Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na1.3. Pathogenic Na1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

Fetuses with isolated agenesis of the corpus callosum (ACC) are associated with a broad spectrum of neurodevelopmental disability that cannot be specifically predicted in prenatal neuroimaging. We hypothesized that ACC may be associated with aberrant cortical folding. In this study, we determined altered patterning of early primary sulci development in fetuses with isolated ACC using novel quantitative sulcal pattern analysis which measures deviations of regional sulcal features (position, depth, and area) and their intersulcal relationships in 7 fetuses with isolated ACC (27.1 ± 3.8 weeks of gestation, mean ± SD) and 17 typically developing (TD) fetuses (25.7 ± 2.0 weeks) from normal templates. Fetuses with ACC showed significant alterations in absolute sulcal positions and relative intersulcal positional relationship compared to TD fetuses, which were not detected by traditional gyrification index. Our results reveal altered sulcal positional development even in isolated ACC that is present as early as the second trimester and continues throughout the fetal period. It might originate from altered white matter connections and portend functional variances in later life.

Late life depression is related to pathologic burdens, such as cerebral small vascular disease (CSVD) and amyloid, which are associated with brain network changes and cortical thinning. To examine the associations of various CSVD imaging markers, amyloid, and network changes with depression in cognitively impaired patients, we prospectively recruited 228 cognitively impaired patients having various degrees of amyloid and CSVD who underwent diffuse tensor image and PiB PET. Greater CSVD burden was associated with greater Geriatric Depression Scale (GDS) (white matter hyperintensities, WMH: p = 0.025, lacunes: p  0.001) but not with amyloid (p = 0.095), and cortical thinning (p = 0.630) was not associated with greater GDS. The changes in white matter networks were related to GDS with decreasing integration (global efficiency: p  0.001) and increasing segregation (clustering coefficient: p = 0.009). The network changes mediated the relationships of WMH and lacunes with GDS. Our findings provide insight to better understand how CSVD burdens contribute to depression in cognitively impaired patients having varying degrees of amyloid and vascular burdens.

BACKGROUND: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. OBJECTIVE: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. METHODS: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. RESULTS: Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. CONCLUSION: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability) , studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans, but have little effect on the brains of mice; this probably reflects evolutionarily divergent functions of ASPM. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25-40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.

BACKGROUND AND PURPOSE: Aberrant gyral folding is a key feature in the diagnosis of many cerebral malformations. However, in fetal life, it is particularly challenging to confidently diagnose aberrant folding because of the rapid spatiotemporal changes of gyral development. Currently, there is no resource to measure how an individual fetal brain compares with normal spatiotemporal variations. In this study, we assessed the potential for automatic analysis of early sulcal patterns to detect individual fetal brains with cerebral abnormalities. MATERIALS AND METHODS: Triplane MR images were aligned to create a motion-corrected volume for each individual fetal brain, and cortical plate surfaces were extracted. Sulcal basins were automatically identified on the cortical plate surface and compared with a combined set generated from 9 normal fetal brain templates. Sulcal pattern similarities to the templates were quantified by using multivariate geometric features and intersulcal relationships for 14 normal fetal brains and 5 fetal brains that were proved to be abnormal on postnatal MR imaging. Results were compared with the gyrification index. RESULTS: Significantly reduced sulcal pattern similarities to normal templates were found in all abnormal individual fetuses compared with normal fetuses (mean similarity [normal, abnormal], left: 0.818, 0.752; < .001; right: 0.810, 0.753; < .01). Altered location and depth patterns of sulcal basins were the primary distinguishing features. The gyrification index was not significantly different between the normal and abnormal groups. CONCLUSIONS: Automated analysis of interrelated patterning of early primary sulci could outperform the traditional gyrification index and has the potential to quantitatively detect individual fetuses with emerging abnormal sulcal patterns.

BACKGROUND AND PURPOSE: To determine the apparent diffusion coefficient (ADC) in specific infratentorial brain structures during the first week of life and its relation with neuromotor outcome for Hypoxic-ischemic encephalopathy (HIE) in term neonates with and without whole-body hypothermia (TH). MATERIALS AND METHODS: We retrospectively evaluated 45 MRI studies performed in the first week of life of term neonates born between 2010 and 2013 at Boston Children's Hospital. Selected cases were classified into three groups: 1) HIE neonates who underwent TH, 2) HIE normothermics (TN), and 3) controls. The neuromotor outcome was categorized as normal, abnormal and death. The ADCmean was calculated for six infratentorial brain regions. RESULTS: A total of 45 infants were included: 28 HIE TH treated, 8 HIE TN, and 9 controls. The mean gestational age was 39 weeks; 57.8% were male; 11.1% were non-survivors. The median age at MRI was 3 days (interquartile range, 1-4 days). A statistically significant relationship was shown between motor outcome or death and the ADCmean in the vermis (P = 0.002), cerebellar left hemisphere (P = 0.002), midbrain (P = 0.009), pons (P = 0.014) and medulla (P = 0.005). In patients treated with TH, the ADC mean remained significantly lower than that in the controls only in the hemispheres (P = 0.01). In comparison with abnormal motor outcome, ADCmean was lowest in the left hemisphere (P = 0.003), vermis (P = 0.003), pons (P = 0.0036) and medulla (P = 0.008) in case of death. CONCLUSION: ADCmean values during the first week of life in the left hemisphere, vermis, pons and medulla are related to motor outcome or death in infants with HIE either with or without hypothermic therapy. Therefore, this objective tool can be assessed prospectively to determine if it can be used to establish prognosis in the first week of life, particularly in severe cases of HIE.

