Artificial intelligence in neurology: opportunities, challenges, and policy implications.

Neurological conditions are the leading cause of disability and mortality combined, demanding innovative, scalable, and sustainable solutions. Brain health has become a global priority with adoption of the World Health Organization's Intersectoral Global Action Plan in 2022. Simultaneously, rapid advancements in artificial intelligence (AI) are revolutionizing neurological research and practice. This scoping review of 66 original articles explores the value of AI in neurology and brain health, systematizing the landscape for emergent clinical opportunities and future trends across the care trajectory: prevention, risk stratification, early detection, diagnosis, management, and rehabilitation. AI's potential to advance personalized precision neurology and global brain health directives hinges on resolving core challenges across four pillars-models, data, feasibility/equity, and regulation/innovation-through concerted pursuit of targeted recommendations. Paramount actions include swift, ethical, equity-focused integration of novel technologies into clinical workflows, mitigating data-related issues, counteracting digital inequity gaps, and establishing robust governance frameworks balancing safety and innovation.

Reliable evaluation of functional connectivity and graph theory measures in source-level EEG: How many electrodes are enough?

OBJECTIVE: Using EEG to characterise functional brain networks through graph theory has gained significant interest in clinical and basic research. However, the minimal requirements for reliable measures remain largely unaddressed. Here, we examined functional connectivity estimates and graph theory metrics obtained from EEG with varying electrode densities. METHODS: EEG was recorded with 128 electrodes in 33 participants. The high-density EEG data were subsequently subsampled into three sparser montages (64, 32, and 19 electrodes). Four inverse solutions, four measures of functional connectivity, and five graph theory metrics were tested. RESULTS: The correlation between the results obtained with 128-electrode and the subsampled montages decreased as a function of the number of electrodes. As a result of decreased electrode density, the network metrics became skewed: mean network strength and clustering coefficient were overestimated, while characteristic path length was underestimated. CONCLUSIONS: Several graph theory metrics were altered when electrode density was reduced. Our results suggest that, for optimal balance between resource demand and result precision, a minimum of 64 electrodes should be utilised when graph theory metrics are used to characterise functional brain networks in source-reconstructed EEG data. SIGNIFICANCE: Characterisation of functional brain networks derived from low-density EEG warrants careful consideration.

Intelligent digital tools for screening of brain connectivity and dementia risk estimation in people affected by mild cognitive impairment: the AI-Mind clinical study protocol.

More than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual's risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AI-Mind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind's innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contributions.

Introducing Region Based Pooling for handling a varied number of EEG channels for deep learning models.

Introduction: A challenge when applying an artificial intelligence (AI) deep learning (DL) approach to novel electroencephalography (EEG) data, is the DL architecture's lack of adaptability to changing numbers of EEG channels. That is, the number of channels cannot vary neither in the training data, nor upon deployment. Such highly specific hardware constraints put major limitations on the clinical usability and scalability of the DL models. Methods: In this work, we propose a technique for handling such varied numbers of EEG channels by splitting the EEG montages into distinct regions and merge the channels within the same region to a region representation. The solution is termed Region Based Pooling (RBP). The procedure of splitting the montage into regions is performed repeatedly with different region configurations, to minimize potential loss of information. As RBP maps a varied number of EEG channels to a fixed number of region representations, both current and future DL architectures may apply RBP with ease. To demonstrate and evaluate the adequacy of RBP to handle a varied number of EEG channels, sex classification based solely on EEG was used as a test example. The DL models were trained on 129 channels, and tested on 32, 65, and 129-channels versions of the data using the same channel positions scheme. The baselines for comparison were zero-filling the missing channels and applying spherical spline interpolation. The performances were estimated using 5-fold cross validation. Results: For the 32-channel system version, the mean AUC values across the folds were: RBP (93.34%), spherical spline interpolation (93.36%), and zero-filling (76.82%). Similarly, on the 65-channel system version, the performances were: RBP (93.66%), spherical spline interpolation (93.50%), and zero-filling (85.58%). Finally, the 129-channel system version produced the following results: RBP (94.68%), spherical spline interpolation (93.86%), and zero-filling (91.92%). Conclusion: In conclusion, RBP obtained similar results to spherical spline interpolation, and superior results to zero-filling. We encourage further research and development of DL models in the cross-dataset setting, including the use of methods such as RBP and spherical spline interpolation to handle a varied number of EEG channels.

