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1.  Walk on the Bright Side: Physical Activity and Affect in Major Depressive Disorder 
Journal of abnormal psychology  2011;121(2):297-308.
Although prescribed exercise has been found to improve affect and reduce levels of depression, we do not know how self-initiated everyday physical activity influences levels of positive affect (PA) and negative affect (NA) in depressed persons. Fifty-three individuals diagnosed with Major Depressive Disorder (MDD) and 53 never-depressed controls participated in a seven-day experience sampling study. Participants were prompted randomly eight times per day and answered questions about their physical activity and affective state. Over the week, the two groups of participants did not differ in average level of physical activity. As expected, participants with MDD reported lower average PA and higher average NA than did never-depressed controls. Both participants with MDD and controls reported higher levels of PA at prompts after physical activity than at prompts after inactive periods; moreover, for both groups of participants, PA increased from a prompt after an inactive period to a subsequent prompt at which activity was reported. Depressed participants in particular showed a dose-response effect of physical activity on affect: longer duration and/or higher intensity of physical activity increased their PA significantly more than did short duration and/or lower intensity physical activity. Physical activity did not influence NA in either group. In contrast to previous treatment studies that examined the effects of prescribed structured exercise, this investigation showed that self-initiated physical activity influences PA. These findings also underscore the importance of distinguishing between PA and NA to gain a more comprehensive understanding of the effects of physical activity on affect in MDD.
PMCID: PMC3982878  PMID: 21553939
depression; experience sampling; positive affect; negative affect; exercise
2.  Neural Systems Approaches to Understanding Major Depressive Disorder: An Intrinsic Functional Organization Perspective 
Neurobiology of disease  2012;52C:4-11.
Recent research detailing the intrinsic functional organization of the brain provides a unique and useful framework to gain a better understanding of the neural bases of Major Depressive Disorder (MDD). In this review, we first present a brief history of neuroimaging research that has increased our understanding of the functional macro-architecture of the brain. From this macro-architectural perspective, we examine the extant body of functional neuroimaging research assessing MDD with a specific emphasis on the contributions of default-mode, executive, and salience networks in this debilitating disorder. Next, we describe recent investigations conducted in our laboratory in which we explicitly adopt a neural-systems perspective in examining the relations among these networks in MDD. Finally, we offer directions for future research that we believe will facilitate the development of more detailed and integrative models of neural dysfunction in depression.
PMCID: PMC3596788  PMID: 23477309
Major Depressive Disorder; neural systems; intrinsic functional organization; default-mode network; salience network; executive network; rumination
3.  Memory for affectively valenced and neutral stimuli in depression: Evidence from a novel matching task 
Cognition & emotion  2011;25(7):1246-1254.
Depressed persons have better memory for affectively negative than positive stimuli, a pattern generally not exhibited by non-depressed individuals. The mechanisms underlying this differential memory are not clear. In this study we examined memory for valenced and neutral stimuli in depressed and non-depressed individuals under conditions of relatively unconstrained encoding. We developed a novel task based on the game, Concentration, in which participants tried to match pairs of positive and negative words, and pairs of neutral words, hidden under squares in as few turns as possible. Whereas non-depressed participants selected and turned over positive squares more frequently than they did negative squares, depressed participants selected and turned over positive and negative squares equally often. Depressed participants also matched fewer positive word pairs within the first five minutes of the task than did non-depressed participants, and they exhibited poorer learning of positive words. Depressed and non-depressed participants did not differ in their matching of neutral words. These findings add to a growing literature indicating that depression is characterised by difficulties in the processing of positive stimuli.
