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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.
doi:10.1037/a0023533
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.
doi:10.1016/j.nbd.2012.01.015
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.
doi:10.1080/02699931.2010.538374
PMCID: PMC3971381  PMID: 21432643
Depression; Memory; Encoding; Retrieval; Valenced stimuli
4.  ELUCIDATING BRAIN CONNECTIVITY NETWORKS IN MAJOR DEPRESSIVE DISORDER USING CLASSIFICATION-BASED SCORING 
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.
doi:10.1109/ISBI.2014.6867855
PMCID: PMC4287315  PMID: 25580184
Major Depressive Disorder (MDD); graph theoretical analysis; machine learning; support vector machine (SVM); small-world
5.  Differences between suicide attempters and non-attempters in depressed older patients: Depression severity, white matter lesions, and cognitive functioning 
Objectives
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.
Setting
Data from the Neurocognitive Outcomes of Depression in the Elderly.
Participants
Depressed patients (60+) who had ever attempted suicide (n=23) were compared to depressed patients (60+) who had not attempted suicide (n=223).
Measurements
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jagp.2013.01.063
PMCID: PMC4155401  PMID: 23933424
Geriatric; major depression; white matter lesions
6.  CHARACTERIZING WHITE MATTER CONNECTIVITY IN MAJOR DEPRESSIVE DISORDER: AUTOMATED FIBER QUANTIFICATION AND MAXIMUM DENSITY PATHS 
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.
doi:10.1109/ISBI.2014.6867940
PMCID: PMC4273938  PMID: 25540677
Major Depressive Disorder (MDD); automated fiber quantification (AFQ); maximum density paths (MDP); diffusion-weighted imaging; tractography
7.  Anomalous Gray Matter Structural Networks in Major Depressive Disorder 
Biological psychiatry  2013;74(10):777-785.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2013.03.005
PMCID: PMC3805751  PMID: 23601854
Connectivity; depression; graph analysis; gray matter; small world; structural network
8.  Interoceptive Awareness, Positive Affect, and Decision Making in Major Depressive Disorder 
Journal of affective disorders  2013;151(2):780-785.
Background
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.
Methods
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.
Results
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.
Limitations
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.
Conclusions
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.
doi:10.1016/j.jad.2013.06.044
PMCID: PMC3797260  PMID: 23972662
depression; interoception; affect; decision making
9.  Structural abnormality of the corticospinal tract in major depressive disorder 
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/2045-5380-4-8
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)
10.  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.
doi:10.1037/a0030923
PMCID: PMC3773498  PMID: 23244316
11.  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
12.  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.
doi:10.3389/fpsyg.2012.00489
PMCID: PMC3495336  PMID: 23162521
depression; MDD; neuroimaging; amygdala; interpretation bias; attention bias; memory bias; cognitive control
13.  Neural and behavioral effects of interference resolution in depression and rumination 
Individuals diagnosed with major depressive disorder (MDD) often ruminate about their depression and their life situations, impairing their concentration and performance on daily tasks. We examined whether rumination might be due to a deficit in the ability to expel negative information from short-term memory (STM), and fMRI was used to examine the neural structures involved in this ability. MDD and healthy control (HC) participants were tested using a directed-forgetting procedure in a short-term item recognition task. As predicted, MDD participants had more difficulty than did HCs in expelling negative, but not positive, words from STM. Overall, the neural networks involved in directed forgetting were similar for both groups, but the MDDs exhibited more spatial variability in activation in the left inferior frontal gyrus (a region critical for inhibiting irrelevant information), which may contribute to their relative inability to inhibit negative information.
doi:10.3758/s13415-010-0014-x
PMCID: PMC4006074  PMID: 21264648
fMRI; Interference; Depression; Short-term memory; Rumination
14.  Feeling Blue or Turquoise? Emotional Differentiation in Major Depressive Disorder 
Psychological science  2012;23(11):1410-1416.
