Jeffrey I. Berman

Opposing Brain Differences in 16p11.2 Deletion and Duplication Carriers

Deletions and duplications of the recurrent ∼600 kb chromosomal BP4–BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development.

White Matter Changes of Neurite Density and Fiber Orientation Dispersion during Human Brain Maturation

Diffusion tensor imaging (DTI) studies of human brain development have consistently shown widespread, but nonlinear increases in white matter anisotropy through childhood, adolescence, and into adulthood. However, despite its sensitivity to changes in tissue microstructure, DTI lacks the specificity to disentangle distinct microstructural features of white and gray matter. Neurite orientation dispersion and density imaging (NODDI) is a recently proposed multi-compartment biophysical model of brain microstructure that can estimate non-collinear properties of white matter, such as neurite orientation dispersion index (ODI) and neurite density index (NDI). In this study, we apply NODDI to 66 healthy controls aged 7–63 years to investigate changes of ODI and NDI with brain maturation, with comparison to standard DTI metrics. Using both region-of-interest and voxel-wise analyses, we find that NDI exhibits striking increases over the studied age range following a logarithmic growth pattern, while ODI rises following an exponential growth pattern. This novel finding is consistent with well-established age-related changes of FA over the lifespan that show growth during childhood and adolescence, plateau during early adulthood, and accelerating decay after the fourth decade of life. Our results suggest that the rise of FA during the first two decades of life is dominated by increasing NDI, while the fall in FA after the fourth decade is driven by the exponential rise of ODI that overcomes the slower increases of NDI. Using partial least squares regression, we further demonstrate that NODDI better predicts chronological age than DTI. Finally, we show excellent test—retest reliability of NODDI metrics, with coefficients of variation below 5% in all measured regions of interest. Our results support the conclusion that NODDI reveals biologically specific characteristics of brain development that are more closely linked to the microstructural features of white matter than are the empirical metrics provided by DTI.

Aberrant White Matter Microstructure in Children with 16p11.2 Deletions

Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV.

Maturational differences in thalamocortical white matter microstructure and auditory evoked response latencies in autism spectrum disorders

White matter diffusion anisotropy in the acoustic radiations was characterized as a function of development in autistic and typically developing children. Auditory-evoked neuromagnetic fields were also recorded from the same individuals and the latency of the left and right middle latency superior temporal gyrus auditory ~50ms response (M50)(1) was measured. Group differences in structural and functional auditory measures were examined, as were group differences in associations between white matter pathways, M50 latency, and age. Acoustic radiation white matter fractional anisotropy did not differ between groups. Individuals with autism displayed a significant M50 latency delay. Only in typically developing controls, white matter fractional anisotropy increased with age and increased white matter anisotropy was associated with earlier M50 responses. M50 latency, however, decreased with age in both groups. Present findings thus indicate that although there is loss of a relationship between white matter structure and auditory cortex function in autism spectrum disorders, and although there are delayed auditory responses in individuals with autism than compared with age-matched controls, M50 latency nevertheless decreases as a function of age in autism, parallel to the observation in typically developing controls (although with an overall latency delay). To understand auditory latency delays in autism and changes in auditory responses as a function of age in controls and autism, studies examining white matter as well as other factors that influence auditory latency, such as synaptic transmission, are of interest.

Left Hemisphere Diffusivity of the Arcuate Fasciculus: Influences of Autism Spectrum Disorder and Language Impairment

The authors used DTI measurements of the arcuate fasciculus in 14 children with language impairment, in 16 autistic children with language impairment, 18 autistic children without language impairment, and 25 controls. Although white matter abnormalities appeared similar in language impairment and autism spectrum disorder when examining broad white matter measures, detailed analysis indicated different mechanisms for the white matter microstructural anomalies associated with these disorders. BACKGROUND AND PURPOSE: There has been much discussion whether brain abnormalities associated with specific language impairment and autism with language impairment are shared or are disorder specific. Although white matter tract abnormalities are observed in both specific language impairment and autism spectrum disorders, the similarities and differences in the white matter abnormalities in these 2 disorders have not been fully determined. MATERIALS AND METHODS: Diffusion tensor imaging diffusion parameters of the arcuate fasciculus were measured in 14 children with specific language impairment as well as in 16 children with autism spectrum disorder with language impairment, 18 with autism spectrum disorder without language impairment, and 25 age-matched typically developing control participants. RESULTS: Language impairment and autism spectrum disorder both had (elevating) main effects on mean diffusivity of the left arcuate fasciculus, initially suggesting a shared white matter substrate abnormality. Analysis of axial and radial diffusivity components, however, indicated that autism spectrum disorder and language impairment differentially affect white matter microstructural properties, with a main effect of autism spectrum disorder on axial diffusivity and a main effect of language impairment on radial diffusivity. CONCLUSIONS: Although white matter abnormalities appear similar in language impairment and autism spectrum disorder when examining broad white matter measures, a more detailed analysis indicates different mechanisms for the white matter microstructural anomalies associated with language impairment and autism spectrum disorder.

Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications

Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention‐deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833–2848, 2016.

Massive cortical reorganization is reversible following bilateral transplants of the hands: evidence from the first successful bilateral pediatric hand transplant patient

In this repeated measures case study, we show that sensory deafferentation after limb amputation leads to changes in cortical somatotopic maps which are reversible after restoration of sensory input. Using magnetoencephalography (MEG), we observed in a child with bilateral hand transplants large‐scale shifts in somatosensory lip cortical representation from anatomic hand area to anatomic face region. After recovery of tactile sensation in the digits, responses to finger stimulation were localized to orthotopic sensory cortex, but with atypical electrophysiologic features (amplitude and frequencies).

Lower Extremity Vascular Access in Neonates and Infants: A Single Institutional Experience

PURPOSE To demonstrate feasibility and evaluate outcomes of direct-stick saphenous and single-incision tunneled femoral noncuffed central venous catheters (CVCs) placed in a large series of neonates and infants at a single institution. MATERIALS AND METHODS A retrospective review was performed for all neonates and infants receiving a lower extremity CVC by interventional radiology between 2007 and 2012. Technical success, mechanical and infectious complications, and catheter outcomes were recorded. RESULTS There were 271 primary insertions performed in 243 children by interventional radiologists in the interventional radiology suite or at the bedside. CVCs were placed via the femoral vein with single-incision technique (84.9%) or the saphenous vein via a direct-stick technique (15.1%), with a technical success rate of 100%. The total number of catheter-days was 7,917 days (median, 19 d; range, 0-220 d). The number of primary catheter-days was 5,333 days (median, 15 d; range, 0-123.0 d), and salvage procedures prolonged catheter life by 2,584 days (median, 15 d; range, 1.0-101.0 d). The mechanical and adjusted infectious complication rates were 1.67 and 0.44 per 100 catheter-days. CONCLUSIONS Image-guided placement of saphenous or tunneled femoral catheters using a single incision is a safe and feasible method for vascular access in neonates and infants.

Review of diffusion tensor imaging and its application in children

Diffusion MRI is an imaging technique that uses the random motion of water to probe tissue microstructure. Diffusion tensor imaging (DTI) can quantitatively depict the organization and connectivity of white matter. Given the non-invasiveness of the technique, DTI has become a widely used tool for researchers and clinicians to examine the white matter of children. This review covers the basics of diffusion-weighted imaging and diffusion tensor imaging and discusses examples of their clinical application in children.

Validation of an automated tractography method for the optic radiations as a biomarker of visual acuity in neurofibromatosis-associated optic pathway glioma

Introduction: Fractional anisotropy (FA) of the optic radiations has been associated with vision deficit in multiple intrinsic brain pathologies including NF1 associated optic pathway glioma, but hand‐drawn regions of interest used in previous tractography methods limit consistency of this potential biomarker. We created an automated method to identify white matter tracts in the optic radiations and compared this method to previously reported hand‐drawn tractography. Method: Automated tractography of the optic radiation using probabilistic streamline fiber tracking between the lateral geniculate nucleus of the thalamus and the occipital cortex was compared to the hand‐drawn method between regions of interest posterior to Meyers loop and anterior to tract branching near the calcarine cortex. Reliability was assessed by two independent raters in a sample of 20 healthy child controls. Among 50 children with NF1‐associated optic pathway glioma, the association of FA and visual acuity deficit was compared for both tractography methods. Results: Hand‐drawn tractography methods required 2.6 ± 0.9 min/participant; automated methods were performed in < 1 min of operator time for all participants. Cronbachs alpha was 0.83 between two independent raters for FA in hand‐drawn tractography, but repeated automated tractography resulted in identical FA values (Cronbachs alpha = 1). On univariate and multivariate analyses, FA was similarly associated with visual acuity loss using both methods. Receiver operator characteristic curves of both multivariate models demonstrated that both automated and hand‐drawn tractography methods were equally able to distinguish normal from abnormal visual acuity. Conclusion: Automated tractography of the optic radiations offers a fast, reliable and consistent method of tract identification that is not reliant on operator time or expertise. This method of tract identification may be useful as DTI is developed as a potential biomarker for visual acuity. HIGHLIGHTSAn automated process for the identification of optic radiations is described.Automated tractography is fast, reliable and not reliant on operator expertise.New and old tractography methods equally distinguishes visual acuity loss in OPG.Automated tractography may help support DTI as a biomarker of vision in OPG.