Welcome to our Neuroscience Neuromodulation Treatment for SUD session. And I'm Jiabei Wan from NIDA. I'm the co-chair for this session. So Will is not here, Will Eklund, so I will be solo. And for today's session, we are talking about the most recent advance in neuromodulation. We are so lucky to have three outstanding clinicians and scientists to highlight their recent research data and to show how neuromodulation, a promising approach for neurological or psychiatric disorders, especially for substance use disorder. Due to the time, I will not give too much on the background. However, I just want to make everybody aware of our arrangement. So we have three speakers, and each one will have 25 minutes or less. And then at the last 15 minutes, we will leave the time for Q&A. So all the questions will be saved for the end. And our first speaker is Dr. Ali Rezai. And I'm sure you probably all know Dr. Rezai. And he is the vice dean of neuroscience at West Virginia University and also the director of Rockefeller Research Institute at WVU. And he is an outstanding researcher, has been focusing his research on neuromodulation for many neurological disorders, including SUD. And he is NIDILRR grantee, a Hill-supported grantee. And just last year, Dr. Rezai was awarded a Hill Excellent Researcher Award. So without further ado, let's welcome Dr. Rezai. Good morning, and thank you very much for the kind introduction. And I want to thank Nida Norovolka, Will Acklin, Jai Bei, Wang, and other colleagues who have been instrumental in accelerating this research. So thank you. Can you hear me OK? Yes, thank you. OK, very good. So I'm going to speak, if I can get this going here. Good, OK. So I'm going to speak about the work that our team has been doing for the past almost six years, looking at deep brain stimulation of the nucleus accumbens and focused ultrasound technologies recently for patients with substance use disorders. So many of you are experts in the audience, so addiction is a big problem, substance use, alcohol, and drug use, and then the growing problem with opioid and other overdoses of 110,000 deaths in 2022. And Lancet article said that these numbers are likely to double by 2029. And then there's the behavioral addictions, the social media, sports gambling, eating disorders that are really increasing in numbers. And current treatments, medications are available, supplicate, suboxone, methadone for opioid, but there is no medication available for cocaine or for treatments of meth. For opioid addictions, despite these good treatments, less than 50% can be successful over time, but people with severe addiction and those severe addictions also leading the 28-day residential program, 75% can relapse within one week of discharge. So clearly, there's a need for other options for helping these individuals. So neuroscience has really developed a lot of options for targeting using neuromodulation in the brain. There are a number of nodes that can be targeted with transcranial magnetic stimulation or transcranial direct current stimulation. Deep brain stimulation for the deeper structures and focused ultrasound. So the focused ultrasound, DBS, can target deep structures like the accumbens, eight to nine centimeters deep into the brain. And that's an area that we focused our efforts with deep brain stimulation and focused ultrasound. So with deep brain stimulation, these are brain implants. 250,000 patients have had it worldwide for Parkinson's and tremor and epilepsy and OCD. But with regards to accumbens and DBS, a handful of cases published in Germany and in Europe and in China that have showed with DBS of the accumbens itself, you get improvements in opioid, alcohol, and cocaine addiction with safety and reduction in substance cravings, but the numbers are small. We decided to start looking in the US for the deep brain stimulation, and that was a NIDA HEAL award to our team. We got FDA and IRB approval, and looking at safety and feasibility of an open-label study, looking at individuals with severe primary opioid use disorder with comorbid use of other substances, and they have failed multiple treatments, inpatient, outpatient, residential, and multiple overdoses. This first group of patients, on the average, there were four individuals that had five to 11 overdoses and multiple different substances, and time since their last use before being admitted again was one week, so they are really treatment-resistant individuals. The target in the brain is a target that's similar to the OCD target that's FDA-approved, but in this case is modified for addiction to get more of the accumbens, and this is the nucleus accumbens and ventral anterior internal capsule, and this target is stereotactically by anatomical and tractography localization. Tractography allows you to get ventral medial prefrontal cortex connectivity. The results, I'm gonna play this video, hopefully the video will play. This is looking at acute craving and the individuals in surgery, and is looking at visual cues and rating their scores for different substances. Craving for heroin, 100 being the most. Can you hear? Give it a 25, honestly. Okay, that's with implant on. How about opioids? Before? Same, about a 25, 30, yeah. How about benzos? Benzos, we'll still give it a 50. So very acutely, you can get acute reduction of multiple substances immediately with deep brain stimulation. So the results of these studies, this is a NIDA-sponsored study, DBS is well-tolerated, no serious adverse events. We saw reductions in craving and anxiety in all participants. Two had complete abstinence with these many days, and the FDG-PET revealed increased glucose metabolism in the frontal region with abstinence, but numbers are small. One participant had reduction in use, but did have recurrences, and this individual's discontinued three years later due to protocol fatigue and noncompliance, and one participant was explanted due to noncompliance persistently. So with the summary of this was that DBS is safe. It's been used 30 years across different areas, but results are encouraging, but it's an invasive brain surgery procedure. It requires significant time, follow-up from maintenance, management, programming device, and recruitment and compliance are very significant challenges, so scaling is limited. We decided to observe and see if we can do focused ultrasound and that is a non-invasive procedure, non-surgical outpatient procedure. The most standard application is for tremor and Parkinson's disease. 