Sex effects on development of brain structure and executive functions: Greater variance than mean effects

Although male brains have consistently reported to be 8-10% larger than female brains, it remains not well understood whether there are differences between sexes (average or variance) in developmental trajectories. Furthermore, if sex differences in average brain growth or variance are observed, it is unknown whether these sex differences have behavioral relevance. The present longitudinal study aimed to unravel sex effects in cortical brain structure, development, and variance, in relation to the development of educationally relevant cognitive domains and executive functions (EFs). This was assessed with three experimental tasks including working memory, reading comprehension, and fluency. In addition, real-life aspects of EF were assessed with self- and parent-reported Behavior Rating Inventory of Executive Function scores. The full data set included 271 participants (54% female) aged between 8 and 29 years of which three waves were collected at 2-year intervals, resulting in 680 T1-weighted MRI scans and behavioral measures. Analyses of average trajectories confirmed general age-related patterns of brain development but did not support the hypothesis of sex differences in brain development trajectories, except for left banks STS where boys had a steeper decline in surface area than girls. Also, our brain age prediction model (including 270 brain measures) did not indicate delayed maturation in boys compared with girls. Interestingly, support was found for greater variance in male brains than female brains in both structure and development, consistent with prior cross-sectional studies. Behaviorally, boys performed on average better on a working memory task with a spatial aspect and girls performed better on a reading comprehension task, but there was no relation between brain development and cognitive performance, neither for average brain measures, brain age, or variance measures. Taken together, we confirmed the hypothesis of greater males within-group variance in brain structures compared with females, but these were not related to EF. The sex differences observed in EF were not related to brain development, possibly suggesting that these are related to experiences and strategies rather than biological development.Pathways through Adolescenc

Genetic and environmental influences on structure of the social brain in childhood

Prosocial behavior and empathy are important aspects of developing social relations in childhood. Prior studies showed protracted structural development of social brain regions associated with prosocial behavior. However, it remains unknown how structure of the social brain is influenced by genetic or environmental factors, and whether overlapping heritability factors explain covariance in structure of the social brain and behavior. The current study examined this hypothesis in a twin sample (aged 7-9-year; N = 512). Bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), temporo-parietal junction (TPJ), posterior superior temporal sulcus (pSTS), and precuneus were analyzed. Results showed genetic contributions to surface area and cortical thickness for all brain regions. We found additional shared environmental influences for TPJ, suggesting that this region might be relatively more sensitive to social experiences. Genetic factors also influenced parent-reported prosocial behavior (A = 45%) and empathy (A = 59%). We provided initial evidence that the precuneus shares genetically determined variance with empathy, suggesting a possible small genetic overlap (9%) in brain structure and empathy. These findings show that structure of the social brain and empathy are driven by a combination of genetic and environmental factors, with some factors overlapping for brain structure and behavior.Neuro Imaging Researc

Unraveling age, puberty and testosterone effects on subcortical brain development across adolescence

The onset of adolescence in humans is marked by hormonal changes that give rise to secondary sexual characteristics, noted as puberty. It has, however, proven challenging to unravel to what extent pubertal changes may have organizing effects on the brain beyond chronological age, as reported in animal studies. The present longitudinal study aimed to characterize the unique effects of age and puberty on subcortical brain volumes and included three waves of data collection at two-year intervals and 680 T1-weighted MRI scans of 271 participants (54% females) aged between 8 and 29 years old. Generalized additive mixed model procedures were used to assess the effects of age, self-report pubertal status and testosterone level on basal ganglia, thalamus, hippocampus, amygdala and cerebellum gray matter volumes. We observed age-related increases in putamen and pallidum volumes, and decreases in accumbens and thalamus volumes, all show larger volumes in boys than girls. Only the cerebellum showed an interaction effect of age by sex, such that males showed prolonged increases in cerebellar volume than females. Next, we showed that changes in self-report puberty status better described developmental change than chronological age for most structures in males, and for caudate, pallidum and hippocampal volumes in females. Furthermore, changes in testosterone level were related to development of pallidum, accumbens, hippocampus and amygdala volumes in males and caudate and hippocampal volumes in females. The modeling approach of the present study allowed us to characterize the complex interactions between chronological age and pubertal maturational changes, and the findings indicate puberty unique changes in brain structure that are sex specific.Pathways through Adolescenc

A multisample study of longitudinal changes in brain network architecture in 4-13-year-old children

Pathways through Adolescenc

Genetic and environmental influences on structure of the social brain in childhood

Prosocial behavior and empathy are important aspects of developing social relations in childhood. Prior studies showed protracted structural development of social brain regions associated with prosocial behavior. However, it remains unknown how structure of the social brain is influenced by genetic or environmental factors, and whether overlapping heritability factors explain covariance in structure of the social brain and behavior. The current study examined this hypothesis in a twin sample (aged 7–9-year; N = 512). Bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), temporo-parietal junction (TPJ), posterior superior temporal sulcus (pSTS), and precuneus were analyzed. Results showed genetic contributions to surface area and cortical thickness for all brain regions. We f

