Neuroscience
It has been over 7 years since I defended by Ph.D. dissertation in March 2014 at the University of North Carolina at Chapel Hill. Here, I wanted to share some of the rationale and implications of my graduate research on immediate reward selection bias in humans. While this research encompassed 5+ years of my life and resulted in a 112-page dissertation, I will focus on the key points and findings and why they are important. I have moved on from doing this research in my current role but it will forever be a part of my identity. In addition, I hope my scientific contributions have added a bit more to our understanding of substance abuse risk factors and how we might work to either intervene to support those at risk for addiction proactively or treat some of the behavioral patterns in addicted individuals that can continue the cycle of problematic drug use despite its negative consequences.
What is an intermediate phenotype?
Many psychiatric disorders including schizophrenia and depression are complex and heterogenous (i.e., they have diverse and varied symptoms and potential causes). The highly heritable nature of these disorders, estimated from twin studies to be anywhere from 40 to 80% (Sullivan et al., 2000; Sullivan et al., 2003), suggests that some biological processes mediated by genetics must confer risk for developing the disorders. It has been proposed that the inability to isolate strong biological bases for how genetic variation leads to complex, highly heritable diseases lies in the fact that various intermediate behaviors or traits are more closely tied to the genetics associated with the disease (Rasetti and Weinberger, 2011).
Given that substance use disorders (SUDs) are also complex disorders (people consume and continue to use drugs of abuse due to a variety of factors) with heritability estimates ranging from 40 to 60% (Heath et al., 2001; Verweij et al., 2010; Bierut, 2011; Agrawal et al., 2012), the identification of intermediate phenotypes associated with risk for these disorders is a growing focus of research (Karoly et al., 2013). Behavioral candidates for SUD intermediate phenotypes include reduced response inhibition (Acheson et al., 2011; Norman et al., 2011), increased risk taking behavior (Cservenka and Nagel, 2012; Schneider et al., 2012), aberrant reward responsivity (Wrase et al., 2007; Andrews et al., 2011), and increased discounting of delayed monetary rewards (Mitchell et al., 2005; Boettiger et al., 2007; Claus et al., 2011; MacKillop et al., 2011; MacKillop, 2013).
Given that substance use disorders (SUDs) are also complex disorders (people consume and continue to use drugs of abuse due to a variety of factors) with heritability estimates ranging from 40 to 60% (Heath et al., 2001; Verweij et al., 2010; Bierut, 2011; Agrawal et al., 2012), the identification of intermediate phenotypes associated with risk for these disorders is a growing focus of research (Karoly et al., 2013). Behavioral candidates for SUD intermediate phenotypes include reduced response inhibition (Acheson et al., 2011; Norman et al., 2011), increased risk taking behavior (Cservenka and Nagel, 2012; Schneider et al., 2012), aberrant reward responsivity (Wrase et al., 2007; Andrews et al., 2011), and increased discounting of delayed monetary rewards (Mitchell et al., 2005; Boettiger et al., 2007; Claus et al., 2011; MacKillop et al., 2011; MacKillop, 2013).
Criteria for categorizing a behavior as an intermediate phenotype
For an intermediate phenotype to be useful it must be a quantitative, continuously variable feature or behavior that can be consistently measured. Furthermore, as these intermediate phenotypes are thought to convey genetic risk for a disorder, they should be elevated in those affected with the disorder as well as in those individuals’ close relatives who share genetic similarity with them. Importantly, the level of these phenotypes in affected individuals and their close relatives should be shifted away from a distribution of those otherwise unaffected with no familial risk (Gottesman and Gould, 2003). For example, Egan et al. (2001) found unaffected siblings of those with schizophrenia to display executive function deficits that fell between unaffected nonrelatives and individuals with schizophrenia.