15,000 patients have had it, and that does a small thermal lesion in the thalamus, for example, that's FDA approved and Medicare reimbursed in the US and CE approved in Europe. The second application, not FDA approved, is opening the blood-brain barrier for targeted delivery of antibodies for Alzheimer's, chemotherapy for brain tumors and ALS and others. It's a very active area of exploration. That's not approved. That's non-lesion, but open the blood-brain barrier, and the third application we'll talk about today is neuromodulation that allows you to engage in these circuits that are abnormally functioning to modify the circuitry. So let's talk about that. So the technology we used is this Insitec system. That's the one that's FDA approved for tremor. In this case, you're lying on an MRI and a helmet comes over your head. This helmet has over 1,000 ultrasound probes that it can beam those probes deep into the brain, into the area that you prescribed to stop the tremor or to neuromodulate or to open the blood-brain barrier, and that's been done in 15,000 patients worldwide with this. So this is FDA approved for tremor, but it's not approved for neuromodulation and blood-brain barrier opening and also other applications. So let's talk about neuromodulation. A lot of studies for addictions, TBI, depression, anxiety, PTSD, chronic pain are underway. We wanted to explore substance use disorders. We used the Insitec helmet that we have 10 years of experience with with 1,000 ultrasound probes. Keep in mind, one ultrasound probe looks at a baby in a womb or in the heart. This is 1,000 of them that can be beamed. The beam travels through your hair, through your scalp, through your skull, goes through your brain, and wherever it's focused, that's the area that's exerting its neuromodulation, not outside, so it's a precise area a few millimeters in dimensions. And it's not a lesion, so we're not burning. We're not giving high energy to burn the area. This is a neuromodulation. So this pilot study that we did, first we wanted to understand the dose. It was never done before, so we wanted to understand a unilateral nucleus accumbens ultrasound. We did a safety, dosing, and target determination, and we determined that it was safe and well-tolerated from a safety perspective and targeting of the same structure we target for DBS for several years. And then that led to the open-label study, which has now 20 patients, and that was looking at the safety and tolerability of bilateral accumbens ultrasound in opioid use disorder and comorbid SUD through 90 days. And looking at substance craving, substance use, and functional MRI connectivity was the secondary outcome. And eligible criteria, people from the 28-day residential program, multiple treatment failures, primary opioid use disorder, and they have to be on medications, methadone, supplicate, or suboxone for the opioids. And this is a FDA study, and sponsored with this supplement from NIDA. And this is the first patient published in biological psychiatry from this, and a follow-up report should be published under review now. So the procedure. So this is the ultrasound for open-label study design. We do a baseline screening, and we do safety assessments, cue-induced substance craving visual cues, or you can do tactile cues, smells, sounds, but we picked visual cues. We have a lot of experience with that, and we looked at mood, emotions, cognitive functioning, and functional imaging, functional MRI, and substance use, urine talks. And cue-induced is done baseline before, it's personalized with neutral cues, or individuals that have specific cues that gets their cravings active. So that's an important aspect of this. Then what we do is we do the baselines. This is during the treatment session, and we did the baselines, and then we did a sham of five minutes while they're seeing the cues in MRI with a goggle, and they can hear sounds. And we're showing neutral active cues and increasing the anxiety and the cravings for their drug of choice and other co-drugs. Then there's a sham and then we go to an active treatment. And then during active, we're delivering ultrasound and then we're monitoring all these elements at baseline and multiple time points during the treatment then follow up after the treatment. It's a one treatment, 20 minutes. That was the treatment session. Okay, so this is the MRI and this is the ultrasound system with 1,000 probes. It's outpatient, one hour procedure. You put a head frame on or a dental mold so the patient's head is immobilized and then we target the nucleus accumbens anatomically. The target box is five by five by seven millimeter dimensions and is refined by tractography to the ventromedial prefrontal cortex. And we do personalized cues and you can see in this case, meth for this individual and then when the cravings are high, that's when we deliver the ultrasound. Sham and then treatment, one hour procedure and then they get off the table and are followed up. The characteristics of the first eight participants written for report, 90 days, average number, median of four overdoses. They've used heroin and fentanyl 14 years. Median use of heroin, fentanyl and also prescription pills. Also comorbid substances with this primary OUD. Nine years median meth use, 19 years median cocaine use, 18 years benzos, alcohol 23 years. So these are individuals in adolescence started and then continued for years. And they were treatment resistant. So what's the safety and tolerability of this cohort? Assessed during the procedure, immediately and afterwards. We saw no unexpected AEs or procedure related SAEs throughout the 90 day primary endpoint during or after the procedure. And no change on the MRI imaging, no swelling, no hemorrhage and no other adverse events with the MRI performed at multiple times. What about behavioral and functional outcomes? No worsening of depression, anxiety, HRSD and then the CSSRS was used and then we looked at the SHAPs and the neuro quality of life. We want to make sure that we're not knocking out the incumbents, that these individuals have still functioning with respect to their eating and pleasurable behaviors and their anxiety and mood. And we did not see any elements of safety with these measures. What about the cravings? So that's important. Our goal was to reduce the cravings like we see with the deep brain stimulation and at least try to deal with that aspect that contributes to the bio psychosocial component of addiction to try to help reduce the cravings through the incumbents neuromodulation. These are box plots as the opioid craving, just the median craving for this cohort looking at baseline and then day one, seven, 30 and 90 and there was high cravings for opioid and then a 20 minute ultrasound procedure and the effects were consistently immediate reduction the next day much more and this persisted over time which was interesting to us with just one treatment of ultrasound reduced the cravings for opioid in this severe cohort. What about meth, cocaine and benzos? They all had that as well and we were also surprised to see similar one dose of ultrasound to the incumbents resulted in very significant reductions in the median scores of their cravings for meth, cocaine and benzos and then how about cannabis, alcohol and nicotine? Same, nicotine being most resistant and we all know it's difficult and so that's the results. What about the looking at depression and anxiety? Well, these are the box plots, you can see median for depression and anxiety for this cohort and then after the procedure so there were improvements, reduction in anxiety and depression. How about