Brain imaging studies of appetite in the context of obesity and the menstrual cycle

17 Pages·2009·0.56 MB·English

Human Reproduction Update Advance Access published November 19, 2009
HumanReproductionUpdate,Vol.00,No.00pp.1–17,2009
doi:10.1093/humupd/dmp051
Brain imaging studies of appetite in the
context of obesity and the
menstrual cycle
Dean A. Van Vugt1
DepartmentsofObstetricsandGynaecologyandPhysiology,Queen’sUniversity,Kingston,ON,Canada,K7L3N6
1Correspondenceaddress.Tel:þ1-613-533-2899;Fax:þ1-613-533-6779;E-mail:[email protected]
table of contents
........................................................................................................................... D
o
w
† Introduction n
lo
Obesity ad
e
Article overview d fro
† Methods m
† Regulationof eating http
Neuroendocrine(homeostatic)control ://h
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Hypothalamicdetection of energybalance signals m
u
Hedoniceatingand thecorticolimbicbrain pd
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† Imaging networks affecting ingestion x
fo
Functional magnetic resonanceimaging rd
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Stimulus protocols u
rn
Brainresponsestovisual food cues als
† Appetiteregulationin women .org
Menstrual cycle relatedchanges in appetite b/
y
Effect ofovariansteroids gu
e
Ovariansteroidhormones siteof action st o
Imagingmenstrualcycle dependentchanges in appetite n N
Effect ofmood on brain response tofood cues ov
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m
Imagingeatingdisorders b
e
† Summaryand conclusions r 4
† Supplementary data , 20
1
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background:
Obesityaffects many aspects of health, including reproduction. Despite unrelenting warnings about the health conse-
quencesofobesity,itsprevalencecontinuestorise.Beginningwiththediscoveryofleptinin1994,theendocrinologyofenergyhomeostasis
hasbeensignificantlyadvanced.Morerecently,brainimagingstudieshavebeenprovidingnovelinsightsintohomeostaticandhedonicaspects
of human ingestivebehavior.
methods:
A comprehensive MEDLINE search was conducted on the topic of neuroendocrine control of ingestive behavior with an
emphasis on functional magnetic resonance imaging studies. Additional articles were collected by hand searching the bibliographies of all
relevant articles retrieved.
results:
Thisreviewdescribesrecentadvancesinourunderstandingofendocrinesignalsthatrespondtoacuteandchronicenergystates
andregulateingestivebehaviorsoastoachieveabalancebetweenenergyintakeandenergyexpenditure.Recentlypublishedbrainimaging
studies, describing the neural networks that process endocrine signals of energy state and hedonic cues associated with highly palatable
foods, are highlighted. Brain responses to food cues are described in the context of appetite changes during the menstrual cycle both in
normal physiologyand undertheconditions anorexianervosaand bulimia nervosa.
&TheAuthor2009.PublishedbyOxfordUniversityPressonbehalfoftheEuropeanSocietyofHumanReproductionandEmbryology.Allrightsreserved.
ForPermissions,pleaseemail:[email protected]
2 VanVugt
conclusions:
The prevalence of obesity belies the plethora of endocrine signals in place to ensure energy homeostasis. However,
satietysignalsappeartobecounteractedbyhedonicsignalsderivedfromhighlypalatablefoodstypicaloftoday’sdiet.Abetterunderstanding
oftheinteractionbetweenhomeostaticandhedonicsignalsisneededtodeviseeffectivestrategiesfordealingwithobesity.Menstrualcycle
dependentchangesinbrainresponsestofoodcuesmayprovideinsightintothenormalphysiologicalcontrolofingestivebehavioraswellas
dysfunctional regulationassociated withdisorderedeating.
Keywords: obesity /functional magnetic resonance imaging / appetite/ homeostatic/ menstrual cycle
Introduction has been recommended that fertility therapy be delayed until signifi-
cantweightlossisachieved(Balenetal.,2006).However,sucharec-
Obesity ommendation needs to be accompanied by a comprehensive and
effectiveplantowardsachievingthestatedweightlossgoalsthatistai-
The alarm about increased obesity rates was sounded more than
lored to the patient. Clearly we do not understand the regulation of
20 years ago. The prevalence of obesity has more than doubled in
ingestivebehaviorwellenoughtodeviseeffectivestrategiesfortreat-
the 1980s and 1990s (Flegal et al., 2002). Today, about two-thirds
ing or preventing obesity in today’s obesogenic environment that is
of the USA adult population is either overweight [defined as having
characterized by ready access to highly palatable calorically dense D
a30bkog/dmy2)m.aOssverin3d0e%x o(BfMthIe)¼po2p5u–la2ti9o.n9iksgo/mbe2s]eowrheorebaesse5%(BoMf Ith(cid:1)e foodsand asedentaryworkand leisureenvironment. ownlo
a
population is extremely obese (BMI(cid:1)40kg/m2). The prevalence of Article overview ded
childhood obesity (defined as (cid:1)95th percentile) is most concerning. fro
This article will review our current understanding of appetite regu- m
On the basis of the National Health and Nutrition Examination h
Survey conducted in 1999–2000, childhood obesity occurred at a lation.Theendocrinefactorsthatsignalenergystateandaffectinges- ttp
rate of 17%, which is a 3–4-fold increase compared with the survey tive behavior, so as to achieve a balance between energy intake and ://h
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energyoutput (homeostatic regulation),arereviewed, andthis isfol- m
conducted in 1963–1970 (Ogden et al., 2006). Whereastype II dia- u
beteswasonceconsideredadiseaseofadults(adultonsetdiabetes), lowed by a discussion of non-homeostatic regulation of ingestive be- pd.o
havior, also known as hedonic eating. Recent imaging studies that x
itsincidenceinyouth,particularlyinminorities,hasincreasedmarkedly fo
andnowaccountsforaboutone-thirdofallnewcasesofdiabetesin describe how the brain responds to food cues will be discussed in rdjo
detail. Because food ingestion changes during the menstrual cycle, u
children(Rosenbloometal.,1999).Becauseobesityisassociatedwith rn
an increased risk of cardiovascular disease and cancer in addition to we have initiated functional neuroimaging studies in order to under- als
.o
diabetes (Must et al., 1999), it has been suggested that the average stand the mechanisms whereby ovarian steroids influence ingestive rg
behavior. This review will provide the reader with an up to date b/
lifespancoulddeclineforthefirsttimeinrecordedhistory(Olshansky y
et al., 2005). The financial consequences of obesity in the USA in summary of recent developments in appetite regulation, with an gue
terms of provision of health care as well as the indirect costs of emphasis on brain imaging studies that provide novel insights into st o
n
reduced productivity were estimated in 2004 to be between 75 and thebiologyand psychologyof humaningestive behavior. N
o
v
100billion dollars (Finkelstein et al., 2004; Allison et al., 1999). The e
m
direct costs of obesity in the UK in 2002 were estimated to be Methods be
6billion pounds annually (Rayner and Scarborough, 2005). The r 4, 2
World Health Organization stated in 2003 thatobesity is one of the English language journals were searched using PubMed. Articles were 01
6
mostseriousworld health problems (Kelnerand Helmuth,2003). retrievedusingthefollowingmeshtermsorkeywords:obesity,appetite,
hunger,satiety,eating,anorexianervosa,homeostatic,hedonic,reward,
functional magnetic resonance imaging, functional magnetic resonance
Reproductive effects of obesity
imaging (fMRI), food addiction, dopamine, menstrual cycle, estrogen,
The incidence of several pregnancy associated complications (pre- progesterone and corticolimbic. Additional articles were collected by
eclampsia, gestational diabetes, hypertension and Cesarean section) handsearchingthebibliographiesofthemostrelevantretrievedarticles
and birth defects (cardiac and neural tube) are increased 2–5-fold and using the ‘cited by’ and ‘similar articles’ feature available either
in obese women (Watkins et al., 2003; Cedergren, 2004; Weiss throughPubMedortheelectronicversionofretrievedarticles.
etal.,2004).Obesityisacontributingfactorinanovulatoryinfertility.
