Mari Wakahiro

Variability of Homotopic and Heterotopic Callosal Connectivity in Partial Agenesis of the Corpus Callosum : A 3T Diffusion Tensor Imaging and Q-Ball Tractography Study

BACKGROUND AND PURPOSE: Little is known about the anatomic connectivity of callosal axons in individuals with partial agenesis of the corpus callosum (pAgCC). We used tractography based on both diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) to investigate interhemispheric white matter connectivity in pAgCC. MATERIALS AND METHODS: DTI and HARDI were performed at 3T on 6 individuals with pAgCC and 8 control subjects. For HARDI analysis, a Q-ball reconstruction method capable of visualizing multiple intravoxel fiber orientations was used. In both DTI and HARDI, whole-brain 3D fiber tractography was performed by using deterministic streamline algorithms. Callosal fibers were then segmented to identify separately connections between homologous cortical regions (homotopic fibers) and nonhomologous regions (heterotopic fibers) by using manually drawn regions of interest. RESULTS: In control individuals, we observed densely connected homotopic fibers. However, in individuals with pAgCC, we identified not only homotopic connections but also heterotopic connections in 4 of 6 subjects. Furthermore, the observed homotopic connections in pAgCC did not necessarily correlate with the position or size of the residual callosum. The nature of homotopic and heterotopic connectivity varied considerably among subjects with pAgCC, and HARDI recovered more callosal fibers than DTI. CONCLUSION: Individuals with pAgCC demonstrate a remarkable diversity of callosal connectivity, including a number of heterotopic tracts that are absent in healthy subjects. The patterns of their callosal connections cannot be predicted from the appearance of their callosal fragments on conventional MR imaging. More tracts and more extensive fibers within tracts are recovered with HARDI than with DTI.

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.

Test–Retest Reliability of Computational Network Measurements Derived from the Structural Connectome of the Human Brain

Structural magnetic resonance (MR) connectomics holds promise for the diagnosis, outcome prediction, and treatment monitoring of many common neurodevelopmental, psychiatric, and neurodegenerative disorders for which there is currently no clinical utility for MR imaging (MRI). Before computational network metrics from the human connectome can be applied in a clinical setting, their precision and their normative intersubject variation must be understood to guide the study design and the interpretation of longitudinal data. In this work, the reproducibility of commonly used graph theoretic measures is investigated, as applied to the structural connectome of healthy adult volunteers. Two datasets are examined, one consisting of 10 subjects scanned twice at one MRI facility and one consisting of five subjects scanned once each at two different facilities using the same imaging platform. Global graph metrics are calculated for unweighed and weighed connectomes, and two levels of granularity of the connectome are evaluated: one based on the 82-node cortical and subcortical parcellation from FreeSurfer and one based on an atlas-free parcellation of the gray-white matter boundary consisting of 1000 cortical nodes. The consistency of the unweighed and weighed edges and the module assignments are also computed for the 82-node connectomes. Overall, the results demonstrate good-to-excellent test-retest reliability for the entire connectome-processing pipeline, including the graph analytics, in both the intrasite and intersite datasets. These findings indicate that measurements of computational network metrics derived from the structural connectome have sufficient precision to be tested as potential biomarkers for diagnosis, prognosis, and monitoring of interventions in neurological and psychiatric diseases.

Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.

Absence of the corpus callosum is often associated with cognitive deficits, autism, and epilepsy. Using a genomic microarray, the authors analyzed DNA from 25 patients with radiographically confirmed callosal anomalies and identified three patients with de novo copy number changes in chromosome regions 2q37, 6qter, and 8p. Chromosomal deletions and duplications may be a relatively common cause of cerebral malformations.

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.

Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria

Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (p = 1.48×10−3; odds ratio [OR] = 3.19; 95% confidence interval [CI] = 1.89–5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (p = 0.01; OR = 2.95; 95% CI = 1.69–5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (p = 3.06×10−4; OR = 7.55; 95% CI = 2.40–23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.

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.

Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000–1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted‐in‐Schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well‐characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5′ boundary of exon 11 that dramatically reduces full‐length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development.

Diffusion Abnormalities and Reduced Volume of the Ventral Cingulum Bundle in Agenesis of the Corpus Callosum: A 3T Imaging Study

BACKGROUND AND PURPOSE: Patients with agenesis of the corpus callosum (AgCC) exhibit cognitive and behavioral impairments that are not replicated by surgical transection of the callosum, suggesting that other anatomic changes may contribute to the observed clinical findings. The purpose of this study was to determine whether the ventral cingulum bundle (VCB) is affected in patients with AgCC by using diffusion tensor imaging (DTI) and volumetry. MATERIALS AND METHODS: Twelve participants with AgCC (8 males and 4 females; mean age, 30 ± 20) and 12 control subjects matched for age and sex (mean age, 37 ± 19) underwent MR imaging and DTI at 3T. 3D fiber tracking of the VCB was generated from DTI and the average fractional anisotropy (FA) was computed for the tracked fibers. Additionally, the volume, cross-sectional area, and length of the VCB were measured by manually drawn regions of interest on thin-section coronal T1-weighted images. The Student t test was used to compare these results. RESULTS: Compared with controls, subjects with AgCC demonstrated significantly reduced FA in the right VCB (P = .0098) and reduced volume and cross-sectional areas of both the left and right VCB (P < .001 for all metrics). The length of the VCB was also significantly reduced in the complete AgCC subgroup compared with controls (P = .030 in the right and P = .046 in the left, respectively). CONCLUSIONS: Patients with AgCC have abnormal microstructure and reduced volume of the VCB, suggesting that abnormalities in intrahemispheric white matter tracts may be an important contributor to the clinical syndrome in patients with AgCC.

Resting-State Networks and the Functional Connectome of the Human Brain in Agenesis of the Corpus Callosum

The corpus callosum is the largest white matter fiber bundle connecting the two cerebral hemispheres. In this work, we investigate the effect of callosal dysgenesis on functional magnetic resonance imaging (fMRI) resting-state networks and the functional connectome. Since alternate commissural routes between the cerebral hemispheres exist, we hypothesize that bilateral cortical networks can still be maintained in partial or even complete agenesis of the corpus callosum (AgCC). However, since these commissural routes are frequently indirect, requiring polysynaptic pathways, we hypothesize that quantitative measurements of interhemispheric functional connectivity in bilateral networks will be reduced in AgCC compared with matched controls, especially in the most highly interconnected cortical regions that are the hubs of the connectome. Seventeen resting-state networks were extracted from fMRI of 11 subjects with partial or complete AgCC and 11 matched controls. The results show that the qualitative organization of resting-state networks is very similar between controls and AgCC. However, interhemispheric functional connectivity of precuneus, posterior cingulate cortex, and insular-opercular regions was significantly reduced in AgCC. The preserved network organization was confirmed with a connectomic analysis of the resting-state fMRI data, showing five functional modules that are largely consistent across the control and AgCC groups. Hence, the reduction or even complete absence of callosal connectivity does not affect the qualitative organization of bilateral resting-state networks or the modular organization of the functional connectome, although quantitatively reduced functional connectivity can be demonstrated by measurements within bilateral cortical hubs, supporting the hypothesis that indirect polysynaptic pathways are utilized to preserve interhemispheric temporal synchrony.