‐brain regulation and dysregulation, see Table 11.1) as well as to A.N. Schore and Newton (2012). This assessment focuses on the mother–infant dyad's relational capacity to implicitly interactively upregulate positive affect in a mutual play context and downregulate negative affect in a relationally stressful context. The latter allows for an evaluation of the male infant/toddler's emerging capacity for right‐hemispheric specialization in regulating stress and emotion‐related processes, a developmental achievement that occurs later in male toddlers than it does in female toddlers. As mentioned earlier, there are gender differences in self‐regulation; boys toward autoregulation and girls toward interactive regulation. Yet, for both, accessing each is adaptive during times of stress. In the case of poorly developed right‐brain stress‐regulating systems, an assessment also should be made of the child's defenses under intense relational stress, including dissociative withdrawal.

In addition, an evaluation should be made of the dyad's capacity for intersubjectivity, the contact of the infant's emerging emotional mind with the mother's mind. In other work, I have translated Trevarthen's and Stern's research on emerging intersubjectivity over the first year in terms of the development of more complex right‐brain to right‐brain psychobiological communications within the dyad. I refer the the reader to A.N. Schore (2014) for Saint‐Georges’ et al. (2011) video coding of home movies of spontaneous, reciprocal infant–caregiver emotional interactions over the first and second postnatal semesters. The focus is on the dynamic parent–infant interaction instead of on single behaviors of the infant or the parent.

This assessment can be used with full‐term or high‐risk infants with an immature nervous system at birth. Mento et al. (2010) concluded that

The right hemisphere would sustain the functions necessary for the survival of the species [italics added], such as visuospatial or emotional processes. Consequently the earlier and faster development of the neural substrates underlying these functions is needed to prevent possible impairment during infancy and childhood. (p. 571)

They further noted that “early alteration of the normal hemispheric asymmetry in terms of functional development in extremely immature infants has recently been related to several neurocognitive developmental impairments during childhood and adulthood” (p. 572). In concordant theoretical writings, Saugstad's (1998) emphasized the importance of cerebral lateralization and the rate of that maturation, and proposed that neurodevelopmental psychiatric disorders are associated with late and slow cerebral lateralization.

Most important, gender‐informed assessments of all male infants need to be done in a sequence of right‐brain critical periods. As the preceding sections have documented, developmental neuroscience clearly suggests that both sexes move through a similar pattern of caudal to rostral brain development and subcortical to cortical–limbic maturation. That said, the slower maturation of the developing male versus the developing female brain indicates that male infants and toddlers are more at risk to experience prenatal and postnatal exposure and vulnerability to stressful physical and social environments during the formation of right‐brain circuits that implicitly regulate affects. The ontogenetic progression of attachment imprinting of the evolving right lateralized limbic system is universal; however, the timing and length of stages vary in male/female infants. The fact that there are different maturational rates in the brain growth spurt from the last trimester of pregnancy to the second year suggests separate norms for each gender. These norms need to reflect normal gender differences in slow‐maturing male versus fast‐maturing female infants’ socioemotional functions. Risk would be demarcated at the extremes of normal ranges. These evaluations of efficient versus deficient right‐brain socioemotional functions also may be used to assess the development of evolving masculine versus feminine psychological gender identity in the second year.

An organizing principle of this work dictates that the prenatal and postnatal stages of human infancy represent critical periods of development of both the stress‐regulating HPA axis and the gender‐determining HPG axis, two neuroendocrinological systems that interact and influence each other. In the early developing male, the hormonal end‐product of the former is cortisol, essentially involved in fear regulation, and of the latter is testosterone, involved in aggression regulation. As previously described, the differences in rates of brain maturation between the sexes and the interaction of these two neuroendocrine axes account for gender differences in emotion‐regulation functions. The programming of regulatory limbic–autonomic circuits is epigenetically shaped by both classes of steroid hormones and imprinted prenatally and subsequently postnatally in the maternal and then paternal attachment relationship. In classical attachment theory, Bowlby (1969) heavily and almost exclusively emphasized the negative affect of fear, which is reduced by secure‐base behavior. Modern attachment theory emphasizes regulation of a large number of affects, including aggression, and suggests that the early endocrinological detection of infant boys at risk must include both salivary cortisol and testosterone levels. Early assessment needs to pay more attention to the primordial psychoneurobiological markers of both fearful impulsive and fearless instrumental aggression dysregulation of later appearing externalizing psychopathologies that are now significantly increasing in this and other cultures.

CULTURAL EPIGENETIC MECHANISMS OF INCREASED MALE‐GENDER PSYCHOPATHOGENESIS: EARLY CHILDCARE

Let me return to two questions I raised at the beginning of this work on boys at risk. What early developmental mechanisms are involved in the vulnerability of males to certain psychiatric disorders? What epigenetic mechanisms can account for their recent widespread increase in U.S. culture and beyond? Over 20 years ago, in the last chapter of Affect Regulation and the Origin of the Self, I utilized a neurobiological perspective to overview disturbing research data on the documented increase of insecure, especially avoidant, attachments and levels of aggression associated with early daycare (A.N. Schore, 1994). I suggested that from a neurobiological perspective that focuses on not short‐term cognitive but long‐term enduring emotional effects, these findings were alarming. This problem has continued, if not worsened, since then.