PMCID: PMC3971381  PMID: 21432643
Depression; Memory; Encoding; Retrieval; Valenced stimuli
4.  Cognitive and Neural Aspects of Information Processing in Major Depressive Disorder: An Integrative Perspective 
Researchers using experimental paradigms to examine cognitive processes have demonstrated that Major Depressive Disorder (MDD) is associated not with a general deficit in cognitive functioning, but instead with more specific anomalies in the processing of negatively valenced material. Indeed, cognitive theories of depression posit that negative biases in the processing of information play a critical role in influencing the onset, maintenance, and recurrence of depressive episodes. In this paper we review findings from behavioral studies documenting that MDD is associated with specific difficulties in attentional disengagement from negatively valenced material, with tendencies to interpret information in a negative manner, with deficits in cognitive control in the processing of negative material, and with enhanced memory for negative material. To gain a better understanding of the neurobiological basis of these abnormalities, we also examine findings from functional neuroimaging studies of depression and show that dysfunction in neural systems that subserve emotion processing, inhibition, and attention may underlie and contribute to the deficits in cognition that have been documented in depressed individuals. Finally, we briefly review evidence from studies of children who are at high familial risk for depression that indicates that abnormalities in cognition and neural function are observable before the onset of MDD and, consequently, may represent a risk factor for the development of this disorder. By integrating research from cognitive and neural investigations of depression, we can gain a more comprehensive understanding not only of how cognitive and biological factors interact to affect the onset, maintenance, and course of MDD, but also of how such research can aid in the development of targeted strategies for the prevention and treatment of this debilitating disorder.
PMCID: PMC3495336  PMID: 23162521
depression; MDD; neuroimaging; amygdala; interpretation bias; attention bias; memory bias; cognitive control
5.  Neural correlates of rumination in depression 
Rumination, or recursive self-focused thinking, has important implications for understanding the development and maintenance of depressive episodes. Rumination is associated with the worsening of negative mood states, greater affective responding to negative material, and increased access to negative memories. The present study was designed to use fMRI to examine neural aspects of rumination in depressed and healthy control individuals. We used a rumination induction task to assess differences in patterns of neural activation during ruminative self-focus as compared with a concrete distraction condition and with a novel abstract distraction condition in 14 participants who were diagnosed with major depressive disorder and 14 healthy control participants. Depressed participants exhibited increased activation in the orbitofrontal cortex, subgenual anterior cingulate, and dorsolateral prefrontal cortex as compared with healthy controls during rumination versus concrete distraction. Neural activity during rumination versus abstract distraction was greater for depressed than for control participants in the amygdala, rostral anterior cingulate/medial prefrontal cortex, dorsolateral prefrontal cortex, posterior cingulate, and parahippocampus. These findings indicate that ruminative self-focus is associated with enhanced recruitment of limbic and medial and dorsolateral prefrontal regions in depression.
PMCID: PMC4476645  PMID: 21098808
6.  Recalling happy memories in remitted depression: A neuroimaging investigation of the repair of sad mood 
Major depressive disorder (MDD) is a recurrent mood disorder. The high rate of recurrence of MDD suggests the presence of stable vulnerability factors that place individuals with a history of major depression at an increased risk for the onset of another episode. Previous research has linked the remitted state, and therefore increased vulnerability for depressive relapse, with difficulties in the use of pleasant autobiographical memories to repair sad mood. In the present study, we examined the neural correlates of these difficulties. Groups of 16 currently euthymic, remitted depressed individuals and 16 healthy (control) women underwent functional magnetic resonance imaging (fMRI) during sad mood induction and during recovery from a sad mood state through recall of mood-incongruent positive autobiographical memories. Sad mood was induced in participants by using film clips; participants then recalled positive autobiographical memories, a procedure previously shown to repair negative affect. During both the sad mood induction and automatic mood regulation, control participants exhibited activation in the left ventrolateral prefrontal cortex (vlPFC) and cuneus; in contrast, remitted participants exhibited a decrease in activation in these regions. Furthermore, exploratory analyses revealed that reduced activation levels during mood regulation predicted a worsening of depressive symptoms at a 20-month follow-up assessment. These findings highlight a dynamic role of the vlPFC and cuneus in the experience and modulation of emotional states and suggest that functional anomalies of these brain regions are associated with a history of, and vulnerability to, depression.
PMCID: PMC3995858  PMID: 24146315
Ventral prefrontal cortex; Depression; Affect; Mood; Emotion regulation; fMRI; Autobiographical memory
7.  Children at Risk for Depression: Memory Biases, Self-Schemas, and Genotypic Variation 
Daughters of depressed mothers are at increased risk for developing a depressive disorder. We know relatively little, however, about the specific factors that contribute to this elevated risk. The present study investigated the effects of familial risk for depression and the 5-HTTLPR and COMT Val158Met polymorphisms, which have been associated with risk for depression, on biases in endorsement of and memory for positive and negative adjectives.
