Neural circuits underlying the pathophysiology of mood disorders

Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures.     

Neuroreceptor imaging of stress and mood disorders

Techniques such as positron emission tomography and single photon emission computed tomography allow for the imaging of neurotransmitter receptors and transporters in the brain. These tools have been used to investigate serotonergic, dopaminergic, and opioidergic function in healthy subjects as well as in patients with major depressive disorder, bipolar disorder, and other mood disorders. Pharmacologic challenges, such as amphetamine challenge, and physiologic stressors, such as pain challenge, have been used to further examine the function of these neurotransmitter systems. Neuroimaging of patient populations before and after medication treatment may be useful to understand changes in neurotransmission that accompany disease remission. As new radiotracers with higher selectivity for the various receptors and transporters are developed, imaging techniques may provide new insights into the pathophysiology of mood disorders, leading to improved diagnosis and treatment.     

Gender differences in major depressive disorder and bipolar disorder

This paper reviews the literature on gender differences in major depressive disorder (MDD) and bipolar disorder (BPD). Beginning in adolescence, women are at a higher risk than men of becoming depressed. Avenues of investigation that might ultimately help to explain this phenomenon include studies of gender differences in the processing of emotional stimuli, the psychotropic effects of gonadal steroids, and environment/gene interactions in men and women. With the exception of the elevated suicide rate among men, consistent gender differences in the course and symptoms of MDD have not been found. In BPD, women are more likely than men to develop a rapid-cycling course. Gender differences in treatment response, particularly in regard to mood stabilizing medications, warrant further study.     

Functional connectivity of reflective and brooding rumination in depressed and healthy women

Ruminative thinking is related to an increased risk for major depressive disorder (MDD) and perpetuates negative mood states. Rumination, uncontrollable negative thoughts about the self, may comprise both reflective and brooding components. However, only brooding rumination is consistently associated with increased negativity bias and negative coping styles, while reflective rumination has a less clear relationship with negative outcomes in healthy and depressed participants. The current study examined seed-to-voxel (S2.V) resting-state functional connectivity (FC) in a sample of healthy (HC) and depressed (MDD) adult women (HC: n=50, MDD: n=33). The S2V FC of six key brain regions, including the left and right amygdala, anterior and posterior cingulate cortex (ACC, PCC), and medial and dorsolateral prefrontal cortices (mPFC, dlPFC), was correlated with self-reported reflective and brooding rumination. Results indicate that HC and MDD participants had increased brooding rumination associated with decreased FC between the left amygdala and the right temporal pole. Moreover, reflective rumination was associated with distinct FC of the mPFC, PCC, and ACC with parietal, occipital, and cingulate regions. Depressed participants, compared with HC, exhibited decreased FC between the PCC and a region in the right middle frontal gyrus. The results of the current study add to the understanding of the neural underpinnings of different forms of self-related cognition—brooding and reflective rumination—in healthy and depressed women.     

The impact of borderline personality disorder and anxiety on neuropsychological performance in major depression

Previous studies of neuropsychological performance in borderline personality disorder (BPD) have exhibited mixed results. The high rate of co-occurring major depressive disorder (MDD) in BPD makes it difficult to specify whether neuropsychological deficits in BPD predominantly reflect co-occurring MDD or unique aspects of their psychopathology. To address this issue, 22 participants with borderline personality disorder and concurrent major depressive disorder (BPD-MDD) and 33 participants with MDD and no concurrent personality disorder were compared on a neuropsychological battery that assessed seven domains of performance: general intellectual functioning, motor skill, psychomotor speed, attention, memory, working memory, and executive function. Neuropsychological performance did not differ between BPD-MDD and MDD. However, BPD-MDD participants reported higher levels of anger, anxiety, and of overall emotional distress compared to MDD. When levels of anxiety were controlled, BPD-MDD participants exhibited superior general intellectual performance, psychomotor speed, and attention. Deficits found in previous BPD samples may reflect their susceptibility to co-occurring MDD. The impact of anxiety on neuropsychological performance in BPD, though, indicates a need for future experimental studies of the effects of mood on cognitive function to determine whether mood dysregulation, rather than core depressive symptoms, underlie cognition impairments in BPD.     

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.     

