Stress Hormone Dynamics Are Coupled to Brain Serotonin 4 Receptor Availability in Unmedicated Patients With Major Depressive Disorder: A NeuroPharm Study.

BACKGROUND: A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome. METHODS: Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items. RESULTS: In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome. CONCLUSIONS: Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics.

Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with selective serotonin reuptake inhibitors (SSRIs) due to the side effects of pharmacologic treatment. AIM: To examine the association between sexual function and severity of MDD in drug-naïve patients as compared with healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined. METHODS: In 92 patients with MDD, we measured MDD severity with 6- and 17-item versions of the Hamilton Depression Rating Scale (HDRS6 and HDRS17) and the level of sexual function with the Changes in Sexual Functioning Questionnaire at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared with the sexual function of 73 healthy controls. Linear regression models were used to assess differences in sexual function between healthy controls and patients and change in sexual function from baseline to week 12. Linear mixed models were used to assess differences in change in sexual function between treatment response groups. OUTCOMES: Outcomes included total scores on the HDRS6, HDRS17, and Changes in Sexual Functioning Questionnaire and changes in total scores from baseline to week 12. RESULTS: Unmedicated patients with MDD reported impaired sexual function as compared with healthy controls. Level of sexual function was not associated with severity of MDD at baseline. Patients' sexual function improved significantly during treatment, which was coupled with amelioration of depressive symptoms. Treatment response groups (remitters, intermediate responders, nonresponders) did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment. CLINICAL IMPLICATIONS: Major depression is a risk factor for sexual problems, and improvement in sexual function was coupled with amelioration of depressive symptoms. STRENGTHS AND LIMITATIONS: Among its strengths, this was a naturalistic study reflecting real-world settings in clinical practice. It additionally included a baseline measurement of sexual function and MDD severity on drug-naïve patients prior to the initiation of treatment. Finally, the follow-up of 12 weeks extends beyond the acute phase of treatment in which previous research has observed a peak in sexual side effects. In terms of limitations, there was no placebo arm; thus, the study cannot attribute the effects on sexual function to treatment with antidepressants per se. Also, the patients were young, which may have served as a protective factor against sexual side effects. CONCLUSION: Sexual dysfunction was strongly associated with MDD and improved in parallel with overall symptoms of depression across a standard 12-week treatment with SSRI antidepressants. CLINICAL TRIAL REGISTRATION: NCT02869035 (https://clinicaltrials.gov/ct2/show/NCT02869035).

Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.

BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. DISCUSSION: The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. TRIAL REGISTRATION: Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder: COORDINATE-MDD consortium design and rationale.

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

Brain serotonin transporter is associated with cognitive-affective biases in healthy individuals.

Cognitive affective biases describe the tendency to process negative information or positive information over the other. These biases can be modulated by changing extracellular serotonin (5-HT) levels in the brain, for example, by pharmacologically blocking and downregulating the 5-HT transporter (5-HTT), which remediates negative affective bias. This suggests that higher levels of 5-HTT are linked to a priority of negative information over positive, but this link remains to be tested in vivo in healthy individuals. We, therefore, evaluated the association between 5-HTT levels, as measured with [11 C]DASB positron emission tomography (PET), and affective biases, hypothesising that higher 5-HTT levels are associated with a more negative bias. We included 98 healthy individuals with measures of [11 C]DASB binding potential (BPND ) and affective biases using The Emotional Faces Identification Task by subtracting the per cent hit rate for happy from that of sad faces (EFITAB ). We evaluated the association between [11 C]DASB BPND and EFITAB in a linear latent variable model, with the latent variable (5-HTTLV ) modelled from [11 C]DASB BPND in the fronto-striatal and fronto-limbic networks implicated in affective cognition. We observed an inverse association between 5-HTTLV and EFITAB (ß = -8% EFITAB per unit 5-HTTLV , CI = -14% to -3%, p = .002). These findings show that higher 5-HTT levels are linked to a more negative bias in healthy individuals. High 5-HTT supposedly leads to high clearance of 5-HT, and thus, a negative bias could result from low extracellular 5-HT. Future studies must reveal if a similar inverse association exists in individuals with affective disorders.

Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women.

Hormone transition phases may trigger depression in some women, yet the underlying mechanisms remain elusive. In a pharmacological sex-hormone manipulation model, we previously reported that estradiol reductions, induced with a gonadotropin-releasing hormone agonist (GnRHa), provoked subclinical depressive symptoms in healthy women, especially if neocortical serotonin transporter (SERT) binding also increased. Within this model, we here evaluated if GnRHa, compared to placebo, reduced hippocampal volume, in a manner that depended on the magnitude of the estradiol decrease and SERT binding, and if this decrease translated to the emergence of subclinical depressive symptoms. Sixty-three healthy, naturally cycling women were included in a randomized, double-blind, placebo-controlled GnRHa-intervention study. We quantified the change from baseline to follow-up (n = 60) in serum estradiol (ΔEstradiol), neocortical SERT binding ([11C] DASB positron emission tomography; ΔSERT), subclinical depressive symptoms (Hamilton depression rating scale; ΔHAMD-17), and hippocampal volume (magnetic resonance imaging data analyzed in Freesurfer 7.1, ΔHippocampus). Group differences in ΔHippocampus were evaluated in a t-test. Within the GnRHa group, associations between ΔEstradiol, ΔHippocampus, and ΔHAMD-17, in addition to ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus, were evaluated with linear regression models. Mean ΔHippocampus was not significantly different between the GnRHa and placebo group. Within the GnRHa group, hippocampal volume reductions were associated with the magnitude of estradiol decrease (p = 0.04, Cohen's f2 = 0.18), controlled for baseline SERT binding, but not subclinical depressive symptoms. There was no ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus. If replicated, our data highlight a possible association between estradiol fluctuations and hippocampal plasticity, adjusted for serotonergic contributions.

The role of central serotonergic markers and estradiol changes in perinatal mental health.

OBJECTIVE: Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum. METHODS: Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype. RESULTS: Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (ßΔE2  = 0.73, p = 0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (ß5-HIAA  = 0.002, p = 0.06). CONCLUSION: In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.

Effect of supervised group exercise on psychological well-being among pregnant women with or at high risk of depression (the EWE Study): A randomized controlled trial.

INTRODUCTION: Depression is expected to be the leading cause of disability worldwide by 2030. The prevalence is increasing and is two-fold higher in women than in men, women being at particularly high risk during hormonal transition phases such as pregnancy and the postpartum period. The objective for this trial was to assess the effect of supervised group exercise on psychological well-being and symptoms of depression among pregnant women with or at high risk of depression. MATERIAL AND METHODS: This study was undertaken at the Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Denmark, from August 2016 to September 2018. Pregnant women with a current or previous history of depression and/or anxiety requiring treatment within the last 10 years, or use of antidepressants 3 months before or during pregnancy, were randomly assigned to 12 weeks of supervised group exercise from 17 to 22 weeks of gestation twice weekly, or to a control group. The primary outcome was self-reported psychological well-being at 29-34 weeks of gestation, measured by the five-item World Health Organization Well-being Index (WHO-5). Secondary outcomes included delivery outcomes and psychological well-being (WHO-5) 8 weeks postpartum. RESULTS: The intention-to-treat analysis showed no significant effect on psychological well-being on the primary outcome. Mean WHO-5 score in the intervention group was 2.0 (95% CI -1.3 to 5.2, P = .2) higher than in the control group. Per protocol analysis of women who attended ≥75% of the exercise sessions showed a statistically significant higher mean WHO-5 score relative to the control group at gestational weeks 29-34. Eight weeks postpartum the intervention group reported higher psychological well-being than the control group, mean difference in WHO-5 score of 5.5 (95% CI 1.0-10.1, P = .04). CONCLUSIONS: Supervised group exercise did not improve psychological well-being for women with or at high risk of depression at 29-34 weeks of gestation. Eight weeks postpartum the intervention group reported significantly higher psychological well-being than the control group. Based on our results, supervised exercise in groups is a safe complementary course of treatment alongside the existing antenatal care.

