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1.  Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing 
Molecular psychiatry  2013;19(1):129-139.
SUMMARY
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.
doi:10.1038/mp.2012.193
PMCID: PMC4311877  PMID: 23337945
2.  Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders 
Background
Childhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP).
Results
Compared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age.
Conclusions
Our findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.
doi:10.1186/s13587-014-0015-4
PMCID: PMC4272798  PMID: 25530842
Children; Adolescent; Anxiety; Amygdala; Connectivity; Resting state; fMRI
3.  Increased Coupling of Intrinsic Networks in Remitted Depressed Youth Predicts Rumination and Cognitive Control 
PLoS ONE  2014;9(8):e104366.
Objective
Functional connectivity MRI (fcMRI) studies of individuals currently diagnosed with major depressive disorder (MDD) document hyperconnectivities within the default mode network (DMN) and between the DMN and salience networks (SN) with regions of the cognitive control network (CCN). Studies of individuals in the remitted state are needed to address whether effects derive from trait, and not state or chronic burden features of MDD.
Method
fcMRI data from two 3.0 Tesla GE scanners were collected from 30 unmedicated (47% medication naïve) youth (aged 18–23, modal depressive episodes = 1, mean age of onset = 16.2, SD = 2.6) with remitted MDD (rMDD; modal years well = 4) and compared with data from 23 healthy controls (HCs) using four bilateral seeds in the DMN and SN (posterior cingulate cortex (PCC), subgenual anterior cingulate (sgACC), and amygdala), followed by voxel-based comparisons of the whole brain.
Results
Compared to HCs, rMDD youth exhibited hyperconnectivities from both PCC and sgACC seeds with lateral, parietal, and frontal regions of the CCN, extending to the dorsal medial wall. A factor analysis reduced extracted data and a PCC factor was inversely correlated with rumination among rMDD youth. Two factors from the sgACC hyperconnectivity clusters were related to performance in cognitive control on a Go/NoGo task, one positively and one inversely.
Conclusions
Findings document hyperconnectivities of the DMN and SN with the CCN (BA 8/10), which were related to rumination and sustained attention. Given these cognitive markers are known predictors of response and relapse, hyperconnectivities may increase relapse risk or represent compensatory mechanisms.
doi:10.1371/journal.pone.0104366
PMCID: PMC4146466  PMID: 25162661
4.  Cognitive Functioning, Retirement Status, and Age: Results from the Cognitive Changes and Retirement among Senior Surgeons Study 
Background
Accurate assessment of cognitive functioning is an important step in understanding how to better evaluate both clinical and cognitive competence in practicing surgeons. As part of the Cognitive Changes and Retirement among Senior Surgeons study, we examined the objective cognitive functioning of senior surgeons in relation to retirement status and age.
Study Design
Computerized cognitive tasks measuring visual sustained attention, reaction time, and visual learning and memory were administered to both practicing and retired surgeons at annual meetings of the American College of Surgeons. Data from 168 senior surgeons aged 60 and older were compared with data from 126 younger surgeons aged 45 to 59, with performance below 1.5 standard deviations or more indicating a significant difference between the groups.
Results
Sixty-one percent of practicing senior surgeons performed within the range of the younger surgeons on all cognitive tasks. Seventy-eight percent of practicing senior surgeons aged 60 to 64 performed within the range of the younger surgeons on all tasks compared with 38% of practicing senior surgeons aged 70 and older. Forty-five percent of retired senior surgeons performed within the range of the younger surgeons on all tasks. No senior surgeon performed below the younger surgeons on all 3 tasks.
Conclusions
The majority of practicing senior surgeons performed at or near the level of their younger peers on all cognitive tasks, as did almost half of the retired senior surgeons. This suggests that older age does not inevitably preclude cognitive proficiency. The variability in cognitive performance across age groups and retirement status suggests the need for formal measures of objective cognitive functioning to help surgeons detect changes in cognitive performance and aid in their decisions to retire.
doi:10.1016/j.jamcollsurg.2010.05.022
PMCID: PMC4083243  PMID: 20800185
5.  Emotion regulation through execution, observation, and imagery of emotional movements 
Brain and cognition  2013;82(2):219-227.