A variety of criteria have come to define an intermediate phenotype in psychiatry (Almasy and Blangero, 2001; Gottesman and Gould, 2003; Waldman, 2005; Meyer-Lindenberg and Weinberger, 2006):
To illustrate the intermediate phenotype concept and associated criteria, we can look at research in schizophrenia. Schizophrenia is associated with poor performance (and hyperactivity in an area of the brain known as the dorsolateral prefrontal cortex, dlPFC) on executive function tasks. As mentioned above, Egan et al. (2001) found unaffected siblings of those with schizophrenia to display executive function deficits that fell between unaffected nonrelatives and individuals with schizophrenia. Furthermore, genes affecting dlPFC activity and executive functions such as the catechol-O-methyltransferase (COMT) gene explain variation in schizophrenia risk (see Egan et al., 2001). Thus, by investigating a specific behavior (executive function) and its neural correlate (dlPFC activity) in schizophrenic patients and those at increased genetic risk for the disorder, a genetic factor (COMT) was isolated. Schizophrenia is caused by more than one genetic variation but this example illustrates the value of identifying a link between a behavior associated with schizophrenia (an intermediate phenotype) and a potential biological and genetic basis for said behavior.
A variety of criteria have come to define an intermediate phenotype in psychiatry (Almasy and Blangero, 2001; Gottesman and Gould, 2003; Waldman, 2005; Meyer-Lindenberg and Weinberger, 2006):
- The phenotype should be sufficiently heritable with genetics explaining variance in the behavior.
- The phenotype should have good psychometric properties as it must be reliably measurable to be a useful diagnostic.
- The phenotype needs to be related to the disorder and its symptoms in the general population.
- The phenotype should be stable over time in that it can be measured consistently with repeated testing, potentially to assess treatment effects.
- The behavior should show increased expression in unaffected relatives of those with the disorder as highlighted by Egan et al. (2001), above.
- The phenotype should co-segregate with the disorder in families in that a family member with the disorder should show the behavior or trait to a greater degree than an unaffected sibling and that this unaffected sibling should display the trait to a greater degree than a distant unaffected relative.
- The phenotype should have common genetic influences with the disorder.
To illustrate the intermediate phenotype concept and associated criteria, we can look at research in schizophrenia. Schizophrenia is associated with poor performance (and hyperactivity in an area of the brain known as the dorsolateral prefrontal cortex, dlPFC) on executive function tasks. As mentioned above, Egan et al. (2001) found unaffected siblings of those with schizophrenia to display executive function deficits that fell between unaffected nonrelatives and individuals with schizophrenia. Furthermore, genes affecting dlPFC activity and executive functions such as the catechol-O-methyltransferase (COMT) gene explain variation in schizophrenia risk (see Egan et al., 2001). Thus, by investigating a specific behavior (executive function) and its neural correlate (dlPFC activity) in schizophrenic patients and those at increased genetic risk for the disorder, a genetic factor (COMT) was isolated. Schizophrenia is caused by more than one genetic variation but this example illustrates the value of identifying a link between a behavior associated with schizophrenia (an intermediate phenotype) and a potential biological and genetic basis for said behavior.
What is immediate reward selection (Now) bias?
Delay discounting (DD) behavior reflects the tendency for animals (including humans) to discount the value of delayed (in time) rewards in comparison to those available immediately. DD has also been referred to as immediate reward selection (“Now”) bias as the value of rewards available immediately supersedes waiting for a larger, delayed reward in the future (Rachlin and Green, 1972). Other terms for this behavior include temporal discounting or hyperbolic discounting as plots of the value of time-delayed rewards relative to present value often take a hyperbolic shape with the present value of a reward delivered at longer delays decreasing at a steep, non-linear rate. In other words, $100 in 3 months may only be worth $25 in present value while $100 in 1 month is worth $50 in present value (the discount rate gets steeper moving from a 1-month to a 3-month delay).
Example of temporal discounting behavior. The present value of a reward decreases with the time one must wait to receive it. Individuals differ in the degree to which they discount rewards over time. The individual whose choice behavior is plotted with open circles and fit with the dashed line is a steeper discounter of time than that individual plotted with the filled circles and solid line of best fit.
