New insights into symptoms and neurocircuit function of anorexia nervosa

8/14/2019 New insights into symptoms and neurocircuit function of anorexia nervosa

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Anrxia nra (AN), a dirdr f nknwn ati-gy, i charactrizd by rtrictd ating and a rnt- prit f thinn (BOX 1). AN i piby tht hgn f a pychiatric dirdr. Thri a narrw rang f ag f nt (ary adcnc),trtypic prntatin f ypt and cr, andrati gndr pcificity1. Indiida with AN ha ang-yntnic ritanc t ating and a pwrf pr-it f wight , yt ar paradxicay prccpidwith fd and ating rita t th pint f bin.Indiida ha a ditrtd bdy iag and, n whnaciatd, tnd t th a fat, xpr dniaf bing ndrwight and cpiy r-xrci.Thy ar ftn ritant t tratnt and ack inightrgarding th rin f th dica cnqncf th dirdr.

Tw typ f ating-ratd bhair ar n in AN

(BOX 1). Rtricting-typ anrxic wight pry byditing witht bing ating r prging. Bing-ating/prging-typ anrxic a rtrict thir fd intakt wight, bt ha a pridic diinhibitin frtraint and ngag in bing ating and/r prging ad indiida with biia nra (BN). Cnidringthat tranitin btwn yndr ccr in any, itha bn argd that AN and BN har rik andiabiity factr2,3. Hwr, thi Riw fc nrtricting-typ AN.

Athgh AN i charactrizd a an ating dirdr,it rain nknwn whthr thr i a priary di-trbanc f apptiti pathway, r whthr ditrbd

apptit i cndary t thr phnna, ch aanxity r bina prccpatin with wight gain.Thr ha bn cnidrab intrt in th r f thhypthaa in fd and wight rgatin in AN,athgh it rain ncrtain whthr hypthaaicatratin ar a ca r a cnqnc f th yp-t. Thi Riw fc n anthr prpcti. Thati, athgh th hypthaa i an iprtant rgatrf fd intak and bdy wight, thr i iitd idncthat hypthaaic pptid ha a r in th atigyf AN. Hwr, tdi in ania and hathy hanar ading t a nw ndrtanding f rapping n-ra pathway that cntribt t th datin f rwardand tin in rpn t apptiti tii. Ginth prbab ink btwn fding bhair and affc-ti prc in AN, th nra btrat ndryingth prc ar ptntia candidat rgin fr ndr-

tanding th pathphyigy f thi in. Thi Riwintgrat finding fr pharacgica, bhairaand nriaging tdi that cntribt t th ndr-tanding f apptit rgatin, rward, nrtranittrand nrcircit that ar aciatd with AN.

State and trait

Whn anrihd and aciatd, indiida withAN ha widprad and r atratin f brain andpriphra-rgan fnctin; hwr, it i ncar whthrth chang ar th ca r th cnqnc f a-ntritin and wight . Thrfr, t ndrtand thatigy and cr f in f AN, it i f t diid

*Eating Disorder Treatment &

Research Program,

Department of Psychiatry,

University of California, San

Diego, La Jolla Village

Professional Center, 8950

Villa La Jolla Drive, Suite

C-207, La Jolla, California

92037, USA.Psychiatry & Neurobiology

and Anatomy, University of

Rochester Medical Center,601 Elmwood Avenue,

Rochester, New York 14642,

USA.Laboratory of Biological

Dynamics and Theoretical

Medicine, Department

of Psychiatry, University of

California, San Diego, 8939

Villa La Jolla Dr. Suite 200,

La Jolla, California 92037-

0985, USA.

Correspondence to W.H.K.

e-mail: [email protected]

doi:10.1038/nrn2682

Published online 15 July

New insights into symptomsand neurocircuit functionof anorexia nervosaWalter H. Kaye*, Julie L. Fudge and Martin Paulus

Abstract | Individuals with anorexia nervosa have a relentless preoccupation with dieting and

weight loss that results in severe emaciation and sometimes death. It is controversial whether

such symptoms are secondary to psychosocial influences, are a consequence of obsessionsand anxiety or reflect a primary disturbance of brain appetitive circuits. New brain imaging

technology provides insights into ventral and dorsal neural circuit dysfunction perhaps

related to altered serotonin and dopamine metabolism that contributes to the puzzling

symptoms found in people with eating disorders. For example, altered insula activity could

explain interoceptive dysfunction, and altered striatal activity might shed light on altered

reward modulation in people with anorexia nervosa.

R E V I E W S

NATuRe RevIeWs |NeuroscieNce volume 10 | AuGusT 2009 |573

2009 Macmillan Publishers Limited. All rights reserved
mailto:[email protected]:[email protected]


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Interoception

The sensing and integrating of

afferent proprioceptive and

visceroceptive information,

resulting in feeling the inner

state of the body, which is

important for allocating

attention, evaluating context

and planning actions.

th nrbigica atratin int tw catgri. Firt,thr t b prrbid, gnticay-dtrind traitatratin that cntribt t a nrabiity t dpAN. scnd, thr ar tat atratin cndary tantritin that ight tain th in, and pr-hap accrat th t-f-cntr pira that rt inr aciatin and th hight rtaity rat f anypychiatric dirdr.

Trait-related alterations. larg-ca cnity-badtwin tdi ha hwn that 50% t 80% f th ari-anc in AN and BN can b accntd fr by gnticfactr35. Th gntic nrabiity t ating dirdright b xprd a a diff phntyp f cntinbhaira trait, a ggtd by idnc f ignificanthritabiity f dirdrd ating attitd, wight prc-cpatin, diatifactin with wight and hap, ditaryrtraint, bing ating and f-indcd iting68, andf ignificant faiiaity f bthrhd fr f atingdirdr2,9.

Cnidrab idnc ha ggtd that chid-

hd tprant and prnaity trait can ad ta prdipitin t dp AN dring adcnc.Rcnt tdi1012 dcrib ngati tinaity, haraidanc, prfctini, inhibitin, dri fr thinn,atrd interoceptive awarn and bi-cpiprnaity trait a chidhd prdiping factrthat prcd th nt f an ating dirdr (FIG. 1)and that prit aftr rcry ( bw). stdi ggtthat th trait ar hritab, can b prnt in naffctdfaiy br and ar indpndnt f bdy wight13,priding frthr idnc that thy cnfr iabiity tth dpnt f AN.