The organization of functional neurocognitive networks in focal epilepsy correlates with domain-specific cognitive performance.

Understanding and diagnosing cognitive impairment in epilepsy remains a prominent challenge. New etiological models suggest that cognitive difficulties might not be directly linked to seizure activity, but are rather a manifestation of a broader brain pathology. Consequently, treating seizures is not sufficient to alleviate cognitive symptoms, highlighting the need for novel diagnostic tools. Here, we investigated whether the organization of three intrinsic, resting-state functional connectivity networks was correlated with domain-specific cognitive test performance. Using individualized EEG source reconstruction and graph theory, we examined the association between network small worldness and cognitive test performance in 23 patients with focal epilepsy and 17 healthy controls, who underwent a series of standardized pencil-and-paper and digital cognitive tests. We observed that the specific networks robustly correlated with test performance in distinct cognitive domains. Specifically, correlations were evident between the default mode network and memory in patients, the central-executive network and executive functioning in controls, and the salience network and social cognition in both groups. Interestingly, the correlations were evident in both groups, but in different domains, suggesting an alteration in these functional neurocognitive networks in focal epilepsy. The present findings highlight the potential clinical relevance of functional brain network dysfunction in cognitive impairment.

Navigating in the dark: Meta-synthesis of subjective experiences of gender dysphoria amongst transgender and gender non-conforming youth.

OBJECTIVE: We conducted a meta-synthesis of qualitative research on subjective experiences of gender dysphoria (GD) amongst transgender and gender non-conforming (TGNC) youth in order to improve clinical encounters, complement existing knowledge and potentially influence future research. METHODS: We systematically searched for qualitative studies on GD in English, German, Spanish and Scandinavian languages in seven databases. Starting with 2000 articles, we finally included 12 papers in the meta-synthesis, following Noblit and Hare's (1988) seven steps for qualitative meta-synthesis research. RESULTS: Through the consistent comparison of key concepts, we were able to cluster the findings from the 12 included studies into four meta-themes: (1) the emerging understanding and awareness of GD was described as navigation in the dark, (2) the importance of relationships and societal norms, (3) the role of the body and the exploration of one's own body and (4) sexuality and sexual impulses. The young person's relation with his or her own body and sexuality influences subjective experiences of GD. The experiences are always mediated in relation with other people and societal norms, and they are both long-lasting and changing. CONCLUSION: The phenomenological analysis indicated that GD is a complex phenomenon involving manifold factors that changes across time and place for each individual. GD is not a static phenomenon but an expression of continuous negotiation amongst the body, its impulses, sexual desire and the relationships in which each person participates. Therefore, clinicians who treat TGNC youth should help them to reflect on this developmental process over time as a complement to medical approaches.

Source-level EEG and graph theory reveal widespread functional network alterations in focal epilepsy.

OBJECTIVE: The hypersynchronous neuronal activity associated with epilepsy causes widespread functional network disruptions extending beyond the epileptogenic zone. This altered network topology is considered a mediator for non-seizure symptoms, such as cognitive impairment. The aim of this study was to investigate functional network alterations in focal epilepsy patients with good seizure control and high quality of life. METHODS: We compared twenty-two focal epilepsy patients and sixteen healthy controls on graph metrics derived from functional connectivity of source-level resting-state EEG. Graph metrics were calculated over a range of network densities in five frequency bands. RESULTS: We observed a significantly increased small world index in patients relative to controls. On the local level, two left-hemisphere regions displayed a shift towards greater alpha band "hubness". The findings were not mediated by age, sex or education, nor by age of epilepsy onset, duration or focus lateralisation. CONCLUSIONS: Widespread functional network alterations are evident in focal epilepsy, even in a cohort characterised by successful anti-seizure medication therapy and high quality of life. These findings might support the position that functional network analysis could hold clinical relevance for epilepsy. SIGNIFICANCE: Focal epilepsy is accompanied by global and local functional network aberrancies which might be implied in the sustenance of non-seizure symptoms.