In 2007, Dmitrieva, Steinberg, and Belsky reported,

Evidence indicates clearly that care initiated early in life and experienced for many hours, especially in child‐care centers, is associated with somewhat elevated levels of externalizing behavior problems (e.g., aggression and disobedience), and that these effects are not simply a function of low‐quality care. (p. 1032)

In a later study, this group found that the effects of early childcare extend into late childhood and adolescence (Vandell et al., 2010). In a more recent developmental psychobiological study of older children in childcare outside this country, Sajaniemi et al. (2011) observed a group of children with a cortisol pattern clearly indicating atypical HPA activity. They concluded,

The number of physical and psychological stressors in the lives of children has multiplied in recent years as the number of children with various kinds of behavioural and developmental difficulties has increased. Besides other stressful childhood events such as family turmoil, disruptions or adverse social circumstances, day care may also be challenging for some children. (p. 56)

Citing my work, they concluded, “These findings should be considered alarming since developmental difficulties may be, at least partly, the consequence of chronically‐induced stress which is known to have detrimental effects on brain activity, emotional well‐being and development” (p. 56).

Indeed, the American Academy of Child & Adolescent Psychiatry (n.d.; Campaign for America's Kids) has asserted a “crisis” in children's mental health needs: One in every five children has a diagnosable psychiatric disorder, and 1 in every 10 suffers from a mental illness severe enough to impair everyday living. In a recent volume that I co‐edited, Evolution, Early Experience and Human Development(Narvaez, Panksepp, Schore, & Gleason, 2013), I suggested that this large increase in child psychopathology in the United States is directly related to entry of many of our culture's infants into substandard early daycare, at 6 weeks or less, due to the lack of national parental leave policy. In the United States, approximately 50% of 1‐year‐olds and 60% of 2‐year‐olds regularly attend some form of childcare (Hyson & Tomlinson, 2014). For many, if not most, parents, this placement so soon after birth is a highly stressful event, filled with conflictual emotions. It is at this very time that infants and mothers are just entering into the developmental phase “attachment in the making” (Ainsworth et al., 1978, p. 24).

In a number of contributions, I have offered data indicating that at this same time, 6 weeks, right‐brain subcortical–cortical circuits in the right basolateral amygdala and right anterior cingulate begin a critical period of maturation (A.N. Schore, 2013, 2014). This pair of early emotion‐processing limbic structures optimally evolves in an experience‐dependent fashion, and these socioemotional experiences are embedded in a growth‐facilitating, one‐to‐one, dyadic attachment relationship. On the other hand, early daycare acts as an epigenetic social stressor. Experts in the field of maternal and child health are now asserting “[a] short maternity leave may detract from time available for mothers to care for themselves and their infants” (Guendelman, Goodmann, Kharrizi, & Lahiff, 2014, p. 201). This cultural mechanism promotes a premature disconnection of the burgeoning mother–infant emotional bond in the very earliest stage of their right‐brain to right‐brain intimate attachment relationship. This deprives the infant of the primary affect regulator, thereby providing less than an optimal context for ongoing right‐brain development. In discussing the neural and hormonal bases of the shift from parental to alloparental care, Rilling (2013) asserted, “We need to study daycare and foster care workers who, despite the best intentions, may have limited amounts of empathy and compassion to partition among the many children they are caring for” (p. 14).

Expanding my earlier work, I now suggest that this perinatal separation stress is amplified in male infants, and puts them at even greater risk than female infants. Basic developmental neurobiological research has demonstrated that “males appear to be more vulnerable to a unique long period of early maternal separation” and that this mechanism is associated with the fact that “males are more prone to neuropsychiatric disorders that appear developmentally” (Llorente et al., 2009, p. 240). Conti et al.’s (2012) work on the late health effects of early life adversity has shown that “males are much more effected by early deprivation than females” (p. 8870). Six weeks represents the exact time of the initiation of the postnatal testosterone surge found only in males, which Hines et al. (2015) ascribed to the first months after birth, with the largest sex difference occurring in Postnatal Months 1 to 3. This is a critical period for the ongoing formation of the HPA axis, and due to their slower brain development, male neonates are more at risk for social stressors, including the stressors that are associated with separation from the mother as well as those associated with daycare. I suggest that the heightened circulating androgenic steroids and stress‐regulating corticosteroids in the male limbic brain at this very period act as a cultural psychopathogenetic mechanism for later externalizing disorders in males, including disorganized attachment etiologies of aggression dysregulation in conduct disorders.

In an article on how childcare affects child development, Crockenberg (2003) stated that “in view of an extensive vulnerability to stress (Zaslow & Haynes, 1986), when gender differences in children's reactions to child care are identified, it is boys who show more negative behaviors” (p. 1035). She cited the earlier work of Howes and Olenick (1986), who reported that boys are more adversely affected by lower quality care than are girls; the NICHD Early Child Care Research Network (1998) finding that boys, more than girls, who experienced more than 30 hr per week of nonparental care are insecurely attached at 15 months; and M. Weinberg et al.’s (1999) studies showing that by the middle of the first year, girls are better able to regulate negative arousal than are boys.

Over the last three decades, no studies have been done on the long‐term effects, especially the enduring neurobiological effects of entrance at 6 weeks. In very recent and relevant research on infants entering center care at 3 months (within the postnatal testosterone surge), Albers, Beijers, Riksen‐Walraven, Sweep, and de weerth (2015) followed these infants for the ensuing 9 months. Most mothers had completed higher professional education and had university degrees. Observing the infant both at home and in childcare, Albers et al. reported that attending center care involves separation from the parents and exposure to a novel environment and professional caregivers, and that such experiences may be especially stressful for young infants with both normal and limited coping capacities. With respect to entrance at 14 weeks, they documented that that infant morning and afternoon cortisol concentrations were higher on center care days, as compared with home days, and that infants receiving higher quality of maternal behavior displayed higher morning cortisol in center care, as compared to infants receiving lower quality of maternal behavior. They cited the similar findings of Bernard, Peloso, Laurenceau, Zhang, and Dozier (2015), who also found afternoon cortisol levels to remain elevated throughout a 10‐week transition to a new childcare setting, “possibly indicating that child care continues to serve as a cortisol‐eliciting context, even months into the transition” (Albers et al., 2015, p. 6).