It is estimated that fecundity progressively declines by about 4% for
Regulation of eating
each BMI value above 29kg/m2 (The Practice Committee of the
American Society for Reproductive Medicine, 2008). Conversely,
Neuroendocrine (homeostatic) control
weightlossimprovesfecundity(Clarketal.,1998).In-vitrofertilization
is less effective in the obese patient. Compared with non-obese There has been a significant advancement in our knowledge about
women, a pregnancy odd ratio was calculated as 0.75 for obese appetiteregulationandenergybalanceinthepast15years,beginning
women and 0.5 for women in the very obese category (Wang with the exciting discovery of leptin in 1994 (Zhang et al., 1994).
et al., 2002b). Obese women also have a higher miscarriage rate In addition, a number of gastrointestinal hormones that change in
(Wang et al., 2002b; Fedorcsak et al., 2004). For these reasons, it response to a meal have been discovered subsequent to leptin. The
Imagingstudiesofappetite,obesityandthemenstrualcycle 3
following is a partial list of factors involved in energy balance regu- CCK receptors are obese (Moran et al., 1998). Despite these
lation,alongwith abrief description oftheir physiology. compelling results, chronic CCK administration was ineffective
in reducing food intake and weight. Although CCK reduced
(i) Leptinisa16kDacytokineproducedbytheadipocyte.Thedis- meal size, meal frequency was increased (West et al., 1984).
coveryofleptinin1994generatedmuchexcitementduetothe CCKagonistsarenolongerconsideredtobeviabletherapeutic
remarkable weight loss achieved by leptin replacement in options (Fong, 2005).
a leptin deficient mouse strain called the ob2/ob2 mouse (iv) Peptide YY (PYY) has garnered considerable attention as a
(Campfield et al., 1995; Halaas et al., 1995; Pelleymounter physiological regulator of appetite. PYY is produced in L
1-36
et al., 1995). Although leptin moderately inhibited food intake cells of the distal ileum and colon and is released in the post-
and reduced weight in animals that were not leptin deficient, prandialperiod(McFaddenetal.,1989).PYYcirculatesprimarily
most clinical trials have not demonstrated significant weight asPYY followingcleavageofPYY bydipeptidylpeptidase
3-36 1-36
loss in obese humans (Hukshorn et al., 2002; Heymsfield (Grandt et al., 1994; Le Roux et al., 2006). Several studies
et al., 1999; Zelissen et al., 2005). In contrast, the same leptin showed that PYY administration inhibited food intake in
3-36
formulation melted away the fat when given to obese humans rodentsaswellasinhumanandnon-humanprimates(Batterham
who were leptin deficient due to a rare genetic mutation et al., 2002; Challis et al., 2003; Cox and Randich, 2004;
(Farooqi et al., 1999, 2002; Campfield et al., 1995; Williamson Halatchev et al., 2004; Chelikani et al., 2005; Degen et al.,
etal.,2005).Becauseleptinlevelsinthecirculationarealready 2005; Koegler et al., 2005; Moran et al., 2005; Le Roux et al.,
increasedinthevastmajorityofobeseindividuals,itisnotsur- 2006; Papadimitriou et al., 2007). Circulating PYY levels are Do
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prisingthatelevatingleptinlevelsfurtherhadlittleeffect.Itwas reduced in obese humans, whereas plasma concentrations are n
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concluded that chronically elevated leptin levels lead to leptin increased with anorexia nervosa (Misra et al., 2006; Pfluger ad
e
rweesiigsthatnlcoesswinhtihcheocboensterib(SuctaerspatcoealenpdtiTnu’smeinra,b2i0lit0y1).toAltihnoduugche eAtlthaol.u,gh20i0t7w)aasnidnitdiailslyorpdreorepdoseedatitnhgat(PScYhYeidmigehttaclo.,nt2r0ib0u9t)e. d from
leptin is no longer considered a potential first line therapy for to these phenotypic changes, this appears not to be the case http
weight loss, it has been proposed that leptin may be effective since PYY levels were reduced in a rat model of diet induced ://h
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as an adjunct for weight loss maintenance, presumably after obesity (Le Roux et al., 2006). In addition, PYY levels were m
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leptin sensitivity has been normalized (Fogteloo et al., 2003). increased following bariatric surgery (Ballantyne, 2006; Meguid pd
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The consensus is that low rather than high leptin levels et al., 2008), but these changes may result from weight loss x
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provide important information about energy balance. Low rather than cause weight loss. A limited number of clinical rd
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leptin levels signal a chronic negative energy state, resulting in trials do not support PYY as a viable weight loss drug. Subcu- u
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energyconservationthroughreducedmetabolismandinhibition taneous PYY3-36 administration at doses well tolerated did not als
ofthereproductiveaxis(Ahimaetal.,1996).Stimulationofthe acutely reduce food consumption. Intranasal PYY3-36 adminis- .org
reproductiveaxisoccurredwhenexogenousleptinwasadminis- tration for 2 weeks did not promote weight loss, whereas b/
y
tered for 3 months to lean anovulatory women (Welt et al., higher PYY dosesthatdid resultin reduced food consumption gu
e
2004). A low leptin concentration is a stimulus to eat were associated with nausea (Gantz et al., 2007; Sloth et al., st o
whereas a chronically elevated leptin concentration may have 2007b,a). n N
little effect on food intake. (v) Glucagon likepeptide-1(GLP-1) is apost-translationalproduct ov
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(ii) Adiponectin, like leptin, is a cytokine produced by adipocytes, of the pre-proglucagon gene. GLP-1 is released from the L
b
e
but unlike leptin, adiponectin levels are inversely correlated cellsoftheintestinesinresponsetocarbohydrates.GLP-1inhi- r 4
with adiposity. Adiponectin’s role in energy balance is contro- bitsgastricemptying,inhibitsglucagonandinhibitsfoodintakein , 2
0
1
versial. Although elevated adiponectin is associated with a lean rodents(asreviewedinMurphyetal.,2006)andhumans(Gutz- 6
phenotype,itmayormaynotinhibitfoodintake,anddisruption willer et al., 1999; Edwards et al., 2001). Administration of
of adiponectin signaling, unlike leptin, does not result in an GLP-1togetherwithPYY inhibitedfoodintakeinanadditive
3-36
obesephenotype(HenryandClarke,2008).Thefocusofadipo- fashioninbothrodentsandman(Nearyetal.,2005).Inaddition
nectin is more on aspects of metabolic syndrome other than to inhibiting appetite, GLP-1 has a significant effect on glucose
appetite regulation. Adiponectin increases insulin sensitivity homeostasis. Exenatide, a long acting GLP-1 agonist approved
and its anti-inflammatory action may inhibit vascular wall injury for treating type II diabetes, inhibited glucagon, increased
and atherosclerosis (Diez and Iglesias, 2003; Goldstein and insulin, improved glycemic control and reduced weight in a 30
Scalia, 2004). weeks clinical trial (Buseet al., 2004;DeFronzo et al., 2005).