Following a negative mood induction, 60 girls between the ages of 10 and 14 who had recurrent depressed mothers (high risk for depression) and 91 age-matched daughters of never-disordered mothers (low risk for depression) completed a Self-Referent Encoding Task in which they decided whether negative and positive adjectives described them. Following the task they were asked to recall as many of the adjectives as they could.
Despite the absence of significant group differences in endorsement of positive or negative adjectives, high-risk girls with the COMT Val158Met Val/Val polymorphism recalled more positive (but not negative) words that they had endorsed than did high-risk girls who were homozygous for the Met allele. COMT was not associated with recall of valenced adjectives in low-risk girls. Across risk groups, 5-HTTLPR polymorphism was not associated with recall of valenced adjectives.
Even with over 150 participants, there were relatively small numbers in some of the cells of this study, limiting its statistical power.
These results suggest that assessing the interaction of familial risk status and COMT polymorphism is important in understanding the development of depressive disorders.
PMCID: PMC4000236  PMID: 24679392
depression; familial risk; COMT; memory; genetic
8.  DeCon: A tool to detect emotional concordance in multivariate time series data of emotional responding 
Biological psychology  2013;98:29-42.
The occurrence of concordance among different response components during an emotional episode is a key feature of several contemporary accounts and definitions of emotion. Yet, capturing such response concordance in empirical data has proven to be elusive, in large part because of a lack of appropriate statistical tools that are tailored to measure the intricacies of response concordance in the context of data on emotional responding. In this article, we present a tool we developed to detect two different forms of response concordance—response patterning and synchronization—in multivariate time series data of emotional responding, and apply this tool to data concerning physiological responding to emotional stimuli. While the findings provide partial evidence for both response patterning and synchronization, they also show that the presence and nature of such patterning and synchronization is strongly person-dependent.
PMCID: PMC4016122  PMID: 24220647
emotion; affect; concordance; patterning; synchronization; synchronicity
9.  Activation of the medial prefrontal and posterior cingulate cortex during encoding of negative material predicts symptom worsening in major depression 
Neuroreport  2014;25(5):324-329.
Considerable research indicates that depressed individuals have better memory for negative material than do nondepressed individuals, and that this bias is associated with differential patterns of neural activation. It is not known, however, whether these aberrant activation patterns predict illness course. Using functional neuroimaging, we examined whether change in depressive symptoms is predicted by baseline patterns of neural activation that underlie negative memory biases in Major Depressive Disorder (MDD). Depressed participants viewed negative and neutral pictures during functional magnetic resonance imaging at baseline and completed an incidental memory task for these pictures one week later. Depression severity was assessed by administering the Beck Depression Inventory (BDI) both at baseline (Time 1) and at Time 2, an average of 18 months later. Contrast maps of activation for subsequently remembered negative versus subsequently remembered neutral pictures were regressed against change in BDI scores between Time 1 and Time 2, controlling for initial symptom severity. Results from this analysis revealed no associations between memory sensitivity for negative stimuli and symptom change. In contrast, whole brain analyses revealed significant positive associations between within-subject changes in depressive symptoms and baseline neural activation to successfully recalled negative pictures in the posterior cingulate cortex and medial prefrontal cortex. These findings indicate that neural activation in cortical midline regions is a better predictor of long-term symptomatic outcome than is memory sensitivity for negative material.
PMCID: PMC3947655  PMID: 24356105
posterior cingulate; depression; mri; amygdala; prefrontal cortex; symptom prediction
10.  Affective and physiological responses to stress in girls at elevated risk for depression 
Development and psychopathology  2012;24(2):661-675.