Positive emotion dysregulation across mood disorders: How amplifying versus dampening predicts emotional reactivity and illness course

Maladaptive regulation of positive emotion has increasingly been associated with psychopathology. Little is known, however, about how individual strategies used to manage positive emotion predict concurrent emotional responding and prospective illness course across mood disorders. The present study examined the concurrent and prospective influence of amplification and dampening regulation strategies of positive emotion (i.e., self-focused positive rumination, emotion-focused positive rumination, and dampening) among remitted individuals with bipolar I disorder (BD; n = 31) and major depressive disorder (MDD; n = 31). Rumination over positive emotional states concurrently predicted increased positive emotion across both mood disordered groups during an experimental rumination induction. However, dampening positive emotion concurrently predicted increased emotional reactivity (i.e., heart rate and negative affect) and prospective increases in manic and depressive symptoms for the BD group only. This suggests that amplifying positive emotion transdiagnostically increases positive emotion across mood disordered groups, while attempts to dampen positive emotion may paradoxically exacerbate emotional reactivity and illness course in BD. For individuals with BD, negative thinking about one's positive emotion (via dampening) may be particularly maladaptive.     

A preliminary investigation of cognitive flexibility for emotional information in major depressive disorder and non-psychiatric controls

Clinical research suggests that individuals with major depressive disorder (MDD) are cognitively inflexible, exhibiting ruminative, rigid, and automatic thoughts within a negative schema. However, existing neuropsychological research on cognitive flexibility in this population has not employed emotional stimuli. Because research suggests that the performance of individuals with MDD is modulated when emotional stimuli are used, this study investigates the impact of emotional stimuli on cognitive flexibility performance through a novel emotional modification of the Wisconsin Card Sorting Test. Controls were less flexible when stimuli were positive and individuals with MDD were less flexible when stimuli were negative relative to the controls. These divergent styles of responding to emotional information may contribute to the relative risk or protection from depressed mood.     

Integrated cross-network connectivity of amygdala,insula, and subgenual cingulate associated with facial emotion perception in healthy controls and remitted major depressive disorder

Emotion perception deficits could be due to disrupted connectivity of key nodes in the salience and emotion network (SEN), including the amygdala, subgenual anterior cingulate cortex (sgACC), and insula. We examined SEN resting-state (rs-)fMRI connectivity in rMDD in relation to Facial Emotion Perception Test (FEPT) performance. Fifty-two medication-free people ages 18 to 23 years participated. Twenty-seven had major depressive disorder (MDD) in remission (rMDD, 10 males), as MDD is associated with emotion perception deficits and alterations in rsfMRI. Twenty-five healthy controls (10 males) also participated. Participants completed the FEPT during fMRI, in addition to an 8-minute eyes-open resting-state scan. Seed regions of interest were defined in the amygdala, anterior insula and sgACC. Multiple regression analyses co-varied diagnostic group, sex and movement parameters. Emotion perception accuracy was positively associated with connectivity between amygdala seeds and regions primarily in the SEN and cognitive control network (CCN), and also the default mode network (DMN). Accuracy was also positively associated with connectivity between the sgACC seeds and other SEN regions, and the DMN, particularly for the right sgACC. Connectivity negatively associated with emotion perception was mostly with regions outside of these three networks, other than the left insula and part of the DMN. This study is the first to our knowledge to demonstrate relationships between facial emotion processing and resting-state connectivity with SEN nodes and between SEN nodes and regions located within other neural networks.     

Depression and God: The Effects of Major Depressive Disorder on Theology and Religious Identity

Major depressive disorder (MDD) has deep roots in brain function. Recent physiological research ties brain areas involved with depression to areas that process emotions. Among the research surveyed, a link was found between the activity levels of the prefrontal cortex (PFC), the orbitofrontal cortex (OFC), and parts of the anterior cingulate cortex (ACC). These links prove to be useful in understanding how an individual might have problems processing emotional experiences. This relates directly to how a person interacts in a religious environment. Religious leaders should share the physicians’ mantra of primum non nocere, which means “first, do no harm.” Skewed views of God can emerge from "gaps in understanding" related to topics such as sin, substance abuse, divine intimacy, and end-of-life questions.     

Affect and alcohol use: an ecological momentary assessment study of outpatients with borderline personality disorder

