MDMA enhances positive affective responses to social feedback.

BACKGROUND: The prosocial compound ± 3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has shown promise as an adjunct to psychotherapy in the treatment of post-traumatic stress disorder. MDMA increases positive responses to social images, and it has been suggested that the ability of MDMA to positively bias social perception may underlie its therapeutic efficacy as a psychotherapy adjunct. However, the effect of the compound on affective responses to positive or negative social feedback has not been tested. AIMS: In this study, we aimed to test the effects of MDMA compared to placebo and the prototypical stimulant, methamphetamine (MA), on responses to positive and negative social feedback. METHODS: This was a double-blind, placebo-controlled, crossover trial (NCT03790618), comparing the effects of two doses of MDMA (0.75 mg/kg, 1.5 mg/kg) to both placebo and MA (20 mg) on responses to a personalized social feedback task, similar to a dating app, in healthy adult volunteers ages 18-40 (N = 36, 18 women, 18 men). RESULTS/OUTCOMES: The high dose of MDMA increased positive affective responses to social feedback. CONCLUSIONS/INTERPRETATIONS: These findings suggest one process by which MDMA may facilitate social connection. Further work is needed to understand how MDMA affects responses to more generalized types of social feedback and to understand these effects in clinical populations.

Orbitofrontal and striatal metabolism, volume, thickness and structural connectivity in relation to social anhedonia in depression: A multimodal study.

BACKGROUND: Social anhedonia is common within major depressive disorder (MDD) and associated with worse treatment outcomes. The orbitofrontal cortex (OFC) is implicated in both reward (medial OFC) and punishment (lateral OFC) in social decision making. Therefore, to understand the biology of social anhedonia in MDD, medial/lateral OFC metabolism, volume, and thickness, as well as structural connectivity to the striatum, amygdala, and ventral tegmental area/nucleus accumbens were examined. A positive relationship between social anhedonia and these neurobiological outcomes in the lateral OFC was hypothesized, whereas an inverse relationship was hypothesized for the medial OFC. The association between treatment-induced changes in OFC neurobiology and depression improvement were also examined. METHODS: 85 medication-free participants diagnosed with MDD were assessed with Wisconsin Schizotypy Scales to assess social anhedonia and received pretreatment simultaneous fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI), including structural and diffusion. Participants were then treated in an 8-week randomized placebo-controlled double-blind course of escitalopram. PET/MRI were repeated following treatment. Metabolic rate of glucose uptake was quantified from dynamic FDG-PET frames using Patlak graphical analysis. Structure (volume and cortical thickness) was quantified from structural MRI using Freesurfer. To assess structural connectivity, probabilistic tractography was performed on diffusion MRI and average FA was calculated within the derived tracts. Linear mixed models with Bonferroni correction were used to examine the relationships between variables. RESULTS: A significantly negative linear relationship between pretreatment social anhedonia score and structural connectivity between the medial OFC and the amygdala (estimated coefficient: -0.006, 95 % CI: -0.0108 - -0.0012, p-value = 0.0154) was observed. However, this finding would not survive multiple comparisons correction. No strong evidence existed to show a significant linear relationship between pretreatment social anhedonia score and metabolism, volume, thickness, or structural connectivity to any of the regions examined. There was also no strong evidence to suggest significant linear relationships between improvement in depression and percent change in these variables. CONCLUSIONS: Based on these multimodal findings, the OFC likely does not underlie social anhedonia in isolation and therefore should not be the sole target of treatment for social anhedonia. This is consistent with previous reports that other areas of the brain such as the amygdala and the striatum are highly involved in this behavior. Relatedly, amygdala-medial OFC structural connectivity could be a future target. The results of this study are crucial as, to our knowledge, they are the first to relate structure/function of the OFC with social anhedonia severity in MDD. Future work may need to involve a whole brain approach in order to develop therapeutics for social anhedonia.

Mu Opioid Receptor Dynamics in Healthy Volunteers with a History of Childhood Maltreatment.

