Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes on chromosome 7q11.23 and is characterized by both hypersociability and increases in specific phobia and anticipatory anxiety regarding non-social entities or circumstances. Alterations in amygdala reactivity and prefrontal regulation consistent with the observed behavioral pattern of social versus non-social abnormalities have been previously demonstrated in individuals with WS (Meyer-Lindenberg et al., 2005). However, in that study, the social stimulus (faces) matching task was more difficult than the non-social scene (IAPS stimuli) matching task, making it impossible to disambiguate the relative contributions of task difficulty and stimulus type (social versus non-social). In the present study, we examined the performance of the same group of participants with WS and normal IQs during a more cognitively demanding task using the same scene stimuli as in the prior study. Confirming previous findings, the results indicated (a) a differential response of prefrontal regions as a function of task difficulty and (b) a persistently increased activation of the amygdala to non-social scenes by individuals with WS regardless of cognitive load. These data provide further evidence of disruption in amygdala-prefrontal circuitry in individuals with WS.

As research in developmental and clinical sciences has progressed in the last decades, there have been many important technological and methodological advances in the increasingly complimentary fields of molecular genetics and neuroimaging. These advances have facilitated fruitful collaboration across once disparate disciplines, with early results shedding new light on the mechanisms giving rise to individual differences in complex behaviors and related psychiatric disorders. At the leading edge of such efforts is imaging genetics, an experimental strategy for the effective integration of molecular genetics and neuroimaging technologies for the study of biological mechanisms mediating individual differences in behavior and related risk for psychiatric disorders. Imaging genetic studies have the potential to provide a more complex and nuanced understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes variability in behavior. The broader potential of imaging genetics is to inform risk and resiliency; however, it is likely to be realized only through its orchestrated application within longitudinal developmental studies. To date, no imaging genetic studies of development or of childhood psychiatric disorders have yielded published results, although such studies are underway. The results of these studies may have important implications for the diagnosis and treatment of such psychiatric disorders.

CONTEXTSerotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback.OBJECTIVESTo evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety.DESIGNImaging genetics in participants from an archival database.PARTICIPANTSEighty-nine healthy adults.RESULTSConsistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity.CONCLUSIONSOur findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.

Previous research has shown that depression clusters within families. Adolescents from these families (i.e., high-risk) have approximately a three-fold increased risk of developing depression, an earlier mean age at onset, and greater lifetime morbidity in comparison with low-risk adolescents. Understanding the developmental pathways and mechanisms of susceptibility to depression, especially at the level of neurobiological circuits, is critical for the development of more effective intervention and prevention strategies, particularly in high-risk adolescents. The current study examined the functional reactivity of affect- and reward-related neural circuitries in high-risk and low-risk adolescents, as well as the functional coupling between regions of PFC and amygdala and ventral striatum. Adolescents (aged 12-15 years)—stratified according to familial history of depression (i.e., high- and low-risk)—completed two fMRI paradigms known to reliably elicit threat-related amygdala and reward-related ventral striatal reactivity, respectively. Using a conservative threshold, employed because of the very large sample size (> 300 adolescents), the present analyses failed to detect significant differences between these groups at the level of the amygdala and ventral striatum. When a more liberal threshold was applied, hypothesized differences were observed for both the amygdala reactivity paradigm and the ventral striatal reactivity paradigm: high-risk adolescents displayed relatively greater amygdala reactivity and relatively blunted VS reactivity compared to low-risk adolescents. Additionally, these data offer some evidence to suggest that alterations in functional connectivity of the threat-related amygdala reactivity network (but not reward-related VS reactivity) may vary as a function of risk status during adolescence.

Imaging genetics has been a highly effective and increasingly applied strategy for identifying the impact of genetic polymorphisms on individual differences in neural circuitry supporting complex behaviors. The application of imaging genetics towards further elucidating neural circuitry associated with the pathophysiology of psychiatric illness is of particular interest given its potential to guide the development and improvement of current therapeutic methods. The identification of genetic variants that contribute to or predict the disruption of specific neural pathways associated with psychopathology may also serve as useful markers of risk demarcating individuals with elevated susceptibility for psychiatric illness and affording early or even preemptive treatment strategies. In the continued development of this technique, recent multimodal neuroimaging strategies and studies examining the effects of multiple genes in concert within large subject populations have shown promise in the development of a more complete understanding of the interrelationships between genes, brain function, behavior and associated risk for psychopathology.

The role of the hypothalamic-pituitaryadrenal (HPA) axis in stress-related psychiatric disorders (i.e. depression and anxiety) has been well-established. Recent data indicate that corticotropinreleasing hormone (CRH), the principal neuroregulator of the HPA axis, plays a key role in alcohol dependence and that a gene-environment interaction between a SNP (rs1876831) in the CRH receptor 1 (CRHR1) gene and stressful life events predicts heavy alcohol use patterns in

We employed magnetoencephalography (MEG) to examine amygdala activity during a linguistic affective priming task. The experimental design included positive and negative word pairs. Using synthetic aperture magnetometry in the analysis of MEG data, we identified a left amygdala power increase in the theta frequency range during priming involving negative words. We found that the amygdala displayed a time-dependent intensification in responsiveness to negative stimuli, specifically between 150 and 400 ms after target presentation. This study provides evidence for theta power changes in the amygdala and demonstrates that the analysis of brain oscillations provides a powerful tool to explore mechanisms implicated in emotional processing.

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.

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.

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.