Foundation of Addiction Medicine 2019

1. FHP adolescents had
thicker cortices: bilateral
precentral gyri, left caudal
middle frontal gyrus
(MFG), bilateral
temporo-parietal junction,
left inferior-frontal gyrus
and right inferior-temporal
gyrus.

2. Differences diminished
with age by young
adulthood.

3. Highlight the crucial role
for interventions that
target delay in initiation of
alcohol use during
adolescence in high-risk
vulnerable populations.

151

“Altered Brain Cortical Maturation Is Found In Adolescents
With A Family History Of Alcoholism”

3. Thicker cortices associated with greater Ext
Sx Scores.

➢ Familial AUD risk is associated with
age-related differences in maturation
of several higher order association
cortices – which are critical to ongoing
development in executive function,
emotion regulation and social cognition
during adolescence.

Holla et al (2018) Altered Brain Cortical Maturation Is Found In Adolescents With A Family History Of Alcoholism. Addiction Biology
152

HI-RISK SUBJECTS C
HAVE DEFICITS IN O
FUNCTIONAL BR N
CONNECTIVITIES N
E
Fronto-parietal, C
Cingulo-opercular, TI
Sensorimotor and VI
Cerebellar networks exhibited T
Y
significantly reduced functional
segregation.

153

STUDIES SHOW DIFFERENCES
BETWEEN SUBJECTS AT HIGH & LOW
RISK: STRUCTURE & FUNCTION

BEHAVIORAL RESPONSES TO ENVIRONMENTAL CHALLENGES

COGNITIVE & EMOTIONAL ABILITIES

FUNCTIONAL BRAIN CONNECTIONS

STRUCTURAL BRAIN CONNECTIONS

GENE ENVIRONMENTAL STRESSORS

154

What environmental factors increase
the risk of addiction?

Risk Factors Protective Factors

Aggressive behavior in childhood Good self-control

Lack of parental supervision Parental monitoring and support

Poor social skills Positive relationships

Drug experimentation Good grades
Availability of drugs at school School anti-drug policies

Community poverty Neighborhood resources

From:NIDA

155

Environmental exposures shape temperament and psychopathology

Developmental stressors Externalizing. Internalizing.

Psychosocial stress in pregnancy

PERI-NATA Health problems in mother T=5.25*
L T=7.49**

BIRTH WEIGHT (KG) R=-.110**

EARLY Health problems in 1st year T=11.08** R=-.10**
ADVERSITY (ACE-IQ) Freq Score
R=.19** R=.14**
Positive childhood experiences R=-.18**
R=-.08*
Involvement- Parenting R=-.23**
R=-.12**
**p<0.001; *p<0.01 Experienced discrimination T=8.3**
Academic problems T=11.4**

Support.Acceptance -School T=11.61** T=4.99*

LATE R=-.250** R=-.211**

Univariate correlations: Developmental stressors & Strengths & Difficulties Q dimensio15n6s

Exploring novel Brain Behaviour Relationships:
Adverse Childhood Experiences impact Regional Centrality and

Regional Clustering in adolescence

Regional Centrality measures
the no.of connections passing
through the region, thus
signifying its importance in the
flow of information within brain
networks.

Regional Centrality indicative
of functional hubs of brain
network, predominantly
showed negative correlation
with adversity, only Left Mid

Temporal Gyrus showed a positive
correlation.

Regional clustering indicative
of hyper-connectivity, showed
Positive correlation with
adversity of in certain regions.

At Significance level of P<0.005 Note: Generally regional
centrality and regional
clustering are inversely related.

157

Why do some people become addicted
to drugs, while others do not?

158

HR brains have different responses to
drugs than LR

L 0 – 20 min 20 – 60 min
R

A
L

Baseline C

H
R

Greater CNS “stimulation”….greater reinforcing effect of alcohol;
BUT……lower Subjective Response to Ethanol’s Intox Effects

Jagadeesh AN; Radha Prabhu; CR Mukundan; Vivek Benegal; SK Chaturvedi
Response to Alcohol in Abstinent alcoholics and Social drin1k5e9rs

HOW CAN WE USE OUR KNOWLEDGE
TO HELP PERSONS WITH ADDICTION
AND THEIR FAMILIES?

