Transcript Behavioral Disinhibition and the Development of Early

Behavioral Disinhibition and the
Development of Early-Onset
Addiction: Common and Specific
Influences
William G. Iacono, Stephaen M.
Malone, and Matt McGue
Introduction
• The etiology of substance use disorders (SUDs) is
likely best understood from a developmental
perspective.
• Youths with SUDs show executive function
deficits, suggesting frontal lobe deficits during this
stage contribute to SUD vulnerability
• Individuals inherit a common liability for a
spectrum of traits, disorders, and associated
behaviors reflecting a propensity toward
behavioral disinhibition.
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Explaining Figure 1
 Signs of vulnerability evident in preadolescence
and appear as personality traits reflecting
behavioral undercontrol and dispositional
characteristics typically associated with childhood
disruptive disorders.
 Endophenotypes identifying genetic risk can be
measured at this stage
 Gene-environement interplay over course of
development confers general risk for the
development of the 3 classes of SUDs and ASPD
 Specific genetic and environmental effects work to
differentiate disorders from one another
Comorbidity
 Addiction typically does not occur on its own. Addictive
disorders are frequently comorbid with each other as well as other
psychiatric disorders, particularly ASPD.
 Meta-analysis of twin studies by Krueger & Markon (2006)
showed that the covariance among alcohol dependence, drug
dependence, and the components of ASPD can be modeled by a
single underlying externalizing factor (EXT), suggesting that the
components share common core deficits
 Liability for EXT - quantitative continuum that has similar
underlying structure in males and females, though men have
higher mean liability than women.
 Longitudinal investigation looked at how the structure of EXT
varied from ages 17-24; found mean level of EXT increased with
age, but the amount of overlapping variance among externalizing
disorders declined with age. Disorders showed greater
differentiation over course of development.
Externalizing Liability
 Genes play a substantial role in development of SUDs
 An absence of twin similarity across phenotypes
supports substance specific genetic transmission. MZ
twins show more cross phenotype similarity than DZ
twins which suggests evidence of shared genetic
vulnerability for addiction to different illicit drugs
 Multivariate modeling with twin participants to examine
how genes influence the co-occurrence of SUDs with
other spectrum phenotypes - highly heritable.
 Existing sex differences occur at the level of the
underlying ability, which is higher in men - this
difference in the EXT factor accounts for the fact that
each of the individual disorders is more common in
men
Other pathways?
 Possible genetic vulnerability to affect dysregulation
accounting for comorbidity among mood and anxiety
disorders - captured as a latent internalizing trait
(Kendler et al. 2003c, Krueger et al. 201)
 Internalizing dimension shows moderate correlation
with EXT (r=.50 - remind you of another model?)
 Disorders in internalizing spectrum linked to personality
traits tapping negative emotion or neuroticism - traits
also associated with risk for externalizing
psychopathology (Krueger & Markon 2006)
 What accounts for part of the comorbidity between
SUDs and internalizing psychopathology?
Developmental Origins of
Addiction
 Why a developmental perspective?
 General versus specific processes: alcohol use
prior to 15 associated with increased risk not only
of alcoholism but also of other SUDs and ASPD.
Conversely?
 Association of adolescent problem behavior with
adult externalizing disorders appears to reflect
general disinhibitory processes beginning in
childhood.
 Can you think of any examples from article or
previous lectures?
Environmental Mediation and
Moderation of SUD risk
 It is clear that there are environmental factors
associated with SUD.
 Understanding Risk Mechanisms:
 Risk mechanisms appear to be predominantly general
rather than specific
 Environmental risk is inherently developmentalmultiple exposures across multiple stages of
development convey greater risk than single exposure
at specific stage
 Cumulative risk hypothesis?
Environmental Mediation and
Moderation of SUD risk
 Consider environmental risks jointly with the
contributions of genetic markers of risk.
 Gene-environment (G-E) correlation
 Examples?
 Important to understanding development of externalizing
psychopathology in general and SUDs in particular
 Keyes et al. (2007) - adolescent problem behaviors before 14
were associated with parent conflict, reduced attachment to
school and exposure to peer models of deviance. Both problem
behavior and environmental risk were independently and
strongly predictive of symptoms of SUDs and ASPD at age 18.
 Genes as mediators for these associations with externalizing
psychopathology.
Endophenotypes
 Defined as an endogenous attribute of a person that is
itself a product of the predisposing genotype
 More proximal to a genetic influence - potentially useful
in identifying the genes that contribute to the
development of a disorder
 P300 amplitude reduction (P3AR) - relationship to
behavioral inhibition has been investigated broadly associated with each of the externalizing disorders
(Iacono et al. 2002), also been found in those showing
precocious social deviance (Iacono & McGue 2005),
and has been observed with substance use and misuse
(Yoon et al. 2006).
 Patrick et al. suggest that (P3AR) is associated with the
externalizing latent trait and this association is
genetically mediated (Hicks et al. 2007a).
Genetics and Addiction
 It has been difficult to replicate reports of
specific genes for SUDs
 Many of replicated gene findings involve
genes related to impulsivity and risk taking
(Kreek et al. 2005).
 COGA group findings
Alcohol Sensitivity: Gene-Environment
Modeling of General and Specific
Processes
 Inherited aldehyde dehydrogenase (ALDH)
deficiency and alcoholism risk relatively direct,
but not determinative
 Irons et al. (2007) showed that features of the
rearing environment, and specifically, substance
use, could offset the protective advantages
associated with ALDH deficiency.
 Gateway model did not predict findings in this
study as did the article’s hypothesis that a
vulnerability to disinhibited behavior underlies
substance use and abuse
Neurobehavioral Processes in Behavioral
Disinhibition
 Some similar deficits in those at risk for SUDs as
well as those with SUDs - indicate that they may
be relevant to etiology rather than a consequence
of neural changes induced by chronic abuse
 Prefrontal cortex implicated in inhibiting
inappropriate responses or impulses. A major role
of this structure is cognitive control
 Addiction as an interaction between two neural
systems: one implicated in encoding the rewarding
properties of objects and their incentive salience
and the other involving prefrontal cortex, that is
implicated in reflective, rather than impulsive
behavior
Other Routes to Addiction?
 Perhaps by way of excessive sensitivity to reward. The
common drugs of abuse are all acutely rewarding
because of their actions on a final common pathway:
the dopaminergic reward system
 Despite different properties in drugs, they have similar
effect on brain’s reward system, suggesting a common
mechanism involved in addiction liability
 Given developmental state of brain in youth,
rewarding properties of drugs especially salient.
Combined with gradual development of prefrontal
cortex in adolescence - “window of vulnerability” for
risky behavior is likely.
Other ideas
 Disinhibited, impulsive behavior can occur through
two mechanisms: bottom-up mechanism or a failure of
top-down control mechanisms
 Amygdala activity and connectivity between
amygdala and orbital frontal cortex implicated in
internalizing psychopathology, which is often
comorbid with disinhibitory psychopathology negative emotions and emotional expression also
characteristic features of EXT
 Gray’s motivational systems: overactive
behavioral activation system (BAS) or an
underactive behavioral inhibition system (BIS)
can be associated with EXT
Conclusions
 Highly heritable latent externalizing trait with
diverse manifestations of behavioral disinhibition
 Individual differences in brain processes governing
inhibitory control
 Common v Specific effects - common liability yet
specific forms of substance abuse. Thoughts?
 Future studies would benefit from studying a large
sample that is truly representative, those with
comorbid conditions that are typically the case with
those with externalizing disorders
 More research needed that combines environmental
risk and latent externalizing liability