Emily M. Drabant

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.

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.

Individual Differences in Typical Reappraisal Use Predict Amygdala and Prefrontal Responses

BACKGROUND Participants who are instructed to use reappraisal to downregulate negative emotion show decreased amygdala responses and increased prefrontal responses. However, it is not known whether individual differences in the tendency to use reappraisal manifests in similar neural responses when individuals are spontaneously confronted with negative situations. Such spontaneous emotion regulation might play an important role in normal and pathological responses to the emotional challenges of everyday life. METHODS Fifty-six healthy women completed a blood oxygenation-level dependent functional magnetic resonance imaging challenge paradigm involving the perceptual processing of emotionally negative facial expressions. Participants also completed measures of typical emotion regulation use, trait anxiety, and neuroticism. RESULTS Greater use of reappraisal in everyday life was related to decreased amygdala activity and increased prefrontal and parietal activity during the processing of negative emotional facial expressions. These associations were not attributable to variation in trait anxiety, neuroticism, or the use of another common form of emotion regulation, namely suppression. CONCLUSIONS These findings suggest that, like instructed reappraisal, individual differences in reappraisal use are associated with decreased activation in ventral emotion generative regions and increased activation in prefrontal control regions in response to negative stimuli. Such individual differences in emotion regulation might predict successful coping with emotional challenges as well as the onset of affective disorders.

Experiential, autonomic, and neural responses during threat anticipation vary as a function of threat intensity and neuroticism☆

Anticipatory emotional responses play a crucial role in preparing individuals for impending challenges. They do this by triggering a coordinated set of changes in behavioral, autonomic, and neural response systems. In the present study, we examined the biobehavioral impact of varying levels of anticipatory anxiety, using a shock anticipation task in which unpredictable electric shocks were threatened and delivered to the wrist at variable intervals and intensities (safe, medium, strong). This permitted investigation of a dynamic range of anticipatory anxiety responses. In two studies, 95 and 51 healthy female participants, respectively, underwent this shock anticipation task while providing continuous ratings of anxiety experience and electrodermal responding (Study 1) and during fMRI BOLD neuroimaging (Study 2). Results indicated a step-wise pattern of responding in anxiety experience and electrodermal responses. Several brain regions showed robust responses to shock anticipation relative to safe trials, including the hypothalamus, periaqueductal gray, caudate, precentral gyrus, thalamus, insula, ventrolateral PFC, dorsomedial PFC, and ACC. A subset of these regions demonstrated a linear pattern of increased responding from safe to medium to strong trials, including the bilateral insula, ACC, and inferior frontal gyrus. These responses were modulated by individual differences in neuroticism, such that those high in neuroticism showed exaggerated anxiety experience across the entire task, and reduced brain activation from medium to strong trials in a subset of brain regions. These findings suggest that individual differences in neuroticism may influence sensitivity to anticipatory threat and provide new insights into the mechanism through which neuroticism may confer risk for developing anxiety disorders via dysregulated anticipatory responses.

Neural Mechanisms Underlying 5-HTTLPR-Related Sensitivity to Acute Stress

OBJECTIVE Many studies have shown that 5-HTTLPR genotype interacts with exposure to stress in conferring risk for psychopathology. However, the specific neural mechanisms through which this gene-by-environment interaction confers risk remain largely unknown, and no study to date has directly examined the modulatory effects of 5-HTTLPR on corticolimbic circuit responses during exposure to acute stress. METHOD An acute laboratory stressor was administered to 51 healthy women during blood-oxygen-level-dependent functional magnetic resonance imaging. In this task, participants were threatened with electric shocks of uncertain intensity, which were unpredictably delivered to the wrist after a long anticipatory cue period of unpredictable duration. RESULTS Relative to women carrying the L allele, those with the SS genotype showed enhanced activation during threat anticipation in a network of regions, including the amygdala, hippocampus, anterior insula, thalamus, pulvinar, caudate, precuneus, anterior cingulate cortex, and medial prefrontal cortex. Individuals with the SS genotype also displayed enhanced positive coupling between medial prefrontal cortex activation and anxiety experience, whereas enhanced negative coupling between insula activation and perceived success at regulating anxiety was observed in individuals carrying the L allele. CONCLUSIONS These findings suggest that during stress exposure, neural systems that enhance fear and arousal, modulate attention toward threat, and perseverate on emotional salience of the threat may be engaged preferentially in individuals with the SS genotype. This may be one mechanism underlying the risk for psychopathology conferred by the S allele upon exposure to life stressors.