State-related alterations. staratin and aciatinha prfnd ffct n th fnctining f th brainand thr rgan yt. Thy ca nrchicaditrbanc that cd xaggrat prrbid trait14,adding ypt that aintain r accrat th di-a prc (FIG. 1). Fr xap, bjct with AN haa rdcd brain 15, an atrd tabi infrnta, cingat, tpra and parita rgin16, and argrin t pr-pbrta gnada fnctin17. Th fact

that ch ditrbanc tnd t nraiz aftr wightrtratin ggt that thy ar a cnqnc rathrthan a ca f AN.

It i iky that any f th taratin-drin nd-crin and tabic chang that rt fr AN arcpnatry and attpt t cnr nrgy r ti-at hngr and fding18. Fr xap, bjct with ANha atrd cncntratin19 f nrpptid Y (NPY),ptin, crtictrpin-raing hrn (CRH), ch-cytkinin, bta-ndrphin and pancratic pypptid.It i iprtant t nt that ch atratinar iky tca atratin in d, cgniti fnctin, ipcntr and atnic and hrna yt20, whichindicat that thy ight cntribt t th bhairaypt aciatd with th i tat. Fr xap,intracrbrntricar CRH adinitratin in xpri-nta ania prdc any f th phyigicaand bhaira chang aciatd with AN, incd-ing hypthaaic hypgnadi, atrd tinaity,dcrad xa actiity, hypractiity and dcradfding bhair21. Thrfr, it can b argd that

cndary chang in pptid cncntratin cantain AN bhair (FIGS 1,2) by driing a dir frr diting and wight . mrr, antritin-aciatd atratin xaggrat tina dyrga-tin, cnitnt with th any indiida with ANthat t Dsm-Iv (Diagntic and statitica manaf mnta Dirdr, frth ditin) critria1 fr ajrdprin, bi cpi dirdr (oCD) rthr anxity dirdr22,23.

Do symptoms in individuals with AN reflect trait orstate?Th difficty in ditingihing chang that ard t trait fr th that ar ratd t tat in td-i f bjct with AN ha bn a ajr cnfnd inth rarch f thi dirdr. Prpcti, ngitdinatdi ar diffict gin th yng ag f ptntiabjct, th rarity f th dirdr and th any yarf fw-p rqird. An atrnati tratgy i t tdyindiida wh ha rcrd fr AN, th aidingth cnfnding infnc f antritin and wight n bigica yt. Thr i prnty n agrd-pn dfinitin f rcry fr AN, bt r rarchdfin it a haing a tab and hathy bdy wight frnth r yar, with tab ntritin, rati abncf ditary abnraiti and, in fa,nra n-tratin. Athgh th prc f rcry fr ANi pry ndrtd and, in t ca, prtractd,

apprxiaty 50% t 70% f affctd indiida wintay attain cpt r drat rtin fth in, athgh thi ight nt ccr nti thirary t id 202426. stdi ha dcribd tpra-nt and charactr trait that ti prit aftr ng-trrcry fr AN, ch a ngati tinaity, haraidanc, prfctini, dir fr thinn and idditary prccpatin. It i pib that ch pritntypt ar car cad by chrnic antritin.Hwr, th fact that ch bhair24,27,28 ar iiart th dcribd fr chidrn wh wi dp AN1012arg that thy rfct ndrying trait that cntribtt th pathgni f thi dirdr.

Box 1 | DSM-IV, diagnostic criteria for anorexia nervosa1

Refusaltomaintainbodyweightatoraboveaminimallynormalweightforageand

height(forexample,weightlossleadingtomaintenanceofbodyweightlessthan85%ofthatexpected;orfailuretomakeexpectedweightgainduringperiodofgrowth,

leadingtobodyweightlessthan85%ofthatexpected.)

Intensefearofgainingweightorbecomingfat,eventhoughunderweight.

Disturbanceinthewayinwhichonesbodyweightorshapeisexperienced,undue

influenceofbodyweightorshapeonself-evaluation,ordenialoftheseriousnessof

thecurrentlowbodyweight.

Inpostmenarchealfemales,amenorrhea(thatis,theabsenceofatleastthree

consecutivemenstrualcycles).

Therearetwotypesofanorexianervosa:1.Restrictingtype,inwhichthepersonhas

notregularlyengagedinbinge-eatingorpurgingbehaviour;2.Binge-eating/purging

type,inwhichthepersonhasregularlyengagedinbinge-eatingorpurgingbehaviour

(thatis,self-inducedvomitingorthemisuseoflaxatives,diureticsorenemas).

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Traits

Negative emotionPerfectionismDrive for thinnessIncreased interoceptive awarenessObsessive-compulsive personality

Puberty

Brain developmentHormonesStressCultural factors

Dieting

Weight loss

Neurobiologicalchanges

Denial, rigidity,anxiety, depression,obsessionality

Chronic illness(3050%)

Recovery(5070%)

Childhood

Adolescence

Adulthood

Neurobiology and behaviour

Cn crbid bhair typica f bth rcrdand i AN indiida ar ftn xprd in cncrt.Th incd inhibitin, anxity, dprin and b-inaity, and pzzing ypt ch a bdy iagditrtin, prfctini, and anhdnia. Th bha-ir cd b ncdd in ibic and cgniti circitknwn t dat and intgrat nrna prcthat ar ratd t apptit, tinaity and cgniticntr. Tw nrcircit that ha bn dcribdbad n iaging, nrphyigica and in td-i29,30 ight b f particar ranc t ndrtand-

ing bhair in AN. A ntra (ibic) nrcircitthat incd th aygdaa, ina, ntra triatand ntra rgin f th antrir cingat crtx(ACC) and th rbitfrnta crtx (oFC) t biprtant fr idntifying th tina ignificancf tii and fr gnrating an affcti rpn t thtii29,30. A dra (cgniti) nrcircit i thghtt dat cti attntin, panning and ffrtfrgatin f affcti tat, and incd th hippca-p, dra rgin f th ACC, dratra prfrntacrtx (DlPFC), parita crtx and thr rgin29,30.Indd, arir brain iaging tdi ha hwn thatbjct wh ha rcrd fr AN ha atrd

actiity in frnta, antrir cingat and paritargin3133 sra intigatr ha prpd thatdyrgatin f th tw circit cntribt t rapychiatric dirdr incding ajr dprin, anxi-ty dirdr and oCD. It i pib that abrrant fnc-tin f th circit ca atrd tin rgatin rbinaity bt that th car bai f th dy-fnctin diffr btwn dirdr30. Indd, th nr-bigica ditrbanc in pp with ating dirdray diffr fr th fnd in pp with dprin,anxity r oCD. Fr xap, th binding ptntia fth rtnin (5-HT) rcptr 1A (5-HT

1A) i dcrad

in bjct with dprin34, a w a in pp withcia phbia35 and panic dirdr36, whrait tnd tb incrad in pp with ating dirdr3740.