Now bias as an intermediate phenotype for alcohol use disorders
As delay discounting (DD) behavior has been shown to be highly heritable (Anokhin et al., 2011; Anokhin et al., 2015; Mitchell, 2011), suggesting a strong genetic component, and is elevated in a variety of addictive behaviors (MacKillop et al., 2011), we focused our current work of exploring intermediate phenotypes for addiction on this behavior. Prior work has suggested DD displays many of the necessary criteria of an intermediate phenotype for a variety of neurobehavioral disorders including substance use disorders (SUDs) (Becker and Murphy, 1988; Reynolds, 2006; Perry and Carroll, 2008; Rogers et al., 2010), attention deficit hyperactivity disorder (Barkley et al., 2001; Sonuga-Barke et al., 2008; Paloyelis et al., 2010), and pathological gambling (Alessi and Petry, 2003; Leeman and Potenza, 2012). As these behaviors often co-occur, they may share similar biological and genetic components (Wilens, 2007; Leeman and Potenza, 2012).
An overview of various intermediate phenotype criteria for SUDs met by DD (Now bias) has been recently outlined (MacKillop, 2013). Particularly relevant to the current work, individuals with alcohol use disorders (AUDs) consistently display greater Now bias behavior versus those without AUDs (Petry, 2001; Bjork et al., 2004; Mitchell et al., 2005; Boettiger et al., 2007; Mitchell et al., 2007; MacKillop et al., 2011). Thus, Now bias is elevated in those individuals with an AUD (intermediate phenotype criterion 3).
Conceptually, Now bias can be thought to have some relation to AUDs, as every relapse or excess drink represents a decision favoring immediate over delayed benefits. Furthermore, Now bias behavior has been shown to be heritable and associates with substance use, suggesting common genetic influences with SUDs (Anokhin et al., 2011). Importantly, Now bias as assessed through delay discounting (DD) tasks, has good psychometric properties (responses are highly reliable (Matusiewicz et al., 2013; Weafer et al., 2013)), suggesting it is a trait that is robust to consistent measurement (intermediate phenotype criterion 2). This is further supported by the fact that DD behavior is stable over time (Kirby, 2009). Thus, prior work has demonstrated Now bias satisfies many of the criteria for an intermediate phenotype for AUDs. However, not all criteria have yet to be examined.
Conceptually, Now bias can be thought to have some relation to AUDs, as every relapse or excess drink represents a decision favoring immediate over delayed benefits. Furthermore, Now bias behavior has been shown to be heritable and associates with substance use, suggesting common genetic influences with SUDs (Anokhin et al., 2011). Importantly, Now bias as assessed through delay discounting (DD) tasks, has good psychometric properties (responses are highly reliable (Matusiewicz et al., 2013; Weafer et al., 2013)), suggesting it is a trait that is robust to consistent measurement (intermediate phenotype criterion 2). This is further supported by the fact that DD behavior is stable over time (Kirby, 2009). Thus, prior work has demonstrated Now bias satisfies many of the criteria for an intermediate phenotype for AUDs. However, not all criteria have yet to be examined.
Under-investigated criteria for Now bias as an intermediate phenotype for AUDs
As Now bias is elevated in those with AUDs, we might expect to see this behavior heightened in those on a trajectory toward an AUD as well. Such demonstrations between elevated Now bias and AUD risk would add greatly to the utility of Now bias as an intermediate phenotype. As problematic alcohol use during emerging adulthood (late teens to early twenties) may predict development of an AUD later in life (O'Neill et al., 2001; Merline et al., 2008; Dick et al., 2011), though many individuals mature out of problematic use (Bartholow et al., 2003; Costanzo et al., 2007; Lee et al., 2013), one might expect Now bias is enriched in problematic drinking emerging adults. Only one relatively small behavior study has looked at such a relationship with Now bias observed to be heightened among heavy versus lighter social drinking college students (Vuchinich and Simpson, 1998). This finding requires replication in a larger, more diverse sample.
In addition to being elevated in problematic drinking emerging adults, to satisfy another intermediate phenotype criterion for AUDs, Now bias behavior should also be elevated in unaffected first-degree relatives (parents, siblings) of those suffering from AUDs (intermediate phenotype criterion 5). Elevated Now bias in first-degree relatives of those with AUDs has yet to be adequately demonstrated, however.
