Gender Dysphoria and Sexual Euphoria: A Bayesian Perspective on the Influence of Gender-Affirming Hormone Therapy on Sexual Arousal.

Self-reported sexual orientation of transgender individuals occasionally changes over transition. Using functional magnetic resonance imaging, we tested the hypothesis that neural and behavioral patterns of sexual arousal in transgender individuals would shift from the assigned to the experienced gender (e.g., trans women's responses becoming more dissimilar to those of cis men and more similar to those of cis women). To this aim, trans women (N = 12) and trans men (N = 20) as well as cisgender women (N = 24) and cisgender men (N = 14) rated visual stimuli showing male-female, female-female or male-male intercourse for sexual arousal before and after four months of gender-affirming hormone therapy. A Bayesian framework allowed us to incorporate previous behavioral findings. The hypothesized changes could indeed be observed in the behavioral responses with the strongest results for trans men and female-female scenes. Activation of the ventral striatum supported our hypothesis only for female-female scenes in trans women. The respective application or depletion of androgens in trans men and trans women might partly explain this observation. The prominent role of female-female stimuli might be based on the differential responses they elicit in cis women and men or, in theory, the controversial concept of autogynephilia. We show that correlates of sexual arousal in transgender individuals might change in the direction of the experienced gender. Future investigations should elucidate the mechanistic role of sex hormones and the cause of the differential neural and behavioral findings.The study was registered at ClinicalTrials.gov (NCT02715232), March 22, 2016.

ABCB1 variants and sex affect serotonin transporter occupancy in the brain.

Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [11C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers (n = 26, MAF = 0.18) compared to major allele homozygotes (t73 = 2.73, pFWE < 0.05) as well as in men compared to women (t73 = 3.33, pFWE < 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was -14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, -4.83 ± 2.70% lower per 10 kg bodyweight, and -2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry.

Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy.

BACKGROUND: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity. METHODS: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance. RESULTS: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05). LIMITATIONS: We did not address the influence of transition-related psychological and behavioural changes. CONCLUSION: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.

Escitalopram modulates learning content-specific neuroplasticity of functional brain networks.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

Serotonergic modulation of effective connectivity in an associative relearning network during task and rest.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

Sex Matters: A Multivariate Pattern Analysis of Sex- and Gender-Related Neuroanatomical Differences in Cis- and Transgender Individuals Using Structural Magnetic Resonance Imaging.

Univariate analyses of structural neuroimaging data have produced heterogeneous results regarding anatomical sex- and gender-related differences. The current study aimed at delineating and cross-validating brain volumetric surrogates of sex and gender by comparing the structural magnetic resonance imaging data of cis- and transgender subjects using multivariate pattern analysis. Gray matter (GM) tissue maps of 29 transgender men, 23 transgender women, 35 cisgender women, and 34 cisgender men were created using voxel-based morphometry and analyzed using support vector classification. Generalizability of the models was estimated using repeated nested cross-validation. For external validation, significant models were applied to hormone-treated transgender subjects (n = 32) and individuals diagnosed with depression (n = 27). Sex was identified with a balanced accuracy (BAC) of 82.6% (false discovery rate [pFDR] < 0.001) in cisgender, but only with 67.5% (pFDR = 0.04) in transgender participants indicating differences in the neuroanatomical patterns associated with sex in transgender despite the major effect of sex on GM volume irrespective of the self-identification as a woman or man. Gender identity and gender incongruence could not be reliably identified (all pFDR > 0.05). The neuroanatomical signature of sex in cisgender did not interact with depressive features (BAC = 74.7%) but was affected by hormone therapy when applied in transgender women (P < 0.001).

Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm.

Neural plasticity is a complex process dependent on neurochemical underpinnings. Next to the glutamatergic system which contributes to memory formation via long-term potentiation (LTP) and long-term depression (LTD), the main inhibitory neurotransmitter, GABA is crucially involved in neuroplastic processes. Hence, we investigated changes in glutamate and GABA levels in the brain in healthy participants performing an associative learning paradigm. Twenty healthy participants (10 female, 25 ±â€¯5 years) underwent paired multi-voxel magnetic resonance spectroscopy imaging before and after completing 21 days of a facial associative learning paradigm in a longitudinal study design. Changes of GABA and glutamate were compared to retrieval success in the hippocampus, insula and thalamus. No changes in GABA and glutamate concentration were found after 21 days of associative learning. However, baseline hippocampal GABA levels were significantly correlated with initial retrieval success (pcor = 0.013, r = 0.690). In contrast to the thalamus and insula (pcor>0.1), higher baseline GABA levels in the hippocampus were associated with better retrieval performance in an associative learning paradigm. Therefore, our findings support the importance of hippocampal GABA levels in memory formation in the human brain in vivo.

