In the United States, addictive disorders including substance use disorders and pathological overeating cause an extensive burden in terms of morbidity, mortality, and public health costs, yet treatment strategies are only modestly effective. Better understanding of the biological mechanisms that underlie addictive disorders and increase susceptibility could substantially improve current prevention and intervention efforts. The overarching goal across my line of translational research is to characterize factors that increase risk for addictive disorders. Specifically, I am interested in how early life factors such as period of exposure (e.g., adolescent onset of regular use) or early life stress mediate the neural mechanisms that are associated with addictive disorders, and how genetic risk moderates these effects.
A translational neuroscience approach.The utility of combining genomic and neuroimaging approaches is becoming increasingly evident. Neuroimaging provides a neurobiological phenotype that is proximal to the biological function of genetic variation. Unlike other phenotypes, which may be affected by subjective factors, like reporter bias (e.g., in reporting subjective craving and/or the experience of addictive symptoms), neurobiological phenotypes are less influenced by other variables. Using more objective phenotypes subsequently helps increase the power to detect the influence of the genetic variation. In addition, neuroimaging provides a critical link between molecular changes and behavior, which also makes interpreting and translating the effects of genetic variation much more clear. Over the last several years, I have developed a translational model that links changes at the neural level with changes at the behavioral level (Filbey, et al., 2008; Filbey, Slack, Sunderland, & Cohen, 2006; Filbey, Schacht, Myers, Chavez, & Hutchison, 2009b). The projects below describe how I have taken this approach to fill the knowledge gap on the biobehavioral mechanisms of addictive disorders.
Cue-reactivity in fMRI. While there has been considerable controversy over the subjective “craving” in humans, the study of the biological mechanisms that underlie the positive reinforcing effects of stimuli in animals and humans has historically been much more straightforward. Previous studies have found that the motivation to use drugs is linked to the mesolimbic and mesocortical dopamine pathways in the brain and is an important factor in the etiology of addiction (Robinson & Berridge, 1993). Despite being less addictive than other substances of abuse, the published behavioral studies of marijuana suggest that craving is a reliable and valid phenomenon with this substance, analogous to craving for other drugs of abuse (e.g.,Haughey, Marshall, Schacht, Louis, & Hutchison, 2008). In the first neuroimaging study of cue-reactivity in marijuana users, I utilized a tactile cue paradigm (i.e., used marijuana pipe vs. pencil) in fMRI in marijuana users (Filbey et al., 2009b). The imaging results showed that activity in the orbitofrontal cortex (OFC), anterior cingulate, amygdala, thalamus, insula, nucleus accumbens and ventral tegmental area (VTA) underlie cue-reactivity in marijuana, and that this pattern was positively correlated with marijuana-related problems. This is notable, as it demonstrates that the areas of activation for marijuana are similar to other drugs of abuse such as cocaine, heroin, methamphetamine, alcohol, and tobacco (for review see Volkow et al., 2006).
In a more recent line of research, I have also been examining cue reactivity in tobacco dependent adults and binge eaters who meet criteria for obesity (BMI>30). With tobacco smokers, I utilized video cues in an fMRI paradigm to elicit cue-elicited craving (Filbey et al, 2009). Specifically, I compared the BOLD response to smoking video clips with appetitive (e.g., food) video clips and found greater activation during the smoking cues in the bilateral anterior cingulate, right insula, and right superior and middle temporal gyri. Building upon this work, I have also evaluated the use of olfactory cues to determine the most potent modality in eliciting a stronger response within the reward system in smokers. These analyses are underway.
Regarding obesity, researchers have suggested that aspects of disordered eating share mechanisms that have been previously implicated in addictions, specifically with respect to cue-elicited craving (Sheppard, 1993). People who pathologically overeat, such as binge eaters, report similar clinical symptoms to those that characterize substance addictions including craving, loss of control, impairment of functioning, preoccupation with the substance of choice (e.g., food), and the use of binge eating to regulate emotions and stress (Krahn & Gosnell, 1991). In this project, I examined fMRI BOLD response to food cues among individuals with obesity. The fMRI paradigm consisted of gustatory presentations of the participant’s preferred high-caloric beverage (e.g., coca cola) and a control taste (i.e, water). When high-caloric beverage exposure was contrasted with water exposure, we found greater activation in several expected areas including the dorsal and ventral striatum, anterior cingulate, inferior frontal gyrus (IFG), and insula (Filbey, 2010). These preliminary findings suggest a similar pattern of response for binge eaters as those with substance abuse disorders.