substance use? Those that was all cravings that was reduced so we did urine tox assessments throughout the procedure and we found that five out of the eight during the different time periods were completely abstinent. These people had multiple failures usually within a week and 10 days and those that had relapses, it was often isolated and a very significant reduction in their relapse rates or substance use and it was a lot of psychosocial elements, their environment that was really contributing to that but these are the results from the urine tox. How about subjective outcomes? So this is in general what they said, every one of them that was in the MRI immediately after the procedure, they could not connect to the cues anymore. So those cues that were driving them and high anxiety and wanting the drug and in the MRI when they got the ultrasound, every one of them said that I'm not connecting to it, it doesn't make sense, the picture of heroin or cocaine or these pills. It was an interesting phenomenon that's very consistent and decrease in cravings and familial settings and also some had reduced thoughts and dreams. That was a big driver, the dreams for the addiction. Those have also been very significant, reduced or completely resolved. And then social life, stable desires, as I said, we did not want to knock out the accumbens so we did not see any effects on food or other pleasurable activities. They went back to work or back to school. So so far it's promising and more involved in family, work and education. One individual has a CPS taking their child away and they gave the child back from the CPS to the participant after the treatment. Here's some examples. Do you have a few minutes to show some videos? Yes? Okay, so hopefully this will break. This is a patient, two patients talking about the cravings before and after the procedure. Let's see if this works. Before the procedure, I would see them cue cards and I would think, oh, it'd be nice to have that or I remember, you know, like this things of where I used that drug last or how I did or somebody that I lost on that drug. And then after the procedure, it was just like, I felt bad for the person that I was to be in that situation. And I could not connect with the photos anymore. Like I'm trying to elicit some type of feeling that I knew like previously would excite me or entice me to use and I really just couldn't connect with it. And then this is talking about the feelings afterwards. Let me see if this video plays. Yeah, I think this is like an extra tool for me. You know, the end all, be all. Like I said, it's not a procedure that like cured addiction and now it's gone forever. It's part of, you know, the basket of tools that now feeling a little more stable when I'm able to reach for the other ones. That lifestyle that I lived, it's not even really a distant memory. I mean, I remember it. I remember doing it and waking up every day and chasing it and just, but I don't remember the urge or the need or the desire to want to do drugs. So a very important thing, this is not a cure. This is a reduction in the cravings and it allows the therapist and the psychiatrist and the peer recovery support specialist to be more empowered and taking care of them. So this case will fail. I mean, in fact, if there's no system for continuing treatment, we will reject patients for the study. So you need this continuous coordinated care of individuals more so than ever, because many of these individuals have been living with addiction for 20, 30 years and they don't know how to live otherwise. So you have to start engaging the system to teach them how to live without these having cravings. So that is critical. Otherwise it will not succeed in our opinion. Continuing on here. And how about functional MRI? This is active area. I'll give you some initial results. So what happens in the brain physiologically? There's functional MRI PET scans and others, but I'll show you some resting state functional MRI looking at the nucleus accumbens target connectivity, functional and connected to the rest of the brain. And that was the CIDIS bilateral accumbens. So what we're seeing is that over time, when you compare to the different parts of the brain and some of the reward circuitry, we've observed numbers are small, so we need more, I wanna be cautious about that, but reduction in the anterior cingulate and the posterior cingulate cortex, and then also ventral medial prefrontal cortex as compared to baseline. So it seems that there is decrease in functional connectivity in the brain's reward circuitry and then cognitive control systems are engaged. This needs to be further determined because we're getting more subjects. So in summary, bilateral ultrasound, it's safe and well tolerated with no AEs or procedure related SAEs. We see immediate reduction of cravings after one 20 minute treatment. Reduction was not observed consistently with the sham placebo. I'll talk about the next study. And then reductions in cravings, which was surprising to us, the one time treatment resulted in sustained reduction in cravings ongoing. That was really the most dramatic results that we saw. And the cravings reduced from meth, cocaine, benzos, cannabis, also a sustained reduction. Alcohol, nicotine was the most difficult. And substance use during talks, five of the eighth have remained completely abstinent despite having multiple failures before. No adverse reductions in natural reinforcing eating and pleasurable activities. It's not a lesion of the incumbents. And we saw improvements in self-reported depression, anxiety, and behavioral improvements observed by both the research team and the participants care providers. Next steps, long-term follow-up assessment right now. And we have now, this is open label. So we have now initiated the randomized placebo-controlled sham trial sponsored by NIDA, looking at enrollment and first participant in the next two weeks. So 15 patients sham, 15 patients treatment, 12 weeks, and then we cross over single to see what the effects are. And we need to understand what the mechanisms are. We can talk about that later. Why is this one 20-minute session causing this profound change in cravings? So overall summary, both DBS and ultrasound may have a utility as an adjunctive treatment. It's not a single cure. It needs to be an adjunct, critical point. For OUD and other substances and reducing cravings at use, DBS is effective, has limitations because it's a surgical procedure, requires an implant, a long-term maintenance management. We think ultrasound is preferential because it is non-invasive outpatient procedure. But we need more research to understand the underlying mechanisms and treatment parameters and many other elements. Nothing is done without a team. So Dr. Mahoney and Dr. Finnemore's in the audience right there. We can talk to them later. They're the backbone of the team. And it's really psychiatrists, psychologists, neuroscientists, MR physicists, neuroradiologists, neurosurgeons, clinical trial specialists, and of course the generous support