Elevated Amygdala Activity to Sad Facial Expressions: A State Marker of Bipolar but Not Unipolar Depression

Background: Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BID depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BID and MDD depression. Methods: Sixty adults were recruited: 15 depressed with BID type 1 (BDd), 15 depressed with recurrent MDD, 15 with BID in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results: The BDd-relative to HC, BDr, and MDD-showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions: Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BID but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

Background: Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods: Thirty-one depressed individuals-15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18-55 years, matched for age, age of illness onset, illness duration, and depression severity-and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results: During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions: Abnormal, left-sided, top-down OMPFC-amygdala and right-sided, bottom-up, amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Personality traits are associated with acute major depression across the age spectrum.

Objectives: Psychological predictors, such as personality traits, have aroused growing interest as possible predictors of late-life depression outcome in old age. It remains, however, unclear whether the cross-sectional relationship between personality traits and depression occurrence reported in younger samples is also present in the elderly. Methods: Comparisons amongst 79 outpatients with DSM-IV major depression and 102 healthy controls included assessment of the five-factor model of personality (NEO PI-R), socio-demographic variables, physical health status, as well as depression features. Two sub-groups were considered, defined as young (25-50 years) and old (60-85 years) patients. Results: Depressed patients showed significantly higher levels of Neuroticism and lower levels of Extraversion, Openness to Experience and Conscientiousness compared to controls. Sequential logistic regression models confirmed that the combination of increased physical burden, levels of dependency, and increased Neuroticism strongly predicts the occurrence of acute depressive symptoms. In contrast, the levels of Neuroticism did not allow for differentiating late-life from young age depression. Increased physical burden and decreased depression severity were the main predictors for this distinction. Conclusion: Our data indicate that personality factors and depression are related, independently of patients' age. Differences in this relationship are mainly due to the intensity of depressive symptoms rather than the patients' life period. They also stress the need to consider physical health, level of dependency and severity of symptoms when studying the relationship between personality traits and mood disorders.

Cost-effectiveness of a preventive counseling and support package for postnatal depression

Objectives: This study reports the cost-effectiveness of a preventive intervention, consisting of counseling and specific support for the mother-infant relationship, targeted at women at high risk of developing postnatal depression. Methods: A prospective economic evaluation was conducted alongside a pragmatic randomized controlled trial in which women considered at high risk of developing postnatal depression were allocated randomly to the preventive intervention (n = 74) or to routine primary care (n = 77). The primary outcome measure was the duration of postnatal depression experienced during the first 18 months postpartum. Data on health and social care use by women and their infants up to 18 months postpartum were collected, using a combination of prospective diaries and face-to-face interviews, and then were combined with unit costs ( pound, year 2000 prices) to obtain a net cost per mother-infant dyad. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics at alternative willingness to pay thresholds held by decision makers for preventing 1 month of postnatal depression. Results: Women in the preventive intervention group were depressed for an average of 2.21 months (9.57 weeks) during the study period, whereas women in the routine primary care group were depressed for an average of 2.70 months (11.71 weeks). The mean health and social care costs were estimated at 2,396.9 pound per mother-infant dyad in the preventive intervention group and 2,277.5 pound per mother-infant dyad in the routine primary care group, providing a mean cost difference of 119.5 pound (bootstrap 95 percent confidence interval [Cl], -535.4, 784.9). At a willingness to pay threshold of 1,000 pound per month of postnatal depression avoided, the probability that the preventive intervention is cost-effective is .71 and the mean net benefit is 383.4 pound (bootstrap 95 percent Cl, -863.3- pound 1,581.5) pound. Conclusions: The preventive intervention is likely to be cost-effective even at relatively low willingness to pay thresholds for preventing 1 month of postnatal depression during the first 18 months postpartum. Given the negative impact of postnatal depression on later child development, further research is required that investigates the longer-term cost-effectiveness of the preventive intervention in high risk women.

Effect of pair interactions on transition probabilities between inactive and active states: achieving collective behaviour via pair interactions in social insects

To understand the evolution of well-organized social behaviour, we must first understand the mechanism by which collective behaviour establishes. In this study, the mechanisms of collective behaviour in a colony of social insects were studied in terms of the transition probability between active and inactive states, which is linked to mutual interactions. The active and inactive states of the social insects were statistically extracted from the velocity profiles. From the duration distributions of the two states, we found that 1) the durations of active and inactive states follow an exponential law, and 2) pair interactions increase the transition probability from inactive to active states. The regulation of the transition probability by paired interactions suggests that such interactions control the populations of active and inactive workers in the colony.

