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.

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.

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.

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.

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.

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.

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 Image in Young Gender Dysphoric Adults: A European Multi-Center Study.

The alteration of sex-specific body features and the establishment of a satisfactory body image are known to be particularly relevant for individuals with Gender Dysphoria (GD). The aim of the study was to first develop new scales and examine the psychometric properties of the Hamburg Body Drawing Scale (Appelt & Strauß 1988). For the second part of this study, the satisfaction with different body features in young GD adults before cross-sex treatment were compared to female and male controls. Data collection took place within the context of the European Network for the Investigation of Gender Incongruence (ENIGI) including 135 female-to-male (FtMs) and 115 male-to-female (MtFs) young GD adults and 235 female and 379 male age-adjusted controls. The five female and six male body feature subscales revealed good internal consistency. The ENIGI sample reported less satisfaction with overall appearance (d = 0.30) and with all of their body features than controls, but no subgroup differences for sexual orientation (FtM and MtF) and Age of Onset (FtM) were found. Body dissatisfaction was higher with regard to sex-specific body features (largest effect sizes of d = 3.21 for Genitalia in FtMs and d = 2.85 for Androgen-responsive features and genitalia in MtFs) than with those that appeared less related to the natal sex (d = 0.64 for Facial features in FtMs and d = 0.59 for Body shape in MtFs). Not only medical body modifying interventions, but also psychosocial guidance with regard to body image might be helpful for GD individuals before transitioning.

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.

Sexual behavior of gender-dysphoric individuals before gender-confirming interventions: a European multicenter study.

A transsexual course of development that starts before puberty (early onset) or during or after puberty, respectively (late onset), may lead to diverse challenges in coping with sexual activity. The authors explored the sexual behavior of 380 adult male-to-female and female-to-male individuals diagnosed according to DSM-IV-TR criteria who had not yet undergone gender-confirming interventions. Data originated from the European Network for the Investigation of Gender Incongruence Initiative, conducted in Belgium, Germany, The Netherlands, and Norway. Information on outcome variables was collected using self-administered questionnaires at first clinical presentation. Compared with late-onset male-to-females, early-onset individuals tended to show sexual attraction toward males more frequently (50.5%), involve genitals less frequently in partner-related sexual activity, and consider penile sensations and orgasm as more negative. Early-onset female-to-males predominantly reported sexual attraction toward females (84.0%), whereas those with a late-onset more frequently showed other sexual attractions (41.7%). The study (a) shows that early- and late-onset male-to-females differ considerably with regard to coping strategies involving their body during sexual relations and (b) reveals initial insights into developmental pathways of late-onset female-to-males.

Psychiatric characteristics in transsexual individuals: multicentre study in four European countries.

BACKGROUND: Research into the relationship between gender identity disorder and psychiatric problems has shown contradictory results. AIMS: To investigate psychiatric problems in adults fulfilling DSM-IV-TR criteria for a diagnosis of gender identity disorder. METHOD: Data were collected within the European Network for the Investigation of Gender Incongruence using the Mini International Neuropsychiatric Interview - Plus and the Structured Clinical Interview for DSM-IV Axis II Disorders (n = 305). RESULTS: In 38% of the individuals with gender identity disorder a current DSM-IV-TR Axis I diagnosis was found, mainly affective disorders and anxiety disorders. Furthermore, almost 70% had a current and lifetime diagnosis. All four countries showed a similar prevalence, except for affective and anxiety disorders, and no difference was found between individuals with early-onset and late-onset disorder. An Axis II diagnosis was found in 15% of all individuals with gender identity disorder, which is comparable to the general population. CONCLUSIONS: People with gender identity disorder show more psychiatric problems than the general population; mostly affective and anxiety problems are found.

The Link between Peer Relations, Prosocial Behavior, and ODD/ADHD Symptoms in 7-9-Year-Old Children.

Oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder (ADHD) are characterized by symptoms that hinder successful positive interaction with peers. The main goal of this study was to examine if the presence of symptoms of ODD and ADHD affects the relationship between positive social behavior and peer status found in 7-9-year-old children who show symptoms typical of ADHD and/or ODD. Furthermore, the possible interaction with sex was investigated. We used data collected in the first wave of The Bergen Child Study of mental health (BCS), a prospective longitudinal total population study of children's developmental and mental health. The target population consisted of children in the second to the fourth, in all public, private, and special schools in Bergen, Norway, in the fall of 2002 (N = 9430). All 79 primary schools in Bergen participated in the study. Both teacher (8809 complete cases) and parent (6253 complete cases) report were used in the analyses. ADHD and ODD scores were estimated using the Swanson Noland and Pelham rating scale version IV (SNAP-IV), and peer problems and prosocial behavior were assessed using the Strengths and Difficulties Questionnaire (SDQ). We replicated the relationship between peer problems and prosocial behavior found previously in typically developing children. Our results showed that the relationship between peer problems and prosocial behavior became weaker as the ODD symptoms increased in number and severity. For ADHD this effect was only found in the teacher report of the children. A sex effect for ODD symptoms was found only using the parent report: boys with ODD symptoms showed less prosocial behavior than girls with similar levels of ODD symptoms. Since this effect was not found using the teacher data, it may imply a situational effect (school/home) for girls with high levels of ODD. The moderator effect of ODD/ADHD was comparable for boys and girls. Our findings suggest that even if children with ADHD/ODD symptoms have the opportunity to practice their social skills in peer relationships, this is not necessarily accompanied by an increase in prosocial behavior.

Why the factorial structure of the SCL-90-R is unstable: comparing patient groups with different levels of psychological distress using Mokken Scale Analysis.

Since its introduction, there has been a debate about the validity of the factorial structure of the SCL-90-R. In this study we investigate whether the lack of agreement with respect to the dimensionality can be partly explained by important variables that might differ between samples such as level of psychological distress, the variance of the SCL-90-R scores and sex. Three samples were included: a sample of severely psychiatrically disturbed patients (n=3078), a sample of persons with Gender Incongruence (GI; n=410) and a sample of depressed patients (n=223). A unidimensional pattern of findings were found for the GI sample. For the severely disturbed and depressed sample, a multidimensional pattern was found. In the depressed sample sex differences were found in dimensionality: we found a unidimensional pattern for the females, and a multidimensional one for the males. Our analyses suggest that previously reported conflicting findings with regard to the dimensional structure of the SCL-90-R may be due to at least two factors: (a) level of self-reported distress, and (b) sex. Subscale scores should be used with care in patient groups with low self-reported level of distress.

A study of the dimensionality and measurement precision of the SCL-90-R using item response theory.

We used item response theory (IRT) to (a) investigate the dimensionality of the Symptom Checklist-90-Revised (SCL-90-R) in a severely disturbed patient group, (b) improve the subscales in a meaningful way and (c) investigate the measurement precision of the improved scales. The total sample comprised 3078 patients (72% women, mean age=35±9) admitted to 14 different day hospitals participating in the Norwegian Network of Personality-focused Treatment Programmes. Mokken Scale Analysis was used to investigate the dimensionality of the SCL-90-R and improve the subscales. This analysis was theory-driven: the scales were built on two start items that reflected the content of the disorder that corresponds with the specific scale. The Graded Response Model was employed to determine measurement precision. Our theory-driven IRT approach resulted in a new seven-factor solution including 60 of the 90 items clustered in seven scales: depression, agoraphobia, physical complaints, obsessive-compulsive, hostility (unchanged), distrust and psychoticism. Most of the new scales discriminated reliably between patients with moderately low scores to moderately high scores. In conclusion, we found support for the multidimensionality of the SCL-90-R in a large sample of severely disturbed patients.

Age of onset and sexual orientation in transsexual males and females.