Albers et al. (2015) noted,

On one hand, high quality of maternal caregiving behavior helps infants to regulate stress in challenging situations and, in the long run, to develop self‐regulatory capacities (Loman & Gunnar, 2010; Schore, 2001). On the other hand, young infants accustomed to receiving high‐quality care at home may be less prepared to deal with challenges without such maternal aid, especially if the quality of the care provided by the caregivers in the center is relatively low. (p. 2)

Furthermore, higher concentrations of morning cortisol in this group remain stable throughout the first year of life. They speculated that these young infants have a history in which a sensitive mother can be turned to for the interactive regulation of arousal in stressful situations, and that her unavailability in childcare may induce increased levels of cortisol. I suggest that interactive regulation is at the core of the emerging interpersonal neurobiological attachment dynamic, and that these data indicate that early childcare represents a continuous source of ongoing acute separation stress and therefore potentially less than optimal right‐brain development during the amygdala, anterior cingulate, and orbitofrontal critical periods of the first year. I also suggest it is for this reason that every other industrialized nation but the United States provides extensive policies of parental leave.

In addition, Albers et al. (2015) noted that entrance into center care at 3 months may be even more challenging for children high in negative emotionality (i.e., with a difficult temperament) and that heightened cortisol concentrations in this group may be indicating biologically significant chronic stress. Recall that temperament at birth is a result of epigenetic mechanisms that have evolved prenatally and continue to be shaped or misshaped by the postnatal socioemotional environment. These infants may experience a double stressor, first in utero and then in the extrauterine environment of early childcare with its additional challenges of large group sizes, excessive noise, and multiple caregivers. Interestingly, in discussing difficult temperament, Albers et al. cited the work of Crockenberg (2003), who emphasized the vulnerability of boys in childcare.

Early childcare thus represents a particularly severe stressor to a high‐risk male infant with a poorly developed right‐lateralized HPA axis and consequent immature capacities for both interactive regulation and autoregulation (discussed earlier). These males use a primitive coping mechanism, dissociative disengagement, to cope with chronic stress, and so they may not be behaviorally present with intense protest, yet are intensely homeostatically dysregulated (A.N. Schore, 2003a, 2003b, 2012). Furthermore, this gender difference in elevated cortisol during early critical periods is expressed in childhood in developing right‐brain externalizing psychopathologies. The long‐term effects of early childcare in this group with insecure disorganized attachment is further expressed in adolescence in the form of a predisposition to conduct disorders (Yildirim & Derksen, 2012). The detrimental impact of all‐to‐common inadequate early childcare on these high‐risk male infants may be a later consequence of what Lanius, Vermetten, and Pain (2010) termed The Impact of Early Life Trauma on Health and Disease: The Hidden Epidemic.

Recent attention has been focused on the effects of early childcare at later stages, including adolescence (Vandell et al., 2010), but it has not integrated relevant findings in neuroscience nor disturbing current information from child psychiatry, especially the widely accepted tenet that “most mental illnesses … begin far earlier in life than was previously believed” (Insel & Fenton, 2005, p. 590). Earlier, I offered evidence to show that fetal and postnatal levels of testosterone have permanent organizational programming effects on the developing male limbic system, and that elevated levels of testosterone in adolescence are associated with the initiation of a number of male‐dominant psychiatric disorders. Indeed, a recent psychiatric epidemiological study of 10,000 adolescents documented a “high prevalence” of mental disorders in youth (Merikangas et al., 2010). Merikangas et al. (2010) noted that “Approximately one in every four to five youths in the U.S. meets the criteria for a mental disorder with severe impairment across their lifetime” (p. 980).

In 1994, I reported studies showing that childcare was specifically associated with an increase in avoidant (dismissive) attachment. Where does the increase in this attachment typology show up 20 years later? Indeed, the continuity of attachment styles over the life span has been an essential area of study in child development, attachment theory, and interpersonal neurobiology. A study of 10,000 Adult Attachment Interviews documented 35% dismissing attachment in nonclinical adolescents, as compared with only 23% of adults of the prior generation (Bakermans‐Kranenburg & van IJzendoorn, 2009a). Konrath, Chopik, Hsing, and O'Brien (2014), in a study of over 25,000 American college students, reported that between 1988 and 2011, secure attachment decreased from 49 to 42% while insecure attachment increased from 51 to 58%, with the largest rise (56%) in dismissing attachments. They noted that mothers’ participation in the labor force rose from 38% in the late 1960s to 69% in the early 1990s, “straining parent's collective ability to invest quality time in their children” (p. 338), and suggested that “changes in attachment related early childhood indicators may provide some explanation for changes in attachment styles [italics added]” (p. 338).

In a study of over 75,000 American high‐school and college students from 1938 to 2007, Twenge et al. (2010) reported that the current generation of young adolescents report significantly higher symptoms of psychopathology on the Minnesota Multiphasic Personality Inventory. To understand the underlying mechanism for this significant cultural change, they proposed that “large changes over relatively short periods of time cannot be attributed to genetics [italics added]” (p. 152), and that “there are also strong cultural influences on psychiatric symptoms—that is, an environmental influence outside of the individual family [italics added]” (p. 153). In agreement with Konrath and Twenge and their colleagues, I suggest that the ongoing significant changes in insecure attachment status and reduced socioemotional health of our children are in part due to epigenetic cultural social stressors associated with early daycare, which is generally substandard in this country. This culturally sanctioned premature separation of the early developing brain from the primary caregiver occurs even before the attachment system is fully formed, thereby generating enduring future deficits in right‐brain social, emotional, and stress‐regulating functions.

