Characterization of the Basal Ganglia Using Diffusion Tensor Imaging in Children with Self‐Injurious Behavior and Tuberous Sclerosis Complex

Gipson, Tanjala; Poretti, Andrea; Kelley, Sarah A.; Carson, Kathryn A.; Johnston, Michael V.; Huisman, Thierry A.G.M.

doi:10.1111/jon.12628

Cited by 5 publications

(5 citation statements)

References 42 publications

(45 reference statements)

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“…However, whether this association is due to the severe epilepsy caused by a high tuber load or due to the tuber load itself remains unclear. According to Gipson et al, patients with self-injurious behavior-associated TSC have higher frequencies of tubers in quadrants other than the left posterior neuroanatomical region (15). We found that tuber load and its localization correlate with certain neuropsychiatric symptoms.…”

Section: Discussionsupporting

confidence: 57%

Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

2021

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Objective: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder. The clinical manifestations are extensive and include neurological, dermatological, cardiac, ophthalmic, nephrological, and neuropsychiatric manifestations. The prediction and pathophysiology of neuropsychiatric disorders such as emotional symptoms, conduct problems, hyperactivity, and poor social behavior are poorly understood. The aim of the study was to diagnose neuropsychiatric symptoms in individuals with TSC, and to examine their possible correlations with quantity, magnitude, and spatial location of tubers and radial migration (RM) lines.Methods: The cohort comprised 16 individuals with TSC, aged 5–29 years, with normal or low normal intelligence. The participants or their parents were requested to fill Strengths and Difficulties Questionnaire (SDQ) and the TAND (TSC-associated neuropsychiatric disorders) Checklist for assessment of their neuropsychiatric symptoms. Correlations were examined between these symptoms and the magnitude, quantities, and locations of tubers and white matter RM lines, as identified in T2/FLAIR brain MRI scans.Results: The SDQ score for peer relationship problems showed correlation with the tuber load (r = 0.52, p < 0.05). Tuber load and learning difficulties correlated significantly in the temporal and parietal area. Mood swings correlated with tubers in the parietal area (r = 0.529, p < 0.05). RM lines in the temporal area correlated with abnormal total SDQ (r = 0.51, p < 0.05). Anxiety and extreme shyness were correlated with RM lines in the parietal area, r = 0.513, p < 0.05 and r = 0.593, p < 0.05, respectively. Hyperactive/inattention correlated negatively with RM lines in the parietal area (r = −707, p < 0.01).Conclusions: These observations may lead to future studies for precise localization of neuropsychiatric symptoms, thereby facilitating directed therapy.

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Section: Discussionsupporting

confidence: 57%

Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

2021

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“…(46,52,98). Hence, a number of studies have attempted to use DTI to investigate the anatomical alterations in white and gray matter structures that underlie the neurocognitive morbidity in TSC patients (6,41,66,80). The absence of brain malformations such as tubers in the heterozygous mouse models of Tsc1 +/− and Tsc2 +/− , which both show poor learning and memory performance and social behavior, also suggest that other subtle microscopic structural changes may account for neurologic symptoms (36,87).…”

Section: Introductionmentioning

confidence: 99%

Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging

Hsieh

et al. 2020

Brain Pathology

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Tuberous sclerosis complex (TSC) is a rare hereditary disease, which results from the mutation of either TSC1 or TSC2, and its clinical features include benign tumors and dysfunctions in numerous organs, including the brain. Many individuals with TSC manifest neuropsychiatric symptoms, such as learning impairments, cognitive deficits and anxiety. Current pharmacological treatment for TSC is the use of mTOR inhibitors. However, they are not effective in treating neuropsychiatric symptoms. We previously used curcumin, a diet‐derived mTOR inhibitor, which possesses both anti‐inflammatory and antiproliferative properties, to improve learning and memory deficits in Tsc2+/− mice. Diffusion tensor imaging (DTI) provides microstructural information in brain tissue and has been used to study the neuropathological changes in TSC. In this study, we confirmed that the impaired recognition memory and increased anxiety‐like behavior in Tsc2+/− mice can be reversed by curcumin treatment. Second, we found altered fractional anisotropy and mean diffusivity in the anterior cingulate cortex and the hippocampus of the Tsc2+/− mice, which may indicate altered circuitry. Finally, the mTOR complex 1 hyperactivity was found in the cortex and hippocampus, coinciding with abnormal cortical myelination and increased glial fibrillary acidic protein expression in the hippocampal CA1 of Tsc2+/− mice, both of which can be rescued with curcumin treatment. Overall, DTI is sensitive to the subtle alterations that cannot be detected by conventional imaging, suggesting that noninvasive DTI may be suitable for longitudinally monitoring the in vivo neuropathology associated with the neuropsychiatric symptoms in TSC, thereby facilitating future clinical trials of pharmacological treatments.

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“…Notably, this altered striatal activity was correlated with the presence of RRBs in the TSC children with ASD (Asano et al, 2001). Recently, the presence of self-injurious behavior in individuals with TSC was shown to be associated with structural changes in basal ganglia nuclei (Gipson et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Benthall

Cording

Chen

et al. 2019

Preprint

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Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which individualsfrequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors (RRBs), which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause repetitive behaviors in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and measured the consequences on synaptic function and motor behavior. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. This increased motor learning is associated with an impairment in endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced activation of the striatal direct pathway is a potential contributor to RRBs in TSC.

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Characterization of the Basal Ganglia Using Diffusion Tensor Imaging in Children with Self‐Injurious Behavior and Tuberous Sclerosis Complex

Cited by 5 publications

References 42 publications

Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

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