Children of depressed parents are significantly more likely to develop depression and other mental health disorders than are children of never-depressed parents. Investigations of the physiological mechanisms underlying this elevated risk have generally focused on basal functioning. It is important to note, however, that physiological reactivity or responses to stress are also critical determinants of mental and physical health. In the current study, we examined whether children of depressed parents exhibit altered physiological responses to stress. In two studies, never-depressed adolescent daughters of either recurrently depressed mothers (RISK) or never-depressed mothers (CTL) underwent social stressors while their physiological responses were measured (cortisol in Study 1, heart rate in Study 2). In both studies, affective responses to the stressors predicted physiological responses in RISK girls, but not in never-depressed girls. For RISK girls, decreased positive affect in response to stress predicted increased cortisol reactivity; in addition, decreased positive affect and increased negative affect were associated with poorer heart rate recovery and habituation, respectively. Future research is needed to examine explicitly whether this coherence between affect and physiology is a mechanism underlying the increased risk for psychopathology in children of depressed parents.
PMCID: PMC4353562  PMID: 22559138
11.  Increased Insula Coactivation with Salience Networks in Insomnia 
Biological psychology  2014;97:1-8.
Insomnia is among the most prevalent and costly of all sleep-related disorders. To characterize the neural mechanisms underlying subjective dysfunction in insomnia, we examined brain activity in 17 female insomniacs and 17 female healthy controls using simultaneous functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) while they were resting and while they were trying to fall asleep. In examining the dynamic regional activity within intrinsic brain networks, we found that, compared with controls, insomniacs had greater involvement of the anterior insula with salience networks, as well as insula BOLD correlation with EEG gamma frequency power during rest in insomniacs. This increased involvement of the anterior insula was associated with negative affect in insomniacs. Aberrant activation of the insula, which integrates temporal and bodily states, in arousal networks may underlie the misperception of sleep quality and subjective distress in insomnia.
PMCID: PMC3961550  PMID: 24412227
insomnia; fMRI; EEG; resting state; insula; salience networks
12.  5-HTTLPR Moderates the Effect of Relational Peer Victimization on Depressive Symptoms in Adolescent Girls 
Relational peer victimization is associated with internalizing symptoms. Compared to boys, girls are more likely to be both relationally victimized by peers and distressed by the victimization. While previous studies have reported that a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) moderates the effect of stressful life events on depressive symptoms, the present study is the first to evaluate the interaction of this polymorphism with relational peer victimization to predict level of depressive symptoms in young girls.
Participants were 78 girls ages 10 to 14 who had no current or past Axis I disorder. Girls were genotyped for 5-HTTLPR; peer victimization was assessed with the Social Experiences Questionnaire, and depressive symptoms with the Children's Depression Inventory.
The 5-HTTLPR polymorphism alone did not predict level of depressive symptoms; the interaction of 5-HTTLPR and relational peer victimization, however, was a significant predictor of depressive symptoms. Follow-up analyses indicated that peer victimization significantly predicted level of depressive symptoms only for girls who were homozygous for the short allele, and not for girls homozygous for the long allele or who were heterozygous for the short and long alleles.
The findings support the diathesis-stress model of depression: having two 5-HTTLPR short alleles confers vulnerability to depressive symptoms in adolescent girls when they experience relational peer victimization. These findings also suggest that relational peer victimization, at least for girls with genetic vulnerability, is a significant source of stress and should be recognized in the monitoring and prevention of bullying.
PMCID: PMC2804775  PMID: 19754661
peer victimization; bullying; depression; genetic polymorphisms; 5-HTTLPR
13.  Neural correlates of inhibitory deficits in depression 
Psychiatry research  2010;181(1):30-35.
The present study was designed to examine neural correlates of inhibitory dysfunction in individuals diagnosed with Major Depressive Disorder (MDD). Twelve MDD participants and 12 never-depressed controls completed the negative affective priming (NAP) task in the scanner. Results indicated that, in depressed participants, increased activation in the rostral anterior cingulate cortex (rACC) is associated with inhibition of negative, but not positive, words; in contrast, in nondepressed participants, inhibition of positive, but not negative, words is associated with increased activation in the rACC. These findings indicate that abnormalities in neural function, especially in the rACC, may underlie difficulties experienced by depressed individuals in inhibiting negative thoughts. These results underscore the importance of continuing to examine the relation between cognitive and neural functioning in depression in order to gain a broader and more integrative understanding of this disorder.
