It is unclear whether the research literature on adolescent gender dysphoria (GD) provides sufficient evidence to adequately inform clinical decision making. In the first of a series of three papers, this study sought to systematically review published evidence regarding: the prevalence of GD in adolescence; the proportions of natal males/females with GD in adolescence and whether this changed over time; and the pattern of age at (a) onset (b) referral and (c) assessment. Having searched PROSPERO and the Cochrane library for existing systematic reviews (and finding none), we searched Ovid Medline 1946 –October week 4 2020, Embase 1947–present (updated daily), CINAHL 1983–2020, and PsycInfo 1914–2020. The final search was carried out on the 2^nd November 2020 using a core strategy including search terms for ‘adolescence’ and ‘gender dysphoria’ which was adapted according to the structure of each database. Papers were excluded if they did not clearly report on clinically-verified gender dysphoria, if they were focused on adult populations, if they did not include original data (epidemiological, clinical, or survey) on adolescents (aged at least 12 and under 18 years), or if they were not peer-reviewed journal publications. From 6202 potentially relevant articles (post de-duplication), 38 papers from 11 countries representing between 3000 and 4000 participants were included in our final sample. Most studies were observational cohort studies, usually using retrospective record review (26). A few compared to normative or population datasets; most (31) were published in the past 5 years. There was significant overlap of study samples (accounted for in our quantitative synthesis). No population studies are available, so prevalence is not possible to ascertain. There is evidence of an increase in frequency of presentation to services, and of a shift in the natal sex of referred cases: those assigned female at birth are now in the majority. No data were available on age of onset. Within the included samples the average age was 13 years at referral, 15 years at assessment. All papers were rated by two reviewers using the Crowe Critical Appraisal Tool v1·4 (CCAT). The CCAT quality ratings ranged from 45% to 96%, with a mean of 78%. Almost half the included studies emerged from two treatment centres: there was considerable sample overlap and it is unclear how representative these are of the adolescent GD community more broadly. The increase in clinical presentations of GD, particularly among natal female adolescents, warrants further investigation. Whole population studies using administrative datasets reporting on GD / gender non-conformity may be necessary, along with inter-disciplinary research evaluating the lived experience of adolescents with GD.

It is unclear whether the literature on adolescent gender dysphoria (GD) provides sufficient evidence to inform clinical decision making adequately. In the second of a series of three papers, we sought to review published evidence systematically regarding the extent and nature of mental health problems recorded in adolescents presenting for clinical intervention for GD. Having searched PROSPERO and the Cochrane library for existing systematic reviews (and finding none), we searched Ovid Medline 1946 –October week 4 2020, Embase 1947–present (updated daily), CINAHL 1983–2020, and PsycInfo 1914–2020. The final search was carried out on the 2nd November 2020 using a core strategy including search terms for ‘adolescence’ and ‘gender dysphoria’ which was adapted according to the structure of each database. Papers were excluded if they did not clearly report on clinically-likely gender dysphoria, if they were focused on adult populations, if they did not include original data (epidemiological, clinical, or survey) on adolescents (aged at least 12 and under 18 years), or if they were not peer-reviewed journal publications. From 6202 potentially relevant articles (post deduplication), 32 papers from 11 countries representing between 3000 and 4000 participants were included in our final sample. Most studies were observational cohort studies, usually using retrospective record review (21). A few compared cohorts to normative or population datasets; most (27) were published in the past 5 years. There was significant overlap of study samples (accounted for in our quantitative synthesis). All papers were rated by two reviewers using the Crowe Critical Appraisal Tool v1·4 (CCAT). The CCAT quality ratings ranged from 45% to 96%, with a mean of 81%. More than a third of the included studies emerged from two treatment centres: there was considerable sample overlap and it is unclear how representative these are of the adolescent GD community more broadly. Adolescents presenting for GD intervention experience a high rate of mental health problems, but study findings were diverse. Researchers and clinicians need to work together to improve the quality of assessment and research, not least in making studies more inclusive and ensuring long-term follow-up regardless of treatment uptake. Whole population studies using administrative datasets reporting on GD / gender non-conformity may be necessary, along with inter-disciplinary research evaluating the lived experience of adolescents with GD.

Gamma oscillations facilitate information processing by shaping the excitatory input/output of neuronal populations. Recent studies in humans and nonhuman primates have shown that strong excitatory drive to the visual cortex leads to suppression of induced gamma oscillations, which may reflect inhibitory‐based gain control of network excitation. The efficiency of the gain control measured through gamma oscillations may in turn affect sensory sensitivity in everyday life. To test this prediction, we assessed the link between self‐reported sensitivity and changes in magneto‐encephalographic gamma oscillations as a function of motion velocity of high‐contrast visual gratings. The induced gamma oscillations increased in frequency and decreased in power with increasing stimulation intensity. As expected, weaker suppression of the gamma response correlated with sensory hypersensitivity. Robustness of this result was confirmed by its replication in the two samples: neurotypical subjects and people with autism, who had generally elevated sensory sensitivity. We conclude that intensity‐related suppression of gamma response is a promising biomarker of homeostatic control of the excitation–inhibition balance in the visual cortex.