According to Damasio’s somatic marker hypothesis, emotions are generated by conveying the current state of the body to the brain through interoceptive and proprioceptive afferent input. The resulting brain activation patterns represent unconscious emotions and correlate with subjective feelings. This proposition implies a corollary that the deliberate control of motor behavior could regulate feelings. We tested this possibility, hypothesizing that engaging in movements associated with a certain emotion would enhance that emotion and/or the corresponding valence. Furthermore, because motor imagery and observation are thought to activate the same mirror-neuron network engaged during motor execution, they might also activate the same emotional processing circuits, leading to similar emotional effects. Therefore, we measured the effects of motor execution, motor imagery and observation of whole-body dynamic expressions of emotions (happiness, sadness, fear) on affective state. All three tasks enhanced the corresponding affective state, indicating their potential to regulate emotions.
doi:10.1016/j.bandc.2013.03.001
PMCID: PMC4067484  PMID: 23561915
Body expression of emotion; Nonverbal behavior; Emotion regulation; Embodiment; Simulation; Motor imagery
6.  Identifying a cognitive impairment subgroup in adults with mood disorders 
Journal of affective disorders  2011;132(3):360-367.
Background
We hypothesized that only a minority of patients with mood disorders have measurable cognitive impairment, and this minority drives the small-to-medium effect sizes detected in group studies. Removal of this minority from group statistical analyses will illustrate that the majority appear to have broadly normal cognitive functioning.
Methods
Participants were adults between the ages of 20 and 54, including 659 healthy control subjects, 84 unmedicated outpatients diagnosed with depression, 59 outpatients diagnosed with depression who were on medications at the time of the evaluation, and 43 outpatients with bipolar disorder. All completed the CNS Vital Signs computerized cognitive screening battery.
Results
The prevalence rates of low cognitive test scores were calculated for the healthy control subjects and the patients with mood disorders. Having two scores at or below the 5th percentile occurred in 31.2% of the patients and only 8.2% of the control subjects [χ2(1)=66.67, p<.0001; Odds Ratio=5.1, 95% CI=3.4–7.7]. For the control subjects, this low false positive rate for cognitive impairment was maintained across age groups, sexes, and education levels. A larger proportion of patients with bipolar disorder (41.9%) than patients with depression (27.1–28.6%) met this criterion for cognitive impairment.
Conclusions
This study suggests that cognitive impairment associated with mood disorders is limited to a minority of patients with the majority being broadly cognitively normal. Future research should determine if this identified subgroup has neuroanatomical, neurophysiological, or neuroendocrine abnormalities. Cognitive screening tools of this type might be useful in selecting participants for studies.
doi:10.1016/j.jad.2011.03.001
PMCID: PMC4062916  PMID: 21439647
Computerized testing; Cognitive impairment; Depression; Bipolar disorder
7.  Factor structure, construct validity, and age- and education-based normative data for the Parametric Go/No-Go Test 
The Parametric Go/No-Go (PGNG) test assesses cognitive domains including attention and executive functioning with three levels of increasing difficulty. Level 1 measures accuracy and response time to three targets. Level 2 adds a nonrepeating rule, measuring response time to two targets, accuracy for targets, and accuracy for appropriate inhibition. Level 3 has three targets with the same nonrepeating rule. The task shows good construct validity, and factor analyses show adequate ability to distinguish between processing speed, sustained attention, and inhibition. Normative data for the PGNG, stratified by age and education, as well as strategies for identifying atypical responding, are presented.
doi:10.1080/13803395.2012.758239
PMCID: PMC4040279  PMID: 23289626
Attention; Executive functioning; Normative data; Go/no-go; Inhibitory control; Age; Education
8.  C9ORF72 expansion in a family with bipolar disorder 
Bipolar disorders  2013;15(3):326-332.
Objective
To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis.
Methods
Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder with an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, neurological, and neuropsychological evaluation.
Results
One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kb as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 kb to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogenous expansion of only 8.5 kb.
