Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And joining me today is Dr. Shan Siddiqi. He's the Stephen M. Stahl Associate Professor of Psychiatry and Behavioral Sciences at Northwestern Medicine.

Today, we're highlighting his work surrounding image-guided mapping of human brain function that personalizes treatment and improves TMS outcomes for depression. Dr. Siddiqi, thank you so much for joining us today. And before we get into this fascinating topic, tell us a little bit about yourself and how you came to Northwestern Medicine.

Dr. Shan Siddiqi: Yeah, thank you. I'm a psychiatrist by training. I trained in St. Louis, also grew up in St. Louis. I spent the last nine years in Boston in subspecialty training and building up a lab, but I wanted to come back to the Midwest because it's sort of natural for me. It's where I grew up, and it's the sensibility that I like.

But also, I was really excited about what Northwestern Medicine has been building and growing the psychiatry and behavioral sciences and neurosciences more broadly across the institution.

Melanie Cole, MS: Well, thank you so much. And we're so glad that you're here. Now, you've spent much of your career studying brain circuits and neuromodulation. What drew you to this field, and what excites you most about bringing this unique expertise to Northwestern Medicine?

Dr. Shan Siddiqi: Yeah. So, what drew me to this field was excitement about how it can really change the face of how we practice psychiatry. I went into psychiatry solely because I loved working with these patients. I loved working with these types of challenges and helping people get through some of the most difficult things in their life when they're still relatively early in their life often.

But as I was going through psychiatry training, I felt like although it's very incredibly satisfying when we get our patients better, we're not doing a good enough job. We should be able to get people better faster, earlier. We should be able to standardize our care better. We should be able to improve our training so that every psychiatrist is practicing the same way.

And a lot of those things felt a little bit unsatisfying. And so, I spent a lot of time thinking about how we can solve some of these fundamental limitations in our field. And broadly, I thought the way to do it was to bring neuroscience into the day-to-day clinical practice of psychiatry. Many of us agree this is a good idea, and many people are taking different approaches to it.

But I thought the approach that I wanted to take was the one that will do it the fastest. And the way to do it fast is take the thing that is almost ready for clinical translation within clinical neuroscience and figure out how to push it over the edge. And so, the thing that I thought was closest to being ready was using brain imaging to guide therapeutic brain stimulation treatments. People were already doing it in neurology. The brain stimulation treatments were already working for disorders in psychiatry. So, we figured that we must be able to make them work better if we do a more precise job of mapping a patient's brain. That's what got me excited about it. We've spent the last decade or so building it up, and now we're there.

Increasingly, brain imaging is actually being used by psychiatrists to plan treatments for for major depression, for OCD, and for a wide variety of other disorders. So as neuroscience comes into clinical care, it's starting to help us incentivize people to want to learn more about the brain as they learn how to treat patients with brain disorders.

One thing that really excites me about doing it at Northwestern Medicine is that Chicago is a very large city. Northwestern is one of the best, maybe the best hospital in town. And so, it creates an opportunity to serve a very large community of this whole city with innovative cutting-edge new treatments.

So, what we want to build at Northwestern is something similar to what MD Anderson does for cancer, where any patient who comes in with any neuropsychiatric disorder should have an option for a clinical trial to engage in new innovative treatments without having to pay for it. So, that's something that we're going to be building here, and I think it's a unique opportunity here given, first of all, the size of the city, the strength of Northwestern Medicine throughout the Chicago metro area and the fact that there was really nobody else in town doing it yet unlike LA and New York and Boston. So, there were some studies, but no really large scale neuromodulation trials in psychiatry happening yet in Chicago. So, we're going to fix that.

Melanie Cole, MS: What a fascinating field of study, and so interesting that you had this opportunity to forward this type of studying. So, how does image-guided personalized TMS differ from the conventional TMS for depression that are used at most health systems today?

Dr. Shan Siddiqi: So conventionally, we apply TMS using approximate landmarks on somebody's scalp. And broadly speaking, TMS is a treatment that allows us to stimulate different regions of the brain to help activate things that we think aren't as active as they should be.

When we do that, ideally, you'd want to know which region of the brain you're stimulating a great deal of precision. However, there were a lot of open questions as to where exactly should we be aiming the treatment. And until we figured that out, we didn't have a really great way to justify using advanced brain imaging. So as I mentioned, we spent the last decade figuring it out. And now, we have a clinical trial proving that advanced image-guided brain stimulation actually does improve clinical outcomes relative to conventional brain stimulation.

So to answer your question, the conventional way is somebody comes in, we use some measurements on their scalp to say, "Here's approximately where I think I should be stimulating. Let me aim it there," and hopefully the person gets better. Now instead of guessing, we can be very precise and improve outcomes by quite a bit.

Melanie Cole, MS: Isn't that so amazing? You've taken some of the mystery out of this type of work, and your work specifically focuses on mapping functional brain networks. So, what does image-guided personalization really mean in practice, Dr. Siddiqi? How do you determine where stimulation should be delivered for each individual patient?