Some individuals have very specific and differentiated emotional experiences, such as anger, shame, excitement, and happiness, whereas others have more general affective experiences of pleasure or discomfort that are not as highly differentiated. Considering that individuals with major depressive disorder (MDD) have cognitive deficits for negative information, we predicted that people with MDD would have less differentiated negative emotional experiences than would healthy people. To test this hypothesis, we assessed participants' emotional experiences using a 7-day experience-sampling protocol. Depression was assessed using structured clinical interviews and the Beck Depression Inventory-II. As predicted, individuals with MDD had less differentiated emotional experiences than did healthy participants, but only for negative emotions. These differences were above and beyond the effects of emotional intensity and variability.
doi:10.1177/0956797612444903
PMCID: PMC4004625  PMID: 23070307
emotions; depression; happiness; emotional control; individual differences
15.  The Neural Basis of Difficulties Disengaging From Negative Irrelevant Material in Major Depression 
Psychological science  2013;24(3):334-344.
Recurrent uncontrollable negative thoughts are a hallmark of depressive episodes. Deficits in cognitive control have been proposed to underlie this debilitating aspect of depression. Here, we used functional neuroimaging during an emotional working memory (WM) task to elucidate the neural correlates of these difficulties in cognitive control. In a WM manipulation involving depressed participants, the dorsal anterior cingulate and parietal and bilateral insular cortices were activated significantly more when negative words were removed from WM than when they were maintained in WM; in contrast, nondepressed participants exhibited stronger neural activations in these regions for positive than for negative material. These findings implicate anomalous activation of components of the task-positive network, known to be modulated by cognitive effort, in depression-associated difficulties in expelling negative material from WM. Future studies should examine the association between these aberrations and the maintenance of depressive symptoms.
doi:10.1177/0956797612457380
PMCID: PMC4004633  PMID: 23334445
depression; functional MRI; working memory; dorsal anterior cingulate cortex; insula; neuroimaging; brain
16.  People with bipolar I disorder report avoiding rewarding activities and dampening positive emotion 
Journal of affective disorders  2012;146(3):407-413.
Background
Researchers have linked bipolar disorder to elevations in reward sensitivity and positive affect. Little is known, however, about how people with bipolar disorder respond to rewards and positive affect and how these tendencies relate to functioning or quality of life.
Methods
Persons diagnosed with bipolar I disorder and matched controls completed the Response to Positive Affect (RPA) measure and the Brief Quality of Life in Bipolar Disorder scale. Bipolar participants also completed the Reward Responses Inventory, which we designed to assess the extent to which participants avoid rewarding activities to prevent mania. A subsample of participants with bipolar disorder completed a positive mood induction procedure to examine the validity of the Response to Positive Affect scale.
Results
The majority of bipolar participants reported avoiding at least one rewarding activity as a means of preventing mania. In addition, people with bipolar I disorder reported more dampening responses to positive affect than did control participants. Dampening positive emotions was related to lower quality of life.
Limitations
This study does not address whether responses to affect and reward are related to the longitudinal course of symptoms.
Conclusions
These findings suggest that people with bipolar I disorder seem to be aware of the potential of goal achievements to trigger mania, and many people with bipolar disorder seem to take steps to avoid positive emotion and reward.
doi:10.1016/j.jad.2012.07.027
PMCID: PMC3557770  PMID: 23021378
Bipolar Disorder; Responses to Positive Affect; Reward Sensitivity; Positive Emotion
17.  The role of the medial frontal cortex in the maintenance of emotional states 
Evidence is accruing that people can maintain their emotional states, but how they do it and which brain regions are responsible still remains unclear. We examined whether people maintain emotional states ‘actively’, with explicit elaboration of the emotion, or ‘passively’, without elaboration. Twenty-four participants completed an emotion maintenance task in which they either maintained the emotional intensity from the first picture of a pair to compare to that of the second picture (‘maintain’ condition), or only rated their emotional response to the second picture (‘non-maintain’ condition). Supporting the ‘active’ maintenance hypothesis, when maintaining vs not maintaining emotion, participants exhibited increased height and width of activation in the dorsal medial frontal cortex (MFC) and lateral prefrontal cortex, regions associated with explicit emotion generation and manipulation of contents in working memory, respectively. Supporting the ‘passive’ maintenance hypothesis, however, when viewing negative emotional pictures (vs neutral pictures) that were not explicitly maintained, participants exhibited greater duration of activity in the rostral MFC, a region associated with implicit emotion generation. Supported by behavioral findings, this evidence that people maintain emotional states both naturally in the rMFC and strategically in the dMFC may be critical for understanding normal as well as disordered emotion regulation.
