Abstract:Tubers are cerebral cortical developmental malformations associated with epilepsy and autism in tuberous sclerosis complex (TSC). The disparity between tuber number and severity of neurological impairment often observed in TSC led us to hypothesize that microscopic structural abnormalities distinct from tubers may occur in TSC. Serial frontal to occipital lobe sections were prepared from five postmortem TSC brain specimens. Sections were probed with cresyl violet stain or NeuN antibodies to define cytoarchitec… Show more
“…Furthermore, several studies using MRI diffusion techniques revealed diffuse alterations in the so-called normally appearing WM [3,4], but the relation between WM alterations and neurologic phenotype remains to be clarified. WM alterations seen by MRI studies are in good agreement with diffuse microstructural WM abnormalities found in neuropathological studies in individuals with TSC, reflecting axonal disorganization, reduced/altered myelination, or gliosis [5][6][7]. WM alterations might result from the dysregulation of the mTOR pathway, which is responsible for abnormal connectivity as well as for altered axonal growth [8][9][10].…”
Since a reduced RNFL thickness might be seen as an indicator of chronic axonal degeneration or lack of appropriate neuronal development, our results support the presence of axonal alterations in TSC and also that white matter disorganization could be much more diffuse than originally thought. Since axonal alterations directly derive from mammalian target of rapamycin (mTOR) overactivation, which occurs early during fetus development, the RNFL thinning we observed could represent one of the facets of such early neurodevelopmental abnormalities.
“…Furthermore, several studies using MRI diffusion techniques revealed diffuse alterations in the so-called normally appearing WM [3,4], but the relation between WM alterations and neurologic phenotype remains to be clarified. WM alterations seen by MRI studies are in good agreement with diffuse microstructural WM abnormalities found in neuropathological studies in individuals with TSC, reflecting axonal disorganization, reduced/altered myelination, or gliosis [5][6][7]. WM alterations might result from the dysregulation of the mTOR pathway, which is responsible for abnormal connectivity as well as for altered axonal growth [8][9][10].…”
Since a reduced RNFL thickness might be seen as an indicator of chronic axonal degeneration or lack of appropriate neuronal development, our results support the presence of axonal alterations in TSC and also that white matter disorganization could be much more diffuse than originally thought. Since axonal alterations directly derive from mammalian target of rapamycin (mTOR) overactivation, which occurs early during fetus development, the RNFL thinning we observed could represent one of the facets of such early neurodevelopmental abnormalities.
“…The observed physiologic and imaging phenomena, the presence of robust MEPs from nTMS stimulation and preserved CS tracts identified by DTI tractography, within the tuber tissue in our patient provide functional and structural support of the intermixing of tuber and functional tissue. This is in agreement with current pathological [4], [26] diffusion imaging [27], and with physiological evidence of widespread and variable degrees of pathology in TSC [28], [29], [30], [31].…”
We present a case of preserved corticospinal connectivity in a cortical tuber, in a 10 year-old boy with intractable epilepsy and tuberous sclerosis complex (TSC). The patient had multiple subcortical tubers, one of which was located in the right central sulcus. In preparation for epilepsy surgery, motor mapping, by neuronavigated transcranial magnetic stimulation (nTMS) coupled with surface electromyography (EMG) was performed to locate the primary motor cortical areas. The resulting functional motor map revealed expected corticospinal connectivity in the left precentral gyrus. Surprisingly, robust contralateral deltoid and tibialis anterior motor evoked potentials (MEPs) were also elicited with direct stimulation of the cortical tuber in the right central sulcus. MRI with diffusion tensor imaging (DTI) tractography confirmed corticospinal fibers originating in the tuber. As there are no current reports of preserved connectivity between a cortical tuber and the corticospinal tract, this case serves to highlight the functional interdigitation of tuber and eloquent cortex. Our case also illustrates the widening spectrum of neuropathological abnormality in TSC that is becoming apparent with modern MRI methodology. Finally, our finding underscores the need for further study of preserved function in tuber tissue during presurgical workup in patients with TSC.
“…Recent studies with mouse models of TSC (Meikle et al, 2008; Carson et al, 2012, 2013) suggested that global diffuse changes in white matter might give rise to universal cortical dysfunction together with various neuropsychiatric conditions, in addition to the multifocal tuber pathology. Indeed, Marcotte et al (2012) demonstrated widespread microstructural alterations distinct from tubers in human patients via histological analysis of post-mortem brain specimen. This ex-vivo MRI study with conditional knockouts of Rictor and Tsc2 in Olig2-Cre mice has shown that the developed technique is capable of discovering non-tuber white matter abnormalities, e.g.…”
This paper introduces a multi-compartment model for microscopic diffusion anisotropy imaging. The aim is to estimate microscopic features specific to the intra- and extra-neurite compartments in nervous tissue unconfounded by the effects of fibre crossings and orientation dispersion, which are ubiquitous in the brain. The proposed MRI method is based on the Spherical Mean Technique (SMT), which factors out the neurite orientation distribution and thus provides direct estimates of the microscopic tissue structure. This technique can be immediately used in the clinic for the assessment of various neurological conditions, as it requires only a widely available off-the-shelf sequence with two b-shells and high-angular gradient resolution achievable within clinically feasible scan times. To demonstrate the developed method, we use high-quality diffusion data acquired with a bespoke scanner system from the Human Connectome Project. This study establishes the normative values of the new biomarkers for a large cohort of healthy young adults, which may then support clinical diagnostics in patients. Moreover, we show that the microscopic diffusion indices offer direct sensitivity to pathological tissue alterations, exemplified in a preclinical animal model of Tuberous Sclerosis Complex (TSC), a genetic multi-organ disorder which impacts brain microstructure and hence may lead to neurological manifestations such as autism, epilepsy and developmental delay.
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