Thi Riw fc n th finding drid frra iaging tchngi. stdi ing pitrniin tgraphy (PeT) brain iaging and ratdtchngi ha ad 5-HT and dpain (DA)nrtranittr yt in bjct with AN and inth wh ha rcrd.scnd, rcnt fnctinamRI (fmRI) tdi ha bgn t hd ight n atrdactiity in intrcnnctd brain rgin f th indi-

ida. Tgthr th tdi prid nw inightint nrbigica ditrbanc that charactriz thidady dirdr.

Serotonin function in AN. Th 5-HT yt ha bnintniy tdid in pp with AN a cnidrabidnc ggt that thi nrtranittr ytcd pay a part in ypt ch a nhancd ati-ty41, ip cntr42,43 and d44,45. Indd, thr ich idnc f abnra fnctina actiity f th5-HT yt in bjct with AN46,47(FIG. 2). Fr xap,in ndrwight and anrihd indiida ffr-ing fr AN th crbrpina fid (CsF) ha rdcdant f 5-hydrxyindactic acid (5-HIAA) which i th ajr brain tabit f 5-HT and ithght t rfct xtracar 5-HT cncntratin48.By cntrat, 5-HT tabit wr atd in thCsF f bjct wh had rcrd fr AN.

It i iprtant t nt that th 5-HT yt in14 r r rcptr, and intract withany thrnrtranittr and c. ony a fw f thcpnnt can crrnty b ard in vivo inhan. sti, iaging tdi f 5-HT fnctina acti-ity ar f; athgh th cpxity f 5-HT circitcannt b fy cidatd in han, ch iaging td-

i can charactriz ptntia tat and trait diffrncbtwn indiida with AN and hathy cntr, bd t d ratinhip f 5-HT actiity t bhairand prid nw inight n ptntiay r ffctitratnt targt. In fact, brain iaging tdi cnit-nty hw that, whn cpard with hathy bjct,indiida with r haing rcrd fr ating di-rdr ha atd and diinihd binding ptntiafr ptynaptic 5-HT

1Arcptr and5-HT

2Arcptr,

rpctiy3740,4951. stdi f indiida with r ha-ing rcrd fr AN tnd t prdc iiar find-ing, pprting th ntin that thr ar trait-ratdatratin f 5-HT fnctin in AN.

Figure 1 | T tm an nmngy anxa na. Childhood

personality and temperament traits, which contribute to a vulnerability for developing

anorexia nervosa (AN), become intensified during adolescence as a consequence of the

effects of multiple factors, such as puberty and gonadal steroids, development, stress

and culture. Individuals with AN find that dieting reduces, and eating enhances

dysphoric mood. But with chronic dieting and weight loss, there are neurobiological

changes which increase denial, rigidity and obsessions, as well as depression and anxiety,

so that individuals often enter a downward spiral. Although 50% or more of individuals

with AN recover by their early to mid20s, a significant proportion of subjects develop a

chronic illness or die.

R E V I E W S


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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Dieting

Dysphoric mood

CRH-endorphin

Dysphoric mood

Weight loss

5 10 15 20 25 30 35Novelty seeking

[11C]WAY100635BP

orbitalcortex

10 14 18 22 26 30

0.8

1.0

1.2

1.4

1.6

1.8

2.0

[18F]altamserinBP

orbitofrontalcorte

x

0

11

10

9

8

7

6

5

4

3

5 10 15 20 2 5 30

Harm avoidance

[11C]WAY100635BP

mesialtemporalcortex

+

+

+

+

+

5-HT1A receptor

5HT2A receptor

Normal

AN trait

5-HT overdrive

Dysphoric mood Error detection Inhibition

5-HT production 5HT1A levels

5-HT 5-HT

1A

, 5-HT2A

bindingForced

eating

Harm avoidance

Continuedstarvation

a

b

1

2

3

4

5

6

7

Restrictive eating

Figure 2 | T tnn na ntn n anxa na. It is well known that people with anorexia nervosa

(AN) enter a vicious cycle, whereby malnutrition and weight loss drive the desire for further restricted eating and emaciation.

Evidence suggests that, compared with healthy individuals (a), individuals who are vulnerable to developing an eating

disorder might have a trait for increased extracellular serotonin (5HT) concentrations 68 and an imbalance in postsynaptic

5HT1A

and 5HT2A

receptor activity3740,4951 (b), which together might contribute to increased satiety and an anxious,

harmavoidant temperament. Gonadal steroid changes during menarche or stress related to adolescent individuationissues might further alter activity of the 5HT system and so exacerbate this temperament, resulting in a chronic dysphoric

state. It is important to note that foodmood relationships in AN are very different from those in healthy controls. That is,

palatable foods in healthy subjects are associated with pleasure, and starvation is aversive. By contrast, palatable foods

seem to be anxiogenic in AN, and starvation reduces dysphoric mood. In subjects with AN, starvation and weight loss result

in reduced levels of 5HIAA in the cerebrospinal fluid (CSF)74 (and inferentially reduced extracellular 5HT concentrations)

but exaggerated 5HT1A

receptor binding in limbic and cognitive cortical regions39. Starvationinduced reductions of

extracelluar 5HT levels might result in reduced stimulation of postsynaptic 5HT1A

and 5HT2A

receptors, and thus

decreased dysphoric symptoms. However, when individuals with AN are forced to eat, the resulting increase in extracellular

5HT levels, and thus stimulation of postsynaptic 5HT1A

and 5HT2A

receptors, increases dysphoric mood, which makes

eating and weight gain aversive. Alternatively, if subjects with AN continue to starve, anorexigenic signals related to

neuropeptide disturbances (for example, increased corticotropinreleasing hormone (CRH)21 and reduced endorphin166)might drive further food restriction and changes in behaviour and cognition, which thus promotes AN symptoms.

Scatterplots reproduced, with permission, from REF. 39 (2007) American Medical Association and REF. 40 (2005) Elsevier.

