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Anorexia nervosa – A noradrenergic

dysregulation hypothesis
B. Lask, K. Nunn

Medical Hypotheses

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 Medical Hypotheses xxx (2012) xxx–xxx

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Anorexia nervosa – A noradrenergic dysregulation hypothesis

Ken Nunn a, Ian Frampton b,d,e, Bryan Lask b,c,d,⇑
a
Westmead Children’s Hospital, Sydney, NSW, Australia
b
Gt. Ormond St Hospital, London, UK
c
Ellern Mede Eating Disorders Service, London, UK
d
Regional Eating Disorders Service, Oslo University Hospital, Norway
e
European Centre for Environment and Human Health, Truro, UK

a r t i c l e i n f o a b s t r a c t

Article history: Anorexia nervosa manifests a wide range of features which cannot fully be explained on the basis of
Received 6 January 2012 socio-cultural pressures to be thin, nor by starvation, nor dehydration. Evidence is emerging of a signif-
Accepted 16 January 2012 icant neurobiological contribution to its aetiology. However there has to date been no explanation for its
Available online xxxx
pathogenesis that integrates the previously identified genetic, neurobiological and socio-cultural contrib-
uting factors. In this paper we propose an empirically-based hypothesis that genetically determined nor-
adrenergic dysregulation, interacting with epigenetic factors, leads to high levels of anxiety, impaired
neuroplasticity and regional cerebral hypoperfusion. These, in combination, lead to insula dysfunction.
The resulting impairment in insula homuncular representation explains the pathognomonic body image
distortion. This distortion, combined with high levels of body-focused anxiety, gives rise to intense diet-
ing, noradrenergic precursor depletion, and initial reduction in anxiety. The subsequent rebound exacer-
bation of anxiety leads to a vicious cycle of maintenance. Novel treatment implications based on this
hypothesis are briefly considered.
Ó 2012 Published by Elsevier Ltd.

Introduction
Anorexia nervosa is a complex and life-threatening disorder
with a bewildering phenomenology stretching far beyond patho-
logical fear of weight gain and fatness, intense dieting and weight
loss [1]. Additional features, difficult to explain on the basis of star-
vation alone, include distorted body image, intense body-focused
anxiety, self-disgust, compulsive behaviour and altered informa-
tion processing – i.e. raised pain threshold, reduced sense of taste,
anosognosia, inability to integrate thoughts and feelings, poor vi-
suo-spatial memory, cognitive rigidity and weak central coherence
[2]. There is currently no effective first line treatment [3].
Environmental factors in the aetiology of anorexia nervosa are
insufficient to account for the disparate phenomena [4]. Nor could
they explain why the majority of individuals exposed to such fac-
tors fail to develop the illness. Twin studies have indicated that
additive genetic factors, as yet to be identified, contribute to previ-
ously recorded familial aggregation [5]. However, to date, there has
been no comprehensive explanation of the pathogenesis, complex
phenomenology and maintenance of anorexia nervosa. In our ear-
lier work we have proposed a model of insula dysfunction that ex-
plains much of the phenomenology of anorexia nervosa [2], but
⇑ Corresponding author at: Regional Eating Disorders Service, Oslo University
Hospital, Postboks 4956, Nydalen 0424, Oslo, Norway.
E-mail address: bryanlask@mac.com (B. Lask).
does not account for why there is insula dysfunction, nor for the
pathognomonic distortion of body image.
In this paper we develop this insula dysfunction model into a
hypothesis that attempts to explain the wide range of features of
the disorder, and specifically accounting for the insula dysfunction
and distorted body image. Furthermore, we propose a clear neuro-
biological system to interrogate. We believe that this hypothesis
fulfils the demands of necessity, sufficiency, specificity, empirical
derivation and refutability, as well as informing both future re-
search and treatment.
A noradrenergic dysregulation hypothesis
Fig. 1 provides a generic model of the aetiology and mainte-
nance of anorexia nervosa, illustrating the interaction between a
specific genetic profile, epigenetic phenomena, socio-cultural influ-
ences, precipitating and perpetuating factors.
However, elaboration is required of the specifics of the genetic
and neurobiological mechanisms that contribute to the develop-
ment of the unique characteristics of anorexia nervosa. Neuro-
transmitter studies have suggested that serotonin may play an
important part in the pathophysiology [6]. Such a pathway could
account for obsessionality, rigidity and perfectionism but does
not explain the wide range of other features.
We propose here a hypothesis that purports to explain the path-
ogenesis of the specific and unique features of anorexia nervosa

