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Treating Eating Dysfunction: Understanding Mechanisms to Improve TreatmentsRajita Sinha, Ph.D.Yale University School of Medicine
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Binge Eating Disorder (insufficient restraint, chaotic eating &
binge eat)-- strongly associated with obesity
Obesity (excessive energy intake with lower energy expenditure)
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• CBT and BT – well established , and considered the treatment of choice (50% remit but no weight loss)
• Alternative therapies (IPT, DBT, BWL) have support (but no weight loss)
• CBT superior to pharmacotherapy
• Marked disconnect between big reductions in binge eating and minimal weight change
(nice.org.uk; Reas & Grilo, Obesity 2008; Wilson, Grilo, & Vitousek, Am Psychol 2007)
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An event or series of events that are overwhelming, traumatic or non-traumatic, challenging or threatening - physical, social, emotional, cognitive or physiological in nature.
Multi-modal brain-mind-body responses; under prolonged and repeated conditions, detrimental health effects:– Unpredictable Stress > Predictable Stress
– More Intense > Less Intense Stress
– Prolonged Stress > Acute Stress
– High Repeated Stress > Few Adverse Events
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Total Stress By BMI
Normal Overweight Obese
Mea
n T
ota
l S
tres
s S
core
18
20
22
24
26
28
Normal BMI: 18 – 24.9Overweight: 25 – 29.9Obese: 30 and greater
N=588X2 = 25.47, df=1, P < 0.0001 Odds ratio =1.146 (1.087-1.208)
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“…All you can think about is having that cheesecake. Your mouth waters. You can’t wait to taste that white creamy sweet bite of heaven!… Your heart beats faster… Your eyes scan the creamy cheesecake. Your mouth is watering… You cut a huge piece!… It all looks so good. You can’t wait to taste the sweet creamy texture and soft buttery crust… You cut a piece with your fork. It is dense and soft. You raise the fork to your lips…”
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Motivation and Reward LearningMotivation and Reward Learning
High calorie foodsFood cues
Thal
Ins
Dopamine: – Medications that inhibit
D2 receptors (antipsychotics, e.g.
clozapine) appetite and
weight gain
– Medications that blocks reuptake of DA in presynaptic neurons ( DA) (psychostimulant,
e.g. methylphenidate)
weight
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Stress and MotivationStress and Motivation
Threat, Stress and Metabolic Hormones
Thal
Ins
Stress hormones: Cortisol, ACTH
CRF: Critical brain stress peptide
Noradrenergic Signalls: NE and EPI
Dopamine: Motivation and Adaptive Learning
Serotonin: Regulation of homeostatic states
GABA/Glutamate: Inhibitiona nd excitation
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Page et al., JAMA, 2013
z = -8 z = -4 z = 0
Insula
Hyp
ACC
CaudatePutamen
Thal-2
-6.6
T score
R L
R
T score
Thalamus
Putamen
CaudateHyp
NuAcc
6.51
2
z = -8 z = -3 z = 2
Functional Connectivity after Glucose Ingestion (Hypothalamus seed)
Plasma Glucose (mg/dl)
Hy
po
tha
lam
ic C
BF
(m
l/g
/min
)
r = -0.49, p<.04
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Z= -6 Z= -2 Z= 2 Z= -6 Z= -2 Z= 2
prefrontal cortex
Caudate/puatmenCaudate/puatmen
prefrontal cortexprefrontal cortex
putamenputamen
InsulaInsulaInsulaInsula
HypHyp
ACCACC
RR L L
Z= -6 Z= -2 Z= 2 Z= -6 Z= -2 Z= 2
Hypoglycemia (Hypo) compared to euglycemia (Eu) increases wanting of HP foods and brain response in craving, appetite and food reward regions (shown in blue) and decreases activity in prefrontal self control regions (in red) (p<.05 FWE corrected)
Page, Seo, de AguiarConstable, Sherwin, Sinha, JCI, 2011
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Time
Picture Presentation Rating-Wanting Relax Before
Next Trial
6 secs 3 secs 3-9 secs
+
3 secs
Rating-Liking
0 20 40 60 80 100 120
INSULIN (2mU/kg/min)
90
65
Time (min)
Pla
sma
Glu
cose
(m
g/d
l)
Variable Rate Glucose Infusion
Visual Cues
Euglycemia Euglycemia
Visual Cues
Hypoglycemia Hypoglycemia
Eu HypoEu Hypo Eu 1st Eu 2ndEu 1st Eu 2nd
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striatum
Whole brain, voxel-based correlation analyses. Axial brain slices and corresponding scatter plots showing correlations between a) plasma glucose levels and VMPFC/ACC response to high-calorie food images, b) plasma cortisol levels and left and right insula/striatal response to high-calorie food images, p<0.01, two-tailed, FWE whole brain corrected. Areas in yellow indicate brain regions positively correlated to plasma glucose and plasma cortisol levels. (ACC = anterior cingulate; VMPFC = ventromedial prefrontal cortex; L=left; R=right).
r = .56r = .56
r = .61r = .61 r = .60r = .60
ACC/VMPFC
Z = - 13 Z = 13 Z = - 13 Z = 13
Z = - 6 Z = -2 Z = - 6 Z = -2
insula striatum
Correlation between plasma glucose levels and prefrontal cortex/ACC activation Correlation between plasma glucose levels and prefrontal cortex/ACC activation
Correlation between plasma cortisol levels and bilateral insula/striatum activationCorrelation between plasma cortisol levels and bilateral insula/striatum activation
R LR L
R LR L
Page et al., JCI, 2011
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Is Greater Understanding of the Mechanisms Driving Excessive Food Intake Opening New Treatment Avenues?
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Data in recovering cocaine dependent individuals; From Fox et al., 2012
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Depression Scores Perceived Stress Scale
SBP – Systolic BP Food Craving Scores