The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI.

Functional magnetic resonance imaging (fMRI) successfully disentangled neuronal pathophysiology of major depression (MD), but only a few fMRI studies have investigated correlates and predictors of remission. Moreover, most studies have used clinical outcome parameters from two time points, which do not optimally depict differential response times. Therefore, we aimed to detect neuronal correlates of response and remission in an antidepressant treatment study with 7 T fMRI, potentially harnessing advances in detection power and spatial specificity. Moreover, we modeled outcome parameters from multiple study visits during a 12-week antidepressant fMRI study in 26 acute (aMD) patients compared to 36 stable remitted (rMD) patients and 33 healthy control subjects (HC). During an electrical painful stimulation task, significantly higher baseline activity in aMD compared to HC and rMD in the medial thalamic nuclei of the pulvinar was detected (p = 0.004, FWE-corrected), which was reduced by treatment. Moreover, clinical response followed a sigmoid function with a plateau phase in the beginning, a rapid decline and a further plateau at treatment end. By modeling the dynamic speed of response with fMRI-data, perigenual anterior cingulate activity after treatment was significantly associated with antidepressant response (p < 0.001, FWE-corrected). Temporoparietal junction (TPJ) baseline activity significantly predicted non-remission after 2 antidepressant trials (p = 0.005, FWE-corrected). The results underline the importance of the medial thalamus, attention networks in MD and antidepressant treatment. Moreover, by using a sigmoid model, this study provides a novel method to analyze the dynamic nature of response and remission for future trials.

Correction to: The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI.

The author list was presented as last name, first name. The names should have been listed as:Christoph Kraus, Manfred Klöbl, Martin Tik, Bastian Auer, Thomas Vanicek, Nicole Geissberger, Daniela M. Pfabigan, Andreas Hahn, Michael Woletz, Katharina Paul, Arkadiusz Komorowski, Siegfried Kasper, Christian Windischberger, Claus Lamm, Rupert Lanzenberger.

Structural changes in amygdala nuclei, hippocampal subfields and cortical thickness following electroconvulsive therapy in treatment-resistant depression: longitudinal analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is the treatment of choice for severe mental illness including treatment-resistant depression (TRD). Increases in volume of the hippocampus and amygdala following ECT have consistently been reported.AimsTo investigate neuroplastic changes after ECT in specific hippocampal subfields and amygdala nuclei using high-resolution structural magnetic resonance imaging (MRI) (trial registration: clinicaltrials.gov - NCT02379767). METHOD: MRI scans were carried out in 14 patients (11 women, 46.9 years (s.d. = 8.1)) with unipolar TRD twice before and once after a series of right unilateral ECT in a pre-post study design. Volumes of subcortical structures, including subfields of the hippocampus and amygdala, and cortical thickness were extracted using FreeSurfer. The effect of ECT was tested using repeated-measures ANOVA. Correlations of imaging and clinical parameters were explored. RESULTS: Increases in volume of the right hippocampus by 139.4 mm3 (s.d. = 34.9), right amygdala by 82.3 mm3 (s.d. = 43.9) and right putamen by 73.9 mm3 (s.d. = 77.0) were observed. These changes were localised in the basal and lateral nuclei, and the corticoamygdaloid transition area of the amygdala, the hippocampal-amygdaloid transition area and the granule cell and molecular layer of the dentate gyrus. Cortical thickness increased in the temporal, parietal and insular cortices of the right hemisphere. CONCLUSIONS: Following ECT structural changes were observed in hippocampal subfields and amygdala nuclei that are specifically implicated in the pathophysiology of depression and stress-related disorders and retain a high potential for neuroplasticity in adulthood.Declaration of interestS.K. has received grants/research support, consulting fees and/or honoraria within the past 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier. R.L. received travel grants and/or conference speaker honoraria from Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH.

Reduced task durations in functional PET imaging with [18F]FDG approaching that of functional MRI.

