Treating Eating Dysfunction: Understanding Mechanisms to Improve TreatmentsRajita Sinha, Ph.D.Yale University School of Medicine

Binge Eating Disorder (insufficient restraint, chaotic eating &

binge eat)-- strongly associated with obesity

Obesity (excessive energy intake with lower energy expenditure)

• 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)

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

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)

“…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…”

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

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

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

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

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

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

Is Greater Understanding of the Mechanisms Driving Excessive Food Intake Opening New Treatment Avenues?

Data in recovering cocaine dependent individuals; From Fox et al., 2012

Depression Scores Perceived Stress Scale

SBP – Systolic BP Food Craving Scores