Beyond drugs: Non-invasive focused ultrasound brain stimulation as a novel intervention for mental health

毒品太可怕了。虽然许多精神和神经疾病都是用药物治疗的，但副作用仍然很严重。正如一位癫痫患者所评论的那样：“如果单独考虑抗癫痫药物的副作用，它们将是一个自己的疾病类别。”药物一旦通过血脑屏障，就会影响整个大脑，其影响不仅限于与大脑网络障碍有关的区域。更糟糕的是，药物往往不起作用。对于三分之一的癫痫患者来说，药物在减少癫痫发作次数方面无效，而对于痴呆症等疾病，没有对人类有明显好处的药物。这种情况不太可能得到改善，因为例如，痴呆症临床试验已经失败，越来越多的制药公司正在一起退出大脑障碍药物的开发。大脑不同区域的大脑刺激为新疗法提供了一条潜在的途径。然而，患者之间的效果往往不一致，特别是对于老年受试者，临床医生认为使用植入物的侵入性方法有风险。因此，对于未来取代药物的神经调节，干预需要个性化和非侵入性。在2050年前替代药物治疗许多大脑疾病的解决方案是提议开发一种方法，该方法是(A)通过使用聚焦超声刺激来非侵入性的，(B)通过使用计算机模型来预测哪些网络节点或边缘应该成为目标以及应该使用哪种刺激方案来个性化。通过这种概念证明，计算机模拟可以测试数千种不同的刺激方法，然后再决定针对单个患者的最佳方法。这一点至关重要，因为在人类患者身上进行反复试验不是一种选择。对于帕金森氏症的深部脑刺激，针对每个患者的刺激算法的微调需要几周的时间。虽然这是单独调整协议，但当目标结构也需要确定时，情况将更具挑战性。阶段1将显示预测刺激结果是否可行，从而在阶段2中降低医疗保健实施的风险。

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.