Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine interindividual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging (fMRI) during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced dopamine release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R “Openness to Experience” and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders.

Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD.Twenty-one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy controlsubjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated.CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CSgroup, greater activation in left dorsal anterior cingulatewas related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD.

Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.

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 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) while viewing negative versus neutral words in the right middle temporal/angular gyrus. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared to controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared to 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 SNP rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.

Context

Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proved particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD).

Objective

To determine whether low-expression NPY genotypes are associated with negative emotional processing at three levels of analysis.

Design

Cross-sectional, case-control.

Setting

Academic medical center.

Participants

Forty-four individuals with MDD and 137 healthy controls; 152 (84%) were classified by NPY genotype as low, intermediate, or high, according to previously established haplotype-based expression data.

Main Outcome Measures

Healthy subjects participated in functional magnetic resonance imaging while viewing negative (versus neutral) words (n=58), and rated positive and negative affect during a pain-stress challenge (n=78). Genotype distribution was compared between 113 control and 39 MDD subjects.

Results

Among healthy individuals, negatively valenced words activated medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (p=0.029). Whole-brain regression of responses to negative words showed that rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (p<0.05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (p=0.002). Low-expression NPY genotypes were over-represented in MDD after controlling for age and sex (p=0.004). Population stratification did not account for the results.

Conclusions

These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

Background: Pathophysiologic processes supporting abnormal emotion regulation in major depressive disorder (MDD) are poorly understood. We previously found abnormal inverse left-sided ventromedial prefrontal cortical–amygdala effective connectivity to happy faces in females with MDD. We aimed to replicate and expand this previous finding in an independent participant sample, using a more inclusive neural model, and a novel emotion processing paradigm. Methods: Nineteen individuals with MDD in depressed episode (12 females), and 19 healthy individuals, age, and gender matched, performed an implicit emotion processing and automatic attentional control paradigm to examine abnormalities in prefrontal cortical–amygdala neural circuitry during happy, angry, fearful, and sad face processing measured with functional magnetic resonance imaging in a 3-T scanner. Effective connectivity was estimated with dynamic causal modeling in a trinodal neural model including two anatomically defined prefrontal cortical regions, ventromedial prefrontal cortex, and subgenual cingulate cortex (sgACC), and the amygdala. Results: We replicated our previous finding of abnormal inverse left-sided top-down ventromedial prefrontal cortical–amygdala connectivity to happy faces in females with MDD (p = 0.04), and also showed a similar pattern of abnormal inverse left-sided sgACC–amygdala connectivity to these stimuli (p = 0.03). These findings were paralleled by abnormally reduced positive left-sided ventromedial prefrontal cortical–sgACC connectivity to happy faces in females with MDD (p = 0.008), and abnormally increased positive left-sided sgACC–amygdala connectivity to fearful faces in females, and all individuals, with MDD (p = 0.008; p = 0.003). Conclusion: Different patterns of abnormal prefrontal cortical–amygdala connectivity to happy and fearful stimuli might represent neural mechanisms for the excessive self-reproach and comorbid anxiety that characterize female MDD.

It is poorly understood how stressors modulate neurobiological mechanisms that may contribute to the heterogeneity of Major Depressive Disorder (MDD). Unmedicated patients diagnosed with MDD (n = 15) and individually matched healthy controls (n = 15) completed stress questionnaires and were studied with functional magnetic resonance imaging while viewing emotional words. Significant effects of recent negative life stressors, but not early life stress/trauma, were observed on regional blood oxygen level dependent activity during presentation of negative words in patients with MDD. No significant effects of stress on brain activation to negative words were found in controls. In MDD patients, positive correlations were found bilaterally in orbitofrontal areas 11l/47/12m, which are involved in representing negatively-valenced stimuli. Negative correlations were also found in the right ventrolateral prefrontal area 45, subgenual cingulate area 25, and nucleus accumbens, all of which are implicated in the pathophysiology of MDD. Negative memory bias was additionally positively associated with recent negative life stress and negatively associated with subgenual cingulate activation, suggesting a mechanism by which stress may contribute to these abnormalities. The severity of recent negative life stressors is an important modifier of neurobiological and cognitive function in MDD and may help explain heterogeneity in the disorder.