Conclusions
The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.
doi:10.1111/bdi.12063
PMCID: PMC3660726  PMID: 23551834
atypical bipolar; C9ORF72; repeat expansion
9.  Response of the μ-opioid system to social rejection and acceptance 
Molecular psychiatry  2013;18(11):10.1038/mp.2013.96.
The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n = 18), we used a μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus, and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids play a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG, and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula, and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well-being in the social environment.
doi:10.1038/mp.2013.96
PMCID: PMC3814222  PMID: 23958960
opioid; PET; social; rejection; acceptance; depression; mu; stress
10.  Differential executive functioning performance by phase of bipolar disorder 
Bipolar disorders  2012;14(5):527-536.
Objective
This study examined the influence of illness phase on executive functioning performance using factor-derived cognitive scores in a cross-sectional design.
Methods
Healthy control (HC) subjects (n = 57), and euthymic (E-BD) (n = 117), depressed (D-BD) (n = 73), and hypomanic/mixed (HM/M-BD) (n = 26) patients with bipolar disorder (BD) were evaluated using executive functioning measures (Wisconsin Card Sorting Test, Trail Making Test–Parts A and B, Verbal Fluency, Parametric Go/No-Go, Stroop, and Digit Symbol) comprising Conceptual Reasoning and Set-Shifting (CRSS), Processing Speed with Interference Resolution (PSIR), Verbal Fluency and Processing Speed (VFPS), and Inhibitory Control (IC) factor scores.
Results
Two of the four executive functioning factors were significantly different between groups based upon phase of illness. The HM/M group was significantly worse than both of the other BD groups and the HC group in IC. The VFPS factor was sensitive to the active phase of BD, with the HM/M-BD and D-BD groups worse than HC. Extending our prior work, the PSIR factor, and now the CRSS factor were significantly worse in BD relative to HC, irrespective of phase of illness.
Conclusions
Phase of illness had differential cognitive profiles in executive functioning factors, even after considering and excluding the impact of clinical features, illness characteristics, medications, and demographics. Consolidating executive functioning tasks into reliable factor scores provides unique information to measure and define cognitive deficiencies throughout phases of BD, and to measure intermediate phenotypes in BD, and may aid in tracking and clarifying treatment focus.
doi:10.1111/j.1399-5618.2012.01032.x
PMCID: PMC3773478  PMID: 22834461
bipolar disorder; cognition; executive function
11.  Intermediate Cognitive Phenotypes in Bipolar Disorder 
Journal of affective disorders  2009;122(3):285-293.
Background
Intermediate cognitive phenotypes (ICPs) are measurable and quantifiable states that may be objectively assessed in a standardized method, and can be integrated into association studies, including genetic, biochemical, clinical, and imaging based correlates. The present study used neuropsychological measures as ICPs, with factor scores in executive functioning, attention, memory, fine motor function, and emotion processing, similar to prior work in schizophrenia.
Methods
Healthy control subjects (HC, n=34) and euthymic (E, n=66), depressed (D, n=43), or hypomanic/mixed (HM, n=13) patients with bipolar disorder (BD) were assessed with neuropsychological tests. These were from eight domains consistent with previous literature; auditory memory, visual memory, processing speed with interference resolution, verbal fluency and processing speed, conceptual reasoning and set-shifting, inhibitory control, emotion processing, and fine motor dexterity.
Results
Of the eight factor scores, the HC group outperformed the E group in three (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity), the D group in seven (all except Inhibitory Control), and the HM group in four (Inhibitory Control, Processing Speed with Interference Resolution, Fine Motor Dexterity, and Auditory Memory).
Limitations
The HM group was relatively small, thus effects of this phase of illness may have been underestimated. Effects of medication could not be fully controlled without a randomized, double-blind, placebo-controlled study.
