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Neuropsychoanalysis

An Interdisciplinary Journal for Psychoanalysis and the Neurosciences

ISSN: 1529-4145 (Print) 2044-3978 (Online) Journal homepage: http://www.tandfonline.com/loi/rnpa20

An integrative model of autism spectrum disorder:ASD as a neurobiological disorder of experiencedenvironmental deprivation, early life stress andallostatic overload

William M. Singletary

To cite this article: William M. Singletary (2015) An integrative model of autism spectrumdisorder: ASD as a neurobiological disorder of experienced environmental deprivation,

early life stress and allostatic overload, Neuropsychoanalysis, 17:2, 81-119, DOI:10.1080/15294145.2015.1092334

To link to this article: http://dx.doi.org/10.1080/15294145.2015.1092334

Accepted author version posted online: 21Oct 2015.Published online: 07 Dec 2015.

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An integrative model of autism spectrum disorder: ASD as a neurobiological disorder of

experienced environmental deprivation, early life stress and allostatic overload

William M. Singletary*

Faculty, The Psychoanalytic Center of Philadelphia, Philadelphia, PA

(Received 1 February 2015; accepted 25 August 2015)

A number of recent convergences within neurobiology, and between neurobiology and psychoanalysis, allow us to

view autism through a new lens. This perspective highlights biological risk factors that might operate through nal

common pathways to produce the ASD syndrome. The goal of this article is to integrate and elaborate upon this

conuence of ndings, and to develop a working model of ASD that could parsimoniously account for central

aspects of ASD, promote greater collaboration in research, and lead to more effective treatment. Converging

evidence suggests that ASD is a potentially reversible neurodevelopmental disorder in which neurobiological

factors – not poor parenting – interfere with the child – caregiver interaction. The infant then experiences

deprivation of growth-promoting parental input even though it is available. The model proposed here adds what

seems to have been largely unrecognized in the eld of autism: the child’s experience of social deprivation and

isolation signals threat to the child and may result in overwhelming stress with signi

cant psychological(traumatic or toxic stress) and biological (allostatic overload) components and consequences. Allostatic overload

results when attempts to cope with threat impose too great a burden, resulting in a pathophysiological state or

process that damages the body and predisposes one to the development of disease. Critically, this model

proposes that allostatic overload plays a major role in the course of ASD by amplifying the neurobiological

vulnerabilities generally considered to make primary contributions to the development of autism. Furthermore,

through the process of allostatic overload, neurobiological and psychological factors interact in a nonlinear

fashion and are both seen to underlie the symptoms of ASD which develop through maladaptive coping and

neuroplasticity. Thus, this model might explain both the progression to, and the ongoing symptoms of, the ASD

syndrome. In addition, the model could also account for successful intervention by promoting the reversal of this

process via adaptive coping and neuroplasticity. Factors that may facilitate adaptive neuroplasticity include

providing an enriched environment, increasing social and emotional connection, and decreasing anxiety, stress,

and allostatic load. Personal descriptions of the experience of ASD, as well as psychoanalytic clinical work with

children with ASD, are in accord with this model. Psychoanalysis may thus be considered a research tool that

assists in uncovering the child’s inner world of feelings and meanings, an under-appreciated element in autism.Making sense of the child’s experience of isolation and threat helps the ASD child feel understood and less

afraid. Clinical material will illustrate how, for some children on the higher end of the autism spectrum, recovery

is made more likely by increasing the sense of connection and decreasing the experience of stress.

Keywords: autism; psychoanalytic psychotherapy; allostasis; stress; developmental neurobiology; neuroplasticity

The important thing in science is not so much toobtain new facts as to discover new ways of thinkingabout them.

Sir William Bragg (Nobel Laureate in Physics, 1915) inHu (2014)

[T]he complicated behavior of the world we see aroundus is merely “surface complexity arising out of deep

simplicity.” It is the simplicity that underpins complex-ity, and thereby makes life possible […]John Gribbin (2004), quoting phrase attributed toMurray Gell-Mann.

[A] denitive experiment is a largely mythical conceptin cognitive neuroscience. As in other areas dealingwith behavior, the solution is more a matter of pattern perception of convergent ndings, than theuncovering of the totally convincing clue.

Marcel Kinsbourne (2011)

Introduction

Autism spectrum disorder (ASD) is an urgent social

and mental health problem. Individuals with ASD

typically have dif culty with social interactions;

exhibit problems with emotional regulation (White

et al., 2014); demonstrate hyper-focus on specic

topics of interest; and often engage in repetitive, self-soothing, or self-injurious behavior. Recently found

to affect one in 68 children (Baio, 2014), more than

3.5 million people in the USA (Buescher, Cidav,

Knapp, & Mandell, 2014) and approximately 70

million worldwide are estimated to be living with

autism (Feld, 2015). The lifetime economic cost for a

person with autism has been estimated to be between

$1.4 million (Buescher et al., 2014) and $3.2 million

© 2015 International Neuropsychoanalysis Society

*Email: [email protected]

Neuropsychoanalysis, 2015

Vol. 17, No. 2, 81 – 119, http://dx.doi.org/10.1080/15294145.2015.1092334

http://-/?-mailto:[email protected]:[email protected]://-/?-


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per individual (Ganz, 2007) with a US national cost of

$236 – $262 billion dollars each year (Buescher et al.,

2014). Most importantly, autism causes untold

human suffering to individuals with ASD and their

families.

ASD is an extremely complex, heterogeneous neu-

rodevelopmental disorder involving an ever-growingnumber of genes and multiple biological mechanisms.

These factors interfere with brain development and

functioning at many levels, leading to the disruption

of brain circuits mediating social interaction and

communication, as well as behavioral exibility

(Abrahams & Geschwind, 2010; Amaral et al.,

2008a; DiCicco-Bloom et al., 2006; Geschwind &

Levitt, 2007). Thus, there are different forms of

autism with numerous neurobiological pathways

(Amaral et al., 2008b; DiCicco-Bloom, et al., 2006;

Greenspan & Shanker, 2004; Herbert & Anderson,

2008; Siegel, 2007; Zimmerman, 2008b). All of

these paths converge to shape the individual’s experi-ence and to lead to the clinical manifestations of

ASD, now grouped into two primary areas: (1)

impairments in social communication and interaction

and (2) restricted and repetitive interests and behavior

(DSM-5, 2013).

The heterogeneity and complexity of ASD have

made progress in research and treatment dif cult. At

one extreme, Waterhouse (2008, 2013) concludes that

no unifying brain dysfunction exists and that autism is

not a disorder, or even a spectrum of related disorders,

but rather only a collection of symptoms. More com-

monly, however, investigators do consider ASD to be adisorder, but tend to focus on specic elements among

the many that contribute to ASD. An emphasis on par-

ticular factors has therefore led to a number of somewhat

competing and divergent theories of ASD (see Figure 1).

Some researchers in the eld have thus called for us

to think more broadly and to move beyond simplistic

linear models and unilateral approaches (Zimmerman,

2008a). I agree that multidisciplinary collaboration,

rather than fragmentation, is urgently needed in order

to further our understanding and increase our ability

to intervene effectively. An integrative model of ASD

could bring some degree of order and clarity to the eld.

The integrative model I propose in this paper isbased on a perspective emerging from recent research

in autism that, as Waterhouse (2013) suggested could

be a helpful approach, focuses on risk factors and the

mechanisms of developmental brain disruptions. In

this view, biological heterogeneity can lead to a single

Figure 1. In general, the numerous factors shown to be involved in autism have been considered in isolation from each other,

leading to divergent and competing theories of ASD.

82 W.M. Singletary


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disorder through nal common pathways, which can

then be the targets of successful interventions (Sugathan

et al., 2014). To take one example, Jones and Klin (2013)

found that in infants who are later diagnosed with

autism, attention to eyes begins at normal levels, but

starts to decline between 2 and 6 months of age. They

consider this to indicate that some basic mechanismsand neural foundations of social adaptive behavior, for

example, preferential attention to eyes, voices, and bio-

logical motion, are initially intact but later disrupted.

Thus, disturbance of a variety of normal developmental

pathways for social engagement may lead to a common

outcome – the typical impairments in social functioning

found in ASD. This disturbance may be mediated by

epigenetic changes and maladaptive neuroplasticity.

