Effects of gender-affirming hormone therapy on gray matter density, microstructure and monoamine oxidase A levels in transgender subjects.

MAO-A catalyzes the oxidative degradation of monoamines and is thus implicated in sex-specific neuroplastic processes that influence gray matter (GM) density (GMD) and microstructure (GMM). Given the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy (GHT) represent a valuable cohort to potentially investigate sex steroid-induced changes of GM and concomitant MAO-A density. Here, we investigated the effects of GHT over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men underwent two MRI scans in a longitudinal design. PET scans using [11C]harmine were performed before each MRI session in a subset of 35 individuals. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: pFWE+Bonferroni < 0.025). In terms of MAO-A distribution volume, no significant effects were found. Additionally, the sexual desire inventory (SDI) was applied to assess GHT-induced changes in sexual desire, showing an increase of SDI scores among transgender men. Changes in the GMD of the bilateral insula showed a moderate correlation to SDI scores (rho = - 0.62, pBonferroni = 0.047). The present results are indicative of a reliable influence of gender-affirming hormone therapy on 1) GMD and GMM following an interregional pattern and 2) sexual desire specifically among transgender men.

The influence of season on glutamate and GABA levels in the healthy human brain investigated by magnetic resonance spectroscopy imaging.

Seasonal changes in neurotransmitter systems have been demonstrated in imaging studies and are especially noticeable in diseased states such as seasonal affective disorder (SAD). These modulatory neurotransmitters, such as serotonin, are influencing glutamatergic and GABAergic neurotransmission. Furthermore, central components of the circadian pacemaker are regulated by GABA (the suprachiasmatic nucleus) or glutamate (e.g., the retinohypothalamic tract). Therefore, we explored seasonal differences in the GABAergic and glutamatergic system in 159 healthy individuals using magnetic resonance spectroscopy imaging with a GABA-edited 3D-MEGA-LASER sequence at 3T. We quantified GABA+/tCr, GABA+/Glx, and Glx/tCr ratios (GABA+, GABA+ macromolecules; Glx, glutamate + glutamine; tCr, total creatine) in five different subcortical brain regions. Differences between time periods throughout the year, seasonal patterns, and stationarity were tested using ANCOVA models, curve fitting approaches, and unit root and stationarity tests, respectively. Finally, Spearman correlation analyses between neurotransmitter ratios within each brain region and cumulated daylight and global radiation were performed. No seasonal or monthly differences, seasonal patterns, nor significant correlations could be shown in any region or ratio. Unit root and stationarity tests showed stable patterns of GABA+/tCr, GABA+/Glx, and Glx/tCr levels throughout the year, except for hippocampal Glx/tCr. Our results indicate that neurotransmitter levels of glutamate and GABA in healthy individuals are stable throughout the year. Hence, despite the important correction for age and gender in the analyses of MRS derived GABA and glutamate, a correction for seasonality in future studies does not seem necessary. Future investigations in SAD and other psychiatric patients will be of high interest.

Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort.

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals. Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus). Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men. Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. DATA AVAILABILITY STATEMENT: Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.

Escitalopram administration, relearning, and neuroplastic effects: A diffusion tensor imaging study in healthy individuals.

BACKGROUND: Neuroplastic processes are influenced by serotonergic agents, which reportedly alter white matter microstructure in humans in conjunction with learning. The goal of this double-blind, placebo-controlled imaging study was to investigate the neuroplastic properties of escitalopram and cognitive training on white matter plasticity during (re)learning as a model for antidepressant treatment and environmental factors. METHODS: Seventy-one healthy individuals (age=25.6 ± 5.0, 43 females) underwent three diffusion magnetic resonance imaging scans: at baseline, after 3 weeks of associative learning (emotional/non-emotional content), and after relearning shuffled associations for an additional 3 weeks. During the relearning phase, participants received a daily dose of 10 mg escitalopram or placebo orally. Fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivity (RD) were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. RESULTS: In a three-way repeated-measures marginal model with sandwich estimator standard errors, we found no significant effects of escitalopram and content on AD, FA, MD, and RD during both learning and relearning periods (pFDR>0.05). When testing for escitalopram or content effects separately, we also demonstrated no significant findings (pFDR>0.05) for any of the diffusion tensor imaging metrics. LIMITATIONS: The intensity of the study interventions might have been too brief to induce detectable white matter changes. DISCUSSION: Previous studies examining the effects of SSRIs on white matter tracts in humans have yielded inconclusive outcomes. Our results indicate that relearning under escitalopram does not affect the white matter microstructures in healthy individuals when administered for 3 weeks.

