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Neuropsychoanalysis
An Interdisciplinary Journal for Psychoanalysis and the Neurosciences
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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
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8/17/2019 An Integrative Model of Autism Spectrum Disorder ASD as a Neurobiological Disorder of Experienced Environmenta…
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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: wsingletarymd@gmail.com
Neuropsychoanalysis, 2015
Vol. 17, No. 2, 81 – 119, http://dx.doi.org/10.1080/15294145.2015.1092334
http://-/?-mailto:wsingletarymd@gmail.commailto:wsingletarymd@gmail.comhttp://-/?-
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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.
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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.
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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
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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
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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
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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.
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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.
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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