Human Stem Cell Cultures from Cleft Lip/Palate Patients Show Enrichment of Transcripts Involved in Extracellular Matrix Modeling By Comparison to Controls

Nonsyndromic cleft lip and palate (NSCL/P) is a complex disease resulting from failure of fusion of facial primordia, a complex developmental process that includes the epithelial-mesenchymal transition (EMT). Detection of differential gene transcription between NSCL/P patients and control individuals offers an interesting alternative for investigating pathways involved in disease manifestation. Here we compared the transcriptome of 6 dental pulp stem cell (DPSC) cultures from NSCL/P patients and 6 controls. Eighty-seven differentially expressed genes (DEGs) were identified. The most significant putative gene network comprised 13 out of 87 DEGs of which 8 encode extracellular proteins: ACAN, COL4A1, COL4A2, GDF15, IGF2, MMP1, MMP3 and PDGFa. Through clustering analyses we also observed that MMP3, ACAN, COL4A1 and COL4A2 exhibit co-regulated expression. Interestingly, it is known that MMP3 cleavages a wide range of extracellular proteins, including the collagens IV, V, IX, X, proteoglycans, fibronectin and laminin. It is also capable of activating other MMPs. Moreover, MMP3 had previously been associated with NSCL/P. The same general pattern was observed in a further sample, confirming involvement of synchronized gene expression patterns which differed between NSCL/P patients and controls. These results show the robustness of our methodology for the detection of differentially expressed genes using the RankProd method. In conclusion, DPSCs from NSCL/P patients exhibit gene expression signatures involving genes associated with mechanisms of extracellular matrix modeling and palate EMT processes which differ from those observed in controls. This comparative approach should lead to a more rapid identification of gene networks predisposing to this complex malformation syndrome than conventional gene mapping technologies.

QUASISTATIONARY DISTRIBUTIONS AND FLEMING-VIOT PROCESSES IN FINITE SPACES

Consider a continuous-time Markov process with transition rates matrix Q in the state space Lambda boolean OR {0}. In In the associated Fleming-Viot process N particles evolve independently in A with transition rates matrix Q until one of them attempts to jump to state 0. At this moment the particle jumps to one of the positions of the other particles, chosen uniformly at random. When Lambda is finite, we show that the empirical distribution of the particles at a fixed time converges as N -> infinity to the distribution of a single particle at the same time conditioned on not touching {0}. Furthermore, the empirical profile of the unique invariant measure for the Fleming-Viot process with N particles converges as N -> infinity to the unique quasistationary distribution of the one-particle motion. A key element of the approach is to show that the two-particle correlations are of order 1/N.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

Managing server energy and reducing operational cost for online service providers

The past decade has seen the energy consumption in servers and Internet Data Centers (IDCs) skyrocket. A recent survey estimated that the worldwide spending on servers and cooling have risen to above $30 billion and is likely to exceed spending on the new server hardware . The rapid rise in energy consumption has posted a serious threat to both energy resources and the environment, which makes green computing not only worthwhile but also necessary. This dissertation intends to tackle the challenges of both reducing the energy consumption of server systems and by reducing the cost for Online Service Providers (OSPs). Two distinct subsystems account for most of IDC’s power: the server system, which accounts for 56% of the total power consumption of an IDC, and the cooling and humidifcation systems, which accounts for about 30% of the total power consumption. The server system dominates the energy consumption of an IDC, and its power draw can vary drastically with data center utilization. In this dissertation, we propose three models to achieve energy effciency in web server clusters: an energy proportional model, an optimal server allocation and frequency adjustment strategy, and a constrained Markov model. The proposed models have combined Dynamic Voltage/Frequency Scaling (DV/FS) and Vary-On, Vary-off (VOVF) mechanisms that work together for more energy savings. Meanwhile, corresponding strategies are proposed to deal with the transition overheads. We further extend server energy management to the IDC’s costs management, helping the OSPs to conserve, manage their own electricity cost, and lower the carbon emissions. We have developed an optimal energy-aware load dispatching strategy that periodically maps more requests to the locations with lower electricity prices. A carbon emission limit is placed, and the volatility of the carbon offset market is also considered. Two energy effcient strategies are applied to the server system and the cooling system respectively. With the rapid development of cloud services, we also carry out research to reduce the server energy in cloud computing environments. In this work, we propose a new live virtual machine (VM) placement scheme that can effectively map VMs to Physical Machines (PMs) with substantial energy savings in a heterogeneous server cluster. A VM/PM mapping probability matrix is constructed, in which each VM request is assigned with a probability running on PMs. The VM/PM mapping probability matrix takes into account resource limitations, VM operation overheads, server reliability as well as energy effciency. The evolution of Internet Data Centers and the increasing demands of web services raise great challenges to improve the energy effciency of IDCs. We also express several potential areas for future research in each chapter.

