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Repeated hospitalizations are a characteristic of severe disease courses in patients with affective disorders (PAD). To elucidate how a hospitalization during a nine-year follow-up in PAD affects brain structure, a longitudinal case-control study (mean [SD] follow-up period 8.98 [2.20] years) was conducted using structural neuroimaging. We investigated PAD (N = 38) and healthy controls (N = 37) at two sites (University of Münster, Germany, Trinity College Dublin, Ireland). PAD were divided into two groups based on the experience of in-patient psychiatric treatment during follow-up. Since the Dublin-patients were outpatients at baseline, the re-hospitalization analysis was limited to the Münster site (N = 52). Voxel-based morphometry was employed to examine hippocampus, insula, dorsolateral prefrontal cortex and whole-brain gray matter in two models: (1) group (patients/controls)×time (baseline/follow-up) interaction; (2) group (hospitalized patients/not-hospitalized patients/controls)×time interaction. Patients lost significantly more whole-brain gray matter volume of superior temporal gyrus and temporal pole compared to HC (p FWE  = 0.008). Patients hospitalized during follow-up lost significantly more insular volume than healthy controls (p FWE  = 0.025) and more volume in their hippocampus compared to not-hospitalized patients (p FWE  = 0.023), while patients without re-hospitalization did not differ from controls. These effects of hospitalization remained stable in a smaller sample excluding patients with bipolar disorder. PAD show gray matter volume decline in temporo-limbic regions over nine years. A hospitalization during follow-up comes with intensified gray matter volume decline in the insula and hippocampus. Since hospitalizations are a correlate of severity, this finding corroborates and extends the hypothesis that a severe course of disease has detrimental long-term effects on temporo-limbic brain structure in PAD., (© 2023. The Author(s).)

The role of the amygdala in the experience of emotional states and stress is well established. Connections from the amygdala to the hypothalamus activate the hypothalamic-pituitaryadrenal (HPA) axis and the cortisol response. Previous studies have failed to find consistent whole amygdala volume changes in Major Depressive Disorder (MDD), but differences may exist at the smaller substructural level of the amygdala nuclei. High-resolution T1 and T2-weighted-fluid-attenuated inversion recovery MRIs were compared between 80 patients with MDD and 83 healthy controls (HC) using the automated amygdala substructure module in FreeSurfer 6.0. Volumetric assessments were performed for individual nuclei and three anatomico-functional composite groups of nuclei. Salivary cortisol awakening response (CAR), as a measure of HPA responsivity, was measured in a subset of patients. The right medial nucleus volume was larger in MDD compared to HC (p = 0.002). Increased right-left volume ratios were found in MDD for the whole amygdala (p = 0.004), the laterobasal composite (p = 0.009) and in the central (p = 0.003) and medial (p = 0.014) nuclei. The CAR was not significantly different between MDD and HC. Within the MDD group the left corticoamygdaloid transition area was inversely correlated with the CAR, as measured by area under the curve (AUCg) (p ≤ 0.0001). In conclusion, our study found larger right medial nuclei volumes in MDD compared to HC and relatively increased right compared to left whole and substructure volume ratios in MDD. The results suggest that amygdala substructure volumes may be involved in the pathophysiology of depression., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Effects of major depressive disorder and early life adversity (ELA) on the maternal HPA axis in the perinatal period were examined. Methods: Four groups of women ( n  = 127) were recruited, with the perinatal groups being compared during pregnancy (Preg) and at two months postpartum (PP) - [1] Depressed during pregnancy (Depressed-Preg/PP), [2] Prior history of depression but euthymic during pregnancy (History-Preg/PP), [3] Healthy pregnant women (Control-Preg/PP), and [4] Healthy non-pregnant women (Non-pregnant Control). Serial saliva samples were collected over the course of a day and waking and evening cortisol, total cortisol output and the cortisol awakening response were examined. Results: There were no HPA axis differences among the three groups during pregnancy. A history of ELA, regardless of comorbid depression, was associated with higher evening cortisol levels during pregnancy ( p  = 0.015). Women in the Depressed-PP group had had higher evening cortisol levels compared to the History-PP group ( p  < 0.017). Conclusions: Evening cortisol measures are a potential marker for both ELA and depression, with higher levels during pregnancy being associated with ELA and higher levels postpartum being associated with antenatal depression.

