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

Abstract

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.

Safety, Tolerability and EEG-Based Target Engagement of STP1 (PDE3,4 Inhibitor and NKCC1 Antagonist), in a Randomized Clinical Trial in a Subgroup of Patients with ASD

“…In ASD-Phen1, treatment with STP1 increased alpha waves (Figure 5) in the occipital and prefrontal regions, similar to other studies [18]. Treatment with STP1 showed a significant increase of alpha 2 power in frontal and occipital regions and in brain areas associated with memory function (frontal right poles, right isthmus cingulate) and sensory (right paracentral regions).…”

Assessment of the excitation–inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics

“…Seemingly counterintuitive reductions in fEI ratio (between 12 to 24 Hz) were also recently reported in patients with STXBP1 encephalopathy ( Houtman et al. 2021 ) and tuberous sclerosis complex ( Juarez-Martinez et al. 2022 ).…”

Excitatory/inhibitory balance in epilepsies and neurodevelopmental disorders: Depolarizing γ‐aminobutyric acid as a common mechanism

“…Treatment strategies that enhance intracellular Cl − concentrations are currently under investigation in both patient groups, either as primary medication or as combinational therapies. 35,111,112,113,114 However, several hurdles need to be overcome. The idea that GABA is depolarizing early in development and hyperpolarizing later in development might be too simple.…”

“…The evidence implicating depolarizing GABA in these patient groups is summarized in Table 1. Treatment strategies that enhance intracellular Cl − concentrations are currently under investigation in both patient groups, either as primary medication or as combinational therapies 35,111,112,113,114 . However, several hurdles need to be overcome.…”