In this perspective, one begins to see simplicity

arising out of the complexity of biological heterogen-

eity. Rather than restricting our focus to particular

contributory factors, which inevitably will generate

competing theories, we can now look at the complexinteraction of multiple contributing elements such as

genetic, epigenetic, and neuroanatomical inuences

that affect the development of the social brain and

child – caregiver interactions, and thus lead to the devel-

opment of ASD (see Figure 2).

An integral aspect of the model I propose, a view-

point not often discussed in the current work on

autism, is the psychoanalytic perspective. For many

years, psychoanalysis and neuropsychology have been

in completely opposite camps regarding the under-

standing and treatment of autism. However, my

experiences with clinical work involving intensive psy-

choanalytic treatment with a relatively small number

of children with ASD has inspired me to try to bring

these camps back into dialogue.

When used with adults, psychoanalysis typically

refers to an interpretive method with an emphasis on

free association, fantasy, and dreams. The crucial

difference compared to more behaviorally oriented

approaches is a central concern with inner, mental

experience, which one young boy whose treatment

will be described in some detail later, referred to as

the “missing piece” in the autism puzzle. With chil-

dren, psychoanalytic treatment primarily uses play,

where mental events – conscious and unconscious –

are brought out using dramatizations with dolls or

enactments with the analyst. This intensive, relationaltreatment allows access to the inner world of the

child. In addition, the parents are involved with

varying frequency for parental guidance including

helping them to understand the child’s inner world

and to learn new ways to engage the child.

Looking at the autism literature through the lens of

what I have found to be the ASD child’s central experi-

ence – feeling alone and threatened in a dangerous

world – led me to see new patterns. We can now discern

a remarkable conuence of ndings from multiple disci-

plines, making possible the construction of an integrative

model of ASD as a neurodevelopmental disorder with

psychological as well as behavioral components thatare potentially treatable and even perhaps preventable.

In what follows, I will be integrating ndings and

perspectives from a number of models of ASD that

havebeendevelopedrelatively independently (Chevallier,

Kohls, Troiani, Brodkin, & Schultz, 2012; Dawson, 2008;

Greenspan, 1992;Heltetal., 2008; Herbert & Weintraub,

2012; Kinsbourne, 2011; Kliman, 2011; Mahler,

1968; Markram & Markram, 2010; Mehler & Purpura,

2008; Morgan, 2006; Pelphrey & Carter, 2008; Porges,

1994/ 2011; Ramachandran, 2011; Singletary, 2006,

2009, 2013; Szalavitz & Perry, 2010; Zaki & Ochsner,

2011).1 As I hope to make clear, these disparate lines of

work can be seen to converge under the umbrella of the

integrative model I propose.

In the development of this model which I outline

below, the work of both Dawson (2008) and Herbert

(Herbert, 2010a; Herbert & Anderson, 2008; Herbert

& Weintraub, 2012) has been crucial. First, Dawson

(2008) has proposed that genetic and environmental

risk factors can lead to risk processes. In her view, an

Figure 2. Recent research supports a new integrative model of ASD: heterogeneous biological factors can converge and act

through nal common developmental pathways to produce autism.

Neuropsychoanalysis 83


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altered pattern of child – caregiver interactions deprives

the child of growth-promoting experiences, which

becomes a nal common pathway that heightens the

underlying vulnerabilities to develop ASD. Thus, in

Dawson’s model, the full syndrome of ASD can be

reversed or possibly even prevented by early interven-

tion focusing on optimizing the parent –

child inter-action. Second, Herbert and Weintraub (2012) have

emphasized the major role played by stress, particu-

larly the physiological aspects of stress and allostatic

load. Third, both Dawson and Herbert highlight the

role of maladaptive and adaptive neuroplasticity in

the development of, and potential recovery from,

ASD. To these I have added an expanded consider-

ation of the psychological dimensions related to the

experience of early deprivation of growth-promoting

parental input and psychological stress.

The proposed model of ASD

As I hope to demonstrate in this paper, the major con-

vergences among these neurobiological models and

psychoanalytic formulations can be organized

around three primary factors: (1) neurobiological dys-

function leads to disruption of child – caregiver inter-

actions, resulting in the early deprivation of crucial

social and emotional experiences; (2) stress – both

psychological and biological – plays a central role;

and (3) neuroplasticity is a fundamental element in

both the pathway(s) leading to ASD as well as in the

capacity for signicant adaptive development and

positive change in children with ASD (see Figure 3).

Specically, I propose that:

(1) Predisposing neurobiological factors lead to the

experience of environmental deprivation.

(2) This experience of environmental deprivation

leads to toxic levels of early life stress (both

psychological and allostatic overload).

(3) The amplifying interaction between deprivation

and allostatic overload, in the context of predis-

posing neurobiological factors, drives maladap-

tive neuroplasticity, leading to the underlying

structural and functional impairments of ASD.(4) Early deprivation, traumatic psychological

stress and allostatic overload can therefore

account for the symptoms of ASD, as well as

the experience of the person with ASD.

(5) Interventions that address these underlying

factors and processes can lead to an alleviation

of ASD through adaptive neuroplasticity.

After elaborating on these premises, I will add psy-

choanalytic clinical material to illustrate them. I will

then conclude with a discussion of the potential useful-

ness of this non-reductionistic way of conceptualizing

ASD.

I hope that others will nd this testable model to

have some signicant explanatory power: it seeks to

parsimoniously accommodate most existing theories

of autism, explain the developmental progressioninto the autism syndrome, account for the symptoms

of ASD as well as the individual’s experience of

ASD, and elucidate the developmental processes

involved in the effective treatment of ASD. It also

suggests new avenues for research. In addition, I

believe that the proposed model is quite elastic, has

the capacity to readily expand to include new ndings,

and could provide a useful platform for promoting

cooperation and collaboration.

Perhaps most importantly, with an appreciation of

multiple factors, we should be better able to design

effective interventions and harmonize the competing

visions of treatment. In this vein, Jones and Klin(2013) emphasize that evidence of an early, intact

neural foundation for social development in children

with ASD raises the possibility of successful early

intervention. Furthermore, recent research has

demonstrated adaptive neuroplasticity in ASD. The

model I will propose here has important implications

for establishing an upward spiral based on adaptive

plasticity to reverse the pathological processes in vul-

nerable children. Recently, Insel (2014) proposed that

both psychosocial and medical treatments can alter

the basic functioning of brain circuits. The challenge

is to bring together a “range of things” to harness

adaptive neuroplasticity and “make sure that

someone with a very complicated problem that

involves not just one but multiple circuits and net-

works of networks in the brain … has the greatest

opportunity to recover” (p. 2). I hope that this

model can make a substantial contribution to this

effort.

Neurobiological factors lead to the experience of

environmental deprivation in ASD

Looking at autism through the lens of aloneness andstress, one nds that independent voices from a

number of perspectives converge in seeing the neuro-

biologically based experience of environmental depri-

vation as a primary factor in the development of ASD.

In general, they fall into two major groups. First,

there are those proposing that primary dif culties in

social information processing (Pelphrey, Shultz,

Hudac, & Vander Wyk, 2011) and in social motivation

(Chevallier et al., 2012; Dawson, 2008) interfere with

the infant – caregiver interaction and lead to the

84 W.M. Singletary


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experience of early social deprivation. For example,

Pelphrey and Carter (2008) propose that:

In the case of the child with autism, there is no doubtthat parents, grandparents, siblings, and educatorsprovide an abundance of love, warmth, and care, butthe child does not develop the brain mechanismsthat allow him or her to reach out and take hold of this social fabric. (p. 1084)

Early disruption of the development of the social

brain, the neuroanatomical structures supporting

social information processing, is considered by Pel-

phrey to be the primary factor leading to the develop-ment of ASD. Such abnormal brain development

interferes with the infant’s ability to make use of oppor-

tunities for social reciprocity to develop the capacity

for social engagement and communication (Pelphrey

et al., 2011).