of our donors and also the support and guidance from the NIDA team, Drs. Volkow, Walton, Acklin, Wang, and Wong. So thank you for your attention. Thank you. Thank you, Dr. Rezai, that's a fantastic talk. Our next speaker is Dr. Mary Lee. She is the Chief Psychiatrist and also Director of Neuromodulation Program at Washington, D.C., VA Medical Center. And her research is supported by NIH HALE Initiative and NIDA. Now let's welcome Dr. Lee. Thank you, Dr. Rezai. Okay, well, thank you, Jaibeh, and thank you to Will for arranging this symposium. It's an honor to participate. I'm going to talk today about an ongoing study that we're doing at the Washington, D.C. VA using low-intensity focused ultrasound as a potential treatment for complex patients who are at high risk of opioid overdose and death. So who are these complex patients? This is an analysis of opiate overdose deaths in Medicare recipients age 21 through 64 across three categories of disorders, psychiatric disorders, substance use disorders, and chronic pain disorders. And as you can see here, the group with all three of these disorders had the highest rates of opioid overdose deaths, 23 times the rate in those with none of these disorders. And patients with this clinical triad of disorders accounted for almost 50% of the overdose death rates in this population. So the question is, beyond the usual approach of adding treatments for each individual disorder, can we target, use non-invasive brain stimulation to target neurocircuits or nodes in neurocircuits that are common to all these three disorders? So remarkably, from task-based fMRI studies, we can see here that the anterior insula is activated in all three of these disorders during disorder-relevant tasks. So for patients with anxiety disorders during fear conditioning tests, the anterior insula is activated to a greater degree than match controls. For patients with chronic pain during laboratory measures of evoked pain, the anterior insula is activated more than match controls. And then finally, in patients with opiate use disorder and substance use disorders in general, the anterior insula is activated in response to Q-induced craving more than controls. So we designed a study, and the study is funded by NIDA. It's a UG3UH3 grant. And the aims in the first part of the grant are to assess the safety and feasibility of using low-intensity focused ultrasound to target the anterior insula in this complex patient population with opiate use disorder, chronic back pain being the most common site of chronic pain, and anxiety disorders. The outcomes are safety outcomes, adverse events, clinical changes, repeated structural MRI exams, and then feasibility measures, successful study recruitment, retention, and completion. The second aim will be to get a sense of whether targeting the anterior insula with focused ultrasound in this population has any effect on laboratory measures of pain, evoked pain, and opiate-Q-induced craving. So we'll measure pain thresholds, measures of central sensitization such as condition pain modulation and temporal summation of pain. We'll measure response to opiate-Q-induced craving, again, as Dr. Rezai mentioned, using personalized opiate Qs from a validated set of Qs. And we'll also be measuring heart rate variability, which is relevant to anxiety disorders, both during and after the LIFU and the laboratory procedures. The patient population will be veterans aged 21-65. We'll be recruiting 20 veterans at the Washington. We're planning to do this at two sites. It's ongoing at the Washington, D.C. VA and we're planning also to add in the Salem VA. Patients will have chronic back pain, current opiate use disorder, a current DSM-5 diagnosis of an anxiety disorder. They'll be in treatment with buprenorphine or methadone. And we're going to exclude other substance use disorders other than opiates and tobacco. And we'll also exclude current psychotic disorders, severe medical disorders, and contraindications for MRI. The study design is a double-blind within-subject sham-controlled study consisting of four visits. During the first visit the patients have a brain CT and MRI. And this is used to plan the targeting using the focused ultrasound. We calculate from these measures, from these scans, the focal length, the degree of skull attenuation and skull distortion so we can make sure we're delivering the dose that we need to deliver at the target. Then that's followed by two visits, counterbalanced. One visit is real focused ultrasound, the other visit is sham-focused ultrasound. We do the pain measures and cue reactivity before and after the focused ultrasound and sham sessions. And then this is followed by a fourth session where we follow up with another structural MRI and clinical assessments. So this is the study design. Having described that, I just wanted to talk about a few issues related to the focused ultrasound treatment itself. Just to remind everyone, we are administering ultrasound, which is not audible. Ultrasound is greater than 20 kilohertz. The frequency of ultrasound that we use in our study is 500 kilohertz. I think, Dr. Rezai, you used 220 kilohertz, right? And then as Dr. Rezai mentioned, the biological effects of ultrasound, depending on the intensity that you deliver, can range from thermal ablation to neuromodulation. We're delivering low-intensity focused ultrasound. So we are aiming for not thermal ablation, we're not blood-brain barrier opening, we're not using micro-bubbles, but neuromodulation. And I included this slide just to show you the range of devices that are in use for, the diverse devices that are in use for delivering focused ultrasound. On your left, you can see the device that Dr. Rezai uses, the InSightech device with over 1,000 elements, allowing for exquisite spatial targeting of the ultrasound. And then there are these other devices here, implantable devices that can be used for repeated blood-brain barrier opening. And then the one down there in the middle is the device that we use, just a small handheld transducer, four elements as opposed to 1,000 elements in the InSightech device. So this gives you an idea of the range of devices that are being used. And the mechanism of action of focused ultrasound is thought to be, this is an area of active research, but it's thought to be a modulation of mechanosensitive channels in the cell membrane and perhaps a direct effect of ultrasound on the lipid bilayer itself. So part of the title of this symposium is Target Engagement. So I wanted to talk about how we are experienced with targeting the anterior insula with focused ultrasound using neuro-navigation. We use the BrainSight device, which was largely developed to aid in TMS targeting, may be familiar to some of you in the audience. The BrainSight device involves co-registering a patient's MRI and the patient with anatomical markers. So the ears, tip of the nose, nasion, so that the patient is registered in space with their MRI. Then we target wherever you want to deliver the non-invasive brain stimulation. In this case, we target