1. Behavioral Disinhibition and the Development of Early-Onset Addiction: Common and Specific Influences William G. Iacono, Stephaen M. Malone, and Matt McGue

2. 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. 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.

4. 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  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

5.  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.  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. Comorbidity

6. 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  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

7. 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?  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?

8. 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?  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?

9. 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 developmental- multiple exposures across multiple stages of development convey greater risk than single exposure at specific stage  Cumulative risk hypothesis?  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 developmental- multiple exposures across multiple stages of development convey greater risk than single exposure at specific stage  Cumulative risk hypothesis?

10. 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.  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.

11. 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).  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).

12. 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  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

13. 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  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

14. 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  Why are youth particularly at risk?  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  Why are youth particularly at risk?

15. 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.  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.

16. 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  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

17. 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  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