The role of puberty on physical and brain development: A longitudinal study in male Rhesus Macaques.

This study examined the role of male pubertal maturation on physical growth and development of neurocircuits that regulate stress, emotional and cognitive control using a translational nonhuman primate model. We collected longitudinal data from male macaques between pre- and peri-puberty, including measures of physical growth, pubertal maturation (testicular volume, blood testosterone -T- concentrations) and brain structural and resting-state functional MRI scans to examine developmental changes in amygdala (AMY), hippocampus (HIPPO), prefrontal cortex (PFC), as well as functional connectivity (FC) between those regions. Physical growth and pubertal measures increased from pre- to peri-puberty. The indexes of pubertal maturation -testicular size and T- were correlated at peri-puberty, but not at pre-puberty (23 months). Our findings also showed ICV, AMY, HIPPO and total PFC volumetric growth, but with region-specific changes in PFC. Surprisingly, FC in these neural circuits only showed developmental changes from pre- to peri-puberty for HIPPO-orbitofrontal FC. Finally, testicular size was a better predictor of brain structural maturation than T levels -suggesting gonadal hormones-independent mechanisms-, whereas T was a strong predictor of functional connectivity development. We expect that these neural circuits will show more drastic pubertal-dependent maturation, including stronger associations with pubertal measures later, during and after male puberty.

Distinct Microbial Signatures between Periodontal Profile Classes.

Precise classification of periodontal disease has been the objective of concerted efforts and has led to the introduction of new consensus-based and data-driven classifications. The purpose of this study was to characterize the microbiological signatures of a latent class analysis (LCA)-derived periodontal stratification system, the Periodontal Profile Class (PPC) taxonomy. We used demographic, microbial (subgingival biofilm composition), and immunological data (serum IgG antibody levels, obtained with checkerboard immunoblotting technique) for 1,450 adult participants of the Dental Atherosclerosis Risk in Communities (ARIC) study, with already generated PPC classifications. Analyses relied on t tests and generalized linear models with Bonferroni correction. Men and African Americans had higher systemic antibody levels against most microorganisms compared to women and Caucasians (P < 0.05). Healthy individuals (PPC-I) had low levels of biofilm bacteria and serum IgG levels against most periodontal pathogens (P < 0.05). Subjects with mild to moderate disease (PPC-II to PPC-III) showed mild/moderate colonization of multiple biofilm pathogens. Individuals with severe disease (PPC-IV) had moderate/high levels of biofilm pathogens and antibody levels for orange/red complexes. High gingival index individuals (PPC-V) showed moderate/high levels of biofilm Campylobacter rectus and Aggregatibacter actinomycetemcomitans. Biofilm composition in individuals with reduced periodontium (PPC-VI) was similar to health but showed moderate to high antibody responses. Those with severe tooth loss (PPC-VII) had significantly high levels of multiple biofilm pathogens, while the systemic antibody response to these microorganisms was comparable to health. The results support a biologic basis for elevated risk for periodontal disease in men and African Americans. Periodontally healthy individuals showed a low biofilm pathogen and low systemic antibody burden. In the presence of PPC disease, a microbial-host imbalance characterized by higher microbial biofilm colonization and/or systemic IgG responses was identified. These results support the notion that subgroups identified by the PPC system present distinct microbial profiles and may be useful in designing future precise biological treatment interventions.

Structural development of cortical lobes during the first 6 months of life in infant macaques.

This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2-24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20-24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2-24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2-12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.

A voxel-wise assessment of growth differences in infants developing autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a phenotypically and etiologically heterogeneous developmental disorder typically diagnosed around 4 years of age. The development of biomarkers to help in earlier, presymptomatic diagnosis could facilitate earlier identification and therefore earlier intervention and may lead to better outcomes, as well as providing information to help better understand the underlying mechanisms of ASD. In this study, magnetic resonance imaging (MRI) scans of infants at high familial risk, from the Infant Brain Imaging Study (IBIS), at 6, 12 and 24 months of age were included in a morphological analysis, fitting a mixed-effects model to Tensor Based Morphometry (TBM) results to obtain voxel-wise growth trajectories. Subjects were grouped by familial risk and clinical diagnosis at 2 years of age. Several regions, including the posterior cingulate gyrus, the cingulum, the fusiform gyrus, and the precentral gyrus, showed a significant effect for the interaction of group and age associated with ASD, either as an increased or a decreased growth rate of the cerebrum. In general, our results showed increased growth rate within white matter with decreased growth rate found mostly in grey matter. Overall, the regions showing increased growth rate were larger and more numerous than those with decreased growth rate. These results detail, at the voxel level, differences in brain growth trajectories in ASD during the first years of life, previously reported in terms of overall brain volume and surface area.