The sobering Albers et al. (2015) study began with infants at 14 weeks and was done in the Netherlands, which has a comprehensive national policy of parental leave and a higher quality of childcare than does the United States, where infants are placed at 6 weeks. Although both sexes are negatively impacted, boys, with more slowly developing brains, are even more at risk in both the short‐ and long‐term. Gunnar et al. (2010) asserted that U.S. childcare elevations of cortisol in boys are associated with angry‐aggressive behavior while large rises of cortisol in girls are associated with anxious‐vigilant behavior, and that boys may experience more stress at childcare than do girls. These gender differences reflect early expressions of externalizing and internalizing psychopathologies. Recall, Holden's (2005) assertion that culture helps shape how the two sexes express mental problems.

Citing my work on brain development, Calnen (2007) asserted, “It is biologically necessary that mothers be with their infants, especially during the first few months postpartum [italics added]. This is not likely to become a reality until working families are granted a sufficiently long, and paid, maternity leave as a matter of national policy” (p. 39).

Due to its lack of support of a national policy of parental leave, unique within the industrialized world, and the poor quality of early childcare, U.S. culture is now acting as a source generator of significant increases in the amount of mental problems in its child, adolescent, and adult citizens. That said, the science now exists to formulate evidence‐based models of early intervention and, indeed, prevention of mental disorders.

Based on the developmental neurobiological data, I suggest that this country should legislate and implement the strategies now operating in other industrialized nations: maternal leave of 6 months and paternal leave of 2 months. In addition, we must seriously address the problem of training and upgrading the quality of childcare workers. Toward that effort, I recently served as an independent reviewer of a volume, Transforming the Workforce for Children Birth Through 8: A Unifying Foundation, published by the Institute of Medicine (2015), although in my mind that work is still too focused on later developing left‐brain language and not right‐brain socioemotional functions. Furthermore, developmental neurobiological and neuropsychological studies of infants before, during, and after early daycare are now essential, and it should focus not on later maturing language or motor areas but on brain systems responsible for socioemotional and stress‐regulating functions, essential elements of well‐being (A.N. Schore, 2015b). In a recent article, Layard, Clark, Cornaglia, Powdthavee, & Vernoit (2014) at the London School of Economics concluded, “The most important childhood predictor of adult life‐satisfaction is the child's emotional health, followed by the child's conduct. The least powerful predictor is the child's intellectual development” (p. F720).

CULTURAL EPIGENETIC MECHANISMS OF INCREASED MALE‐GENDER PSYCHOPATHOGENESIS: TOXIC ENVIRONMENTAL ENDOCRINE DISRUPTORS

In earlier sections of this work, I reported linkages between endocrine disruptors that are omnipresent not only here in the United States but worldwide and increased levels of male‐dominant neurodevelopmental disorders such as autism and schizophrenia, and psychiatric disorders such as ADHD and oppositional defiant conduct disorders (Grandjean & Landrigan, 2014; Lanphear, 2015; Miodovnik et al., 2011). I now offer some further thoughts on this second transcultural developmental mechanism that is amplifying male psychopathology in U.S. culture and beyond: widespread exposure of the developing males to environmental toxins that interfere with the developmental programming of the structural brain systems that functionally regulate relational stress. The slower maturation of their fetal and postnatal brain puts males at even greater risk due to an extended window of vulnerability to these toxic environmental chemicals.

Recall that a large body of research in both animal and humans clearly has demonstrated that the developing fetus and infant are much more sensitive to endocrine disruptors than are adults; that extremely low dose exposure during critical periods exerts significant effects on a developing organism by inducing epigenetic modifications in the genome; that early exposure alters the androgen/estrogen balance in specific developing brain regions thereby changing the normally sexually dimorphic structures and behaviors that characterize boys and girls; that these xenobiotic agents have distinct effects on male and female limbic circuits; that male brains are particularly susceptible during the prenatal, postnatal, and pubertal testosterone surges; that some of the effects in early life may not be manifest until adulthood; and that human exposure is “widespread.”

Utilizing an evolutionary perspective in an ethotoxicological study of environmental endocrine‐disrupting chemicals, Parmigiani, Palanza, and vom Saal (1998) concluded, “Pathological changes in behavior lead to reduced social [italics added] adaptation and impaired responsiveness to environmental demands, with consequences for social structure and population dynamics [italics added]” (p. 333). Citing the current increased prevalence of developmental disabilities and autism, ADHD, and conduct disorders in U.S. children, especially boys, Lanphear (2015) asserted, “The impact of toxins on the developing brain is usually subtle for an individual child, but the damage can be substantial at the population level” [italics added] (p. 211). He also noted that causal mechanisms of these disorders are more than genetic; they are epigenetic due to interplay of genes and environment, including the physical environment. Indeed, most exposures to endocrine disruptors do not produce genetic mutations but promote effects on subsequent generations via “epigenetic transgenerational inheritance” (Skinner, 2016, p. 68). In other words, the long‐term effects of the early exposure of developing brains to these ubiquitous environmental toxins can account for not only significant increases in male‐ (and female‐) gender‐related psychopathologies at the individual level, but also for the significant increase of male‐related psychopathologies in large numbers across a multitude of cultures.

