A structural basis for reading fluency: White matter defects in a genetic brain malformation

Chang, Bernard S.; Katzir, Tami; Liu, T.; Corriveau, Kathleen H.; Barzillai, Mirit; Apse, Kira; Bodell, Adria; Hackney, David B.; Alsop, David C.; Wong, Stephen T.C.; Walsh, Christopher A.

doi:10.1212/01.wnl.0000286365.41070.54

Cited by 64 publications

(64 citation statements)

References 41 publications

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“…For display purposes, an additional tractogram was also generated with 100,000 tracks for each participant using the exact same processing constraints. From a technical perspective, this whole brain tractography approach allowed us to avoid potential sources of error inherent in 'seed to target' region-of-interest-based tractography approaches where assessment of structural connectivity, and comparison to control subjects, is complicated by the absence in control subjects of structures corresponding to the ectopic clusters of neurons (27)(28)(29)(30)(31)(32). ( inferior-superior).…”

Section: Whole-brain Csd-based Tractography Mappingmentioning

confidence: 99%

Periventricular Nodular Heterotopia: Detection of Abnormal Microanatomic Fiber Structures with Whole-Brain Diffusion MR Imaging Tractography

Farquharson¹,

Tournier²,

Calamante³

et al. 2016

Radiology

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Advances in knowledge:1. Whole-brain Constrained Spherical Deconvolution (CSD) based fibre tractography and superresolution Track Density Imaging (TDI) mapping revealed abnormal fibre projections in nodular tissue suggestive of abnormal organization of white matter (with abnormal fibres both within nodules and projecting to the surrounding white matter) in patients with bilateral periventricular nodular heterotopia (PVNH).2. The detection of abnormal fibre structures by all four readers in all fourteen patients studied (Fleiss Kappa (κ ) = 1.0 SE = 0.0, 95% CI = 1.0 to 1), indicates that these architectural abnormalities are particularly prevalent in patients with bilateral PVNH. Implications for patient care:Whole-brain tractography mapping techniques provide an opportunity to non-invasively detect in vivo abnormal structures potentially involved in ictal networks; such maps could be used to aid the identification of appropriate surgical targets for individuals undergoing evaluation for epilepsy surgery. Results: Abnormal fibre tracks emanating from one or more regions of heterotopia were reported by all four readers in all 14 patients with PVNH studied (Fleiss Kappa (κ) = 1). These abnormal structures were not visible in the tractography data of any of the control subjects, and not discernable on the conventional T1 weighted images of the PVNH patients. Conclusion:Whole-brain CSD-based fibre tractography and super-resolution TDI mapping reveals abnormal fibre projections in nodular tissue suggestive of abnormal organization of white matter (with abnormal fibres both within nodules and projecting to the surrounding white matter) in patients with bilateral PVNH.

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Section: Whole-brain Csd-based Tractography Mappingmentioning

confidence: 99%

Periventricular Nodular Heterotopia: Detection of Abnormal Microanatomic Fiber Structures with Whole-Brain Diffusion MR Imaging Tractography

Farquharson¹,

Tournier²,

Calamante³

et al. 2016

Radiology

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“…6-11 PNH is a commonly encountered epileptic brain malformation, has a distinct radiological appearance that facilitates its initial diagnosis (Fig 1), 12 and generally presents with the clinical triad of epilepsy, reading disability, and normal intelligence. 13,14 …”

Section: Introductionmentioning

confidence: 99%

Physiological consequences of abnormal connectivity in a developmental epilepsy

Shafi

Vernet

Klooster

et al. 2015

Annals of Neurology

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Objective Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. Methods We employed transcranial magnetic stimulation (TMS) with simultaneous EEG recording in eight patients with epilepsy from periventricular nodular heterotopia (PNH) and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. Results Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in one subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. Interpretation Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions.

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“…Specifically, molecular layer ectopia and microgyria have been seen in the brains of human dyslexics post mortem, and microgyria have also been identified in the neocortex of children with specific language impairment [using MRI; 3–5, 7]. Further, mild forms of heterotopia—which appear as abnormal clusters of cells along the ventricular zone, white matter, or deep cortical layers–have also been associated with specific reading impairments [again using MRI; 1, 2]. These malformations are likely a result of interacting genetic, epigenetic and environmental risk factors that ultimately lead to the disruption of processes within a critical window of cortical development, spanning from the beginning of ventricular zone mitosis to the end of neuronal migration [8–12].…”

Section: Introductionmentioning

confidence: 99%

Developmental learning impairments in a rodent model of nodular heterotopia

Threlkeld

Hill

Cleary

et al. 2009

J Neurodevelop Disord

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Developmental malformations of neocortex—including microgyria, ectopias, and periventricular nodular heterotopia (PNH)—have been associated with language learning impairments in humans. Studies also show that developmental language impairments are frequently associated with deficits in processing rapid acoustic stimuli, and rodent models have linked cortical developmental disruption (microgyria, ectopia) with rapid auditory processing deficits. We sought to extend this neurodevelopmental model to evaluate the effects of embryonic (E) day 15 exposure to the anti-mitotic teratogen methylazoxymethanol acetate (MAM) on auditory processing and maze learning in rats. Extensive cortical anomalies were confirmed in MAM-treated rats post mortem. These included evidence of laminar disruption, PNH, and hippocampal dysplasia. Juvenile auditory testing (P21–42) revealed comparable silent gap detection performance for MAM-treated and control subjects, indicating normal hearing and basic auditory temporal processing in MAM subjects. Juvenile testing on a more complex two-tone oddball task, however, revealed a significant impairment in MAM-treated as compared to control subjects. Post hoc analysis also revealed a significant effect of PNH severity for MAM subjects, with more severe disruption associated with greater processing impairments. In adulthood (P60–100), only MAM subjects with the most severe PNH condition showed deficits in oddball two-tone processing as compared to controls. However, when presented with a more complex and novel FM sweep detection task, all MAM subjects showed significant processing deficits as compared to controls. Moreover, post hoc analysis revealed a significant effect of PNH severity on FM sweep processing. Water Maze testing results also showed a significant impairment for spatial but not non-spatial learning in MAM rats as compared to controls. Results lend further support to the notions that: (1) generalized cortical developmental disruption (stemming from injury, genetic or teratogenic insults) leads to auditory processing deficits, which in turn have been suggested to play a causal role in language impairment; (2) severity of cortical disruption is related to the severity of processing impairments; (3) juvenile auditory processing deficits appear to ameliorate with maturation, but can still be elicited in adulthood using increasingly complex acoustic stimuli; and (4) malformations induced with MAM are also associated with generalized spatial learning deficits. These cumulative findings contribute to our understanding of the behavioral consequences of cortical developmental pathology, which may in turn elucidate mechanisms contributing to developmental language learning impairment in humans.

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A structural basis for reading fluency: White matter defects in a genetic brain malformation

Cited by 64 publications

References 41 publications

Periventricular Nodular Heterotopia: Detection of Abnormal Microanatomic Fiber Structures with Whole-Brain Diffusion MR Imaging Tractography

Periventricular Nodular Heterotopia: Detection of Abnormal Microanatomic Fiber Structures with Whole-Brain Diffusion MR Imaging Tractography

Physiological consequences of abnormal connectivity in a developmental epilepsy

Developmental learning impairments in a rodent model of nodular heterotopia

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