Genome-Wide Association Analysis of Neonatal White Matter Microstructure.

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.

Personalized connectome fingerprints: Their importance in cognition from childhood to adult years.

Structural neural network architecture patterns in the human brain could be related to individual differences in phenotype, behavior, genetic determinants, and clinical outcomes from neuropsychiatric disorders. Recent studies have indicated that a personalized neural (brain) fingerprint can be identified from structural brain connectomes. However, the accuracy, reproducibility and translational potential of personalized fingerprints in terms of cognition is not yet fully determined. In this study, we introduce a dynamic connectome modeling approach to identify a critical set of white matter subnetworks that can be used as a personalized fingerprint. Several individual variable assessments were performed that demonstrate the accuracy and practicality of personalized fingerprint, specifically predicting the identity and IQ of middle age adults, and the developmental quotient in toddlers. Our findings suggest the fingerprint found by our dynamic modeling approach is sufficient for differentiation between individuals, and is also capable of predicting general intellectual ability across human development.

Altered Brain Structure in Infants with Turner Syndrome.

Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.

Minimally Invasive Approach for Diagnosing TMJ Osteoarthritis.

This study's objectives were to test correlations among groups of biomarkers that are associated with condylar morphology and to apply artificial intelligence to test shape analysis features in a neural network (NN) to stage condylar morphology in temporomandibular joint osteoarthritis (TMJOA). Seventeen TMJOA patients (39.9 ± 11.7 y) experiencing signs and symptoms of the disease for less than 10 y and 17 age- and sex-matched control subjects (39.4 ± 15.2 y) completed a questionnaire, had a temporomandibular joint clinical exam, had blood and saliva samples drawn, and had high-resolution cone beam computed tomography scans taken. Serum and salivary levels of 17 inflammatory biomarkers were quantified using protein microarrays. A NN was trained with 259 other condyles to detect and classify the stage of TMJOA and then compared to repeated clinical experts' classifications. Levels of the salivary biomarkers MMP-3, VE-cadherin, 6Ckine, and PAI-1 were correlated to each other in TMJOA patients and were significantly correlated with condylar morphological variability on the posterior surface of the condyle. In serum, VE-cadherin and VEGF were correlated with one another and with significant morphological variability on the anterior surface of the condyle, while MMP-3 and CXCL16 presented statistically significant associations with variability on the anterior surface, lateral pole, and superior-posterior surface of the condyle. The range of mouth opening variables were the clinical markers with the most significant associations with morphological variability at the medial and lateral condylar poles. The repeated clinician consensus classification had 97.8% agreement on degree of degeneration within 1 group difference. Predictive analytics of the NN's staging of TMJOA compared to the repeated clinicians' consensus revealed 73.5% and 91.2% accuracy. This study demonstrated significant correlations among variations in protein expression levels, clinical symptoms, and condylar surface morphology. The results suggest that 3-dimensional variability in TMJOA condylar morphology can be comprehensively phenotyped by the NN.

FSEM: Functional Structural Equation Models for Twin Functional Data.

The aim of this paper is to develop a novel class of functional structural equation models (FSEMs) for dissecting functional genetic and environmental effects on twin functional data, while characterizing the varying association between functional data and covariates of interest. We propose a three-stage estimation procedure to estimate varying coefficient functions for various covariates (e.g., gender) as well as three covariance operators for the genetic and environmental effects. We develop an inference procedure based on weighted likelihood ratio statistics to test the genetic/environmental effect at either a fixed location or a compact region. We also systematically carry out the theoretical analysis of the estimated varying functions, the weighted likelihood ratio statistics, and the estimated covariance operators. We conduct extensive Monte Carlo simulations to examine the finite-sample performance of the estimation and inference procedures. We apply the proposed FSEM to quantify the degree of genetic and environmental effects on twin white-matter tracts obtained from the UNC early brain development study.