Dr. Shan Siddiqi: In practice, what it means is that a person comes in, the doctor sees them. And depending on several logistical factors such as insurance or whether they're in a clinical trial or things like that, we say, "Here's the protocol that we think is most likely to work for you. Here are some other protocols that are available."

We discuss the pros and cons of all the different options. And if we decide in conversation with a patient that image guidance is important, we'll send them for an MRI scan. For the patient, it feels like a normal MRI scan. We use some advanced sequences behind the scenes.

But from the patient's perspective, it's about 45 minutes to an hour in the scanner. No special contrast agent. Nothing needs to be injected. They don't need to do any special tasks. They come out, we get the data from that scan, we analyze it and figure out where the right spot will be. And then, we use a fancy piece of equipment called stereotactic neuronavigation to figure out where exactly on that MRI scan corresponds to a specific spot on the patient's head that we can see with our own eyes.

Using that, we can get within a millimeter or two of the optimal spot and watch live as the patient's brain shows up on our screen. And for example, if they move their head, we can move the simulator to remain in the right spot. That's what it looks like in practice. And we get to a pretty good degree of precision when we do that.

Melanie Cole, MS: Dr. Siddiqi, clinical trials have demonstrated improved outcomes with connectivity-based targeting. What do you believe were the most important findings from that study, and how might they influence clinical care moving forward?

Dr. Shan Siddiqi: Yeah. This was a study that we published in JAMA Psychiatry a couple of months ago. The first author was Joe Taylor, and I was the co-senior author along with Mike Fox. And the fundamental thing that we found was with the best possible TMS protocol we can think of, which involved high-dose treatment, 10 treatments a day over five days, 60% of the time we get people better with only one week of treatment, even without image guidance, and that's consistent with the literature.

But when we added image guidance, that outcome went from 60% to 80%. In other words, instead of three out of five people, we were getting four out of five people better. So, one out of five is a lot, because that means that for every five people we scan, we get one person better. That's pretty good compared to a lot of the other interventions that we have in medicine.

For example, to save one person with mammography, we have to scan over 100 people. Similarly with lung cancer screening, things like that. So, that effect size was quite favorable relative to a lot of the other types of scans that we do in medicine. So, that was the big exciting finding from the perspective of a clinician is that the added value of a scan was pretty large.

Melanie Cole, MS: Yes, that's so interesting. Now, historically, TMS has been viewed primarily as a treatment for depression. How is our new understanding of brain circuits expanding its potential role for anxiety, other psychiatric conditions like bipolar disorder here at Northwestern Medicine?

Dr. Shan Siddiqi: So, we've spent a lot of time thinking about how we can take these victories that we've had for depression and apply them to other disorders. TMS works really well for depression, but there's been a lot of inconsistency around how to apply it for other things.

And so, what we did was we tried to reverse engineer why it works for depression and it turns out that if we study people who had a stroke that caused depression that gives us the same kind of localization as stimulation sites that relieve depression. Then, we applied that to anxiety, to Parkinson's disease, to a lot of other disorders, and found the same thing, that if you look at the network of regions as disrupted by a stroke that causes a symptom, stimulating the same region can also relieve the same symptom, even in somebody who doesn't have a stroke.

That's a useful model, because stroke is so common that if you walk into any hospital, you'll find a few patients who have a stroke at any given time. So, we can study those patients to learn more about people who have the same symptom without a stroke. Stroke or any other types of brain damage.

Based on that, we've now developed essentially an atlas of where you would stimulate for depression, for anxiety, for OCD, for bipolar disorder, for mood regulation, mood stabilization, for psychosis, for addiction, all these other things. Some of these things have been shown to work in clinical trials. I just told you about the clinical trial in depression that was targeting one of these lesion-derived depression circuits. We also recently finished a clinical trial for anxiety with a lesion-derived anxiety circuit, and that also worked. It turns out that if we target the optimal anxiety target as opposed to the optimal depression target, it works way better for anxiety. And in that case, the response rates went from 38% to 70% just by targeting the optimal location in a head-to-head clinical trial.

Similarly, we can now apply that to other disorders, but the clinical trials still need to be done. So, you asked me about clinical trials. We're now getting ready to launch those clinical trials at Northwestern Medicine across a wide variety of disorders including bipolar depression, anxiety disorders, PTSD, Parkinson's disease, dystonia, and we're going to be expanding those opportunities for patients with other disorders also.

The goal is to make Northwestern Medicine, like the MD Anderson of cancer, but for clinical neuroscience, to make it the place where you can go to have a clinical trial for almost anything.

Melanie Cole, MS: Well, it is exciting when you see a modality such as this being expanded to include a larger swath of conditions and disorders. Now, speak a little bit, Dr. Siddiqi, about patient selection. Which patients are most likely to benefit from image-guided TMS? And what should referring psychiatrists look for when they're considering a referral? Are there patient populations who may benefit disproportionately from personalized targeting, some who will not?