R E V I E W S




5/12

mrr, iaging tdi prid inight int hwditrbd 5-HT fnctin i ratd t dyphric din AN52,53. That i, PeT iaging tdi hw trikingand cnitnt piti crratin btwn th bind-ing ptntia f bth 5-HT

1Aand 5-HT

2Arcptr

and har aidanc a tifactd tpranttrait54 that cntain nt f anxity, inhibitin, andinfxibiity. stdi in ania and hathy hanpprt th pibiity that 5-HT

1Aand 5-HT

2Arcptr

actiity ha a r in anxity5558. It i iprtant t ntthat thr i high c-caizatin (80%) f th 5-HT

2A

and 5-HT1A

ptynaptic rcptr in th rdnt frntacrtx59 and thr crtica rgin60. Thrgh intrn-rn, thy diat, rpctiy, dirct hyprparizingand dparizing actin f 5-HT n prfrnta n-rn that prjct t crtica and bcrtica ara61,62.Intractin btwn 5-HT

1Aand 5-HT

2Arcptr

in th dia prfrnta crtx (PFC) and ratdrgin t dat anxity, attntina fnctin-ing63, ipiity and cpi prratin62, andxpratin f nw nirnnt64. It rain t b

dtrind whthr th ibaanc btwn nhancd5-HT

1Aand diinihd 5-HT

2Arcptr binding ptn-

tia cntribt t ch ypt in indiida withating dirdr.

Implications for satiety and the benefit of starvation. Iti thght that, in indiida with AN, ditary rtraintrdc anxity, whra ating tiat dyphricd53,65,66. I atrd 5-HT fnctin th ink btwnrtrictd fding bhair and anxity in bjctffring fr AN? It i w-knwn that carbhydratintak incra xtracar 5-HT cncntratin inth brain thrgh cpx tabic ffct n tryp-tphan, th ain acid prcrr f 5-HT53,67. W pr-p that, bth prrbidy and aftr rcry frAN, a nra ant f fd ingtin i aciatdwith xaggratd xtracar brain 5-HT crtin68.Thi i cnitnt with incrad CsF 5-HIAA inpp wh ha rcrd fr AN68. Incrad 5-HTcncntratin inhibit apptit, prhap thrgh acti-

atin f5-HT2C

rcptr69; hwr, 5-HT2C

rcp-tr binding ha nt bn ard by iaging tdiin indiida with AN. Incrad 5-HT

1Abinding

ptntia i pitiy aciatd with har aidancin bjct wh ha rcrd fr AN40 (FIG. 2), andnhancd anxity and har aidanc ar trait thatar prnt prrbidy and prit aftr rcry fr

AN. It i thrfr pib that carbhydrat-indcdincra in xtracar 5-HT dri anxity andhar aidanc thrgh tiatin f 5-HT

1Arcp-

tr (FIG. 2), ffring a ptntia xpanatin fr fd-ing-ratd dyphric d in AN. By cntrat, whnindiida with AN tar, xtracar 5-HT cn-cntratin ight diinih, rting in a brif rpitfr dyphric d. stdi in ania and hathyhan hw that bth a rtrictd dit (which ignifi-canty wr paa tryptphan) and xprintayrdcd tryptphan dptin dcra 5-HT ynthiin th brain67,70,71. Indd, anrihd and aciatdindiida with AN ha rdcd paa tryptphan

aaiabiity72,73 and rdcd CsF 5-HIAA 74.Iprtanty, xprinta anipatin that rdcth f tryptphan in th brain dcra anxityin bth i and rcrd AN bjct53. Hwr, tar-

atin in AN t b aciatd with a cpna-try incra in ptynaptic 5-HT

1Arcptr binding

ptntia39. mrr, 5-HT2A

rcptr binding i pi-tiy ratd t har aidanc in bjct ffringfr AN. Thrfr, whn indiida with AN arfrcd t at (FIG. 2), it i iky that thy ha a ratiincra in xtracar 5-HT cncntratin in thbrain, ading t an xaggratin f dyphric d.Th, indiida with AN ight pr taratinin an attpt t aid th dyphric cnqnc fating and cnqnty pira t f cntr.

Dopamine and reward processing in AN. Pp withAN ftn xrci cpiy, ar anhdnic andactic, and find itt in if that i rwarding aidfr th prit f wight 1. sch tprantprit, in a r dt fr, aftr rcry24,75,

indicating that th charactritic ar trait rathrthan bing tat ratd.DA dyfnctin, particaryin triata circit, ight cntribt t atrd rwardand affct, dciin-aking and xcti cntr, aw a trtypic tr nt and dcradfd ingtin in bjct with AN76. eidnc thatth DA yt i ind in AN incd rdcdCsF f DA tabit in bth i indiida andth haing rcrd fr AN77, fnctina DA D2rcptr (DRD2) gn pyrphi in bjct withAN78 and ipaird ia dicriinatin arning 79,which i thght t rfct DA-ignaing fnctin, inindiida with AN. A PeT tdy fnd that bjctwh rcrd fr AN had incrad D2/D3 rcp-tr (DRD3) binding in th ntra triat76, a rginthat dat rpn t rward tii80,81. Thicd indicat incrad D2/D3 dniti, dcradxtracar DA, r bth, in indiida wh rcrdfr AN. In additin, D2/D3 rcptr binding in thdra cadatdra ptan crratd pitiywith har aidanc in bjct wh had rcrdfr AN76.