0306-9877/$ - see front matter Ó 2012 Published by Elsevier Ltd.

doi:10.1016/j.mehy.2012.01.033

Please cite this article in press as: Nunn K et al. Anorexia nervosa – A noradrenergic dysregulation hypothesis. Med Hypotheses (2012), doi:10.1016/
j.mehy.2012.01.033
2 K. Nunn et al. / Medical Hypotheses xxx (2012) xxx–xxx

Fig. 1. A generic model of the pathogenesis of anorexia nervosa.

Fig. 2. A noradrenergic dysregulation hypothesis.

(see Fig. 2). It is based upon a specific genetic profile, mediated by
epigenetic factors, that causes noradrenergic dysregulation. The
subsequent sympathetic overactivity, impaired neuroplasticity
and reduction of cerebral blood flow contribute to insula dysfunc-
tion. This in turn leads to inaccurate homuncular representation
and therefore distorted body image, the pathognomonic feature
of the resulting anorexia nervosa. Consequent starvation results
in nutritional depletion of noradrenergic precursors, specifically
tyrosine, and the escalating reinforcement of the disorder.
We now briefly consider each of these components and their
empirical support:
(I). Urwin et al. [7–10] have demonstrated an up to eleven-fold
odds-ratio difference in transmission of more active norad-
renergic gene variants between those with and without anor-
exia nervosa. These studies show that patients have an
increased likelihood of interaction between the long
variant of the Monoamine Oxidase A gene (located on the X