INTRODUCTION: With regard to transsexual developments, onset age (OA) appears to be the starting point of different psychosexual pathways. AIM: To explore differences between transsexual adults with an early vs. late OA. METHODS: Data were collected within the European Network for the Investigation of Gender Incongruence using the Dutch Biographic Questionnaire on Transsexualism (Biografische Vragenlijst voor Transseksuelen) and a self-constructed score sheet according to the DSM-IV-TR (Diagnostic and Statistical Manual, Fourth Edition, Text Revision) criteria of Gender Identity Disorder (GID) and Gender Identity Disorder in Childhood (GIDC). One hundred seventy participants were included in the analyses. MAIN OUTCOME MEASURES: Transsexual adults who, in addition to their GID diagnosis, also fulfilled criteria A and B of GIDC ("a strong cross-gender identification,""persistent discomfort about her or his assigned sex") retrospectively were considered as having an early onset (EO). Those who fulfilled neither criteria A nor B of GIDC were considered as having a late onset (LO). Participants who only fulfilled criterion A or B of GIDC were considered a residual (RES) group. RESULTS: The majority of female to males (FtMs) appeared to have an early OA (EO = 60 [77.9%] compared to LO = 10 [13%] and to RES = 7 [9.1%]). Within male to females (MtFs), percentages of EO and LO developments were more similar (EO = 36 [38.7%], LO = 45 [48.4%], RES = 12 [12.9%]). FtMs presented to gender clinics at an earlier age than MtFs (28.04 to 36.75). The number of EO vs. LO transsexual adults differed from country to country (Belgium, Germany, the Netherlands, Norway). CONCLUSION: OA has a discriminative value for transsexual developments and it would appear that retrospective diagnosis of GIDC criteria is a valid method of assessment. Differences in OA and sex ratio exist between European countries.

Assessing the utility of diagnostic criteria: a multisite study on gender identity disorder.

INTRODUCTION: Studies involving patients with gender identity disorder (GID) are inconsistent with regard to outcomes and often difficult to compare because of the vague descriptions of the diagnostic process. A multisite study is needed to scrutinize the utility and generality of different aspects of the diagnostic criteria for GID. AIM: To investigate the way in which the diagnosis-specific Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria for GID were used to reach a psychiatric diagnosis in four European countries: the Netherlands (Amsterdam), Norway (Oslo), Germany (Hamburg), and Belgium (Ghent). The main goal was to compare item (symptom) characteristics across countries. METHODS: The current study included all new applicants to the four GID clinics who were seen between January 2007 and March 2009, were at least 16 years of age at their first visit, and had completed the diagnostic assessment (N = 214, mean age = 32 ± 12.2 years). Mokken scale analysis, a form of Nonparametric Item Response Theory (NIRT) was performed. MAIN OUTCOME MEASURES: Operationalization and quantification of the core criteria A and B resulted in a 23-item score sheet that was filled out by the participating clinicians after they had made a diagnosis. RESULTS: We found that, when ordering the 23 items according to their means for each country separately, the rank ordering was similar among the four countries for 21 of the items. Furthermore, only one scale emerged, which combined criteria A and B when all data were analyzed together. CONCLUSIONS: Our results indicate that patients' symptoms were interpreted in a similar fashion in all four countries. However, we did not find support for the treatment of A and B as two separate criteria. We recommend the use of NIRT in future studies, especially in studies with small sample sizes and/or with data that show a poor fit to parametric IRT models.

Cross-sex hormone treatment does not change sex-sensitive cognitive performance in gender identity disorder patients.

Cognitive performance in untreated early onset gender identity disorder (GID) patients might correspond to their born sex and not to their perceived gender. As a current mode of intervention, cross-sex hormone treatment causes considerable physical changes in GID patients. We asked, as has been suggested, whether this treatment skews cognitive performance towards that of the acquired sex. Somatically healthy male and female early onset GID patients were neuropsychologically tested before, 3 and 12 months after initiating cross-sex hormone treatment, whereas untreated healthy subjects without GID served as controls (C). Performance was assessed by testing six cognitive abilities (perception, arithmetic, rotation, visualization, logic, and verbalization), and controlled for age, education, born sex, endocrine differences and treatment by means of repeated measures analysis of variance. GID patients and controls showed an identical time-dependent improvement in cognitive performance. The slopes were essentially parallel for males and females. There was no significant three-way interaction of born sex by group by time for the six investigated cognitive abilities. Only education and age significantly influenced this improvement. Despite the substantial somatic cross-sex changes in GID patients, no differential effect on cognition over time was found between C and GID participants. The cognitive performance of cross-sex hormone-treated GID patients was virtually identical to that of the control group. The documented test-retest effect should be taken into consideration when evaluating treatment effects generally in psychiatry.