CLINICAL AND RESEARCH FORUM

Pathologic Fear Conditioning and Anorexia

Nervosa: On the Search for Novel Paradigms

Michael Strober

Eating Disorders Program, Department of Psychiatry and Neuropsychiatric Institute

and Hospital, David Geffen School of Medicine, University of California at Los Angeles,
Los Angeles, California
Accepted 24 November 2003

Abstract: Although eating disorders have been the focus of an unprecedented explosion of
clinical interest in recent years, the etiology of anorexia nervosa remains elusive. It is hypothe-
sized that an underlying causative mechanism involves a propensity to extreme fear condition-
ing and greater than normal resistance to its extinction. Knowledge accrued from recent
behavioral, genetic, and neuroanatomic research on anxiety may yield further insight into the
pathogenesis of anorexia nervosa, which can be subjected to experimental validation using
objective measures of classical fear conditioning and functional neuroimaging of brain struc-
tures mediating fear behavior. # 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 504–508,
2004.

Key words: fear conditioning; anorexia nervosa; novel paradigms

INTRODUCTION

Dissatisfaction with weight pervades the female adolescent psyche, yet only rarely does
this universal angst progress to morbid fear and life-threatening starvation. Anorexia
nervosa is a complex distortion of the human condition and the stark reality is that knowl-
edge of its etiology remains limited. Although research in eating disorders has been
transformed in recent years, and involvement of both social and biologic causative factors
is now the accepted authoritative opinion, validated strategies for studying how these risk
factors culminate in illness are still lacking. Because the combined role of soma and psyche
in etiology is now so widely accepted, the bar for measuring substantive progress must be
elevated lest we confuse scientific validity with simple correlations between variables of

Correspondence to: Michael Strober, University of California Los Angeles Neuropsychiatric Institute, 760
Westwood Plaza, Los Angeles, CA 90024-1759. E-mail: mstrober@mednet.ucla.edu
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/eat.20029
# 2004 by Wiley Periodicals, Inc.
Fear Conditioning 505

interest, associations that tell us little or nothing about pathogenesis of the disease state.
How to advance beyond singular hypotheses to a formulation of specific risk factors that
models key aspects of the anorexia nervosa phenotype is an unmet challenge.
The current article offers a heuristic framework for elucidating one of the fundamental
psychological elements of anorexia nervosa, morbid fear of weight. This diagnostic feature
compels particular attention, both theoretically and clinically, because the preoccupation
bridges cognitive, affective, and appetitive aspects of the disease, and, at least outwardly, it
is the patient’s avowed motivation for sustained food avoidance. The framework draws on
insights gained from research on genetic and neural processes underlying anxiety and fear
behavior in suggesting empirically derived approaches to modeling this phenotypic prop-
erty of the illness. To illustrate the applicability of this work to anorexia nervosa, converging
strands of supportive evidence are highlighted, parallels between phobic anxiety and the
fear of fat are noted, specific testable hypotheses are articulated, and experimental strategies
that can be employed for their evaluation are described briefly. Anorexia nervosa will never
be simply understood, and it is hardly the author’s belief that facile solutions are within easy
reach. As with other complex psychopathologies, shedding new light on the illness will
likely hinge on identifying the mechanisms by which molecular variants involved in
regulating complex behavioral and physiological processes interface with risk factors in
psychosocial domains. But in regard to this particular diagnostic characteristic, the argu-
ments set forth are theoretically intuitive, buttressed by an impressive array of empiric
findings, and amenable to scientific investigation.
Fear and avoidance have long been emphasized in theoretic models of anorexia
nervosa that viewed starvation as a means of aborting psychosexual maturation. The
merit of these formulations is not disputed, nor is it the article’s intention to cast doubt on
approaches suggesting cultural determinants of eating pathology. At the same time, these
perspectives slide by the imperative theoretic question. The greater intrigue, I would
submit, is the striking rarity of anorexia nervosa in a culture marked by such extra-
ordinary pervasiveness of dieting and weight dissatisfaction. It is the parallel on the one
hand, and disjunction on the other, between culture and disease that suggests an inherent
tendency for persons with anorexia nervosa to overexpress mechanisms that normally
operate in anxiety and fear conditioning (Quirk & Gehlert, 2003). Simply stated, the
etiologic question asks: What differentiates the majority of young people who naturally
register anxious distress over weight as puberty unfolds from the unfortunate few who
inexplicably succumb to a fear of weight that is irrational, unrelenting, and disabling?
A consideration of possible etiologic links between anxiety and anorexia nervosa is
supported by several observations. First, anxiety disorders are frequent in persons with
anorexia nervosa, vastly exceeding rates in the general population and often preceding
the onset of dieting and weight loss (Bulik, Sullivan, Fear, & Joyce, 1997; Godart, Flament,
Perdereau, & Jeammet, 2002). Consistent with this comorbidity is the association of
anorexia nervosa with personality traits associated with anxiety, such as harm avoidance
and reduced novelty seeking, reflecting the strong tendency of persons with anorexia
nervosa to be more restrained, cautious, regimented, and perfectionistic compared with
women without eating disorders. Both anxiety disorders and the anxious temperament
have inherited components and some of the loci involved may overlap, suggesting the
existence of genetic variants with broad effects on emotional behavior (Smoller et al.,
2001; Talbot, Radcliffe, Fullerton, Hitzemann, Wehner, & Flint, 2003). Moreover, anxious
temperaments are not exclusive to human beings. They have been well documented in
nonhuman species as well, suggesting these phenotypes have been broadly conserved by
natural selection to regulate the organism’s affective response to environmental threat
506 Strober

