Browsing by Author "Hariri, Ahmad R"

The goal of this dissertation is to characterize goal directed proactive behavioral responses to threat as well as reactive responses to threat exposure, and to identify the neural and personality correlates of individual differences in these responses. Three specific studies are reported wherein participants completed a novel shock avoidance paradigm while concurrent measures of behavioral, muscular, and sympathetic autonomic activity were collected; self-report was used to measure mood and trait personality; and blood oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI) was used to measure individual differences in threat-related amygdala reactivity and intrinsic connectivity within the corticolimbic circuit.

Results from Study 1 demonstrate that during threat exposure, participants exhibit increased avoidance behavior, faster reaction times, and increased muscular and sympathetic activity. Moreover, results demonstrate that two broad patterns characterize individual differences in how participants respond during avoidance: 1) a generalized tendency to exhibit magnified threat responses across domains; and 2) a tendency to respond either with proactive behavioral responses or reactive autonomic responses. Heightened state anxiety during the shock avoidance paradigm, and increased trait anxiety were both associated with the generalized tendency to exhibit magnified threat responses. However, gender moderated the relationship between trait anxiety and generalized increases in threat responses during avoidance, such that only male participants exhibited a positive relationship between these two factors. Study 2 demonstrates that intrinsic connectivity between the dorsomedial prefrontal cortex and centromedial region of the amygdala prospectively predicts whether participants will respond proactively or reactively during active avoidance. Finally, Study 3 provides evidence that responses to threat-related facial expressions within the centromedial region of the amygdala are associated with more reactive and less proactive responses during avoidance.

These results demonstrate that patterns observed in animal models of avoidance, specifically the competition between proactive and reactive responses to threat cues, extend to human participants. Moreover, our results suggest that while anxious mood during performance and heightened trait anxiety are associated with a generalized facilitation of threat responses across domains, measures of neural circuit function within the corticolimbic system predict whether individuals will exhibit increased proactive or reactive responses during active avoidance. In addition to facilitating the search for the neural processes underlying how the brain responds dynamically to threat, these results have the potential to aide researchers in characterizing the symptoms and neural processes underlying anxiety disorders.

Accumulating mental health research encourages a shift in focus towards transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology – called the ‘p factor’ – that underlies shared risk for a wide range of mental disorders. Identifying the behavioral, neural, and genetic correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the p factor contributes to risk. In the current series of studies, I investigate the behavioral, neural, and genetic correlates of the p factor in two independent samples in order to better understand the mechanisms underlying a general liability for mental illness. I first investigate these correlates in the Duke Neurogenetics Study (DNS) comprised of 1,246 young adult volunteers aged 18-22. I then determine whether the correlates identified in the DNS replicate in a subsample of 481 45 year-old members of a birth cohort from the ongoing Dunedin Longitudinal Study (Dunedin). The Dunedin Study includes over 1,000 participants from Dunedin, New Zealand who have been followed since birth.

In Study 1 (Chapter 3), I show that the p factor, which previously has been identified and related to maladaptive behaviors in the Dunedin cohort, is identifiable in the DNS, a high-functioning young adult sample, and demonstrate that p factor scores map onto a broad range of dysfunctional behaviors. In Study 2 (Chapter 4), using high-resolution multimodal structural neuroimaging in the DNS, I demonstrate that individuals with high p factor scores show reduced structural integrity of pons white matter pathways and reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, I observe a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher p factor scores. In Study 3 (Chapter 5), I replicate and extend these structural alterations in the Dunedin cohort. In Study 4 (Chapter 6), I demonstrate that liabilities for internalizing, externalizing, and thought disorders overlap with some structural neural correlates of the p factor, but also have unique correlates with brain structure in both samples. Finally, in Study 5 (Chapter 7), I show that polygenic risk for schizophrenia is associated with higher p factor scores, and that this association is partly mediated by cortico-cerebellar circuitry in the DNS, but not the Dunedin, sample.