PMCID: PMC2795107  PMID: 19962859
anterior cingulate cortex; inhibition; negative priming; functional magnetic resonance imaging
14.  Support Vector Machine Classification of Major Depressive Disorder Using Diffusion-Weighted Neuroimaging and Graph Theory 
Recently, there has been considerable interest in understanding brain networks in major depressive disorder (MDD). Neural pathways can be tracked in the living brain using diffusion-weighted imaging (DWI); graph theory can then be used to study properties of the resulting fiber networks. To date, global abnormalities have not been reported in tractography-based graph metrics in MDD, so we used a machine learning approach based on “support vector machines” to differentiate depressed from healthy individuals based on multiple brain network properties. We also assessed how important specific graph metrics were for this differentiation. Finally, we conducted a local graph analysis to identify abnormal connectivity at specific nodes of the network. We were able to classify depression using whole-brain graph metrics. Small-worldness was the most useful graph metric for classification. The right pars orbitalis, right inferior parietal cortex, and left rostral anterior cingulate all showed abnormal network connectivity in MDD. This is the first use of structural global graph metrics to classify depressed individuals. These findings highlight the importance of future research to understand network properties in depression across imaging modalities, improve classification results, and relate network alterations to psychiatric symptoms, medication, and comorbidities.
PMCID: PMC4332161  PMID: 25762941
major depressive disorder; diffusion-weighted imaging; graph theory; support vector machine; small world network; subgenual anterior cingulate cortex
15.  Neural Processing of Reward and Loss in Girls at Risk for Major Depression 
Archives of general psychiatry  2010;67(4):380-387.
Deficits in reward processing and their neural correlates have been associated with major depression. It is unclear, however, if these deficits precede the onset of depression or are a consequence of this disorder.
To determine whether anomalous neural processing of reward characterizes children at familial risk for depression in the absence of a personal history of psychopathology.
Comparing neural activity of children at low and high risk for depression as they process reward and loss.
University fMRI facility.
Thirteen 10– 14-year-old never-disordered daughters of mothers with recurrent depression (“high risk”) and 13 age-matched never-disordered daughters with no family history of depression (“low risk”).
Main Outcome Measure
Neural activity, as measured with fMRI, in key reward and attention neural circuitry during anticipation and receipt of reward and loss.
While anticipating gains, high-risk participants showed less activation than did their low-risk counterparts in the putamen and left insula, but greater activation in the right insula. When receiving punishment, high-risk participants showed greater activation in the dorsal anterior cingulate gyrus than did low-risk participants, who showed greater activation in the caudate and putamen.
Familial risk for depression affects neural mechanisms underlying the processing of reward and loss; young girls at risk for depression exhibit anomalies in the processing of reward and loss prior to the onset of depressive symptoms. Longitudinal studies are needed to examine whether these characteristics predict the subsequent onset of depression.
PMCID: PMC2852176  PMID: 20368513
depression; reward; anticipation; incentive; familial risk
16.  Does Processing of Emotional Stimuli Predict Symptomatic Improvement and Diagnostic Recovery From Major Depression? 
Emotion (Washington, D.C.)  2007;7(1):201-206.
This study was designed to examine whether processing of emotional stimuli predicts both symptomatic improvement and recovery from depression. Participants diagnosed with Major Depressive Disorder (MDD) (N = 63) completed information-processing tasks to assess attention to and memory for sad, physically threatening, socially threatening, and happy stimuli. At a follow-up session an average of nine months later, participants were reassessed to determine diagnostic status and depression severity. None of the measure of attention or memory predicted diagnostic status at follow-up. Those depressed participants who remembered a higher proportion of positive words that they had endorsed as self-descriptive exhibited greater symptomatic improvement. After controlling for memory of positive self-referential words, attentional measures did not predict symptomatic change. These results are consistent with a growing literature highlighting the importance of emotionally relevant memory processes for understanding the course of major depression.