Pharmacological sex hormone manipulation as a risk model for depression.

Sex hormone transition may trigger severe depressive episodes in some women. In order to map mechanisms related to such phenomena we developed a pharmacological preclinical human model using sex hormone manipulation with gonadotropin releasing hormone agonist (GnRHa) in a placebo-controlled design. Here the findings from this model is synthesized and discussed in the context of related literature on hormonal contributions to reproductive mental health disorders. The GnRha model work points to an estradiol-dependent depressive response in healthy women undergoing short-term sex hormone manipulation with GnRHa, which is linked to serotonin transporter changes (a key regulator of synaptic serotonin), a disengagement of hippocampus, and overengagement of brain networks recruited when processing emotional salient information. Further, the GnRHa model suggest that key brain regions in the reward circuit are less engaged in positive stimuli when undergoing sex hormone manipulation, which may underlie anhedonia. Also, the work supports that enhanced sensitivity to estrogen signaling at the level of gene expression may drive increased risk for depressive symptoms when exposed to sex steroid hormone fluctuations. In conclusion, the GnRHa model work highlights the brain signatures of rapid and profound changes in sex steroid hormone milieu, which reflect plausible mechanisms by which risk for mood disorders works. This model points to the role of estrogen dynamics and sensitivity, and offers a rationale for personalized prevention in hormonal transition phases, for example pregnancy to postpartum transition, perimenopause, and hormone treatments, which now can move into clinical translation and ideally pave the way for protecting mental and cognitive health.

Optimization of preprocessing strategies in Positron Emission Tomography (PET) neuroimaging: A [11C]DASB PET study.

Positron Emission Tomography (PET) is an important neuroimaging tool to quantify the distribution of specific molecules in the brain. The quantification is based on a series of individually designed data preprocessing steps (pipeline) and an optimal preprocessing strategy is per definition associated with less noise and improved statistical power, potentially allowing for more valid neurobiological interpretations. In spite of this, it is currently unclear how to design the best preprocessing pipeline and to what extent the choice of each preprocessing step in the pipeline minimizes subject-specific errors. To evaluate the impact of various preprocessing strategies, we systematically examined 384 different pipeline strategies in data from 30 healthy participants scanned twice with the serotonin transporter (5-HTT) radioligand [11C]DASB. Five commonly used preprocessing steps with two to four options were investigated: (1) motion correction (MC) (2) co-registration (3) delineation of volumes of interest (VOI's) (4) partial volume correction (PVC), and (5) kinetic modeling. To quantitatively compare and evaluate the impact of various preprocessing strategies, we used the performance metrics: test-retest bias, within- and between-subject variability, the intraclass-correlation coefficient, and global signal-to-noise ratio. We also performed a power analysis to estimate the required sample size to detect either a 5% or 10% difference in 5-HTT binding as a function of preprocessing pipeline. The results showed a complex downstream dependency between the various preprocessing steps on the performance metrics. The choice of MC had the most profound effect on 5-HTT binding, prior to the effects caused by PVC and kinetic modeling, and the effects differed across VOI's. Notably, we observed a negative bias in 5-HTT binding across test and retest in 98% of pipelines, ranging from 0 to 6% depending on the pipeline. Optimization of the performance metrics revealed a trade-off in within- and between-subject variability at the group-level with opposite effects (i.e. minimization of within-subject variability increased between-subject variability and vice versa). The sample size required to detect a given effect size was also compromised by the preprocessing strategy, resulting in up to 80% increases in sample size needed to detect a 5% difference in 5-HTT binding. This is the first study to systematically investigate and demonstrate the effect of choosing different preprocessing strategies on the outcome of dynamic PET studies. We provide a framework to show how optimal and maximally powered neuroimaging results can be obtained by choosing appropriate preprocessing strategies and we provide recommendations depending on the study design. In addition, the results contribute to a better understanding of methodological uncertainty and variability in preprocessing decisions for future group- and/or longitudinal PET studies.

Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study.

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5-HT2A R) agonist psilocybin. However, no studies have investigated whether 5-HT2A R availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5-HT2A R binding in neocortex imaged with [18 F]altanserin or [11 C]Cimbi-36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory-Revised. No significant associations between neocortical 5-HT2A R binding and trait Openness were found for [18 F]altanserin (p = 0.5) or [11 C]Cimbi-36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5-HT2A R availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5-HT2A R with compounds such as psilocybin may contribute to long-term changes in trait Openness, there is no evidence in favor of an association between 5-HT2A R and trait Openness.

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study.

BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations. AIM: Testing if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes. METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa. RESULTS: Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up. CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers. DECLARATION OF INTEREST: V.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.

Delirium assessment in neuro-critically ill patients: A validation study.

BACKGROUND: Delirium is underinvestigated in the neuro-critically ill, although the harmful effect of delirium is well established in patients in medical and surgical intensive care units (ICU).To detect delirium, a valid tool is needed. We hypothesized that delirium screening would be feasible in patients with acute brain injury and we aimed to validate and compare the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist against clinical International Classification of Diseases-10 criteria as reference. METHODS: Nurses assessed delirium using the Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist in adult patients with acute brain injury admitted to the Neurointensive care unit (Neuro-ICU), Copenhagen University Hospital, if their Richmond agitation-sedation scale score was -2 or above. As the reference, a team of psychiatrist assessed patients using the International Classification of Diseases-10 criteria. RESULTS: We enrolled 74 patients, of whom 25 (34%) were deemed unable to assess by the psychiatrists, leaving 49 (66%) for final analysis. Sensitivity and specificity for the Confusion Assessment Method for the ICU was 59% (95% CI: 41-75) and 56% (95% CI: 32-78), respectively, and 85% (95% CI: 70-94) and 75% (95% CI: 51-92), respectively, for the Intensive Care Delirium Screening Checklist. CONCLUSIONS: Our findings suggest that the Intensive Care Delirium Screening Checklist may be a valid tool and the Confusion Assessment Method for the ICU is less suitable for delirium detection for patients in the Neuro-ICU. In the neuro-critically ill, delirium screening is challenged by limited feasibility.

Neuroticism Associates with Cerebral in Vivo Serotonin Transporter Binding Differently in Males and Females.

Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P=.008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P=.014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.

The Center for Integrated Molecular Brain Imaging (Cimbi) database.

We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank.

Preserved consciousness in vegetative and minimal conscious states: systematic review and meta-analysis.

Active, passive and resting state paradigms using functional MRI (fMRI) or EEG may reveal consciousness in the vegetative (VS) and the minimal conscious state (MCS). A meta-analysis was performed to assess the prevalence of preserved consciousness in VS and MCS as revealed by fMRI and EEG, including command following (active paradigms), cortical functional connectivity elicited by external stimuli (passive paradigms) and default mode networks (resting state). Studies were selected from multiple indexing databases until February 2015 and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 37 studies were identified, including 1041 patients (mean age 43 years, range 16-89; male/female 2.1:1; 39.5% traumatic brain injuries). MCS patients were more likely than VS patients to follow commands during active paradigms (32% vs 14%; OR 2.85 (95% CI 1.90 to 4.27; p<0.0001)) and to show preserved functional cortical connectivity during passive paradigms (55% vs 26%; OR 3.53 (95% CI 2.49 to 4.99; p<0.0001)). Passive paradigms suggested preserved consciousness more often than active paradigms (38% vs 24%; OR 1.98 (95% CI 1.54 to 2.54; p<0.0001)). Data on resting state paradigms were insufficient for statistical evaluation. In conclusion, active paradigms may underestimate the degree of consciousness as compared to passive paradigms. While MCS patients show signs of preserved consciousness more frequently in both paradigms, roughly 15% of patients with a clinical diagnosis of VS are able to follow commands by modifying their brain activity. However, there remain important limitations at the single-subject level; for example, patients from both categories may show command following despite negative passive paradigms.