OBJECTIVE: To evaluate the differences between early-onset subcortical vascular cognitive impairment (EO-SVCI) and late-onset subcortical vascular cognitive impairment (LO-SVCI) with regard to pathologic burden, structural changes, and cognitive function. METHODS: We prospectively recruited 142 patients from a single referral center. Patients were divided into EO-SVCI (n = 30, age at onset 65 years) and LO-SVCI (n = 112, age at onset ≥ 65 years) groups. All patients underwent neuropsychological tests, 3T brain MRI, and [(11)C] Pittsburgh compound B (PiB)-PET. We compared pathologic burden such as small vessel disease and amyloid burden; structural changes such as structural network, cortical thickness, and hippocampal volume; and cognitive function between EO-SVCI and LO-SVCI. RESULTS: EO-SVCI patients had more lacunes, while LO-SVCI patients had higher PiB standardized uptake value ratios. EO-SVCI patients exhibited more severe structural network disruptions in the frontal area, while LO-SVCI patients exhibited more severe cortical and hippocampal atrophy. Although disease severity did not differ between the 2 groups, frontal-executive dysfunction was more severe in EO-SVCI patients. CONCLUSIONS: EO-SVCI patients showed more vascular related factors, while LO-SVCI patients exhibited more Alzheimer disease-related characteristics. The greater number of lacunes in EO-SVCI might account for the more severe frontal network disruption and frontal-executive dysfunction, while the greater amyloid burden in LO-SVCI might account for the more severe cortical and hippocampal atrophy. Our findings suggest that the age at onset is a crucial factor that determines distinct features in SVCI patients, such as pathologic burden, structural changes, and cognitive function.

Developmental dyslexia (DD) is highly heritable and previous studies observed reduced cortical volume, white matter integrity, and functional alterations in left posterior brain regions in individuals with DD. The primary sulcal pattern has been hypothesized to relate to optimal organization and connections of cortical functional areas. It is determined during prenatal development and may reflect early, genetically influenced, brain development. We characterize the sulcal pattern using graph-based pattern analysis and investigate whether sulcal patterns in parieto-temporal and occipito-temporal regions are atypical in elementary school-age children with DD and pre-readers/beginning readers (preschoolers/kindergarteners) with a familial risk (elementary school-age children: n [males/females], age range = 17/11, 84-155 months; preschoolers/kindergarteners: 16/15, 59-84 months). The pattern of sulcal basin area in left parieto-temporal and occipito-temporal regions was significantly atypical (more sulcal basins of smaller size) in children with DD and further correlated with reduced reading performance on single- and nonword reading measures. A significantly atypical sulcal area pattern was also confirmed in younger preschoolers/kindergarteners with a familial risk of DD. Our results provide further support for atypical early brain development in DD and suggest that DD may originate from altered organization or connections of cortical areas in the left posterior regions.

Tuberous sclerosis complex (TSC) is characterized by benign hamartomas in multiple organs including the brain and its clinical phenotypes may be associated with abnormal neural connections. We aimed to provide the first detailed findings on disrupted structural brain networks in TSC patients. Structural whole-brain connectivity maps were constructed using structural and diffusion MRI in 20 TSC (age range: 3-24 years) and 20 typically developing (TD; 3-23 years) subjects. We assessed global (short- and long-association and interhemispheric fibers) and regional white matter connectivity, and performed graph theoretical analysis using gyral pattern- and atlas-based node parcellations. Significantly higher mean diffusivity (MD) was shown in TSC patients than in TD controls throughout the whole brain and positively correlated with tuber load severity. A significant increase in MD was mainly influenced by an increase in radial diffusivity. Furthermore, interhemispheric connectivity was particularly reduced in TSC, which leads to increased network segregation within hemispheres. TSC patients with developmental delay (DD) showed significantly higher MD than those without DD primarily in intrahemispheric connections. Our analysis allows non-biased determination of differential white matter involvement, which may provide better measures of "lesion load" and lead to a better understanding of disease mechanisms.