Clinical and Physiological Correlates of Irritability in Depression: Results from the Netherlands Study of Depression and Anxiety

Objective. Irritable and nonirritable depressed patients differ on demographic and clinical characteristics. We investigated whether this extends to psychological and physiological measures. Method. We compared irritable and nonirritable unipolar depressed patients on symptomatology, personality, and (psycho)physiological measures (cortisol, cholesterol, and heart rate variability). Symptomatology was reassessed after one year, and we also compared depressed patients who were irritable or non-irritable at both time points (Irr++ versus Irr−−). Results. Almost half (46%; N = 420) of the sample was classified as irritable. These patients scored higher on depression severity, anxiety, hypomanic symptoms, and psychological variables. No differences were observed on physiological markers after correction for depression severity. The same pattern was found when comparing Irr++ and Irr−− groups. Conclusion. Irritable and non-irritable depressed patients differ on clinical and psychological variables, but not on the currently investigated physiological markers. The clinical relevance of the distinction and the significance of the hypomanic symptoms remain to be demonstrated

Orbitofrontal gray matter relates to early morning awakening: a neural correlate of insomnia complaints?

Sleep complaints increase profoundly with age; prevalence estimates of insomnia in elderly people reach up to 37%. The three major types of nocturnal complaints are difficulties initiating sleep (DIS), difficulties maintaining sleep (DMS) and early morning awakening (EMA), of which the latter appears most characteristic for aging. The neural correlates associated with these complaints have hardly been investigated, hampering the development of rational treatment and prevention. A recent study on structural brain correlates of insomnia showed that overall severity, but not duration, of insomnia complaints is associated with lower gray matter (GM) density in part of the left orbitofrontal cortex. Following up on this, we investigated, in an independent sample of people not diagnosed with insomnia, whether individual differences in GM density are associated with differences in DIS, DMS and EMA.65 healthy participants filled out questionnaires and underwent structural magnetic resonance imaging. Three compound Z-scores were computed for questionnaire items relating to DIS, DMS and EMA. Whole-brain voxel-based morphometry was used to investigate their association with GM density. Results show that participants with lower GM density in a region where the left inferior orbitofrontal cortex borders the insula report more EMA, but not DIS or DMS.This is the first study to investigate structural brain correlates of specific sleep characteristics that can translate into complaints in insomniacs. The selective association of EMA with orbitofrontal GM density makes our findings particularly relevant to elderly people, where EMA represents the most characteristic complaint. It is hypothesized that low GM density in aforementioned orbitofrontal area affects its role in sensing comfort. An intact ability to evaluate comfort may be crucial to maintain sleep, especially at the end of the night when sleep is vulnerable because homeostatic sleep propensity has dissipated

Resting-State Functional Connectivity Characteristics of Resilience to Traumatic Stress in Dutch Police Officers

BackgroundInsights into the neurobiological basis of resilience can have important implications for the prevention and treatment of stress-related disorders, especially in populations that are subjected to high-stress environments. Evaluating large-scale resting-state networks (RSNs) can provide information regarding resilient specific brain function which may be useful in understanding resilience. This study aimed to explore functional connectivity patterns specific for (high) resilience in Dutch policemen after exposure to multiple work-related traumatic events. We investigated resting-state functional connectivity (RSFC) of the salience network (SN), limbic network, and the default-mode network (DMN).MethodsResting-state functional MRI scans were obtained from trauma-exposed executive personnel of the Dutch police force and non-trauma-exposed recruits from the police academy. Participants were divided into three groups: a resilient group (n = 31; trauma exposure; no psychopathology), a vulnerable group (n = 32; trauma exposure, psychopathology), and a control group (n = 19; no trauma exposure, no psychopathology). RSFC of the three networks of interest was compared between these groups, using an independent component analysis and a dual regression approach.ResultsWe found decreased resilience-specific positive RSFC of the salience network with several prefrontal regions. The DMN and limbic network RFSC did not show resilience-specific patterns.ConclusionThis study shows a differential RSFC specific for resilient police officers. This differential RSFC may be related to a greater capacity for internal-focused thought and interoceptive awareness, allowing more effective higher-order responses to stress in highly resilient individuals

Associations between depression, lifestyle and brain structure:A longitudinal MRI study