T dtrin whthr indiida wh ha rc-rd fr AN ha fndantay diffrnt rpnt rward cpard with hathy cntr, an nt-ratd fmRI tdy xaind th bd xygn -dpndnt (BolD) igna whi participant prfrd

a ip chic and fdback tak82. Th tak waadaptd fr a w-charactrizd ging-gaprtc83 that i knwn t actiat th ntra triatand bgna ACC, with cntr participant hwingdiffrntia actiity in th ara in rpn t pitiand ngati ntary fdback. In th bjct whhad rcrd fr AN actiity in th bgna ACCand it ntra triata targt wa iiar dring pi-ti and ngati fdback82, ggting that indiid-a with AN ha a circit-bad abnraity dringthi ip tak and ight ha difficty dicriinat-ing btwn piti and ngati fdback. Aniatdi hw that DA ha a r in th prcing f

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3358&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3358&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=9&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=9&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3358&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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Hedonic

A sensation related to or

characterized by pleasure

tiatina apct t tii in th ntra triat:DA dat th infnc f ibic inpt n tri-ata actiity30,80,81 and i thght t thrby diat thbinding fhedonic aatin f tii t bjct ract (wanting rpn)84. Th ntra triata rpnin bjct wh had rcrd fr AN82 ight rfct afair t apprpriaty bind, dat r dicriinatrpn t aint tii. Th data pprt th p-ibiity that indiida wh ha rcrd fr ANight ha an ipaird abiity t idntify th tinaignificanc f tii30, which cd b iprtant inndrtanding why it i diffict t tiat th tngag in tratnt r apprciat th cnqnc fthir bhair85.

mrr, th wn wh had rcrd fr ANhad xaggratd actiatin in th cadatdra tria-t and in th cgniti crtica rgin that prjct tthi ara, pcificay th DlPFC and th parita cr-tx82. Th cadat nc i actiatd by tak in whichthr i bth a prcid cnnctin btwn actinand tc, and ncrtainty abt whthr th

actin wi ad t th dird tc86. many f thwn indicatd an attpt at tratgic (a ppdt hdnic) rpn t ipr th rati f win t, which prhap cntribtd t th gratr actia-tin f thi rgin. In th abnc f apprpriat rwardprcing thrgh ntra-triata/DA path, indiidawh ha rcrd fr AN ight fc n a dtaidtratgy rathr than th ra itatin87. Fr anthrprpcti, cntr wn apprpriaty id in thnt. That i, thy raizd thy had t ak a gand thn d n t th nxt tak. By cntrat, bjctwith AN tnd t xaggratdy and biy wrryabt th cnqnc f thir bhair kingfr r whn thr ar nn and ar ry cn-crnd abt aking itak. A rcnt fmRI iagingtdy, ing a t hifting tak, hwd ratiy iiarfinding in indiida with AN88, nay hypactia-tin in th ntra antrir cingat-triat-thaaicp, with prdinant actiatin f frntparitantwrk. Tgthr th data ggt that indiid-a with AN ight b ab t prciy dataffcti rpn t idiaty aint tii btha incrad actiity in nrcircit cncrnd withpanning and cnqnc.

Serotonindopamine interactions. D intractinbtwn 5-HT and DA yt cntribt t ypt

in AN? It ha bn pcatd that 5-HT i th crciabtrat f an ari tiatina yt whichight pp a DA-ratd apptiti yt89,90. Indd,tdi f ania hw that 5-HT

2Crcptr tnicay

inhibit DA nrn91,92. A PeT tdy in bjct thathad rcrd fr ating dirdr fnd piti cr-ratin btwn 5-HT tranprtr and D2/D3 rcp-tr binding in th ntra triat and dra cadat(u. F. Bair and W.H.K.,npbihd bratin).Fr anthr prpcti, tdi ggt that 5-HTha a r in actin chic by cntring th ticaf dayd rward thrgh diffrntia ffct n n-tra and dra triata circit93,94. Thi i cnitnt with

idnc that rdcd and incrad 5-HT actiity araciatd with ipi, aggri bhair andbhaira inhibitin, rpctiy43,93,95. Cnidrdtgthr, indiida with AN ight ha a trait twardan ibaanc btwn 5-HT and DA pathway, whichcd ha a r in an atrd intractin btwn

ntra and dra nrcircit.Dpit cnidrab idnc f 5-HT abnr-

aiti, indiida with AN hw itt rpn, intr f iprnt f d r rdctin f crating dirdr ypt, whn tratd with ctirtnin r-ptak inhibitr (ssRI)96. Th fficacyf ssRI i dpndnt n nrna ra f 5-HT 97,and 5-HT ra in trn rt in dnitizatin fth 5-HT

1Arcptr98. It i pib that atd acti-

ity f 5-HT1A

rcptr in th raph nc f bjctwith AN (FIG. 2) rt in rdcd 5-HT nrna firing,and th dcrad xtracar 5-HT 74, cnit-nt with th rdcd CsF 5-HIAA fnd in thindiida. Thrfr, it i pib that ssRI ar ntffcti in indiida with AN bca ssRI wd

nt ha ch ffct if ynaptic 5-HT ar dptdby antritin. Priinary data rai th pibiitythat anzapin (Zyprxa; ei liy) which ha ffctn bth DA and 5-HT rcptr and piby thratypica antipychtic ight b f fr incraingwight gain and rdcing anxity and binaityin AN99.

Neurocircuitry of appetite

Hw can indiida with AN rtrict thir fd intakry day, aintain a w wight fr any yar andti di f taratin, whn t pp trg-g t a fw pnd? Apptit i a cpx incn-ti tiatina dri and i thght t dpnd nintrratd pychbigica factr incding fdrwarding prprti, an indiida htaticnd and th cgniti abiity t far atrnati (tating) bhair100102. Apptit i cary ditrbd inbjct with AN: thy diik high-fat fd103,104, dnt find cr ari whn atiatd and fai t ratfd a piti whn hngry105,106. Th rpntnd nt t chang fwing wight rgain and, antd ab, thr i idnc that ditary rtraintrdc anxity and that ating rt in dyphricd in indiida with AN53,65,66. Th cpx fdcnatry ypt f ating dirdr ar ra-tiy niq and ha a trtypic and rnt

xprin, pprting th pibiity that thy rfct abrrant fnctin f nra circit ind inrgating ating bhair.

Athgh a wt-tat prcptin tak d nt ttth cpxity f fd chic107, it can b d in brainiaging tdi t actiat brain ara ind in app-tit rgatin.swt-tat prcptin (FIG. 3) i priph-ray diatd by tng rcptr108 thrgh a nrayt cniting f crania nr, th nc tractitarii, and thaaic ntrptrir dia nc,t th priary gtatry crtx, which in han c-pri th frnta prc and th antrir ina109113.Th antrir ina and aciatd gtatry crtx

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Planning futureconsequences

Reward

Workingmemory

Bodyspace

Incentive learning(flexible)

Conflictmonitoring

Interoceptiveawareness

Affectiverelevance

DLPFCParietalcortex

ACC

Spinal cord

Chemoreceptorsof the tongue

Sensory input

C

P

OFC

Amygdala

Thalamictaste centre

NTSMedulla

Brainstem

Gustatorycortex

Anteriorinsula

Visceroception

A sensation originating from

the internal organs.