For Dawson (2008) and Dawson et al. (2005), the

numerous dif culties involving reduced social engage-

ment, such as problems with face processing, are con-

sidered to be secondary to a fundamental impairment

Figure 3. (a) In vulnerable children, several processes interact in a nonlinear manner: neurobiological factors, the experience of

environmental deprivation, the resulting psychological stress, and allostatic overload. Through maladaptive coping and neuro-

plasticity this interaction leads to ASD. (b) In contrast, interventions that are helpful in relieving the pathological contributions

of any of these interacting factors can contribute to the alleviation of ASD through adaptive coping and neuroplasticity.



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in social motivation that leads to decreased attention

to and engagement with people. Furthermore, as men-

tioned earlier, Dawson (2008) has developed a model

whereby genetic and environmental risk factors can

lead to risk processes: for example, an altered pattern

of child – caregiver interactions, which heighten the

underlying vulnerabilities to develop ASD. Suchaltered interactions with the environment interfere

with the child’s experiencing essential social and pre-

linguistic input, and result in functional environmental

deprivation. This deciency hinders the development

of social and linguistic brain circuits, further amplify-

ing the effects of early risk factors (Dawson, 2008).

The second group is composed of those who

emphasize the role of excessive fear in leading to the

deprivation of necessary social and emotional experi-

ence. Both Perry (Perry, 2006; Szalavitz & Perry,

2010) and the Markrams, who developed the Intense

World Theory of autism (Markram, Rinaldi, &

Markram, 2007; Markram, 2010; Markram &Markram, 2010), concur that sensory overload, heigh-

tened fear, and increased stress could lead to ASD

symptoms, including social withdrawal and impaired

interactions, as well as repetitive behavior. These mala-

daptive strategies for coping with excessive fear lead to

deprivation of key social experiences necessary for

development. For Perry (Szalavitz & Perry, 2010),

with the lack of social experiences, which “exercise”

the neuronal pathways of the social brain, this brain

network “atrophies” like a muscle. Perry concludes

that, as with neglected children, extreme stress and

deprivation of timely appropriate social stimulation

may be the cause of the social problems seen in ASD.

Schultz, Kohls, and Chevallier (2012) provide a

bridge between the group that focuses on the role of

primary dif culties in social processes leading to the

experience of environmental deprivation, and the

second group, which focuses on the role of excessive

fear. Schultz and colleagues highlight the nding of a

high prevalence of anxiety as an associated symptom

in autism and emphasize that anxiety has an aversive

inuence on motivation and behavior. Dawson (Sulli-

van, Stone, & Dawson, 2014) also affords a link

between these groups with an emphasis on the impor-

tance of both positive social engagement and arousalmodulation in addressing decits in social motivation.

A recent fMRI study involving pivotal response

treatment, which focuses on social motivation and

communication, of 10 preschool-aged children with

ASD (Ventola et al., 2015) provides some preliminary

support for both the social motivation hypothesis and

the intense world hypothesis. At baseline, in response

to a task involving biological motion perception, ve

children evidenced hypoactivation of the right pos-

terior superior temporal sulcus, which is involved in

social perception, and ve others, who had signicantly

greater dif culties with anxiety and behavioral control,

exhibited hyperactivation in the same area. Following

treatment, all children demonstrated substantial gains

in social communication skills, and both groups exhib-

ited more normal activation in the right posterior

temporal sulcus on post-treatment scans. However,consistent with the social motivation hypothesis, fol-

lowing treatment the hypoactivation group evidenced

increased activation in regions involved in reward path-

ways, the putamen and ventral striatum. In contrast,

after treatment the hyperactivation group, consistent

with the intense world theory, exhibited decreased acti-

vation in subcortical regions involved in regulating the

ow of stimulation to the cortex. Although no strong

conclusions can be drawn from this study, given the

small sample size, the ndings illustrate the possibility

that both factors – impaired social motivation and

excessive fear – may operate in ASD, perhaps to differ-

ent degrees in different children.

The experience of environmental deprivation leads to

toxic levels of early life stress (both psychological

and allostatic overload)

During the rst few months of life, the newborn faces a

major developmental challenge – maintaining homeo-

static regulation outside the womb. Both Bowlby

(1969, 1973) and Mahler (1968) emphasized the

importance of the infant’s relationship to her mother

for homeostasis, well-being, and survival, and under-

scored the infant’s experience of threat and intense

anxiety when the bond with the caregiver is disrupted.

Their work built on the earlier observations of Spitz

(1945, 1946), who had concluded that severe emotional

deprivation in a foundling home led to the deaths of 23

of 88 children up to the age of 2.5 years. Indeed, Perry,

Pollard, Blakley, Baker, and Vigilante (1995) have

argued that deprivation of critical experiences during

development may be the most destructive yet least

understood area of child maltreatment (p. 276).

According to the National Scientic Council on the

Developing Child (2012), since “responsive relation-

ships are developmentally expected and biologicallyessential, their absence signals a serious threat to a

child’s well-being, particularly during the earliest

years, and this absence activates the body’s stress

response systems” (National Scientic Council on the

Developing Child, 2012) (p. 1). The stress response

system evolved to help us cope with change and react

to emergencies thereby protecting us and “ensuring

our safety and survival” (McEwen & Lasley, 2002,

p. 4). Infants, even neonates, can experience intense

physical and psychological pain and can feel an event

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to be life-threatening (Coates, in press). For the infant,

separation from mother is considered to represent the

loss of a number of regulatory processes shaping infant

behavior, physiology, development, and adaptive

capacities (Hofer, 1995, 2014). Because the functioning

of the stress response system is critically regulated by

the child –

caregiver relationship, deprivation, evenmore than physical abuse, can cause disruptions of the

body’s stress response system (National Scientic

Council on the Developing Child, 2012).

Indeed, we are developing an appreciation for the

major role that the social environment plays in homeo-

static regulation and the sense of well-being. This is

evidenced by the recent use of the term “social allosta-

sis” to refer to the crucial inuence of interaction with

the social environment for regulation of the internal

state (Schulkin, 2011). For Eisenberger (2011), social

pain due to the loss of protective social bonds is con-

sidered to be among the most painful experiences for

humans. Because of the importance of social ties forinfant survival, “threats to social connection may be

just as detrimental to survival as threats to basic phys-

ical safety and thus may be processed by some of the

same underlying neural circuitry” (2011, p. 3). These

neural substrates of social pain are thought to

include the anterior cingulate cortex, which Eisenber-

ger suggests may be crucial for social motivation.

While “homeostasis” refers to our need to maintain

a stable internal physiological state, the term “allosta-

sis” is used to emphasize that our systems of stress

response help provide stability for the body through

their ability to adjust themselves to actively cope with

changes in the environment (McEwen & Lasley,

2002). “Allostatic load” or “overload” refers to the

pathological process that occurs when the protective

allostatic response functions improperly and causes

damage due to chronic mobilization of the body’s

stress response system (McEwen, 2012; McEwen &

Lasley, 2002). Children, who are chronically perceiving

and experiencing deprivation due to neurobiological

decits (not actual parental neglect), are likely experi-

encing a high allostatic load, which must be toxic.

The term “toxic stress” has been used in the child

development literature to refer to the process of

“strong, frequent, or prolonged activation of thebody’s stress management system” … often provoked

by stressful events that are “chronic, uncontrollable,

and/or experienced without children having access to

support from caring adults” (National Scientic

Council on the Developing Child, 2005/2014, p. 2).

Over 45 years ago Mahler (1968) brought the

experience of environmental deprivation and early

life stress together. In her theory, ASD results from a

deciency in the infant such that he is unable to per-

ceive and use the mother for homeostatic regulation,

resulting in a felt absence of the mother. This percep-

tion of early deprivation is experienced by the infant

as a threat to survival and leads to traumatic anxiety

that, in a vicious circle, further interferes with the

infant’s experience of having a protective parent. The

autistic syndrome is thus seen to represent the child’s

defensive use of emergency “

maintenance mechan-isms” (Mahler, 1968, p. 52) felt to be essential for sur-

vival. In keeping with this perspective, Hofer (1995)

has emphasized the intertwining of the physiological,

nonverbal responses to maternal separation and loss

with the later developing symbolic levels of respond-

ing, both of which contribute to the formation of

mental representations of signicant others. In fact,

Hofer states that such events take place “in us simul-

taneously at molecular, cellular, organ systems, cogni-

tive/emotional, and experiential levels” (2014, p. 9).