160

Lessons learnt

1. Chronic brain Illness → Not one time, but long
term treatment, with likelihood of relapse (like
other chronic illnesses)

2. Combination of pharmacological, physical and
psychological treatments ---including public
health measures

3. Focus on multiple areas
(Vuln-NeuroAdapt-PsychSoc) and multiple
outcomes possible (Abstinence—Harm
reduction)

161

STRATEGIES

1. VULNERABILITY ✓Understanding: Reframing, motivating

Late Onset ←Coping –Loss:❖DESTIGMATIZE-DE CRIMINALIZE

Dep-Anx ✓Interventions & Strategies
Early Onset ←Ext temp: ❖Rx – ADHD Meds etc
coping with cogdef ❖Bx – Therapy for ADHD, CD, A-ADD

❖INCREASE RESILIENCE AND SKILLS

❖RECOGNIZE & PROMOTE STRENGTHS

2. NEUROADAPTATIO • Relapse prevention and extinction tts:
N ❖Rx

→ Memory of Addiction ❖Bx –RELAPSE PREVENTION, LAPSE MGT

3. COLLATERAL DAMAGE ❑ Appropriate psycho-social interventions

➢ Spouse, Family,
Children

➢ Job, Socialization,
Legal

162

Deactivation Activation of
of Insula ACC &
DLPFC
Baclofen
reduces Holla et al, 2017.
activation Clinical
due to Psycho-pharmac
craving ology and
imagery Neuro-science
[In press]

163

TREAT THE
VULNERABILITY/
DIATHESIS

164

PUFA supplementation

• In seven RCTs (n=534 ) n-3 PUFAs supplementation improves ADHD clinical
symptom scores (g=0.38, ;p<0.0001) and in three RCTs, (n=214) in youth with
ADHD, n-3 PUFAs supplementation improves cognitive measures associated
with attention (g=1.09, p=0.001).

• Children and adolescents with ADHD have lower levels of DHA, EPA

• n-3 PUFAs supplementation monotherapy improves clinical symptoms and
cognitive performances in children and adolescents with ADHD

• Support to the rationale for using n-3 PUFAs as a treatment option for
ADHD.

Jane Pei-Chen Chang, Kuan-Pin Su, Valeria Mondelli & Carmine M Parian (2018) Omega-3 Polyunsaturated Fatty Acids in Youths
with Attention Deficit Hyperactivity Disorder: a Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies.

Neuropsychopharmacology; 43, 534–45
165

Delay the Onset of Use & Access

• Interventions to delay the onset of regular use from
early teen years to early adult years in order to
prevent long-term neuronal damage

• General psychoeducation + personalized feedback
regarding effects of drug use on thinking abilities and
brain health integrated into current prevention,
screening, and treatment programs.

• Coping Skills training - Treat the DIATHESIS

• Reduce Access [Demand Reduction+ Supply
Reduction]

166

Bio-psycho-social model

Addiction is indeed many things—a maladaptive response to env stressors, a
dev disorder, a disorder caused by dysregulation of brain circuits, and a
learned behavior.
• Biopsychosocial framework: complex interactions between biology,

behavior, and environment. Social -economic deprivation raises risks is
interventions necessary for healthy family, school, and community
environments.
• Neuroplasticity framework -reward and self-control circuits evolved to
enable us to discover important, healthy rewards, remember them, and
pursue them; drugs “hijack” those circuits.
• Inter-individual biological variability that makes some people more
susceptible than others to this hijacking.
• Treatable medical problem (framework) from which people can and do
recover - crucial for public-health–focused response to ensure access to
effective treatments and lessen stigma surrounding a condition that
afflicts nearly 10 percent of our population.

Volkow 2018 NIDA website 167

Is Addiction
Heritable?

Dr. Bharath Holla, MD (Psychiatry), PDF (Addiction
Medicine),

Assistant Professor (Clinician Scientist - ADBS),
Department of Psychiatry, National Institute of Mental

Health and Neurosciences (NIMHANS),
Bengaluru 560029, India.

