Plain English Summary

Drugs are horrible. While many psychiatric and neurological conditions are treated with pharmaceutical drugs, side effects remain severe. As one sufferer of epilepsy commented: “If the side effects of anti-epileptic drugs would be considered on their own, they would be an own disease category”. Drugs, once passing through the blood-brain-barrier, affect the entire brain and its effect is not just limited to the regions that are linked to brain network disorders. Even worse, often the drugs don’t work. For a third of epilepsy patients, drugs are ineffective in reducing the number of seizures, and for diseases such as dementia, there are no drugs with obvious benefits in humans. This situation is unlikely to improve as, for example, dementia clinical trials have failed, and more and more pharmaceutical companies are quitting brain disorder drug development altogether.

Brain stimulation of distinct regions of the brain offers a potential route to new treatments. However, the effects are often inconsistent between patients and, in particular for older subjects, invasive approaches using implants are seen as risky by clinicians. Therefore, for neuromodulation to replace drugs in the future, interventions need to be personalised and non-invasive. The solution to replace pharmaceutical drugs for many brain disorders before 2050 is the proposed development of an approach that is (a) non-invasive through using focused ultrasound stimulation and (b) personalised through using computer models to predict which network nodes or edges should be targeted and which stimulation protocol should be used.

Enabled by this proof of concept, computer simulations can test thousands of different stimulation approaches before deciding on an optimal approach for an individual patient. This is crucial, as trial-and-error in human patients is not an option. For deep-brain stimulation in Parkinson’s disease, the fine-tuning of the stimulation algorithm for each patient takes several weeks. Whereas this is tuning the protocol alone, the situation will be more challenging when also the target structure needs to be determined. Phase 1 will show whether predicting stimulation outcomes is feasible and will therefore de-risk the healthcare implementation in phase 2.