In discussing the experience of social deprivation in

autism, Schulkin (2011) suggests that the social iso-

lation experienced in autism perhaps provokes “a pro-pounded sense of fear that goes along with the

isolation” (p. 3). Since, as Loman and Gunnar (2010)

have emphasized, deprivation and disruptions in par-

ental care are particularly powerful sources of early

life stress, the neurobiologically based experience of

social and emotional deprivation in ASD can certainly

be considered a form of toxic stress which can lead to

allostatic overload. Again, it is important to emphasize

that the traumatic effects of early life stress would

necessarily include not only disruption of the body’s

functioning, but also maladaptive coping behaviors

as well as a pathological foundation for the developing

child’s internal world of human relationships.

The interaction between deprivation and allostatic

overload, in the context of predisposing

neurobiological factors, drives maladaptive

neuroplasticity and leads to the underlying structural

and functional impairments of ASD

Thompson and Levitt (2010) recently proposed that

allostatic overload during early development may

underlie neurodevelopmentally based psychiatric dis-

orders. This is in keeping with McEwen’s assertionthat “ … the revelation that the brain could be the

target as well as the initiator of the stress response

opened the door to understanding many of the pro-

blems and illnesses associated with allostatic load”

(McEwen & Lasley, 2002, p. 54).

Since thoughts and emotions can activate the stress

response (McEwen & Lasley, 2002; Sapolsky, 1998,

2010), psychological and general biological factors

interact to either exacerbate or ameliorate the patho-

logical effects of chronic stress on the function of the



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brain. In fact, as I will review here, converging evi-

dence indicates that early life stress and allostatic over-

load interact with the neurobiological factors and

processes central to autism in a circular fashion, hin-

dering their development and functioning which in

turn leads to increased stress. As noted earlier, the

brain in ASD is the target of both biological andpsychological stress as well as the initiator of the

stress response (McEwen & Lasley, 2002). Through

maladaptive neuroplasticity this interaction then con-

tributes to the progression to ASD.

McEwen (2003) linked unstable parent – child

relationships to allostatic overload and depression

that leads to further allostatic load and structural

changes in the brain. I suggest that a similar process

happens with autism. In describing the process of allo-

static load, McEwen (2006) emphasizes the nonlinear

interaction among several systems and processes includ-

ing psychological stress, the HPA axis, the autonomic

nervous system, the immune system, inammation,and the metabolic system including the mitochondria

and oxidative stress (see Figure 4). Indeed, these very

factors have been implicated in ASD.

While oxidative stress and mitochondrial dysfunc-

tion have been found to be involved in the pathophy-

siology of ASD (Gu, Chauhan, & Chauhan, 2014),

inammation has been emerging as an area of particu-

lar interest and will be briey considered here.2 A

number of years ago, Vargas, Nascimbene, Krishnan,

Zimmerman, and Pardo (2005) demonstrated the pres-

ence of active neuroinammation in the brain of

patients with ASD, as well as marked activation of

astroglia and microglia along with a signicant increase

in pro-inammatory cytokines in the cerebrospinal

uid. Since then the role of the immune system and

inammation in ASD has been further explored and

developed by a number of researchers, including

Martha Herbert (Herbert & Weintraub, 2012) whose

work will be described in more detail below. Recently,

Pramparo et al. (2015) found dysregulation of

immune and in

ammation gene networks in toddlerswith ASD compared to typically developing toddlers

and toddlers with other developmental delays who

were studied around the time of the typical emergence

of the rst clinical risk signs of ASD. Finally, two

recent studies not involving individuals with ASD may

nevertheless be relevant to our understanding of

autism. Eisenberger and colleagues (Moieni et al.,

2015a) found evidence that inammation interferes

with social cognitive processing and can impair the

ability to accurately understand emotional information

from others. Thus, one process involved in allostatic

overload, inammation, has been found to interfere

with an essential aspect of social interactions, a funda-mental area of impairment in autism. Furthermore,

this same group (Moieni et al., 2015b) found that indi-

viduals who are more sensitive to social disconnection

(such as this model proposes for ASD) show enhanced

pro-inammatory responses and up-regulation of

genes related to inammation.

In a literature review exploring the possibility that

autism is a stress disorder, Morgan (2006) found that

neurobiological factors involved in the stress response

are remarkably similar to those involved in autism.

Such factors include the HPA axis, the autonomic

nervous system, the locus coeruleus-noradrenergic

(LC-NE) system, and the amygdala as well as neuro-

modulators and neurotransmitters such as the

opioids. Furthermore, Herbert and Sage (2013)

emphasize that a major role for stress in ASD is

nding a growing level of support from both clinical

experience and research. For example, Hirstein,

Iversen, and Ramachandran (2001) suggest, based on

a study of skin conductance in autistic children, that

a child with ASD might prefer sameness and routine,

and engage in self-stimulating behavior, to calm a

hyperactive sympathetic autonomic nervous system.

In addition, from a study of skin conductance in

ASD children compared to typically developing chil-dren, Chang et al. (2012) proposed that in ASD, high

sympathetic reactivity to sound may lie beneath pro-

blematic responses to sound.

Naviaux (2014) has proposed a model of ASD as a

response to threat focused at the level of the cell. In this

model, the cell danger response, the metabolic

response protecting cells as well as the entire organism

from threats (including psychological trauma, which is

signicant in the present discussion), leads to ASD

through the disruption of mitochondrial functioning.

Figure 4. The same factors that interact to produce allostatic

overload, as emphasized by McEwen (2006), have also been

implicated in ASD.

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While human trials have not been completed, treat-

ment aimed at the level of mitochondrial function

and purine metabolism, single-dose antipurinergic

therapy with suramin, has been found to reverse

autism-like metabolism and behaviors in a mouse

model of autism (Naviaux et al., 2013; 2014).

Genetic and epigenetic mechanisms

Recent evidence suggests that genetic factors can inter-

fere with the functioning of the social brain and

emotional experience through disruptive effects on

the functioning of crucial brain regions, neural path-

ways, and neuromodulators. Such interferences will

adversely impact emotional regulation (Mazefsky, Pel-

phrey, & Dahl, 2012) and parent – child interactions

(Dawson, 2008). In addition, Dawson (2008) proposes

that the resulting altered interactions between child

and parents might lead to epigenetic changes whichamplify the inuences of autism susceptibility genes.

Indeed, it is now generally accepted that genetic

factors play a pivotal role in autism (Amaral et al.,

2008a; DiCicco-Bloom et al., 2006). The siblings of

autistic individuals are over 20 times more likely to

have ASD than the general population, and apparently

unaffected siblings have been shown to share with the

autistic sibling similar brain responses to certain

stimuli, including such psychologically meaningful

stimuli as the facial expression of emotion (Belmonte,

Gomot, & Baron-Cohen, 2010; Dalton et al., 2005;

Spencer et al., 2011).

Genetic factors can interfere with the development

and functioning of the brain and can (as in Figure 3a)

“disrupt neural systems that process cognition and

social behaviors” (Amaral et al., 2008a, p. 385).

Some genetic abnormalities may disrupt synaptic for-

mation and function (neuroligin/neurexin) and there-

fore produce widespread interference (Amaral et al.,

2008a). For example, variants in the autism risk gene

CNTNAP2 (a member of the neurexin superfamily)

have been found to predispose an individual to

autism through modulation of frontal lobe connec-

tivity, including increased connectivity within the

frontal lobe and decreased connectivity with otherparts of the brain (Scott-Van Zeeland et al., 2010).

This nding is of obvious importance since the

frontal lobe is crucial for a number of higher order cog-

nitive, social, and communication functions and is

implicated in the mirror neuron system as well as in

joint attention (Mundy, 2003). In fact, Geschwind

and Levitt (2007) suggest that autism spectrum dis-

orders be considered disconnection syndromes, pro-

posing that “disconnection of dorsolateral prefrontal

regions and anterior cingulate cortex from other

regions necessary to develop joint attention in early

infancy, which is the foundation of language and

social behavior, would probably have widespread

reverberations during development” (pp. 105 – 106).