It is unclear whether the literature on adolescent gender dysphoria (GD) provides evidence to inform clinical decision making adequately. In the final of a series of three papers, we sought to review published evidence systematically regarding the types of treatment being implemented among adolescents with GD, the age when different treatment types are instigated, and any outcomes measured within adolescence. Having searched PROSPERO and the Cochrane library for existing systematic reviews (and finding none at that time), we searched Ovid Medline 1946 –October week 4 2020, Embase 1947–present (updated daily), CINAHL 1983–2020, and PsycInfo 1914–2020. The final search was carried out on 2nd November 2020 using a core strategy including search terms for ‘adolescence’ and ‘gender dysphoria’ which was adapted according to the structure of each database. Papers were excluded if they did not clearly report on clinically-likely gender dysphoria, if they were focused on adult populations, if they did not include original data (epidemiological, clinical, or survey) on adolescents (aged at least 12 and under 18 years), or if they were not peer-reviewed journal publications. From 6202 potentially relevant articles (post deduplication), 19 papers from 6 countries representing between 835 and 1354 participants were included in our final sample. All studies were observational cohort studies, usually using retrospective record review (14); all were published in the previous 11 years (median 2018). There was significant overlap of study samples (accounted for in our quantitative synthesis). All papers were rated by two reviewers using the Crowe Critical Appraisal Tool v1·4 (CCAT). The CCAT quality ratings ranged from 71% to 95%, with a mean of 82%. Puberty suppression (PS) was generally induced with Gonadotropin Releasing Hormone analogues (GnRHa), and at a pooled mean age of 14.5 (±1.0) years. Cross Sex Hormone (CSH) therapy was initiated at a pooled mean of 16.2 (±1.0) years. Twenty-five participants from 2 samples were reported to have received surgical intervention (24 mastectomy, one vaginoplasty). Most changes to health parameters were inconclusive, except an observed decrease in bone density z-scores with puberty suppression, which then increased with hormone treatment. There may also be a risk for increased obesity. Some improvements were observed in global functioning and depressive symptoms once treatment was started. The most common side effects observed were acne, fatigue, changes in appetite, headaches, and mood swings. Adolescents presenting for GD intervention were usually offered puberty suppression or cross-sex hormones, but rarely surgical intervention. Reporting centres broadly followed established international guidance regarding age of treatment and treatments used. The evidence base for the outcomes of gender dysphoria treatment in adolescents is lacking. It is impossible from the included data to draw definitive conclusions regarding the safety of treatment. There remain areas of concern, particularly changes to bone density caused by puberty suppression, which may not be fully resolved with hormone treatment.

This paper presents a unifying theory for autism by applying the framework of a pathogenetic triad to the scientific literature. It proposes a deconstruction of autism into three contributing features (an autistic personality dimension, cognitive compensation, and neuropathological risk factors), and delineates how they interact to cause a maladaptive behavioral phenotype that may require a clinical diagnosis. The autistic personality represents a common core condition, which induces a set of behavioral issues when pronounced. These issues are compensated for by cognitive mechanisms, allowing the individual to remain adaptive and functional. Risk factors, both exogenous and endogenous ones, show pathophysiological convergence through their negative effects on neurodevelopment. This secondarily affects cognitive compensation, which disinhibits a maladaptive behavioral phenotype. The triad is operationalized and methods for quantification are presented. With respect to the breadth of findings in the literature that it can incorporate, it is the most comprehensive model yet for autism. Its main implications are that (1) it presents the broader autism phenotype as a non-pathological core personality domain, which is shared across the population and uncoupled from associated features such as low cognitive ability and immune dysfunction, (2) it proposes that common genetic variants underly the personality domain, and that rare variants act as risk factors through negative effects on neurodevelopment, (3) it outlines a common pathophysiological mechanism, through inhibition of neurodevelopment and cognitive dysfunction, by which a wide range of endogenous and exogenous risk factors lead to autism, and (4) it suggests that contributing risk factors, and findings of immune and autonomic dysfunction are clinically ascertained rather than part of the core autism construct.

Objectives: Individual anatomical biomarkers have limited power for the classification of autism. The present study introduces a multivariate classification approach using structural magnetic resonance imaging data from individuals with and without autism.Methods: The classifier utilizes z‐normalization, parameter weighting, and interindividual comparison on brain segmentation data, for estimation of an individual summed total index (TI). The TI indicates whether the gross morphological pattern of each individual's brain is in the direction of cases or controls.Results: Morphometric analysis found significant differences within subcortical gray matter structures and limbic areas. There was no significant difference in total brain volume. A case‐control pilot‐study of TIs in normally intelligent individuals with autism (24) and without (21) yielded a maximal accuracy of 78.9% following cross‐validation. It showed a high accuracy compared with machine learning methods when tested on the same dataset. The TI correlated well with the autism quotient (R = 0.51) across groups.Conclusion: These results are on par with studies on autism using machine learning. The main contributions are its transparency and simplicity. The possibility of including additional neuroimaging data further increases the potential of the classifier as a diagnostic aid for neuropsychiatric disorders, as well as a research tool for neuroscientific investigations.