High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument

Taki, Masako; Harada, Masafumi; Mori, Koichi; Kubo, Hitoshi; Nose, Ayumi; Matsuda, Tsuyoshi; Nishitani, Hiromu

doi:10.1016/j.neuroimage.2009.05.060

Cited by 11 publications

(7 citation statements)

References 30 publications

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“…We also observed a trend for increased GABA within the cortical lesions, consistent with the magnetic resonance spectroscopy findings of elevated GABA within the cortical tubers of epileptic infants with tuberous sclerosis complex. 26 However, it is important to note that any potential significant differences may have been obscured by the high variability of GABA levels observed across patients, a variability that is likely attributable to the use of various AEDs. 27,28 Meaningful statistical analyses of the effects of AEDs on GABA levels were precluded because of the high variability in the AED regimens and the small sample size of patients who were on GABAergic medications only.…”

Section: Epileptogenic Hippocampal and Cortical Sitesmentioning

confidence: 99%

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program

Çavuş

Romanyshyn

Kennard

et al. 2016

Annals of Neurology

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Our findings indicate that chronically elevated extracellular glutamate is a common pathological feature among epilepsies with different etiology. Contrary to our predictions, GABA and glutamine levels were not decreased in any of the measured areas. Whereas variability in GABA levels may in part be attributed to the use of GABAergic antiepileptic drugs, the stability in glutamine across patient groups indicate that extracellular glutamine levels are under tighter metabolic regulation than previously thought. Ann Neurol 2016;80:35-45.

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Section: Epileptogenic Hippocampal and Cortical Sitesmentioning

confidence: 99%

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program

Çavuş

Romanyshyn

Kennard

et al. 2016

Annals of Neurology

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“…Preclinical and clinical findings have implicated neuronal E/I imbalances in TSC pointing toward a reduced inhibition ( White et al, 2001 ; Wang et al, 2007 ; Taki et al, 2009 ; Fu et al, 2012 ; Mori et al, 2012 ; Talos et al, 2012 ; Bateup et al, 2013 ; Aronica and Crino, 2014 ; Ruffolo et al, 2016 ; Nadadhur et al, 2019 ; Afshar Saber and Sahin, 2020 ; Haji et al, 2020 ). This may be important as E/I balance is a key principle for neuronal network organization and synchronization of neuronal oscillations, which are crucial for cognitive processes (e.g., cognitive integration, information processing, sensory binding, association, and memory) ( Turrigiano and Nelson, 2004 ; Kinouchi and Copelli, 2006 ; Avramiea et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Cortical tubers are a hallmark in TSC linked to epilepsy and neurobehavioral symptoms ( Aronica and Crino, 2014 ). In humans, non-invasive measurements of GABA and glutamate levels in cortical tubers using MR spectroscopy revealed an excess of GABA molecules but decreased number of GABA A receptors ( Taki et al, 2009 ; Mori et al, 2012 ). Pathological examination of cortical tuber tissue (postsurgical excision and postmortem) has shown decreased expression of GABA A receptor subunits ( White et al, 2001 ; Talos et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

et al. 2022

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Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide—a chloride-regulating agent—improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8–21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.Clinical Trial RegistrationEU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

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“…The severity of epilepsy and autism in TSC tends to correlate with number and location of cortical tubers (Goodman et al 1997;Wiznitzer 2004), and there is clear evidence for dysregulated mTORC1 pathway activity in the ''giant'' cells present within cortical tuber specimens (Crino 2004). At the neural network level, molecular abnormalities involving inhibitory as well as excitatory neurons in cortical tubers have been suggested to underlie the correlation with epilepsy and autism (White et al 2001;Valencia et al 2006;Taki et al 2009).…”

Section: Introductionmentioning

confidence: 99%

GABAergic Interneuron Development and Function Is Modulated by the Tsc1 Gene

Fu¹,

Cawthon²,

Clinkscales³

et al. 2011

Cerebral Cortex

106

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Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.

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High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument

Cited by 11 publications

References 30 publications

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

GABAergic Interneuron Development and Function Is Modulated by the Tsc1 Gene

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