Furthermore, these genetic factors can be modied

by social conditions and stress. Chronic early life

stress has been found to lead to long-lasting epigeneticalterations that negatively impact the stress response

system and development and, in addition, increase the

risk for a number of psychiatric and physical disorders

(National Scientic Council on the Developing Child,

2010). In addition, recent ndings in human social

genomics indicate that certain genes are subject to regu-

lation by different social – environmental conditions,

such as social isolation (Slavich & Cole, 2013). For

example, social stress has been found to regulate inam-

matory gene expression (Powell et al., 2013).

Environmental factors

Recent evidence showing that monozygotic concor-

dance rates are lower and dizygotic rates are higher

than previously believed for ASD has been considered

to highlight the importance of the prenatal and early

postnatal environment for autism susceptibility – esti-

mated to be about 55% – along with moderate genetic

heritability (Hallmayer et al., 2011; Szatmari, 2011).

These nongenetic risk factors are hypothesized to

include maternal illnesses during pregnancy, environ-

mental toxins during pregnancy, maternal – fetal immu-

noreactivity, parental age, low birth weight, and

twinning (Hallmayer et al., 2011; Szatmari, 2011).

The risk to children posed by environmental toxins

is of particular concern since there is much support for

the idea that the developing brain is extremely vulner-

able to the impact of toxins (Herbert & Weintraub,

2012). The evidence that genetic factors in ASD can

heighten the adverse effects triggered by exposures

(Herbert, 2010b; Herbert & Weintraub, 2012; Pessah

& Lein, 2008) makes the threat due to environmental

toxins of even greater concern. Herbert (2005) has pos-

tulated that environmental toxins could contribute to an

increased “excitation – inhibition ratio” in ASD and that

“the degree of environmental exposure may affect bothwhether genetic vulnerability turns into disease and how

severe this disease becomes” (p. 2). Furthermore,

McEwen and Tucker (2011) suggest that the network

for the stress response provides a pathway through

which psychosocial stress may interact with toxins and

lead to allostatic load, thereby increasing the health

risks conferred by environmental exposures.

In light of the role that the experience of threat and

heightened anxiety may play in ASD, it is signicant

that prenatal stress, including factors such as prenatal



11/41

exposure to hurricanes and tropical storms, has been

associated with an increased risk of ASD (Kinney,

Munir, Crowley, & Miller, 2008; Kinney, Miller,

Crowley, Huang, & Gerber, 2008). In a similar vein,

Roberts, Lyall, Rich-Edwards, Ascherio, and Weiss-

kopf (2013) found an increased risk of autism in chil-

dren whose mothers had been exposed to childhoodabuse with the risk for autism increasing directly with

the severity of abuse. Finally, Baron-Cohen et al.

(2015) found elevated levels of fetal cortisol (a

central component of the stress response) as well as

other fetal steroidogenic activity in autism and con-

cluded that fetal steroid hormones may play an impor-

tant role in “epigenetic fetal programming mechanisms

for autism” (p. 8).

Neuroanatomy

As in other areas in ASD, the evidence for functionalor structural neuroanatomical considerations in indi-

viduals with ASD is certainly not clear-cut. Amaral,

Rubenstein, and Rogers (2008a) emphasize that ASD

does not involve a single region of the brain, and

suggest that there may be phenotypic variations in

brain pathology. Many brain areas and certain types

of neurons play a signicant role in social functioning,

including the anterior cingulate (Di Martino, Ross

et al., 2009; Di Martino, Shehzad et al., 2009), the

anterior insula (Di Martino, Ross et al., 2009; DiMar-

tino, Shehzad et al., 2009; Uddin & Menon, 2009),

mirror neurons (Ramachandran & Oberman, 2006;

Vivanti & Rogers, 2014), and Von Economo neurons

(Allman, Watson, Tetreault, & Hakeem, 2005), and

these have all been implicated in ASD. Here, I will

conne the discussion to the mirror neuron system,

the amygdala, the fusiform face area (as it relates to

the amygdala), and the cerebellum.

First, Ramachandran has proposed that the mirror

neuron system, a large interconnected circuit which

includes small groups of cells in many brain regions,

evolved in order to form internal models of others’

actions and intentions as well as to develop self-rep-

resentations and self-awareness (Ramachandran,

2011; Ramachandran & Oberman, 2006; Oberman &Ramachandran, 2007).3 Furthermore, he proposed

that the functions of mirror neurons, including

empathy, understanding others’ feelings, actions and

intentions, imitation, and the use of language for

social communication, are disrupted in ASD because

of a potentially reversible dysfunction in the mirror

neuron system (Ramachandran, 2011; Ramachandran

& Oberman, 2006; Oberman & Ramachandran, 2007).

Also, Ramachandran (2011) suggested possible inter-

actions between the mirror neuron system and neural

pathways (including the amygdala) involved in deter-

mining the emotional salience or potential signicance

of others.

In addition, Gallese (2006) and Cossu et al. (2012)

consider early impairment of the mirror neuron system

and the subsequent dif culties in motor planning and

in understanding the goals of others’

actions tounderlie many of the dif culties in social cognition

manifested by children with ASD. However, from a

different vantage point, Vivanti and Rogers (2014)

consider the mirror neuron system in the context of

the positive effects of the Early Start Denver Model

on children with ASD. They suggest that impairments

in mirror neuron system functioning might be the

result, rather than the cause, of early dif culties in

social interactions. Furthermore, similar to the model

of ASD presented here, they propose that a pathologi-

cal cascade results in which the dysfunction of the

mirror neuron system then leads to further impairment

at the level of social interactions that, however, couldrespond to early interventions such as Early Start

Denver Model (ESDM) which will be described later.

Next, the amygdala, a key mediator of emotional

memory, is a central node in the fear circuits of the

brain, involved with the evaluation of stimuli for

threat, the detection of danger, fear conditioning,

fear extinction (critical to the possibility of change),

and the evaluation of facial expressions (LeDoux,

2000). In addition, the amygdala is linked to the

emotional processing of sensory information and

plays a role in moderating social interactions

(Amaral, Rubenstein, et al., 2008a; Meaney,

LeDoux, & Liebowitz, 2008). The amygdala also pro-

jects to the LC-NE system (LeDoux, 2000), a crucial

component of the stress response system, which has

been considered to play a central role in ASD

(Mehler & Purpura, 2008).

While earlier research led to an “amygdala theory

of autism” which postulated a hypoactive amygdala

(Baron-Cohen et al., 2000), more recent research sup-

ports a model of amygdala hyperactivity (Dalton et al.,

2005; Dalton, Nacewicz, Alexander, & Davidson,

2007; Nacewicz et al., 2006). When processing faces,

subjects with autism were found to have hypoactiva-

tion in the fusiform gyrus and increased activation inthe amygdala. This nding was considered to suggest

a heightened emotional response to gaze xation and

a hypersensitivity to social stimuli in autism (Dalton

et al., 2005). Such disruptions in processing of social

and emotional stimuli could lead to the problems in

social behavior associated with ASD (Rossman &

DiCicco-Bloom, 2008). Recently, Kleinhans et al.

(2009) found that, in response to socially relevant

stimuli, adults with ASD showed reduced neural

habituation in the amygdala and concluded that the

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social decits observed in ASD may be related to sus-

tained amygdala arousal.

The cerebellum is another brain region thought to

play a signicant role in social information processing

(Cozolino, 2006) and to be of importance in ASD,

since it is involved in higher order functions including

attention regulation and speech (Rossman & DiCicco-Bloom, 2008). Both neuroanatomically and

functionally, the cerebellum (Courchesne, Webb, &

Schurmann, 2011) has been consistently found to be

abnormal in ASD patients. In fact, the gene

ENGRAILED2, which regulates cerebellar develop-

ment, has been considered to be an ASD-susceptibility

gene (Rossman & DiCicco-Bloom, 2008). Interest-

ingly, Cozolino (2006) considers the cerebellum to be

a “hub of social processing” and focuses primarily on

the cerebellum in his consideration of the social dif -

culties found in autism. In addition to the cerebellum’s

role in the coordination of motor function and in

balance and equilibrium, he suggests that the cerebel-lum may be important in the timing and modulation

of language and affective regulation. According to

Cozolino (2006), cerebellar damage “appears to

disrupt many of the very functions that serve as the

basis for vital interpersonal attunement” and to inter-

fere with the development of empathy and interperso-

nal relationships (p. 288). Obviously, this suggests one

pathway whereby impaired neurobiological function-

ing could contribute to a pathological experience of

isolation and danger and, thus, to the ultimate devel-

opment of the ASD syndrome.