168

Outline

• Addiction Heritability – essential ingredients?

• Evidence from

✔ Genetic Epidemiology (Family, Twin & Adoption)
✔ Molecular Genetics (Linkage, Association and

Polygenic studies)

✔ Gene vs Environment (rGE, intGxE)
✔ Neurobiological Studies (Imaging studies)

• Take home message 169

February 26, 2019

Drugs

Essential ingredients? licit (alcohol,

Epidemiological Agent nicotine) psychoactive
Triad illicit (cannabis, nature,
cocaine, opiates)
of Causation pharmacokin
Behavioral etics,
Gambling,
gaming, internet mode of use

Demographic Addiction drug availability,
age, sex, age at first use peer influences,
Genotype : Phenotype social support,

Externalizing-Internalizing childhood
Spectrum adversity,
parenting style,
Preexisting addictive/mental socioeconomic
illness)
Environmstatus
Host ent

February 26, 2019 170

Epidemiological Triad of
Causation

• Alone are Host, Agent, or Environment sufficient?
• No

• But are all three of them necessary?
• Yes and relative importance of these factors varies
• across the lifespan and
• at different stages of addiction

• For example, 171
Environmental factors may be important for drug
initiation &
Host-Agent factors may be important for drug
continuation & dependence

February 26, 2019

Questions that arise…

•Given this multifactorial background, how
does one study addiction heritability?

•Does one inherit an addiction, or a
susceptibility to it?

•Is it possible that people with susceptibility
may never develop addiction unless exposed
to stressful environment?

February 26, 2019 172

Outline

• Addiction Heritability – essential ingredients?

• Evidence from

✔ Genetic Epidemiology (Family, Twin &
Adoption)

✔ Molecular Genetics (Linkage, Association and
Polygenic studies)

✔ Gene vs Environment (rGE, intGxE)

✔ Neurobiological Studies (Electrophysiology,
Imaging studies)

February 26, 2019 173

Glossary Relative risk (RR)

Heritability (h2) • Elevation (or reduction)
in the risk of a disorder
• proportion of variability associated with a given
in a characteristic (i.e., an risk (or protective) factor
attribute, behavior, or
disorder) that is caused RR = Incidence of disorder
by genetic differences in in
a population
(with the risk factor /
h2 = Genetic variability / without the risk factor)

Total variability Family Studies

Twin & Adoption Studies

February 26, 2019 174

Family Studies (Familial clustering of
Addiction)

• Data from population health surveys and controlled
family studies

• RR = substance use disorders given a positive family
history in FDR

substance use disorders with no family history in
FDR

• “4- to 8-fold increased risk” of substance use
disorders given a positive family history in FDR
(Merikangas & Risch, 2003b).

• Risk could arise from either (or both) shared genetics
and environment

February 26, 2019 175

Adoption Studies G h Y
E
• First-Degree relatives h Y1
are 50% genetically
similar 1 rY1Y
(Parent/offspring,
sibling) h Y2 2

• The degree to which, E2 2 176
despite not sharing an
environment, they
resemble each other.

h2 = 2(rY1Y2) G
E1
where rPO is the
correlation between birth
parents and adopted-away
offspring

February 26, 2019

Adoption Studies in AUDs

6,548
Parent-Offprings

February 26, 2019 Psychol Med. 2015 Apr;
45(5): 1061–1072. 177

Twin Studies rUE=0
rCE=1

1 for MZ & 0.5 for DZ
rAG

UC A ACU
EE G GE E

EC A AC E

TW TW
11

rMZ/ rDZ

February 26, 2019 h2 = 178
2(rMZ-rDZ)

where rMZ is the correlation between members of MZ twin pairs
and rDZ is the correlation between members of DZ twin pairs

Twin Studies in AUDs

96,982
twins

February 26, 2019 Psychol Med. 2015 Apr; 45(5): 1061–1719072.