A massive amount of basic and clinical research exists on early exposure to bisphenol A (BPA), an endocrine disruptor that has antiandrogenic effects on the androgen receptor (Lee, Chattopadhyay, Gong, Ahn, & Lee, 2003) in both animals and humans. BPA is one of the highest volume chemicals produced worldwide and is used in the manufacture of plastics and epoxy resins, including food and beverage containers. More than 90% of the U.S. population has measurable levels of BPA in bodily fluids, with children typically exhibiting higher internal levels than do adults (Vandenberg et al., 2010). Exposure to BPA in utero inhibits the testosterone surge in the neonatal period, thereby disrupting the endocrine environment in the neonatal male (Tanaka et al., 2006). Females exposed to low doses of BPA during the last stage of pregnancy show altered maternal behavior in adulthood through an epigenetic mechanism that modifies gene activity (Palanza, Howdeshell, Parmigiani, & vom Saal, 2002).

Note the negative effects on both sides of the mother–infant dyad, a focus of modern attachment theory (A.N. Schore, in press; J.R. Schore & Schore, 2008). Palanza et al. (2002) asserted “slight perturbations of any of the components of the mother‐infant interaction [italics added] may result in alterations of the behavior of the mother and/or the offspring” (p. 415). In more recent research on the impact of BPA on the social behaviors between infants and their mothers, Nakagami et al. (2009) reported prenatal exposure to a “relatively low dose” of this endocrine disruptor alters the behavior of the male infant toward its mother, and that “male infants and male‐nursing mothers were more vulnerable to BPA exposure than female infants and female‐nursing mothers” (p. 1194). In this assessment, both showed more “outward looking” behaviors, suggesting an altered mother–infant interaction. Note that due to the epigenetic programming effects of sex steroids in critical periods, toxic endocrine‐disrupting chemicals in the shared mother–infant physical environment induce the structural organization of a dyadic system that is functionally less adapted to deal with stressors in the mother–infant social environment.

These data on the detrimental effects of developmental endocrine disruptors on male social and emotional functions in postnatal periods reflect dysfunctions of gender‐related attachment behaviors that I described earlier. These environmental toxins thus interfere with the necessary co‐creation of the maternal–infant attachment relationship, and they preclude the interactive regulation that is required for the ongoing maturation of the slowly developing male limbic system. In utero and perinatal exposure to BPA alters spontaneous novelty‐seeking and impulsive behaviors (Adriani, Della Seta, Dessi‐Fulgheri, Farabollini, & Laviola, 2003), decreases reception of fear‐provoking stimuli (Negishi, Kawasaki, Suzaki, Maeda, Ishii, Kyuwa, et al., 2004), and increases aggressiveness in males (Kawai et al., 2003). The reduction of postnatal testosterone caused by BPA also decreases the availability of androgens for regulating cell death in sexually dimorphic nuclei such as the hypothalamic preoptic area, and for the imprinting and preservation of emerging right‐lateralized coricolimbic regulatory circuits. These enduring structural defects and functional relational deficits represent the earliest etiological expressions of the previously mentioned gender‐related predisposition to psychiatric disorders associated with endocrine‐disrupting chemicals (Grandjean & Landrigan, 2014). Evans et al. (2014) documented that prenatal exposure to BPA is associated with externalizing aggression, oppositional/defiant, and conduct disorder in 6‐ to 10‐year‐old boys, but not in girls.

In a recent study entitled “Perinatal Exposure to Low‐Dose Bisphenol A Affects the Neuroendocrine Stress Response” Panagiotidou, Zerva, Mitsiou, Alexis, and Kitraki (2014) showed that low, but chronic, exposure throughout pregnancy and lactation alters the HPA axis at puberty in a sexually dimorphic manner. Exposed males exhibited a more active HPA axis under stress, reflected in higher and more extended rises in plasma corticosterone, thus appearing “less mature regarding their pituitary stress responsiveness” (p. 216). Under resting conditions, exposed females had higher basal corticosteroid levels, and under stress did not downregulate HPA activation. They concluded that exposure of a pregnant female to this endocrine‐disrupting chemical induces “a sex‐specific effect on their offspring's physiology and behavior … including reduction or reversal of existing sex differences [italics added]” (p. 210).

Chen, Zhou, Bai, Zhou, and Chen (2014) demonstrated that sex differences in the adultHPA axis are altered by perinatal exposure to low‐dose bisphenol A. They concluded that the hormonal basis of normal gender differences lies in different impacts of estrogen and androgen on the HPA's response to stress: “Ovarian steroids (estrogen) have been found to increase HPA‐axis activity, and enhance the HPA‐axis response to psychological stress… . Conversely, testosterone attenuates HPA‐axis activity” (p. 13). They demonstrated that exposing the developing male brain to an endocrine disruptor in a perinatal period reduces testosteroneand increases corticosteroidresponse to mild stress in adulthood, a reversal of the normal male HPA pattern of affective behavior.

As mentioned earlier, there is now an intense interest in the impact of endocrine disruptors on early development across a very large number of scientific research and clinical disciplines, yet little to none of this has been incorporated into psychology and psychiatry, especially their developmental branches. To give an example of the wide range of these disciplines, in this work I have cited studies from such journals as the Journal of Endocrinology, Brain Research, Neurotoxicology, Journal of Neurological Sciences, Lancet Neurology, Acta Paediatrica, Neuropharmacology, Environmental Health Perspectives, Toxicology and Industrial Health, and Human and Experimental Toxicology, among others. For some time, the field has been controversial, but now that the harmful effects of these developmental toxins have been firmly established and the research is directed toward the underlying neurobiological mechanisms, the main controversy is about what level can be considered a “safe dose” (for conflicts with industry and legal matters, see Grandjean & Ozonoff, 2013). Presently, acceptable dose is designated at adult levels, which is considerably higher than maternal and infant levels, and does not take into consideration the unique susceptibility of mothers and infants to very low levels of these environmental toxins.