Finally, in discussing the role of the cerebellum in

autism, Aamodt and Wang (2011) emphasize that

“the cerebellum is essential for translating sensory

events, such as the sight of a mother’s smiling face

into a message with social import” and therefore that

“brains of autistic children may have trouble translat-

ing everyday social experiences into a meaningful

signal – thereby, depriving themselves of a necessary

experience early in life” (p. 234).

These structural differences found in autism may

be related to emotional stress, at least in part. David-

son and McEwen (2012) note that human research

suggests that early life stress leads to structural

changes in the brain. In particular, areas of the pre-frontal cortex show decreased volume while there is

an increase in amygdala volume. Such changes could

interfere with the development of emotional regulation

which is thought to involve interactions between the

prefrontal cortex and amygdala (Davidson &

McEwen, 2012; Ochsner & Gross, 2005; Wager, David-

son, Hughes, Lindquist, & Ochsner, 2008). Further-

more, Davidson and McEwen (2012) point out that

early hypertrophy of the amygdala caused by early

life stress may be followed by later atrophy (Davidson

& McEwen, 2012; McEwen, 2006) and that this

pattern may occur in autism (Davidson & McEwen,

2012; Mosconi et al., 2009; Nacewicz et al., 2006; Tot-

tenham and Sheridan, 2010).

In addition, Teicher, Polcari, Andersen, Anderson,

and Navalta (2003) conclude that early life stress is

likely to disrupt the functioning of the cerebellarvermis. Schmahmann (2010) considers the vermis to

be part of the limbic cerebellum, an area which he

suggests may play a central role in ASD. In an fMRI

study of post-institutionalized children who had been

raised in foreign orphanages and adopted, Bauer,

Hanson, Pierson, Davidson, and Pollack (2009)

found that these children had smaller volume

superior-posterior cerebellar lobes, which was related

to poorer outcomes on tests of planning and memory.

Neuromodulators and neurotransmittersA number of neurotransmitters and neuromodulators

have been implicated in ASD, including oxytocin, glu-

tamate, dopamine, norepinephrine, serotonin, acetyl-

choline, and the opioids (Panksepp, 1979). Indeed,

the LC-NE system, a widespread neuromodulatory

system which plays a major role in the stress response

system is the central component in a recent model of

ASD; Mehler and Purpura (2008) propose that core

autistic symptoms are the result of developmental dys-

regulation of a functionally intact LC-NE system

which is transiently restored by fever. Here, I will

limit the discussion to oxytocin and glutamate, both

of which are likely to be involved in crucial ways.

First, based on their roles in forming social attach-

ments in nonhuman mammals, the neuromodulators

oxytocin and vasopressin have long been considered

to be potential factors in ASD (Insel, 1997). A

growing body of evidence has demonstrated oxytocin’s

role in facilitating human connectedness. In healthy

human subjects, oxytocin has been shown to improve

the ability to understand the mental state of others

from subtle social cues (Domes, Heinrichs, Michel,

Berger, & Herpertz, 2007), reduce amygdala responses

to angry, fearful, and happy facial expressions (Domes

et al., 2007), increase focus on the eye region of humanfaces (Guastella, Mitchell, & Dadds, 2008), and

increase trust (Kosfeld, Heinrichs, Zak, Fischbacher,

& Fehr, 2005). Moreover, in healthy subjects, oxytocin

receptor (OXTR) gene variation is linked to increased

stress reactivity and decreased empathy (Rodrigues,

Saslow, Garcia, John, & Keltner, 2009).

At this point, there is considerable interest in

research directly exploring the connection between

oxytocin and ASD. Variations in the OXTR gene

have been linked to an increased risk of autism



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(Gregory et al., 2009; Jacob et al, 2007; Lerer et al.,

2008; Liu et al., 2010; Wu et al., 2005). Another line

of evidence is related to clinical trials investigating

the effects of intravenous or intranasal oxytocin in

individuals with ASD (Insel, 2010). Initial trials were

only suggestive, showing reduced repetitive behaviors

(Hollander et al., 2003), increased recognition of social information (Hollander et al., 2007), improved

recognition of emotion in others (Guastella et al.,

2010), and increased social approach and comprehen-

sion (Andari et al., 2010).

However, two recent studies involving oxytocin

and ASD are of particular relevance for the model pre-

sented here. First, Feldman (Singer, 2012) found that

children with ASD had lower baseline levels of periph-

eral oxytocin. However, after the children with autism

played with a parent for only 20 minutes, their oxytocin

levels rose and became similar to those of controls for

approximately 40 minutes (Singer, 2012). Next, in

more denitive research to be described later, in anfMRI study, Gordon et al. (2013) found that the

administration of intranasal oxytocin enhanced func-

tioning of the social brain in children with ASD.

Next, excessive glutamate, the primary excitatory

neurotransmitter, leads to a general overreactivity to

sensory input (Herbert & Weintraub, 2012). Gluta-

mate seems to play a major role driving excitotoxicity,

a pathological process in which excessive levels or

activity of glutamate and other excitotoxins damage

or kill neurons. Also, an imbalance between excitation

and inhibition related to glutamatergic dysregulation

has been proposed to modulate numerous risk

factors in ASD (Evers & Hollander, 2008) and may

play a critical role in causing autism (Herbert & Wein-

traub, 2012).

Several lines of research indicate that these neuro-

transmitter systems may be affected by allostatic

load in autism. Chronic stress, especially through the

action of glucocorticoids, affects the glutamatergic

synapse, alters glutamate neurotransmission, and

impairs functioning of the prefrontal cortex (Popoli,

Yan, McEwen, & Sanacora, 2011). Oxytocin and vaso-

pressin neuropeptide systems have been shown to be

affected by early neglect and deprivation in children

reared in foreign orphanages and later adopted(Wismer Fries, Ziegler, Kurian, Jacoris, & Pollack,

2005). In addition, the structure and function of the

LC-NE system is regulated by diverse stressors and is

considered to play a signicant role in stress-related psy-

chiatric disorders (Valentino & Van Bockstaele, 2008).

Finally, allostatic overload, both acute and

chronic, leads to both structural and functional

changes in serotonergic and dopaminergic neural

systems as well as in the LC-NE system (Beauchaine,

Neuhaus, Zalewski, Crowell, & Potapova, 2011).

Neural networks, connectivity, and sensory

processing

A broad array of factors – ranging from the micro-

scopic to the psychological – involved in neural net-

works, connectivity, and processing are implicated in

the development, maintenance, and treatment of

ASD. Minshew, Williams, and McFadden (2008)have developed a highly useful model, the “complex

information processing-disconnectivity-neuronal organ-

ization model of autism” (p. 383). While there are

differences, Minshew and colleagues note certain simi-

larities to other conceptualizations such as the “devel-

opmental disconnection syndrome” (Geschwind &

Levitt, 2007) mentioned earlier. The model presented

by Minshew et al. (2008) includes cortical connection

disturbances that, in high-functioning ASD, primarily

involve increased local frontal connectivity and les-

sened connectivity among neural systems. This leads

to impaired complex information processing, includ-

ing disturbances in processing social information thatare thought to underlie the social impairments seen

in ASD. For example, Kana, Keller, Cherkassky,

Minshew, and Just (2009) found a functional under-

connectivity between frontal and posterior regions in

the brain during the attribution of mental states in

adults with autism. In addition, Bachevalier and Love-

land (2006) have presented evidence that dif culties in

self-regulation of social-emotional behavior in ASD

are related to dysfunction of the orbitofrontal – amyg-

dala circuit in the brain. Finally, a recent fMRI study

involving high-functioning adolescents with ASD

compared to normal adolescents found signi

cantdecreases in connectivity between three regions of the

social brain in those with ASD (Gotts et al., 2012).