Background: Depression has been associated with decreased regional grey matter volume, which might partly be explained by an unhealthier lifestyle in depressed individuals which has been ignored by most earlier studies. Also, the longitudinal nature of depression, lifestyle and brain structure associations is largely unknown. This study investigates the relationship of depression and lifestyle with brain structure cross-sectionally and longitudinally over up to 9 years. Methods: We used longitudinal structural MRI data of persons with depression and/or anxiety disorders and controls (Nunique participants = 347, Nobservations = 609). Cortical thickness of medial orbitofrontal cortex (mOFC), rostral anterior cingulate cortex (rACC) and hippocampal volume were derived using FreeSurfer. Using Generalized Estimating Equations, we investigated associations of depression and lifestyle (Body mass index (BMI), smoking, alcohol consumption, physical activity and sleep duration) with brain structure and change in brain structure over 2 (n = 179) and 9 years (n = 82). Results: Depression status (B = -.053, p = .002) and severity (B = -.002, p = .002) were negatively associated with rACC thickness. mOFC thickness was negatively associated with BMI (B = -.004, p < .001) and positively with moderate alcohol consumption (B = .030, p = .009). All associations were independent of each other. No associations were observed between (change in) depression, disease burden or lifestyle factors with brain change over time. Conclusions: Depressive symptoms and diagnosis were independently associated with thinner rACC, BMI with thinner mOFC, and moderate alcohol consumption with thicker mOFC. No longitudinal associations were observed, suggesting that regional grey matter alterations are a long-term consequence or vulnerability indicator for depression but not dynamically or progressively related to depression course trajectory

On the connection between level of education and the neural circuitry of emotion perception

Through education, a social group transmits accumulated knowledge, skills, customs, and values to its members. So far, to the best of our knowledge, the association between educational attainment and neural correlates of emotion processing has been left unexplored. In a retrospective analysis of The Netherlands Study of Depression and Anxiety (NESDA) functional magnetic resonance imaging (fMRI) study, we compared two groups of fourteen healthy volunteers with intermediate and high educational attainment, matched for age and gender. The data concerned event-related fMRI of brain activation during perception of facial emotional expressions. The region of interest (ROI) analysis showed stronger right amygdala activation to facial expressions in participants with lower relative to higher educational attainment (HE). The psychophysiological interaction analysis revealed that participants with HE exhibited stronger right amygdala-right insula connectivity during perception of emotional and neutral facial expressions. This exploratory study suggests the relevance of educational attainment on the neural mechanism of facial expressions processing

White matter architecture in major depression with anxious distress symptoms

Background: Comorbid anxious distress is common in Major Depressive Disorder (MDD), and associated with significantly worse clinical course and treatment response. While DSM-5 recently introduced the Anxious Distress (AD) specifier as a potentially useful symptom-based subtyping scheme for MDD, its neurobiological underpinnings remain unclear. The current study hence uniquely probed whether MDD with co-occurring AD (MDD/AD+) relates to distinct perturbations in frontolimbic white matter (WM) pathways tentatively theorized in MDD/AD+ pathophysiology. Methods: Tract-based spatial statistics (TBSS) was therefore used to analyze diffusion tensor imaging data on WM microstructure, in MDD/AD+ patients (N = 20) relative to MDD patients without AD (MDD/AD-; N = 29) and healthy controls (HC; N = 39). Using TBSS, we probed fractional anisotropy and axial/radial/mean diffusivity as proxies for WM integrity. Categorical (between-groups) and dimensional (within-patients) analyses subsequently assessed how Anxious Distress in MDD impacts frontolimbic WM connectivity. Receiver-Operating Characteristics additionally assessed classification capabilities of between-groups WM effects. Results: Compared to MDD/AD- and HC participants, MDD/AD+ patients exhibited diminished integrity within the anterior thalamic radiation (ATR). Higher AD specifier scores within MDD patients additionally related to diminished integrity of the uncinate fasciculus and cingulum pathways. These effects were not confounded by key clinical (e.g., comorbid anxiety disorder) and sociodemographic (e.g., age/sex) factors, with altered ATR integrity moreover successfully classifying MDD/AD+ patients from MDD/AD- and HC participants (90% sensitivity vertical bar 73% specificity vertical bar 77% accuracy). Conclusions: These findings collectively link MDD/AD+ to distinct WM anomalies in frontolimbic tracts important to adaptive emotional functioning, and may as such provide relevant, yet preliminary, clues on MDD/AD+ pathophysiology

