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

超声波最为人所知的是对未出生的婴儿进行成像。在这种情况下，声波在人体内传播，其回声被用来形成图像，体内剩余的能量非常有限。通过将声波聚焦到太空中的一个小区域，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，这可以用来以一种安全、短暂和可逆的方式改变我们大脑的运作方式。这具有治疗大脑疾病的潜力，如神经疾病(帕金森氏症)，但也包括精神疾病(成瘾、抑郁)。这项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等人)。2023年)。由于这些变化超过了干预期，这些影响促进了神经可塑性-大脑重新连接自身的能力，这是考虑脑部疾病的新治疗方法时的一个关键功能。尽管TUS有可能彻底改变我们一生中治疗大脑的方式，无论是在一般健康还是疾病方面，TUS的结果是多种多样的。在我们之前的工作中，我们观察到TUS效应取决于人所处的“状态”，例如清醒或睡眠(生理状态)，或休息或专注于一项任务(认知状态)。生理或认知状态的改变会引起大脑区域活动的变化，从而改变TUS对这些大脑区域的影响。在这个新的项目中，我们将首次调查大脑状态和TUS之间的关系(目标1)，以及目标脑区域的招募是否提高了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治疗设计。对于目标1，我们将使用三个工作包(WP1-3)，都集中在同一TUS干预对不同状态的影响：1)不同的意识状态(在不同的麻醉深度下操纵)，2)不同的疼痛敏感状态(通过疼痛发展的实验操纵)，以及3)不同的认知负荷(通过复杂的学习任务操纵)。更好地完善TUS和状态之间的关系将是为有效的临床干预铺平道路的关键，特别是那些结合认知行为治疗和脑刺激的干预。TUS的另一个重要方面是，它可以到达大脑中的任何区域--大约几毫米--甚至深入大脑，而不像更传统的方法那样只停留在表面，在空间上不准确。当试图评估特定核团在大脑或特定区域中的作用时，这一点很重要。大脑的一些区域有特定的功能，例如，一个区域A可以连接到一个功能A，而另一个大脑区域B可以连接到一个功能B。通过在不同的日子调节区域A和B，人们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，而不仅仅是与区域本身有关。理论上，可以通过同时刺激这两个区域的大脑来评估这一点。在这一新的研究路线中，我们还将追求TUS可以同时在大脑的不同位置使用的想法，以改变大脑区域之间的通信(目标2-工作包4[WP4])。我们想要证明并行的多部位TUS是安全的，并可以通过提供更多的脑干预方法来增加结果测量。这将增加TUS应用的潜力，并为考虑脑网络动力的非侵入性脑刺激开辟一条新的途径。

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.