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Emerging evidence suggests that the human amygdala undergoes extensive growth through adolescence, coinciding with the acquisition of complex socioemotional learning. Our objective was to longitudinally map volumetric growth of the nonhuman primate amygdala in a controlled, naturalistic social environment from birth to adulthood. Magnetic resonance images were collected at five time-points in 24 male and female rhesus macaques from 6 months to adulthood at 5 years. We then compared amygdala growth to other brain regions, including newly collected isocortical gray and white matter volumes, and previously published data on the same cohort. We found that amygdala volume increases by nearly 50% from age 6 months to 5 years. This dramatic growth is in contrast to overall brain and hippocampal volume, which peak near 3 years, white matter, which slows from 3 to 5 years, and isocortical gray, which has a net decrease. Similar to isocortical gray and hippocampal volumes, amygdala volume is ~8% larger in males than females. Rate of growth does not differ by sex. Although the underlying neurobiological substrate for protracted amygdala growth into adulthood is unclear, we propose it may be due in part to the unique cellular development of immature neurons in paralaminar nucleus that mature in size and connectivity with age. Prolonged amygdala maturation raises the possibility that environmental and genetic perturbations that disrupt this trajectory may contribute to the emergence of psychiatric disorders, such as anxiety, depression, schizophrenia, and autism; all in which the amygdala is strongly implicated.

Background/aimsNonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction.MethodsWe contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events.ResultsDystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants.ConclusionPatient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

BackgroundWe previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism.MethodsIn this case-control MRI study, children with autism spectrum disorder or with typical development aged 2-4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset.FindingsBetween July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm3 [SE 3·33] in autism group vs 101·40 cm3 [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p

Occurring in at least 1 in 3,000 live births, chromosome 22q11.2 deletion syndrome (22q11DS) produces a complex phenotype that includes a constellation of medical complications such as congenital cardiac defects, immune deficiency, velopharyngeal dysfunction, and characteristic facial dysmorphic features. There is also an increased incidence of psychiatric diagnosis, especially intellectual disability and ADHD in childhood, lifelong anxiety, and a strikingly high rate of schizophrenia spectrum disorders, which occur in around 30% of adults with 22q11DS. Using innovative computational connectomics, we studied how 22q11DS affects high-level network signatures of hierarchical modularity and its intrinsic geometry in 55 children with confirmed 22q11DS and 27 Typically Developing (TD) children. Results identified 3 subgroups within our 22q11DS sample using a K-means clustering approach based on several midline structural measures-of-interests. Each subgroup exhibited distinct patterns of connectome abnormalities. Subtype 1, containing individuals with generally healthy-looking brains, exhibited no significant differences in either modularity or intrinsic geometry when compared with TD. By contrast, the more anomalous 22q11DS Subtypes 2 and 3 brains revealed significant modular differences in the right hemisphere, while Subtype 3 (the most anomalous anatomy) further exhibited significantly abnormal connectome intrinsic geometry in the form of left-right temporal disintegration. Taken together, our findings supported an overall picture of (a) anterior-posteriorly differential interlobar frontotemporal/frontoparietal dysconnectivity in Subtypes 2 and 3 and (b) differential intralobar dysconnectivity in Subtype 3. Our ongoing studies are focusing on whether these subtypes and their connnectome signatures might be valid biomarkers for predicting the degree of psychosis-proneness risk found in 22q11DS. Hum Brain Mapp 39:232-248, 2018. © 2017 Wiley Periodicals, Inc.

ObjectiveThe objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity.MethodA resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls).ResultsThe ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05).ConclusionThese findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity.

We have longitudinally assessed normative brain growth patterns in naturalistically reared Macaca mulatta monkeys. Postnatal to early adulthood brain development in two cohorts of rhesus monkeys was analyzed using magnetic resonance imaging. Cohort A consisted of 24 rhesus monkeys (12 male, 12 female) and cohort B of 21 monkeys (11 male, 10 female). All subjects were scanned at 1, 4, 8, 13, 26, 39, and 52 weeks; cohort A had additional scans at 156 weeks (3 years) and 260 weeks (5 years). Age-specific segmentation templates were developed for automated volumetric analyses of the T1-weighted magnetic resonance imaging scans. Trajectories of total brain size as well as cerebral and subcortical subdivisions were evaluated over this period. Total brain volume was about 64 % of adult estimates in the 1-week-old monkey. Brain volume of the male subjects was always, on average, larger than the female subjects. While brain volume generally increased between any two imaging time points, there was a transient plateau of brain growth between 26 and 39 weeks in both cohorts of monkeys. The trajectory of enlargement differed across cortical regions with the occipital cortex demonstrating the most idiosyncratic pattern of maturation and the frontal and temporal lobes showing the greatest and most protracted growth. A variety of allometric measurements were also acquired and body weight gain was most closely associated with the rate of brain growth. These findings provide a valuable baseline for the effects of fetal and early postnatal manipulations on the pattern of abnormal brain growth related to neurodevelopmental disorders.

BackgroundIndividuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population.MethodsWe measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety.ResultsWe included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group.LimitationsShape alterations are not specific to hippocampal subfields.ConclusionAlterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection.

