Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of ...pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy (1HMRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. 1HMRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin-neurexin signaling complex.
Myelination, the elaboration of myelin surrounding neuronal axons, is essential for normal brain function. The development of the myelin sheath enables rapid synchronized communication across the ...neural systems responsible for higher order cognitive functioning. Despite this critical role, quantitative visualization of myelination in vivo is not possible with current neuroimaging techniques including diffusion tensor and structural magnetic resonance imaging (MRI). Although these techniques offer insight into structural maturation, they reflect several different facets of development, e.g., changes in axonal size, density, coherence, and membrane structure; lipid, protein, and macromolecule content; and water compartmentalization. Consequently, observed signal changes are ambiguous, hindering meaningful inferences between imaging findings and metrics of learning, behavior or cognition. Here we present the first quantitative study of myelination in healthy human infants, from 3 to 11 months of age. Using a new myelin-specific MRI technique, we report a spatiotemporal pattern beginning in the cerebellum, pons, and internal capsule; proceeding caudocranially from the splenium of the corpus callosum and optic radiations (at 3-4 months); to the occipital and parietal lobes (at 4-6 months); and then to the genu of the corpus callosum and frontal and temporal lobes (at 6-8 months). Our results also offer preliminary evidence of hemispheric myelination rate differences. This work represents a significant step forward in our ability to appreciate the fundamental process of myelination, and provides the first ever in vivo visualization of myelin maturation in healthy human infancy.
Human voices play a fundamental role in social communication, and areas of the adult “social brain” show specialization for processing voices and their emotional content (superior temporal sulcus, ...inferior prefrontal cortex, premotor cortical regions, amygdala, and insula) 1–8. However, it is unclear when this specialization develops. Functional magnetic resonance (fMRI) studies suggest that the infant temporal cortex does not differentiate speech from music or backward speech 9, 10, but a prior study with functional near-infrared spectroscopy revealed preferential activation for human voices in 7-month-olds, in a more posterior location of the temporal cortex than in adults 11. However, the brain networks involved in processing nonspeech human vocalizations in early development are still unknown. To address this issue, in the present fMRI study, 3- to 7-month-olds were presented with adult nonspeech vocalizations (emotionally neutral, emotionally positive, and emotionally negative) and nonvocal environmental sounds. Infants displayed significant differential activation in the anterior portion of the temporal cortex, similarly to adults 1. Moreover, sad vocalizations modulated the activity of brain regions involved in processing affective stimuli such as the orbitofrontal cortex 12 and insula 7, 8. These results suggest remarkably early functional specialization for processing human voice and negative emotions.
► Specialization for the human voice was found in the anterior STS in human infants ► This voice-sensitive area is right lateralized and in a similar location to adults ► Orbitofrontal cortex and insula activate when infants process sad vocal emotions
Experimental data on monkeys and functional studies in humans support the existence of a complex fronto-parietal system activating for cognitive and motor tasks, which may be anatomically supported ...by the superior longitudinal fasciculus (SLF). Advanced tractography methods have recently allowed the separation of the three branches of the SLF but are not suitable for their functional investigation. In order to gather comprehensive information about the functional organisation of these fronto-parietal connections, we used an innovative method, which combined tractography of the SLF in the largest dataset so far (129 participants) with 14 meta-analyses of functional magnetic resonance imaging (fMRI) studies. We found that frontal and parietal functions can be clustered into a dorsal spatial/motor network associated with the SLF I, and a ventral non-spatial/motor network associated with the SLF III. Further, all the investigated functions activated a middle network mostly associated with the SLF II. Our findings suggest that dorsal and ventral fronto-parietal networks are segregated but also share regions of activation, which may support flexible response properties or conscious processing. In sum, our novel combined approach provided novel findings on the functional organisation of fronto-parietal networks, and may be successfully applied to other brain connections.
•We used a novel approach to investigate fronto-parietal functions.•These are segregated into a dorsal spatial and a ventral non-spatial network.•These networks rely on the superior longitudinal fasciculus (1st and 3rd branch).•They overlap on areas with flexible response properties that rely on the 2nd branch.
ObjectiveChromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge ...the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.MethodThe 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years.ResultsAttention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills.ConclusionsTo the authors’ knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.
Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ...ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.
Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain ...function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our 'shiftability' paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.
Background
Robot-assisted laparoscopic surgery is being performed more frequently for the minimally invasive management of rectal cancer. The objective of this meta-analysis was to compare the ...clinical and oncologic safety and efficacy of robot-assisted versus conventional laparoscopic surgery.
Methods
A search of the Medline and Embase databases was performed for studies that compared clinical or oncologic outcomes of conventional laparoscopic proctectomy with robot-assisted laparoscopic proctectomy for rectal cancer. The methodological quality of the selected studies was critically assessed to identify studies suitable for inclusion. Meta-analysis was performed by a random effects model and analyzed by Review Manager. Clinical outcomes evaluated were conversion rates, operation times, length of hospital stay, and complications. Oncologic outcomes evaluated were circumferential margin status, number of lymph nodes collected, and distal resection margin lengths.
Results
Eight comparative studies were assessed for quality, and seven studies were included in the meta-analysis. Two studies were matched case-control studies, and five were unmatched. A total of 353 robot-assisted laparoscopic surgery proctectomy cases and 401 conventional laparoscopic surgery proctectomy cases were analyzed. Robotic surgery was associated with a significantly lower conversion rate (
P
= 0.03; 95% confidence interval 1–12). There was no difference in complications, circumferential margin involvement, distal resection margin, lymph node yield, or hospital stay (
P
= NS).
Conclusions
Robot-assisted surgery decreased the conversion rate compared to conventional laparoscopic surgery. Other clinical outcomes and oncologic outcomes were equivalent. The benefits of robotic rectal cancer surgery may differ between population groups.
The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for ...neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case-control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = -0.96; p < 0.001); total grey matter (g = -0.81, p < 0.001); and total white matter (g = -0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = -0.47; p < 0.001), temporal lobe (g = -0.84; p < 0.001), parietal lobe (g = -0.73; p = 0.053), cerebellum (g = -1.25; p < 0.001) and hippocampus (g = -0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.
Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this ...aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
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