PMCID: PMC2847494  PMID: 17352575
depression; recovery; information processing; memory; attention
Graph theory is increasingly used in the field of neuroscience to understand the large-scale network structure of the human brain. There is also considerable interest in applying machine learning techniques in clinical settings, for example, to make diagnoses or predict treatment outcomes. Here we used support-vector machines (SVMs), in conjunction with whole-brain tractography, to identify graph metrics that best differentiate individuals with Major Depressive Disorder (MDD) from nondepressed controls. To do this, we applied a novel feature-scoring procedure that incorporates iterative classifier performance to assess feature robustness. We found that small-worldness, a measure of the balance between global integration and local specialization, most reliably differentiated MDD from nondepressed individuals. Post-hoc regional analyses suggested that heightened connectivity of the subcallosal cingulate gyrus (SCG) in MDDs contributes to these differences. The current study provides a novel way to assess the robustness of classification features and reveals anomalies in large-scale neural networks in MDD.
PMCID: PMC4287315  PMID: 25580184
Major Depressive Disorder (MDD); graph theoretical analysis; machine learning; support vector machine (SVM); small-world
18.  Differences between suicide attempters and non-attempters in depressed older patients: Depression severity, white matter lesions, and cognitive functioning 
Older adults with major depressive disorder (MDD) have the highest population-rate of suicide. White matter brain lesions (WML) are a potential biological marker for suicidality in young and middle-age adults and are correlated with cognitive impairment (CI) in older adults. In the current study of older patients with MDD, we examined 1) if a history of suicide attempts was associated with a more severe course of MDD; 2) if WML are a biological marker for suicide; and 3) if suicide attempt history is associated with CI mediated by WML.
Data from the Neurocognitive Outcomes of Depression in the Elderly.
Depressed patients (60+) who had ever attempted suicide (n=23) were compared to depressed patients (60+) who had not attempted suicide (n=223).
Baseline and follow-up assessments were obtained for depressive symptoms (every 3 months) and cognitive functioning (every six months) over two years. Three MRI scans were conducted.
At baseline, suicide attempters reported more severe past and present symptoms (e.g., depressive symptoms, current suicidal thoughts, psychotic symptoms, earlier age of onset, and more lifetime episodes) than non-attempters. Suicide attempters had more left WML at baseline, and suicide attempt history predicted a greater growth in both left and right WML. WML predicted cognitive decline; nonetheless, history of suicide attempt was unrelated to cognitive functioning.
Severity of depressive symptoms and WML are associated with suicide attempts in geriatric depressed patients. Suicide attempts predicted neurological changes, which may contribute to poorer long-term outcomes in elder attempters.
PMCID: PMC4155401  PMID: 23933424
Geriatric; major depression; white matter lesions
19.  Reduced Caudate Gray Matter Volume in Women with Major Depressive Disorder 
Psychiatry research  2008;164(2):114-122.
Previous brain imaging studies have reported that Major Depressive Disorder (MDD) is characterized by decreased volumes of several cortical and subcortical structures, including the hippocampus, amygdala, anterior cingulate cortex, and caudate nucleus. The purpose of the present study was to identify structural volumetric differences between MDD and healthy participants using a method that allows a comparison of gray and white matter volume across the whole brain. In addition, we explored the relation between symptom severity and brain regions with decreased volumes in MDD participants. Twenty-two women diagnosed with MDD and 25 healthy women with no history of major psychiatric disorders participated in this study. Magnetic resonance brain images were analyzed using optimized voxel-based morphometry to examine group differences in regional gray and white matter volume. Compared with healthy controls, MDD participants were found to have decreased gray matter volume in the bilateral caudate nucleus and the thalamus. No group differences were found for white matter volume, nor were there significant correlations between gray matter volumes and symptom severity within the MDD group. The present results suggest that smaller volume of caudate nucleus may be related to the pathophysiology of MDD and may account for abnormalities of the cortico-striatal-pallido-thalamic loop in MDD.