Overall, these findings provide initial evidence that structural alterations in occipital and cortico-cerebellar circuitry supporting core functions related to the basic integration, coordination, and monitoring of information may contribute to a general liability for mental disorders and are robust to differences in sample characteristics. Links between genes, brain, and behavior in the DNS suggest that polygenic risk for schizophrenia may confer increased behavioral risk for general psychopathology through its influence on the capacity to communicate and process information between the cerebrum and the cerebellum through the pons. Failure to replicate these latter associations in the Dunedin cohort suggests important future research directions such as examining more specific genetic influences as well as their interactions with early life experiences on brain structure and general risk for psychopathology.

Accumulating mental health research encourages a shift in focus towards transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology – called the ‘p factor’ – that underlies shared risk for a wide range of mental disorders. Identifying the behavioral, neural, and genetic correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the p factor contributes to risk. In the current series of studies, I investigate the behavioral, neural, and genetic correlates of the p factor in two independent samples in order to better understand the mechanisms underlying a general liability for mental illness. I first investigate these correlates in the Duke Neurogenetics Study (DNS) comprised of 1,246 young adult volunteers aged 18-22. I then determine whether the correlates identified in the DNS replicate in a subsample of 481 45 year-old members of a birth cohort from the ongoing Dunedin Longitudinal Study (Dunedin). The Dunedin Study includes over 1,000 participants from Dunedin, New Zealand who have been followed since birth.

In Study 1 (Chapter 3), I show that the p factor, which previously has been identified and related to maladaptive behaviors in the Dunedin cohort, is identifiable in the DNS, a high-functioning young adult sample, and demonstrate that p factor scores map onto a broad range of dysfunctional behaviors. In Study 2 (Chapter 4), using high-resolution multimodal structural neuroimaging in the DNS, I demonstrate that individuals with high p factor scores show reduced structural integrity of pons white matter pathways and reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, I observe a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher p factor scores. In Study 3 (Chapter 5), I replicate and extend these structural alterations in the Dunedin cohort. In Study 4 (Chapter 6), I demonstrate that liabilities for internalizing, externalizing, and thought disorders overlap with some structural neural correlates of the p factor, but also have unique correlates with brain structure in both samples. Finally, in Study 5 (Chapter 7), I show that polygenic risk for schizophrenia is associated with higher p factor scores, and that this association is partly mediated by cortico-cerebellar circuitry in the DNS, but not the Dunedin, sample.

Overall, these findings provide initial evidence that structural alterations in occipital and cortico-cerebellar circuitry supporting core functions related to the basic integration, coordination, and monitoring of information may contribute to a general liability for mental disorders and are robust to differences in sample characteristics. Links between genes, brain, and behavior in the DNS suggest that polygenic risk for schizophrenia may confer increased behavioral risk for general psychopathology through its influence on the capacity to communicate and process information between the cerebrum and the cerebellum through the pons. Failure to replicate these latter associations in the Dunedin cohort suggests important future research directions such as examining more specific genetic influences as well as their interactions with early life experiences on brain structure and general risk for psychopathology.

Of the two most common forms of genetic variation in the human genome, Single Nucleotide Polymorphisms (SNPs) and Variable Number Tandem Repeat Polymorphisms (VNTRs), SNPs are much more easily and inexpensively assayed in a high-throughput manner. For this reason, we seek to explore methods that can allow us to use the more readily available SNP genotype information to infer VNTR genotypes in nearby genomic regions. We focus in particular on imputing a VNTR polymorphism, 5-HTTLPR, in the promoter region of the serotonin transporter gene in a small sample of individuals from an ongoing neuroimaging genetics study, a portion of whom have both manual 5-HTTLPR genotypes and genome wide SNP data. We investigate four imputation methods: Tagger, Vertex Discriminant Analysis (VDA), IMPUTE2, and BEAGLE. We achieve an accuracy of 93% with VDA in our subsample of Caucasians with manual 5-HTTLPR genotypes. Further, we find that for the entire Caucasian subsample without manual genotypes, a majority of the imputation methods tested make the same 5-HTTLPR genotype call.