Most of the intermediate phenotype literature considers the expression of the behavior or trait in first-degree relatives as critical in demonstrating that behavior as an intermediate phenotype. In the field of AUDs, however, positive family history of an AUD is often defined as having at least one parent with an AUD (Acheson et al., 2011) or father with an AUD (Crean et al., 2002; Petry et al., 2002), or some combination of parental history or sufficient density of AUD history in second-degree relatives (Herting et al., 2010). In these previous studies, the effects of family history on Now bias was either only observed in females (Petry et al., 2002), was not found at all (Crean et al., 2002; Herting et al., 2010), or was not present when controlling for group differences in IQ and antisocial behavior (Acheson et al., 2011).
Measuring Now bias behavior in individuals with any first-degree relatives with AUDs expands the classic family history positive AUD definition to include siblings, who display greater genetic concordance with a particular individual than their parents. To our knowledge, though, this definition of first-degree family member positive or negative for AUDs has not been applied to the study of Now bias. Thus, while Now bias possesses many properties that suggest it could be a good intermediate phenotype for AUDs, further investigation of this possibility is warranted, particularly work focusing on examining whether Now bias is elevated in unaffected individuals with first degree relatives with AUDs.
Given our review of the literature and past work in this area (Mitchell et al., 2005), we focused on better demonstrating the utility of Now bias as an intermediate phenotype for AUDs in a large group of individuals who ranged in age, level of alcohol use, and family history of AUDs. This work was published in Frontiers in Human Neuroscience in 2015, but I share the key takeaways from the study, below.
In addition to being elevated in problematic drinking emerging adults, to satisfy another intermediate phenotype criterion for AUDs, Now bias behavior should also be elevated in unaffected first-degree relatives (parents, siblings) of those suffering from AUDs (intermediate phenotype criterion 5). Elevated Now bias in first-degree relatives of those with AUDs has yet to be adequately demonstrated, however.
Most of the intermediate phenotype literature considers the expression of the behavior or trait in first-degree relatives as critical in demonstrating that behavior as an intermediate phenotype. In the field of AUDs, however, positive family history of an AUD is often defined as having at least one parent with an AUD (Acheson et al., 2011) or father with an AUD (Crean et al., 2002; Petry et al., 2002), or some combination of parental history or sufficient density of AUD history in second-degree relatives (Herting et al., 2010). In these previous studies, the effects of family history on Now bias was either only observed in females (Petry et al., 2002), was not found at all (Crean et al., 2002; Herting et al., 2010), or was not present when controlling for group differences in IQ and antisocial behavior (Acheson et al., 2011).
Measuring Now bias behavior in individuals with any first-degree relatives with AUDs expands the classic family history positive AUD definition to include siblings, who display greater genetic concordance with a particular individual than their parents. To our knowledge, though, this definition of first-degree family member positive or negative for AUDs has not been applied to the study of Now bias. Thus, while Now bias possesses many properties that suggest it could be a good intermediate phenotype for AUDs, further investigation of this possibility is warranted, particularly work focusing on examining whether Now bias is elevated in unaffected individuals with first degree relatives with AUDs.
Given our review of the literature and past work in this area (Mitchell et al., 2005), we focused on better demonstrating the utility of Now bias as an intermediate phenotype for AUDs in a large group of individuals who ranged in age, level of alcohol use, and family history of AUDs. This work was published in Frontiers in Human Neuroscience in 2015, but I share the key takeaways from the study, below.
New evidence supporting Now bias as an intermediate phenotype for AUDs
As mentioned earlier, adults with addictive disorders, including alcohol use disorders (AUDs), tend to choose smaller, sooner over larger, delayed rewards in the context of delay-discounting (DD) tasks more frequently than do adults with no addiction history (Petry, 2001; Mitchell et al., 2005; MacKillop et al., 2011). This immediate reward selection (or “Now”) bias persists even after years of abstinence and does not correlate with abstinence duration (Mitchell et al., 2005), suggesting irreversible consequences of chronic alcohol abuse and/or a pre-existing risk trait, or intermediate phenotype (Meyer-Lindenberg and Weinberger, 2006; MacKillop, 2013). If Now bias was a pre-existing risk trait for AUDs, we would predict heightened Now bias among young people who engage in at-risk drinking but who do not meet clinical criteria for alcohol dependence, relative to age-matched light or moderate drinkers. In addition, we would also predict heightened Now bias among light or moderate drinkers with problem-drinking first degree relatives if this behavior was an intermediate phenotype for AUDs.