Heritability estimates for addictions range
between 0.4 (hallucinogens) to 0.7 (cocaine)

Goldman D, Oroszi G, Ducci F. The genetics of addictions: 180
February 26, 2019 uncovering the genes. Nat Rev Genet 2005;6(7):521–32.

Outline

• Addiction Heritability – essential ingredients?

• Evidence from

✔ Genetic Epidemiology (Family, Twin & Adoption)

✔ Molecular Genetics (Linkage, Association and
Polygenic studies)

✔ Gene vs Environment (rGE, intGxE)

✔ Neurobiological Studies (Electrophysiology,
Imaging studies)

• Take home message

February 26, 2019 181

Molecular Genetic Methods

Penetrance is a measure of the
proportion of individuals in a
population carrying a particular
allele that expresses the related
phenotype.

Mendelian diseases have a high
penetrance and very rare allele
frequency.

In contrast multifactorial
diseases, have low penetrance
and associated with small to
modest effect size common
Linkage Genome/ Genome-wide allele.
exome SNP

sequencing; chips
CNV calling

February 26, 2019 (McCarthy, Nat Review Genet, 2008) 182

Polygenic & Pleiotropic Genetic
Influences

February 26, 2019 J. of Cardiovasc. Trans. Res. (2015) 8:506–527 183

The common disease–common variant The infinitesimal model:
model: a large number of small-effect variants
moderate effect and common variant across the entire allele frequency
each explain several % of disease risk spectrum

The rare allele model: The broad sense heritability model:
a large number of large-effect rare some combination of genotypic,
variants environmental and epigenetic
interactions
February 26, 2019
(Gibson G, Nat Rev Genet. 2012) 184

Examples of GWAS significant genes
(<p 1 x 10 -8)

February 26, 2019 185

Post- GWAS approaches

• Polygenic Risk Scores
• LD Score Regression
• Enrichment using “omics” data (epigenomics,
transcriptomics)
• Genome-wide Complex Trait Analysis
• Multi-trait Analysis

Post-GWAS in psychiatric genetics:
Genes, Brain and Behavior. 2018;17:e12447.

February 26, 2019 The Post-GWAS Era: From Association to 186
Function
The American Journal of Human Genetics 102,
717–730, May 3, 2018

Polygenic risk scores

is a sum of trait-associated alleles across
many genetic loci,
typically weighted by effect sizes estimated
from a GWA study

PRS models
aggregate the
effect of SNPs
(alleles) associated
with disease status

Dima D, Breen G. Polygenic risk scores

in imaging genetics: Usefulness and

applications. Journal of

February 26, 2019 Psychopharmacology. 2015 187

Summary of molecular genetics in
Addiction:

Despite high heritability, major genes involved have
not been identified!
“Missing heritability”

GWAS Pitfalls (Common variants vs Rare variants)
a large number of small-effect variants across the entire
allele frequency spectrum

Post-GWAS approaches are promising & can explain
larger proportion of variances

February 26, 2019 188

Outline

• Addiction Heritability – essential ingredients?

• Evidence from

✔ Genetic Epidemiology (Family, Twin & Adoption)

✔ Molecular Genetics (Linkage, Association and
Polygenic studies)

✔ Gene vs Environment (rGE, intGxE)

✔ Neurobiological Studies (Electrophysiology,
Imaging studies)

• Take home message

February 26, 2019 189

Interplay between Genetic and
Environmental Factors

• Gene (nature) vs Environment (nurture)
independence is often violated

1. Gene × environment correlation (rGE)

the degree to which exposure to certain
environmental conditions is due to genetic
influences.

2. Gene x environment interaction (G × E)

the degree to which measured environmental

factors moderate genetic influences on a

behavior

February 26, 2019 190

Examples for
Genetic and Environmental
Interplay …. 1

• Protective effect of ADH1B was negated among
individuals whose peer groups consisted of mainly
drinkers (G × E) Alcohol Clin Exp Res. 2014;38:2541-2549

• Association between CHRNA5, and nicotine
dependence was stronger under conditions of low
parental monitoring. (G × E)

Addiction. 2009;104:1731-1740.