Evidence suggests that adults with a history of childhood maltreatment, the experience of emotional or physical neglect and/or abuse within the family during childhood, have blunted reward and stress processing, and higher risk of depression. The mu opioid receptor rich nucleus accumbens and amygdala are critical to reward and stress processing respectively. We hypothesized that nucleus accumbens and amygdala mu opioid receptor densities and activity (change in receptor binding due to endogenous opioid release or receptor conformation change) were negatively associated with childhood maltreatment in healthy young adults. Maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Healthy participants, n = 75 (52% female) completed [11C]carfentanil positron emission tomography imaging labeling mu opioid receptors. The relationship between CTQ score and binding potential (BPND, proportional to density of unoccupied receptors) was evaluated with a linear mixed effects model. No significant relationship was found between CTQ score and BPND (f = 3.28; df = 1, 73; p = 0.074) or change in BPND (activity) (t = 1.48; df = 198.3; p = 0.14). This is the first investigation of mu opioid receptors in those with childhood maltreatment. We did not identify a significant relationship between mu opioid receptor dynamics and severity of maltreatment in those without psychopathology. Because this cohort has a low CTQ score average, this may indicate that those with low severity of maltreatment may not have associated changes in mu opioid receptor dynamics. Future directions include evaluating a cohort with increased severity of childhood maltreatment.

Rejection sensitivity and mu opioid receptor dynamics associated with mood alterations in response to social feedback.

Rejection sensitivity (RS) is the heightened expectation or perception of social rejection and is a feature of many psychiatric disorders. As endogenous opioid pathways have been implicated in response to social rejection and reward, we hypothesize that RS will be negatively associated with mu opioid receptor (MOR) baseline binding and activity during rejection and acceptance stimuli. In exploratory analyses, we assessed the relationships between MOR activity and changes in mood and self-esteem before and after stimuli. Healthy participants, N = 75 (52% female), completed rejection and acceptance tasks during [11C]carfentanil positron emission tomography (PET) scans. MOR activity in the amygdala, midline thalamus, anterior insula, and nucleus accumbens (NAc) was evaluated. RS was not related to MOR baseline binding potential or activity during acceptance or rejection tasks in any region. Increased MOR activity in the NAc was associated with increase in ratings of self-esteem and positive mood during the period between acceptance task administration and approximately 5 min after the task completion. Our results suggest that endogenous opioid response to social rejection is independent of RS in healthy individuals. MOR activity in the NAc was associated with increase self-esteem and positive mood after experiencing social feedback, warranting further investigation.

Common neural responses to romantic rejection and acceptance in healthy adults.

Although romantic rejection and acceptance have a strong impact on mood in adults, their neural response patterns are relatively unexplored. The present study used functional magnetic resonance imaging (fMRI) to examine neural responses to romantic rejection and acceptance in 36 healthy men and women, ages 18-53 years. Activations during rejection showed extensive anatomical overlap with activations during acceptance in the ventrolateral prefrontal cortex (vlPFC) and anterior insula (AI). In an analysis of sex differences, men and women did not differ in behavioral responses; however, men showed greater activation to romantic rejection and acceptance in the left vlPFC and AI compared to women. The vlPFC and AI may play a role in social cognition, tuned to detect the intentions and feelings of others whether they are positive or negative. In the context of romantic rejection and acceptance, this activation may signal the intent of others who are desired by the individual, leading to changes in mood, self-esteem, and social motivation.

Dissociable Neural Responses to Monetary and Social Gain and Loss in Women With Major Depressive Disorder.

Neuroimaging studies have revealed aberrant reward and loss processing in patients with major depressive disorder (MDD). While most studies use monetary stimuli to study these processes, it is important to consider social stimuli given that the social environment plays a significant role in the development and maintenance of MDD. In the present study, we examined whether monetary gain/loss and social acceptance/rejection would elicit dissociable salience-related neural responses in women diagnosed with MDD compared to healthy control (HC) women. Twenty women diagnosed with MDD and 20 matched HC women performed the monetary incentive delay task (MID) and the social feedback task (SFT) during functional magnetic resonance imaging (fMRI). This study focused on women since women have a higher rate of MDD, higher frequency of relapse, and are more likely to develop MDD as a consequence of negative interpersonal relationships compared to men. We found that during the MID, HCs but not MDD patients demonstrated strong overlapping activations in the right anterior insula (AI) in response to both monetary gain and loss. During the SFT, MDD patients but not HCs showed overlapping activations in the AI in response to social acceptance and rejection. Our results may suggest a dissociation such that MDD patients show decreased sensitivity to monetary stimuli whether gain or loss, and increased sensitivity to social stimuli whether acceptance or rejection, although this will need to be verified in larger samples with direct comparisons between groups and stimuli. These data demonstrate distinct abnormalities in reward and loss processing that converge within the AI. Our findings also highlight the critical need to assess across both non-social and social domains when examining reward and loss systems in MDD to broaden our understanding of the disorder and identify novel targets for treatment.

