Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders

Abstract

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy

“…Identifying the pathological brain connectivity patterns in TSC individuals with ASD may yield neurophysiological markers, facilitating early intervention. 101 , 105 , 160 In particular, the study by Sato et al 105 suggests that white-matter microstructural integrity is associated with connectivity dysfunction, underlying co-occurring NDD. Evidence that large-scale network aberrations are associated with both ASD and mTOR-related connectopathy (characterized by fronto-cortico-striatal hyperconnectivity and rescued by inhibition of mTOR) has recently been reported using resting-state fMRI, electrophysiology and in silico modelling in Tsc2 haplo-insufficient mice.…”

A Case Report of Pediatric Patient with Tuberous Sclerosis and Radiologically Isolated Syndrome

“…From a clinical point of view, up to 85% of patients with TSC present with epilepsy, and more than 90% of patients present at least one neuropsychiatric disorder (including learning disability, ASD, attention deficit hyperactivity disorder, mood and/or anxiety disorders and academic difficulties) throughout their life [9]. Although the underlying neuropathological substrate of these neuropsychiatric conditions are not known, it has been demonstrated in different studies that diffuse alterations in white matter seem to be associated with higher rates of neuropsychiatric comorbidities [14][15][16].…”

Recognizing Pediatric Tuberous Sclerosis Complex Based on Multi-Contrast MRI and Deep Weighted Fusion Network

“…Tuberous sclerosis complex (TSC) is a rare neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes [1,2]. It is characterized by angiofibromas of the face, epilepsy, an intellectual disability, and hamartomas in multiple organs including the heart, kidneys, brain, and lungs [3][4][5]. The majority of pediatric TSC patients experience their initial seizure in the first year of life [6][7][8], which has a severe impact on the lives of TSC children [9,10].…”