INTRODUCTION: The brain's energy budget can be non-invasively assessed with different imaging modalities such as functional MRI (fMRI) and PET (fPET), which are sensitive to oxygen and glucose demands, respectively. The introduction of hybrid PET/MRI systems further enables the simultaneous acquisition of these parameters. Although a recently developed method offers the quantification of task-specific changes in glucose metabolism (CMRGlu) in a single measurement, direct comparison of the two imaging modalities is still difficult because of the different temporal resolutions. Thus, we optimized the protocol and systematically assessed shortened task durations of fPET to approach that of fMRI. METHODS: Twenty healthy subjects (9 male) underwent one measurement on a hybrid PET/MRI scanner. During the scan, tasks were completed in four blocks for fMRI (4 × 30 s blocks) and fPET: participants tapped the fingers of their right hand repeatedly to the thumb while watching videos of landscapes. For fPET, subjects were randomly assigned to groups of n = 5 with varying task durations of 10, 5, 2 and 1 min, where task durations were kept constant within a measurement. The radiolabeled glucose analogue [18F]FDG was administered as 20% bolus plus constant infusion. The bolus increases the signal-to-noise ratio and leaves sufficient activity to detect task-related effects but poses additional challenges due to a discontinuity in the tracer uptake. First, three approaches to remove task effects from the baseline term were evaluated: (1) multimodal, based on the individual fMRI analysis, (2) atlas-based by removing presumably activated regions and (3) model-based by fitting the baseline with exponential functions. Second, we investigated the need to capture the arterial input function peak with automatic blood sampling for the quantification of CMRGlu. We finally compared the task-specific activation obtained from fPET and fMRI qualitatively and statistically. RESULTS: CMRGlu quantified only with manual arterial samples showed a strong correlation to that obtained with automatic sampling (r = 0.9996). The multimodal baseline definition was superior to the other tested approaches in terms of residuals (p < 0.001). Significant task-specific changes in CMRGlu were found in the primary visual and motor cortices (tM1 = 18.7 and tV1 = 18.3). Significant changes of fMRI activation were found in the same areas (tM1 = 16.0 and tV1 = 17.6) but additionally in the supplementary motor area, ipsilateral motor cortex and secondary visual cortex. Post-hoc t-tests showed strongest effects for task durations of 5 and 2 min (all p < 0.05 FWE corrected), whereas 1 min exhibited pronounced unspecific activation. Percent signal change (PSC) was higher for CMRGlu (∼18%-27%) compared to fMRI (∼2%). No significant association between PSC of task-specific CMRGlu and fMRI was found (r = 0.26). CONCLUSION: Using a bolus plus constant infusion protocol, the necessary task duration for reliable quantification of task-specific CMRGlu could be reduced to 5 and 2 min, therefore, approaching that of fMRI. Important for valid quantification is a correct baseline definition, which was ideal when task-relevant voxels were determined with fMRI. The absence of a correlation and the different activation pattern between fPET and fMRI suggest that glucose metabolism and oxygen demand capture complementary aspects of energy demands.

Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Individual brain regulation as learned via neurofeedback is related to affective changes in adolescents with autism spectrum disorder.

BACKGROUND: Emotions often play a role in neurofeedback (NF) regulation strategies. However, investigations of the relationship between the induced neuronal changes and improvements in affective domains are scarce in electroencephalography-based studies. Thus, we extended the findings of the first study on slow cortical potential (SCP) NF in autism spectrum disorder (ASD) by linking affective changes to whole-brain activity during rest and regulation. METHODS: Forty-one male adolescents with ASD were scanned twice at rest using functional magnetic resonance imaging. Between scans, half underwent NF training, whereas the other half received treatment as usual. Furthermore, parents reported on their child's affective characteristics at each measurement. The NF group had to alternatingly produce negative and positive SCP shifts during training and was additionally scanned using functional magnetic resonance imaging while applying their developed regulation strategies. RESULTS: No significant treatment group-by-time interactions in affective or resting-state measures were found. However, we found increases of resting activity in the anterior cingulate cortex and right inferior temporal gyrus as well as improvements in affective characteristics over both groups. Activation corresponding to SCP differentiation in these regions correlated with the affective improvements. A further correlation was found for Rolandic operculum activation corresponding to positive SCP shifts. There were no significant correlations with the respective achieved SCP regulation during NF training. CONCLUSION: SCP NF in ASD did not lead to superior improvements in neuronal or affective functioning compared to treatment as usual. However, the affective changes might be related to the individual strategies and their corresponding activation patterns as indicated by significant correlations on the whole-brain level. Trial registration This clinical trial was registered at drks.de (DRKS00012339) on 20th April, 2017.

The influence of sex steroid treatment on insular connectivity in gender dysphoria.

BACKGROUND: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. METHODS: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. RESULTS: A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests demonstrated an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. CONCLUSION: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.

Effects of bilateral sequential theta-burst stimulation on functional connectivity in treatment-resistant depression: First results.