The goal of this dissertation is two-fold: 1) to identify novel biological pathways implicating individual differences in reward and threat processing in the emergence of risk and resilience for psychopathology, 2) to identify novel genetic and epigenetic predictors of the inter-individual variability in these biological pathways. Four specific studies are reported wherein blood oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI) was used to measure individual differences in threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity; self-report was used to measure of mood and psychopathology as well as the experience of stressful life events. In addition, DNA was derived from peripheral tissues to identify specific genetic and epigenetic markers.

Results from Study 1 demonstrate that individuals with relatively low reward-related VS reactivity show stress-related reductions in positive affect, while those with high VS reactivity remain resilient to these potentially depressogenic effects. Heightened VS reactivity was, however, associated with stress-related increases in problem drinking in Study 2. Importantly, this effect only occurred in individuals showing concomitantly reduced threat-related amygdala reactivity. Study 3 demonstrates that using a multilocus genetic profile capturing the cumulative impact of five functional polymorphic loci on dopamine signaling increases power to explain variability in reward-related VS reactivity relative to an approach considering each locus independently. Finally, Study 4 provides evidence that methylation in the proximal promoter of the serotonin transporter gene is negatively correlated with gene expression and positively correlated with threat-related amygdala reactivity above and beyond the effects of commonly studied functional DNA-sequence based variation in the same genomic vicinity.

The results from these studies implicate novel biological pathways, namely reward-related VS reactivity and threat-related amygdala reactivity, as predictors of relative risk or resilience for psychopathology particularly in response to stressful life events. Moreover, the results suggest that genetic and epigenetic markers may serve as easily accessible peripheral tissue proxies for these neural phenotypes and, ultimately, risk and resilience. Such markers may eventually be harnessed to identify vulnerable individuals and facilitate targeted early intervention or prevention efforts.

The global population is aging with projections that the number of people over 60 will more than triple by 2050. While many organ systems are impacted by aging, deterioration of the brain is a particularly debilitating form of age-related disease. Alzheimer's disease and related dementias (ADRD) represent neurodegeneration that results in a loss of the ability to perform everyday tasks, maintain independence, and care for oneself. To date, ADRD interventions targeting older adults have largely proven to be ineffective at limiting morbidity and disability, suggesting that interventions may be failing to slow age-related disease because they are implemented too late in the aging process after decline has taken hold. However, to target ADRD interventions to younger adults we will need surrogate biomarkers that track sub-clinical signs of accelerated brain-aging that has yet to be fully cemented. This dissertation consists of 4 original studies that aim to measure and begin to validate magnetic resonance imaging (MRI)-based surrogate biomarkers for accelerated brain-aging in midlife adults. Each of these studies utilizes the Dunedin Study, a population-representative birth cohort of 1,037 adults, who have been followed longitudinally from birth to the most recent wave of data collection, completed when Study members were 45 years old. In Chapter 1, I found that individual differences in WMH volume, an established marker of dementia risk, cognitive decline, and dementia in older adults, were associated with cognitive decline from childhood to age-45. In Chapter 2, I found that individual differences in brainAGE were also associated with cognitive decline from childhood to age-45. In Chapter 3, I found that a known neurotoxicant, lead, was associated with cognitive decline from childhood to age 45, as well as with several MRI measures at age 45 including hippocampal volume, surface area, fractional anisotropy, and brainAGE. In chapter 4, I found that an accelerated Pace of Aging was associated with a thinner cortex, smaller surface area, lower hippocampal volume, higher WMH volume, and older brainAGE. Together, by triangulating evidence from cognitive aging, neurotoxic exposure, and biological aging, these studies help motivate the critical need for researchers to embrace midlife brain aging as a tool for better understanding the aging brain and dementia risk. I conclude with a discussion of the limitations of this research and opportunities for future research to target midlife brain aging itself as a target for clinical translation.