We present the work towards strengthening the security of DNA-sequencing functionality of future bioinformatics systems against bio-computing attacks. Recent research has shown how using common tools, a perpetrator can synthesize biological material, which upon DNA-analysis opens a cyber-backdoor for the perpetrator to hijack control of a computational resource from the DNA-sequencing pipeline. As DNA analysis finds its way into practical everyday applications, the threat of bio-hacking increases. Our wetlab experiments establish that malicious DNA can be synthesized and inserted into E. coli, a common contaminant. Based on that, we propose a new attack, where a hacker to reach the target hides the DNA with malicious code on common surfaces (e.g., lab coat, bench, rubber glove). We demonstrated that the threat of bio-hacking can be mitigated using dedicated input control techniques similar to those used to counter conventional injection attacks. This article proposes to use genetic similarity of biological samples to identify material that has been generated for bio-hacking. We considered freely available genetic data from 506 mammary, lymphocyte and erythrocyte samples that have a bio-hacking code inserted. During the evaluation we were able to detect up to 95% of malicious DNAs confirming suitability of our method.

Ireland has the second-highest birth rate in Europe and poorly developed perinatal psychiatry services. There are no screening services for antenatal depression and no data available on prevalence rates of depression among women attending the Irish obstetric services. The aim of this study was to assess the prevalence rates of depression during pregnancy in a population sample in Ireland using the Edinburgh Postnatal Depression Scale (EPDS) as a screening tool. Pregnant women during all stages of pregnancy were recruited from five maternity hospitals throughout the Republic of Ireland. Approximately 5000 EPDS questionnaires were collected. Information on the participant's age, gestational week, gravidity, parity, and level of education attained was also collected. A score of > 12 was used as a measure of probable depression. Overall, 15.8% of pregnant women scored > 12 in the EPDS. There was a significant association between gestational week and rates of depression, with increasing rates occurring with advancing pregnancy (p < 0.001). Overall, higher socioeconomic groups were over-represented in the sample although we replicated the well-established findings of higher EPDS scores in women with lower educational attainment (p < 0.005). This study demonstrates that prevalence rates of probable antenatal depression are high among women attending the obstetric services in Ireland and highlight the importance of increasing awareness of antenatal depression. These high rates of antenatal depression may be related to certain conditions that are specific to an Irish setting: the absence of screening for depression in the context of grossly under-resourced perinatal psychiatry services. These findings provide indirect confirmatory evidence for the need for streamlined mental health services within reproductive health services.

Background: Smaller hippocampus volume represents a consistent finding in major depression (MDD). Hippocampal neuroplasticity due to chronic stress might have differential effect on hippocampal subfields. We investigated the effects of the rs1360780 polymorphism of the hypothalamic-pituitary-axis related gene FKBP5 in combination with early life stress (ELA) on the structure of hippocampal subfields in MDD., Methods: We assessed the hippocampal subfields volumes in 85/67 MDD/healthy controls. We investigated the effects of diagnosis, FKBP5 allelic status and their interaction as predictors of hippocampal subfield volumes as well as the effect of ELA and its interaction with FKBP5., Results: MDD patients had smaller hippocampal volumes, in particular within the cornu ammonis (CA) and dentate gyrus (DG) regions. Patients exposed to ELA had larger hippocampi, in particular within the CA and DG. Among the patients exposed to ELA, the T allele carriers displayed lower volumes within the hippocampus-amygdala-transition-area (HATA) as those subjects homozygous for the C allele., Limitations: We pooled the subjects from 2 centers in order to increase the sample size. We did not include the cumulative lifetime exposure to medication., Conclusions: Hippocampal volume reductions in MDD were present particularly in the CA and DG. MDD with ELA display differential volume changes compared to MDD without ELA. The significant interaction between ELA and the rs1360780 polymorphism in HATA suggests a role of FKBP5 in the pathophysiology of structural alterations in depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The objective of this study was to determine the effect of major depressive disorder (MDD) on white matter microstructures after a 6-year period compared to healthy controls (HC). This study included a small sample size of 26 participants, including 14 patients with MDD clinically diagnosed at baseline, and 12 HCs. MRI brain scans were conducted at baseline and follow-up, 75.32 (±2.25) months after the initial scan. Tractography of 7 regions including the