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.Peer reviewe

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

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 signifi-cant 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 met-rics obtained from EEG with varying electrode densities.Methods: EEG was recorded with 128 electrodes in 33 participants. The high-density EEG data were sub-sequently 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 net-work 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 elec-trodes 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 care-ful consideration.(c) 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

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 [125l]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

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 [125l]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

Recalled gender-related play behavior and peer-group preferences in childhood and adolescence among adults applying for gender-affirming treatment

Norms are considered to influence expectations toward gender-related behavior. Deviations from these norms are often perceived negatively by the social environment. The objective of this study was to investigate adults diagnosed with a Gender Identity Disorder (GID), their recalled play behavior, and peer preferences in childhood and adolescence. Differences between individuals who applied for transition from female to male (FtMs) and those who applied for transition from male to female (MtFs) and between age-of-onset subgroups were explored. Data collection took place as part of the European Network for the Investigation of Gender Incongruence. The sample consisted of N = 634 participants (mean age = 30.6) diagnosed with GID according to DSM-IV-TR who were recruited between 2007 and 2012. Participants answered two questions regarding recalled play behavior and three questions on peer preferences. Nonconforming gender expression was more frequently recalled in FtMs than MtFs. Within gender groups, individuals who were categorized as early-onset recalled nonconforming gender expression more frequently than individuals who were categorized as late-onset. The results of the study are in line with previous findings indicating different phenomenological pathways in individuals applying for gender-affirming treatment that warrant attention. Factors that are considered to impact on gender-related differences in nonconforming gender expression are discussed