(Clarke & Boinski, 1995; Flint, 2003; Smoller et al., 2001). In this vein, Treasure and Owen
(1997) described syndromes of abnormal behavior in the animal kingdom strikingly
reminiscent of features of anorexia nervosa in advancing the argument that genetic and
psychobiologic study of certain animal phenotypes may help to inform models of the
pathogenesis of human eating disorders.
Second, like anxiety and its temperamental variants, anorexia nervosa runs in families. For
example, first-degree female relatives have a greater than 10-fold higher risk of the illness
compared with relatives of unaffected controls (Strober, Freeman, Lampert, Diamond, &
2000). In addition, twin studies (Holland, Hall, Murray, Russell, & Crisp, 1984; Holland,
Sicotte, & Treasure, 1988; Klump, Miller, Keel, McGue, & Iacono, 2001; Wade, Bulik, Neale, &
Kendler, 2000) indicate that this familial resemblance arises partly from heritable factors.
Furthermore, and of central importance to the hypothesis, twin and family studies (Keel,
Klump, Miller, McGue, & Iacono, 2003; Stavro, Klump, McGue, & Iacono, 2003) suggest that
some of the transmitted liability influencing anxiety states on the one hand, and anorexia
nervosa on the other, may overlap, thus tempting speculation that anorexia nervosa (or
perhaps subforms of the illness), certain types of anxiety disorders, and anxious tempera-
ments are etiologically related phenotypes that share inherited risk factors in common,
including functional abnormalities in neural systems regulating emotional behavior.
In regard to behavioral phenomenology, anorexia nervosa and phobic anxiety have
elements in common. As discussed by Mineka and Ohman (2002), fear behaviors have a
tightly organized structure comprising interdependent mental, behavioral, and neural
processes that were evolutionarily conserved to assist adaptation to life-threatening ele-
ments in the environment of our mammalian ancestors. These include a genetically encoded
‘‘preparation’’ of the organism to fear objects that have an implicitly threatening connota-
tion; rapid recruitment of the fear complex when threat is perceived (referred to as ‘‘auto-
maticity’’); resistance of the fear complex, once activated, to rational cognitive control
(referred to as ‘‘encapsulation’’); and a dedicated limbically organized neural circuitry.
Extensive empiric evidence from both animal and human research affirms these central
properties of fear, along with key roles played by of the amygdala, hippocampus, and
medial prefrontal cortex in the acquisition and extinction of fear learning (Fendt & Fanselow,
1999; LeDoux, 1998; Mineka & Ohman 2002; Quirk & Gehlert, 2003). Clearly, it would be far-
fetched to include body weight among the potential threats in the evolutionary history of
human beings. By the same token, an innate, preferential fear of body weight in anorexia
nervosa seems equally dubious. Rather, it is hypothesized that at least one of the genetically
influenced factors conferring risk to the illness is a pathologic ‘‘overexpression’’ of fear-
based learning (Quirk & Gehlert, 2003); specifically, and following Mineka and Ohman
(2002), a far greater than normal acquisition of conditioned fear to weight, progressing
rapidly thereafter to absolute, unrelenting morbid dread necessitating food avoidance.
Consider, in this regard, these ‘‘facts’’ about anorexia nervosa in relation to the
phenomenology of fear behavior as described by Mineka and Ohman (2002). First,
progression from essentially normative teenage dissatisfaction with weight to morbid
fear and maniacally compulsive dieting is, in most cases, astonishingly rapid (extreme
automaticity). Second, once weight phobia crystallizes, it is utterly resistant to rational
argument (encapsulation). Third, although more tentative, recent research using positron
emission tomography (Frank et al., 2002) has shown altered binding of the serotonin2a
receptor in the amygdala, hippocampus, and cingulate in weight-recovered women with
anorexia nervosa compared with normal controls, suggesting overexpression of neuronal
circuitry known to be involved in regulating fear conditioning. In short, parallels are
plainly evident between certain key facets of the evolutionarily conserved fear module
Fear Conditioning 507