BACKGROUND: Previous studies suggest that transcranial magnetic stimulation exerts antidepressant effects by altering functional connectivity (FC). However, knowledge about this mechanism is still limited. Here, we aimed to investigate the effect of bilateral sequential theta-burst stimulation (TBS) on FC in treatment-resistant depression (TRD) in a sham-controlled longitudinal study. METHODS: TRD patients (n = 20) underwent a three-week treatment of intermittent TBS of the left and continuous TBS of the right dorsolateral prefrontal cortex (DLPFC). Upon this trial's premature termination, 15 patients had received active TBS and five patients sham stimulation. Resting-state functional magnetic resonance imaging was performed at baseline and after treatment. FC (left and right DLPFC) was estimated for each participant, followed by group statistics (t-tests). Furthermore, depression scores were analyzed (linear mixed models analysis) and tested for correlation with FC. RESULTS: Both groups exhibited reductions of depression scores, however, there was no significant main effect of group, or group and time. Anticorrelations between DLPFC and the subgenual cingulate cortex (sgACC) were observed for baseline FC, corresponding to changes in depression severity. Treatment did not significantly change DLPFC-sgACC connectivity, but significantly reduced FC between the left stimulation target and bilateral anterior insula. CONCLUSIONS: Our data is compatible with previous reports on the relevance of anticorrelation between DLPFC and sgACC for treatment success. Furthermore, FC changes between left DLPFC and bilateral anterior insula highlight the effect of TBS on the salience network. LIMITATIONS: Due to the limited sample size, results should be interpreted with caution and are of exploratory nature.

Brain Stimulation for Emotion Regulation in Adolescents With Psychiatric Disorders: Study Protocol for a Clinical-Transdiagnostical, Randomized, Triple-Blinded and Sham-Controlled Neurotherapeutic Trial.

Background: Anxiety, conduct and depressive disorders represent three highly prevalent psychiatric conditions in adolescents. A shared underpinning of these disorders is a shortcoming in emotion regulation, connected to the functioning of the ventromedial prefrontal cortex. Thus, an intervention able to target the suggested neural correlate seems to be highly desirable, aiming to hinder a maladaptive development of emotion regulation abilities and chronification of associated psychiatric disorders. As transcranial direct current stimulation (tDCS) was repeatedly demonstrated as a safe and non-invasive method to modulate specific brain activity, research is in demand to evaluate neurotherapeutic applications in adolescents with psychiatric disorders. Method: This transdiagnostic, randomized, triple-blind and sham-controlled clinical neurostimulation trial primary aims to investigate if emotion regulation abilities are increased after tDCS in adolescents with psychiatric disorders. Secondly, disorder-specific changes in the anxiety, depression or conduct disorder will be investigated, as well as changes in quality of life, and cognitive and emotional functioning after tDCS intervention. We will include 108 adolescents with psychiatric disorders, displaying a substantial deficit in emotion regulation. Of these, one third each has to be primarily diagnosed with a depressive, anxiety or conduct disorder, respectively. Participants will be randomized to the experimental group (n = 54) receiving real anodal tDCS, or to the control group (n = 54) receiving sham tDCS. Brain stimulation will be applied for 20 min on five consecutive days twice targeting the ventromedial prefrontal cortex (vmPFC). Changes in emotion regulation, together with changes in disorder-specific clinical symptoms will be recorded by multi-informant psychological ratings. To inspect changes in behavior and gaze, computerized tasks and an eye tracker system will be used. Changes in brain responses to emotional and cognitive stimuli will be examined with three functional magnetic resonance imaging (fMRI) paradigms. In addition, a resting state MRI will be acquired to investigate possible changes in brain connectivity. Discussion: By investigating "emotion regulation" as transdiagnostic treatment target, this project is oriented toward the Research Domain Criteria framework with a dimensional view on mental illness. The study aims at investigating the potential of tDCS as non-invasive intervention for depressive, anxiety and conduct disorders in adolescents and broadening the scientific foundation for its clinical application. Clinical Trial Registration: The study is ongoing and has been registered in the German Registry of Clinical Trials (DRKS-ID: DRKS00025601X) on the 28.06.2021.

Enrichment of Disease-Associated Genes in Cortical Areas Defined by Transcriptome-Based Parcellation.

