Attentional bias in individuals with depression and adverse childhood experiences: influence of the noradrenergic system?

Rationale: Major depressive disorder (MDD) is a severe mental disorder with affective, cognitive, and somatic symptoms. Mood congruent cognitive biases, including a negative attentional bias, are important for development, maintenance, and recurrence of depressive symptoms. MDD is associated with maladaptive changes in the biological stress systems such as dysregulations of central noradrenergic alpha2-receptors in the locus coeruleus-noradrenergic system, which can affect cognitive processes including attention. Patients with adverse childhood experiences (ACE), representing severe stress experiences in early life, might be particularly affected. Objectives: With an experimental design, we aimed to gain further knowledge about the role of noradrenergic activity for attentional bias in MDD patients with and without ACE. Methods: We tested the effect of increased noradrenergic activity induced by the alpha2-receptor blocker yohimbine on attentional bias in a placebo-controlled repeated measures design. Four groups were included as follows: MDD patients with and without ACE, and healthy participants with and without ACE (total N = 128, all without antidepressant medication). Results: A significant effect of MDD on attentional bias scores of sad face pictures (p = .037) indicated a facilitated attentional processing of sad face pictures in MDD patients (compared to non-MDD individuals). However, we found no such effect of ACE. For attentional bias of happy face pictures, we found no significant effects of MDD and ACE. Even though a higher increase of blood pressure and salivary alpha-amylase following yohimbine compared to placebo indicated successful noradrenergic stimulation, we found no significant effects of yohimbine on attentional bias of happy or sad face pictures. Conclusions: Our results are consistent with the hypothesis of a negative attentional bias in MDD patients. However, as we found no effect of ACE or yohimbine, further research is needed to understand the mechanisms by which ACE increases the risk of MDD and to understand the biological basis of the MDD-related negative attentional bias

Directional recordings of somatosensory evoked potentials from the sensory thalamus in chronic poststroke pain patients.

OBJECTIVE The aim of this feasibility study was to investigate the properties of median nerve somatosensory evoked potential (SEPs) recorded from segmented Deep Brain Stimulation (DBS) leads in the sensory thalamus (VP) and how they relate to clinical and anatomical findings. METHODS We analyzed four patients with central post-stroke pain and DBS electrodes placed in the VP. Median nerve SEPs were recorded with referential and bipolar montages. Electrode positions were correlated with thalamus anatomy and tractography-based medial lemniscus. Early postoperative clinical paresthesia mapping was performed by an independent pain nurse. Finally, we performed frequency and time-frequency analyses of the signals. RESULTS We observed differences of SEP amplitudes recorded along different directions in the VP. SEP amplitudes did not clearly correlate to both atlas-based anatomical position and fiber-tracking results of the medial lemniscus. However, the contacts of highest SEP amplitude correlated with the contacts of lowest effect-threshold to induce paraesthesia. CONCLUSIONS SEP recordings from directional DBS leads offer additional information about the neurophysiological (re)organization of the sensory thalamus. SIGNIFICANCE Directional recordings of thalamic SEPs bear the potential to assist clinical decision-making in DBS for pain

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age- and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others’ emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD

Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1 beta, or TNF-alpha. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes

Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1 beta, or TNF-alpha. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes

HR-MAS NMR based quantitative metabolomics in breast cancer

High resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy is increasingly used for profiling of breast cancer tissue, delivering quantitative information for approximately 40 metabolites. One unique advantage of the method is that it can be used to analyse intact tissue, thereby requiring only minimal sample preparation. Importantly, since the method is non-destructive, it allows further investigations of the same specimen using for instance transcriptomics. Here, we discuss technical aspects critical for a successful analysis—including sample handling, measurement conditions, pulse sequences for one- and two dimensional analysis, and quantification methods—and summarize available studies, with a focus on significant associations of metabolite levels with clinically relevant parameters

The Draft Assembly of the Radically Organized Stylonychia lemnae Macronuclear Genome.

Stylonychia lemnae is a classical model single-celled eukaryote, and a quintessential ciliate typified by dimorphic nuclei: A small, germline micronucleus and a massive, vegetative macronucleus. The genome within Stylonychia's macronucleus has a very unusual architecture, comprised variably and highly amplified "nanochromosomes," each usually encoding a single gene with a minimal amount of surrounding noncoding DNA. As only a tiny fraction of the Stylonychia genes has been sequenced, and to promote research using this organism, we sequenced its macronuclear genome. We report the analysis of the 50.2-Mb draft S. lemnae macronuclear genome assembly, containing in excess of 16,000 complete nanochromosomes, assembled as less than 20,000 contigs. We found considerable conservation of fundamental genomic properties between S. lemnae and its close relative, Oxytricha trifallax, including nanochromosomal gene synteny, alternative fragmentation, and copy number. Protein domain searches in Stylonychia revealed two new telomere-binding protein homologs and the presence of linker histones. Among the diverse histone variants of S. lemnae and O. trifallax, we found divergent, coexpressed variants corresponding to four of the five core nucleosomal proteins (H1.2, H2A.6, H2B.4, and H3.7) suggesting that these ciliates may possess specialized nucleosomes involved in genome processing during nuclear differentiation. The assembly of the S. lemnae macronuclear genome demonstrates that largely complete, well-assembled highly fragmented genomes of similar size and complexity may be produced from one library and lane of Illumina HiSeq 2000 shotgun sequencing. The provision of the S. lemnae macronuclear genome sets the stage for future detailed experimental studies of chromatin-mediated, RNA-guided developmental genome rearrangements

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-angstrom sberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences

Mutations in the von Hippel-Lindau Tumour Suppressor Gene in Central Nervous System Hemangioblastomas

Central nervous system hemangioblastomas (cHAB) are rare tumours which most commonly arise in the cerebellum. Most tumours are sporadic, but as many as one third of cHABs occur in the course of the hereditary disorder - von Hippel-Lindau disease (VHL). In order to diagnose new VHL families in Poland we performed sequencing of the entire VHL gene in archival material (paraffin embedded hemangioblastoma tissues) in a large series of 203 unselected patients with cHAB. VHL gene mutations were detected in 70 (41%) of 171 tumour samples from which DNA of relatively good quality was isolated. We were able to obtain blood samples from 19 of mutation positive cases. Eight (42%) of these harboured germline mutations in persons from distinct undiagnosed VHL families