fornix, cingulum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus were conducted using ExploreDTI software. Both groups showed significant reduction in tract integrity between time points. MDD diagnosis was shown to have an effect on longitudinal FA of the left dorsal cingulum and the left parahippocampal cingulum. A significant inverse relationship was found between ΔFA [baseline FA - follow-up FA] of the right uncinate fasciculus and the left rostral cingulum with ΔHAM-D [baseline HAM-D - follow-up HAM-D] within the MDD group. These preliminary findings support the hypothesis that limbic structures including the cingulum are involved in MDD pathophysiology and may be affected even after remission. Moreover, they indicate that recovery from depression symptoms may slow the rate of WM degradation associated with aging in these regions of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Hippocampal volume reduction is the most replicated finding in neuroimaging studies of major depressive disorder (MDD). Varying hippocampal volume definition is a well-established problem in this field. Given that hippocampal function can be mapped onto anatomically defined substructures and that detailed examination of substructure volumes is now possible, we examined different hippocampal composite measures in MDD to look for hippocampal markers of MDD., Methods: Magnetic resonance imaging brain scans were compared between 80 patients with a range of MDD duration and 83 healthy control subjects. High-resolution T1-weighted and T2-weighted-fluid-attenuated inversion recovery magnetic resonance images were examined using the automated hippocampal substructure module in FreeSurfer 6.0. Between-group volumetric assessments were performed at substructure and composite substructures levels., Results: Patients with MDD showed a bilateral pattern of volume reduction in principal hippocampal substructures: the cornu ammonis (CA1-CA4), dentate gyrus, and subiculum. Changes were more pronounced on the left of these structures and in recurrent depression. CA2 to CA4 were the only substructures reduced in first-presentation depression. Overall changes were most marked in the left CA1, and CA1 volume was a predictor of illness duration., Conclusions: Hippocampal involvement in MDD is confined to principal substructures only. Differences between patients with MDD and healthy control subjects increased with progressively restricted hippocampal definitions, with the left CA1 emerging as a potential marker of MDD. Changes were more extensive in patients with recurrent, as opposed to first-presentation, MDD, suggesting a hippocampal disease process. These findings identify core hippocampal regions in the pathology of MDD, suggesting a potential marker of disease progression in MDD., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC)., Methods: A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC-MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer., Results: Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally., Discussion: This study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula's principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo , opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b -value 1500 mm 3 ). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment.

The gene for the glucocorticoid receptor regulator FK506 binding protein 5 (FKBP5) plays a role for risk, response to treatment, and changes in brain areas in major depressive disorder (MDD). Chronic stress is associated with lower methylation of FKBP5. Our aim was to investigate whether methylation of FKBP5 reflected exposure to childhood adversity in MDD and controls and whether it was associated with structure and function of emotional processing regions. FKBP5 intron 7 GR response element region methylation and rs1360780 allelic status were assessed from whole blood in 56 MDD adults and 50 controls. Using magnetic resonance imaging, we assessed gray matter concentration of selected areas and their function during valence recognition of emotional images. Childhood adversity was investigated using the Childhood Trauma Questionnaire. In MDD patients carrying the high-risk T allele of rs1360780, lower methylation of FKBP5 was predicted by childhood adversity (F=4.95, p=0.04). In all participants, lower FKBP5 intron methylation levels were associated with reduced gray matter concentration in the inferior frontal orbital gyrus bilaterally (Wald chi-square=11.93, p FDR <0.01) and, in MDD, with its bilaterally higher activation during valence recognition (Wald chi-square=5.58, p=0.02). Activation of this region, regardless of side, was found to be lower in MDD compared to controls (Wald chi-square=3.88, p=0.049) and to be inversely correlated with depression severity (Wald chi-square=4.65, p=0.03). Our findings support the hypothesis that, in genetically predisposed individuals carrying a high-risk variant of the gene, childhood maltreatment might induce demethylation of FKBP5. This is in turn associated with structural and functional changes in the inferior frontal orbital gyrus, a relevant area for the clinical symptoms of MDD.