Development and psychometric validation of the verbal affective memory test.

We here present the development and validation of the Verbal Affective Memory Test-24 (VAMT-24). First, we ensured face validity by selecting 24 words reliably perceived as positive, negative or neutral, respectively, according to healthy Danish adults' valence ratings of 210 common and non-taboo words. Second, we studied the test's psychometric properties in healthy adults. Finally, we investigated whether individuals diagnosed with Seasonal Affective Disorder (SAD) differed from healthy controls on seasonal changes in affective recall. Recall rates were internally consistent and reliable and converged satisfactorily with established non-affective verbal tests. Immediate recall (IMR) for positive words exceeded IMR for negative words in the healthy sample. Relatedly, individuals with SAD showed a significantly larger decrease in positive recall from summer to winter than healthy controls. Furthermore, larger seasonal decreases in positive recall significantly predicted larger increases in depressive symptoms. Retest reliability was satisfactory, rs ≥ .77. In conclusion, VAMT-24 is more thoroughly developed and validated than existing verbal affective memory tests and showed satisfactory psychometric properties. VAMT-24 seems especially sensitive to measuring positive verbal recall bias, perhaps due to the application of common, non-taboo words. Based on the psychometric and clinical results, we recommend VAMT-24 for international translations and studies of affective memory.

Functional connectivity of the dorsal and median raphe nuclei at rest.

Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined with structural MRI from 49 healthy volunteers, we delineated DR and MR and performed a seed-based resting-state FC analysis. The DR and MR seeds produced largely similar FC maps: significant positive FC with brain regions involved in cognitive and emotion processing including anterior cingulate, amygdala, insula, hippocampus, thalamus, basal ganglia and cerebellum. Significant negative FC was observed within pre- and postcentral gyri for the DR but not for the MR seed. We observed a significant association between DR and MR FC and regional 5-HTT binding. Our results provide evidence for a resting-state network related to DR and MR and comprising regions receiving serotonergic innervation and centrally involved in 5-HT related behaviors including emotion, cognition and reward processing. These findings provide a novel advance in estimating resting-state FC related to 5-HT signaling, which can benefit our understanding of its role in behavior and neuropsychiatric illnesses.

BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels.

Brain-derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address this, we evaluated whether BDNF val66met was predictive of a putative marker of brain serotonin levels, serotonin 4 receptor (5-HT4 ) binding assessed with [11C]SB207145 positron emission tomography, which has also been associated with the serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We applied a linear latent variable model (LVM) using regional 5-HT4 binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain-wide and region-specific genotype effects on 5-HT4 binding. Our data supported an LVM wherein BDNF val66met significantly predicted a LV reflecting [11C]SB207145 binding across regions (P = 0.005). BDNF val66met met-carriers showed 2-9% higher binding relative to val/val homozygotes. In contrast, 5-HTTLPR did not predict the LV but S-carriers showed 7% lower neocortical binding relative to LL homozygotes (P = 7.3 × 10(-6)). We observed no evidence for genetic interaction. Our findings indicate that BDNF val66met significantly predicts a common regulator of brain [11C]SB207145 binding, which we hypothesize reflects brain serotonin levels. In contrast, our data indicate that 5-HTTLPR specifically affects 5-HT4 binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5-HTTLPR on behavior and related risk for neuropsychiatric illness in humans.