White matter microstructure alterations of the medial forebrain bundle in melancholic depression

BACKGROUND The medial forebrain bundle (MFB) is a key structure of the reward system and connects the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortex (mOFC, lOFC) and the dorsolateral prefrontal cortex (dlPFC). Previous diffusion tensor imaging (DTI) studies in major depressive disorder point to white matter alterations of regions which may be incorporated in the MFB. Therefore, it was the aim of our study to probe white matter integrity of the MFB using a DTI-based probabilistic fibre tracking approach. METHODS 22 patients with major depressive disorder (MDD) (12 melancholic-MDD patients, 10 non-melancholic-MDD patients) and 21 healthy controls underwent DTI scans. We used a bilateral probabilistic fibre tracking approach to extract pathways between the VTA and NACC, mOFC, lOFC, dlPFC respectively. Mean fractional anisotropy (FA) values were used to compare structural connectivity between groups. RESULTS Mean-FA did not differ between healthy controls and all MDD patients. Compared to healthy controls melancholic MDD-patients had reduced mean-FA in right VTA-lOFC and VTA-dlPFC connections. Furthermore, melancholic-MDD patients had lower mean-FA than non-melancholic MDD-patients in the right VTA-lOFC connection. Mean-FA of these pathways correlated negatively with depression scale rating scores. LIMITATIONS Due to the small sample size and heterogeneous age group comparisons between melancholic and non-melancholic MDD-patients should be regarded as preliminary. CONCLUSIONS Our results suggest that the melancholic subtype of MDD is characterized by white matter microstructure alterations of the MFB. White matter microstructure is associated with both depression severity and anhedonia.

Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients.

Repetitive transcranial magnetic stimulation (rTMS) is a recent putative treatment for affective disorders. Several studies have demonstrated antidepressant effects of rTMS in younger patients; we aimed to assess its effect in older outpatients with treatment-resistant major depression. Twenty-four outpatients (mean age=62 years, S.D.=12) with major depression were randomized for sham or real stimulation and received 10 daily rTMS sessions (20 Hz, 2-s trains, 28-s intertrain intervals, 100% of motor threshold) in addition to the antidepressant medication. For sham stimulation, the coil was tilted 90 degrees. Depression severity was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, items from the NIMH self-rated symptom scale, and a visual analog depression scale. Mini-Mental Status Examination performance, memory, and executive and attentional functions were measured to control for cognitive side effects. Depression ratings revealed significant antidepressant effects within 2 weeks in both sham and real stimulation groups; however, there were no between-group differences. Treatment with rTMS was safe; adverse events were rare and not more prevalent in either group, and cognitive assessment did not show any deterioration. We were unable to demonstrate any additional antidepressant effects of real stimulation in elderly patients with treatment-resistant major depression. Therapeutic effects of rTMS in this clinically challenging patient group remain to be demonstrated.

Olfactory bulb volume predicts therapeutic outcome in major depression disorder

The volume of the olfactory bulb (OB) is strongly reduced in patients with major depressive disorder (MDD) and this group exhibits markedly decreased olfactory function. It has been suggested that olfactory input is important for maintaining balance in limbic neurocircuits. The aim of our study was to investigate whether reduced OB volume is associated with response to therapy in MDD. Twenty-four inpatients (all women, age 21-49 years, mean 38 ± 10 years SD) with MDD and 36 healthy controls (all women, age 20-52 years, mean 36 ± 10 years SD) underwent structural MRI. OB volume was compared between responders (N = 13) and non-responders (N = 11) to psychotherapy. Retest of OB volume was performed about 6 months after the end of therapy in nine of the patients. Therapy responders exhibited no significant difference in OB volume compared to healthy controls. However, average OB volume of non-responders was 23 % smaller compared to responders (p = .0011). Furthermore, OB volume was correlated with the change of depression severity (r = .46, p = .024). Volume of the OB did not change in the course of therapy. OB volume may be a biological vulnerability factor for the occurrence and/or maintenance of depression, at least in women.

Elevated amygdala activity to sad facial expressions:a state marker of bipolar but not unipolar depression

Background - Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression. Methods - Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results - The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions - Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression

Objectives - The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods - We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results - There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F = 9.8; p = .05, corrected). Whole brain post hoc analyses (all t = 4.2; p = .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions - White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

Impaired sustained attention and executive dysfunction:bipolar disorder versus depression-specific markers of affective disorders

Objective - To identify neurocognitive measures that could be used as objective markers of bipolar disorder. Methods - We examined executive function, sustained attention and short-term memory as neurocognitive domains in 18 participants with bipolar disorder in euthymic state (Beuth), 14 in depressed state (Bdep), 20 with unipolar depression (Udep) and 28 healthy control participants (HC). We conducted four-group comparisons followed by relevant post hoc analyses. Results - Udep and Bdep, but not Beuth showed impaired executive function (p = 0.045 and p = 0.046, respectively). Both Bdep and Beuth, but not Udep, showed impaired sustained attention (p = 0.001 and p = 0.045, respectively). The four groups did not differ significantly on short-term memory. Impaired sustained attention and executive dysfunction were not associated with depression severity, duration of illness and age of illness onset. Only a small number of abnormal neurocognitive measures were associated with medication in Bdep and Beuth. Conclusion - Impaired sustained attention appears specific to bipolar disorder and present in both Beuth and Bdep; it may represent an objective marker of bipolar disorder. Executive dysfunction by contrast, appears to be present in Udep and Bdep and likely represents a marker of depression.