(iii) Cholecystokinin (CCK) wasthe first gut hormone identified to (vi) Oxyntomodulin,likeGLP-1,isproducedintheLcellsfromthe
have satiety effects (Gibbs et al., 1973). CCK is released pre-proglucagon gene. Oxyntomodulin is released post-
within minutes of eating, inhibits gastric emptying, and is prandially, inhibits gastric emptying and reduces food intake
thought to play a role in meal termination. CCK appears to (as reviewed in Murphy et al., 2006). Oxyntomodulin may act
inhibit food intake through multiple mechanisms. The satiety attheGLP-1receptortoinhibitfoodintake.Inadditiontosup-
effects of CCK are mediated in part by vagal afferents (Moran pressing appetite, oxyntomodulin increases energyexpenditure
and Kinzig, 2004). In addition, CCK receptors are present in (Wynneet al., 2006).
the hypothalamus, and intra-hypothalamic injection of CCK (vii) Amylin is a 37 amino acid peptide produced in b cells of the
can inhibit food intake (Blevins et al., 2000). Rats that lack pancreas and is released along with insulin after a meal.
4 VanVugt
Amylin slows gastric emptying and inhibits glucagon release. stimulate food intake (de Lecea et al., 1998; Sakurai et al., 1998).
Exogenous amylin reduces food intakein rodents (Lutz, 2005). Orexins are also important in wakefulness as orexin knockout
The resulting weight loss is primarily due to a reduction in fat animals are narcoleptic (Siegel, 1999). Orexin positive neurons orig-
mass (Roth et al., 2006). Pramlintide, a long acting amylin inatinginthelateralhypothalamusprojecttotheamygdala,ventralteg-
agonist,whenusedincombinationwithinsulin,improvedglyce- mental area, and thenucleus accumbens and maybe responsible for
miccontrolandpreventedtheweightgainthatnormallyaccom- reward related eating (Berridge, 1996; Boutrel and de Lecea, 2008).
paniesinsulintherapy(Pullmanetal.,2006).Pramlintidetherapy The precise mechanisms whereby stimulation or inhibition of orexi-
(compared with placebo) together with life style modification genic NPY/AgRP and orexin neurons and anorexigenic POMC/
produced significant and sustained weight loss (Smith et al., CART neurons within the arcuate nucleus and lateral hypothalamus
2008). lead to a change in ingestive behavior is poorly understood. These
(viii) Ghrelin is a 28 amino acid peptide, discovered in 1999, which peptidergic neurons project to the paraventricular nucleus within the
binds to the growth hormone secretagogue receptor (Kojima hypothalamus as wellasto extrahypothalamic areas. In addition, glu-
et al., 1999). In addition to stimulating growth hormone, tamatergic and GABAergic efferents mediate the effect of these
exogenousghrelinstimulatesfoodintake(theonlyknowncircu- neuropeptides on eating through projections to corticolimbic regions
latingorexigenichormone).Ghrelinisreleasedfromthefundus (Zhengetal.,2003).However,themechanismwherebytheseprojec-
of the stomach and appears to be a physiological regulator of tions influence ingestivebehaviorisyettobe defined.
eating (Wren et al., 2001; Wang et al., 2002a). Ghrelin levels
are highest just before a meal and decline shortly after food Do
Hedonic eating and the corticolimbic brain w
ingestion. Ghrelin levels are reduced with obesity and may n
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reflect dysregulated ghrelin secretion as a result of chronic Eatingisacomplexbehaviorthatisnotsimplyturnedonorturnedoff ad
e
hpyaptieernptshaagniad.hIanscboenetnraimst,plgicharteeldininisthinecrheyapseerdphiangiParoadfethri–sWsynill-i byhormonesthatsignalenergystate.Thepleasuresderivedfromthe d from
drome(Cummingsetal.,2002a).Adramaticreductioninghrelin http
levels following gastric bypass surgery may contribute to the ://h
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success of this procedure in achieving long-term weight loss m
u
(Cummings et al., 2002b). Ghrelin agonists may prove useful pd
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in treating cahexia whereas antagonists may be developed as x
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a medical treatment for obesity. The reader is referred to rd
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(Jayasena and Bloom, 2008) for more details about these gut u
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derivedhormones. als
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rg
b/
Hypothalamic detection of energy balance y
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signals e
s
t o
Thehypothalamusplaysacriticalroleinthereceiptandtransduction n N
oftheaforementionedcirculatingsignalsofenergystate.Receptorsfor ov
e
m
thesehormonesarepresentwithinhypothalamicpeptidergicneurons
b
e
thataffectingestivebehavior.Activationofneurons,withinthearcuate r 4
nucleus of thehypothalamus, thatco-express neuropeptide Y(NPY) , 2
0
1
and agouti regulatedpeptide (AgRP) playa pivotal role in stimulating 6
food intake, whereas activation of arcuate neurons that co-express
pro-opiomelanocortin (POMC) and cocaine-amphetamine regulated
Figure 1 Neuroendocrine control of ingestive behavior. The
transcript (CART) inhibit food consumption (Schwartz et al., 1996,
effects of leptin, insulin and ghrelin on the hypothalamus and
1997; Elias et al., 1998, 1999; Baskin et al., 1999; Cowley et al.,
ventral tegmental area (VTA) are shown. Leptin and insulin inhibit
2001;Halatchevetal.,2004)(Fig.1).Theseneuronscontainreceptors
food intake by stimulating POMC/CART neurons and inhibiting
for leptin (Mercer et al., 1996), PYY, GLP-1(Christophe, 1998) and NPY/AgRP neurons in the arcuate nucleus whereas ghrelin has the
ghrelin (Nakazato et al., 2001; Zigman et al., 2006). Leptin, PYY3-36 opposite effects. Leptin and insulin inhibit dopamine neurons in the
and GLP-1 inhibit food intake by inhibiting NPY/AgRP neurons VTA whereas ghrelin stimulates dopamine. Hypothalamic and VTA
whereas ghrelin stimulates food intake by stimulating NPY/AgRP control of appetite is further coordinated through communication
neurons. In contrast, leptin, PYY and GLP stimulate POMC/ between the lateral hypothalamus and VTA. Dopamine neurons in
3-36
CART neurons whereas ghrelin inhibits them. A coordinated neuro- the VTA project to the nucleus accumbens. Connections between
the corticolimbic brain (hippocampus, amygdala, prefrontal cortex
chemical response is ensured by inhibitory synaptic communication
andinsula)andthenucleusaccumbenssynthesizesthe‘appropriate’
between NPY/AgRP and POMC/CART neurons (Broberger et al.,
behavioral response based on input by leptin, insulin and ghrelin
1997; Elmquist et al., 1998; Elias et al., 1999). In addition to the
about energy state and reward potential determined by experi-
arcuate nucleus, the lateral hypothalamus regulates energy intake.