the anterior insula as shown here in the lower right. And then the device also allows you to mark where you're going to put the transducer on the surface of the head. So it defines a trajectory from your target on the MRI out to the surface of the skull where you place your transducer. And to target the anterior insula, we are going through the temporal window here, which is actually the thinnest part of the skull, which is important for reasons that I'll explain. And then this figure in the middle, this image in the middle, shows you the actual ultrasound beam that is targeting the anterior insula at focal lengths of about 30 to 40 millimeters, which is where most people's insula is. We can get a resolution with this transducer, four element transducer, of about 10 millimeters in axial length there and about a diameter of about six millimeters. So beyond targeting, how do we decide what stimulation parameters to use for focused ultrasound? And this is also an area of active research, and it's kind of where the field of TMS was several decades ago. We chose our stimulation parameters based on previous focused ultrasound studies that examined changes in motor evoked potentials using TMS. So there have been several focused ultrasound studies showing that when you target the motor cortex and then measure the motor evoked potential from a single pulse TMS stimulus, that there are certain parameters of focused ultrasound that actually reduce the motor evoked potential. So basically, I'm showing here a recent study by Zadeh that uses focused ultrasound in concert with single pulse TMS and measures the evoked motor potential. And what they did here was they varied the pulse repetition frequency of the focused ultrasound to see which pulse repetition frequency optimized the reduction in motor evoked potential. So on the top here, you see that the stimulation is kind of like a continuous theta burst protocol where you deliver a high frequency stimulation. In this case, it's our fundamental frequency of 500 kilohertz. So you deliver that in bursts at a certain repetition rate. They use three repetition rates here, 10 hertz, 100 hertz, and 1,000 hertz. And then the other parameter in focused ultrasound that's very important is the duty cycle. So you deliver these pulses, but then you actually deliver the ultrasound in only a fraction of that pulse. So in this protocol, the duty cycle was 10%. So for example, for a 100 hertz pulse repetition frequency, the period is the inverse of that or 100 milliseconds. And then the ultrasound is on for only 10% of that or 10 milliseconds. And then that is continuously pulsed over two minutes. And then the intensity and the time averaged intensity of this protocol is below the FDA guidelines for diagnostic ultrasound, which is an important safety consideration. So these are the results of this motor evoked potential study shown here. And what you can see is that over an hour after the focused ultrasound, the pulse repetition frequencies of 100 hertz reduced. There was a significant reduction in motor evoked potential over an hour post-stimulation. So that's the parameter that we chose to use in our studies because we needed an hour window to perform our outcome measures. And we have experience with some of our outcome measures and targeting the anterior insula in healthy controls. This is a study from Dr. Ligon's lab, our collaborator in the grant. And he demonstrated that targeting the anterior insula in healthy controls results in a reduction in pain, perceived pain. This was a trend effect in healthy controls. And then in terms of heart rate variability, targeting the anterior insula resulted in an increase in heart rate variability, which is relevant to anxiety disorders. If you have an increase in heart rate variability, there's evidence that that represents an engagement of the parasympathetic nervous system, which is anxiolytic. So the last two issues I wanted to talk about were the efforts we go through to target and to make sure that we're dosing correctly at the target that we've chosen for the study. And a barrier to that is the skull. The skull reduces ultrasound transmission. It reduces the energy, the level of energy delivered to the target. And it also distorts the beam. And this, as you can see here, so with increasing skull thickness, there's a decreased transmission of ultrasound energy. And there's also a more pronounced distortion of the beam. And different parts of the skulls have different thicknesses. And as you can see here from these three different human skulls, there's a lot of inter-individual variability in how skulls transmit ultrasound. So we put a lot of effort with this four-element device we have to doing modeling beforehand to make sure that we measure each person's individual skull attenuation. And then we can make sure that we're delivering outside the head enough energy to take into account each person's skull attenuation so we know that we're delivering the adequate dose or the planned intensity at the target. And then the other issue with focused ultrasound is the auditory confound, which has been reported in several studies. So basically, obviously, the 500 kilohertz fundamental frequency is not audible. But these pulse repetition frequencies that the fundamental frequency is modulated at being 100 hertz, 1,000 hertz, that is audible. And you can actually hear. It's subtle, but you can hear the pulsing. So that confounds. That's a confounder. It confounds the sham condition, obviously. So what we do to experimentally to mitigate that is to deliver a masking noise that's matched to the pulse repetition frequency that we're using. And we deliver that before, during, and after, you know, across the delivery of the ultrasound and sham. So for example, for our study, we deliver 100 hertz masking sound. And that, in this Brown study that's shown here, that reduced the detection of real versus sham to chance. And also for offline studies, it's less of an issue. So basically, if you're doing your outcome measures, you know, apart from the delivery of ultrasound, it's less significant a confound in general. And then lastly, the safety of focused ultrasound to the insula is what we, the data that we have from 35 patients between my lab and Dr. Levon's lab is shown here. All this represents, as I said, 35 patients, about 150 sessions of focused ultrasound and 80 sessions of sham. All the effects were mild. There were no moderate or severe adverse events. The side effects are mostly sleepiness and tiredness that is transient. It goes away in about an hour. Some scalp discomfort, headache, balance difficulties, some tingling, paresthesias. And the actual difference between these symptoms, between focused ultrasound sessions and placebo and sham sessions was not significant. So as I said, our study is ongoing. And hopefully next year, we'll be able to give, report some data. So I wanted to thank my team at the Washington DC VA and our collaborators, Dr. Levon's lab at Fralin Biomedical Research Institute at Virginia Tech and at NIDA and at