Sexual risk behavior among young adults is a serious public health concern; 50% will contract a sexually transmitted infection (STI) before the age of 25. The current study collected self-report personality and sexual history data, as well as neuroimaging, experimental behavioral (e.g., real-time hypothetical sexual decision making data), and self-report sexual arousal data from 120 heterosexual young adults ages 18-26. In addition, longitudinal changes in self-reported sexual behavior were collected from a subset (n = 70) of the participants. The primary aims of the study were (1) to predict differences in self-report sexual behavior and hypothetical sexual decision-making (in response to sexually explicit audio-visual cues) as a function of ventral striatum (VS) and amygdala activity, (2) test whether the association between sexual behavior/decision-making and brain function is moderated by gender, self-reported sexual arousal, and/or trait-level personality factors (i.e., self-control, impulsivity, and sensation seeking) and (3) to examine how the main effects of neural function and interaction effects predict sexual risk behavior over time. Our hypotheses were mostly supported across the sexual behavior and decision-making outcome variables, such that neural risk phenotypes (heightened reward-related ventral striatum activity coupled with decreased threat-related amygdala activity) were associated with greater lifetime sexual partners at baseline measured and over time (longitudinal analyses). Impulsivity moderated the relationship between neural function and self-reported number of sexual partners at baseline and follow up measures, as well as experimental condom use decision-making. Sexual arousal and sensation seeking moderated the relationship between neural function and baseline and follow up self-reports of number of sexual partners. Finally, unique gender differences were observed in the relationship between threat and reward-related neural reactivity and self-reported sexual risk behavior. The results of this study provide initial evidence for the potential role for neurobiological approaches to understanding sexual decision-making and risk behavior. With continued research, establishing biomarkers for sexual risk behavior could help inform the development of novel and more effective individually tailored sexual health prevention and intervention efforts.

Research on extreme deviations in early life caregiving has provided valuable insight into the effects of early adversity on brain development and risk for psychopathology. However, much remains unknown about the impact of normative range variation in parenting on these same processes. The primary aim of this dissertation is to begin to address this gap in the literature.

I first examined associations between variability in family functioning and threat-related amygdala reactivity. Analyses revealed that greater familial affective responsiveness was associated with increased amygdala reactivity to explicit, interpersonal threat. Moreover, this association was moderated by the experience of recent stressful life events such that higher affective responsiveness was associated with higher amygdala reactivity in adolescents reporting low but not high stress. I hypothesized that these paradoxical associations may suggest a mechanism through which parental overprotection manifests as psychosocial dysfunction. Centering this hypothesis as the focus of my next study, I examined more detailed aspects of both early caregiving experiences and corticolimbic circuitry. Analyses revealed that participants who reported higher maternal control exhibited increased amygdala reactivity to explicit, interpersonal threat and decreased structural integrity of the uncinate fasciculus. While not a direct replication, these findings supported my hypotheses regarding parental overprotection and expanded Study 1 findings into structural connectivity between the amygdala and regulatory regions of the prefrontal cortex.

I next conducted a scoping review of the extant literature centered on the question, “Is variability in normative range parenting associated with variability in brain structure and function?” This review yielded 23 records for qualitative review and revealed not only how few studies have explored associations between brain development and normative range parenting, but also how little methodological consistency exists across published studies. In light of these limitations, I proposed recommendations for future research on normative range parenting and brain development and highlighted a path forward. Lastly, I applied these recommendations to my own empirical analyses. In the same sample of young adults used in Study 2, I examined associations among parental care and control, neural structural phenotypes, and mood and anxiety symptoms. Analyses revealed no significant associations among parenting and structural indices of interest, suggesting that neural structure is robust to more subtle variability in parenting even while neural function is not.

This dissertation provides critical first steps in empirically investigating how normative parenting shapes brain development with the data currently available. Further, it highlights the work of others similarly investigating this question and establishes an agenda for advancing future research on this topic.