The Autism Phenome Project is the largest, single site, longitudinal magnetic resonance imaging (MRI) study of young children with autism spectrum disorder (ASD). Previous analyses from this cohort have shown that the children with autism have a total brain volume at time 1 (∼3 years of age) that is 6% larger than typically developing (TD) children. This finding is driven primarily by 15% of the boys with ASD that have disproportionate megalencephaly (ASD-DM) or brain size that is 1.5 standard deviations above what would be expected for the child's height. In the current study, cerebral cortical grey matter volume, thickness, and surface area were assayed from MRI scans of 112, 3-year-old boys with ASD and 50 age-matched TD boys. The boys with ASD-DM (n = 17) were analyzed separately from the boys with normal brain size (ASD-N, n = 95). Previous studies of cortical thickness and surface area for ASD children in this age range have come to diametrically different conclusions concerning the significance of cortical thickness vs. surface area. Current analyses indicate that cortical thickness was comparable across the ASD and TD groups. However, surface area was significantly greater in the ASD group compared to the TD group. This result was driven largely by the children with ASD-DM. Even in the ASD-DM group, not all cortical regions demonstrated increased surface area. These results provide strong evidence that the early cortical overgrowth associated with ASD is due primarily to increased surface area and not to increased cortical thickness.

Volumetric assessments of the hippocampus and other brain structures during childhood provide useful indices of brain development and correlates of cognitive functioning in typically and atypically developing children. Automated methods such as FreeSurfer promise efficient and replicable segmentation, but may include errors which are avoided by trained manual tracers. A recently devised automated correction tool that uses a machine learning algorithm to remove systematic errors, the Automatic Segmentation Adapter Tool (ASAT), was capable of substantially improving the accuracy of FreeSurfer segmentations in an adult sample [Wang et al., 2011], but the utility of ASAT has not been examined in pediatric samples. In Study 1, the validity of FreeSurfer and ASAT corrected hippocampal segmentations were examined in 20 typically developing children and 20 children with autism spectrum disorder aged 2 and 3 years. We showed that while neither FreeSurfer nor ASAT accuracy differed by disorder or age, the accuracy of ASAT corrected segmentations were substantially better than FreeSurfer segmentations in every case, using as few as 10 training examples. In Study 2, we applied ASAT to 89 typically developing children aged 2 to 4 years to examine relations between hippocampal volume, age, sex, and expressive language. Girls had smaller hippocampi overall, and in left hippocampus this difference was larger in older than younger girls. Expressive language ability was greater in older children, and this difference was larger in those with larger hippocampi, bilaterally. Overall, this research shows that ASAT is highly reliable and useful to examinations relating behavior to hippocampal structure.

Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Noncoronary artery aneurysms (NCAA) in extraparenchymal, muscular arteries occur in a minority of patients with KD who also have CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-β (TGF-β) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-β signaling pathway revealed increased expression of TGF-β2, TGF-β receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-β signaling pathway in this process.

The fornix is the primary subcortical output fiber system of the hippocampal formation. In children with 22q11.2 deletion syndrome (22q11.2DS), hippocampal volume reduction has been commonly reported, but few studies as yet have evaluated the integrity of the fornix. Therefore, we investigated the fornix of 45 school-aged children with 22q11.2DS and 38 matched typically developing (TD) children. Probabilistic diffusion tensor imaging (DTI) tractography was used to reconstruct the body of the fornix in each child׳s brain native space. Compared with children, significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) was observed bilaterally in the body of the fornix in children with 22q11.2DS. Irregularities were especially prominent in the posterior aspect of the fornix where it emerges from the hippocampus. Smaller volumes of the hippocampal formations were also found in the 22q11.2DS group. The reduced hippocampal volumes were correlated with lower fornix FA and higher fornix RD in the right hemisphere. Our findings provide neuroanatomical evidence of disrupted hippocampal connectivity in children with 22q11.2DS, which may help to further understand the biological basis of spatial impairments, affective regulation, and other factors related to the ultra-high risk for schizophrenia in this population.

BackgroundAfrican Americans have the highest incidence and mortality from colorectal cancer (CRC). Despite guidelines to initiate screening with colonoscopy at age 45 in African Americans, the CRC incidence remains high in this group.ObjectiveTo examine the rates and predictors of CRC screening uptake as well as time to screening in a population of African Americans and non-African Americans in a health care system that minimizes variations in insurance and access.DesignRetrospective cohort study.SettingGreater Los Angeles Veterans Affairs (VA) Healthcare System.PatientsRandom sample (N = 357) of patients eligible for initial CRC screening.Main outcome measurementsUptake of any screening method; uptake of colonoscopy, in particular; predictors of screening; and time to screening in African Americans and non-African Americans.ResultsThe overall screening rate by any method was 50%. Adjusted rates for any screening were lower among African Americans than non-African Americans (42% vs 58%; odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31-0.77). Colonoscopic screening was also lower in African Americans (11% vs 23%; adjusted OR 0.43; 95% CI, 0.24-0.77). In addition to race, homelessness, lower service connectedness, taking more prescription drugs, and not seeing a primary care provider within 2 years of screening eligibility predicted lower uptake of screening. Time to screening colonoscopy was longer in African Americans (adjusted hazard ratio 0.43; 95% CI, 0.25-0.75).LimitationsThe sample may not be generalizable.ConclusionsWe found marked disparities in CRC screening despite similar access to care across races. Despite current guidelines aimed at increasing CRC screening in African Americans, participation in screening remained low, and use of colonoscopy was infrequent.

The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human β2-microglobulin (hβ2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/hβ2m and hβ2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene.

Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 'high-risk' infants having an older sibling with autism spectrum disorder and 22 'low-risk' infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.