Georgetown University Imaging Center and at George Mason. And thanks to our funding sources, the NIDA HEAL Initiative and to the Veterans Administration Office of Clinical Sciences Research and Development. Thank you for your attention. Thank you, Mary. That's an excellent talk with a lot of technical details. And our next speaker is Dr. Elliot Hong, and he is a psychiatrist and also professor at the University of Texas Health Medical Center in Houston. And he also is the director of Houston Psychosis Research Center. And Dr. Hong's research is focused on brain imaging and neuromodulation for schizophrenia and also substance use disorders. Let's welcome Dr. Hong. How do I close this slide? Yes. This slide. Thank you so much. Thank you, Jave, for organizing and for the kind introduction. So we switch gear a little bit to TMS. So these are my disclosures. The funding are mainly from NIDA, and the many collaborators for this study. The main person is Dr. Michael Du, he did most of the TMS and imaging part of the study. So it's a quick introduction about smoking, that this is for my CDC. Cigarette smoking remain the leading cause of preventable disease, disability, and death in the United States. Smoking costs the United States hundreds of billions of dollars each year still. The state do not spend much of the money they got from tobacco taxes and lawsuits to prevent smoking and help smokers quit. In 2021, there's still 11.5% of the U.S. adults, about 28 billion people currently smoking cigarettes. Now obviously there's a quickly emerging scene of vaping, nicotine, and e-cigarettes. So in 2023, CDC reports those used, average reported e-cigarettes, approximately half reported currently using them, indicating that what's coming down is that many youth who try will continue to use them. So this is the second slide to go into smoking in schizophrenia, why do we focus on that? So I don't have a very recent national survey on smoking in severe mental illnesses. So this is, I thought it's a very good study, over 1,000 people surveyed. So it's from about year 1999 to 2016. The top is the people under age 30, below is over age 30. So this is three groups, schizophrenia, bipolar, and neuropsychiatric disorders. I want to first focus on the top slides on the solid line, okay? So in about 20 years, healthy non-psychiatric disorder people, the smoking rate is down from about 30-some percentage to now about 11 percentage. Now we should see this as one of the most major public health achievement in our country, which is that reduction of smoking in the general population. Now let's look at the bipolar disorder. This is small reduction, okay, it's about 30-40% people smoke, but look at schizophrenia. After 20 years, after all these major public health campaigns, we still have a subgroup of patients, people in our society, they still smoke a lot, and more difficult for patients with schizophrenia to quit, and they smoke much more heavily. So why patients with schizophrenia smoke in this way, and why it's so hard for them to quit? Now there's a number of theory about that, like people think nicotine may help them to counter their cognitive deficits. There's some truth to that, but if you think about the chronic smoking schizophrenia patient, they continue to have a lot of cognitive deficits. So alternatively, we're thinking about overlapping circuit hypothesis. It goes roughly like this. Nicotine addiction is associated with a reward and craving-related circuitry, and schizophrenia also associated with multiple circuitry abnormalities. So maybe a dysfunction in certain brain circuit that increase the risk to nicotine addiction overlaps with those impaired by schizophrenia, and the overlap disposes patient to a much higher risk of smoking. So how do we cautiously test it? The idea is that if we can identify and then modulate the overlapping circuit, we should help schizophrenic patient to quit smoking. So this is the study. We tried this attempt on discovering the overlapping connectivity. The way we did it is that we first target the ACC. So you hear from the previous two speakers. They both speak to the importance of the ACC in many substance use disorders, and no difference for nicotine addiction. So what we first did is that we do resting state functional connectivity analysis, looking at the ACC as a seed and comparing to the rest of the brain and looking for connectivity. Here we just compare schizophrenic patient who are non-smoker and healthy control who are non-smoker. So we identify the brain functional connectivity, then marking the schizophrenia independent of smoking. Then we go to this side, on the right side. We're looking at, again, an ACC, but we're looking at the nicotine addiction severity using a Fagerstrom test for nicotine dependence, only in smokers without any schizophrenia. Then we find out the ACC related to a number of brain regions that indicate nicotine addiction severity. So on one side, we find a map to schizophrenia, another map to nicotine addiction. And if we're just overlapping the two maps, we identify a few regions that are actually overlapped. You can see on the green, underneath, several green regions marked. In particular, you can see that at the hippocampus, amygdala, ventral striatum regions. So these are the regions that we think may make a schizophrenic patient more vulnerable to nicotine addiction. So that's basically the illustration of that. You can see that it's not a single focal region. It's multiple regions in these areas between the ACC and the subcortical regions. We call it extended amygdala, roughly. So what do we do next? We try to basically, using brain imaging, to quote, unquote, dissect the extended amygdala. So you can see we divide them into a caudate, putamen, salamence, nucleus accumbens, amygdala, hippocampus. And now we use this as a seed. And looking for the whole brain connectivity, and see which connectivity is related to nicotine addiction severity. So in the figure B, so the top, say, hippocampus is basically saying that that's the seed. And we're looking for the whole brain. We find a few regions that are associated with nicotine addiction. We move to amygdala. We move to a substantial nomenclature, and then nucleus accumbens. So each map gives us a little bit of a different variation in regions associated with nicotine addiction. If we overlap all of them, we're a little bit lucky. We find one region. It's at the dorsal medial prefrontal cortex, right at the figure C. Basically, the functional connectivity between the DMPFC with many of the subcortical extended amygdala, they are weakened connectivity. It's associated with stronger nicotine addiction. So basically, if we plot this out, the x-axis is the resting state functional connectivity. The y-axis is the nicotine addiction severity. You can see that both schizophrenic patients, which is the red, and healthy controls, which is the black, the folks with a lower functional connectivity between the DMPFC with the extended amygdala, they will have a more severe nicotine addiction. So armed with this