Alcohol use may be viewed as an attempt (albeit maladaptive) to regulate negative emotional states. We examined associations between both negative and positive affects and alcohol use in outpatient women diagnosed with borderline personality disorder (BPD; n=74), a prototype of emotional dysregulation, as well as a psychiatric control group of women with current depressive disorder (major depressive disorder/dysthymic disorder [MDD\DYS]; n=50). Participants completed randomly prompted reports of mood and alcohol use up to six times a day over a 28-day period using electronic diaries. Mean levels of either positive or negative affects did not distinguish between drinkers and nondrinkers in either diagnostic group. However, levels of both negative and positive affects were positively associated with alcohol use at the momentary level in BPD drinkers. More robust findings were obtained with respect to within-person affective variability, which was related to alcohol use in multiple ways. BPD drinkers showed higher within-person variability for most negative affects than BPD nondrinkers; MDD\DYS drinkers in general showed less within-person variability than MDD\DYS nondrinkers for negative affects. Multilevel lagged analyses for BPD drinkers indicated that alcohol use was positively related to variability in all affects, concurrently, but fewer significant effects of affect variability on the next day's drinking or significant effects of alcohol use on the next day's affect variability were observed. Among MDD\DYS drinkers, we observed more significant associations between affect variability on next day's alcohol use and of alcohol use on next day's affect variability. We discuss theoretical and methodological issues relevant to these findings as well as implications for future research.     

Ambulatory emotional reactivity to negative daily life events predicts remission from major depressive disorder

Major depressive disorder (MDD) is often associated with altered emotional reactivity. However, the functional significance of altered emotional reactivity in MDD is uncertain. This study was the first to examine the predictive relationship between intensely sampled ambulatory emotional reactivity and the clinical course of MDD. Forty-six outpatients who met criteria for MDD underwent six days of experience sampling of their ambulatory reactivity to everyday negative and positive life events. After experience sampling, all outpatients received pharmacotherapy with supportive psychotherapy and were followed clinically for 18 months. At one month, less emotional reactivity to negative and positive daily events predicted higher depressive symptom severity. Importantly, patients who exhibited less negative emotional reactivity to daily negative life events were less likely to recover from MDD over the 18 month follow-up. Relationships between ambulatory emotional reactivity and MDD course were not accounted for by the duration or the severity of initial MDD symptoms. Diminished ambulatory emotional reactivity appears to be functionally significant in depression. Intensive sampling of ambulatory emotions may have utility for predicting the clinical course of MDD.     

Emotional variability and clarity in depression and social anxiety

Recent research has underscored the importance of elucidating specific patterns of emotion that characterise mental disorders. We examined two emotion traits, emotional variability and emotional clarity, in relation to both categorical (diagnostic interview) and dimensional (self-report) measures of major depressive disorder (MDD) and social anxiety disorder (SAD) in women diagnosed with MDD only (n?=?35), SAD only (n?=?31), MDD and SAD (n?=?26) or no psychiatric disorder (n?=?38). Results of the categorical analyses suggest that elevated emotional variability and diminished emotional clarity are transdiagnostic of MDD and SAD. More specifically, emotional variability was elevated for MDD and SAD diagnoses compared to no diagnosis, showing an additive effect for co-occurring MDD and SAD. Similarly diminished levels of emotional clarity characterised all three clinical groups compared to the healthy control group. Dimensional findings suggest that although emotional variability is associated more consistently with depression than with social anxiety, emotional clarity is associated more consistently with social anxiety than with depression. Results are interpreted using a threshold and dose–response framework.     

Linking major depression and the neural substrates of associative processing

It has been proposed that mood correlates with the breadth of associative thinking. Here we set this hypothesis to the test in healthy and depressed individuals. Generating contextual associations engages a network of cortical regions including the parahippocampal cortex (PHC), retrosplenial complex, and medial prefrontal cortex. The link between mood, associative processing, and its underlying cortical infrastructure provides a promising avenue for elucidating the mechanisms underlying the cognitive impairments in major depressive disorder (MDD). The participants included 15 nonmedicated individuals with acute major depressive episodes and 15 healthy matched controls. In an fMRI experiment, participants viewed images of objects that were either strongly or weakly associated with a specific context (e.g., a beach chair vs. a water bottle) while rating the commonality of each object. Analyses were performed to examine the brain activation and structural differences between the groups. Consistent with our hypothesis, controls showed greater activation of the contextual associations network than did depressed participants. In addition, PHC structural volume was correlated with ruminative tendencies, and the volumes of the hippocampal subfields were significantly smaller in depressed participants. Surprisingly, depressed participants showed increased activity in the entorhinal cortex (ERC), as compared with controls. We integrated these findings within a mechanistic account linking mood and associative thinking and suggest directions for the future.     

