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Ahmad R Hariri

Publications and source records attributed to Ahmad R Hariri.

At least 19 recordsLinked to original sources
PubMed2022

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from -0.08 to -0.11), tested cognitive deficits (β's from -0.36 to -0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Alzheimer’s disease↗
PubMed2006

Preference for immediate over delayed rewards is associated with magnitude of ventral striatal activity.

Discounting future outcomes as a function of their deferred availability underlies much of human decision making. Discounting, or preference for immediate over delayed rewards of larger value, is often associated with impulsivity and is a risk factor for addictive disorders such as pathological gambling, cigarette smoking, and drug and alcohol abuse. The ventral striatum (VS) is involved in mediating behavioral responses and physiological states associated with reward, and dysregulation of the VS contributes to addiction, perhaps by affecting impulsive decision-making. Behavioral tests of delay discounting (DD), which index preference for smaller immediate over larger delayed rewards, covary with impulsive tendencies in humans. In the current study, we examined the relationship between individual differences in DD, measured in a behavioral assessment, and VS activity measured with blood oxygenation level-dependent functional magnetic resonance imaging, in 45 adult volunteers. VS activity was determined using a task involving positive and negative feedback with monetary reward. Analyses revealed that individual differences in DD correlate positively with magnitude of VS activation in response to both positive and negative feedback, compared with a no-feedback control condition. Variability in DD was also associated with differential VS activation in response to positive, compared with negative, feedback. Collectively, our results suggest that increased preference for smaller immediate over larger delayed rewards reflects both a relatively indiscriminate and hyper-reactive VS circuitry. They also highlight a specific neurocognitive mechanism that may contribute to increased risk for addiction.

Adult↗
PubMed2006

Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation.

BACKGROUND: A polymorphism of the human serotonin transporter gene (SCL6A4) has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers. However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers. METHODS: Functional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men. RESULTS: Amygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions. CONCLUSIONS: This finding suggests that s carriers show stronger amygdala reactivity to stimuli and contexts that are relatively uncertain, which we propose are stressful.

Adult↗
PubMed2006

Facial expressions of emotion reveal neuroendocrine and cardiovascular stress responses.

BACKGROUND: The classic conception of stress involves undifferentiated negative affect and corresponding biological reactivity. The present study hypothesized a new conception, disaggregating stress into emotion-specific, contrasting patterns of biological response. Specifically, it hypothesized contrasting patterns for indignation (comprised of anger and disgust) versus fear. Moreover, it hypothesized that facial expressions of these emotions would signal corresponding biological stress responses. METHODS: Ninety-two adults engaged in annoyingly difficult stress-challenge tasks, during which cardiovascular responses, hypothalamic-pituitary-adrenocortical (HPA) axis responses (i.e., cortisol), emotional expressions (i.e., facial muscle movements), and subjective emotional experience were assessed. RESULTS: Pronounced individual differences emerged in specific emotional responses to the stressors. Analyses of facial expressions revealed that the more fear individuals displayed in response to the stressors, the higher their cardiovascular and cortisol responses to stress. By contrast, the more indignation individuals displayed in response to the same stressors the lower their cortisol levels and cardiovascular responses. CONCLUSIONS: Facial expressions of emotion signal biological responses to stress. Fear expressions signal elevated cortisol and cardiovascular reactivity; indignation signals attenuated cortisol and cardiovascular reactivity, patterns that implicate individual differences in stress appraisals. Rather than conceptualizing stress as generalized negative affect, studies can be informed by this emotion-specific approach to stress responses.

Adolescent↗
PubMed2006

Human choline transporter gene variation is associated with corticolimbic reactivity and autonomic-cholinergic function.

BACKGROUND: Our previous work has shown genetic variation in the human choline transporter gene (CHT1) to be associated with depressive symptoms and autonomic cardiac (cholinergic) dysregulation. Here, functional magnetic resonance imaging (fMRI) was used to examine the relation between a single nucleotide polymorphism (SNP) in CHT1 on regional brain reactivity relevant to autonomic (cholinergic) function. METHODS: Thirty-two participants of European ancestry (18 men, 14 women; age: 33-54 years) completed an fMRI protocol using corticolimbic reactivity and prefrontal inhibitory control paradigms. Resting cholinergic function, as measured by heart rate variability (HRV), was quantified from electrocardiogram. Subjects were genotyped for a CHT1 G/T SNP. RESULTS: GG homozygotes had greater right (R) dorsal amygdala (p < .008), bilateral anterior cingulate (p < .009), and R caudate reactivity (p < .015) than T-allele carriers. Heart rate variability was related to R frontal cortex (Brodmann Areas 6, 9, and 46), R hippocampal formation, bilateral caudate, and bilateral anterior cingulate reactivity (p's < .007). CONCLUSIONS: CHT1 variation is related to differences in a distributed corticolimbic circuitry mediating behavioral and physiologic arousal. These relations may contribute to a biological mechanism by which genetic variation in cholinergic neurotransmission affects cognition, mood, and autonomic cardiac function.

Adult↗
PubMed2006

Neural mechanisms of genetic risk for impulsivity and violence in humans.

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.

Alleles↗
PubMed2006

Genetics of emotional regulation: the role of the serotonin transporter in neural function.

Identifying biological mechanisms through which genes lead to individual differences in emotional behavior is paramount to our understanding of how such differences confer risk for neuropsychiatric illness. The emergence of techniques such as in vivo imaging of brain function in humans and genetic engineering in rodents has provided important new insights into the impact of serotonin (5-HT), a key modulator of emotional behavior, on neural systems subserving anxiety and depression. A major finding has been the discovery of genetic variation in a crucial regulatory molecule within the 5-HT system, the 5HT transporter (5-HTT), and its influence on emotional traits. The study of the 5-HTT provides a new foundation for understanding the neurobiological and genetic basis of emotional regulation and affective illness.

