Dr. Krishna has personally performed successful focused ultrasound (FUS) treatment on more than a dozen patients with essential tremor (ET) or Parkinson’s disease (PD). His research interests include functional neuroimaging, tractography, neurophysiology, and neuromodulation mechanisms of action.
Dr. Krishna, how did you get involved in FUS?
I got interested in FUS during my fellowship training at the University of Toronto in Canada. While there, I was able to assist in treating several patients as part of an ET pivotal clinical trial at Sunnybrook Health Sciences Centre with Dr. Andres Lozano, which led to the 2016 approval of FUS to treat ET in Canada. I also helped initiate the FUS program at Toronto Western Hospital and participated in the first FUS ET case there. Then, I started the FUS program here at Ohio State.
Tell us more about your areas of interest relating to FUS.
One of my primary areas of interest is exploring new indications for the therapy. I also am very interested in learning how to make outcomes after FUS better, in terms of the effectiveness of therapy, improving the safety of the therapy, and in bringing more sophistication to it so we can perform the procedure in a shorter period of time, for example. We have come a very long way in recent years in terms of advancing the treatment, but there is always more work to be done, and improvements to discover.
What specific mechanisms and clinical indications related to FUS do you study?
Our team at Ohio State was involved in the six-site continued access phase III pivotal trial for ET, in which we investigated the use of FUS to treat tremors in patients who have not responded to medication or are not candidates for alternative treatments. I am also principal investigator for the Insightec-sponsored Phase I clinical trial for PD, which is evaluating the safety and initial efficacy of FUS to create a unilateral lesion in the brain (globus pallidus) as an adjunct to PD medications. And of course, thanks to the Foundation, I will soon be leading an epilepsy trial in which we will be using FUS to ablate the anterior nucleus of the thalamus in patients with partial-onset epilepsy. Farther down the line, I also hope to research new areas, like psychiatric indications for the treatment.
When it comes to your patients, how would you describe the goal of your work?
The patients I see are often suffering from mobility issues and decreased functionality, which can greatly impact their quality of life. They often come to me worried about treatment options – too scared to undergo invasive surgery, for example – and are hoping to maintain their independence and regain their normal activities to some degree. So my goal is always to improve their quality of life and improve their functionality by decreasing their motor disability. Happily, we have achieved that for many patients, which is very rewarding. So far we have treated 12 patients with ET, and three with PD, and they are all doing very well.
Tell us more about your clinical research. Any highlights you want to share?
Our research is focused on improving outcomes in patients. We have two major directions of research here at Ohio State: one is looking at how to precisely localize the therapeutic targets in the brain, and the other relates to obtaining feedback from the brain while performing FUS (mid-treatment) to improve the procedure – for example, being able to better gauge when we have done enough sonications while treating a patient.
Regarding the first area of research, we are using a new tractography-based approach (called “T-VIM”) to better identify targets in the brain, both for PD and ET. Some of this work with patients with ET was recently published in the Journal of Neurosurgery and in Movement Disorders. Simply put, our goal is to precisely locate areas in the brain to improve the effectiveness and efficacy of the treatment, while at the same time avoiding unwanted side effects from ablating or lesioning important critical structures around the areas that we are treating. The hope or expectation is that these new imaging sequences can lead to better outcomes, and perhaps someday be applied to other brain targets in the treatment of ET or PD.
So far we have conducted 12 ET procedures at Ohio State with excellent results – for example, we achieved 53% efficacy at three months, with no side effects related to sensory deficits or paralysis, and we were able to decrease the surgical time to less than 80 minutes with an average number of just 13 sonications.
In the next line of research, we are investigating the use of functional MRI to study brain networks during FUS treatments. In ET, for example, abolishing tremor is the treatment goal. However, for other diseases – like epilepsy or psychiatric indications – immediate clinical improvement may be lacking. This work will help us define whether enough ablation has been done or more sonications are required for long-term therapeutic benefits.
What areas of study would be on your “research wish list”?
This is a great question. From a process or procedural standpoint for patients, I think we need to look into how FUS can be performed without the head frame or helmet, and without shaving the hair. Then in terms of software, I think we need improvements in the software so that we don’t have to spend so much time acquiring two-dimensional images; 3D images would greatly speed up the process. I also think we need to advance our capabilities with physiological feedback – meaning, we would benefit from finding a way to better test the brain while the patient is being treated, and perhaps use MRI paired with physiological feedback to better assess if we’re in the right location and have done enough ablation. Lastly, I would love to better explore the predictors of long-term outcomes, as well as what new indications can be used for this therapy.
Why in your opinion should the global community care about FUS?
FUS is a very powerful, noninvasive modality for brain ablation and neuromodulation. This modality is going to be used for indications for movement disorders, epilepsy, and pain control – but also for targeted drug delivery and even modulating the function of the brain. It’s a very exciting time for the technology.
There are literally millions of patients with a variety of disabling movement disorders and neurological disorders who may be candidates for FUS. For some, surgery is an effective way to treat some of these problems, but a lot of these patients are not willing to undergo invasive surgery. We need options for these people, to make an impact in their lives, and for many patients FUS is providing that solution. FUS has the potential to drastically impact patient care, global health policy, cost of treatment, etc.
How has the Foundation helped your work with FUS?
The Foundation has been extremely supportive, and I cannot thank you all enough – I mean that from the bottom of my heart. I have enjoyed the opportunity to speak to the broader FUS community through your seminars and symposia, and to interact with others who are as enthusiastic and passionate about the technology as I am. It is both assuring and rewarding to have a dedicated group in the same interest of mine. I greatly appreciate Dr. Kassell’s guidance, your group’s funding on critical research areas, the assistance from the entire staff, the willingness to share ideas and databases, all of it. I look forward to even more collaboration in the future as we all work tirelessly to advance FUS to a mainstream standard of care.
Finally, is there anything you’d like to say to patients and their families who may be reading this article, perhaps about the use of FUS to treat ET, or your thoughts on future ET treatments?
For patients with ET, I am happy to share that we now have several surgical treatment options to consider: conventional DBS, MRI-guided DBS (also called 'asleep DBS'), and most recently, FUS ablation. I am excited about future improvements in FUS technology, which will enable us to treat a variety of neurological diseases that may currently be incurable today. Lastly, I realize that ET can be disabling, and I strongly encourage patients to seek care from experts in movement disorders and neuromodulation.