In fact, the interdisciplinary findings are so convincing that a large number of different scientific and clinical disciplines are now simultaneously expressing a worldwide call for action on endocrine disruptors. To give some examples, in the Journal of Steroid Biochemistry & Molecular Biology, Rubin (2011) asserted,

[T]here is currently sufficient evidence to raise concern and to warrant practice of the precautionary principle, particularly for protection of the developing fetus, neonate and young children as they may be the most vulnerable to adverse effects of this ubiquitous compound. (p. 32)

A 2014 editorial in Hormones and Behavior signed by 20 Journal Editors‐in‐Chief and 28 Journal Associate Editors declared,

Thousands of published studies have revealed the health effects of endocrine disrupting chemicals on wildlife and laboratory animals and, moreover, have shown associations of endocrine disrupting chemicals with effects in humans… . Of particular concern is incontrovertible evidence … that there are critical life stages, especially during early development, when hormones dictate the differentiation and development of tissues. Any perturbation of the delicate hormonal balance, whether due to the absence of natural hormones or presence of exogenous hormones, can have irreversible effects on endocrine‐sensitive organs. Endocrine disrupting chemicals are known to upset the balance (Gore et al., 2014, p. 190).

In a position statement in Endocrinology, authors offered recommendations for strengthening the Endocrine Disruptor Screening Program (Zoeller et al., 2012), and in Lancet Neurology, Grandjean and Landrigan (2014) called for an urgent formation of an international clearinghouse. Writing in Annual Review of Public Health, Lanphear (2015) argued, “The optimal strategy to prevent the development of brain‐based disorders is to identify and restrict or ban the use of potential toxins before they are marketed or discharged into the environment” (p. 222).

In a Special Communication in a 2015 issue of the International Journal of Gynecology and Obstetrics, an international group of authors declared,

Exposure to toxic environmental chemicals during pregnancy and breastfeeding is ubiquitous and is a threat to healthy human reproduction… . Exposure to toxic environmental chemicals and related health outcomes are inequitably distributed within and between countries; universally, the consequences of exposure are disproportionately borne by people with low incomes [italics added]… . On the basis of accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals the International Federation of Gynecology and Obstetrics (FIGO) joins other leading reproductive health professional societies in calling for timely action to prevent harm (Di Renzo, Conry, Blake, DeFrancesco, DeNicola, Martin, et al., 2015, p. 219).

In a recent issue of NeuroToxicology, Mustieles, Pérez‐Lobato, Olea, and Fernandez (2015) applied science to practice: “Physicians, especially gynecologists and pediatricians, should be aware of the hazards of endocrine disrupting chemicals exposure, allowing then to make lifestyle recommendations for preventing and/or reducing exposure, especially in high‐risk populations [italics addded]” (p. 182).

Although all mothers and their male and female infants are susceptible to the enduring untoward effects of early exposures to environmental toxins, those in lower socioeconomic groups are especially at high‐risk. Expanding on studies demonstrating that toddlers from low‐income families are at risk for poorer neurodevelopment (Black, Hess, & Berenson‐Howard, 2000), research in the environmental health literature has documented the enduring effects of environmental contaminants in American Indian and Alaska Native 24‐month‐old children (Hoover et al., 2012) and has described how prenatal and postnatal exposure to agricultural pesticides impair neurodevelopment in Mexican American toddlers (Eskenazi et al., 2007). In an inner city cohort of 3‐ to 5‐year‐old African American and Dominican children, Perera et al. (2012) observed that maternal bisphenol concentrations during the third trimester of pregnancy are associated with more problems with emotional reactivity and increased aggressive behavior syndromes in boys, but not in girls. Thus, economically disadvantaged boys, who all too frequently are exposed to low‐quality early childcare, are most at risk to the long‐term detrimental effects of environmental endocrine disruptors on stress regulation and affective behavior.

In 1962, Rachel Carson published the groundbreaking and transformational volume Silent Spring, which triggered a national debate on the worldwide unrestricted proliferation of environmental toxins (chemical pesticides) as well as on the role of the responsibilities of science, the chemical industry, and the government. She also questioned the wisdom of the government in allowing toxic chemicals to be so massively discharged into the environment before knowing the long‐term consequences. This work rapidly galvanized a public environmental consciousness; in the following decade, DDT was banned in this country, and Congress established the Environmental Protection Agency. In this exceedingly forward‐looking work, Carson proposed that one detrimental consequence of these toxins was the alteration of the proper balance between male and female hormones that would lead to an excessive accumulation of either, a foreshadowing of the later discovered developmental toxicity of endocrine‐disrupting chemicals, another aspect of human‐induced climate change.

Mothers and infants are vulnerable to low levels of a wide variety of environmental toxins that have lifelong impact on the ability to function, especially on social dysfunction (Lanphear, 2015). Both the developing male and the developing female brain are routinely exposed and therefore at risk for detrimental, long‐term effects in affective, social, and stress‐regulating functions, but in a sexually dimorphic manner. The very recent interdisciplinary integration of developmental neuroscience and developmental endocrinology has increased our understanding of both early human development and the specific windows of vulnerability of specific rapidly maturing brain systems to endocrine disruptors. These advances in science are, in turn, generating more powerful clinical models of the disturbing increased prevalence of gender‐related developmental and psychiatric disorders. In addition to a more comprehensive and extended national policy and an improvement of childcare, a major contribution to our children's development of mental and physical health would be governmental regulatory policy measures that protect our future citizens from early exposure to environmental toxins.

CODA: DO BOYS EVER CATCH UP?