Longitudinal brain changes in MDD during emotional encoding:effects of presence and persistence of symptomatology

The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are state-dependent and whether they are affected by the persistence of depressive symptoms.Methods Thirty-nine patients with major depressive disorder and 28 healthy controls were included from the longitudinal functional magnetic resonance imaging (fMRI) sub-study of the Netherlands Study of Depression and Anxiety. Participants performed an emotional word-encoding and -recognition task during fMRI at baseline and 2-year follow-up measurement. At baseline, all patients were in a depressed state. We investigated state-dependency by relating changes in brain activation over time to changes in symptom severity. Furthermore, the effect of time spent with depressive symptoms in the 2-year interval was investigated.Results Symptom change was linearly associated with higher activation over time of the left anterior hippocampus extending to the amygdala during positive and negative word-encoding. Especially during positive word encoding, this effect was driven by symptomatic improvement. There was no effect of time spent with depression in the 2-year interval on change in brain activation. Results were independent of medication- and psychotherapy-use.Conclusion Using a longitudinal within-subjects design, we showed that hippocampal-amygdalar activation during emotional memory formation is related to depressive symptom severity but not persistence (i.e. time spent with depression or 'load'), suggesting functional activation patterns in depression are not subject to functional 'scarring' although this hypothesis awaits future replication

Default Mode Network Connectivity and Social Dysfunction in Major Depressive Disorder

Though social functioning is often hampered in Major Depressive Disorder (MDD), we lack a complete and integrated understanding of the underlying neurobiology. Connectional disturbances in the brain’s Default Mode Network (DMN) might be an associated factor, as they could relate to suboptimal social processing. DMN connectional integrity, however, has not been explicitly studied in relation to social dysfunctioning in MDD patients. Applying Independent Component Analysis and Dual Regression on resting-state fMRI data, we explored DMN intrinsic functional connectivity in relation to social dysfunctioning (i.e. composite of loneliness, social disability, small social network) among 74 MDD patients (66.2% female, Mean age = 36.9, SD = 11.9). Categorical analyses examined whether DMN connectivity differs between high and low social dysfunctioning MDD groups, dimensional analyses studied linear associations between social dysfunction and DMN connectivity across MDD patients. Threshold-free cluster enhancement (TFCE) with family-wise error (FWE) correction was used for statistical thresholding and multiple comparisons correction (P < 0.05). The analyses cautiously linked greater social dysfunctioning among MDD patients to diminished DMN connectivity, specifically within the rostromedial prefrontal cortex and posterior superior frontal gyrus. These preliminary findings pinpoint DMN connectional alterations as potentially germane to social dysfunction in MDD, and may as such improve our understanding of the underlying neurobiology

Whole brain resting-state analysis reveals decreased functional connectivity in major depression

Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within six months before inclusion) and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxelwise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: 1) decreased bilateral amygdala and left anterior insula connectivity in an affective network, 2) reduced connectivity of the left frontal pole in a network associated with attention and working memory, and 3) decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or grey matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder

Beta receptor-mediated modulation of the late positive potential in humans

RATIONALE Electrophysiological studies have identified a scalp potential, the late positive potential (LPP), which is modulated by the emotional intensity of observed stimuli. Previous work has shown that the LPP reflects the modulation of activity in extrastriate visual cortical structures, but little is known about the source of that modulation. OBJECTIVES The present study investigated whether beta-adrenergic receptors are involved in the generation of the LPP. METHODS We used a genetic individual differences approach (experiment 1) and a pharmacological manipulation (experiment 2) to test the hypothesis that the LPP is modulated by the activation of β-adrenergic receptors. RESULTS In experiment 1, we found that LPP amplitude depends on allelic variation in the β1-receptor gene polymorphism. In experiment 2, we found that LPP amplitude was modulated by the β-blocker propranolol in a direction dependent on subjects' level of trait anxiety: In participants with lower trait anxiety, propranolol led to a (nonsignificant) decrease in the LPP modulation; in participants with higher trait anxiety, propranolol increased the emotion-related LPP modulation. CONCLUSIONS These results provide initial support for the hypothesis that the LPP reflects the downstream effects, in visual cortical areas, of β-receptor-mediated activation of the amygdala.Stress-related psychiatric disorders across the life spa