PMCID: PMC2600594  PMID: 18930633
Major Depressive Disorder (MDD); magnetic resonance imaging (MRI); voxel-based morphometry (VBM); caudate; depression; brain
Diffusion-weighted imaging allows for in vivo assessment of white matter structure, which can be used to assess aberrations associated with disease. Several new methods permit the automated assessment of important white matter characteristics. In the current study we used Automated Fiber Quantification (AFQ) to assess differences between depressed and nondepressed individuals in 18 major white matter tracts. We then used the Maximum Density Path (MDP) method to further characterize group differences identified with AFQ. The results of the AFQ analyses indicated that fractional anisotropy (FA; an index of white matter integrity) along bilateral corticospinal tracts (CST) was higher in depressed than in nondepressed individuals. MDP analyses revealed that white matter anomalies were restricted to four subregions that included the corona radiata and the internal and external capsules. These results provide further evidence that MDD is associated with abnormalities in cortical-to-subcortical connectivity.
PMCID: PMC4273938  PMID: 25540677
Major Depressive Disorder (MDD); automated fiber quantification (AFQ); maximum density paths (MDP); diffusion-weighted imaging; tractography
21.  HPA-Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression 
Biological psychiatry  2007;63(9):847-851.
Recent evidence indicates that individuals who are homozygous for the short (s) allele in the promoter region of the serotonin transporter gene have higher rates of depression and other psychiatric disorders as a function of exposure to increasing levels of stressful life events than do individuals who have one or two copies of the long (l) allele. Despite the reliability of this association, the mechanism by which this polymorphism confers risk for psychopathology in the presence of stress is not understood. The present study was designed to examine the formulation that individuals who are homozygous for the s allele are characterized by a greater biological reactivity to stress than are their counterparts who have one or two copies of the l allele.
Girls at high (n = 25) and low (n = 42) risk for depression by virtue of the presence or absence of a family history of this disorder were genotyped and exposed to a standardized laboratory stress task. Cortisol levels were assessed before the stressor, after the stressor, and during an extended recovery period.
Girls who were homozygous for the s-allele produced higher and more prolonged levels of cortisol in response to the stressor than did girls with an l allele.
These findings indicate that the 5-HTTLPR polymorphism is associated with biological stress reactivity, which may increase susceptibility to depression in the face of stressful life events.
PMCID: PMC2373542  PMID: 18005940
22.  Anomalous Gray Matter Structural Networks in Major Depressive Disorder 
Biological psychiatry  2013;74(10):777-785.
Major depressive disorder (MDD) is characterized by abnormalities in structure, function, and connectivity in several brain regions. Few studies have examined how these regions are organized in the brain or investigated network-level structural aberrations that might be associated with depression.
We used graph analysis to examine the gray matter structural networks of individuals diagnosed with MDD (n = 93) and a demographically similar healthy comparison group (n = 151) with no history of psychopathology. The efficiency of structural networks for processing information was determined by quantifying local interconnectivity (clustering) and global integration (path length). We also compared the groups on the contributions of high-degree nodes (i.e., hubs) and regional network measures, including degree (number of connections in a node) and betweenness (fraction of short path connections in a node).
Depressed participants had significantly decreased clustering in their brain networks across a range of network densities. Compared with control subjects, depressed participants had fewer hubs primarily in medial frontal and medial temporal areas, had higher degree in the left supramarginal gyrus and right gyrus rectus, and had higher betweenness in the right amygdala and left medial orbitofrontal gyrus.
Networks of depressed individuals are characterized by a less efficient organization involving decreased regional connectivity compared with control subjects. Regional connections in the amygdala and medial prefrontal cortex may play a role in maintaining or adapting to depressive pathology. This is the first report of anomalous large-scale gray matter structural networks in MDD and provides new insights concerning the neurobiological mechanisms associated with this disorder.
PMCID: PMC3805751  PMID: 23601854
Connectivity; depression; graph analysis; gray matter; small world; structural network
23.  Interoceptive Awareness, Positive Affect, and Decision Making in Major Depressive Disorder 
Journal of affective disorders  2013;151(2):780-785.