BACKGROUND: Parcellation of the cerebral cortex serves the investigation of the emergence of uniquely human brain functions and disorders. Transcriptome data enable the characterization of the molecular properties of cortical areas in unprecedented detail. Previously, we predicted the expression of 18,686 genes in the entire human brain based on microarray data. Here, we employed these data to parcellate the cortex and study the regional enrichment of disease-associated genes. METHODS: We performed agglomerative hierarchical clustering based on normalized transcriptome data to delineate areas with distinct gene expression profiles. Subsequently, we tested these profiles for the enrichment of gene sets associated with brain disorders by genome-wide association studies and expert-curated databases using gene set enrichment analysis. RESULTS: Transcriptome-based parcellation identified borders in line with major anatomical landmarks and the functional differentiation of primary motor, somatosensory, visual, and auditory areas. Gene set enrichment analysis based on curated databases suggested new roles of specific areas in psychiatric and neurological disorders while reproducing well-established links for movement and neurodegenerative disorders, for example, amyotrophic lateral sclerosis (motor cortex) and Alzheimer's disease (entorhinal cortex). Meanwhile, gene sets derived from genome-wide association studies on psychiatric disorders exhibited similar enrichment patterns driven by pleiotropic genes expressed in the posterior fusiform gyrus and inferior parietal lobule. CONCLUSIONS: The identified enrichment patterns suggest the vulnerability of specific cortical areas to various influences that might alter the risk of developing one or several brain disorders. For several diseases, specific genes were highlighted, which could lead to the discovery of novel disease mechanisms and urgently needed treatments.

Learning induces coordinated neuronal plasticity of metabolic demands and functional brain networks.

The neurobiological basis of learning is reflected in adaptations of brain structure, network organization and energy metabolism. However, it is still unknown how different neuroplastic mechanisms act together and if cognitive advancements relate to general or task-specific changes. Therefore, we tested how hierarchical network interactions contribute to improvements in the performance of a visuo-spatial processing task by employing simultaneous PET/MR neuroimaging before and after a 4-week learning period. We combined functional PET and metabolic connectivity mapping (MCM) to infer directional interactions across brain regions. Learning altered the top-down regulation of the salience network onto the occipital cortex, with increases in MCM at resting-state and decreases during task execution. Accordingly, a higher divergence between resting-state and task-specific effects was associated with better cognitive performance, indicating that these adaptations are complementary and both required for successful visuo-spatial skill learning. Simulations further showed that changes at resting-state were dependent on glucose metabolism, whereas those during task performance were driven by functional connectivity between salience and visual networks. Referring to previous work, we suggest that learning establishes a metabolically expensive skill engram at rest, whose retrieval serves for efficient task execution by minimizing prediction errors between neuronal representations of brain regions on different hierarchical levels.

Increased left dorsolateral prefrontal cortex density following escitalopram intake during relearning: a randomized, placebo-controlled trial in healthy humans.

Background: Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives: The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design: Randomized double blind placebo control, monocenter study. Methods: In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results: Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion: The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration: ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors; URL: https://clinicaltrials.gov/ct2/show/NCT02753738.

Repeated Sessions of Transcranial Direct Current Stimulation on Adolescents With Autism Spectrum Disorder: Study Protocol for a Randomized, Double-Blind, and Sham-Controlled Clinical Trial.

Background: Social-emotional difficulties are a core symptom of autism spectrum disorder (ASD). Accordingly, individuals with ASD have problems with social cognition such as recognizing emotions from other peoples' faces. Various results from functional magnetic resonance imaging and electroencephalography studies as well as eye-tracking data reveal a neurophysiological basis of these deficits by linking them to abnormal brain activity. Thus, an intervention targeting the neural origin of ASD impairments seems warranted. A safe method able to influence neural activity is transcranial direct current stimulation (tDCS). This non-invasive brain stimulation method has already demonstrated promising results in several neuropsychiatric disorders in adults and children. The aim of this project is to investigate the effects of tDCS on ASD symptoms and their neural correlates in children and adolescents with ASD. Method: This study is designed as a double-blind, randomized, and sham-controlled trial with a target sample size of 20 male participants (aged 12-17 years) diagnosed with ASD. Before randomization, the participants will be stratified into comorbid depression, comorbid ADHS/conduct disorder, or no-comorbidity groups. The intervention phase comprises 10 sessions of anodal or sham tDCS applied over the left prefrontal cortex within 2 consecutive weeks. To engage the targeted brain regions, participants will perform a social cognition training during the stimulation. TDCS-induced effects on ASD symptoms and involved neural circuits will be investigated through psychological, neurophysiological, imaging, and behavioral data at pre- and post-measurements. Tolerability will be evaluated using a standardized questionnaire. Follow-up assessments 1 and 6 months after the intervention will examine long-lasting effects. Discussion: The results of this study will provide insights into the changeability of social impairments in ASD by investigating social and emotional abilities on different modalities following repeated sessions of anodal tDCS with an intra-simulation training. Furthermore, this trial will elucidate the tolerability and the potential of tDCS as a new treatment approach for ASD in adolescents. Clinical Trial Registration: The study is ongoing and has been registered in the German Registry of Clinical Trials (DRKS00017505) on 02/07/2019.