Coexpression of Gene Transcripts with Monoamine Oxidase A Quantified by Human In Vivo Positron Emission Tomography.

The monoamine oxidase A (MAO-A) is integral to monoamine metabolism and is thus relevant to the pathophysiology of various neuropsychiatric disorders; however, associated gene-enzyme relations are not well understood. This study aimed to unveil genes coexpressed with MAO-A. Therefore, 18 179 mRNA expression maps (based on the Allen Human Brain Atlas) were correlated with the cerebral distribution volume (VT) of MAO-A assessed in 36 healthy subjects (mean age ± standard deviation: 32.9 ± 8.8 years, 18 female) using [11C]harmine positron emission tomography scans. Coexpression analysis was based on Spearman's ρ, over-representation tests on Fisher's exact test with false discovery rate (FDR) correction. The analysis revealed 35 genes in cortex (including B-cell translocation gene family, member 3, implicated in neuroinflammation) and 247 genes in subcortex (including kallikrein-related peptidase 10, implicated in Alzheimer's disease). Significantly over-represented Gene Ontology terms included "neuron development", "neuron differentiation", and "cell-cell signaling" as well as "axon" and "neuron projection". In vivo MAO-A enzyme distribution and MAOA expression did not correlate in cortical areas (ρ = 0.08) while correlation was found in subcortical areas (ρ = 0.52), suggesting influences of region-specific post-transcriptional and -translational modifications. The herein reported information could contribute to guide future genetic studies, deepen the understanding of associated pathomechanisms and assist in the pursuit of novel therapeutic targets.

Disrupted relationship between blood glucose and brain dopamine D2/3 receptor binding in patients with first-episode schizophrenia.

An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval.

Animal studies using selective serotonin reuptake inhibitors (SSRIs) and learning paradigms have demonstrated that serotonin is important for flexibility in executive functions and learning. SSRIs might facilitate relearning through neuroplastic processes and thus exert their clinical effects in psychiatric diseases where cognitive functioning is affected. However, translation of these mechanisms to humans is missing. In this randomized placebo-controlled trial, we assessed functional brain activation during learning and memory retrieval in healthy volunteers performing associative learning tasks aiming to translate facilitated relearning by SSRIs. To this extent, seventy-six participants underwent three MRI scanning sessions: (1) at baseline, (2) after three weeks of daily associative learning and subsequent retrieval (face-matching or Chinese character-noun matching) and (3) after three weeks of relearning under escitalopram (10 mg/day) or placebo. Associative learning and retrieval tasks were performed during each functional MRI (fMRI) session. Statistical modeling was done using a repeated-measures ANOVA, to test for content-by-treatment-by-time interaction effects. During the learning task, a significant substance-by-time interaction was found in the right insula showing a greater deactivation in the SSRI cohort after 21 days of relearning compared to the learning phase. In the retrieval task, there was a significant content-by-time interaction in the left angular gyrus (AG) with an increased activation in face-matching compared to Chinese-character matching for both learning and relearning phases. A further substance-by-time interaction was found in task performance after 21 days of relearning, indicating a greater decrease of performance in the placebo group. Our findings that escitalopram modulate insula activation demonstrates successful translation of relearning as a mechanism of SSRIs in human. Furthermore, we show that the left AG is an active component of correct memory retrieval, which coincides with previous literature. We extend the function of this region by demonstrating its activation is not only stimulus dependent but also time constrained. Finally, we were able to show that escitalopram aids in relearning, irrespective of content.

The Influence of Acute SSRI Administration on White Matter Microstructure in Patients Suffering From Major Depressive Disorder and Healthy Controls.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain's WM microstructure are lacking. METHODS: In this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. RESULTS: The repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present. CONCLUSIONS: Our investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier NCT02711215.

Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm.

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI). In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis. A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found. Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.

Volitional modification of brain activity in adolescents with Autism Spectrum Disorder: A Bayesian analysis of Slow Cortical Potential neurofeedback.

Autism spectrum disorder is (ASD) characterized by a persisting triad of impairments of social interaction, language as well as inflexible, stereotyped and ritualistic behaviors. Increasingly, scientific evidence suggests a neurobiological basis of these emotional, social and cognitive deficits in individuals with ASD. The aim of this randomized controlled brain self-regulation intervention study was to investigate whether the core symptomatology of ASD could be reduced via an electroencephalography (EEG) based brain self-regulation training of Slow Cortical Potentials (SCP). 41 male adolescents with ASD were recruited and allocated to a) an experimental group undergoing 24 sessions of EEG-based brain training (n1 = 21), or to b) an active control group undergoing conventional treatment (n2 = 20), that is, clinical counseling during a 3-months intervention period. We employed real-time neurofeedback training recorded from a fronto-central electrode intended to enable participants to volitionally regulate their brain activity. Core autistic symptomatology was measured at six time points during the intervention and analyzed with Bayesian multilevel approach to characterize changes in core symptomatology. Additional Bayesian models were formulated to describe the neural dynamics of the training process as indexed by SCP (time-domain) and power density (PSD, frequency-domain) measures. The analysis revealed a substantial improvement in the core symptomatology of ASD in the experimental group (reduction of 21.38 points on the Social Responsiveness Scale, SD = 5.29), which was slightly superior to that observed in the control group (evidence Ratio = 5.79). Changes in SCP manifested themselves as different trajectories depending on the different feedback conditions and tasks. Further, the model of PSD revealed a continuous decrease in delta power, parallel to an increase in alpha power. Most notably, a non-linear (quadratic) model turned out to be better at predicting the data than a linear model across all analyses. Taken together, our analyses suggest that behavioral and neural processes of change related to neurofeedback training are complex and non-linear. Moreover, they have implications for the design of future trials and training protocols.

Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity-impulsivity symptoms in ADHD measured with PET.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a robust genetic influence. The norepinephrine transporter (NET) is of particular interest as it is one of the main targets in treatment of the disorder. As ADHD is a complex and polygenetic condition, the possible regulation by epigenetic processes has received increased attention. We sought to determine possible differences in NET promoter DNA methylation between patients with ADHD and healthy controls. DNA methylation levels in the promoter region of the NET were determined in 23 adult patients with ADHD and 23 healthy controls. A subgroup of 18 patients with ADHD and 18 healthy controls underwent positron emission tomography (PET) with the radioligand (S,S)-[18F]FMeNER-D2 to quantify the NET in several brain areas in vivo. Analyses revealed significant differences in NET methylation levels at several cytosine-phosphate-guanine (CpG) sites between groups. A defined segment of the NET promoter ("region 1") was hypermethylated in patients in comparison with controls. In ADHD patients, a negative correlation between methylation of a CpG site in this region and NET distribution in the thalamus, locus coeruleus, and the raphe nuclei was detected. Furthermore, methylation of several sites in region 1 was negatively associated with the severity of hyperactivity-impulsivity symptoms. Our results point to an epigenetic dysregulation in ADHD, possibly due to a compensatory mechanisms or additional factors involved in transcriptional processing.

The "sugar dilemma".

Type 2 diabetes mellitus is characterized by insulin resistance and elevated blood glucose levels. Treatment protocols generally include dietary restriction of sugar, as well as drugs aiming at a reduction of blood glucose, mainly by activating the insulin system or supplementing insulin. This established approach does not take into account the outstanding physiological role of glucose as a key molecule in metabolism. Glucose is crucial to meet the high energy demand of the brain, which depends on it as an exclusive nutrient. Insulin independent glucose transporters GLUT1 import glucose into the brain. Reduction of blood glucose, as in current treatment concepts, may lead to energy deficiency in the brain and consecutively to worsening of - possibly already impaired - neurocognitive function. Reduced cell membrane fluidity of the vascular endothelium of the bloodbrain-barrier (BBB) - due to malnutrition and/or aging - is considered a major factor in pathogenesis of the cerebral metabolic syndrome, which is a key step in neurodegeneration. Under this aspect we suggest a novel approach to prophylaxis and treatment focusing on a sufficient supply of glucose to the brain.