Throughout this work, I have provided evidence that the brain development of the male fetus, infant, and boy is slower than that of its female counterparts, and thereby more at risk. According to Zahn‐Waxler et al. (2008) “The curve of development of the frontal cortex, caudate, and temporal lobes in girls is considerably faster than in boys, by as much as 20 months” (p. 279). At ages 7 to 12, boys lag behind girls by as much as 2 years in the development of social sensitivity (Baron‐Cohen, O'Riordan, Jones, Stone, & Plaisted, 1999). Especially in terms of social and emotional development, do they ever catch up after childhood? What about the next phase, adolescence?

Recall that the male brain experiences three testosterone surges: in the prenatal, postnatal, and adolescent stages of development. The male brain initiates puberty through increased androgenic hormone release, leading to the maturation of the gonads and the production and release of increasing levels of these sex steroids. Earlier, I offered evidence that the right orbitofrontal cortex which regulates the right amygdala matures later in male than in female toddlers. I also cited the study of Raznahan et al. (2010) on androgen signaling and cortical maturation in adolescence showing a focally accentuated “protracted cortical maturation” in males, as compared to females, in the orbitofrontal and ventromedial cortices. I noted that the delayed maturation of this emotion processing and regulating cortical system in males, earlier expressed in infancy and childhood, is still operating in adolescence.

In an MRI study of face processing in both male and female adolescents, Schneider et al. (2011) reported that14‐year‐old males show a sex‐dependent amygdala lateralization during the processing of faces, especially angry faces. They observed that the right amygdala is more strongly activated than is the left in males, but not in females. They contrasted this male gender lateralized amygdala with females who exhibit a progressive increase in prefrontal relative to amygdala activation in the left hemisphere with age (Killgore, 2001), suggesting that “males and females might have different developmental gradients” (p. 1852). Schneider et al. interpreted this gender data to demonstrate that the functional connectivity of the amygdala with the medial prefrontal cortex is reduced in normal male adolescents, as compared with adults, suggesting a weaker link between emotion, memory, and higher cognitive processes. This, in turn, is expressed in increased emotional vulnerability, one that is associated with a potential etiological pathway associated with mental disorders that are most frequent in adolescence, such as conduct disorders. They also noted that this sex‐dependent amygdala lateralization during basic emotional processes in adolescence is the precursor of the lateralization in emotional memory observed in adulthood. Clearly, the development of the male brain is still behind that of the female in early adolescence.

That said, testosterone levels rise dramatically in males over the course of adolescence. Testosterone starts to increase with the initiation of puberty and reaches adult levels by about 17 years of age (Griffin & Wilson, 1998), and so it is considerably higher in the 20‐ to 24‐year‐old adult than in the15‐ to 19‐year‐old adolescent. In adult males, androgens suppress the HPA axis, and activation of the stress response results in the inhibition of glucocorticoid pathways (Clifton, 2010; Handa, Burgess, Ker, & O'Keefe, 1994), thereby allowing for an increased gender‐specific stress‐regulating capacity. According to Davis and Emory (1995), “sex differences in maturity eventually equalize, yet stress responses remain sexually dimorphic through adulthood” (p. 24). Supporting this view that boys catch up in adulthood, Bakermans‐Kranenburg and van IJzendoorn (2009b) documented studies indicating that at 6 to 14 years of age, 49% of boys compared with 64% of girls are securely attached; while in adulthood, an equivalent 48% of males and 50% of females are securely attached on the Adult Attachment Interview.

Evidence that male socioemotional functions do mature in early adulthood was provided by De Pisapia et al. (2014), who reported a neuroimaging study of “interpersonal competence” in healthy male young adults, defined as “the capacity to interact and communicate with others, to share personal views, to understand the emotions and opinions of others, and to cooperate with others or resolve conflict should it occur” (p. 1257). They documented that an increased level of interpersonal competence is associated with higher white matter integrity in several major tracts of the right hemisphere, a finding that underscores its fundamental role in social cognition. They concluded,

According to this line of research, the development of emotional and social intelligence in the individual—from childhood to adulthood—depends on the quality of their relationship with a principal caregiver and those socioemotional competencies heavily rely on right brain function. The finding may have implications for theories claiming that the right hemisphere plays a major role in modulating emotion and nonverbal communication during the first interpersonal relationship that every human being experiences, namely the infant–mother relationship (A.N. Schore, 1997, 2000, 2009) (p. 1262)

Hecht (2014) marshalled a great deal of neurobiological studies to show that in adults, “the right hemisphere has a relative advantage over the left hemisphere mediating social intelligence—identifying social stimuli, understanding the intentions of other people, awareness of the dynamics in social relationships, and successful handling of social interactions” (p. 1). These expanded right‐brain social and emotional functions allow the adult male to enter into an intimate emotional relationship with a same‐aged female. Research has described important hormonal changes in men associated with marriage and fatherhood (both involving activation of right‐brain attachment mechanisms). Testosterone levels are lower in married versus single men (Booth & Dabbs, 1993) and in fathers (Gray, Yang, & Pope, 2006). Interestingly, fathers’ testosterone levels drop during their partners’ late pregnancy and early postpartum period (Perini et al., 2012; Storey, Walsh, Quinton, & Wynne‐Edwards, 2000), and men who provide more parental care have lower baseline testosterone levels than do fathers who provide less care or fathers without children (Gettler, McDade, Feranil, & Kuzawaa, 2011). Lower levels of paternal testosterone have been linked with developing paternal nurturance by increasing empathy for and suppressing aggression toward infants. It is tempting to speculate that this socially mediated reduction of testosterone is the result of increased aromatization of testosterone into estrogen in the adult male becoming a father's brain and body.