Please cite this article in press as: Nunn K et al. Anorexia nervosa – A noradrenergic dysregulation hypothesis. Med Hypotheses (2012), doi:10.1016/
j.mehy.2012.01.033
 K. Nunn et al. / Medical Hypotheses xxx (2012) xxx–xxx
chromosome) and genes on chromosomes 16 (16q12.2) and
17 (17q11.1–q12) which regulate noradrenergic (NET) and
serotonergic (SERT) mechanisms, respectively. Thus the sero-
tonergic gene variant alone does not account for the
differences between those with and without anorexia
nervosa, but does so in interaction with the noradrenergic
variant.
(II). Epigenetic factors implicated in the pathogenesis of anorexia
nervosa include obstetric complications [11] and a spring
season of birth bias [12], possibly explained by exposure to
ultra-violet sunlight radiation during early pregnancy con-
tributing to abnormal neurodevelopment [13]. Genes likely
to have a major impact, if affected, include PHOX1 and
PHOX2, which regulate brain and sympathetic nervous sys-
tem development and the noradrenergic system itself [14].
(III). Noradrenergic dysregulation: noradrenaline has multiple
functions. In relation to this model these include regulating
sympathetic arousal [15] and therefore levels of anxiety;
mediation of neuroplasticity including cortical representa-
tion [16] and regulation of cerebral blood flow [17]. Premor-
bidly, and after weight restoration [18], there is excessive
noradrenergic activity due to increased noradrenaline
metabolism. This leads to sympathetic arousal and increased
anxiety, impaired neuroplasticity and reduced cerebral
blood flow, each of which are discussed below.
(IV). Sympathetic over-activity: overactivity of the sympathetic
nervous system generates high levels of anxiety, which in
anorexia nervosa tends to be focused on weight and shape.
The normal inhibitory parasympathetic modulation of such
activity by the insula is likely to be disrupted in the context
of insula dysfunction.
(V). Impaired neuroplasticity: neuroplasticity is mediated
through noradrenergic [16], anticholinergic, serotonergic
and glutamate systems [19]. Dysregulation in any of these
systems could lead to impairment of cortical neuroplasticity,
including the tertiary somatosensory cortex located in the
insula: see (VII) and (VIII) below.
(VI). Reduction of cerebral blood flow: noradrenergic mecha-
nisms are also implicated in the regulation of cerebral vascu-
lature [20]. Patients with anorexia nervosa have reduced
cerebral blood flow, particularly in the medial temporal
Fig. 3. Insula neural circuitry in anorexia nervosa.
Please cite this article in press as: Nunn K et al. Anorexia nervosa – A noradrenergic dysregulation hypothesis. Med Hypotheses (2012), doi:10.1016/
j.mehy.2012.01.033
3
region [21]. The location of this hypoperfusion implicates
the middle cerebral artery, of which a major segment (M2)
supplies the insula, i.e. the insular opercular branches.
(VII). Insula: we have previously hypothesised that neural circuit
abnormality centred on the insula plays a major role in anor-
exia nervosa (see Fig. 3) [2,22].
The insula has been postulated to have a vast range of func-
tions including:
 Interoception [23].
 Body scheme representation [24].
 Visual perception [25].
 Perception of pain [26] and taste [27].
 Regulation of empathy [28].
 Regulation of disgust [29].
 Regulation of the autonomic nervous system especially the
parasympathetic nervous system [30].
 Attention and intention [31].
 Integration of thoughts and feelings [32].
Put succinctly ‘‘the insula is involved in the engendering of
human awareness’’ [33] and the assessment of what is salient
in the internal and external milieus, with the appropriate alloca-
tion of neural system resources [34]. It seems reasonable to pos-
tulate that insula dysfunction could therefore lead to the wide
range of quite specific abnormalities found in anorexia nervosa,
including intense body awareness and body image distortion.
(VIII). Homunculus dysfunction and distorted body image: expe-
rience of body image is mediated through the sensory
homunculi, of which there are three components: (i) pri-
mary (or perceptual), located in the post-central gyrus;
(ii) secondary (or interpretative), located in the inferior
post-central gyrus; (iii) tertiary (integrative), located in
the insula and insulo-parietal posteromedial cortical net-
works [35]. Tertiary homuncular dysfunction may lead to
impaired somato-sensory integration and subsequent dis-
torted body image. This is particularly pronounced during
the rapid pubertal growth spurt when the relative space
for different components of homuncular representation
must also change. This could also explain why anorexia
nervosa affects girls more than boys, given their more rapid
and extensive growth spurt. Those parts of the body most
commonly misrepresented (the thighs, hips and trunk)
4 K. Nunn et al. / Medical Hypotheses xxx (2012) xxx–xxx
have the lowest density of sensory representation and the
greatest and most rapid increase in size associated with
secondary sexual maturation.
(IX). This cascade leads to the development of anorexia nervosa.
(X). Precursor depletion: in the early stages of the illness, diet-
ing leads to a relative depletion of noradrenaline due to
reduced availability of its dietary precursors. The conse-
quent reduction in anxiety confers an enhanced sense of
well-being and reinforced motivation to diet. Dieting thus
intensifies. Gradually the noradrenergic system adjusts to
the precursor depletion with subsequent re-emergence of
anxiety. Re-feeding treatment leads to precursor repletion,
restoration and exacerbation of pre-morbid noradrenergic
activity, further increasing anxiety.
In summary, we propose that genetically determined noradren-
ergic dysregulation with subsequent sympathetic overactivity, im-
paired neuroplasticity and reduced regional cerebral blood flow,
leads to insula cortex dysfunction. This in turn leads to the devel-
opment of distorted body image through a failure of the homuncu-
lus to respond adequately to pubertal growth. Subsequent intense
dieting leads to noradrenergic precursor depletion and an initial
reduction in anxiety, with reinforcement of food restriction. Re-
feeding leads to increased anxiety and exacerbation of illness-re-
lated emotions and behaviours.
Validity and testing of the hypothesis