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory systems is a consistent finding in patients with Major Depressive Disorder (MDD). Cortisol is often assessed by measurement of the cortisol awakening response (CAR) and/or diurnal cortisol levels. Some methods of cortisol measurement overestimate cortisol concentration due to detection of other glucocorticoids including the relatively inert cortisone, therefore this study aimed to assess the presence of both cortisol and cortisone, and the cortisol-cortisone catalyzing enzyme 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), in depressed patients and controls. Because the HPA axis is known to regulate the body's immune system, relationships between measures of cytokines and cortisol were also assessed. Saliva samples were collected from 57 MDD patients and 40 healthy controls at five post-wakening time points (0, +30, +60, +720 and +750 min). Glucocorticoid concentrations were measured by liquid chromatography mass spectrometry. Whole blood mRNA expression of several inflammatory markers was measured by quantitative polymerase chain reaction. This study replicated the common finding of elevated morning cortisol and reduced CAR reactivity in MDD and found no differences in cortisone or 11β-HSD1 mRNA measures. There was a negative association between interleukin 1-β (IL-1β) mRNA and morning cortisol reactivity within the depressed group, indicating that dysregulation of the HPA axis and immune system may be interconnected., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Major depression is characterized by an impaired ability to evaluate and modify emotional responses as well as attention deficits, however the neural origins of these features are unresolved. The aim of the study was to investigate activation and functional connectivity changes during recognition and voluntary attentional regulation of emotion in 34 patients with major depressive disorder (MDD) compared to 35 controls., Methods: We employed an fMRI task in which participants assessed the valence or the shape of emotional stimuli. Then we analysed BOLD responses and functional connectivity using psycho-physiological interaction during the two conditions., Results: Patients showed more incorrect responses across both trial types. Recognition trials recruited areas belonging to the ventral system, which is involved in the generation and automatic processing of emotion. Shift of attention away from the emotional content activated areas belonging to the dorsal emotion regulation system. Patients showed hyper-connectivity between and within the default mode and task positive networks. While shifting attention away from emotion, patients had a reduced response of the anterior insula and increased connectivity across areas involved in emotion generation and regulation. Connectivity between the amygdala and visual areas was also altered in patients compared to controls during evaluation of negative and positive pictures, which might be related to biased valence processing. Finally, during regulation of negative trials and recognition of positive trials patients showed decreased coupling in areas involved in attention allocation and emotional regulation., Limitations: Most of the patients were medicated, although potential effects of treatment were investigated., Conclusions: Overall, our findings are compatible with abnormal functional coupling in MDD of regions involved in perception, recognition and attention allocation, especially during regulation of negative images and valence evaluation of positive images., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Exercise increases wellbeing and improves mood. It is however unclear how these mood changes relate to brain function. We conducted a randomized controlled trial investigating resting-state modifications in healthy adults after an extended period of aerobic physical exercise and their relationship with mood improvements. We aimed to identify novel functional networks whose activity could provide a physiological counterpart to the mood-related benefits of exercise. Thirty-eight healthy sedentary volunteers were randomised to either the aerobic exercise group of the study or a control group. Participants in the exercise group attended aerobic sessions with a physiotherapist twice a week for 16 weeks. Resting-state modifications using magnetic resonance imaging were assessed before and after the programme and related to mood changes. An unbiased approach using graph metrics and network-based statistics was adopted. Exercise reduced mood disturbance and improved emotional wellbeing. It also induced a decrease in local efficiency in the parahippocampal lobe through strengthening of the functional connections from this structure to the supramarginal gyrus, precentral area, superior temporal gyrus and temporal pole. Changes in mood disturbance following exercise were correlated with those in connectivity between parahippocampal gyrus and superior temporal gyrus as well as with the amount of training. No changes were detected in the control group. In conclusion, connectivity from the parahippocampal gyrus to motor, sensory integration and mood regulation areas was strengthened through exercise. These functional changes might be related to the benefits of regular physical activity on mood., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)