knowledge, we design a four-week, randomized, sham-controlled, radar-blinded trial using 10 hertz repeated TMS. So the idea is to enhance the functional connectivity by stimulating the DMPFC and see if we can modulate the extended amygdala function. So it's an empirically determined target using brain imaging. So we finished the first phase of the study, what NIDILRR called the UG3 phase. So in this study, we consented 44 people, randomized 30, 2 to 1, about 18 randomized to active, and 12 to sham. And we have 16 people completed the active, 10 completed the sham. But two people, we cannot use the imaging data. So we ended up with, for the imaging data, with 14 and 10. So this is looking at the demographics, two groups. So you can see the age is about the same. The gender ratio is about the same. They smoke about 20, 30 cigarettes per day. They are nicotine addiction severely, as measured by FTND, is about 34 to 42. Now this is a, we really mainly tried to understand the circuit. So we actually did not require people coming to study as treatment-seeking. So these are not necessary treatment-seeking patients at this point. But we do ask them to quit, but there are no other requirements. So most people did not quit in this short study. So only one in the active and two in the sham quit. But here's the results. So first looking at cigarette per day. You can see that the gray color is the baseline, the dark color is the end of the treatment. You can see that in the active TMS group, there's a reduction that's significant. In the sham, it also has a reduction. It seems not significant, but there is a smaller sample. And on the right side are the individual patient data. So you can see the sham, one of the things that one of the patients that smoked 40 ended up quitting. But again, it's a very small sample. That's the main caveat. So there's a lot of eccentricity in the data. Here's looking at the Fekerstrom test for nicotine dependence score. You can see again that there's a reduction in the active TMS. Here you can see in the sham there's no reduction at all. And you can also examine the individual patient data. Now the most important part of the study is looking at whether we can modulate the circuits. So the Y-axis is the dorsal medial prefrontal cortex to the extended amygdala resting state functional connectivity. And you can see that we were able to enhance the connectivity between this circuit using the active TMS. You can see that in the sham, actually when you don't stimulate it, except there's some sounds and all that, it's an actual reduction. This is the way to look at it across the timeline. So we basically have a baseline and then we scan them in first week and second week. We skip the scanning on the third week and we scan them again at the end of the treatment. So it's four scans per person. On the Figure A you can see the change of resting state functional connectivity. It's a subtraction from the baseline. If you look at the blue line, it's the sham. You can see that basically about the same and slowly reducing over the four-week period. But if you look at the active TMS, it's actually we can steadily increase, sorry about that, we can steadily increase the resting connectivity in this circuit using this mode of TMS. If you're looking at the effect on the FTND, nicotine addiction severity, again the blue line on the sham, you can see that it's roughly the same over the four-weeks period. But after two weeks or so, starting the third week, we're starting to see patient smokers reporting reduced nicotine addiction severity rating. And it's significant at week three and week four. Now the important question is that is the change in the connectivity related change in smoking behavior? So that's the key question, which is this last slide of the data. So on the C is the reduction of FTND morning smoking score. So for those people who are familiar with FTND, the six questions, three of them are related, how severe, how frequent, how heavily people crave a cigarette when they first woke up. And the x-axis, it's a change score or the connectivity. And you can see there's a reasonable correlation there such that those patients, they have more enhancement of the resting connectivity. They have a more reduction on the nicotine addiction severity reporting during the morning. On the figure D, it's looking at a reduction of cigarette per day, CPD. And you can also see that those folks have a large increase in resting connectivity. They report more reduction in cigarette per day. So the conclusion is that this early phase study enrolled and randomized 30 patients. Initial evidence demonstrated that the MPFC to extend the amygdala resting state functional connectivity engagement in active RTMS, which is superior over sham. And we found association between increase in this circuit connectivity and reduction in smoking consumption. So what we are currently doing is that based on what we learned from the UG3 phase, we are conducting the next phase of the project supported neither UH3 mechanism on 50 patients with a slightly modified design. We expect to complete it within the next two years. The other research directions, we are very interested, we know that it's unlikely smoking addiction is such a severe problem to solve. It's probably not controlled by a single circuit. So we are actively looking for other potential circuits that can serve as addition targets to more comprehensively helping patients. Obviously, with the e-cigarette become more prevalent, some of the patient also become addicted to it. I think it become a challenge. How do we, how do field deal with that? And maybe TMS also have a role in it. Those are some of the future directions we are thinking of doing. Thank you. Thank you, Dr. Hong, which is a very insightful talk and thanks to all the speakers gave us an excellent talk and also excellent control of their time. So now we have at least 25 minutes to have four questions. Please use the microphone if you have any questions. Hi, excellent talk, thank you very much. Any experience with gambling and this treatment? Gambling? Hi, that's a good question. So we have seen a few of our patients have had gambling issues and that has been reduced as well. But that was not the primary goal. But we have observed incidental reduction in gambling, yes. Hi, I'm Helerin Räikkönen from Finland. I was thinking about asking the first presentation about stimulating the nucleus accumbens. We know that it kind of works differently, the shell and the core. So if you do fuss on this nucleus accumbens, how do you think it influences the shell and the core? Is there differences? Yes, we are targeting the core at this point. The core and the ventral anterior internal capsule. So the shell may be more of an extension to amygdala and all that. So we're targeting the core at this point. Hi, I had a question about the anterior insula and its interoceptive qualities and whether you had seen any effect of that focused ultrasound on any, I don't know, epiphanies or I know consciousness, they're more sleepy, but