ence/memory and gustatory input from corticolimbic regions
TheneuropeptidesOrexinAandB(alsocalledhypocretins)aresyn-
[adaptedfromPalmiter(2007)withpermissionfromElsevier].
thesized in the lateral hypothalamus and as their name implies,
Imagingstudiesofappetite,obesityandthemenstrualcycle 5
taste, smell and texture of food promote eating despite the brain’s Functional magnetic resonance imaging
receptionofpositiveenergybalancesignals(increasedconcentrations
Functional MRI is a powerful tool for studying brain activation. Func-
ofleptin,insulin,glucose,amylin,PYY,GLP-1andoxyntomodulin,and
tional MRI provides an indirect measure of activation by quantifying
decreasedconcentrationsofghrelin).Thistypeofeatingisclassifiedas
the Blood Oxygen Level Dependent (BOLD) signal. The BOLD
hedoniceatingindistinction tohomeostaticeating.Asitsdescription
signalisderivedfromchangesintheratioofoxyhemoglobintodeox-
implies, hedonic eating can override the satiety effect of positive
yhemoglobin. Because deoxyhemoglobin is paramagnetic, changes in
energy balance signals (Saper et al., 2002; Harrold and Williams,
this ratio can be detected in the MRI magnetic field. Blood flow is
2003;Kringelbach, 2004;Mela, 2006;Loweet al., 2009).
increased to activated brain regions in order to meet the increased
Manyregionsofthecorticolimbicandmesolimbicbraininvolvedin
metabolicdemands.Thishemodynamicresponsecausesdeoxyhemo-
learning and memory, emotion and reward processing have been
globin levels to decline and this change is detected in the form of a
implicated in hedonic eating. These include the prefrontal cortex,
BOLD signal (Ogawa et al., 1990; Arthurs and Boniface, 2002;
lateral and medial orbitofrontal cortex, anteriorcingulate,insula, hip-
LogothetisandWandell,2004;Nair,2005).Inrecentyears,thistech-
pocampus, amygdala, nucleus accumbens (ventral striatum),
nologyhasbeenappliedtothestudyofappetite.Therearenowasig-
caudate/putamen (dorsal striatum), pallidum, ventral tegmental area
nificant number of imaging studies describing the brain’s response to
andfusiform.Acomprehensivedescriptionofthecomplexanatomical
various food cues. Response differences achieved under fed or
andfunctionalconnectivityofthesebrainregionsisbeyondthescope
fasted conditions in normal weight and obese subjects are providing
of this review, and the reader is referred to an excellent review
newinsights intothecontrolof ingestivebehavior.
(Morganeetal.,2005).Becausetheregionsincludedinthecorticolim- Do
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bicbrainarehighlyinterconnectedandarenotlimitedtothecontrol n
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ofingestivebehavior,itissimplistictoascribestimulatoryorinhibitory Stimulus protocols ad
e
idnegsecsrtiipvteorsbeshuacvhioarsalreewffaercdt,scotognistipoenc,ifiecxerceugtiiovensf.unIcntsitoenadandbrgouasdtear- Food cues usedin fMRI protocolsto elicit a BOLD response include d from
tnoertywaorrekuasfefedcttoindgeesstcirviebebhehoawviobrr.ainFigruergeion1siswiathsinimtphleificeodrtdiceopliicmtiboinc tvaissutea,l fsomodellcuaensdcsoignhsits.tinBgecoafuseeithoefr tahcetuiralrfeolaotdiveorepasicetuorefsdoeflivfoeoryd, http://h
are commonly used. Visual food cues are effective because stimuli u
of the brain regions that regulate homeostatic and hedonic eating m
and their interconnections. The prefrontal cortex and the amygdala associated with primary rewards acquire motivational potency and upd
triggerwantingduetotheiracquiredabilitytostimulaterewardcircuits .o
are important in reward evaluation, inhibitory control and executive x
decision-making (Schoenbaum et al., 1998; Petrovich et al., 2002; (classical conditioning). Brain activation due to visual food cues is ford
quantifiedbysubtractingtheBOLDsignalelicitedbycontrolpictures jo
Gottfried et al., 2003; Holland and Gallagher, 2004; Kringelbach and u
Rolls,2004;Kringelbach,2004;Rolls,2004;Petrovichetal.,2005;Pet- (pictures of items not associated with food or eating) from BOLD rnals
rovich and Gallagher, 2007). The amygdala receives input from the signalthatoccurswhile viewing picturesof food. .org
ventral tegmental area (dopaminergic), insula and fusiform (visual b/
y
cortex). The insula, considered to be the primary gustatory cortex, gu
Brain responses to visual food cues e
receives visceral information by way of afferent inputs from the st o
nucleus tractus solitarius and lateral parabrachial nucleus. In addition Thecorticolimbicbrainregionsthatareconsistentlyactivatedbyvisual n N
to innervating the amygdala, the insula sends efferent projections to foodcuesincludetheprefrontalcortex,lateralandmedialorbitofron- ov
e
the anterior cingulate, orbitofrontal cortex, striatum, pallidum, thala- talcortex,amygdala,hippocampus,parahippocampus,anteriorcingu- m
b
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mus, lateral hypothalamus and nucleus accumbens. The nucleus late, insula, hypothalamus, striatum, pallidum, ventral tegmental area r 4
accumbensandadjacentventralpallidummayaffectingestivebehavior and fusiform (Tataranni et al., 1999; LaBar et al., 2001; Killgore , 2
0
1
by integrating hedonic signals from mesolimbic/corticolimbic regions et al., 2003; Pelchat et al., 2004; Wang et al., 2004; St-Onge et al., 6
with homeostatic input from the hypothalamus (Berthoud, 2002; 2005;Beaveretal.,2006;Holsenetal.,2006;KillgoreandYurgelun-
Kelley,2004;Abizaid et al., 2006). Todd,2006;Porubskaetal.,2006;Uheretal.,2006;Baicyetal.,2007;
Cornier et al., 2007; Farooqi et al., 2007; Rolls and McCabe, 2007;
Rothemund et al., 2007; Malik et al., 2008; Stoeckel et al., 2008).
