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

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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.