Independent contribution of individual white matter pathways to language function in pediatric epilepsy patients

Background and purpose Patients with epilepsy and malformations of cortical development (MCDs) are at high risk for language and other cognitive impairment. Specific impairments, however, are not well correlated with the extent and locale of dysplastic cortex; such findings highlight the relevance of aberrant cortico-cortical interactions, or connectivity, to the clinical phenotype. The goal of this study was to determine the independent contribution of well-described white matter pathways to language function in a cohort of pediatric patients with epilepsy. Materials and methods Patients were retrospectively identified from an existing database of pediatric epilepsy patients with the following inclusion criteria: 1. diagnosis of MCDs, 2. DTI performed at 3 T, and 3. language characterized by a pediatric neurologist. Diffusion Toolkit and Trackvis (http://www.trackvis.org) were used for segmentation and analysis of the following tracts: corpus callosum, corticospinal tracts, inferior longitudinal fasciculi (ILFs), inferior fronto-occipital fasciculi (IFOFs), uncinate fasciculi (UFs), and arcuate fasciculi (AFs). Mean diffusivity (MD) and fractional anisotropy (FA) were calculated for each tract. Wilcoxon rank sum test (corrected for multiple comparisons) was used to assess potential differences in tract parameters between language-impaired and language-intact patients. In a separate analysis, a machine learning algorithm (random forest approach) was applied to measure the independent contribution of the measured diffusion parameters for each tract to the clinical phenotype (language impairment). In other words, the importance of each tract parameter was measured after adjusting for the contribution of all other tracts. Results: Thirty-three MCD patients were included (age range: 3–18 years). Twenty-one patients had intact language, twelve had language impairment. All tracts were identified bilaterally in all patients except for the AF, which was not identified on the right in 10 subjects and not identified on the left in 11 subjects. MD and/or FA within the left AF, UF, ILF, and IFOF differed between language-intact and language-impaired groups. However, only parameters related to the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with the clinical phenotype. Conclusions: Scalar metrics derived from the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with language function. These results support the importance of these pathways in human language function in patients with MCDs

Failure to Identify the Left Arcuate Fasciculus at Diffusion Tractography Is a Specific Marker of Language Dysfunction in Pediatric Patients with Polymicrogyria

Background:. Polymicrogyric cortex demonstrates interindividual variation with regard to both extent of dyslamination and functional capacity. Given the relationship between laminar structure and white matter fibers, we sought to define the relationship between polymicrogyria (PMG), intrahemispheric association pathways, and network function. Methods:. Each arcuate fasciculus (AF) was categorized as present or absent. Language was characterized by a pediatric neurologist. The presence of dysplastic cortex in the expected anatomic locations of Broca's (BA) and Wernicke's areas (WA) was evaluated by two pediatric neuroradiologists blinded to DTI and language data. Results:. 16 PMG patients and 16 age/gender-matched controls were included. All normative controls had an identifiable left AF. 6/7 PMG patients with dysplastic cortex within BA and/or WA had no left AF; PMG patients without involvement of these regions had a lower frequency of absence of the left AF (p < 0.006). All patients without a left AF had some degree of language impairment. PMG patients without a left AF had a significantly greater frequency of language impairment compared to those PMG patients with a left AF (p < 0.003). Conclusion:. In patients with PMG (1) the presence of dysplastic cortex within WA and/or BA is associated with absence of the left AF and (2) absence of the left AF is associated with language impairment

Evidence of novel finescale structural variation at autism spectrum disorder candidate loci

Background: Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods: As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results: Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. Conclusions: These results provide additional support for the role of rare structural variation in ASD

Failure to Identify the Left Arcuate Fasciculus at Diffusion Tractography Is a Specific Marker of Language Dysfunction in Pediatric Patients with Polymicrogyria

Background. Polymicrogyric cortex demonstrates interindividual variation with regard to both extent of dyslamination and functional capacity. Given the relationship between laminar structure and white matter fibers, we sought to define the relationship between polymicrogyria (PMG), intrahemispheric association pathways, and network function. Methods. Each arcuate fasciculus (AF) was categorized as present or absent. Language was characterized by a pediatric neurologist. The presence of dysplastic cortex in the expected anatomic locations of Broca’s (BA) and Wernicke’s areas (WA) was evaluated by two pediatric neuroradiologists blinded to DTI and language data. Results. 16 PMG patients and 16 age/gender-matched controls were included. All normative controls had an identifiable left AF. 6/7 PMG patients with dysplastic cortex within BA and/or WA had no left AF; PMG patients without involvement of these regions had a lower frequency of absence of the left AF (p<0.006). All patients without a left AF had some degree of language impairment. PMG patients without a left AF had a significantly greater frequency of language impairment compared to those PMG patients with a left AF (p<0.003). Conclusion. In patients with PMG (1) the presence of dysplastic cortex within WA and/or BA is associated with absence of the left AF and (2) absence of the left AF is associated with language impairment