Beyond the Average Brain: Individual Differences in Social Brain Development are Associated with Friendship Quality

We tested whether adolescents differ from each other in the structural development of the social brain, and whether individual differences in social brain development predicted variability in friendship quality development. Adolescents (N = 299, Mage T1 = 13.98 years) were followed across three bi-annual waves. We analysed self-reported friendship quality with the best friend at T1 and T3, and bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), posterior superior temporal sulcus (pSTS), temporo-parietal junction (TPJ), and precuneus across all waves. At the group level, growth curve models confirmed non-linear decreases of surface area and cortical thickness in social brain regions. We identified substantial individual differences in levels and change rates of social brain regions, especially for surface area of the mPFC, pSTS, and TPJ. Change rates of cortical thickness varied less between persons. Higher levels of mPFC surface area and cortical thickness predicted stronger increases in friendship quality over time. Moreover, faster cortical thinning of mPFC surface area predicted a stronger increase in friendship quality. Higher levels of TPJ cortical thickness predicted lower friendship quality. Together, our results indicate heterogeneity in social brain development and how this variability uniquely predicts friendship quality development

Neural and behavioral signatures of social evaluation and adaptation in childhood and adolescence: The Leiden consortium on individual development (L-CID)

The transition period between early childhood and late adolescence is characterized by pronounced changes in social competence, or the capacity for flexible social adaptation. Here, we propose that two processes, self-control and prosociality, are crucial for social adaptation following social evaluation. We present a neurobehavioral model showing commonalities in neural responses to experiences of social acceptance and rejection, and multiple pathways for responding to social context. The Leiden Consortium on Individual Development (L-CID) provides a comprehensive approach towards understanding the longitudinal developmental pathways of, and social enrichment effects on, social competence, taking into account potential differential effects of such enrichment. Using Neurosynth based brain maps we point towards the medial prefrontal cortex as an important region integrating social cognition, self-referential processing and self-control for learning to respond flexibly to changing social contexts. Based on their role in social evaluation processing, we suggest to examine medial prefrontal cortex connections with lateral prefrontal cortex and the ventral striatum as potential neural differential susceptibility markers, in addition to previously established markers of differential susceptibility

