E7. Lennart Verhagen – Ultrasound Brain Stimulation

0:06 – Why is a psychology department looking at ultrasound?

2:25 – Why are we making breakthroughs with an old technology like ultrasound?

We’ve known since the 1950s that neuron firing rates can be altered using focused ultrasound. However, recent advances in computational capacity mean we can now model how the ultrasound will travel through the skull and brain tissue, enabling ultrasound to be precisely focused and directed.  To date, ultrasound brain stimulation has been online, meaning that the effects only last while stimulation is ongoing. Lennart’s group has developed a protocol that enables longer lasting effects, up to an hour after the stimulation stops.

7:15 – On the relationship of focused ultrasound to the high intensity ultrasound used in medicine.

The technology being used by Lennart’s group is similar to the high intensity focused ultrasound being used in medicine to lesion and ablate brain tissue without surgery, though at a lower intensity.

8:35 – Why is low intensity focused ultrasound important as a brain stimulation technology?

Focused ultrasound is one of two technologies heralding a new era of deep brain neuromodulation. Prior to these two technologies, the only way to stimulate deep in the brain was invasive; surgically implanting electrodes. The other new non-invasive technology, electrical temporal interference, was first reported in 2017 and relies on electrical interference patterns. Lennart believes that focused ultrasound will prove superior due to its greater precision.

10:40 – On his team’s work and why it is significant.

Quite remarkably, the literature had contained hints of the potential for the effects of ultrasound stimulation protocols to have relatively enduring effects; there were cases where the effects were still present one minute later when the researchers stopped measuring. By utilising repetitive and slightly longer duration and therefore higher energy protocols than had previously been explored, Lennart’s team and their collaborators around the world, (including Jean-Francois Aubry), had achieved effects that lasted up to an hour. These effects are apparent not just at the neuronal level, but in subtle measures of behaviour. For example, the saccade behaviour of monkeys.

15:10 – On the clinical significance of longer duration effects and mechanisms of action.

The clinical significance of longer duration effects vs. repeated shorter duration effects as seen in TMS is an open question. Mechanisms of action include: (a) altered neuronal firing patterns, which, since neurons that fire together wire together, could lead to lasting change, and (b) increasing the ability of certain circuits to display plasticity, that is, to become more susceptible to retraining.

Enhanced plasticity is closely related to long-term potentiation (increased strength of connections that neurons form) understood to be relevant to clinical depression. Fascinatingly, the clinical utility of inducing a ‘plasticity window’ effects is likely to require either: (a) psychotherapy, where treatment efficacy relies both on the quality of the psychotherapy and how ‘plastic’ or susceptible to training and change the brain is, or (b) continued lived experience from which the client may  be able to better learn and grow. Long term plasticity is a key research focus of the group because it is this effect that has the potential for a significant role in mental health treatments.

20:35 – On next steps in his research program.

Next steps include indexing long term plasticity via changes in neurotransmitter ratios, investigating how learning might be effected, and confirming the risk profile of long term usage.

23:13 – On the safety profile of the new longer duration protocols .

No new adverse effects have been detected.

27:10 – On the outlook to widespread clinical usage and lessons learned from the development of TMS protocols

Clinical trials are required, so widespread clinical use is some years away but likely significantly less than a newly discovered drug. However, clinical efficacy is yet to be established, so talking timeframes to market is hypothetical at this point. And in fact, given the promise, Lennart often finds himself having to try to temper expectations. In doing so, he hopes to avoid the rushed and ultimately somewhat wasted efforts in studying TMS protocols, due to the hype that initially surrounded the technology.

33:00 – On the clinical potential for focused ultrasound neuromodulation and what treatments might look like.

Major Depressive Disorder is an obvious first target given its impact and association with deep brain structures. However, MDD is a very heterogeneous disorder, and only certain subtypes are likely to be more amenable to treatment with focused ultrasound. Anxiety and PTSD may also be profitable targets. Neurological disorders, such as Parkinsons, Alzheimers and Tinnitus are also potential targets, where focused ultrasound will likely be used in preventative and complementary ways. Again, effective treatment is likely to require both the physiological changes brought about by the ultrasound stimulation, and people incorporating their subjective experiences whether with a therapist or just living life.

41:30 – On what undergoing ultrasound brain stimulation would involve.

The first thing is to take a high fidelity image of the skull, ideally a CT scan. This enables detailed modelling of how the ultrasound will travel through the skull.  Then, after applying a gel to your head, infrared sensors would direct the ultrasound from a small head-mounted transducer, perhaps in a kind of helmet. No anaesthesia is required. Further developments will see the gels done away with, and radiation-free MR scans used instead of CT scans.

46:20 – On its potential as a tool in basic neuroscience research.

Focused ultrasound holds significant potential as a basic neuroscience tool, and in fact these are likely to be the first applications of the technology. We are able to image the whole brain well, but we have not been able to non-invasively stimulate deeper brain structures. Doing so, will enable us to better establish causal relationships of deep brain structures and circuits. Other use cases include sonogenetics, which is likely to supplement optogenetics in basic neuroscience research, and selectively opening the blood brain barrier which can facilitate drug delivery.

Ultrasound is also likely to be used as an imaging tool, which could deliver micrometer accuracy with millisecond temporal resolution; “FMRI on steroids”. This may be a decade away, but it is largely an engineering problem from this point, as high fidelity, high temporal and spatial resolution performance has already been achieved in rodents (with their thinner skulls).