Cross Talk proposal: Human‐derived brain tissue is a better epilepsy model than animal‐based approaches

Cunningham, Mark O.

doi:10.1113/jp282185

Cited by 2 publications

(2 citation statements)

References 54 publications

(58 reference statements)

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“…Ex vivo electrophysiologic, pharmacologic and gene expression profiling of surgically-resected material has enabled important advances into brain function in health and disease. 11,12 The analysis from implanted electrodes, placed to guide surgical decisions has also enabled studies of human brain function 13 , including elucidating network behaviour during seizure onset, 14 and how epileptiform activity can interfere with memory. 15 Intracranial electroencephalography (EEG) recordings from stereotactically-implanted electrodes (known as stereoelectroencephalography or SEEG) are performed for a subset of patients with difficult-to-localize focal epilepsy to identify seizure-onset zones.…”

Section: Introductionmentioning

confidence: 99%

High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

Dwiwedi,

Mahesh,

Sanfeliu

et al. 2024

Preprint

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Understanding neurological disorders necessitates systems-level approaches that integrate multimodal data, but progress has been hindered by limited sample availability, and the absence of combined electrophysiological and molecular data from live patients. Here, we demonstrate that intracranial stereoelectroencephalography (SEEG) electrodes used for identifying the seizure focus in epilepsy patients enable the integration of RNA sequencing, genomic variants and epigenome maps with in vivo recordings and brain imaging. Specifically, we report a method, MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes) that recovers extensive protein-coding transcripts, DNA methylation and mutation profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function in human patients. Our study shows that epilepsies of different aetiologies have distinct molecular landscapes and identify transcripts correlating with neurophysiological signals, including immediate early genes, inflammation markers, and axon guidance molecules. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states. While gene expression gradients corresponded with the assigned epileptogenicity index, we found outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. These findings validate that RNA profiles, genetic variation and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. Our transformative MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.

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Section: Introductionmentioning

confidence: 99%

High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

Dwiwedi,

Mahesh,

Sanfeliu

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Prof Cunningham (Cunningham, 2022) succinctly argues that erroneous extrapolation between rodent and human brain tissues may underlie the well‐documented clinical treatment gap for epilepsy, where approximately one third of patients continue to experience seizures, even with optimal medication (Janmohamed et al., 2020). Prof Cunningham argues that reliance on animal models has not delivered drugs that differentiate from older therapies, and that network signals from animal brain slices, including pathological high‐frequency oscillations (HFOs), do not provide insights into the circuit mechanisms underlying these oscillations.…”

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confidence: 99%

Rebuttal from Amy Richardson and Gareth Morris

Richardson

Morris

2022

The Journal of Physiology

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Cross Talk proposal: Human‐derived brain tissue is a better epilepsy model than animal‐based approaches

Cited by 2 publications

References 54 publications

High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

Rebuttal from Amy Richardson and Gareth Morris

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