anything else that you care to comment on? Yeah, I think the sleepiness is sort of a nonspecific effect. We don't really understand it, obviously, but I think it's not target dependent. It's been reported across several targets using focused ultrasound. But no, I think that your question is a good point. We're actually doing a different study using focused ultrasound targeting the insula with pain, patients with another pain study. And the tasks that we developed for laboratory measures of evoked pain include testing the effects of ultrasound on the affective component. I didn't go into the laboratory pain measures here, but we are investigating the affective component of pain for as much as you can isolate it in a person, the affective aspect of pain versus the actual pain level. So that's to be determined. Thanks. Also for Dr. Lee, I understood the reason as to why you chose the anterior insula for this study because it was the anxiety and pain and substance use. If you were doing a study only in anxiety disorders, would you have chosen that same brain region? Well, I think the neural imaging results studies in fear conditioning, the insula is a reasonable target activated during fear conditioning. So I think, yeah, it would be a reasonable target. The other thing, it's a practical target because of the depth of the insula for the kind of transducer that we're using. It's a practical target. We can target it well with spatial specificity and the temporal bone, going through the temporal bone is also practical because there's less distortion and interference with the beam. So for those reasons, for that complex of reasons, I would. Thank you. Yeah. Dr. Rezai, wonderful proof of concept. Do you think the surgical ultrasound system is practical for these kind of applications and whether the MRI is also practical for these kind of applications and are there ways around that? Yeah. And that's a good question. So the applicability, the helmet cost a million and a half dollars and it's expensive and it's non-surgical, so we're not doing surgeries, but it's the helmet is very expensive and it requires you to use real time MRI. In my opinion, it's probably not practical down the long term to scale this. It's good for proof of concept and optimizing the dose, understanding what dose you need to cause this reduction in cravings, and then scale it by using the other systems that are easier and can be done and can be prescribed or managed by psychiatrists and others. The system uses a neurosurgical managed system, but I don't think that's scalable or practical in long term. Do you think there's a way beyond MRI? So elimination of MRI also? I think it is because we're not seeing any acute changes in MRI. So MRI is necessary for lesioning where we're doing MRI thermometry or looking at the lesion or blood brain barrier opening. In this case, the MRI just serves the targeting purpose. We're not seeing any change in temperature or swelling or any other effects of MRI. So you can easily use a system where you obtain an MRI before, like in TMS or the systems using an integrated image guidance and put a mark on the skull. That's the direction and you know how many centimeters from there. So I think it's not necessary for this in the long term. Right now, it's proof of concept. We're trying to standardize many different elements, but in the future, this should be scaled broadly, in my opinion, beyond MRI. Thank you. I'd like to ask to the Dr. Hong, the pyramids to simulate in TMS is high frequency and about the design of coil usage. The double-coned coil? Good question. This particular study, just using a standard figure 8 coil targeting the TMFC is 10 hertz. Obviously, the FDA just recently approved H4 coil, which is to more diffuse the stimulation on the including insular, but also the most of the frontal areas to short-term smoking cessation in general population. So we also have a lot of interest to see whether that will also help patients with schizophrenia. Thank you. Have you made any efforts to correlate this with some of the neurochemistry with glucagon peptide agonists, in terms of reducing craving? Because that's one of the things that's being reported. Do you mean, yes, the- I'm trying to understand how the functional ultrasound affects the neurochemistry specifically. Right. So measuring peptide levels as a consequence of administering focused ultrasound to see if those concentrations are changing. Yeah, that's an excellent idea. There's actually a body of work targeting the gut-brain axis using focused ultrasound to the projection fields of the vagus nerve in the liver to modulate insulin resistance. So I think that your idea to measure peptide levels would be particularly interesting in that kind of application of focused ultrasound. Because trying to understand the chemistry that happens with these various stimulation is really going to be key, I think, for the future. Yes. Thank you. The other application is for GLP-1 that's being used worldwide now for people with eating and diabetes and obesity. So this target can also potentially serve as a reduction in cravings for food target. And that's a study- And opiates and other- Exactly. So I think it needs to be studied. It's an important point. Yes. Thank you. I have a question for all the speakers here. And we know neuromodulation are such a promising approach now for many substance use disorders. And however, among those patient population, I think one of them, I think, NIDA specifically interested is adolescents. So we don't know if adolescent population can be included in the neuromodulation study. Certainly, for TMS, there's been a lot of more and more study used targeting adolescents because it's relatively safe. Go ahead. I think so. Right now, it's for us as adults because of FDA regulatory. But I do believe it's important to look at adolescents because many of these conditions start in adolescents and they compound. So catching it earlier before these networks are really changed, I think, is important. So I do believe it's important to look at it. But because of a regulatory and other constraints of people who are adolescents, we have not done so. But I think it should definitely be explored. Yeah. I think we need to do more work. Certainly, it's very early days in the field of focused ultrasound. And we don't even really understand the duration of some of these effects. I showed the result of the motor potential being suppressed an hour out from one session. So the question is, what's the duration of even that effect? So I think before we get into applying this to adolescents, we should probably understand some of those basic consequences. We have to make sure the safety is first. Any more questions? OK. If no, we are formally ending our session. Thank you for coming. Thanks again for all the speakers. Thank you.

neuromodulation

substance use disorders

non-invasive brain stimulation

deep brain stimulation

focused ultrasound

nucleus accumbens

low-intensity focused ultrasound

anterior insula

TMS

nicotine addiction

schizophrenia