doi:10.1093/scan/nsu011
PMCID: PMC4249480  PMID: 24493835
emotion; working memory; medial frontal cortex; affect maintenance; emotion regulation
18.  5-HTTLPR Moderates the Effect of Relational Peer Victimization on Depressive Symptoms in Adolescent Girls 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1469-7610.2009.02149.x
PMCID: PMC2804775  PMID: 19754661
peer victimization; bullying; depression; genetic polymorphisms; 5-HTTLPR
19.  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.
doi:10.1016/j.pscychresns.2009.07.010
PMCID: PMC2795107  PMID: 19962859
anterior cingulate cortex; inhibition; negative priming; functional magnetic resonance imaging
20.  Reward Processing in Adolescents with Bipolar I Disorder 
Objective
Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward-seeking. Because youth with bipolar disorder are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to “prime” affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood prior to reward processing in adolescents with and without BD.
Method
Neural activity and behaviors during the anticipation of and response to monetary reward and loss following an affective prime were compared using functional magnetic resonance imaging (fMRI) in 13- to 18-year-old adolescents with a recent onset of bipolar I disorder (“BD,” n=24) and demographically matched healthy comparison youth (“HC,” n=24).
Results
Relative to HC, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming.
Conclusions
Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.
doi:10.1016/j.jaac.2012.10.004
PMCID: PMC3530159  PMID: 23265635
reward processing; fMRI; adolescent; bipolar disorder; affective prime
21.  A longitudinal study of differences in late and early onset geriatric depression: Depressive symptoms and psychosocial, cognitive, and neurological functioning 
Aging & mental health  2012;17(1):1-11.
Objectives
Studies suggest early onset depression (EOD) is associated with a more severe course of the depressive disorder, while late onset depression (LOD) is associated with more cognitive and neuroimaging changes. This study examined if older adults with EOD, compared with those with LOD, would exhibit more severe symptoms of depression and, consistent with the glucocorticoid cascade hypothesis, have more hippocampal volume loss. A second goal was to determine if LOD, compared with EOD, would demonstrate more cognitive and neuroimaging changes.
Method
At regular intervals over a four year period non-demented, older, depressed adults were assessed on the Mini Mental Status Examination (MMSE) and the Montgomery-Asberg Depression Rating Scale (MADRS). They were also assessed on Magnetic Resonance Imaging (MRI).
Results
Compared with LOD, EOD had more depressive symptoms, more suicidal thoughts, and less social support. Growth curve analyses indicated that EOD demonstrated higher levels of residual depressive symptoms over time. The LOD group exhibited a greater decrement in cognitive scores. Contrary to the glucocorticoid cascade hypothesis, participants with EOD lost right hippocampal volume at a slower rate than did participants with LOD. Right cerebrum gray matter was initially smaller among participants with LOD.
Conclusions
EOD is associated with greater severity of depressive illness. LOD is associated with more severe cognitive and neurological changes. These differences are relevant to understanding cognitive impairment in geriatric depression.
doi:10.1080/13607863.2012.717253
PMCID: PMC3535510  PMID: 22934752
late-onset depression; early-onset depression; cognition; hippocampus
22.  Neural Processing of Reward and Loss in Girls at Risk for Major Depression 
Archives of general psychiatry  2010;67(4):380-387.
Context
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.
Objective
To determine whether anomalous neural processing of reward characterizes children at familial risk for depression in the absence of a personal history of psychopathology.
Design
Comparing neural activity of children at low and high risk for depression as they process reward and loss.
Setting
University fMRI facility.
Participants
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.
Results
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.
Conclusions
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.
doi:10.1001/archgenpsychiatry.2010.13
PMCID: PMC2852176  PMID: 20368513
depression; reward; anticipation; incentive; familial risk
23.  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.
doi:10.1037/1528-3542.7.1.201
PMCID: PMC2847494  PMID: 17352575
depression; recovery; information processing; memory; attention
24.  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.
doi:10.1016/j.pscychresns.2007.12.020
PMCID: PMC2600594  PMID: 18930633
Major Depressive Disorder (MDD); magnetic resonance imaging (MRI); voxel-based morphometry (VBM); caudate; depression; brain
25.  HPA-Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression 
Biological psychiatry  2007;63(9):847-851.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2007.10.008
PMCID: PMC2373542  PMID: 18005940

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