As the Alcohol Use Disorders Identification Test (AUDIT) is an effective means of measuring problem drinking behavior (Fiellin et al., 2000; Barbor and Higgins-Biddle, 2001; Kokotailo et al., 2004), we recruited high and low AUDIT individuals across a group of 18-40 year old social drinkers not reporting any AUD. We hypothesized that Now bias would be elevated in high but not low AUDIT emerging adults (defined as ages 18-21 or 18-24). Furthermore, we sought to test whether Now bias was elevated in those otherwise unaffected individuals (light/moderate social drinkers; low AUDIT) with a first degree relative with an AUD. We used the intermediate phenotype criteria of first-degree biological relative status (father, mother, or sibling with AUD), excluding those with mothers with an AUD to rule out potential fetal alcohol effects. We hypothesized that Now bias would be elevated in low AUDIT individuals with a first-degree relative with an AUD but not in those with no first-degree AUD relative.
Considering the effect of age on Now bias
As this study was underway, we began to wonder how age might impact Now bias independent of problematic alcohol use. Our lab had previously found marked Now bias among emerging adults (18-25 yrs), regardless of drinking behavior. This suggests elevated DD generally among individuals transitioning from adolescence to adulthood. The observation that adult controls (average age of 26-28) with no AUD diagnosis display reduced Now bias compared to abstinent alcoholic adults (Mitchell et al., 2005; Boettiger et al., 2007) suggests that this bias should decline between emerging adulthood and adulthood, at least among moderate, non-problem drinkers. While emerging adults are widely regarded as impulsive (Chambers and Potenza, 2003; de Wit, 2009), and DD normally decreases from childhood to the early 30’s (Green, 1994; Scheres et al., 2006; Olson et al., 2007; Eppinger et al., 2012), little is known about specific changes in DD from late adolescence to adulthood. Some data show trait impulsivity declining linearly with age from early adolescence to age 30 (Steinberg et al., 2008). Thus, given positive correlations between DD and trait impulsivity (Mitchell et al., 2005; de Wit et al., 2007), we hypothesized DD should decline with age from adolescence into the 30s, but, to our knowledge, no prior studies have explicitly investigated age effects on DD in detail from ages 18 to 40. Moreover, we do not know whether heavy alcohol use moderates any such age-related changes in DD. Thus, a secondary aim of our work was to investigate age-related differences in Now bias in our population as a whole and separately in those reporting heavy, problematic versus light/moderate drinking.
Confirming and extending on prior work, we found that emerging adults (defined as either aged 18-21 or aged 18-24) regardless of their drinking status (light/moderate vs heavy drinkers) showed equally high Now bias behavior, which did not support our first hypothesis that this behavior would be elevated in heavy drinkers. Follow-up analyses concluded that Now bias generally declined with age in our light/moderate drinker population (r=-0.28, p=0.022) but not in the heavy drinkers (r=-0.03, p=0.39). We measured Now bias in our study as an impulsive choice ratio (ICR), which can range from 0 (no Now bias) to 1 (complete Now bias). The age-related decline in Now bias began to asymptote around age 25. Thus, we organized our data into emerging adult (aged 18-24) and adult (aged 26-40) groups for further analyses.
Our measure of Now bias, ICR, was found to decline with age in light/moderate drinkers but not in heavy drinkers.
Now bias as intermediate phenotype for AUDs in adults
We did confirm our second hypothesis that Now bias (measured via ICR) was elevated in light/moderate drinking adults (aged 26-40) with first-degree relatives with an alcohol use disorder (AUD). Plotting our adult population by first-degree relative status and comparing it to heavy drinking adults and abstinent alcoholic adults studied previously (Mitchell et al., 2005), we found strong evidence supporting Now bias as an intermediate phenotype for AUDs.