Early life factors. Early life stress has been found to negatively impact brain structure and function. In addition, studies have shown that the resultant neurobiological changes confer vulnerability for the development of brain disorders, specifically those related to stress such as substance abuse (Hayatbakhsh et al., 2008). However, despite clear links between early life stress and drug abuse, the neurobiological mechanisms that underlie this association remain unknown. We recently found that total score on the Early Life Stress Questionnaire was positively correlated with activation in the nucleus accumbens (NAc) during a cue exposure paradigm with heavy drinking adults. These findings suggest that exposure to early life stress is associated with increased neural response in an important area within the reward system during exposure to alcohol taste cues. This illustrates a possible mechanism by which early stress causes alterations in the dopaminergic system, which may subsequently increase one’s vulnerability to developing substance use disorders.
There is also growing literature suggesting that exposure to substances increases the brain’s sensitivity to their harmful effects. Contrary to the animal literature, the long-term effects of human adolescent substance abuse are not as clearly delineated. Studies have indicated that while other parts of the brain have matured by adolescence (areas controlling language, for example), cognitive control over high-risk behaviors is still maturing during adolescence, making teens more apt to engage in risky behaviors. Also, with the brain's emotion-related areas and connections still maturing, adolescents may additionally be more vulnerable to potential brain assaults that could impact the development of psychological disorders during this time.To examine this, we evaluated the role of early potential age of onset of marijuana use and fMRI BOLD response to marijuana cues. The results showed a positive correlation between neural activation and age of onset (range = 9 – 22 years of age), such that the earlier the age of onset, the less the response to cues in the mid-frontal gyrus and anterior cingulate gyrus. These findings suggest that exposure to regular marijuana use at an early age (i.e., adolescence) leads to alterations in brain function, particularly in frontal executive control areas.
Genetic risk factors. Basic research on the human genome is progressing at a rapid pace. Twin and adoption studies have indicated that genetic variation accounts for approximately 50% of the variance in substance use disorders (for review see (Dick & Bierut, 2006). With regards to marijuana dependence, the psychoactive substance, cannabinoid-Δ9-tetrahydrocannabinol (THC), binds to central cannabinoid or CB1 receptors, which are widely distributed in the brain (Matsuda, Lolait, Brownstein, Young, & Bonner, 1990). Subsequently, the logical candidate genes are those that regulate the cannabinoid system. I recently reported the first neuroimaging study of the genetic factors that impact the neurobiological processes in marijuana dependence. In this study, I examined the modulatory effects of both the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genotypes on neural response to marijuana cues. I found that the CNR1 and FAAH each moderated neural response to cues in reward areas of the brain, with an interactive effect between the two SNPs, such that the greater the number of risk alleles, the greater the neural response in reward areas (Filbey, Schacht, Myers, Chavez, & Hutchison, 2009a). In sum, these findings provide evidence for the strong influence of cannabinoid system modulating genes in moderating sensitivity to the effects of marijuana. I plan to extend this work to my tobacco using and binge eating samples.
In conclusion,I believe that my research is important since the determination of intermediate phenotypes on the path to brain disorders such as addictive disorders is a necessity if we are to determine those at risk, develop treatments designed to prevent the development of the disease, and apply them safely, economically and expeditiously.
2010 NIDA “Frontiers in Addiction Research” Travel Award
NIDA CPDD Travel Award
UCLA Advanced NeuroImaging Training Program Fellowship
2009 NIDA “Frontiers in Addiction Research” Travel Award
2008 The International Society of Psychiatric Genetics Travel Award
2007 Research Society on Alcoholism Junior Investigator Meeting Award
Enoch Gordis Award Finalist
2006 NIDA Research Training Institute Award
2004 International Conference on Biomagnetism Young Investigator Award
2002 Summer Institute in Cognitive Neuroscience McDonnell Foundation Fellowship
2001 NIMH Postdoctoral Intramural Research Training Award
2000 World Congress on Schizophrenia Research Young Scientist Award
International Congress on Psychiatric Genetics Scholarship
BrainTravel Grant Award
1998 Psychological Medicine Graduate Program Scholarship
1997 Dallas Veterans Affairs Medical Center Performance Award
American College of Neuropsychopharmacology
College on Problems of Drug Dependence
Human Brain Mapping
Society for Neuroscience
Cognitive Neuroscience Society
Society for Behavioral Medicine
Research Society for Alcoholism