Ahmad R. Hariri

5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

Carriers of the short allele of a functional 5′ promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.

Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.

Modulating emotional responses: effects of a neocortical network on the limbic system.

Humans share with animals a primitive neural system for processing emotions such as fear and anger. Unlike other animals, humans have the unique ability to control and modulate instinctive emotional reactions through intellectual processes such as reasoning, rationalizing, and labeling our experiences. This study used functional MRI to identify the neural networks underlying this ability. Subjects either matched the affect of one of two faces to that of a simultaneously presented target face (a perceptual task) or identified the affect of a target face by choosing one of two simultaneously presented linguistic labels (an intellectual task). Matching angry or frightened expressions was associated with increased regional cerebral blood flow (rCBF) in the left and right amygdala, the brains primary fear centers. Labeling these same expressions was associated with a diminished rCBF response in the amygdalae. This decrease correlated with a simultaneous increase in rCBF in the right prefrontal cortex, a neocortical region implicated in regulating emotional responses. These results provide evidence for a network in which higher regions attenuate emotional responses at the most fundamental levels in the brain and suggest a neural basis for modulating emotional experience through interpretation and labeling.

Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine.

Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val158-met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-“U” functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.

Neocortical modulation of the amygdala response to fearful stimuli.

BACKGROUND The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. METHODS In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. RESULTS Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. CONCLUSIONS The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal.

Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis

BACKGROUND We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship. METHODS We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry. RESULTS Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes. CONCLUSIONS Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.

The Amygdala Response to Emotional Stimuli: A Comparison of Faces and Scenes

As a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function.

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.

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.

Neurophysiological correlates of age-related changes in human motor function

BackgroundThere are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. ObjectiveTo delineate age-related changes in the physiology of brain systems subserving simple motor behavior. MethodsTen strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced “button-press” motor task with their dominant right hand alternating with a rest state. ResultsAlthough the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score ± SD, young subjects = 547 ± 97 ms, elderly subjects = 794 ± 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. ConclusionsThe results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.