Amygdala↗
PubMed2006

Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing.

Advances in molecular biology and neuroimaging have provided a unique opportunity to explore the relationships between genes, brain, and behavior. In this review, we will briefly outline the rationale for studying genetic effects on brain function with neuroimaging. We will then use studies of genetically driven variation in serotonin transporter function on corticolimbic structure and function to highlight the effectiveness of this strategy to delineate biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. In a series of studies, a relatively frequent regulatory variant of the human serotonin transporter gene (5-HTTLPR) has been demonstrated to bias the reactivity of the amygdala to salient environmental cues. Moreover, the 5-HTTLPR affects the development of a broader corticolimbic circuit and alters the functional integration of emotional information between the amygdala and medial prefrontal cortex. In turn, corticolimbic circuit function predicts individual differences in an experimental index of temperamental anxiety and, thus, might reflect a predictive biological marker of increased risk for mood disorders associated with the 5-HTTLPR.

Alleles↗
PubMed2006

Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.

CONTEXT: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

Adult↗
PubMed2006

Developmental imaging genetics: challenges and promises for translational research.

Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy.

Antisocial Personality Disorder↗
PubMed2006

Neural basis of individual differences in impulsivity: contributions of corticolimbic circuits for behavioral arousal and control.

The objective of the current study was to analyze the neural correlates of behavioral arousal and inhibitory control as they relate to individual differences in impulsivity via well-established functional MRI amygdala reactivity and prefrontal inhibitory control paradigms in healthy adult subjects. Impulsivity correlated positively with activity of the bilateral ventral amygdala, parahippocampal gyrus, dorsal anterior cingulate gyrus (BA 32), and bilateral caudate. Conversely, impulsivity correlated negatively with activity of the dorsal amygdala and ventral prefrontal cortex (BA 47). Together, these findings suggest that dispositional impulsivity is influenced by the functional interplay of corticolimbic behavioral arousal and control circuits.

Adult↗
PubMed2006

Serotonin.

Explore the source record for details and available documents.

Amygdala↗
PubMed2006

Neuroimaging studies of serotonin gene polymorphisms: exploring the interplay of genes, brain, and behavior.

Because of the unique ability it provides to investigate information processing at the level of neural systems, functional neuroimaging is a powerful tool to explore the relationship between genes, brain, and behavior. Recently, functional neuroimaging has provided dramatic illustrations of how a promoter polymorphism in the human serotonin transporter gene, which has been weakly related to several dimensions of emotional behaviors (such as neuroticism and anxiety traits), is strongly related to the engagement of neural systems--namely, the amygdala and subgenual prefrontal cortex, subserving emotional information processing. This review will outline the experimental strategy by which these genetic effects on brain function have been explored and highlight the effectiveness of this strategy to delineate biological pathways and mechanisms contributing to the emergence of individual differences in brain function that potentially bias behavior and risk for psychiatric illness.

Animals↗
PubMed2005

Facial expressions of emotion reveal neuroendocrine and cardiovascular stress responses.

BACKGROUND: The classic conception of stress involves undifferentiated negative affect and corresponding biological reactivity. The present study hypothesized a new conception that disaggregates stress into emotion-specific, contrasting patterns of biological response. METHODS: Ninety-two healthy adults engaged in stress-challenge tasks, during which cardiovascular responses, hypothalamic-pituitary-adrenocortical (HPA) axis responses (i.e., cortisol), emotional expressions (i.e., facial muscle movements), and subjective emotional experience (self-reported) were assessed. RESULTS: Pronounced individual differences emerged in specific emotional responses to the stressors. Analyses of facial expressions revealed that the more fear individuals displayed in response to the stressors, the higher their cardiovascular and cortisol responses to stress. By contrast, the more anger and disgust (indignation) individuals displayed in response to the same stressors, the lower their cortisol levels and cardiovascular responses. Individual differences in optimistic appraisals appeared to mediate these correlated patterns. CONCLUSIONS: Facial expressions of emotion signal biological responses to stress. Fear expressions signal elevated cortisol and cardiovascular reactivity; anger and disgust signal attenuated cortisol and cardiovascular reactivity, patterns that implicate individual differences in stress appraisals. Rather than conceptualizing stress as generalized negative affect, studies can be informed by this emotion-specific approach to stress responses.

Adult↗
PubMed2005

Neurophysiological correlates of age-related changes in working memory capacity.

Cognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age=29) and twelve older subjects (>55 years of age; mean age=59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE=24 ms, TR=56 ms, FA=60 degrees , voxel dimensions=3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (1-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p=0.4), but performed worse than the younger subjects at 2-Back (p<0.01) and 3-Back (p=0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p<0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in 1-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs.

Adult↗
PubMed2005

Neural correlates of genetically abnormal social cognition in Williams syndrome.

Williams-Beuren syndrome (WBS), caused by a microdeletion of approximately 21 genes on chromosome 7q11.23, is characterized by unique hypersociability combined with increased non-social anxiety. Using functional neuroimaging, we found reduced amygdala activation in individuals with WBS for threatening faces but increased activation for threatening scenes, relative to matched normal controls. Activation and interactions of prefrontal regions linked to amygdala, especially orbitofrontal cortex, were abnormal, suggesting a genetically controlled neural circuitry for regulating human social behavior.

Amygdala↗
PubMed2005

Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.

Adult↗