Although there are significant differences in the regions reported to
Imaging networks affecting be activated by visual food cues in the individual studies, it is likely
that experimental variables such as stimulus paradigms, gender,
ingestion
hungerlevelandadiposityareattherootofthesedifferences.Collec-
tively, these studies show that brain regions involved in processing
Althoughregulationofingestivebehaviorcanbecompartmentalizedas
reward, emotion and cognition are activated when subjects are
homeostaticorhedonicbasedonneuroanatomicalandfunctionalpar-
exposed to food pictures. The fusiform, amygdala, hippocampus,
ameters, communication between these two compartments deter-
insula, lateral orbitofrontal cortex and dorsal striatum are activated
mines when, what and how much we eat. Our ability to study the
by visual food cues in the majority of studies. It is instructive to
neural networks that influence ingestive behavior in humans has
examine how brain responses to visual food cues are affected by
improved immensely with significant advances in imaging technology
hunger, adiposity and metabolic/endocrine cues in order to begin
in the past 15 years. These exciting neuroimaging results are
understanding how the corticolimbic brain influences ingestive
summarizedbelow.
behavior.
6 VanVugt
Influence of adiposity and hunger compared with lean women (Karhunen et al., 1997). Subsequent
Two recent fMRI studies reported a greater brain response to food PET studies compared rCBF in lean and obese men and women
pictures in obese women compared with normal weight women before and after consuming a liquid meal (Gautier et al., 2000,
(Rothemundetal.,2007;Stoeckeletal.,2008).Bothstudiesreported 2001). Meal-induced satiation increased rCBF to the prefrontal
greater activation in the lateral orbitofrontal cortex, insula, hippo- cortex in obese and normal weight men and women (obese men.
campus, anterior cingulate and dorsal striatum of obese compared leanmen)andreducedbloodflowtothethalamus,insula,parahippo-
with normal weight women in response to pictures of high calorie campusandcerebellumofleanandobesewomenandtothehippo-
foods compared with low calorie foods or control pictures. BMI campus,striatumandcerebellumofobesemenmorethanleanmen.
was positively correlated with the degree of activation elicited by Cerebral blood flow to the hypothalamus, amygdala, cingulate and
high calorie food pictures specifically in several regions including the nucleus accumbens was reduced in obese women, but not lean
dorsal striatum, anterior insula, claustrum, posterior cingulate, post- women, whereas reduced rCBF to the hypothalamus and thalamus
central and lateral orbitofrontal cortex. These studies indicate that was attenuated in obese men compared with lean men. These
brain regions involved in learning and habit formation, emotion and results indicate that brain activity in several corticolimbic regions as
motivation are stimulated by food stimuli to a greater extent in measured by cerebral blow flow is reduced after a meal and that
obese women. One of the studies observed significantly more acti- responses are influenced by adiposity and gender (DelParigi et al.,
vationextendingtothemedialprefrontalcortex,medialorbitofrontal 2002). Increased activity in the prefrontal cortex in sated subjects
cortex,ventralpallidum,amygdalaandventralstriatum(Stoeckeletal., was observed in men and women. The prefrontal cortex plays a
2008). Greater activation was attributed to subjects being hungry at role in suppressing inappropriate response tendencies, which in the Do
w
thetimeofthescan,whereashungrysubjectswereexplicitlyexcluded contextofthecurrentstudy,wouldbeeatingwhensated.Thesignifi- nlo
intheotherstudy(Rothemundetal.,2007).Theconclusionthatfood canceofgreateractivationoftheprefrontalcortexinobesemenisnot ad
e
pBiOctLuDresrehsapveongsreeaitsersusaplpieonrcteedinbtyheafapstreedviosutastefManRdI esvtuodkyeaingrwehaticehr csolelaatre,raaltlhporuegfhroanntoatlhceorrstteuxdyforlelopworintegdathmateianlcrweaassegdrerCatBeFrininthneordmora-l d from
normal weight male and female subjects had greater activation in weight men compared with obese men (Le et al., 2006). Reduced http
the amygdala, parahippocampus and anterior fusiform in the fasted rCBF to numerous corticolimbic regions in sated subjects compared ://h
u
state(LaBaret al., 2001). Another studyreported thatfood pictures withhungrysubjectsisconsistentwithfMRIstudiesshowingactivation m
u
causedmoreactivationintheinferiortemporalvisualcortex,posterior of these regions by visual food cues. However, the significance of a pd
parietal cortex, premotor cortex, hippocampus and hypothalamus in meal-induced reduction in rCBF to the hypothalamus, amygdala, cin- .ox
fo
subjects maintained on a eucaloric diet comparedwith subjects who gulate and nucleus accumbens in obese women, but not lean rd
jo
ate in excess for several days prior to scanning (Cornier et al., women, and the hippocampus, striatum and cerebellum of obese urn
2007). When food cravings were induced by placing participants on men more than lean men, is not readily apparent and perhaps para- als
a bland diet for 2 days before undergoing fMRI, more activation was doxical if one considers reduced rCBF to corticolimbic structures is .org
seeninthehippocampus,insulaandcaudatewhensubjectsimagined part of the normal response to meal-induced satiation. Another b/
y
their favorite foods (Pelchat et al., 2004). Striking differences were group studied subjects whereas they imagined selecting food items gu
e
observedwhenresponsesinhealthyweightcontrolswerecompared from a restaurant menu. Subjects were normal weight men and st o
with individuals with Prader–Willi Syndrome, a genetic disorder were studied either after an overnight fast or within 1h of having n N
characterized by hyperphagia-induced early onset obesity. Whereas eaten. Increased rCBF in the hypothalamus, amygdala, striatum, ov
e
normalweightcontrolshadgreateractivationintheamygdala,orbito- insula and anterior cingulate cortex was observed when fasted, mb
e
frontal cortex, medial prefrontal cortex and frontal operculum in whereas increased activity in the lateral orbitofrontal and temporal r 4
response to food pictures in the pre-prandial state compared with cortexwasobservedwhensated(Hintonet al., 2004). , 20
1
the post-prandial state, Prader–Willi patients had greater activation Tosummarize,numerousimagingstudiesshowthatbrainactivityas 6
in the amygdala, orbitofrontal cortex, insula, parahippocampus and measuredbyBOLDsignalorrCBFisincreasedinmanybrainregions
fusiformpost-prandially(Holsenetal.,2006).Anotherstudyreported involved in processing reward and motivation in response to food
that food pictures presented after an oral glucose load activated the cues. Activation of the orbitofrontal cortex, insula, hippocampus,
medial prefrontal cortex of Prader–Willi patients, but not normal amygdala, anterior cingulate, and striatum are reported in most, but
weightcontrols(Milleretal.,2007).Theseresultssuggestthatthesal- not all studies. A greater BOLD effect occurs in more brain regions
ience of food cues is not only maintained but increased in Prader– in response to pictures of high calorie versus low calorie foods, and
Willi patients despite having eaten and that this abnormal response the response is more robust in obese subjects. The motivational
maycontributetohyperphagia and obesity. potency of visual food cues is increased by hunger (Cabanac, 1971;
Positronemissiontomography(PET)imagingstudieswerethefirst Stoeckel et al., 2007). Increased brain activation in specific regions
imaging studies of appetite. Differences between PET and fMRI in inassociationwithhungerandobesityispresumablythebasisforsti-
terms of signal detection, as well as spatial and temporal resolution, mulatingingestivebehavior.Anabnormalbrainresponsemaypredis-
present some challenges when comparing results achieved by the pose some individuals to obesity. However, in the absence of
twoimagingmodalities.ThefirstPETimagingstudyofappetitecom- longitudinalstudies,anequallyfeasibleinterpretationisthatabnormal
pared the regional cerebral blood flow (rCBF) in response to food brain responses result from obesity. In this scenario, abnormal
images in normal weight and obese women. Food images induced a responses to food cues may contribute to maintenance of an obese
greater rCBF in the parietal and temporal cortices of obese women state.