• Effect of CHRNA5 on smoking behavior was found to
be stronger among those who initiate cigarette use
earlier. (G × E) Arch Gen Psychiatry. 2012;69:854-860.

February 26, 2019 191

Examples for

Genetic and Environmental

Interplay …. 2
• Marriage had a stronger protective effect on those with
the low-risk genotype of GABRA2, those with the high
risk genotype were less likely to enter into marriage or
stay married (G × E, rGE)
J Stud Alcohol. 2006;67:185-194

• Polygenic risk scores (PRS) were more strongly
associated with alcohol problems & externalizing
behaviors under conditions of low parental monitoring

and high peer deviance. (G × E)

Genes (Basel). 2014;5:330-346. Clin Psychol Sci. 2015;3:189-201.

• The effect of polygenic risk scores on smoking was
mitigated in neighborhoods with greater social
cohesion. (G × E)
Transl Psychiatry. 2013;3:e290.

February 26, 2019 192

Outline

• Addiction Heritability – essential ingredients?

• Evidence from

✔ Genetic Epidemiology (Family, Twin & Adoption)
✔ Molecular Genetics (Linkage, Association and

Polygenic studies)

✔ Gene vs Environment (rGE, intGxE)
✔ Neurobiological Studies (Imaging studies)

• Take home message 193

February 26, 2019

Addiction: from genes to symptoms

through imaging

Endophenotyp

feedb feedb es feedb feedb
ack ack
ack ack

Gen Expres Molec Ce Brain Sympt
eRsNA sion uleRsNA, nellusron Boemhasvioral
Structur
genes, proteins, developm e, tests
metabolite ent,
protein-co Transscript circuits, Diagno
orgCaenlel lle Nepuhryogesysiociloenc sis
dGinegnogemniecs
Imaging Self-re
s omics biology Brain port

EpmigiecsnmodueotmnanisctooEiovdponiifgsiecantoim Proteomics Neurosci interactome

Metabolo ence

mics

Interactom

icEsnvironmental, social and

psychological factors

Endophenotypes: Intermediate Phenotype
Closer to the action of genes and can explain the behavior.
Genetically tractable.

Zhao Y, Castellanos FX (2016) J Child Psychol Psychiatry. 571: 94421-439

• Endophenotypes can be thought of as a catalyst

that will aid both genotype discovery and

phenotype refinement
End
Genoty Phenoty

pe o- pe
Discov Refinem
phenot
ery ype ent

February 26, 2019 195

February 26, 2019 196

February 26, 2019 Cortical Thickness of 75 male alcohol-naïve
children from high-density AUD families and
65 male control families were compared.

Familial AUD risk is associated with Delays in
maturation of higher order association
cortices – which are critical to ongoing
development in executive function, emotion
regulation and social cognition during
adolescence.

(TDiemlaeysdelipnekendetonteexftfeercntasl)izing behaviors
Genotype --> Intermediate Phenotype --> ?
NDoifPfehreennocetyspdeiminished with age by young
adulthood. Delays rather than Deficits197

Smaller volumes of total CC, genu
and isthmus

• FA values in these tracts were reduced and negatively correlated with FH
density

• Lower FA values corresponded to higher radial diffusivity suggesting
reduced axonal myelination

Acheson, A, et al. Human brain mapping 35.11 (2014): 5401-5413.

February 26, 2019 198

February 26, 2019 Resting brain graphs of alcohol-naïve children from
high-density AUD (n=40) and control (n=30) families were
compared.

Fronto-parietal, Cingulo-opercular, Sensorimotor and
Cerebellar networks exhibited significantly reduced
functional segregation.

The network disruptions incrementally predicted greater
externalizing symptoms.

(Phenotype Refinement)

The network disruptions were also proportional to the
alcoholism familial density.

(Genotype Refinement)

199

Multilocus genetic profile scores for DA signaling
predict reward-related VS reactivity.

Individual profile scores accounted for 10.9% of the variability within the
VS activation cluster

Neuropsychopharmacology. 2011 Aug; 36(9): 1940–1947.

February 26, 2019 200