Specically, the affective processing limbic region

was less connected with regions more involved in the

language/communication aspects of social behavior

and regions supporting socially relevant sensorimotor

processes, that is, the visual perception of “socially rel-

evant form and action” (p. 11). Adolescents with ASD

who showed the greatest decreases in connectivity

among the social brain regions were found to have

more severe social symptoms. The “thinking brain”

does indeed seem to be disconnected from the

“feeling brain” (Sherkow, personal communication,May 20, 2007).

In focusing on the autistic mind, Bryson (2005)

links information processing to emotion and thought.

She concludes that in autism, the mind is hypersensi-

tive to sensory stimulation and therefore vulnerable

to sensory overload; the mind then attempts to adapt

to this overarousal by narrowing the focus of attention.

This hypersensitivity extends to the emotions, which

can be experienced as overwhelming and – because

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of this heightened intensity and dif culties in reecting

on thoughts and experiences – are poorly modulated

by thought. Thus, emotionally signicant events lead

to narrowed attention and a heightened tendency to

engage in repetitive (self-regulating) behaviors. She

adds that “under such circumstances, positive

emotion can readily be experienced as aversive”

(p. 41). This observation is of utmost importance in

understanding the experience and behavior of individ-

uals with ASD, which can seem so paradoxical, for

example, pleasurable interactions are often followed

by disruptions.

Supporting the model proposed in this paper, a

series of ndings link early life stress with changes in

connectivity. First, both acute, uncontrollable stress

and chronic stress interfere with synaptic functioning

and disrupt emotional regulatory networks leading to

decreased modulation of emotions by the prefrontal

cortex and increased amygdala activity (Arnsten,

Mazure, & Sinha, 2012). Furthermore, early life stressis associated with alterations in cortical network con-

nectivity in brain regions associated with social cogni-

tion and emotional regulation (Teicher, Anderson,

Ohashi, & Polcari, 2014).

Early neglect is also associated with disruptions in

white matter directional organization in the PFC and

in white matter tracts connecting the PFC and the tem-

poral lobe (Hanson et al., 2013).

In summary, autism is widely considered to involve

increased local connectivity within brain regions and

decreased connectivity among more distant brain

regions, leading to problems in processing tasks requir-

ing “large, highly integrated brain networks such as

language and social-emotional functions” (Williams,

2008, p. 14). Supporting this conclusion, aberrant

development in white matter ber tracts from 6 to 24

months in infants with autism has recently been

found, suggesting that differences in white matter

pathways could precede the manifestations of ASD

symptoms (Wolff et al., 2012). In addition, eight 12-

year-old boys with ASD were shown to have decreased

white matter connectivity in sensory pathways, along

with impaired white matter connectivity in tracts

subserving social-emotional processing (Chang et al.,

2014).

Early deprivation, traumatic psychological stress and

allostatic overload can therefore account for the

symptoms of ASD, as well as the experience of the

person with ASD

As noted above, one of the major developments in

neurobiology has been the dramatic rise in our under-

standing of the brain’s capacity to change –

neuroplasticity. According to Hebb’s Law (Hebb,

2014), “neurons that re together wire together”

(Shatz, 1992, p. 21). Thus, the brain operates in a

“use it or lose it,” fashion referred to as “use-depen-

dent plasticity” (Cozolino, 2010, p. 325). Considering

brain development to be self-organizing and using a

dynamic systems theory model, Lewis (2005) describescortical developmental change as a reorganization of

synaptic connections between neurons, which change

and stabilize based on neuronal activity. Stabilization

in the cortex and limbic system occurs because of

synaptic sculpting so that these synaptic structural

changes become self-perpetuating (Lewis, 2005). The

mechanism of “cascading constraints,” such that

early developmental structures limit characteristics of

structures evolving later, contributes to the develop-

mental trajectory of an individual (Lewis, 2005).

Thus, alongside of the potential for progressive devel-

opment of the brain in an optimal fashion, there

exists the possibility for maladaptive plasticity orpathological brain organization (Helt et al., 2008).

Allostatic overload represents an important

pathway contributing to maladaptive neuroplasticity

in ASD (Herbert & Weintraub, 2012). For example,

Schore (2014) has suggested that allostatic overload

during critical periods of neuronal development

might interfere with the development of neurons and

brain circuits that play crucial roles in emotional regu-

lation and social interactions. In addition, an emerging

body of work on depression has particular relevance to

this model of ASD. The cognitive model of depression

has evolved to include the interaction of genetic and

neurobiological factors with early traumatic experi-

ences and cognitive factors including cognitive distor-

tions and dysfunctional beliefs (Beck, 2008). In

addition, the role of early life stress, inammation,

and allostatic overload in neuroprogression and the

pathway to the development of mood disorders has

received considerable attention recently and sparked

interest in the development of novel biomarkers as

well as prevention and intervention strategies related

to increasing both physiological and psychological

resilience (Walker et al., 2014).

One asset of the model I propose here is its ability

to provide an integrative explanation of the develop-mental progression to ASD, one that involves both

neurobiological and psychological elements “within”

the child, as it were, as well as interactions with care-

givers. Neurobiological factors and processes, environ-

mental deprivation, psychological stress, and

biological stress or allostatic overload all interact in a

nonlinear way and contribute to the nal outcome

(see Figure 3a).

I suggest that this complex process is as follows.

Neurobiological factors make a child vulnerable to



15/41

respond aversively to subjective experience, for

example, overarousal in response to novel, unpredict-

able stimuli – including, crucially, human interaction

or social information (Dawson & Lewy, 1989). This

aversive response disrupts the functioning of the

social brain and, in a circular way, further impairs

adaptive social interactions. The subsequent impairedsocial information processing and social motivation

negatively impacts both the child’s relationships with

others and subjective psychological experience. Thus

deprived of appropriate social-emotional input and

the neurobiological consequences of that input, the

child fails to experience mother’s comforting presence

and protection, and, instead registers heightened

anxiety, stress, and a sense of threat (Mahler, 1968).

Even with loving reactions from parents, the child

may make inaccurate and pathological meanings of

these experiences and conclude that human inter-

actions are not only unrewarding, but also dangerous

and frightening and must be avoided. Thus, neurobio-logical elements might obstruct the infant’s experience

of comforting and rewarding relationships with care-

givers and interfere with the child’s feeling a sense of

safety and calm well-being. Instead, the experience of

deprivation – the absence of human connections –

could lead to further overarousal, a sense of threat,

maladaptive coping, and toxic stress or allostatic

overload.

Moreover, the child’s efforts to make sense of and

cope with the experience of aloneness and danger

might lead to a defensive withdrawal from others and

to the development of psychological conicts regard-

ing relationships. What originates in the child as an

attempt at an adaptive response to perceived (not

actual) threat is truly maladaptive. Because of fear,

the child shuts out what he needs the most, loving

and helpful human interactions. For example, the

child could feel both a great need for emotional

contact with parents and, simultaneously, a dread of

such closeness. This heightened anxiety and fear sur-

rounding the world of people, and the ensuing social

isolation, both would further hinder accurate social

cognition and empathic accuracy and, to an even

greater degree, interfere with social motivation and

adaptive social interaction.In a vicious circle, the child’s self-regulating and

protective efforts could therefore make it more dif cult

for parents to help and, thereby, further constrain

adaptive parent – child interaction and the development

of the social brain. Thus, I suggest that these interlock-

ing neurobiological and emotional/psychological

impairments come together in a nal common

pathway leading to the various clinical manifestations

of the syndrome of ASD, both in its development and

maintenance (Singletary, 2009).

As noted above, in this model, stress from all

sources, including both emotional and biological

stress, plays a central role in the multiple processes

leading to the autistic syndrome. As Herbert and Wein-

traub (2012) suggest, at the cellular level, emotional

stress can trigger toxic processes, such as the activation

of microglia (a type of glial cell which plays a majorrole in the brain’s immune system) which drives oxi-

dative stress and triggers the release of immune chemi-

cals – chemokines and cytokines – that promote

inammation. In turn, at the circuit level, neuroinam-

mation can interfere with neural connectivity and

social cognition, which could exacerbate social with-

drawal and increase stress, which can further increase

neuroinammation. Through the actions of cortico-

tropin-releasing hormone and the sympathetic

nervous system, emotional stress can lead to immune

suppression and inammation in the entire body,

including the brain. Likewise, oxidative stress and

inammation can contribute to neuronal overexcitabil-ity and increased emotional stress.