Dr. Shan Siddiqi: We think that the patients that benefit most from personalized targeting are the same as the patients who benefit most from TMS in general. It doesn't seem like there's a particular patient population for whom personalized targeting is particularly good. I think there probably is a population like that, we just haven't found it yet.

So right now, for a referring clinician, I would recommend anybody who has treatment-resistant depression, has tried at least two antidepressants and hasn't had benefit, that's a good TMS candidate. If somebody's tried two or three medications, the chance of responding to the third or fourth medication is less than 20%, probably less than 10%. For that same patient, the probability of responding to TMS is more than 50%, and with image guidance, that probability seems to go up even more. So for a referring clinician, I think anybody with depression is a good candidate.

One conception that's existed in the field is that TMS works better for people who don't have anything other than just pure depression. So, people with addiction, people with personality disorders, people with OCD, people with a lot of anxiety have often been thought of as not the ideal candidate for TMS. Our recent studies suggest that's actually not true. It turns out that people with personality disorders, along with depression, respond just as well to TMS as people without personality disorders. People with bipolar disorder respond just as well, perhaps even better. People with comorbid anxiety disorders also respond just as well, perhaps even better, but only when we choose the right target for comorbid anxiety.

So, if there's one thing that I would like the referring clinicians to learn, it's that most patients who haven't gotten better with medications actually are pretty good TMS candidates. We don't have to be very selective about it.

Melanie Cole, MS: Well, thank you for telling us about that. That's really great to learn. So, how do you envision integrating image-guided neuromodulation into Northwestern Medicine's broader interventional psychiatry program, including existing TMS, ketamine, ECT services? Tell us how you're going to put all this together bench to bedside.

Dr. Shan Siddiqi: Yeah. So between the downtown main Northwestern Medicine Hospital and various collaborating clinics around the metro area, especially downtown, the goal is to offer image-guided high-dose accelerated TMS, which packs the whole treatment course into five days both clinically and in clinical trials.

One reason why we do both is because not everybody has insurance coverage available for these advanced procedures, and the treatments can be quite expensive if you don't have insurance coverage available. Of course, if somebody wants to pay for it out of pocket, we're happy to figure out how to work that out for them. But we also want to have an option available for people who don't have insurance coverage, which is most insurances, and people who can't afford to pay out of pocket, which is most people.

And so, within the interventional psychiatry program, what's going to happen is physicians who are broadly trained in all these different modalities. They'll know how to get a patient into the right clinical trials or how to get them into the right clinic. And that'll be available for everybody. We're also starting a training program for psychiatrists who want to spend an entire year learning how to subspecialize in interventional psychiatry and brain stimulation. We're going to take our first trainee next summer, and we'll be one of the first few accredited fellowship training programs in brain stimulation.

So, it's going to be a robust service involving, again, education, research, and clinical services. But from the patient perspective, what that means is there will be an option for hopefully almost everybody.

Melanie Cole, MS: Such an exciting time in your field, Dr. Siddiqi. And looking forward, do you think psychiatry is moving toward a future where brain imaging and circuit mapping routinely guide treatment decisions? What role do you see Northwestern Medicine playing in that evolution? And what would you like the key takeaways from this fascinating discussion today?

Dr. Shan Siddiqi: Yeah. So, that's definitely the goal. The goal is, like I said at the beginning, to make all psychiatrists want to learn a little bit about clinical neuroscience. Right now, it's not a mandatory part of psychiatry training because it doesn't directly influence day-to-day care. When it starts directly influencing day-to-day care, people will want to learn about it.

And so, I do envision a future in which every psychiatrist at least knows how to use TMS broadly, and that we have a broader range of subspecialists in brain stimulation who all know how to use image-guided treatment when the regular things aren't working.

The role that Northwestern Medicine is going to play involves all three of those components that I mentioned: the clinical part, the research part, and the educational part. Like I said, we'll be one of the first accredited fellowship programs in this subspecialty. I'm actually leading the national effort to get this accreditation. So, I'll make sure that we have the best at all times. We're going to be leading this broad-scale clinical trial that enrolls people across all types of neuropsychiatric disorders that doesn't exist anywhere else.

At most places, if you go to the hospital, odds are you don't qualify for a clinical trial in psychiatry. We're going to do it differently here. Odds are that you will qualify for a clinical trial, because the clinical trials will be broadly inclusive. That's thanks to the help of our philanthropic supporters, the Daughton Behavioral Health Institute from the Daughton family and the Steven Stahl Center for Psychiatric Neuroscience, thanks to the Stahl family. They've given us the funding and the opportunity to launch clinical trials for almost everybody.

And from a clinical perspective, it means that when a new cutting-edge treatment gets to the point where our doctors think the scientific evidence is strong enough to start offering it to patients, we'll be the first place where it'll be available.

Melanie Cole, MS: Wow. Thank you so much, Dr. Siddiqi, for joining us today and sharing your incredible expertise for other providers, and we're so glad that you could join us. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/psychiatry to get connected with one of our providers. And that concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.