Consensus Parameter: Research Methodologies to Evaluate Neurodevelopmental Effects of Pubertal Suppression in Transgender Youth.

Purpose: Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment. Methods: A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter. Results: The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning. Conclusion: An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth.

Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain.

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin-releasing hormone receptor (GnRH-R) antagonists with nanomolar binding affinity. A small library of GnRH-R antagonists was synthesised in 20-67 % overall yield with the aim of identifying a high-affinity antagonist capable of crossing the blood-brain barrier. Binding affinity to rat GnRH-R was determined by autoradiography in competitive-binding studies against [125 I]buserelin, and inhibition constants were calculated by using the Cheng-Prusoff equation. The radioligands were obtained in 46-79 % radiochemical yield and >95 % purity and with a molar activity of 19-38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor-saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.

The Predictive Value of Depression in the Years After Heart Transplantation for Mortality During Long-Term Follow-Up.

OBJECTIVE: Current understanding of the prognostic impact of depression on mortality after heart transplantation (HTx) is limited. We examined whether depression after HTx is a predictor of mortality during extended follow-up. Subsequently, we explored whether different symptom dimensions of depression could be identified and whether they were differentially associated with mortality. METHODS: Survival analyses were performed in a sample of 141 HTx recipients assessed for depression, measured by self-report of depressive symptoms (Beck Depression Inventory - version 1A [BDI-1A]), at median 5.0 years after HTx, and followed thereafter for survival status for up to 18.6 years. We used uni- and multivariate Cox proportional hazard models to examine the association of clinically significant depression (BDI-1A total score ≥10), as well as the cognitive-affective and the somatic subscales of the BDI-1A (resulting from principal component analysis) with mortality. In the multivariate analyses, we adjusted for relevant sociodemographic and clinical variables. RESULTS: Clinically significant depression was a significant predictor of mortality (hazard ratio = 2.088; 95% confidence interval = 1.366-3.192; p = .001). Clinically significant depression also was an independent predictor of mortality in the multivariate analysis (hazard ratio = 1.982; 95% confidence interval = 1.220-3.217; p = .006). The somatic subscale, but not the cognitive-affective subscale, was significantly associated with increased mortality in univariate analyses, whereas neither of the two subscales was an independent predictor of mortality in the multivariate analysis. CONCLUSIONS: Depression measured by self-report after HTx is associated with increased mortality during extended follow-up. Clinical utility and predictive validity of specific depression components require further study.

Multiple Microelectrode Recordings in STN-DBS Surgery for Parkinson's Disease: A Randomized Study.

BACKGROUND: Subthalamic nucleus deep brain stimulation improves motor symptoms and fluctuations in advanced Parkinson's disease, but the degree of clinical improvement depends on accurate anatomical electrode placement. Methods used to localize the sensory-motor part of the nucleus vary substantially. Using microelectrode recordings, at least three inserted microelectrodes are needed to obtain a three-dimensional map. Therefore, multiple simultaneously inserted microelectrodes should provide better guidance than single sequential microelectrodes. We aimed to compare the use of multiple simultaneous versus single sequential microelectrode recordings on efficacy and safety of subthalamic nucleus stimulation. METHODS: Sixty patients were included in this double-blind, randomized study, 30 in each group. Primary outcome measures were the difference from baseline to 12 months in the MDS-UPDRS motor score (part III) in the off-medication state and quality of life using the Parkinson's Disease Questionnaire-39 (PDQ-39) scores. RESULTS: The mean reduction of the MDS-UPDRS III off score was 35 (SD 12) in the group investigated with multiple simultaneous microelectrodes compared to 26 (SD 10) in the single sequential microelectrode group (p = 0.004). The PDQ-39 Summary Index did not differ between the groups, but the domain scores activities of daily living and bodily discomfort improved significantly more in the multiple microelectrodes group. The frequency of serious adverse events did not differ significantly. CONCLUSIONS: After 12 months of subthalamic nucleus stimulation, the multiple microelectrodes group had a significantly greater improvement both in MDS-UPDRS III off score and in two PDQ-39 domains. Our results may support the use of multiple simultaneous microelectrode recordings. TRIAL REGISTRATION: http://ClinicalTrials.gov Identifier: NCT00855621 (first received March 3, 2009).