Herbert and Weintraub (2012) thus outline the

decline into autistic functioning as follows: some

degree of genetic vulnerability plus increased

demands on the whole body from the environment

(toxins, infectious agents, poor nutrition, and stress)

leads to inammation and oxidative stress which inter-

fere with the functioning of the glia, including the

astrocytes. This produces still more oxidative stress

which further impairs glial functioning and leads to

an excessive level of neuronal excitation. A tipping

point then occurs when the allostatic load (the total

load of physical and emotional stress) is too great. At

this juncture astrocytic networks, which, as noted

above, are involved in brain information processing

as well as brain network coordination and connec-

tivity, begin to malfunction. This further impaired

astrocytic functioning then leads to excessive levels of

glutamate, sensory overreactivity, and impaired

complex information processing in the brain. Autistic

behaviors are the nal outcome of this pathway that

involves many different interlocking vicious circles,

including those formed by anxiety (Herbert & Wein-

traub, 2012).

The symptoms of ASD

In proposing this model of ASD arising from a vulner-

ability to experience social deprivation which is then

exacerbated by attempts to cope with the stress of

that deprivation, one of my main aims is to account

for the common cluster of ASD symptoms. A

number of researchers and clinicians have already

linked ASD symptoms with stress in various ways.

94 W.M. Singletary


16/41

Tustin (1994) considered ASD to be an infantile

version of a post-traumatic disorder with contributions

from both constitutional and environmental factors

which interfere with the mother – child interaction and

ongoing development (Tustin, 1990). More recently,

Kliman (2011) has also noted the symptomatic as

well as neurobiological similarities between autisticdisorders and post-traumatic stress disorder. Kins-

bourne sees autistic symptoms, including both repeti-

tive behavior as well as dif culties with social

communication and interaction, as attempts to avoid

or to self-regulate in the face of hyperarousal (Kins-

bourne, 1987, 2011; Kinsbourne & Helt, 2011).

Groden, Cautela, Prince, and Berryman (1994) high-

lighted the major role played by maladaptive coping

strategies in response to excessive stress and anxiety

in ASD. Schore (2014) has proposed that autistic

infants, because of early neurobiological dif culties

perhaps involving the right amygdala prenatally,

experience a chronic intense state of fear which persiststhroughout early childhood and may lead to the defen-

sive use of dissociation as well as to the development of

allostatic overload. Mahler (1968) also considered

ASD to represent maladaptive coping in response to

the traumatic experience of social and emotional

deprivation. And recently Mazefsky et al. (2013)

place maladaptive coping strategies and emotional

dysregulation at the heart of ASD.

Sapolsky (2010) outlines an adaptive response to

stress: seeking social support; trying to obtain a

reasonable degree of predictability, stability, and

control; and utilizing constructive outlets for frustra-

tion. It is striking that the symptoms of ASD represent

the opposite or a maladaptive form of coping (see

Figure 5). Instead of turning to others for social

support, the autistic child isolates himself. A reason-

able desire for predictability and stability is replaced

by repetitive behaviors and excessive demands for

sameness. The child with ASD requires absolute

control instead of a realistic sense of control.

Constructive outlets for frustration such as fantasy

and play are replaced by ts of rage and temper tan-

trums – a most maladaptive way to cope with over-

whelming stress.

Another line of evidence linking stress with the

symptoms of ASD is the clinical picture of neurotypi-

cal infants responding to stress and trauma. It must beemphasized that the experience of deprivation and

sense of threat in infants who develop ASD arises

from biologically based internal factors, and therefore

has a different outcome (ASD) from infants who do

not have this genetic and neurobiological vulnerability

and are subject to real external threat and trauma.

However, the defensive responses to deprivation and

early trauma in non-autistic infants may still indicate

similarities with the subjective experiences and defen-

sive or coping maneuvers found in ASD. Inspired by

the work of Spitz on maternal deprivation, Fraiberg

(1982) described a group of defensive behaviors in

infants from 3 to 18 months of age who had experi-enced extreme deprivation and threat. Of particular

interest is her description of avoidance of social inter-

action, including gaze aversion, beginning as early as

three months of age – approximately the age Jones

and Klin (2013) recently found for the onset of

decreased attention to eyes in infants later diagnosed

with ASD. Other defenses included freezing and ght-

ing. Fraiberg (1982) considered all of these to be based

on the biological model of “ight or ght.”

Coates’s (in press) description of the symptom clus-

ters in traumatized infants and Perry’s (Perry et al.,

1995; Perry & Pollard, 1998) description of basic

response patterns to threat are particularly relevant.

Coates describes a symptom cluster related to

“numbing of responsiveness,” and Perry notes a disas-

sociative response pattern; both involve social withdra-

wal and disengagement from the external world, which

correspond to the characteristic impairments in social

communication and interaction found in ASD. Both

also note a key role for hyperarousal, which has long

been considered to play a major role in ASD, as dis-

cussed earlier (Kinsbourne, 1987; Kinsbourne & Helt,

2011). Moreover, Coates’s description of the symptom

cluster related to re-experiencing the trauma through

compulsive play and repetitive re-enactment of thetrauma resembles the restricted and repetitive interests

and behavior found in ASD. For example, in my own

clinical experience, a 4-year-old boy with ASD who

was deathly afraid of separation from his parents

showed an extreme preoccupation with stop signs and

exit signs. This interest seemed to express his desire to

have absolute control over the comings and goings of

the people he needed most. His excessive preoccupa-

tions could be considered to represent a maladaptive

way of coping with the threat of loss.

Figure 5. Symptoms of ASD, such as social isolation and

repetitive behavior, are maladaptive ways to cope with

psychological stress, and represent the opposite of adaptive

coping mechanisms such as turning to others for social

support.



17/41

Finally, Porges’s body of work regarding polyvagal

theory links the early experience of threat, defensive

avoidance of social interaction, and withdrawal to

the symptoms of ASD through neurophysiological

pathways. In particular, he focuses on pathways for

autonomic arousal and social engagement. To

survive and develop optimally, humans must be ableto process sensory information from both the external

and internal environments in order to evaluate risk,

distinguish between friend and foe, determine

whether an environment is safe or dangerous, and

communicate and act in an adaptive way with the

social group (Porges, 2004/ 2011; Porges, 2009; Van

Der Kolk, 2011). This process, which Porges calls

“neuroception,” connects the evaluation of risk with

social behavior (Porges, 2004/ 2011). Once the process

of neuroception, which operates outside of conscious

awareness, determines whether people or situations are

safe or dangerous, either prosocial or defensive beha-

viors result as adaptive responses (Porges, 2004/ 2011).In order to form social bonds and lasting relation-

ships, we must be able to inhibit defensive strategies

and become socially engaged under conditions of

safety, for example, with the appearance of a loving

caregiver. The social engagement system depends

upon autonomic regulation of the muscles of the face

and head which play a major role in social and

emotional communication and interaction (Porges,

1994/ 2011, 2004/ 2011). These muscles collectively

“function as lters that limit social stimuli (e.g.,

observing facial features, listening to the human

voice)” and as “determinants of engagement with the

social environment” (Porges, 1994/ 2011, p. 220).

With the neuroception of safety comes behavior con-

ducive to social engagement: making eye contact,

making contingent facial expressions, vocalizing with

appropriate rhythm and inection, and a greater

ability to distinguish the human voice from back-

ground sounds (Porges, 2004/ 2011).

Porges (1994/ 2011, 2004/ 2011) suggests that there

is an intact, but functionally disrupted, social engage-

ment system in ASD. He raises the possibility that

faulty neuroception – an inability to assess accurately

whether the environment is safe or dangerous or a

person is trustworthy or not –

may be at the heart of the psychopathology of children with autistic spectrum

disorder, as well as those with reactive attachment dis-

order. Thus, in children with disrupted social engage-

ment systems, defensive behaviors may occur in safe

environments, and social engagement behaviors may

occur in risky environments.

Quite likely because of the experience of threat,

social engagement behaviors are frequently disrupted

in children with ASD. Porges posits that the neurocep-

tion of danger (whether from an internal or external

source) leads to d

an integrative model of autism spectrum disorder asd as a neurobiological disorder of experienced...

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