Imagingstudiesofappetite,obesityandthemenstrualcycle 7
D
o
w
Figure2 Ghrelinstimulatesactivationelicitedbyfoodpictures.Activationmapsintheaxialandcoronalviewshighlightactivationelicitedbyfood nlo
a
picturesinsubjectsinfusedwithghrelin.TheregionandMontrealNeurologicalInstitutecoordinateofpeakactivationislistedonthetop.Withthe d
e
exceptionofthefusiformgyrus,alldepictedregionswereactivatedbyfoodpicturesduringghrelinbutnotsalineinfusion.OFC¼Orbitofrontalcortex d fro
[fromMaliketal.(2008)withpermissionfromElsevier]. m
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ttp
://h
Imaging the effects of energy homeostasis hormones corticolimbic structures that evaluate the emotional, memory, taste um
u
Four recent studies described effects of leptin and ghrelin, two hor- and reward aspects of food. pd
moneswithoppositeeffectsonenergyhomeostasis,onbrainactivity Another recent fMRI studyexamined the effect of the gut derived .ox
elicitedbyvisualfoodcues.Administrationoftheorexigen,ghrelin,in satiety factor PYY on brain activity (Batterham et al., 2007). Unlike ford
comparison to saline, produced greater activation of orbitofrontal the previously described studies, this study did not use visual food jou
rn
cortex, prefrontal cortex, amygdala, insula and striatum when sub- cues. Infusion of PYY3-36 thatproduced post-prandial concentrations als
jects viewed food pictures (Malik et al., 2008). These finding are of PYY increased the BOLD signal in the caudolateral orbitofrontal .org
depicted in Fig. 2. Furthermore, the magnitude of the response in cortex and significantly reduced the number of calories consumed b/
y
the orbitofrontal cortex and amygdala correlated with increased when subjects were given unlimited access to a buffet meal sub- gu
e
hunger levels elicited by ghrelin, suggesting that the BOLD effects sequent to the scan session. The magnitude of the BOLD response st o
andbehavioraleffectsofghrelinwererelated.TwofMRIstudiescom- in the caudolateral orbitofrontal cortex was inversely correlated n N
pared responses to visual food cues in leptin deficient patients with the number of calories eaten, suggesting that PYY-induced acti- ov
e
whereas on or off leptin replacement therapy (Baicy et al., 2007; vationoftheorbitofrontalcortexwasinpartresponsibleforinhibiting m
b
e
Farooqietal.,2007).FoodpictureselicitedagreaterBOLDresponse appetite. Although PYY infusion increased BOLD signal in the hypo- r 4
intheinsula,parietallobe,andstriatumandincreasedhungerratings thalamus, hypothalamic activity (unlike the orbitofrontal cortex) did , 2
0
when patients suspended leptin therapy for a few weeks, whereas not correlatewith foodconsumption. Thisimportant findingdemon- 16
activation in the prefrontal cortex was increased and hunger ratings stratesthatavitalcomponentofhomeostaticcontrolofeating,namely
were reduced in the same patients when leptin replacement the postprandial rise in PYY, may inhibit eating by activating a
therapy resumed. A third leptin study measured brain responses to hedonic–corticolimbic region (orbitofrontal cortex) rather than tra-
visualfoodcuesinobesepatientswhohadachieveda10%reduction ditional homeostatic brain centers(hypothalamus).
inbodyweight.Patientswereinjectedtwicedailywitheithersalineor Collectively,thesefiveimagingstudiessuggestthattheneuralcircui-
leptin in a crossover design (Rosenbaum et al., 2008). Visual food try involved in metabolic homeostatic feedback is not limited to the
cues presented during the placebo arm following weight loss pro- hypothalamus and brainstem, but involves hedonic brain regions.
duced greateractivation of the brainstem, culmen, parahippocampal Theseeffectsmaybeindirectthroughreceptorsignalinginthehypo-
gyrus, inferior and middle frontal gyri, middle temporal gyrus and thalamus or direct since receptors for leptin, ghrelin and PYY are
lingual gyrus, but less activation in the hypothalamus, cingulate present in the ventral tegmental area, amygdala and hippocampus
gyrus and middle frontal gyrus when compared with activation eli- (Gustafson et al., 1997; Dumont et al., 1998; Kaga et al., 2001;
cited prior to weight loss. These responses were reversed when Figlewicz et al., 2003; Diano et al., 2006; Hommel et al., 2006).
leptinlevelswerereinstatedtopre-weightlosslevelswithexogenous These studies also demonstrate the utility of fMRI to study human
leptin, indicating that these specific brain regions are responsive to brain responses to metabolic signals, either separately or in combi-
changesinleptinconcentrations.Collectively,thesefourstudiesindi- nation with visual food cues, thus providing a powerful method to
cate that leptin and ghrelin, in addition to their effects on the hypo- studytheinteractionsbetweenhomeostaticandhedonicsignalscon-
thalamus, influence ingestive behavior through effects on trolling eating.
8 VanVugt
Appetite regulation in women 1985). This effect of ovariectomy and gonadal steroid replacement
wasconfirmedinmonkeys(Kemnitzetal.,1989).Theeffectsofovari-
Menstrual cycle related changes in appetite ectomy and estrogen replacement on food intake are transient,
whereas their effects on weight remain, suggesting peripheral effects
Significantchangesinfoodintakeduringthemenstrualcyclehavebeen
of chronic ovarian steroid exposure (Wade and Gray, 1979).
documentedinbothhumanandnon-humanprimates.Menstrualcycle
Gonadal steroid replacement in post-menopausal women did not
dependentchangesinwomenandinrhesusmonkeysdocumentedby
affect food intake or body weight (Reimer et al., 2005), but did
food diaries or food weighing indicate that food intake is reduced in
reduce abdominal fat whereas not affecting total body fat (Haarbo
the periovulatory phase and increased during the luteal phase
et al., 1991; Reubinoff et al., 1995; Gambacciani et al., 1997). A sys-
(Czaja, 1978; Rosenblatt et al., 1980; Dalvit, 1981; Kemnitz et al.,
tematic review found no evidence that either estrogen alone or in
1984; Lissner et al., 1988; Gong et al., 1989; Lyons et al., 1989;
combination with a progestin affected weight gain in peri- or post-
Buffenstein et al., 1995; Barr et al., 1995; Dye and Blundell, 1997;
menopausal women (Kongnyuy et al., 2009). Since continuous
Reimer et al., 2005). Figure 3 shows food intake normalized to the
hormone replacement does not mimic cyclical changes in ovarian
day of the luteinizing hormone surge in rhesus monkeys. Food
steroids, a lack of effect of hormone replacement on weight in the
intake reaches a nadir around the time of ovulation when estrogen
clinical setting is not in conflict with the conclusion that ovarian
iselevatedandprogesteroneislowandincreasesfollowingovulation
steroidsinfluence energy balanceduring themenstrual cycle.
