Changes in Synaptic Dynamics Underlies Benzodiazepine Resistance in Paediatric Status Epilepticus
Abstract number :
2.019
Submission category :
3. Neurophysiology / 3B. ICU EEG
Year :
2023
Submission ID :
1031
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Tommaso Fedele, PhD – University Children's Hospital Zurich
Richard Burman, MD PhD – University Hospital of Bern, Bern, Switzerland; Anne Steinberg, MSc – University Children's Hospital Zurich; Giorgio Selmin, MSc – University Children's Hospital Zurich; Ramantani Georgia, MD PhD – University Children's Hospital Zurich; Richard Rosch, MD PhD – King's College Hospital NHS Foundation Trust
Rationale: Over a third of children in status epilepticus (SE) do not respond to first-line treatment with benzodiazepines. Experimental data from animal models has suggested that dynamic changes in fast synaptic inhibitory signalling may lead to benzodiazepine resistance. However, it is unknown whether these synaptic mechanisms are indeed relevant in paediatric patients. Here we utilize EEG recordings as a clinically accessible insight into pathological brain dynamics that occur during SE. Through dynamic causal modelling (DCM) we then infer excitatory-inhibitory coupling parameters of cortical microcircuits in different brain states.
Methods: We use DCM to test key hypotheses regarding benzodiazepine effects directly on EEG data recorded in patients during SE: (1) that benzodiazepines modulate inhibitory coupling in SE, and (2) that there are differences in the balance of excitatory-inhibitory coupling in benzodiazepine responders vs non-responders. We investigated a cohort of 26 peadiatric patients (eight benzodiazepine responders) who were managed at the University Children’s Hospital Zürich for SE. Using the DCM framework, we fitted hierarchical neural mass models to (1) identify which synaptic parameters best explain the observed EEG changes, and (2) infer group differences in synaptic parameters between responders and non-responders.
Results: The fitted DCMs captured the following changes in EEG broadband spectra associated with benzodiazepine treatment: (1) the observed changes across conditions were best explained through alterations in inhibitory coupling, and (2) responders and non-responders differed in the modulation of inhibitory synaptic connections in the neural mass model.
Conclusions: Overall, this study demonstrates that the effect of benzodiazepines on macroscopic brain dynamics in paediatric patients with SE is best explained by dynamic shifts in inhibitory cortical synaptic signalling. The described group differences suggest that there may be baseline differences in cortical synaptic coupling which may be captured by DCM and used to help predict and optimise treatment responses in patients with paediatric SE.
Funding: Anna Mueller Grocholski Foundation (TF, RJB, GR, RER)
Wellcome Trust (RER)
Theodor und Ida Herzog-Egli Stiftung (RJB, GR, RER)
Swiss National Science Foundation under grants agreement 208184 (GR)
Neurophysiology