Influence of childhood adversity, approach motivation traits, and depression on individual differences in brain activation during reward anticipation.

Reward anticipation dysfunction is associated with major depressive disorder (MDD), but is not universally observed in individuals with MDD. Reward anticipation deficits have also been linked to childhood adversity (CA) and approach/avoidance traits. The present study evaluated whether severity of CA (as measured by the Childhood Trauma Questionnaire) and approach/avoidance traits predict individual differences in blood oxygen level dependent (BOLD) response to reward anticipation beyond MDD diagnosis alone. Participants were individuals with MDD (n = 23) and healthy controls (n = 27). Multiple regression was conducted using CTQ scores, trait approach/avoidance scores, and diagnosis to predict activation during reward anticipation in a monetary incentive delay fMRI task. Across groups, higher trait reward responsiveness predicted increased activation in the hippocampus, cingulate cortex, and medial frontal gyrus. Greater CTQ scores predicted increased reward network activation. Overall, CTQ and reward responsiveness scores predicted more variance in reward anticipation activation than diagnosis. These findings suggest that clinicians should assess history of childhood adversity and trait reward responsiveness when treating individuals with MDD.

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Multidimensional imaging techniques for prediction of treatment response in major depressive disorder.

A large number of studies have attempted to use neuroimaging tools to aid in treatment prediction models for major depressive disorder (MDD). Most such studies have reported on only one dimension of function and prediction at a time. In this study, we used three different tasks across domains of function (emotion processing, reward anticipation, and cognitive control, plus resting state connectivity completed prior to start of medication to predict treatment response in 13-36 adults with MDD. For each experiment, adults with MDD were prescribed only label duloxetine (all experiments), whereas another subset were prescribed escitalopram. We used a KeyNet (both Task derived masks and Key intrinsic Network derived masks) approach to targeting brain systems in a specific match to tasks. The most robust predictors were (Dichter et al., 2010) positive response to anger and (Gong et al., 2011) negative response to fear within relevant anger and fear TaskNets and Salience and Emotion KeyNet (Langenecker et al., 2018) cognitive control (correct rejections) within Inhibition TaskNet (negative) and Cognitive Control KeyNet (positive). Resting state analyses were most robust for Cognitive control Network (positive) and Salience and Emotion Network (negative). Results differed by whether an -fwhm or -acf (more conservative) adjustment for multiple comparisons was used. Together, these results implicate the importance of future studies with larger sample sizes, multidimensional predictive models, and the importance of using empirically derived masks for search areas.

The Public Face of Rhinoplasty: Impact on Perceived Attractiveness and Personality.

BACKGROUND: The authors assess the impact of rhinoplasty on public perception of a patient's appearance and personality. METHODS: A survey was created using standardized before-and-after photographs of 10 Caucasian women who had undergone primary rhinoplasty. Photographs of two additional women who had not undergone facial surgery were randomly included as controls, for a total of 12 survey items. Preoperative and postoperative photographs were placed side by side. The survey was administered by means of crowd-sourcing. Respondents were asked to evaluate which photograph better represented 11 traits of appearance or personality, according to a seven-point Likert scale. A score of 1 meant the preoperative photograph was much better, 7 meant the postoperative photograph was much better, and 4 meant no difference. T tests and analyses of variance were used to evaluate rating changes for each trait and differences between demographic groups. RESULTS: There were 264 responses received. Averaged scores across the 10 survey patients produced a value for each appearance or personality trait. In 10 of 11 categories (i.e., symmetry, youthfulness, facial harmony, likeability, trustworthiness, confidence, femininity, attractiveness, approachability, and intelligence), the postoperative photograph was significantly favorable compared with the preoperative photograph (p < 0.00001). The preoperative photograph was rated higher only in aggressiveness (p < 0.001). The same scores were calculated for the controls; no significant difference in any category was seen except confidence, where the right image was viewed as more confident (mean, 4.19; p < 0.005). CONCLUSION: Aesthetic rhinoplasty improves the public perception of a person's appearance and personality in multiple aspects.