whenprogesteroneisdominant.Increasedfoodintakepremenstrually
has been documented in women diagnosed with premenstrual dys- D
Ovarian steroid hormones site of action o
phoric syndrome (Bowen and Grunberg, 1990; Cross et al., 2001; w
n
Reedet al., 2008). Ovarian steroid effects on food intake and body weight were first lo
a
d
reported in 1974. It is remarkable that the mechanisms that cause e
d
Effect of ovarian steroids this large physiological change in ingestive behaviorin humans areso from
poorly understoodmany yearslater h
Prior to primate studies that showed menstrual cycle dependent ttp
changes in food intake, rodent studies demonstrated estrous cycle (i) Leptin,ghrelinandPYYlevelsduringthemenstrualcycle:Numerous ://h
u
studies have measured leptin levels throughout the menstrual m
dependentchangesinfoodintakeandthatchangesinovariansteroids u
during the estrous cycle were responsible for changes in food con- cycle. Most studies report a slight elevation during the luteal pd.o
phase as compared with the follicular phase (Hardie et al., x
sumption. Ovariectomy led to increased food intakeand weight gain fo
in rats. These effects of ovariectomy were reversed by estrogen, 1997; Shimizu et al., 1997; Riad-Gabriel et al., 1998; Teirmaa rdjo
et al., 1998; Cella et al., 2000; Ludwig et al., 2000; Geisthovel u
whereastheanorexigeniceffectofestrogenwaspreventedwhenpro- rn
gesteronewasco-administered(TarttelinandGorski,1973;Jankowiak et al., 2004; Wunder et al., 2006; Asimakopoulos et al., 2009). als
andStern,1974;Wade,1975;BlausteinandWade,1976;Wadeetal., Increased leptin during the luteal phase may signal a period of .org
positive energy balance. Thus, the pattern of leptin secretion b/
y
during the menstrual cycle may reflect (rather than affect) gu
e
changes in caloric intake. Two studies noted a small increase in st o
leptinduringthelatefollicularphasecomparedwiththeearlyfol- n N
licularphasewhichcouldexplainreducedfoodintakeduringthe ov
e
m
periovulatory phase (Geisthovel et al., 2004; Asimakopoulos
b
e
et al., 2009), but this was not observed in the majority r 4
of studies. There is only one report on ghrelin levels during , 2
0
1
the menstrual cycle, and it showed that ghrelin was unchanged 6
(Dafopoulos et al., 2009). There are no reports on PYY levels
during the menstrual cycle. We measured PYY levels in rhesus
monkeys on a daily basis both pre- and post-prandially and
found no pattern of change during the menstrual cycle (Van
Vugt, unpublished).
(ii) Estrogenreceptors:Thesiteofactionandthespecificneurotrans-
mitters/neuromodulators mediating these steroid effects have
not been established. Both alpha estrogen receptors (ERa) and
beta estrogen receptors (ERb) are present in the brain. ERa is
concentrated in the hypothalamus, whereas ERb is distributed
Figure 3 Food intake during the rhesus monkey menstrual cycle. more broadly in the brain (Shughrue et al., 1997; Laflamme
Food intake values are the mean of three consecutive days during
et al., 1998; Kuiper et al., 1998). The hippocampus, substantia
the menstrual cycle (n¼7) relative to the day of the LH surge.
nigra, dorsal raphe, striatum, nucleus accumbens and pontine
Food intake progressively decreased during the periovulatory
nucleus are densely labeled with ERb mRNA (Gundlah et al.,
period, before rebounding after ovulation (*P,0.05 compared
2000; Ostlund Hann et al., 2003). Co-labeling of dopamine and
with Days 22/0; Anova followed by Dunnetts; Van Vugt,
ERb showed that both dopamine and non-dopamine neurons
unpublished).
were ERb positive (Creutz and Kritzer, 2002). Ovariectomy
Imagingstudiesofappetite,obesityandthemenstrualcycle 9
reduced dopamine binding in the striatum and the nucleus between the two phases in 10 women. Food pictures activated the
accumbenscore(LeSauxetal.,2006).Thiseffectwasreversed lateralorbitofrontalcortex,prefrontalcortex,hippocampus,amygdala
byestradioloran ERb agonist,but not byan ERaagonist,indi- and fusiform of women scanned in the periovulatoryphase, whereas
cating that the stimulatory effects of estrogen on dopamine only the fusiform was activated in the luteal phase. Table I lists the
receptors were mediated through ERb rather than ERa. This regions that were significantly activated by the various contrasts.
conclusion is supported by the finding that a specific ERb Most regions were activated by food pictures regardless of category
agonist stimulated amphetamine-induced place preference in (high versus low calorie foods). An exception was the insula, which
ovariectomized rats (Silverman and Koenig, 2007). Reduced was stimulated by pictures of low calorie foods, but not by high
dopamine signaling in the reward circuit of ovariectomized rats calorie foods in the follicular phase. Interestingly, the opposite effect
could lead to a compensatory increase in food consumption. was observed during the luteal phase as the insula was activated by
However, the report that estrogen replacement inhibited food high calorie foods,butnot lowcalorie foods.
intake and reduced body weight in ovariectomized wild type In a separate study, we asked women to rate the appeal of high
and ERb knockout mice, but not in ERa knockout mice is con- calorie and low calorie foods on multiple occasions over the course
trary to the conclusion that ERb mediates estrogen-induced of a menstrual cycle. Women rated pictures of high calorie foods as
anorexia(Gearyetal.,2001).Itisconceivablethatestrogensig- moreappealing thanlowcalorie foods in Weeks1, 3and 4,but not
nalingatERaisimportantforhomeostaticcontroloffoodintake Week 2 of the menstrual cycle (Kim and Van Vugt, 2008). Since the
whereas estrogen signaling at ERb is more relevant to hedonic insulawasactivatedby lowcalorie butnot high calorie food pictures
eating. when women were scanned during Week 2 of the menstrual cycle, Do
w
(iii) Otherpossibleneuroendocrinemechanisms:Aninteractionbetween whereas the insula was activated by high calorie but not low calorie n
lo
estrogen and leptin is suggested by the considerable overlap in ad
e
thhyepodtihstarlaibmutuison(oDfiarneocepettorsalf.o,r1e9s9tr8o)g.enEsatnrodgelenptinrepwlaitcheinmethnet d from
increased leptin-induced anorexia in ovariectomized rats (Clegg http
etal.,2006).However,thisapparentincreaseinleptinsensitivity ://h
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wasnotassociatedwithincreasedleptinreceptornumber.Cur- m
u
rently,thereisnoconsensusonwhetherestrogenstimulatesor pd
.o
inhibits leptin receptor expression. Additionally, the report that x
fo
estrogen can induce anorexia in leptin deficient mice suggests rd
jo
involvement of mechanisms in addition to leptin (Tritos et al., u
rn
2004). Increased sensitivity to CCK-induced meal termination als
hasbeen proposed(AsarianandGeary,1999).Estrogenpoten- .org
tiated CCK-induced anorexia, and estradiol replacement to b/
y
ovariectomized rats increased CCK-induced c-fos expression (a gu
e
marker of neuronal activation) in the paraventricular nucleus, st o
nucleus tractus solitarius and central amygdala (Eckel et al., n N
2002; Asarian and Geary, 2006). Involvement of serotonin is ov
e
suggested by the observation that buspirone, a serotonin m
b
e
agonist, was more potent in stimulating food intake in the r 4
luteal phase compared with the follicular phase (Goodall et al., , 2
0
1
1995). 6
Imaging menstrual cycle dependent changes
in appetite
It appears that changes in leptin, PYY or ghrelin secretion do not
explain changes in food intakethatoccur during themenstrual cycle.