Early Developmental Trajectories of Functional Connectivity Along the Visual Pathways in Rhesus Monkeys.

Early social interactions shape the development of social behavior, although the critical periods or the underlying neurodevelopmental processes are not completely understood. Here, we studied the developmental changes in neural pathways underlying visual social engagement in the translational rhesus monkey model. Changes in functional connectivity (FC) along the ventral object and motion pathways and the dorsal attention/visuo-spatial pathways were studied longitudinally using resting-state functional MRI in infant rhesus monkeys, from birth through early weaning (3 months), given the socioemotional changes experienced during this period. Our results revealed that (1) maturation along the visual pathways proceeds in a caudo-rostral progression with primary visual areas (V1-V3) showing strong FC as early as 2 weeks of age, whereas higher-order visual and attentional areas (e.g., MT-AST, LIP-FEF) show weak FC; (2) functional changes were pathway-specific (e.g., robust FC increases detected in the most anterior aspect of the object pathway (TE-AMY), but FC remained weak in the other pathways (e.g., AST-AMY)); (3) FC matures similarly in both right and left hemispheres. Our findings suggest that visual pathways in infant macaques undergo selective remodeling during the first 3 months of life, likely regulated by early social interactions and supporting the transition to independence from the mother.

Genome-wide association analysis identifies common variants influencing infant brain volumes.

Genome-wide association studies (GWAS) of adolescents and adults are transforming our understanding of how genetic variants impact brain structure and psychiatric risk, but cannot address the reality that psychiatric disorders are unfolding developmental processes with origins in fetal life. To investigate how genetic variation impacts prenatal brain development, we conducted a GWAS of global brain tissue volumes in 561 infants. An intronic single-nucleotide polymorphism (SNP) in IGFBP7 (rs114518130) achieved genome-wide significance for gray matter volume (P=4.15 × 10-10). An intronic SNP in WWOX (rs10514437) neared genome-wide significance for white matter volume (P=1.56 × 10-8). Additional loci with small P-values included psychiatric GWAS associations and transcription factors expressed in developing brain. Genetic predisposition scores for schizophrenia and ASD, and the number of genes impacted by rare copy number variants (CNV burden) did not predict global brain tissue volumes. Integration of these results with large-scale neuroimaging GWAS in adolescents (PNC) and adults (ENIGMA2) suggests minimal overlap between common variants impacting brain volumes at different ages. Ultimately, by identifying genes contributing to adverse developmental phenotypes, it may be possible to adjust adverse trajectories, preventing or ameliorating psychiatric and developmental disorders.

Mapping White Matter Microstructure in the One Month Human Brain.

White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth.

Newborn insula gray matter volume is prospectively associated with early life adiposity gain.

BACKGROUND: The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk. METHODS: A total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks). RESULTS: Insula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (ß=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables. CONCLUSIONS: Altogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism.

BACKGROUND: We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS: A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS: Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen's d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS: This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Three-dimensional regional displacement after surgical-orthodontic correction of Class III malocclusion.

OBJECTIVES: To investigate how displacements of maxillo-mandibular structures are associated with each other at splint removal and 1 year post-surgery following 1-jaw and 2-jaw surgeries for correction of Class III malocclusion. SETTING AND SAMPLE POPULATION: Fifty patients who underwent surgical correction with maxillary advancement only (n = 25) or combined with mandibular setback (n = 25) were prospectively enrolled in this study. METHODS: Cone-beam computed tomographies were taken pre-surgery, at splint removal and at 1 year post-surgery. Three-dimensional cranial base superimpositions and shape correspondence were used to measure the outcomes from pre-surgery to splint removal (surgical changes) and splint removal to 1 year post-surgery (post-surgical adaptations). Pearson's correlation coefficients were used to evaluate the association between the regional displacements. RESULTS: Both surgery groups presented mandibular clockwise rotation with surgery and post-surgical adaptive counterclockwise rotation. In patients treated with maxillary advancement only, the surgical changes of the maxilla were significantly correlated with chin changes. The amount and direction of chin autorotation were significantly correlated with right and left ramus autorotation. Right and left condylar displacements were significantly correlated. One year post-surgery, adaptive displacements and bone remodeling of both rami were correlated with the chin and condylar changes. For the 2-jaw group, the few correlations between the positional and remodeling changes in the anatomic regions of interest observed due to the surgery were different than those observed after post-surgical adaptations, suggesting that these changes occurred independently. CONCLUSION: Our results indicate that surgical displacements and post-surgical adaptations are often correlated in one-jaw surgery and are, in general, independent in two-jaw surgery.

Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease.

BACKGROUND: Krabbe disease is a fatal neurodegenerative disease caused by rapid demyelination of the central and peripheral nervous systems. The only available treatment, unrelated umbilical cord blood transplantation, is effective only if performed before clinical symptoms appear. Phenotypic expressions of disease-causing mutations vary widely, but genotype-phenotype relationships are unclear. Therefore, we evaluated diffusion tensor imaging (DTI) tractography with volumetric analysis as a biomarker of early white matter changes and functional disability in presymptomatic infants. METHODS: We obtained DTI and structural scans of newborns with early-infantile Krabbe disease (n = 9) diagnosed by family history or newborn screening. We compared white matter fiber tract properties to those of normal controls (n = 336) and assessed the ability of tract-based properties to predict longitudinal development in four functional domains (cognitive, fine motor, gross motor, adaptive behavior) after treatment with unrelated umbilical cord blood transplantation. We also assessed the relationship between the standard evaluation (modified Loes score) and DTI results, and the volumetric differences between the Krabbe subjects and normal controls. FINDINGS: Reductions in fractional anisotropy were significant in the corticospinal tract in the Krabbe patients compared to controls, which strongly correlated with motor and cognitive outcomes after transplantation. Significant regional differences were observed in the splenium and uncinate fasciculus in Krabbe patients and these differences correlated only with cognitive outcomes. Regional brain volumes of Krabbe patients were slightly larger than controls. Loes scores did not correlate with DTI results. INTERPRETATION: Neonatal microstructural abnormalities correlate with neurodevelopmental treatment outcomes in patients treated for infantile Krabbe disease. DTI with quantitative tractography is an excellent biomarker for evaluating infants with Krabbe disease identified through newborn screening.

3D superimposition and understanding temporomandibular joint arthritis.

OBJECTIVES: To investigate the 3D morphological variations in 169 temporomandibular ioint (TMJ) condyles, using novel imaging statistical modeling approaches. SETTING AND SAMPLE POPULATION: The Department of Orthodontics and Pediatric Dentistry at the University of Michigan. Cone beam CT scans were acquired from 69 subjects with long-term TMJ osteoarthritis (OA, mean age 39.1±15.7 years), 15 subjects at initial consult diagnosis of OA (mean age 44.9±14.8 years), and seven healthy controls (mean age 43±12.4 years). MATERIALS AND METHODS: 3D surface models of the condyles were constructed, and homologous correspondent points on each model were established. The statistical framework included Direction-Projection-Permutation (DiProPerm) for testing statistical significance of the differences between healthy controls and the OA groups determined by clinical and radiographic diagnoses. RESULTS: Condylar morphology in OA and healthy subjects varied widely with categorization from mild to severe bone degeneration or overgrowth. DiProPerm statistics supported a significant difference between the healthy control group and the initial diagnosis of OA group (t=6.6, empirical p-value=0.006) and between healthy and long-term diagnosis of OA group (t=7.2, empirical p-value=0). Compared with healthy controls, the average condyle in OA subjects was significantly smaller in all dimensions, except its anterior surface, even in subjects with initial diagnosis of OA. CONCLUSION: This new statistical modeling of condylar morphology allows the development of more targeted classifications of this condition than previously possible.

3D osteoarthritic changes in TMJ condylar morphology correlates with specific systemic and local biomarkers of disease.