This hypothesis fulfils necessity by explaining the specific dis-
tortions of body image and the variations in anxiety during the ill-
ness. It is sufficient in its ability to account for the full range of
neurocognitive, emotional and behavioural components of the ill-
ness. Its specificity lies in its ability to explain the convergence,
persistence and severity of all these features which do not occur
in combination in any other disorder. Most components of the
hypothesis are empirically-derived. The hypothesis as a whole
could be refuted by examining about 20 main genes and their vari-
ants underlying the noradrenergic, dopaminergic and serotonergic
neurotransmitter systems. Subsequent stages in the model also
lend themselves to refutability. Each element relies upon the integ-
rity of the previous elements and thus the hypothesis is potentially
refutable at each step.
Comparison with alternative hypotheses
A number of other neurotransmitter systems have been studied,
specifically relating to serotonin, dopamine and GABA. Previous re-
search has explored the unique contribution of each, as well as the
interactions between them.
Serotonin studies have focused largely on receptor status,
cerebrospinal fluid (CSF) levels at various stages of depletion or
repletion, and response to serotonin selective re-uptake inhibitors.
Persistent alterations in serotonin receptors in a number of brain
regions have been shown following recovery from anorexia nerv-
osa [36] suggesting a trait-related abnormality. With regard to
CSF, Kaye et al. [6] have shown that serotonin metabolites are
elevated in subjects recovered from anorexia nervosa, again sug-
gesting trait-related factors. However, a Cochrane review of the
use of selective serotonin uptake inhibitors, such as fluoxetine, in
anorexia nervosa, indicates that these have little, if any, therapeu-
tic value [37]. This implies that disruption to the serotonin system
is unlikely to have a major causal and specific role. In summary,
these empirical studies lack any integrating hypothesis implicating
the serotonin system.
Studies have also explored dopamine and its role in reward and
reinforcement [6]. These posit that anorexia nervosa is caused by
Please cite this article in press as: Nunn K et al. Anorexia nervosa – A noradrenergic dysregulation hypothesis. Med Hypotheses (2012), doi:10.1016/
j.mehy.2012.01.033
an abnormality in the reward and reinforcement neural circuit
pathway with the primary reward of food no longer being a biolog-
ical and behavioural imperative. However, we believe that food
does continue to be conventionally rewarding in anorexia nervosa
but is ‘‘trumped’’ by a competing reward – that of anxiety being re-
duced by starvation. The noradrenergic hypothesis proposes that
an intact reinforcement reward system sustains the restrictive
behaviours through partial, intermittent reinforcement of food
restriction, paired with anxiety reduction.
No neurotransmitter system operates in isolation and so it is
important to consider the potential relationships between them
[38]. Kaye et al. [6] have formulated a hypothesis that individuals
with anorexia nervosa might have a trait bias towards an imbal-
ance between serotonin and dopamine pathways. Additionally
serotonin, dopamine and noradrenaline are all broken down by
mono-amine oxidase. Urwin et al. [9] have noted an interaction be-
tween the monoamine oxidase gene and the serotonin transporter
gene (SERT), where the former is the active partner.
The relationship between noradrenaline and dopamine is more
complex. Dopamine is part of the noradrenergic synthesis pathway
which challenges any hypothesis that dopamine dysregulation is of
primary significance in anorexia nervosa. Since dopamine is a pre-
cursor of noradrenaline (and is therefore ‘‘up stream’’ in the path-
way) anything that increases noradrenaline activity will have also
increased dopamine activity. Our position is that serotonin and
dopamine systems may be involved, and at times even have pro-
found alterations. However, we see them as secondary to the cau-
sal disruption of noradrenergic activity. In summary, it is doubtful
that abnormalities in dopamine-mediated reward systems or sero-
tonin regulated neuromodulation systems are central to the causal
mechanisms of anorexia nervosa.
A number of other neurotransmitter systems need to be consid-
ered in relation to our noradrenergic dysregulation hypothesis. For
example gamma-amino butyric acid (GABA) is an inhibitor of nor-
adrenaline in anxiety circuitry. Examples of other neurotransmit-
ters implicated in the noradrenergic account of AN include both
dynorphin and acetylcholine. Dynorphin is implicated in pain
threshold, appetite and temperature regulation [39,40], and is co-
expressed with noradrenaline in autonomic sympathetic nerves
[41]. It is also associated with more complex social cognitions
and behaviours associated with depression, stress and empathy
[42], all functions known to be altered significantly in AN [22].
Acetylcholine subserves limbic arousal of executive and other
cognitive function and is implicated at multiple levels of parasym-
pathetic regulation [41], including cardiac function [43]. These
functions are also known to be altered significantly in anorexia
nervosa, raising the intriguing possibility that the characteristic
bradycardia may not be due solely to the effects of starvation [2].
Finally, oestrogen, as an inhibitor of monoamine oxidase (MAO)
with further widespread neuromodulatory functions [44,45], offers
some gender-specific possibilities of neurotransmitter and neuro-
modulator interactions with the noradrenergic system, worthy of
investigation.
While these links are currently speculative, they illustrate how
a very specific hypothesis can give rise to a rich variety of refutable
sub-hypotheses for a research program to explore further. This
contrasts with earlier research based largely on empirical explora-
tion of neurotransmitter systems and functional brain regions,
without testing any a priori hypothesis.
Clinical implications
The noradrenegic dysregulation hypothesis allows for a number
of novel approaches to supplement conventional treatment. These
include interventions at different levels in the process including
supplementation with noradrenergic precursors, the use of medi-
 K. Nunn et al. / Medical Hypotheses xxx (2012) xxx–xxx 5