Proprioception

A sensation originating from

the joints and the

subcutaneous tissues.

rpnd t th tat and phyica prprti f fd, anday a rpnd t it rwarding prprti114117.

othr rgin cpriing th ntra nrcircitntind ab ar intrcnnctd with th ina(FIG. 3), incding th aygdaa, th ntra ACC andth oFC. Th ACC i inkd t hypthaaic and brain-t pathway that diat atnic and icra cn-tr118,119. Th prgna ACC i ipicatd in cnfict

nitring and dtct ing nprdictd tc tgid bqnt bhair80,120122. Th oFC i a-ciatd with fxib rpn t changing tii: itrpnd t th anticipatd ngati (r piti) af xtrna tii and fxiby atr rpn bad nchanging incnti a f a ti123126. Th ant-rir ina, ACC and oFC a innrat a brad rginf th rtra ntra triat, in which bhairarprtir ar cptd bad n th inpt. Thintrcnnctd rgin f th ntra nrcircit payan iprtant part in dtrining htatic app-titi nd (FIG. 3). Indd, brain iaging tdi hacnitnty hwn that fd dpriatin (cpardt haing bn fd) in hathy indiida actiat thina and th oFC117,127130. Crtica rgin incdd inth dra nrcircit ch a th DlPFC, th pari-ta crtx and th ptrir inar rgin diatcgniti fnctin ch a panning and qncing.Th rgin nd inpt t r dratra part fth triat, bt a ight intrfac and rap with

ntra triata ara131,132. Tgthr, th inpt ar

thght t dat th triata actiity that ndrith apprach r aidanc f fd.

Adinitring cr r watr t bjct whha rcrd fr AN rt in a rdcd BolDrpn in th ina, ACC and triat a cpardwith cntr bjct133. In hathy cntr, f-ratingf paantn f th gar tat crratd pitiywith th BolD rpn in th ina, th ACC and th

ntra and dra ptan133. Cnitnt with th idathat th abiity t prci a paatab tat i fndan-tay atrd in AN, indiida wh had rcrd frAN faid t hw any ratinhip btwn actiity inth rgin and f-rating f th paantn f thcr tat. Th finding ar pprtd by thrbrain iaging tdi in which th bratin f fdpictr by ndrwight bjct with AN d t atrdactiity in th ina, th oFC, th ia tpra andparita crtx and th ACC134138. mrr, th atrdactiity in th prgna ACC and dia prfrn-ta crtx pritd aftr rcry33. Atrd actiityin th antrir ina, it visceroceptive and propriocep-tive affrnt, and it ffrnt t th oFC, th ACC,th aygdaa and th ntra triat ight ndri thatratin fnd in bjct with AN in inking nry-hdnic xprinc t th tiatina cpnntf rward139.

A central role for the anterior insula?Th antririna i crciay ind in intrcpti prc-ing140142. Intrcptin incd a rang f natinbynd tat, incding th prcptin f pain, t-pratr, itch, tick, na tch, c tnin, airhngr, tach pH and inttina tnin. Intgratinf th intrna fing prid an intgratd n fth phyigica cnditin f th ntir bdy143 and icrcia fr th intantiatin f th f bca it pr-

id th ink btwn cgniti and affcti prcand th crrnt bdy tat140142,144,145.

It i thght that atrd intrcpti awarn ightb a prcipitating and rinfrcing factr in AN10,146148.

Figure 3 | cta-tata atway wt a n tat. Chemoreceptors on the

tongue detect a sweet taste. The signal is then transmitted through brainstem and

thalamic taste centres to the primary gustatory cortex, which lies adjacent to and is

densely interconnected with the anterior insula. The anterior insula is an integral part of

a ventral (limbic) neurocircuit through its connections with the amygdala, the anterior

cingulate cortex (ACC) and the orbitofrontal cortex (OFC). Afferents from the corticalstructures involved in the ventral neurocircuit (anterior insula and interconnected limbic

cortices) are directed to the ventral striatum, whereas cortical structures involved in

cognitive strategies (forming a dorsal neurocircuit) send inputs to the dorsolateral

striatum. Therefore, the sensory aspects of taste are primarily an insula phenomenon,

whereas higher cortical areas modulate pleasure, motivation and cognitive aspects of

taste. These aspects are then integrated, resulting in an eat or do not eat decision.

Coding the awareness of pleasant sensation from the taste experience via the anterior

insula might be altered in subjects with anorexia nervosa, tipping the balance of striatal

processes away from normal, automatic reward responses mediated by the ventral

striatum and towards a more strategic approach mediated by the dorsal striatum. The

figure links each cortical structure with arrows, indicating that all cortical structures

project to striatum in a topographic manner.DLPFC, dorsolateral prefrontal cortex; NTS,

nucleus tractus solitarii.

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C

P

C

P

Foodpresentation

Foodpresentation

Interoceptivesignals

Interoceptivesignals

Amygdala

DLPFC

Anterior insulaParietalcortex

Posteriorinsula

Positivevaluation

Negativevaluation

Top-downmodulatoryinfluence

Approach foodEat food

Dont approach foodAvoid food in the future

Short-term Long-term Short-term Long-term

Consequences Consequences

Satisfyinghunger

Stayingthin

Healthy Anorexia nervosa Th r f th antrir ina in intgrating intrcp-ti infratin and th atrd ina actiity that habn fnd in indiida with AN ( arir) pprtth ida that thy ight ffr fr a fndantay andphyigicay atrd n f f149. Indd, any f thypt f AN, ch a ditrtd bdy iag, ack frcgnitin f th ypt f antritin (fr xap,a fair t apprpriaty rpnd t hngr) and diin-ihd tiatin t chang, cd b ratd t ditrbdintrcpti awarn. In particar, thr ight b aqaitati chang in th way that pcific intrcptiinfratin i prcd. Fr xap, indiida withAN ight xprinc an ari icra natin whnxpd t fd r fd-ratd tii. Thi xprincight fndantay atr th rward-ratd prprtif fd and rt in a bia tward ngati tinaity.mrr, th ari intrcpti xprinc aciatdwith fd ight triggr tp-dwn datry prcaid at anticipating and iniizing th xpr tfd tii (har aidanc), which ad t incradanticipatry prcing aid t rdc th xpr t

th ariy ad ti. Thrfr, indiida withAN ight xhibit attnatd rpn t th idiatrward-ratd igna f fd (rdcing hngr) bt hwincrad rpn t th ng-tr rward-igna a-ciatd with th ga f wight rdctin r thr idacgniti cntrct. Finay, th antrir ina ha bnipicatd in rik prdictin rrr150, ggting thatipairnt in ina fnctin ight ad t anaattitd in a cntxt f ncrtainty and th cntribtt har aidanc.