Voxel-Based Morphometry-from Hype to Hope. A Study on Hippocampal Atrophy in Mesial Temporal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Automated volumetry of the hippocampus is considered useful to assist the diagnosis of hippocampal sclerosis in temporal lobe epilepsy. However, voxel-based morphometry is rarely used for individual subjects because of high rates of false-positives. We investigated whether an approach with high dimensional warping to the template and nonparametric statistics would be useful to detect hippocampal atrophy in patients with hippocampal sclerosis. MATERIALS AND METHODS: We performed single-subject voxel-based morphometry with nonparametric statistics within the framework of Statistical Parametric Mapping to compare MRI from 26 well-characterized patients with temporal lobe epilepsy individually against a group of 110 healthy controls. The following statistical threshold was used: P < .05 corrected for multiple comparisons with family-wise error over the region of interest right and left hippocampus. RESULTS: The sensitivity for the detection of atrophy related to hippocampal sclerosis was 0.92 (95% CI, 0.67-0.99) for the right hippocampus and 0.60 (0.31-0.83) for the left, and the specificity for volume changes was 0.98 (0.93-0.99). All clusters of decreased hippocampal volumes were correctly lateralized to the seizure focus. Hippocampal volume decrease was in accordance with neuronal cell loss on histology reports. CONCLUSIONS: Nonparametric voxel-based morphometry is sensitive and specific for hippocampal atrophy in patients with mesial temporal lobe epilepsy and may be useful in clinical practice.

Machine learning classification of ADHD and HC by multimodal serotonergic data.

Serotonin neurotransmission may impact the etiology and pathology of attention-deficit and hyperactivity disorder (ADHD), partly mediated through single nucleotide polymorphisms (SNPs). We propose a multivariate, genetic and positron emission tomography (PET) imaging classification model for ADHD and healthy controls (HC). Sixteen patients with ADHD and 22 HC were scanned by PET to measure serotonin transporter (SERT') binding potential with [11C]DASB. All subjects were genotyped for thirty SNPs within the HTR1A, HTR1B, HTR2A and TPH2 genes. Cortical and subcortical regions of interest (ROI) were defined and random forest (RF) machine learning was used for feature selection and classification in a five-fold cross-validation model with ten repeats. Variable selection highlighted the ROI posterior cingulate gyrus, cuneus, precuneus, pre-, para- and postcentral gyri as well as the SNPs HTR2A rs1328684 and rs6311 and HTR1B rs130058 as most discriminative between ADHD and HC status. The mean accuracy for the validation sets across repeats was 0.82 (±0.09) with balanced sensitivity and specificity of 0.75 and 0.86, respectively. With a prediction accuracy above 0.8, the findings underlying the proposed model advocate the relevance of the SERT as well as the HTR1B and HTR2A genes in ADHD and hint towards disease-specific effects. Regarding the high rates of comorbidities and difficult differential diagnosis especially for ADHD, a reliable computer-aided diagnostic tool for disorders anchored in the serotonergic system will support clinical decisions.

Acute stress alters neural patterns of value representation for others.

Acute stress is often evoked during social interactions, by feelings of threat or negative evaluation by other people. We also constantly interact with others while under stress - in the workplace or in private alike. However, it is not clear how stress affects social interactions. For one, individuals could become more selfish and focused on their own goals. On the other hand, individuals might also become more focused on affiliating with potential social partners, in order to secure their support. There is, indeed, accumulating behavioral evidence that prosocial behaviors increase rather than decrease under stress. Here, we tested the underlying brain processes of such findings, by assessing the effects of stress on the neural representations of (monetary) value for self and other. Participants (N â€‹= â€‹30; male, 18-40 years) played a gambling task for themselves and for another participant while undergoing functional magnetic resonance imaging (fMRI). Each participant played the gambling task twice: once immediately following acute stress induction, and once in a control session. We compared neural patterns of value representation in the dorsomedial prefrontal cortex (dmPFC), ventromedial prefrontal cortex (vmPFC) and striatum using representational similarity analysis (RSA). We found that under stress, dmPFC and striatum showed higher dissimilarity between neural patterns underlying high and low value for the other. Dissimilarity of neural patterns underlying high and low value for the self was unaffected by stress. These findings suggest that participants track the magnitude of possible rewards for others more under stress, suggesting increased prosocial orientation.