cations targeting the noradrenergic system and the GABA system
(the main brake on the noradrenergic system), the implementation
[15]
of cognitive remediation therapy [46] or neurobiofeedback [47] to
strengthen neural circuitry, or strategies to regulate an unre- [16]
strained anxiety neurocircuitry [48].
[17]
Conclusion
[18]
We have proposed a novel hypothesis that explains the patho-
genesis, phenomenology and maintenance of anorexia nervosa. It [19]
is rooted in genetically determined noradrenergic dysregulation,
[20]
which, with epigenetic influences, leads to high levels of anxiety,
impaired neuroplasticity and regional cerebral hypoperfusion.
[21]
These, in combination, lead to insular dysfunction, with deficits
in connectivity and dysfunctional homuncular representation. [22]
The consequent body image distortion and high levels of body-fo-
cused anxiety give rise to intense dieting, noradrenergic precursor [23]
depletion, initial and intermittent partially re-inforced reduction in [24]
anxiety, followed by a rebound exacerbation, and a cycle of
maintenance. [25]
We are unaware of any other hypothesis that attempts to ac-
count for all the features of anorexia nervosa. Our hypothesis, [26]
which fulfils the requirements of necessity, sufficiency, specificity,
empirically-based and refutability, purports to do so. Attempts to [27]
refute it are now under way.
[28]
Conflict of interest
[29]
None declared.
[30]
Acknowledgements
[31]
The many members of our various teams for their truly invalu- [32]
able contributions. Lucy Watson for her considerable and skilled
help with preparation of the manuscript.
[33]
[34]
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Please cite this article in press as: Nunn K et al. Anorexia nervosa – A noradrenergic dysregulation hypothesis. Med Hypotheses (2012), doi:10.1016/
j.mehy.2012.01.033