described by Mineka and Ohman (2002) and the weight phobia in persons with anorexia
nervosa. Hence, whereas the culture-driven, socially reinforced unease with weight is the
impetus for dieting in the initiating phase of the illness, genetically driven variations in
mechanisms underlying fear conditioning are posited as the second-stage contributor to
the morbid level of fear that quickly ensues, and its prolonged resistance to extinction.
In sum, the following points concerning the pathogenesis of anorexia nervosa are
speculated: (a) weight aversion and compulsive dieting express a heritable tendency
for rapid fear-based learning and phobic avoidance, effects of which likely interact
with personality traits that accelerate emotional conditioning; (b) a property of this
overexpressed fear-based learning is that weight phobia is encapsulated from cognitive
control, accounting for the unusually protracted and frequently chronic course of the
illness; and (c) underlying the conditioning of weight-related fear are abnormalities in
limbic structures known to be involved in emotion-driven behavior, specifically the
propensity to fear and to rapidly acquire conditioned fear behavior.
A virtue of this hypothesis is that fear conditioning is easy to measure using the classic
Pavlovian conditioning paradigm of recording electrodermal skin conductance in
response to pairings of neutral and fear relevant stimuli. The phenomenon is under
partial genetic control (Hettema, Annas, Neale, Kendler, & Fredrikson, 2003) and is
mediated by brain circuitry involving the amygdala and hippocampus (Mineka &
Ohman, 2002; Fendt & Fanselow, 1999). As heritability estimates of fear conditioning
(Hettema et al., 2003) are roughly equivalent to those reported for clinical anxiety
disorders, it has been suggested that the measure may serve as an easily measured
endophenotype expressing a genetic substrate for anxiety proneness. Accordingly, the
study of fear conditioning may be a reliable means of testing the hypothesis that a trait
predisposing to anorexia nervosa is extreme rapidity of fear conditioning coupled with
heightened resistance to extinction of associative fear learning. The hypothesis predicts
straightforwardly that anorexic subjects (tested when weight recovered to minimize
confounds of starvation) would differ from normal controls in the speed of fear con-
ditioning; that conditioned fear responses in this illness would have slower rates of
extinction compared with controls; that biologic relatives of subjects would show differ-
ential conditioning when compared with relatives of healthy controls; that extreme
patterns of conditionability would cosegregate with full and partial syndromes of anor-
exia nervosa in families; that anorexia nervosa would be associated with differentially
extreme patterns of activation of the amygdala and other relevant subcortical structures
by emotionally valent probes in functional neuroimaging experiments (see Rauch Shin, &
Wright, 2003); and that specific genetic variants linked to rapid versus slow fear con-
ditioning (Garpenstrand, Annas, Ekblom, Oreland, and Fredrikson, 2001; Hariri et al.,
2002; Talbot et al., 2003) would be more common in persons with anorexia nervosa
compared with controls without the illness, or at least in subgroups of the illness. It is
likely that multiple genes contribute risk to anorexia nervosa. Therefore, if fear con-
ditioning and neuroimaging paradigms ultimately prove helpful in characterizing an
endophenotype for the illness, these measures may be crucial to future genetic analyses
that continue the search for susceptibility loci within specific subgroups that are likely to
comprise the larger spectrum of anorexia nervosa (Devlin et al., 2002).
A value of the hypotheses described in the current article is that they are as easy to verify
as they are to refute. If they cannot withstand experimental scrutiny, the insights gained
will only encourage more fruitful areas of inquiry. Moreover, the framework offered is
only a beginning, as the arguments will certainly give rise to compelling questions: What
accounts for variations in the clinical expression of the hypothesized deficit in neuronal
508 Strober

circuitry underlying extreme fear conditioning? If a common liability to extreme fear

conditioning exists among persons with diverse anxiety disorders, why does anorexia
nervosa develop in some persons and phobic states in others? Does acute starvation
unmask this hypothesized liability, and, if so, through what perturbation of metabolic,
hormonal, or neurochemical processes? The roads waiting to be traveled in the search for
new paradigms applied to the riddle of anorexia nervosa are many.