Some researchers have suggested that an inverted U‐shaped function in which moderate (regulated) levels of testosterone are associated with better infant care than either high or low levels, and that the testosterone reduction in fatherhood seems to be a consequence rather than a cause in becoming a father (Rilling, 2013). Researchers have proposed that the reduction of testosterone in a committed romantic relationship is related to “pair bonding” (attachment) and that “affiliative interactions with a partner may decrease testosterone levels” (Burnham et al., 2003, p. 121). I propose that these adaptive hormonal changes are a direct result of the implicit reciprocal right‐brain to right‐brain bodily based affective attachment communications between the mother and the father, and then the infant and the father, especially in father–male toddler child play (discussed earlier). These interactions may have organizational, programming effects on the growth of paternal circuits in the father's brain, paralleling documented increased growth in the mother's brain in the postpartum months (P. Kim et al., 2010). Indeed, a recent functional MRI study has revealed that the father's brain is sensitive to childcare experiences, and that while maternal caregiving involves an “evolutionarily ancient” brain–hormone–behavior subcortical–paralimbic network involved in emotional processing, paternal caregiving activates a later developing brain–hormone–behavior cortical circuit involved in socio cognitive understanding, mentalizing, and future planning (Abraham et al., 2014).

In the past, the physical sciences have focused on biological gender, and the social sciences on psychological gender. At this point, however, updated models of gender differences are understood to represent a dynamic interaction between biological and social factors (Wood & Eagley, 2015). Current developmental interpersonal neurobiological models of early gender development have indicated that in both males and females, there are different early emotional identifications around gender. In a common social scenario of a secure attachment, males and female infants/toddlers internalize a maternal estrogen‐dominant imprinted and then an androgen‐dominant imprinted paternal‐attachment relationship. In the second year, in both sexes, psychological gender (the sense of maleness or femaleness) is not only genetically encoded but also epigenetically molded by early experiences with feminine and masculine caregivers. This allows resilient androgynous access to both affiliative, communal, expressive, and nurturant feminine aspects as well as instrumental masculine aspects of the evolving personality (Bem, 1974; Spence & Helmreich, 1978). In this manner, optimal human male gender functioning in adulthood is associated with regulated testosterone levels that underlie adaptive sexual functions (Stoleru, Ennaji, Cournot, & Spira, 1993), pair bonding (van Anders, Goldey, & Kuo, 2011), and fathering (Gettler et al., 2011) as well as implicit power motivation and achievement motivation (Stanton & Schultheiss, 2009). The activational effects of this androgenic steroid are triggered at implicit levels in social contexts, like corticosteroids (Quirin, Kazen, Rohrmann, & Kuhl, 2009), producing behavioral changes in seconds to minutes.

Confirming my earlier speculations (A.N. Schore, 1994), recent research has indicated that

Sex differences in orbitofrontal cortex activity may be due to organizational effects of gonadal hormones early in life. The behavioral and neurobiological differences between men and women are an expression of more general sex differences in the regulation of emotions (van den Bos, Homberg, & de Visser, 2013, p. 95)

There is now consensus that in adulthood, male and female brains use different strategies during emotional processing (Whittle, Yucei, Yap, & Allen, 2011), and that men's subjective affective experience is relatively more rooted in sensations from the world whereas women's affective experience is more rooted in sensations from within the body (Moriguchi, Touroutoglou, Dickerson, & Barrett, 2014). This underlies the well‐known social tendencies of males to utilize cognitive empathy while females access bodily based affective empathy. The same socioemotional gender difference also is expressed in a general predisposition of males to autoregulate stress while females use more interactive regulation (“tend and befriend,” S.E. Taylor et al., 2000). In parallel to and echoing this, the two genders also show different situational triggers and coping strategies in stress regulation. Men show greater adrenocortical responses to achievement challenges whereas women show significant cortisol responses to social‐rejection stressors (Stroud, Salovey, & Epel, 2002).

Basic research has demonstrated that testosterone exerts differential effects in males and females, that in male adults the magnitude of the HPA response of corticosteroid release to stress is negatively related to plasma testosterone, that androgens inhibit the stress axis, and that testosterone can block stress‐induced corticosteroid release inducing anxiolytic effects and reducing fear (Bingham et al., 2011; Viau & Meaney, 1996). In light of the gender‐specific interactions and mutual inhibition between the HPG and the HPA axes, ongoing testosterone‐driven aggression or sexual experience in males can transiently decrease stress reactions (Cunningham et al., 2012). On the other hand, cortisol can suppress circulating testosterone levels in normal adult men (Cummings, Quigley, & Yen, 1983; Doerr & Pirke, 1976), and so both testosterone and cortisol jointly regulate masculine dominance, an assertive and self‐assured behavioral style that is mediated by the effects of these dual hormones on the neural activity in the orbitofrontal cortex and amygdala (P.H. Mehta & Josephs, 2010).

Furthermore, Ingalhalikar et al. (2014) demonstrated that male brains are structured to facilitate connectivity between perception and coordinated action, as opposed to female brains that are designed to facilitate communication between analytical and intuitive processing modes. They noted that male brains are optimized for communicating within hemispheres, as opposed to female brains for interhemispheric communication. They concluded that “the developmental trajectories of males and females separate at a young age” (p. 823) and that these dominant forms “are established early on and preserved throughout the course of development” (p. 825). In total, the preceding pages of this work suggest that differences between the sexes in brain wiring patterns that account for gender differences in social and emotional functions are established at the very beginning of life; that the developmental programming of these differences is more than genetically coded, but epigenetically shaped by the early social and physical environment; and that the adult male and female brains represent an adaptive complementarity for optimal human function.