Little work has examined the relation between interoceptive awareness and symptoms of Major Depressive Disorder (MDD). Existing research suggests that depressed individuals exhibit impaired heartbeat perception, though the results of this research have been equivocal. Importantly, depressed participants in these studies have had comorbid anxiety disorders, making it difficult to draw inferences about interoceptive awareness in MDD. The current study addresses this issue by assessing heartbeat perception in depressed women without current anxiety disorders and exploring the relation between interoception and perturbations in both affective intensity and decision making, components of MDD postulated to be related to bodily awareness.
Depressed women without concurrent anxiety disorders (n=25) and never-disordered controls (n=36) performed a heartbeat perception task. Participants completed the self-report Affect Intensity Measure (AIM), and decision-making difficulty was assessed in MDD participants using the Structured Clinical Interview for DSM-IV.
Depressed women exhibited poorer heartbeat perception accuracy than did control participants. Impaired accuracy in MDD participants was associated with reduced positive affectivity and difficulty in decision making.
Our sample was composed exclusively of females and was heterogeneous with respect to treatment status, thereby limiting our ability to generalize results to depressed males and to exclude the contribution of exogenous factors to the observed group differences.
Results of this study suggest that for depressed individuals without anxiety comorbidities, disrupted perception of bodily responses reduces both the experience of positive arousal and the ability to use interoceptive feedback to inform decision making.
PMCID: PMC3797260  PMID: 23972662
depression; interoception; affect; decision making
24.  Structural abnormality of the corticospinal tract in major depressive disorder 
Scientists are beginning to document abnormalities in white matter connectivity in major depressive disorder (MDD). Recent developments in diffusion-weighted image analyses, including tractography clustering methods, may yield improved characterization of these white matter abnormalities in MDD. In this study, we acquired diffusion-weighted imaging data from MDD participants and matched healthy controls. We analyzed these data using two tractography clustering methods: automated fiber quantification (AFQ) and the maximum density path (MDP) procedure. We used AFQ to compare fractional anisotropy (FA; an index of water diffusion) in these two groups across major white matter tracts. Subsequently, we used the MDP procedure to compare FA differences in fiber paths related to the abnormalities in major fiber tracts that were identified using AFQ.
FA was higher in the bilateral corticospinal tracts (CSTs) in MDD (p’s < 0.002). Secondary analyses using the MDP procedure detected primarily increases in FA in the CST-related fiber paths of the bilateral posterior limbs of the internal capsule, right superior corona radiata, and the left external capsule.
This is the first study to implicate the CST and several related fiber pathways in MDD. These findings suggest important new hypotheses regarding the role of CST abnormalities in MDD, including in relation to explicating CST-related abnormalities to depressive symptoms and RDoC domains and constructs.
PMCID: PMC4187017  PMID: 25295159
Major depressive disorder (MDD); Diffusion tensor imaging (DTI); Tractography; Clustering; Automated fiber quantification (AFQ); Maximum density path (MDP); Corticospinal tract (CST); Fractional anisotropy (FA)
25.  An Attentional Scope Model of Rumination 
Psychological bulletin  2012;139(5):1036-1061.
Rumination, defined as repetitive thinking about negative information, has been found to lead to serious maladaptive consequences, including longer and more severe episodes of major depression. In this review, we present and discuss research findings motivated by the formulation that individual differences in cognitive processes that control how information is processed influence the likelihood that thoughts will become repetitive and negative. A number of studies have demonstrated that a tendency to ruminate (i.e., trait rumination) is related to difficulties updating working memory (WM) and disengaging from and forgetting no-longer-relevant information. Other investigators have documented that trait rumination is also associated with an enhanced ability to ignore distracting information and to more stable maintenance of task-relevant information. In contrast to trait rumination, a state of rumination has been found to be related to widespread deficits in cognitive control. In this paper we discuss how the current accounts of control functioning cannot explain this pattern of anomalous control functioning. To explain these findings, including unexpected and contradictory results, we present an attentional scope model of rumination that posits that a constricted array of thoughts, percepts, and actions that are activated in WM or available for selection from LTM affects the control functioning of trait ruminators. This model explains, at a cognitive level, why rumination is particularly likely to arise when individuals are in a negative mood state; it also accounts for a number of findings outside of the rumination-control literature and generates several novel predictions.
PMCID: PMC3773498  PMID: 23244316

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