Abnormal emotional and neural responses to romantic rejection and acceptance in depressed women.

INTRODUCTION: Responding adaptively to one's social environment is a key factor predicting the course of major depressive disorder (MDD). Socially rejecting events can exacerbate, whereas socially accepting events can ameliorate depressive symptoms. The neural responses to rejection and acceptance in MDD are relatively unexplored. METHODS: We used functional magnetic resonance imaging (fMRI) to measure neural responses to romantic rejection and acceptance in women diagnosed with current MDD (n = 19) and a matched group of healthy controls (HCs) (n = 19). During fMRI, participants received rejecting, accepting, and neutral feedback from self-selected potential romantic partners. RESULTS: In women with MDD but not HCs, rejection significantly increased activity in the right anterior insula relative to neutral feedback. Greater activation during rejection was found in the dorsal anterior cingulate cortex in MDD compared to HCs. Women with MDD reported stronger emotional responses than HCs to both rejection and acceptance. In addition, left and right nucleus accumbens (NAcc) activity mediated the relationship between trait reward responsiveness and increased ratings of feeling "happy and accepted" following acceptance in HCs, but not the MDD group. DISCUSSION: Women with MDD were behaviorally and neurally hyperresponsive to rejection. Although both groups were behaviorally responsive to acceptance, in MDD this was dissociated from NAcc activity. These findings highlight abnormal behavioral and neural responses to social cues in MDD, with implications for disease prognosis and the development of novel and sensitive biomarkers for MDD focused on neural pathways for social-affective processing. LIMITATIONS: Conclusions may be limited to depressed women in a romantic context.

Oxytocin modulates hemodynamic responses to monetary incentives in humans.

RATIONALE: Oxytocin is a neuropeptide widely recognized for its role in regulating social and reproductive behavior. Increasing evidence from animal models suggests that oxytocin also modulates reward circuitry in non-social contexts, but evidence in humans is lacking. OBJECTIVES: We examined the effects of oxytocin administration on reward circuit function in 18 healthy men as they performed a monetary incentive task. METHODS: The blood oxygenation level-dependent (BOLD) signal was measured using functional magnetic resonance imaging in the context of a randomized, double-blind, placebo-controlled, crossover trial of intranasal oxytocin. RESULTS: We found that oxytocin increases the BOLD signal in the midbrain (substantia nigra and ventral tegmental area) during the late phase of the hemodynamic response to incentive stimuli. Oxytocin's effects on midbrain responses correlated positively with its effects on positive emotional state. We did not detect an effect of oxytocin on responses in the nucleus accumbens. Whole-brain analyses revealed that oxytocin attenuated medial prefrontal cortical deactivation specifically during anticipation of loss. CONCLUSIONS: Our findings demonstrate that intranasal administration of oxytocin modulates human midbrain and medial prefrontal function during motivated behavior. These findings suggest that endogenous oxytocin is a neurochemical mediator of reward behaviors in humans-even in a non-social context-and that the oxytocinergic system is a potential target of pharmacotherapy for psychiatric disorders that involve dysfunction of reward circuitry.

Comorbid anxiety increases cognitive control activation in Major Depressive Disorder.

BACKGROUND: Major Depressive Disorder (MDD) and anxiety disorders often co-occur, with poorer treatment response and long-term outcomes. However, little is known about the shared and distinct neural mechanisms of comorbid MDD and anxiety (MDD+Anx). This study examined how MDD and MDD+Anx differentially impact cognitive control. METHODS: Eighteen MDD, 29 MDD+Anx, and 54 healthy controls (HC) completed the Parametric Go/No-Go (PGNG) during fMRI, including Target, Commission, and Rejection trials. RESULTS: MDD+Anx had more activation in the anterior dorsolateral prefrontal cortex, hippocampus, and caudate during Rejections, and inferior parietal lobule during correct Targets than MDD and HC. During Rejections HC had greater activation in a number of cognitive control regions compared to MDD; in the posterior cingulate compared to MDD+Anx; and in the fusiform gyrus compared to all MDD. During Commissions HC had greater activation in the right inferior frontal gyrus than all MDD. MDD had more activation in the mid-cingulate, inferior parietal lobule, and superior temporal gyrus than MDD+Anx during Commissions. CONCLUSIONS: Despite similar performance, MDD and MDD+Anx showed distinct differences in neural mechanisms of cognitive control in relation to each other, as well as some shared differences in relation to HC. The results were consistent with our hypothesis of hypervigilance in MDD+Anx within the cognitive control network, but inconsistent with our hypothesis that there would be greater engagement of salience and emotion network regions. Comorbidity of depression and anxiety may cause increased heterogeneity in study samples, requiring further specificity in detection and measurement of intermediate phenotypes and treatment Targets.