Thrfr, gin th prinnt atratin in inaactiity in indiida with AN, n ight pcat thatthy xprinc an atrd nitiity t r intgratin fintrna bdy igna. spcificay, th prjctin f thantrir ina t th antrir cingat ay datth dgr t which cgniti cntr i ngagd t atrbhair tward pr dciin aking that d ntbr th htatic wight baanc bt intadrt in prgri wight .

A neurocircuitry of appetite regulation in AN. Badn th ab prc and aciatd brain ara, wcan bgin t ab a nra yt prcingd f AN (FIG. 4). spcificay, tp-dwn (crtica)apificatin f anticipatry igna ratd t fdr tii aciatd with atity igna (intgratdwithin th ina)cd triggr bhaira tratgifr aiding xpr t fd. Th anticipatry int-rcpti tii ar aciatd with an ari bdytat that rb apct f th phyigica tatf th bdy aftr fding. Thi abnra rpn tfd anticipatin ight fnctin a a arning ig-na t frthr incra aidanc bhair, that i,t ngag in actiiti aid at iniizing xpr tfd. spcificay, tii that prdict fd intak, cha dipay f fd r fd , cd gnrat abdy prdictin rrr, rting fr cparing thcrrnt bdy tat with th anticipatd bdy tat (frxap, fing atiatd) aftr fding. Thi prdictinrrr wd gnrat a tiatina r apprach igna

Figure 4 | ima baan btwn ntt an wa ng. We

propose that subjects with anorexia nervosa (AN) experience a strong conflict between

the biological need for food and the acquired aversive association with food. In healthy

individuals, the presentation of foodrelated stimuli is associated with ascending

interoceptive afferents that converge on the anterior insula, which processes

staterelated positive or negative valuation of these signals. In individuals with AN this

interoceptive information is biased towards the negative or aversive properties of food.

As a consequence, topdown, cortical circuits (dotted box) are engaged to resolve theconflict between the need for food and the aversive interoceptive evaluation,

processed in the anterior insula. Thus, topdown modulatory circuits are overengaged

in people with AN, which emerges on a symptomatic level as high anticipatory

reactivity, behavioural rigidity and excessive worry about future events. On a biological

level, these dysfunctions are implemented in a neural system consisting of the

ascending interoceptive pathways, the insular cortex, the amygdala and the anterior

cingulate cortex (not shown). This information converges in the striatum, which receives

inputs from the anterior insula (for the integrated bottomup information) and the

prefrontal cortex (for the topdown modulation relating to cognitive control circuits).

The excessive topdown cognitive control in subjects with AN in response to

interoceptive stimuli alters the striatal responses, shifting the behavioural event horizon

towards satisfying longterm goals (avoiding food, getting thin) rather than shortterm

goals (eating food).

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in hathy indiida bt ight ad t an aidancigna in AN.

Th dra and ntra nrcircit dcribd ariright b ind in th prc: Th ACC, n fth prjctin ara f th inar crtx, i iprtantin prcing th cnfict btwn aaiab bhairand tc, fr xap, ha I at thi cak and at-ify y hngr nw r ha I nt at thi cak and taythin?151. Th oFC, anthr prjctin ara f th ant-rir inar crtx152, can dynaicay adjt rward

aatin bad n th crrnt bdy tat f th indi-ida153. Th DPlFC can witch btwn cptingbhaira prgra bad n th rrr igna itrci fr th ACC154.

Athgh w d nt prp hr that AN i an ina-pcific dirdr, w pcat that an atrd inarpn t fd-ratd tii i an iprtant cp-nnt f thi dirdr. If thi i indd th ca, n wdnd t dtrin whthr ina-pcific intrntin,ch a nitizatin r habitatin f intrcpti ni-tiity thrgh ra-ti nitring f th inar crtx

actiatin, ight hp. mrr, cptatina dch a th that ha bn prpd fr addictin155ight prid a thrtica apprach t bttr ndrtandth cpx pathgy f thi dirdr.

Within th frawrk f th ntra and dranrcircit dcribd arir, thr ar a ptn-tia xpanatin fr thr cr cpnnt f cinicadyfnctin in AN. Ngati affct ch a anxityand har aidanc and anhdnia cd b ratdt difficti in accraty cding r intgrating pi-ti and ngati tin within ntra triata cir-cit.Thr i cnidrab rap btwn circitthat dat tinaity and th rwarding apctf fd cnptin156. Fd i parab in hathyindiida bt fding i anxignic in indiida withAN, and taratin ight r t rdc dyphricd tat. Th nrbigic chani rpni-b fr ch bhair rain t b cidatd, bt it ipib that an nhancnt f 5-HT-ratd aritiatin, and/r diinihd DA-ratd apptitidri89,90 cntribt t th bhair.

Finay, it i pib that prfctini and b-ina prnaity trait ar ratd t xaggratd cgni-ti cntr by th DlPFC. Th DlPFC ight dpxci inhibitry actiity t dapn infratinprcing thrgh rward pathway157. Atrnatiy,incrad actiatin f cgniti pathway ight c-

pnat fr priary dficit in ibic fnctin: whnthr ar dficit in tina rgatin, rdpnd-nc pn cgniti r i a ranab tratgy ff-anagnt158. Th inabiity t fw n gt(r hart) that i, ak ffcti f intrcp-ti infratin i ipaird in indiida with AN.mrr, thr i a car hift away fr aing i-diat tc t th aciatd with dayd r ng-tr tc. Thi bhair i at cptyppit t that brd in indiida with ach rbtanc ab159 and i cnitnt with th bra-tin that indiida with AN ha w crbidity withdrg and ach dirdr160.

