Stefan Dukic

I began my neural engineering career in 2014. I was awarded a full stipend for a MSc programme between the University of Groningen and Trinity College Dublin. During my internship, I was introduced to a technique for recording electrical brain signals known as electroencephalography (EEG). Right after graduating with distinction (top 10%), I started my EEG work within the ALS centre in Trinity College Dublin, which then soon segued into a PhD training and became a strong international collaboration between the ALS centresin Dublin and Utrecht.

At the very start, I was introduced to the need to objectively quantify and subgroup motor neurone disease (MND) patients with the overarching aim to improve efficiency of clinical trials and to find successful treatments. On this path, I showed that we can differentiate EEG activity of ALS patients from controls using a simple resting task, which is suitable for use in a clinical setting. This research became ‘top 10% most downloaded paper for 2018/19’ in a high-impact journal it was published. The findings from this study laid down the firm basis for my pioneering work on subgrouping ALS. Namely, I showed that ALS patients can be divided into four subgroups with differential brain network impairments and survival outcomes. This clinicallyrelevant finding could aid future clinical trials in better stratification of patients into more homogeneous groups that are tailored for specific treatments. Now, I endeavour to further develop this low-burden electrophysiological approach and to integrate it with other research groups, to address the significant need for detection of early MND.

My hypothesis is that subclassification of patients by patterns of electrical brain dysfunctionand by integratingMND patient and family data, together can provide earlier, more informative biomarkers and subgroups that will increase success rate of clinical trials and help in personalised treatment strategies. My early findings, from the EEG project that I am leading at the ALS Centre Utrecht, support this notion and show that EEG can detect subtle changes in electrical brain and brain-muscle functioning in asymptomatic C9orf72carriers.

Survival time from symptom onset, disease spreading and the combination of motor and non-motor symptoms are extremely variable in ALS. The power of clinical trials remainslimited by this heterogeneity and by the currently used measures of disease progression (i.e.,slope of ALSFRS-R), but also by the fact that the optimal therapeutic window is likely to be at an earlier stage in high-risk, genetically susceptible populations. Current attempts to limit the impact of this heterogeneity involverestrictive recruitment criteria that often deny the majority of the patient population access to clinical trials. It is clear that objective biomarkers that can early in the disease characterise distinct disease subtypes are urgently required. This will help us better inform patients at the time of diagnosis and to overcome substantial limitations in current clinical trial designs.

The unique support for research and career development that the ALS foundation provides, combined with my wellestablished skills in neural signal analysis, will enable me to test my hypothesis and establish myself as a more independent researcher. The ability to lead the testing of my own hypothesis, in addition to the further research tr aining and experience I will gain from this fellowship, will bring me towards my long-term career aspiration of dedicating my career to neuroelectric biomarker development of early ALS. Findings and experience gained through this fellowship will form the strong basis for my application to the NWO’s VENI scheme and/or European Research Council (ERC) Starting Grants, which would secure more funding and further perpetuate our ALS research.

Finally, this allows me to further strengthen our international collaboration with other ALS centres abroad and to establish the ALS Centre in Utrecht as an international expertise hub for ALS biomarker therapeutic development. With my strong background in neural engineering, I hope to fill in the knowledge gap in the world of clinical trials. This novel, collaborative, integrated approach will attract pharmaceutical interest, paving the path to successful clinical trials in MND.

Aanvrager project: ALS Centrum Nederland