Pharmacological modulation of pulvinar resting-state regional oscillations and network dynamics in major depression.

The pulvinar, the largest thalamus nucleus, has rich anatomical connections with several different cortical and subcortical regions suggesting its important involvement in high-level cognitive and emotional functions. Unfortunately, pulvinar dysfunction in psychiatric disorders particularly major depression disorder has not been thoroughly examined to date. In this study we explored the alterations in the baseline regional and network activities of the pulvinar in MDD by applying spectral analysis of resting-state oscillatory activity, functional connectivity and directed (effective) connectivity on resting-state fMRI data acquired from 20 healthy controls and 19 participants with MDD. Furthermore, we tested how pharmacological treatment with duloxetine can modulate the measured local and network variables in ten participants who completed treatment. Our results revealed a frequency-band dependent modulation of power spectrum characteristics of pulvinar regional oscillatory activity. At the network level, we found MDD is associated with aberrant causal interactions between pulvinar and several systems including default-mode and posterior insular networks. It was also shown that duloxetine treatment can correct or overcompensate the pathologic network behavior of the pulvinar. In conclusion, we suggest that pulvinar regional baseline oscillatory activity and its resting-state network dynamics are compromised in MDD and can be modulated therapeutically by pharmacological treatment.

Affective personality predictors of disrupted reward learning and pursuit in major depressive disorder.

Anhedonia, the diminished anticipation and pursuit of reward, is a core symptom of major depressive disorder (MDD). Trait behavioral activation (BA), as a proxy for anhedonia, and behavioral inhibition (BI) may moderate the relationship between MDD and reward-seeking. The present studies probed for reward learning deficits, potentially due to aberrant BA and/or BI, in active or remitted MDD individuals compared to healthy controls (HC). Active MDD (Study 1) and remitted MDD (Study 2) participants completed the modified monetary incentive delay task (mMIDT), a behavioral reward-seeking task whose response window parameters were individually titrated to theoretically elicit equivalent accuracy between groups. Participants completed the BI Scale and BA Reward-Responsiveness and Drive Scales. Despite individual titration, active MDD participants won significantly less money than HCs. Higher Reward-Responsiveness scores predicted more won; Drive and BI were not predictive. Remitted MDD participants' performance did not differ from controls', and trait BA and BI measures did not predict r-MDD performance. These results suggest that diminished reward-responsiveness may contribute to decreased motivation and reward pursuit during active MDD, but that reward learning is intact in remission. Understanding individual reward processing deficits in MDD may inform personalized intervention addressing anhedonia and motivation deficits in select MDD patients.

Indirect effect of corticotropin-releasing hormone receptor 1 gene variation on negative emotionality and alcohol use via right ventrolateral prefrontal cortex.

Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.

Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood.

The purpose of this review is to describe how the function and connections of the paraventricular thalamic nucleus (Pa) may play a role in the regulation of stress and negative emotional behavior. Located in the dorsal midline thalamus, the Pa is heavily innervated by serotonin, norepinephrine, dopamine (DA), corticotropin-releasing hormone, and orexins (ORX), and is the only thalamic nucleus connected to the group of structures comprising the amygdala, bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAcc), and infralimbic/subgenual anterior cingulate cortex (sgACC). These neurotransmitter systems and structures are involved in regulating motivation and mood, and display abnormal functioning in several psychiatric disorders including anxiety, substance use, and major depressive disorders (MDD). Furthermore, rodent studies show that the Pa is consistently and potently activated following a variety of stressors and has a unique role in regulating responses to chronic stressors. These observations provide a compelling rationale for investigating the Pa in the link between stress and negative emotional behavior, and for including the Pa in the neural pathways of stress-related psychiatric disorders.

Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing.

The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and a preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation level-dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) in the right middle temporal/angular gyrus while subjects were viewing negative versus neutral words. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared with controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared with controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 single nucleotide polymorphism rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.