Emotion regulation and brain plasticity: expressive suppression use predicts anterior insula volume.

Expressive suppression is an emotion regulation strategy that requires interoceptive and emotional awareness. These processes both recruit the anterior insula. It is not known, however, whether increased use of expressive suppression is associated with increased anterior insula volume. In the present study, high-resolution anatomical MRI images were used to calculate insula volumes in a set of 50 healthy female subjects (mean 21.9 years) using both region of interest (ROI) and voxel-based morphometry (VBM) approaches. Participants also completed trait measures of expressive suppression usage, cognitive reappraisal usage, and negative emotional reactivity (the latter two served as control measures). As predicted, both ROI and VBM methods found that expressive suppression usage, but not negative affect and cognitive reappraisal, was positively related to anterior insula volume. These findings are consistent with the idea that trait patterns of emotion processing are related to brain structure.

Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions

The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

Anterior cingulate cortex volume and emotion regulation: is bigger better?

Emotion dysregulation is a key feature of mood and anxiety disorders. Many of these disorders also involve volumetric reductions in brain regions implicated in emotion regulation, including the dorsal anterior cingulate cortex (dACC). Investigating this relationship in healthy individuals may clarify the link between emotion regulation and volumetric reductions in this key brain region. High-resolution anatomical MRI images were used to calculate dACC volumes in 50 healthy female subjects. Trait measures of emotion regulation (cognitive reappraisal and expressive suppression) and negative affect were also obtained. As predicted, cognitive reappraisal was positively related to dACC volume, but not the volume of a control region, the ventral ACC. Expressive suppression, negative affect, and age were not related to dACC volume. These findings indicate that individual differences in cognitive reappraisal are related to individual differences in dACC volume in healthy participants.

Sleep quality and neural circuit function supporting emotion regulation

BackgroundRecent laboratory studies employing an extended sleep deprivation model have mapped sleep-related changes in behavior onto functional alterations in specific brain regions supporting emotion, suggesting possible biological mechanisms for an association between sleep difficulties and deficits in emotion regulation. However, it is not yet known if similar behavioral and neural changes are associated with the more modest variability in sleep observed in daily life.MethodsWe examined relationships between sleep and neural circuitry of emotion using the Pittsburgh Sleep Quality Index and fMRI data from a widely used emotion regulation task focusing on cognitive reappraisal of negative emotional stimuli in an unselected sample of 97 adult volunteers (48 women; mean age 42.78±7.37 years, range 30–54 years old).ResultsEmotion regulation was associated with greater activation in clusters located in the dorsomedial prefrontal cortex (dmPFC), left dorsolateral prefrontal cortex (dlPFC), and inferior parietal cortex. Only one subscale from the Pittsburgh Sleep Quality Index, use of sleep medications, was related to BOLD responses in the dmPFC and dlPFC during cognitive reappraisal. Use of sleep medications predicted lesser BOLD responses during reappraisal, but other aspects of sleep, including sleep duration and subjective sleep quality, were not related to neural activation in this paradigm.ConclusionsThe relatively modest variability in sleep that is common in the general community is unlikely to cause significant disruption in neural circuits supporting reactivity or regulation by cognitive reappraisal of negative emotion. Use of sleep medication however, may influence emotion regulation circuitry, but additional studies are necessary to determine if such use plays a causal role in altering emotional responses.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.