Diagnostische en prognostische waarde van PCA3

In the Netherlands, prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men. Detection of prostate cancer relies on an abnormal (digital) rectal examination, a positive family history of prostate cancer and/or an elevated serum prostate specific antigen (PSA). The natural ageing of the population and the widespread implementation of the PSA have resulted in the increase of men diagnosed with (organ-confined) prostate cancer. The use of PSA has its limitations. Firstly, PSA is prostate-specific but not prostate cancer specific. The PSA level can also be increased in non-malignant prostatic diseases. Because of the low specificity up to 75% of men with PSA values in the 3-10 ng/ ml range have a negative first biopsy. The second limitation is the risk of overdiagnosing and overtreatment. Nowadays many of the detected prostate cancers are clinical insignificant. In men with a limited life-expectancy diagnosing prostate cancer has no consequences and finding prostate cancer in young men often leads to overtreatment. Thirdly, PSA cannot predict clinical-pathological features of the tumour; therefore it is hard to decide which treatment is best. The Gold standard in the diagnosis of prostate cancer is biopsy of the prostate, although this too has its limitations and associated morbidities. Almost 25 % of prostate cancers are missed on the first biopsy, so in case of initial negative biopsy and persistently elevated serum PSA there is a continued suspicion of prostate cancer and repeated biopsy might be necessary. There is a need for a test to increase the probability of prostatecancer detection, reduce the unnecessary biopsies and predict the clinical-pathological features of the tumour. In 1999 a new prostate-specific gene was identified, which is a non-coding mRNA highly overexpressed in malignant prostate tissue and named prostate cancer antigen 3 (PCA3). PCA3 mRNA can be quantified in urine. An easy to use and relatively fast transcription-mediated amplification (TMA)-based PCA3 urine test has been developed for use in the clinical setting: the Progensa PCA3-test. Multiple studies have proved that PCA3 was superior to PSA for prostate cancer detection at repeat biopsy. The PCA3 testing in urine resulted in an improved specificity and PCA3 can predict more accurately the outcome of repeat biopsy. In the relationship between the clinical-pathological features and the PCA3-score no consensus has been reached. The primary objective of this study is to determine the performance characteristics of the Progensa PCA3-test in men tested in UMC St. Radboud. It has been hypothesized that because of the PCA3 over expression in prostate cancer, men with positive biopsies have a higher PCA3 score than men with negative biopsies. The expectancy is that less differentiated cells are more invasive and more likely to mobilize into the urine than well differentiated prostate cancer cells, so less differentiated prostate tumours score a higher PCA3. In the here reported study the diagnostic and prognostic value of the PCA3-test will be analysed. In the period of 2006-2010 692 men were tested by the Progensa PCA3-test in the RUNMC (UMC St. Radboud, Nijmegen). Patients were seen at the outpatient clinic because of a high serum PSA level, an abnormal (digital) rectal examination or a positive family history of prostate cancer. Of this group, 342 men were included in our study protocol because the time between PCA3 testing and biopsy was limited to a period of 6 months before or 12 months after the PCA3-test was taken. The diagnostic performance of the Progensa PCA3-test was evaluated in terms of sensitivity and specificity by comparing the PCA3 score to the biopsy result. The area under the curve (AUC) of the receiver operating characteristics (ROC) was used to compare the performance of PCA3 to serum PSA. The relationship between PCA3 and prostate volume, presence of high grade prostatic intra epithelial neoplasia (HGPIN), PSA, Gleason score and clinical stage was also evaluated. The non-parametric Mann-Whitney U-test and the Krusal-Wallis test were used to test for differences and assess significance levels. To test for a correlation the Spearman's rho test has been used. A P-value <0,05 was considered significant. In 43% of the 342 men one or more positive biopsy for prostate cancer was found. This 43% was significantly older, had a significantly higher serum PSA and PCA3-score and a significantly lower prostate volume than the 181 men where, based on the biopsies, prostate cancer could not be identified. The median PCA3-score for the biopsy negative men was 22 and biopsy positive men 60. The difference between the two groups was highly significant (p<1,0x10-6). It seems that the determination of the PCA3 level appears to have value in the prediction of the biopsy outcome. The AUC was 0.732 for the PCA3 and 0.667 for PSA, indicating that in the study PCA3 has a greater diagnostic accuracy than PSA for predicting prostate biopsy outcome. As in the group with prostate cancer as well as in the group with negative biopsies, a wide range of PCA3-scores exists, so no clear conseesus is reached on the adequate cut-off value. A PCA3 cut-off value of 38 provided a good balance between sensitivity (69.4%) and specificity (65.7%). The other two cut-off values with a good balance are 23 with a sensitivity of 85% and 53 with a specificity of 76.2%. When the aim is to decrease the number of missed prostate cancers by PCA3 use, the cut-off point should be low. When the aim is to reduce the number of unnecessary biopsies the higher cut-off point must be chosen. It might be best not to work with a cut-off point, but to use a scale on which the doctor in consultation with the patient can decide what to do with which PCA3-score. The study population turned out to be very heterogeneous. Contrary to other studies, there was a wide range in PSA levels and half of the men did not had prostate biopsies taken prior PCA3 testing, as is recommended in several studies. So within this population it was possible to compare the value of PCA3 in patients from which biopsies had been taken before (AUC; 0,684) with patients without previous biopsies (AUC; 0,766). In the here described study the PCA3 turned out to be of great value in patients without previous biopsies, which means PCA3 might be able to play a role in the screening of prostate cancer. If PCA3 is higher in patients with HGPIN in the biopsies, it can be suggested that PCA3 could identify men at risk of developing prostate cancer, as it has been shown that HGPIN is associated with an increased risk of prostate cancer. In this study the described association, although present, was not significant. The significant correlation between serum PSA and PCA3 is not of much value as the PCA3-score consists of the ratio between PCA3 mRNA and PSA mRNA. The sum of both tests though, can increase the chance of finding prostate cancer. Incorporation of PCA3 and PSA in a ‘risk calculator’ can improve the diagnostic accuracy. It seems that a higher PCA3 corresponds with clinical-pathological features known to be associated with prostate cancer aggressiveness as indicated with a higher Gleason score and clinical stage. These differences were not statistically significant though. In conclusion the PCA3 is of diagnostic value. The probability of a positive first biopsy sample, or positive repeat biopsy increases with rising PCA3-scores. The PCA3 was superior to the serum PSA for predicting prostate biopsy outcome. The predictive value of PCA3 for prostate cancer prognosis could not be proved.

Genetic and environmental influences on structural brain development from childhood to adolescence: A longitudinal twin study on cortical thickness, surface area, and subcortical volume

The human brain undergoes structural development from childhood to adolescence, with specific regions in the sensorimotor, social, and affective networks continuing to grow into adulthood. While genetic and environmental factors contribute to individual differences in these brain trajectories, the extent remains understudied. Our longitudinal study, utilizing up to three biennial MRI scans (n=485), aimed to assess the genetic and environmental effects on brain structure (age 7) and development (ages 7–14) in these regions. Heritability estimates varied across brain regions, with all regions showing genetic influence (ranging from 18 % to 59 %) with additional shared environmental factors affecting the primary motor cortex (30 %), somatosensory cortex (35 %), DLPFC (5 %), TPJ (17 %), STS (17 %), precuneus (10 %), hippocampus (22 %), amygdala (5 %), and nucleus accumbens (10 %). Surface area was more genetically driven (38 %) than cortical thickness (14 %). Longitudinal brain changes were primarily driven by genetics (ranging from 1 % to 29 %), though shared environment factors (additionally) influenced the somatosensory cortex (11 %), DLPFC (7 %), cerebellum (28 %), TPJ (16 %), STS (20 %), and hippocampus (17 %). These findings highlight the importance of further investigating brain-behavior associations and the influence of enriched and deprived environments from childhood to adolescence. Ultimately, our study can provide insights for interventions aimed at supporting children's development