Tolner and Van den Maagdenberg labs

‘What are the genetic and functional mechanisms underlying attacks of migraine and comorbid epilepsy?’

‘Can we predict, and prevent, attacks?’

Within a multidisciplinary team, functional geneticist prof. dr. Arn van den Maagdenberg and neurobiologist dr. Else Tolner (team member since 2011) lead a wide range of translational studies in mice, and more recently, stem-cell derived models. Overall aims are to unravel disease pathophysiology and develop novel therapeutic strategies for paroxysmal disorders migraine and epilepsy, as well as of comorbid brain disorders such as depression and stroke.

Main research topics are:

1) Molecular genetic causes of paroxysmal brain disorders, foremost migraine and epilepsy. Genes and mutations contributing to disease susceptibility are identified, and omics technology and bioinformatics are implemented for uncovering molecular pathways underlying pathophysiology.

2) Neurobiological mechanisms underlying migraine attack initiation and consequences. Using in vivo approaches (e.g. DC-EEG, LFP, MUA, and LDF) in transgenic migraine mouse models with human pathogenic mutations, we unravel neuronal network characteristics (e.g. excitation/inhibition balance, brain region interactions) of cortical spreading depression and other migraine-relevant features. Non-invasive neuromodulation paradigms are tested to develop long-term normalization of cortical excitation/inhibition dynamics and prevent attacks.

3) Neurobiological mechanisms of seizure initiation and termination. Using a similar in vivo neurophysiological approach, we study the role of cerebellar-thalamo-cortical interactions for seizure termination (collaboration with the Hoebeek lab, Erasmus University Rotterdam), and identify mechanisms contributing to the risk for ‘Sudden Unexpected Death in Epilepsy’(SUDEP). Invasive (i.e. deep brain stimulation) and non-invasive neuromodulation (i.e. optogenetics) approaches aim to develop paradigms to intervene with seizure termination.

4) Neurophysiological features of the diseased human ‘brain-in-a-dish’. Neuronal networks from patient-derived induced pluripotent stem cells (iPSCs) are grown in 2D (or 3D) configuration on commercial or custom-made (collaborations with TU Delft and TU Eindhoven) multi-electrode devices with the aim to establish functional human neural networks, as a basis for identification of disease biomarkers and drug testing.

Embedding of our team within the departments of Human Genetics and Neurology (in close collaboration with prof. dr. Michel Ferrari and dr. Gisela Terwindt) makes possible genetic and EEG studies in migraine and epilepsy patients, ensures optimal translation of genetic findings and clinical questions, and provides an inspiring environment for technical, biomedical and clinical MSc and PhD candidates. Clinical collaborations outside the LUMC involve epilepsy referral clinic ‘Stichting Epilepsie Instellingen Nederland’ (SEIN) in Heemstede. Technical partners include TU Delft (neuromodulation; brain-computer interfaces; EEG analysis including 4D-EEG), TU Twente (biosensors; brain-on-chip) and TU Eindhoven (brain-on-chip).

Team members:

Dr. Thijs Houben (post-doctoral fellow - LUMC): Characteristics and consequences of optogenetically-induced cortical spreading depression in migraine mice

Drs. Inge Loonen (PhD student - LUMC): The role of spreading depression in migraine and SUDEP mouse models

Drs. Inge Mulder (PhD student - LUMC): Mouse stroke MRI and MS-imaging studies

Drs. Thas Phisonkunkasem (PhD student - LUMC): Modulation of cortical spreading depression and its consequences in migraine mice

Drs. Thijs Perenboom (PhD student - LUMC): Visual and TMS-evoked EEG changes in migraine patients

Drs. Nico Jansen (PhD student - LUMC): SUDEP prevention by cortical counter-stimulation, and deep brain stimulation for seizure termination (collaboration with the Hoebeek lab)

Joost Brinks (Master student - LUMC): Optimization of cerebellar deep brain stimulation paradigms for seizure prevention in an absence epilepsy mouse model

Robin Schoonderwoerd (Master student - LUMC): Functional characterization of mouse and human neuro-iPSCs

Hanieh Mastyani (Master student - TU Delft): Development of a microfluidics chamber for brain-on-chip studies

Chengyu Huang (Master student -Serdijn lab, TU Delft): Improving the brain-computer interface characteristics used for studying neurological disease

Technicians: Ludo Broos, Lisanne Vijfhuizen, Sandra van Heiningen and Maarten Schenke

 

 

The Tolner and van den Maagdenberg labs are currently supported by grants from:

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