Conclusions
Use of the factor scores can assist in determining ICPs for BD and related disorders, and may provide more specific targets for development of new treatments. We highlight strong ICPs (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity) for further study, consistent with the existing literature.
doi:10.1016/j.jad.2009.08.018
PMCID: PMC3773480  PMID: 19800130
Bipolar disorder; cognition; executive function; emotion; phenotype; intermediate phenotype; mania; depression
12.  Sleep quality during euthymia in bipolar disorder: the role of clinical features, personality traits, and stressful life events 
Background
Poor sleep quality is known to precede the onset of mood episodes and to be associated with poor treatment outcomes in bipolar disorder (BD). We sought to identify modifiable factors that correlate with poor sleep quality in BD independent of residual mood symptoms.
Methods
A retrospective analysis was conducted to assess the association between the Pittsburgh Sleep Quality Index and clinical variables of interest in euthymic patients with DSM-IV BD (n = 119) and healthy controls (HC; n = 136) participating in the Prechter Longitudinal Study of Bipolar Disorder. Multivariable linear regression models were constructed to investigate the relationship between sleep quality and demographic and clinical variables in BD and HC participants. A unified model determined independent predictors of sleep quality.
Results and discussion
Euthymic participants with BD and HC differed in all domains. The best fitting unified multivariable model of poor sleep quality in euthymic participants with BD included rapid cycling (β = .20, p = .03), neuroticism (β = .28, p = 2 × 10−3), and stressful life events (β = .20, p = .02). Poor sleep quality often persists during euthymia and can be a target for treatment. Clinicians should remain vigilant for treating subjective sleep complaints independent of residual mood symptoms in those sensitive to poor sleep quality, including individuals with high neuroticism, rapid cycling, and recent stressful life events. Modifiable factors associated with sleep quality should be targeted directly with psychosocial or somatic treatment. Sleep quality may be a useful outcome measure in BD treatment studies.
doi:10.1186/2194-7511-1-16
PMCID: PMC4230686  PMID: 25505683
Bipolar disorder; Sleep; Neuroticism; Rapid cycling; Stress
13.  Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder 
Journal of affective disorders  2011;136(3):350-358.
Background
Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol.
Method
Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined.
Results
A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups.
Limitations
The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account.
Conclusions
Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.
doi:10.1016/j.jad.2011.11.027
PMCID: PMC3683957  PMID: 22154566
Bipolar; Suicide; Cortisol; HPA axis; Biomarker
14.  Modality-specific alterations in the perception of emotional stimuli in Bipolar Disorder compared to Healthy Controls and Major Depressive Disorder 
Objectives
Affect identification accuracy paradigms have increasingly been utilized to understand psychiatric illness including Bipolar Disorder (BD) and Major Depressive Disorder (MDD). This investigation focused on perceptual accuracy in affect identification in both visual and auditory domains among patients with BD, relative to Healthy Controls (HC) and patients with MDD. Demographic and clinical variables, in addition to medications were also investigated.
Methods
The visual Facial Emotion Perception Test (FEPT) and auditory Emotional Perception Test (EPT) were administered to adults with BD (n = 119) and MDD (n = 78) as well as HC (n = 66).
Results
Performance on the FEPT was significantly stronger than on the EPT irrespective of group. Performance on the EPT did not significantly differentiate the groups. On the FEPT, BD samples had the greatest difficulty relative to HC in identification of sad and fearful faces. BD participants also had greater difficulty identifying sad faces relative to MDD participants though not after controlling for severity of illness factors. For the BD (but not MDD) sample several clinical variables were also correlated with FEPT performance.
Conclusions
The findings suggest that disruptions in identification of negative emotions such as sadness and fear may be a characteristic trait of BD. However, this effect may be moderated by greater illness severity found in our BD sample.
doi:10.1016/j.cortex.2011.03.017
PMCID: PMC3660134  PMID: 21683948
Bipolar Disorder; Major Depressive Disorder; Affect perception
15.  Greater executive and visual memory dysfunction in comorbid bipolar disorder and substance use disorder 
Psychiatry research  2012;200(0):252-257.