OBJECTIVE: To assess 3D morphological variations and local and systemic biomarker profiles in subjects with a diagnosis of temporomandibular joint osteoarthritis (TMJ OA). DESIGN: Twenty-eight patients with long-term TMJ OA (39.9 ± 16 years), 12 patients at initial diagnosis of OA (47.4 ± 16.1 years), and 12 healthy controls (41.8 ± 12.2 years) were recruited. All patients were female and had cone beam CT scans taken. TMJ arthrocentesis and venipuncture were performed on 12 OA and 12 age-matched healthy controls. Serum and synovial fluid levels of 50 biomarkers of arthritic inflammation were quantified by protein microarrays. Shape Analysis MANCOVA tested statistical correlations between biomarker levels and variations in condylar morphology. RESULTS: Compared with healthy controls, the OA average condyle was significantly smaller in all dimensions except its anterior surface, with areas indicative of bone resorption along the articular surface, particularly in the lateral pole. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were significantly correlated with bone apposition of the condylar anterior surface. Serum levels of ENA-78, MMP-3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFßb1, IFNγg, TNFαa, IL-1αa, and IL-6 were significantly correlated with flattening of the lateral pole. Expression levels of ANG were significantly correlated with the articular morphology in healthy controls. CONCLUSIONS: Bone resorption at the articular surface, particularly at the lateral pole was statistically significant at initial diagnosis of TMJ OA. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were correlated with bone apposition. Serum levels of ENA-78, MMP-3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFß1, IFNγ, TNFα, IL-1α, and IL-6 were correlated with bone resorption.

Network inefficiencies in autism spectrum disorder at 24 months.

Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral symptoms that emerge during the first years of life. Associated with these symptoms are differences in the structure of a wide array of brain regions, and in the connectivity between these regions. However, the use of cohorts with large age variability and participants past the generally recognized age of onset of the defining behaviors means that many of the reported abnormalities may be a result of cascade effects of developmentally earlier deviations. This study assessed differences in connectivity in ASD at the age at which the defining behaviors first become clear. There were 113 24-month-old participants at high risk for ASD, 31 of whom were classified as ASD, and 23 typically developing 24-month-old participants at low risk for ASD. Utilizing diffusion data to obtain measures of the length and strength of connections between anatomical regions, we performed an analysis of network efficiency. Our results showed significantly decreased local and global efficiency over temporal, parietal and occipital lobes in high-risk infants classified as ASD, relative to both low- and high-risk infants not classified as ASD. The frontal lobes showed only a reduction in global efficiency in Broca's area. In addition, these same regions showed an inverse relation between efficiency and symptom severity across the high-risk infants. The results suggest delay or deficits in infants with ASD in the optimization of both local and global aspects of network structure in regions involved in processing auditory and visual stimuli, language and nonlinguistic social stimuli.

Regional 3D superimposition to assess temporomandibular joint condylar morphology.

OBJECTIVES: To investigate the reliability of regional three-dimensional registration and superimposition methods for assessment of temporomandibular joint condylar morphology across subjects and longitudinally. METHODS: The sample consisted of cone beam CT scans of 36 patients. The across-subject comparisons included 12 controls, mean age 41.3 ± 12.0 years, and 12 patients with temporomandibular joint osteoarthritis, mean age 41.3 ± 14.7 years. The individual longitudinal assessments included 12 patients with temporomandibular joint osteoarthritis, mean age 37.8 ± 16.7 years, followed up at pre-operative jaw surgery, immediately after and one-year post-operative. Surface models of all condyles were constructed from the cone beam CT scans. Two previously calibrated observers independently performed all registration methods. A landmark-based approach was used for the registration of across-subject condylar models, and temporomandibular joint osteoarthritis vs control group differences were computed with shape analysis. A voxel-based approach was used for registration of longitudinal scans calculated x, y, z degrees of freedom for translation and rotation. Two-way random intraclass correlation coefficients tested the interobserver reliability. RESULTS: Statistically significant differences between the control group and the osteoarthritis group were consistently located on the lateral and medial poles for both observers. The interobserver differences were ≤0.2 mm. For individual longitudinal comparisons, the mean interobserver differences were ≤0.6 mm in translation errors and 1.2° in rotation errors, with excellent reliability (intraclass correlation coefficient >0.75). CONCLUSIONS: Condylar registration for across-subjects and longitudinal assessments is reliable and can be used to quantify subtle bony differences in the three-dimensional condylar morphology.