However, a change in sensitivity to these molecules remains a viable
explanation for menstrual cycle dependent changes in food intake.
Giventhe recent reportsthatbrain effects of leptin, PYYand ghrelin
can be measuredwith fMRI, it maybe possible to use fMRI to study Figure 4 Effect of menstrual cycle phase on brain activation.
thisquestion.Wehaveundertakenbrainimagingstudiesduringdiffer- Women viewed pictures of food while undergoing functional mag-
netic resonance imaging during the late follicular phase and luteal
enttimesofthemenstrualcycleinordertodetermineifcorticolimbic
phaseofthemenstrualcycle.Foodpictureselicitedgreateractivation
structuresresponddifferentlytovisualfoodcuesdependingonmen-
in the follicular phase. Activation of the left orbitofrontal cortex
strual cycle phase. Our results, whereas preliminary, indicate that
(L. OFC), amygdala and hippocampus (not shown) in the follicular
visual food cues elicit a stronger BOLD response in several brain
phase, but not luteal phase may influence reward perception of
regions during the periovulatory period compared with that during
foodcuesandeffectingestivebehavior(VanVugt,unpublished).
the luteal phase of the menstrual cycle. Figure 4 contrasts activation
10 VanVugt
TableI Brainactivationinresponsetovisualfoodcues;influenceofthemenstrualcycle
Follicularphase ROI Hemisphere Cluster tstat MNICoordinates
.............................................................................................................................................................................................
Foodversuscontrol Fusiform L 137 7.23 233,254,215
R 22 5.54 33,254,218
OFC L 14 7.75 221,30,218
Amygdala L 14 6.25 215,0,215
R 21 6.54 24,23,212
Hippocampus L 10 5.18 227,227,26
R 13 6.04 21,227,26
PFC R 15 6.04 48,42,12
Highcalversuscontrol Fusiform L 183 8.91 230,269,26
R 116 6.75 30,275,23
Amygdala L 25 6.57 224,29,212
R 29 7.27 21,26,212
Hippocampus L 25 6.05 215,236,6
R 11 6.68 24,224,29
OFC L 24 5.93 221,30,215
Lowcalversuscontrol Fusiform L 5 5.01 233,254,212 D
o
Amygdala R 9 5.74 30,26,215 wn
PFC R 31 7.79 42,42,15 lo
a
d
OFC L 7 6.69 221,30,215 e
d
Insula R 4 4.99 42,3,212 fro
m
Lutealphase h
Foodversuscontrol Fusiform L 18 5.73 236,257,218 ttp
Highcalversuscontrol Fusiform L 10 7.02 224,272,26 ://hu
m
Insula L 5 5.3 239,26,3 u
p
Lowcalversuscontrol Fusiform L 10 5.92 233,257,221 d.o
x
fo
ROIreferstoregionofinterest;Clusterreferstothenumberofcontiguousvoxelswhichwereactivated;t-statisameasureofactivationinthepeakvoxel;MNI¼MontrealNeurological rd
Institute. jou
rn
a
ls
.o
rg
food pictures in the luteal phase, we speculate that menstrual cycle more frequently during the luteal phase (Cockerill et al., 1994), b/
y
dependentactivationoftheinsulareflectsmenstrualcycledependent menstrual cyclephase mayhave beenacontributing factor. gu
e
changesinfoodappeal.Anincreasedpreferenceforlowcaloriefoods st o
inthesecondhalfofthefollicularphasemaycontributetotheperio- n N
Imaging eating disorders o
vulatory reduction in caloric intake. v
e
m
Bingeeating,bulimianervosaandanorexianervosaareextremeeating
b
e
disorders that are more prevalent in women than in men (Hudson r 4
etal.,2007).Astudycomparingresponsesinsubjectswithdisordered , 2
Effect of mood on brain response to food 01
eating (binge eating disorder or bulimia nervosa) reported that food 6
cues
pictures activated the orbitofrontal cortex, anterior cingulate and
Although ours is the first study to examine the effect of menstrual insula in both patient groups and in controls, but overweight binge
cycle phase on the BOLD response to visual food cues, another eaters had a stronger response in the medial orbitofrontal cortex
fMRI study similar to our own reported BOLD responses to food compared with overweight healthy controls (Schienle et al., 2009).
images in women. However, rather than menstrual cycle phase, Theauthorssuggestthatincreasedactivationofthemedialorbitofron-
affect was the primary variable of interest. The lateral orbitofrontal talcortexreflectsincreasedprocessingofrewarddrivethatmaytrans-
cortex was activated in response to high calorie food images, late into compulsive overeating. In contrast, bulimic subjects had
whereas the medial orbitofrontal cortex and insula were increased greater activation of the insula and anterior cingulate compared with
by low calorie food images in women reporting positive affect. The either binge eatersorcontrols(Schienle et al. 2009). Both the insula
oppositeactivationpatternwasobservedinwomenreportingnegative and anterior cingulate are involved in processing emotional stimuli,
affect (Killgore and Yurgelun-Todd, 2006). This differential effect of attention and response selection, and their activity correlates with
high and lowcalorie food pictureson theinsula depending on mood autonomicarousal(Critchleyetal.,2002;Phanetal.,2002).Increased
parallels whatwesawwith menstrualcycle phase; i.e. the insulawas activation of the insula and cingulate in bulimic subjects may reflect
activatedbypicturesoflowcaloriefoodswhenwomenwereperiovu- increased stress associated with a perceived loss of control over
latory(likewomenwhoreportedpositiveaffect),butwasactivatedby ingestingillicitfoods.Anothergroupreportedthatpatientsdiagnosed
highcaloriefoodswhensubjectswerescannedinthelutealphase(like with either anorexia nervosa or bulimia compared with healthy con-
women who reported negative affect). Since negative affect occurs trols had greater activation of the ventral medial prefrontal cortex