FDG-based quantitative comparison of glucose metabolism in vitro, exemplified by a head-to-head comparison between a triple-negative breast cancer cell line and a non-malignant foetal cell line.

BACKGROUND: Glucose metabolism can be studied in vitro by a variety of means, also by fluorodeoxyglucose (FDG). As an example of the potential use we have compared the high glucose consumption in cancer cells and in transformed non-malignant foetal cells. The high glucose metabolism in cancer cells is not primarily for the production of energy, a large proportion is transformed to lactate only, producing two instead of potentially 32 ATP equivalents. The secreted lactate reduces the pH in the local microenvironment and gives malignant cells, more apt to thrive in hypoxic and acid environments, a competitive advantage. PURPOSE: To demonstrate the use of FDG in head-to-head comparison of glucose uptake and lactate production in a highly malignant and a highly proliferative non-malignant cell line. MATERIALS AND METHODS: Cell cultures of a foetal kidney cell line and a triple negative breast cancer cell line were incubated with FDG for one hour, washed, harvested and the radioactivity content in the cells was measured in a well counter. The lactate concentration was measured in conditioned medium. RESULTS: The FDG uptake was consistently higher in the non-malignant foetal cell line. The levels of lactate in the conditioned medium were similar. CONCLUSION: Quantitative comparison of glucose metabolism by in vitro use of FDG is a practical, cheap and rapid method. Some foetal cells have higher glucose uptake and produce as much lactate as this highly malignant cell line. This is an argument against the high glucose consumption being related solely to malignancy.

Recent Development of Non-Peptide GnRH Antagonists.

The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications.

Cognitive function among long-term survivors of heart transplantation.

BACKGROUND: Cognitive impairment is documented early after heart transplantation (HTx), but we lack data on cognitive function beyond the fourth year post-transplant. Against the background of good long-term survival, this knowledge is necessary to improve clinical care throughout the entire post-transplant period. METHODS: We assessed cognitive function with a neuropsychological test battery in a sample of HTx recipients ≥16 years post-transplant. To improve clinical utility, we also applied adapted consensus criteria for Mild Cognitive Impairment (MCI). Furthermore, we explored sociodemographic and clinical characteristics possibly related to cognitive function. RESULTS: Thirty-seven subjects were included 20.3 (±3.8) years after HTx. Mean age was 57.5 (±14.2) years, and 18.9% were women. Up to 38.9% exhibited impaired test performance (ie, performance at least 1.5 standard deviations below the normative mean) on several individual cognitive measures, especially on measures of processing speed, executive functions, memory, and language functions. One subject was diagnosed with dementia, and 30.1% qualified for MCI. Those with MCI had lower hemoglobin than those without. CONCLUSIONS: A substantial proportion of long-term survivors of HTx might be cognitively impaired. The level of impairment appears comparable to what is defined as MCI in the literature. Modifiable factors related to cognitive impairment might exist.

Cognitive function after heart transplantation: Comparing everolimus-based and calcineurin inhibitor-based regimens.

BACKGROUND: Studies have shown conflicting results concerning the occurrence of cognitive impairment after successful heart transplantation (HTx). Another unresolved issue is the possible differential impact of immunosuppressants on cognitive function. In this study, we describe cognitive function in a cohort of HTx recipients and subsequently compare cognitive function between subjects on either everolimus- or calcineurin inhibitor (CNI)-based immunosuppression. METHODS: Cognitive function, covering attention, processing speed, executive functions, memory, and language functions, was assessed with a neuropsychological test battery. Thirty-seven subjects were included (everolimus group: n=20; CNI group: n=17). The extent of cerebrovascular pathology was assessed with magnetic resonance imaging. RESULTS: About 40% of subjects had cognitive impairment, defined as performance at least 1.5 standard deviations below normative mean in one or several cognitive domains. Cerebrovascular pathology was present in 33.3%. There were no statistically significant differences between treatment groups across cognitive domains. CONCLUSIONS: Given the high prevalence of cognitive impairment in the sample, plus the known negative impact of cognitive impairment on clinical outcome, our results indicate that cognitive assessment should be an integrated part of routine clinical follow-up after HTx. However, everolimus- and CNI-based immunosuppressive regimens did not show differential impacts on cognitive function.

Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor.

In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound 8a showed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.

Cognitive, Emotional, and Psychosocial Functioning of Girls Treated with Pharmacological Puberty Blockage for Idiopathic Central Precocious Puberty.

Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow-release GnRHa (triptorelin acetate-Decapeptyl SR® 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the children's parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohen's d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohen's d = 1.03); lower heart rate was associated with longer treatment duration (r = -0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health.

Brain penetrant small molecule (18)F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats.

INTRODUCTION: The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood-brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [(18)F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these (18)F-labeled compounds in brain of living rats. METHODS: We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for (18)F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo. RESULTS: A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The (18)F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5-15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the (18)F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding in vivo. CONCLUSIONS: The novel small molecule (18)F-fluorinated GnRH-R antagonist compounds show high receptor affinity in vitro, and may prove useful for quantitative autoradiographic studies in vitro. The compounds were permeable to the blood-brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain.

Measuring Gender Dysphoria: A Multicenter Examination and Comparison of the Utrecht Gender Dysphoria Scale and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults.

This study examined two instruments measuring gender dysphoria within the multicenter study of the European Network for the Investigation of Gender Incongruence (ENIGI). The Utrecht Gender Dysphoria Scale (UGDS) and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA) were examined for their definitions of gender dysphoria and their psychometric properties, and evaluated for their congruence in assessing the construct. The sample of 318 participants consisted of 178 male-to-females (MtF) and 140 female-to-males (FtM) who were recruited from the four ENIGI gender clinics. Both instruments were significantly correlated in the group of MtFs. For the FtM group, there was a trend in the same direction but smaller. Gender dysphoria was found to be defined differently in the two instruments, which led to slightly different findings regarding the subgroups. The UGDS detected a difference between the subgroups of early and late onset of gender identity disorder in the group of MtFs, whereas the GIDYQ-AA did not. For the FtM group, no significant effect of age of onset was found. Therefore, both instruments seem to capture not only similar but also different aspects of gender dysphoria. The UGDS focusses on bodily aspects, gender identity, and gender role, while the GIDYQ-AA addresses subjective, somatic, social, and sociolegal aspects. For future research, consistency in theory and definition of gender dysphoria is needed and should be in line with the DSM-5 diagnosis of gender dysphoria in adolescents and adults.

Body Satisfaction and Physical Appearance in Gender Dysphoria.

Gender dysphoria (GD) is often accompanied by dissatisfaction with physical appearance and body image problems. The aim of this study was to compare body satisfaction with perceived appearance by others in various GD subgroups. Data collection was part of the European Network for the Investigation of Gender Incongruence. Between 2007 and 2012, 660 adults who fulfilled the criteria of the DSM-IV gender identity disorder diagnosis (1.31:1 male-to-female [MtF]:female-to-male [FtM] ratio) were included into the study. Data were collected before the start of clinical gender-confirming interventions. Sexual orientation was measured via a semi-structured interview whereas onset age was based on clinician report. Body satisfaction was assessed using the Body Image Scale. Congruence of appearance with the experienced gender was measured by means of a clinician rating. Overall, FtMs had a more positive body image than MtFs. Besides genital dissatisfaction, problem areas for MtFs included posture, face, and hair, whereas FtMs were mainly dissatisfied with hip and chest regions. Clinicians evaluated the physical appearance to be more congruent with the experienced gender in FtMs than in MtFs. Within the MtF group, those with early onset GD and an androphilic sexual orientation had appearances more in line with their gender identity. In conclusion, body image problems in GD go beyond sex characteristics only. An incongruent physical appearance may result in more difficult psychological adaptation and in more exposure to discrimination and stigmatization.