Repetitive enhancement of serum BDNF subsequent to continuation ECT.

INTRODUCTION: Continuation electroconvulsive therapy (c-ECT) is highly effective for the prevention of depressive symptom relapse. There is a lack of understanding, about how c-ECT works in humans, particularly with regard to its effects on brain derived neurotrophic factor (BDNF) concentrations. Here, we aimed to close a gap in the literature by evaluating BDNF levels in patients receiving c-ECT. METHODS: We included 13 patients with either unipolar or bipolar depression (mean age ± SD: 55.5 ± 17.1; f/m: 10/3; unipolar/bipolar: 10/3) who received between one and four c-ECT (average per patient: 2.8). Serum BDNF (sBDNF) levels were assessed before and after each c-ECT sessions. Clinical assessments were also administered both before and after treatment. RESULTS: Our analysis revealed a significant increase in sBDNF after each treatment (c-ECT 1-3: P < 0.001, c-ECT 4: P = 0.018). The application of multiple c-ECT treatments was not, however, associated with further sBDNF enhancements. Psychometric scores were not significantly altered following c-ECT. DISCUSSION: An increase in sBDNF concentrations subsequent to c-ECT parallel data from the animal literature, which has linked regularly applied electrical stimulation to neuroplastic processes. This finding suggests a relationship between ECT-induced sBDNF concentrations and (sustained) remission status, considering a stable clinical condition across c-ECT.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

The influence of the rs6295 gene polymorphism on serotonin-1A receptor distribution investigated with PET in patients with major depression applying machine learning.

Major depressive disorder (MDD) is the most common neuropsychiatric disease and despite extensive research, its genetic substrate is still not sufficiently understood. The common polymorphism rs6295 of the serotonin-1A receptor gene (HTR1A) is affecting the transcriptional regulation of the 5-HT1A receptor and has been closely linked to MDD. Here, we used positron emission tomography (PET) exploiting advances in data mining and statistics by using machine learning in 62 healthy subjects and 19 patients with MDD, which were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. All the subjects were genotyped for rs6295 and genotype was grouped in GG vs C allele carriers. Mixed model was applied in a ROI-based (region of interest) approach. ROI binding potential (BPND) was divided by dorsal raphe BPND as a specific measure to highlight rs6295 effects (BPDiv). Mixed model produced an interaction effect of ROI and genotype in the patients' group but no effects in healthy controls. Differences of BPDiv was demonstrated in seven ROIs; parahippocampus, hippocampus, fusiform gyrus, gyrus rectus, supplementary motor area, inferior frontal occipital gyrus and lingual gyrus. For classification of genotype, 'RandomForest' and Support Vector Machines were used, however, no model with sufficient predictive capability could be computed. Our results are in line with preclinical data, mouse model knockout studies as well as previous clinical analyses, demonstrating the two-pronged effect of the G allele on 5-HT1A BPND for, we believe, the first time. Future endeavors should address epigenetic effects and allosteric heteroreceptor complexes. Replication in larger samples of MDD patients is necessary to substantiate our findings.

Simple and rapid quantification of serotonin transporter binding using [11C]DASB bolus plus constant infusion.

INTRODUCTION: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data. METHODS: [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol 160-179min and one scan after [11C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT-70 for 60-70min after start of tracer infusion, VT-90 for 75-90min, VT-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects. RESULTS: A Kbol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. VT-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for VT-90 and 0.77-0.93 for VT-120 in these regions. BPND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BPND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at VT-90. Cortical BPND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BPND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at VT-90 with ICC 0.70 and 0.63, respectively. CONCLUSIONS: We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both VT and BPND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT VT and BPND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.