Measures of cognitive dysfunction in Bipolar Disorder (BD) have identified state and trait dependent metrics. An influence of substance abuse (SUD) on BD has been suggested. This study investigates potential differential, additive, or interactive cognitive dysfunction in bipolar patients with or without a history of SUD. Two hundred fifty-six individuals with BD, 98 without SUD and 158 with SUD, and 97 Healthy Controls (HC) completed diagnostic interviews, neuropsychological testing, and symptom severity scales. The BD groups exhibited poorer performance than the HC group on most cognitive factors. The BD with SUD exhibited significantly poorer performance than BD without SUD in visual memory and conceptual reasoning/set-shifting. In addition, a significant interaction effect between substance use and depressive symptoms was found for auditory memory and emotion processing. BD patients with a history of SUD demonstrated worse visual memory and conceptual reasoning skills above and beyond the dysfunction observed in these domains among individuals with BD without SUD, suggesting greater impact on integrative, gestalt-driven processing domains. Future research might address longitudinal outcome as a function of BD, SUD, and combined BD/SUD to evaluate neural systems involved in risk for, and effects of, these illnesses.
doi:10.1016/j.psychres.2012.06.013
PMCID: PMC3650480  PMID: 22769049
Mood disorders; Alcohol; Dual diagnosis; Cognition; Neuropsychology
16.  DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience 
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.
doi:10.1016/j.cortex.2012.01.010
PMCID: PMC3381848  PMID: 22424959
imaging; dopamine; DLPFC; reward; emotion
17.  Impact of Chronic Hypercortisolemia on Affective Processing 
Neuropharmacology  2011;62(1):217-225.
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.
doi:10.1016/j.neuropharm.2011.07.006
PMCID: PMC3196277  PMID: 21787793
HPA; cortisol; ACTH; emotion; affect; fMRI; Cushings
18.  Auditory Memory Decrements, Without Dissimulation, among Patients with Major Depressive Disorder 
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.
doi:10.1093/arclin/acr041
PMCID: PMC3201698  PMID: 21593060
Depression; Malingering/symptom validity testing; Learning and memory
19.  Variation in the Corticotropin-Releasing Hormone Receptor 1 (CRHR1) Gene influences fMRI Signal Responses during Emotional Stimulus Processing 
The Journal of Neuroscience  2012;32(9):3253-3260.
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.
doi:10.1523/JNEUROSCI.5533-11.2012
PMCID: PMC3297975  PMID: 22378896
20.  Emotional processing, major depression, and functional genetic variation of neuropeptide Y 
Archives of general psychiatry  2011;68(2):158-166.
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.
doi:10.1001/archgenpsychiatry.2010.197
PMCID: PMC3091621  PMID: 21300944
21.  Abnormal Left-Sided Orbitomedial Prefrontal Cortical–Amygdala Connectivity during Happy and Fear Face Processing: A Potential Neural Mechanism of Female 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.
doi:10.3389/fpsyt.2011.00069
PMCID: PMC3233901  PMID: 22163223
major depressive disorder; effective connectivity; emotion regulation; dynamic causal modeling; amygdala; prefrontal cortex
22.  FMRI BOLD responses to negative stimuli in the prefrontal cortex are dependent on levels of recent negative life stress in major depressive disorder 
Psychiatry research  2010;183(3):202-208.
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.
doi:10.1016/j.pscychresns.2009.12.002
PMCID: PMC2938037  PMID: 20685091
orbital; subgenual; ventrolateral; accumbens; memory; depression
23.  Gender Specific Disruptions in Emotion Processing in Younger Adults with Depression 
Depression and anxiety  2009;26(2):182-189.
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.
doi:10.1002/da.20502
PMCID: PMC3013355  PMID: 18800371
psychiatric disorders; affect perception; sex differences
24.  Substance use, trait measures, and subjective response to nicotine in never-smokers stratified on parental smoking history and sex 
Nicotine & Tobacco Research  2009;11(9):1055-1066.
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.
doi:10.1093/ntr/ntp099
PMCID: PMC2725008  PMID: 19633275
25.  Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder 
Biological psychiatry  2007;62(11):1272-1280.
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.
doi:10.1016/j.biopsych.2007.02.019
PMCID: PMC2860742  PMID: 17585888
Depression; executive functioning; fMRI; imaging; inhibitory control; mood disorders; SSRIs; treatment response

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