- Now bias (ICR) is high in individuals who drink heavily and problematically but without an AUD (orange bar in graph, below)
- Heavy drinker ICR is nearly equivalent to that seen in abstinent alcoholics (red bar in graph, below) despite these individuals not meeting the criteria of having an AUD
- Now bias is elevated in light/moderate drinking adults with first-degree relatives with an AUD (FH+) relative to those without a first-degree relative with an AUD (FH-; blue bars in graph, below)
Among adults, Now bias as measured by ICR is elevated in individuals at risk for AUDs. The dark blue line and red bar represent prior data measuring ICR in abstinent alcoholics and healthy controls. New data from heavy or light/moderate drinking adults with (FH+) and without (FH-) a family history of AUDs are plotted in the orange and blue bars, respectively.
Implications of our findings - Could reducing Now bias lower one's risk of an AUD?
Our work has added additional support to Now bias being an intermediate phenotype for alcohol use disorders (AUDs). The fact that Now bias was elevated in heavy drinking adults without an AUD was suggestive that this behavior may proceed and AUD diagnosis. More work is needed to follow up on this finding, however. Specifically, longitudinal studies need to be conducted to measure Now bias in individuals in their early teens (prior to exposure to drinking) and continue to measure this behavior over the lifespan, especially as these individuals enter their late teens and early twenties when problematic drinking behavior often emerges. Only through careful study of the trajectory of Now bias during adult development in both non-problematic and problematic drinkers can we begin to truly determine the utility of this measure as an intermediate phenotype for alcohol use disorders or substance use disorders in general.
Ongoing work taking place as part of the Adolescent Brian Cognitive Development (ABCD) Study seeks to understand adolescent brain and cognitive development generally and the various behavioral (including Now bias) and neural risk factors that can emerge in adolescence that lead to mental or psychiatric disorders in adulthood.
Learn more about this ambitious study here and view current publications emerging from the dataset here.
Ongoing work taking place as part of the Adolescent Brian Cognitive Development (ABCD) Study seeks to understand adolescent brain and cognitive development generally and the various behavioral (including Now bias) and neural risk factors that can emerge in adolescence that lead to mental or psychiatric disorders in adulthood.
Learn more about this ambitious study here and view current publications emerging from the dataset here.
Since our study on Now bias as a potential intermediate phenotype for AUDs was published in Frontiers in Human Neuroscience, other work has shown:
- Large individual differences in intertemporal choice behavior (Review; Keidel et al., 2021)
- Genomic basis of delayed reward discounting (Gray et al., 2019)
- Steep Discounting of Future Rewards as an Impulsivity Phenotype: A Concise Review (Levitt et al., 2020)
- Individuals with two parents with addiction have significantly higher rates of discounting compared to those with no or only one parent with addiction (Athamneh et al., 2017)
- The density of familial alcoholism interacted with binge-drinking status to predict impulsive choice (Jones et al., 2017)
- A review of age & impulsive behavior in drug addiction (Argyriou et al., 2017)
With increased confidence in Now bias as an intermediate phenotype for alcohol use disorders, our next step is better understanding the neural and biological bases of this behavior. This information may then offer a means to potentially reduce Now bias in individuals at risk for alcohol use disorders. Making at-risk individuals more future-focused could assist them in considering the long-term consequences of problematic alcohol use and reduce the temptation to drink heavily in the moment. Targeting the dopaminergic system is one potential approach to modulating Now bias as some of my and others' work has shown. Delving into that topic will have to wait for a future post, though. Stay tuned.
Explore more of my work on Now bias:
And additional neuroscience topics on the blog:
- Age modulates the effect of COMT genotype on delay discounting behavior
- Ovarian cycle effects on immediate reward selection bias in humans: a role for estradiol
- Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults
- Neural Systems Underlying Individual Differences in Intertemporal Decision-making
And additional neuroscience topics on the blog:
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