Conclusions and future directions

W prp that atic, atnic and icra infr-atin i abrranty prcd in pp wh ar -nrab t dping AN. Brain chang aciatdwith pbrty ight frthr chang th prc.Fr xap, rbita and dratra prfrnta crtxrgin dp graty dring and aftr pbrty161, andincrad actiity f th crtica ara ight b a caf th xci wrry, prfctini and tratgizingin pp with AN. It i pib that in bjct withAN, hypractiity f cgniti ntwrk in th dranrcircit (fr xap, DlPFC t dra triat)dirct tiatd actin whn th abiity f th ntratriata pathway t dirct r atatic r intititiatd rpn i ipaird. Anthr pibiity ithat in indiida with AN (thrwi adqat) ibic-triata infratin prcing in th ntra circit i ttrngy inhibitd by cnrging inpt fr cgnitidain ch a th DlPFC and th parita crtx.

It i pib that ch trait-ratd ditrbanc arratd t atrd nain nrna datin that

prdat th nt f AN and cntribt t prrbidtprant and prnaity ypt. spcificay,ditrbanc in th 5-HT yt cntribt t a nr-abiity fr rtrictd ating, bhaira inhibitin anda bia tward anxity and rrr prdictin, whraditrbanc in th DA yt cntribt t an atrdrpn t rward. sra factr ight act n th

nrabiiti t ca th nt f AN in adcnc.Firt, pbrty-ratd fa gnada trid r ag-ratd chang ight xacrbat 5-HT and DA ytdyrgatin. scnd, tr and/r ctra and ci-ta prr ight cntribt by incraing anxiand bina tprant. Indiida find thatrtricting fd intak i pwrfy rinfrcing bcait prid a tprary rpit fr dyphric d.Pp with AN ntr a ici cyc which cdaccnt fr th chrnicity f thi dirdr bcaating xaggrat, whra fd rfa rdc, ananxi d.

Th tprant and prnaity trait that ightcrat a nrabiity t dp AN ight a ha apiti apct. Th trait incd attntin t dtai,cncrn abt cnqnc and a dri t accpihand ccd. It i r cinica xprinc that anyindiida wh rcr fr AN d w in if. It itpting t pcat that th abiity t pan ahad, cn-tr ip, and aid har ight ha had highy

adapti a fr anctr wh id in nirnntwhr fd ppi wr cntraind by ng pridf cd wathr (fr xap, wrry in Jy abt fdppi in Janary). Adcnc i a ti f tranitin:indiida a th crity f thir h nirnntand t arn t baanc idiat and ng-trnd and ga t achi indpndnc158. Fr chindiida, arning t fxiby intract with and atrcpx and ixd ctra and cita ag andprr and cp with tr, ight b diffict andrwhing, which cd xacrbat pib ndr-ying trait f har aidanc and a dir t achiprfctin.

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AN ha th hight rtaity rat f any pychi-atric dirdr. It i xpni t trat and w ha

inadqat thrapi. It i crcia t ndrtand thnrbigic cntribtin and thir intractinwith th nirnnt, in rdr t dp r ffc-ti thrapi. Thrfr, ftr iaging tdi hdfc n charactrizing nra circit, thir fnctin

and thir ratinhip t bhair in indiida withAN. Gntic tdi ight hd ight n th cpx

intractin f c within th nra circit.Finay, prpcti and ngitdina tdi hdfc n idntifying th nrbigic trait andxtrna factr (BOX 2) that crat a cptibiity frdping AN.

Box 2 | From vulnerability to illness the complex aetiology of anorexia nervosa

Anorexianervosa(AN)isthoughttobeadisorderofcomplexaetiology,inwhichgenetic,biological,psychologicaland

socioculturalfactors,andinteractionsbetweenthem,seemtocontributesignificantlytosusceptibility10,11,158,162.Because

nosinglefactorhasbeenshowntobeeithernecessaryorsufficientforcausinganorexianervosa,amultifactorial

thresholdmodelmightbemostappropriate(forareviewseeREF. 158).Typically,ANbeginswitharestrictivedietand

weightlossduringteenageyears,whichprogressestoanout-of-controlspiral(FIG. 1).Therefore,individualsmightcross

athresholdinwhichapremorbidtemperament,interactingwithstressand/orpsychosocialfactors,progressestoan

illnesswithimpairedinsightandapowerful,obsessivepreoccupationwithdietingandweightloss.Adolescenceisatimeofprofoundbiological,psychologicalandsocioculturalchange,anditdemandsaconsiderabledegreeofflexibilityto

successfullymanagethetransitionintoadulthood.Psychologically,changemightchallengetheperfectionism,harm

avoidanceandrigidityofthoseatriskofANandthusfuelanunderlyingvulnerability.Thebiologicalchangesof

adolescenceorpubertymightalsoincreasetheriskofonsetofeatingdisorders.Thispossibilityissupportedbytwin

studies163whichimpliedthatpubertymighthavearoleinactivatingthegeneticpredispositionforeatingdisorder

symptoms.Moreover,thebiologicalchangesassociatedwithadolescencedifferbetweenmalesandfemales,which

couldexplainthesexualdimorphismofAN.Forexample,menarcheisassociated158witharapidchangeinbody

compositionandneuropeptidesmodulatingmetabolism.Littleisknownaboutwhethertheriseinoestrogenlevels

associatedwithpubertyinfemalesiscontributorytoAN,butitcouldaffectneuromodulatorysystemssuchas

serotonin164orneuropeptides165thataffectfeeding,emotionalityandotherbehaviours.

1. American Psychiatric Association. Diagnostic and

Statistical Manual of Mental Disorders 4th edn

(American Psychiatric Association, Washington, DC

1994).

2. Lilenfeld, L. R. et al. A controlled family study of

anorexia nervosa and bulimia nervosa: psychiatric

disorders in first-degree relatives and effects of proband

comorbidity.Arch.Gen.Psychiatry55, 603610

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AcknowledgementsMuch of the research incorporated into this Review was sup-

ported for W.H.K. by the National Institute of Mental Health

(NIMH) (046001, 042984, 066122 and 001894) and the

Price Foundation, for J.L.F. by the NIMH (063291) and for

M.P. by the National Institute on Drug Abuse (016663,

018307 and 020687) and the Center of Excellence in Stress

and Mental Health.

DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

5HT1A

| 5HT2A

|DRD2 | DRD3

FURTHER INFORMATIONWalter H. Kayes homepage:http://eatingdisorders.ucsd.edu/

All liNks Are AcTive iN The oNliNe pdf

R E V I E W S

584 | AuGusT 2009 | volume 10 / /
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=9&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=9&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://eatingdisorders.ucsd.edu/http://eatingdisorders.ucsd.edu/http://eatingdisorders.ucsd.edu/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=9&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3356&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3350&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

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