Optimising deep brain stimulation for treatment of epilepsy: a networks based approach

Project description

This PhD provides the opportunity to work with clinicians and scientists from GOS Institute of Child Health and a UK based biotechnology SME, Amber therapeutics, to develop deep brain stimulation (DBS) techniques for the treatment of childhood epilepsy.

Epilepsy is a common and chronic neurological condition affecting 1% of the population. One-third of children with epilepsy continue to have epileptic seizures despite multiple trials of anti-seizure medications. For selected candidates with focal-onset seizures, epilepsy surgery to resect the epileptogenic zone is a therapeutic option and is associated with high rates of seizure freedom. However, for those patients with a non-identifiable seizure-onset zone or generalised-onset seizures, and drug resistance, there currently exist few efficacious treatment options. These children suffer multiple co-morbidities and reduced quality of life. There is a pressing need to develop effective therapy.

Increasingly epilepsy is considered a network disorder: these network disorders may underpin not only the seizure disorder but also associated co-morbidities such as cognitive, behavioural and social communication abnormalities. A small number of studies have shown that the network alterations gleaned from MRI and EEG are associated with clinical response to DBS therapy and may give information to its therapeutic mechanisms. The thalamus has long been implicated as a critical propagation hub in the epileptogenic network of patients with drug-resistant seizures and is a focus for our current research. The centromedian nucleus of the thalamus is the stimulation target for our current studies and therefore an area of investigation for the detection of preoperative biomarkers of treatment success.

DBS is an emerging therapy that reduces seizure frequency and severity by preventing the propagation of epileptiform activity in the brain. There is provisional evidence that DBS is effective in treating patients with both focal and generalised onset. DBS provides a unique opportunity to modulate brain networks yet effects on brain networks and optimal stimulation paradigms are not yet well elucidated.

The CADET Project (the ‘Children’s Adaptive Deep brain stimulation for Epilepsy Trial’) is a series of funded clinical trials investigating the safety, feasibility and effectiveness of a first-in-child application of a novel DBS device to treat 26 children with Lennox-Gastaut syndrome (LGS) – a severe, complex form of drug-resistant epilepsy. The CADET Project has commenced recruitment of subjects and is funded to run over the next three-years. NCT webpage: https://clinicaltrials.gov/ct2/show/NCT05437393. In addition the study team has recently obtained an NIHR i4i grant to develop a responsive DBS capability in this cohort of patients, planned to run from August 2024 – August 2027.

The successful PhD applicant will utilise the multi-modal imaging and neurophysiological data emerging from the CADET studies to develop understanding and efficacy of deep brain stimulation for epilepsy. These data include: preoperative neuroimaging measures (diffusion MRI/tractography), scalp electroencephalography and local-field potentials measured directly from the thalamus using the Amber Picostim device.

They will utilise preoperative diffusion MRI from subjects entering the CADET studies to define network abnormalities in this cohort of children with LGS and specifically to investigate alterations in thalamic connectivity. The supervisory team has significant experience in diffusion connectomic analysis. Using outcome data from the CADET Project, the PhD Fellow will investigate pre-operative imaging correlates of treatment response in attempt to refine DBS targeting strategies.  

Serial longitudinal scalp EEG and telemetrically acquired intracranial thalamic EEG recorded via the DBS stimulating electrodes will be used to investigate dynamic network effects of thalamic deep brain stimulation over time and relate these to clinic outcomes.

Exploring the effects of thalamic DBS on scalp EEG and functional networks will inform a study to develop bioengineering modelling techniques to predict neural entrainment effects of deep brain stimulation. These studies working in partnership with Amber will progress development of stimulation therapy paradigms for the treatment of epilepsy.

The supervisory team provides a unique breadth of experience encompassing clinical and translational neuroscience provided by the UCL team (Tisdall and Baldeweg), coupled with bioengineering and industry expertise from the Amber team (Prof Denison and Dr Knowles). The successful candidate will join a cohesive team with a proven track record of successful peer reviewed grant application and publications in high impact journals. This approach is ideal to develop translational development of medical devices.

References

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2. Khan M, Paktiawal J, Piper RJ, et al. Intracranial neuromodulation with deep brain stimulation and responsive neurostimulation in children with drug resistant epilepsy: a systematic review. J. Neurosurg. Pediatr. 2022;29(2):208–217.
3. Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51(5):899–908.
4. Dalic LJ, Warren AEL, Bulluss KJ, et al. DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial). Ann. Neurol. 2022;91(2):253–267.
5. Stavropoulos I, Selway R, Hasegawa H, et al. Low frequency centromedian thalamic nuclei deep brain stimulation for the treatment of super refractory status epilepticus: A case report and a review of the literature. Brain Stimul. 2020;14(2):226–229.
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7. Middlebrooks EH, Jain A, Okromelidze L, et al. Acute Brain Activation Patterns of High- Versus Low-Frequency Stimulation of the Anterior Nucleus of the Thalamus During Deep Brain Stimulation for Epilepsy. Neurosurgery 2021;89(5):901–908.
8. Piper RJ, Fleming J, Valentín A, et al. Neurostimulation devices for children: lessons learned. Lancet Child Adolesc. Heal. 2022;6(6):359–361.