REFERENCES
Bulik, C.M., Sullivan, P.F., Fear, J.L., & Joyce, P.R. (1997). Eating disorders and antecedent anxiety states. Acta
Psychiatrica Scandanavica, 96, 101–107.
Clarke, A., & Boinski, S. (1995). Temperament in non-human primates. American Journal of Primatology, 37,
103–125.
Devlin, B., Bacanu, S.A., Klump, K.L., Bulik, C.M., Fichter, M.M., Halmi, K.L., Kaplan, A.S., Strober, M.,
Treasure, J., Woodside, D.B., Berrettini, W.H., & Kaye, W.H. (2002). Linkage analysis of anorexia nervosa
incorporating behavioral covariates. Human Molecular Genetics, 11, 689–696.
Fendt, M., & Fanselow, M.S. (1999). The neuroanatomical and neurochemical basis of conditioned fear. Neuro-
science and Biobehavioral Review, 23, 743–760.
Flint, J. (2003). Animal models of anxiety and their molecular dissection. Seminars in Cell and Developmental
Biology, 14, 37–42.
Frank, G.K., Kaye, W.H., Meltzer, C.C., Price, J.C., Greer, P., McConaha, C., & Skovira, K. (2002). Reduced
5-HT2A receptor binding after recovery from anorexia nervosa. Biological Psychiatry, 52, 896–906.
Garpenstrand, H., Annas, P., Ekblom, J., Oreland, L., & Fredrikson, M. (2001). Human fear conditioning is
related to dopaminergic and serotonergic biological markers. Behavioral Neuroscience, 115, 358–364.
Godart, N.T., Flament, M.F., Perdereau, F., & Jeammet, P. (2002). Comorbidity between eating disorders and
anxiety disorders: A review. International Journal of Eating Disorders, 32, 253–270.
Hariri, A.R., Mattay, V.S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., Egan, M.F., & Weinberger, D. (2002).
Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400–403.
Hettema, J.M., Annas, P., Neale, M.C., Kendler, K.S., & Fredrikson, M. (2003). A twin study of the genetics of
fear conditioning. Archives of General Psychiatry, 60, 702–708.
Holland, A.J., Hall, A., Murray, R, Russell, G.F., & Crisp, A.H. (1984). Anorexia nerovosa: A study of 34 twin
pairs and one set of triplets. British Journal of Psychiatry, 145, 414–419.
Holland, A.J., Sicotte, N., & Treasure, J. (1988). Anorexia nervosa: Evidence for a genetic basis. Journal of
Psychosomatic Research, 32, 561–571.
Keel, P., Klump, K.L., Miller, K.B., McGue, M., & Iacono, W.G. (2003). Shared transmission of eating disorders
and anxiety disorders. Manuscript submitted for publication.
Klump, K.L., Miller, M.D., Keel, P.K., McGue, M., & Iacono, W.G. (2001). Genetic and environmental influences
on anorexia nervosa syndromes in a population-based twin sample. Psychological Medicine, 31, 737–740.
LeDoux, J. (1998). Fear and the brain: Where have we been, and where are we going? Biological Psychiatry, 44,
1229–1238.
Mineka, S., & Ohman, A. (2002). Phobias and preparedness: The selective, automatic, and encapsulated nature
of fear. Biological Psychiatry, 52, 927–937.
Quirk, G.J., & Gehlert, D.R. (2003). Inhibition of the amygdala: Key to pathological states. Annals of the New
York Academy of Sciences, 985, 263–272.
Rauch, S.L., Shin, L.M., & Wright, C.I. (2003). Neuroimaging studies of amygdala function in anxiety disorders.
Annals of the New York Academy of Sciences, 985, 389–410.
Smoller, J.R., Rosenbaum, J.F., Biederman, J., Susswein, L.S., Kennedy, J., Kagaan, J., Snidman, N., Laird, N.,
Tsuang, M.T., Faraone, S.V., Schwarz, A., & Slaugenhaupt, S.A. (2001). Genetic association analysis of behav-
ioral inhibition using candidate loci from mouse models. American Journal of Medical Genetics, 105, 226–235.
Stavro, G., Klump, K.L., McGue, M., & Iacono, W.G. (2003). Anorexia nervosa and anxiety disorders: An
example of comorbidity and shared transmission. Manuscript submitted for publication.
Strober, M., Freeman, R., Lampert, C., Diamond, J., & Kaye, W. (2000). Controlled family study of anorexia
nervosa and bulimia nervosa: Evidence of shared liability and transmission of partial syndromes. American
Journal of Psychiatry, 157, 393–401.
Talbot, C.J., Radcliffe, R.A., Fullerton, J., Hitzemann, R., Wehner, J.M., & Flint, J. (2003). Fine scale mapping of a
genetic locus for conditioned fear. Mammalian Genome, 14, 223–230.
Treasure, J., & Owen, J.B. (1997). Intriguing links between animal behavior and anorexia nervosa. International
Journal of Eating Disorders, 21, 307–311.
Wade, T.D., Bulik, C.M., Neale, M., & Kendler, K.S. (2000). Anorexia nervosa and major depression: Shared
genetic and environmental risk factors. American Journal of Psychiatry, 157, 469–471.