Multi-site and state-dependent effects of Transcranial Ultrasound Stimulation on brain function and cognition

超声波最出名的是对未出生的婴儿进行成像。在这种情况下，声波通过身体传播，其回声用于形成图像，体内剩余的能量非常有限。通过将声波聚焦到空间中的一个小区域，有点像放大镜聚焦阳光将热能增加到一个地方，聚焦的超声波能量增加，这可以用来改变细胞在体内的行为方式。通过头骨，这可以用来改变我们的大脑如何以安全，短暂和可逆的方式运作。这对治疗大脑疾病具有治疗潜力，如神经系统疾病（帕金森病），但也有精神疾病（成瘾，抑郁症）。该技术被称为经颅超声刺激（TUS）。在一系列研究中，我们的团队已经证明，TUS可以在干预后两小时内安全且可逆地改变大脑活动（Yaakub et al. 2023）。由于这些变化超过了干预期，其影响促进了神经可塑性-大脑重新连接自身的能力，这是考虑大脑疾病新疗法时的一个关键功能。尽管TUS有可能彻底改变我们在整个生命中治疗大脑的方式，无论是在一般健康还是疾病中，TUS的结果都是可变的。在我们之前的工作中，我们已经观察到TUS效应取决于人所处的“状态”，例如清醒或睡眠（生理状态），或者休息或专注于任务（认知状态）。生理或认知状态的变化会导致大脑区域活动的变化，从而改变TUS对这些大脑区域的影响。在这个新项目中，我们将首次研究大脑状态和TUS之间的关系（目标1），以及目标大脑区域的招募是否会改善TUS诱导的可塑性。这对于优化未来的治疗设计至关重要，特别是那些在TUS治疗期间利用认知行为任务的设计。对于目标1，我们将使用三个工作包（WP 1 -3），所有工作包都集中在相同TUS干预对不同状态的影响：1）不同的意识状态（使用不同的麻醉深度操作），2）不同的疼痛敏感性状态（通过疼痛发展的实验操作操作）和3）不同的认知负荷（通过复杂与简单的学习任务操作）。更好地完善TUS和国家之间的关系将是至关重要的，为有效的临床干预铺平道路，特别是那些结合认知行为治疗和脑刺激。TUS的另一个重要方面是，它可以到达大脑中的任何区域-毫米级-甚至在大脑深处，不像更传统的方法，仍然是表面的，空间不准确。当试图评估大脑或特定区域中特定核团的作用时，这一点很重要。大脑的某些区域具有特定的功能，例如，区域A可以链接到功能A，而另一个大脑区域B可以链接到功能B。通过在不同日期调节区域A和B，可以评估这些区域的作用。然而，有时一个功能与区域之间的通信方式有关，而不仅仅是区域本身。理论上，这可以通过同时刺激两个区域来评估。在这项新的研究中，我们还将追求TUS可以同时用于大脑不同位置的想法，以改变大脑区域之间的通信（目标2 -工作包4 [WP 4]）。我们希望证明同时进行多部位TUS是安全的，并且可以通过提供额外的干预大脑的方法来增加结果指标。这将增加TUS应用的潜力，并为考虑大脑网络动态的非侵入性脑刺激开辟新的思路。

Ultrasound is best known for imaging unborn babies. In this instance, sound waves travel through the body and their echoes are used to form images, with a very limited amount of energy remaining in the body. By focusing the sound waves to a small region in space, a bit like a magnifying glass focusing sunlight increases the heat energy to one place, the focused ultrasound energy increases, and this can be used to change the way cells behave in the body. Through the skull, this can be used to change how our brain functions in a safe, transient, and reversible way. This has therapeutic potential for treating disorders of the brain, like neurological disorders (Parkinson's disease) but also psychiatric disorders (addiction, depression). The technique is called Transcranial Ultrasound Stimulation (TUS).In a series of studies, our team have shown that TUS can safely and reversibly change brain activity up to two hours after intervention (Yaakub et al. 2023). Because these changes exceed the intervention period, the effects promote neuroplasticity - the ability of the brain to re-wire itself, a key function when considering new treatment for disorders of the brain.Although TUS has the potential to revolutionize how we treat the brain throughout life, both in general health and disease, TUS outcomes are variable. In our prior work, we have observed that the TUS effects depend on the "state" that the person is in, for example awake or sleeping (physiological state), or resting or focusing on a task (cognitive state). Changes in physiological or cognitive states cause changes in brain regional activity which consequently change how TUS impacts these brain regions.In this novel project, we will investigate for the first time the relationships between brain states and TUS (Aim 1) and whether recruitment of targeted brain regions improves TUS-induced plasticity. This is crucial for optimizing future treatment designs, particularly those leveraging cognitive-behavioral tasks during TUS therapies. For Aim 1, we will use three work packages (WP1-3), all focusing on the effects of the same TUS intervention on different states: 1) different states of consciousness (manipulated with different depth of anaesthesia), 2) different states of pain sensitivity (manipulated through experimental manipulation of pain development) and 3) different cognitive load (manipulated through complex versus simple learning tasks). Better refining the relationship between TUS and states will be vital to pave the way for effective clinical interventions, particularly those combining cognitive-behavioral therapy and brain stimulation. Another important aspect of TUS is that it can reach any region in the brain - in the order of millimetres - even deep in the brain, unlike more traditional methods that remain superficial and not spatially accurate. This is important when trying to assess the role of specific nuclei in the brain or specific regions. Some regions of the brain have specific functions, for example, a region A can be linked to a function A, while another brain region B can be linked to a function B. By modulating regions A and B on different days, one can assess the role of these regions. However, sometimes a function is linked to the way regions communicate with one other and not solely on the region themselves. In theory, this could be assessed through concurrent brain stimulation of the two regions. In this new line of research, we will also pursue the idea that TUS can be used at different locations of the brain at the same time, in order to change communication between brain regions (Aim 2 - Work Package 4 [WP4]). We want to show that concurrent multisite TUS is safe and can increase outcome measures by providing additional ways of intervening in the brain. This will increase the potential of TUS applications and open a new avenue for thinking about non-invasive brain stimulation which considers the dynamism of brain networks.