Cognitive Insight in Inpatients with Psychotic, Bipolar, and Major Depressive Disorders

The Beck Cognitive Insight Scale (BCIS; Beck, Baruch, Balter, Steer, & Warman, 2004) was administered to 42 (28%) inpatients with psychotic disorders, 52 (35%) with a bipolar disorder, and 56 (37%) with a major depressive disorder (MDD). The hypotheses were (a) that the mean level of cognitive insight in a psychotic or a bipolar disorder is lower than that in a MDD, (b) that the mean levels of cognitive insight in psychotic and bipolar disorders were comparable, and (c) that the mean BCIS index score for a bipolar disorder in which the most recent episode had been mania is lower than the mean BCIS index score for a bipolar disorder in which the most recent episode had been mixed or depressed. All three hypotheses were supported. The results were discussed as supporting cognitive insight as a psychological construct that varies predictably according to the nature of a psychiatric disorder.     

The “Brightening” Effect: Reactions to Positive Events in the Daily Lives of Individuals With Major Depressive Disorder and Generalized Anxiety Disorder

Depressed individuals are less reactive than healthy individuals to positive stimuli in the laboratory, but accumulating evidence suggests that they are more emotionally reactive to positive events in their daily lives. The present study probed the boundaries of this curious “mood brightening” effect and investigated its specificity to major depressive disorder (MDD) vis-à-vis generalized anxiety disorder (GAD), its closest boundary condition. We used ecological momentary assessment to measure reactions to positive events over one week in individuals with MDD (n = 38), GAD (n = 36), comorbid MDD-GAD (n = 38), and no psychopathology (n = 33). Depressed individuals responded to positive events with larger changes in affect, cognition, reported withdrawal (but not approach) behavior, and symptoms than healthy controls. More severe depression assessed before the sampling week predicted greater brightening. Altered reactivity to positive events was relatively specific to MDD when compared with GAD, similar to patterns found for other positive emotional processes. The robustness, scope, and relative specificity of the brightening effect highlights the need to resolve conflicting findings across laboratory and non-laboratory studies to advance understanding of altered reactivity in emotional disorders.     

Structural-functional correlations between hippocampal volume and cortico-limbic emotional responses in depressed children

Although hippocampal atrophy and altered functional brain responses to emotional stimuli have been found in major depressive disorder (MDD), the relationship between the two is not yet well understood. The present study focused on children with and without a history of preschool onset MDD (PO-MDD) and directly examined the relations between hippocampal volume and functional brain activation to affect-eliciting stimuli. Children completed annual diagnostic assessments starting at preschool. When children were school-aged, high-resolution structural MRI and task-related functional MRI data were acquired from N = 64 nonmedicated children. During fMRI, subjects were shown emotional faces. Results from the total sample indicated that smaller bilateral hippocampal volumes were associated with greater cortico-limbic (e.g., amygdala, hippocampus, dorsolateral prefrontal cortex) activation to sad or negative faces versus neutral faces. Left hippocampal volume was negatively associated with the cortico-limbic activation in both the PO-MDD and healthy children. Right hippocampal volume was negatively correlated with amygdala responses in the PO-MDD group, but not in the healthy comparison group. These findings suggest that there may be important interrelationships between reduced hippocampal volume and hyperactivation of brain responses in children, both those with and those without a history of PO-MDD.     

Unexpected reduction in migraine and psychogenic headaches following rTMS treatment for major depression: a report of two cases

Our objective is to report a coincident reduction in headache pain in patients treated with repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD). Two patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, non-responsive to prior antidepressant treatment who were enrolled in a sham-controlled, double-blind study of rTMS for MDD. After the study, it was revealed that both were in the active-treatment arm. Both patients suffered from near daily headaches and kept logs of headache frequency and severity before, during, and after the study. Headache pain was significantly reduced under double-blind conditions with rTMS treatment, but returned to baseline following cessation of rTMS treatment. Ultimately, when receiving rTMS post-study as a maintenance intervention for MDD (approximately 2 rTMS sessions/week), the positive effects on headache amelioration were sustained. Headache pain is frequently comorbid with mood disorders and has been reported as the most common side effect with rTMS. In these subjects, rTMS was, in fact, associated with relief of depressive symptoms and preexisting headache pain. This indicates that rTMS may be beneficial for both disorders in some patients.     

The Relationship Among Child Maltreatment,Parental Bonding,and a Lifetime History of Major Depressive Disorder in Latino College Students

This study examined the relationship among child maltreatment, parental bonding, and a lifetime history of major depressive disorder (MDD) in a sample of 119 Latino students. Forty-five students reported a lifetime history of MDD and 74 reported not having a lifetime history of MDD. The results indicated that emotional abuse and maternal overprotection were significantly associated with having a lifetime history of MDD. The findings support the importance of examining these factors among depressed Latinos. Future research should continue to explore both the role of child maltreatment and parental bonding in relation to a lifetime history of MDD in this population.