Background

One of the principal theories regarding the biological basis of Major Depressive Disorder (MDD) implicates a dysregulation of emotion processing circuitry. Gender differences in how emotions are processed and relative experience with emotion processing might help to explain some of the disparities in the prevalence of MDD between women and men. The current study sought to explore how gender and depression status relate to emotion processing.

Methods

This study employed a 2 (MDD status) × 2 (gender) factorial design to explore differences in classifications of posed facial emotional expressions (N = 151).

Results

For errors, there was an interaction between gender and depression status. Women with MDD made more errors than did non-depressed women and men with MDD, particularly for fearful and sad stimuli (ps < .02), which they were likely to misinterpret as angry (ps < .04). There was also an interaction of diagnosis and gender for response cost for negative stimuli, with significantly greater interference from negative faces present in women with MDD compared with non-depressed women (p = .01). Men with MDD, conversely, performed similarly to control men (p = .61).

Conclusions

These results provide novel and intriguing evidence that depression in younger adults (< 35 years) differentially disrupts emotion processing in women as compared to men. This interaction could be driven by neurobiological and social learning mechanisms, or interactions between them, and may underlie differences in the prevalence of depression in women and men.

Introduction

Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine.

Methods

We recruited nicotine-exposed never-smokers with two never-smoking biological parents (PH−) or two ever-smoking biological parents (PH+). After completing a baseline assessment battery focusing on conditions or behaviors associated with smoking, participants were tested for subjective and hedonic effects in response to administration of three different nicotine doses (0.0, 0.5, and 1.0 mg) via nasal spray. Physiological and biochemical reactivity also was monitored.

Results

PH+ were significantly more likely to report having experienced a “buzz” upon early smoking experimentation and to have histories of alcohol abuse and alcoholism; they also scored higher on disordered eating. In response to nicotine dosing, PH+ reported an increase in depressed mood, compared with a minimal response in PH−, in keeping with our expectation that nicotine would have more pronounced effects in PH+. Regardless of parental history, women reported experiencing greater anxiety in response to the highest nicotine dose, compared with men.

Discussion

Further exploration in larger samples, using more stringent selection criteria, a wider range of measures, and a less aversive dosing method, may provide a full test of the possible utility of the parental history model for illuminating biobehavioral mechanisms underlying response to nicotine. Also important would be broadening the scope of inquiry to include comparisons with ever-smokers to determine what protected PH+ from becoming smokers, despite the presence of factors that might be expected to decrease resilience and increase susceptibility.

Background

Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD.

Methods:

Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram.

Results:

There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms.

Conclusions:

The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.

The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data shows substantial inter-individual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1A receptor expression. We used positron emission tomography and [11C]WAY-100635 to quantify 5-HT1A receptors in a group of 31 healthy and un-medicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. Analysis of variance of 5-HT1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p<0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1A receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p<0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.

When using fMRI to study age-related cognitive changes, it is important to establish the integrity of the hemodynamic response because, potentially, it can be affected by age and disease. However, there have been few attempts to document such integrity and no attempts using higher cognitive rather than perceptual or motor tasks. We used fMRI with 28 healthy young and older adults on an inhibitory control task. Although older and young adults differed in task performance and activation patterns, they had comparable hemodynamic responses. We conclude that activation during cognitive inhibition, which was predominantly increased in elders, was not due to vascular confounds or specific changes in hemodynamic coupling.

Prior work by our group and others has implicated the basal ganglia as important in age-related differences in tasks involving motor response control. The present study used structural and functional MRI approaches to analyze this region of interest (ROI) toward better understanding the contributions of structural and functional MRI measures to understanding age-related and task performance-related cognitive differences. Eleven healthy elders were compared with 11 healthy younger adults while they completed the “go” portion of a complex Go/No-go task. Separate ROI’s in the bilateral caudate (C) and putamen/globus pallidus (PGp) were studied based upon previous findings of age-related functional MRI differences in basal ganglia for this portion of the task. Structural volumes and functional activation (in percent area under the curve during correct responses) were independently extracted for these ROI’s. Results showed that age correlated with ROI volume in bilateral PGp and C, while multiple task performance measures correlated with functional activation in the left PGp. The Go/No-go task measures were also significantly correlated with traditional attention and executive functioning measures. Importantly, fMRI activation and volumes from each ROI were not significantly inter-correlated. These findings suggest that structural and functional MRI make unique contributions to the study of performance changes in aging.