Nolan R. Williams - US grants

Project Summary/Abstract Integrative medicine is, by definition, designed to combine mainstream scientific medical care with the best of practices that have been demonstrated to enhance our ability to prevent or live better with illness. Both rTMS and hypnosis have proven ability to reduce pain. Our aim is to integrate recent functional imaging data regarding hypnosis with that associated with the neural effects of repetitive transcranial magnetic stimulation (rTMS) in the treatment of fibromyalgia. Fibromyalgia is a poorly understood but common disorder characterized by the combination of widespread pain, fatigue, and sleep disruption. Our plan is to understand the brain mechanism of augmenting hypnosis and hypnotic analgesia with rTMS. We propose to identify 90 moderately hypnotizable subjects with fibromyalgia syndrome and measure their response to hypnosis, standardized pain stimuli and rTMS in the fMRI scanner before and during rTMS- augmented hypnosis and hypnotic analgesia. We will randomly assign subjects to receive either active DLPFC rTMS or sham rTMS augmentation so that we can compare results. We will have two scan sessions for each subject, one in which they receive hypnosis session where they receive control scan, control scan + hypnosis, rTMS, control scan + rTMS, and rTMS-augmented hypnosis and the other is the hypnotic analgesia session where the participant receives control scan, control scan + pain thresholds, rTMS, post rTMS scan, and rTMS-augmented hypnotic analgesia. We have three specific aims: 1) Understand the effect and neural basis of rTMS-augmentation of hypnotizability; 2) understand the effect of rTMS on hypnotizability and depth of hypnosis; 3) understand the effect and brain basis of combining hypnotic analgesia with rTMS, and 4) compare the condition of stimulation (active versus sham) with the subjective pain reduction. This approach will establish both common ground and differences between hypnotic and neuromodulatory pain relief and the potential for combining these two approaches, thereby integrating traditional and modern biomedical means of effectively treating pain. The goal is to provide a scientific basis for augmenting both approaches by combining them, thereby providing better analgesia with fewer side effects, while enhancing the ability to manage pain.

ABSTRACT Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited in part by insufficient understanding of the mechanism of disease remission. In turn, efforts to elucidate mechanisms have been challenging due to disease heterogeneity and limited effectiveness of treatments, which require weeks-to-months to induce remission. In this application, we propose to focus on applying a novel neurostimulation strategy to participants with TRD. We recently developed a form of repetitive transcranial magnetic stimulation that induces remission in 90% of individuals with severe, treatment resistant MDD in 1-5 days which we called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). This methodology provides a new tool to begin exploring the network-level mechanisms of MDD remission. Following SAINT, fc significantly decreases default mode network (DMN)-subgenual cingulate cortex (sgACC) which is correlated with change in clinical scales. In this application, we propose to target the L-DLPFC-sgACC target with active (n=50) versus sham (n=50) SAINT and determine if active SAINT (Aim 1) attenuates sgACC-DMN connectivity and (Aim 2) significantly reduces symptoms of depression. Decreases in fc may underlie reductions in depression; thus, we will relate reductions in these potential moderators to identify the best symptom targets. Completion of this proposal will further establish a safe, effective, and non-invasive device-based treatment for TRD along with the iterative neural circuitry changes at each daily dose of stimulation that summate to produce the clinical effect.

Narcotic use in chronic pain treatment has played a major role in the ongoing opioid crisis. Convergent evidence indicates that the activity of the anterior cingulate cortex (ACC) is critical in the pathophysiology of chronic pain. Local therapies directed to the ACC yield benefit for chronic pain clinically and preclinical data suggest that locally applying the drug ketamine to the ACC should yield acute-onset and long-acting remission of the pain phenotype through a non-opioid mechanism. In this manner, local ketamine infusion into this critical brain target is a promising non-opioid pain treatment that could yield remission of chronic pain with potentially more predictable dose-response relationships than systemic administration, with personalization based on the imaging defined sensitivity of the ACC to pain, and without limiting side effects due to off-target drug action in the rest of the brain or body. To translate these results into a clinical treatment, one would ideally be able to locally apply ketamine to only the ACC, without any off-target ketamine action and without invasive interventions to the brain. Towards this end, we have developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. We have validated that we can use this technique for selective ultrasound-induced release of ketamine, and that ultrasonic uncaging yields drug effects that are limited precisely by when and where the ultrasound is applied. Further, we have developed a straightforward path to translate this technology to clinical practice. We now propose to clinically translate ultrasonic ketamine uncaging for chronic pain therapy. Given the variety of potential therapeutic effects that are increasingly ascribed to ketamine, we anticipate that this first-in-human clinical trial would establish the safety of this technique and generate the efficacy data necessary to enable regulatory approval for larger clinical trials for each application of ultrasonic ketamine uncaging. Overall, we expect that completion of this proposal will provide the prototype for subsequent translation of ultrasonic drug uncaging for numerous other drugs of interest. Specifically, in the proposed preclinical UG3 phase, we will scale up our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. We will also complete the animal testing needed to obtain regulatory approval for an initial clinical trial. In the proposed clinical UH3 phase, we will complete a first- in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose, and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. Successful completion of this proposal will yield a novel, noninvasive, and non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

ABSTRACT The overarching aim of this proposal is to test the efficacy and safety of a highly efficient and personalized repetitive transcranial magnetic stimulation (rTMS) method, termed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). In this proposal, we will utilize SAINT as a rapid-acting intervention for the reduction of explicit and implicit suicidal cognition within the context of an emergency psychiatric admission for suicidal thoughts and behaviors. Although rTMS is FDA approved for treatment-resistant depression (TRD), the average required treatment application is 6 weeks before signs of symptomatic improvement, which is not an optimal strategy for symptomatic treatment of an acute suicidal crisis. This application is motivated by three recent findings in the neuromodulation field. First is a sham-controlled pilot study evaluating an accelerated conventional rTMS protocol, where multiple stimulation sessions were safely delivered to the left dorsolateral prefrontal cortex (L-DLPFC) across three days in patients with suicidal ideation. This study demonstrated that conventional rTMS can be ?accelerated? as well as demonstrated a signal of reductions in explicit suicidal cognition. Second, there are two notable randomized trials of intermittent theta-burst stimulation applied to the L-DLPFC that demonstrated the efficacy of intermittent theta burst stimulation (iTBS) as a treatment for TRD, a condition commonly associated with suicidal cognition. iTBS has been demonstrated to have 5X the pulse potency of conventional rTMS, which allows for a much-reduced stimulation session time in comparison to traditional rTMS and therefore makes multiple treatments per day a feasible intervention. The final innovation is that rTMS targeting utilizing resting state functional connectivity improves antidepressant outcomes of rTMS. We designed an approach, which we termed SAINT, which utilizes numerous applications of iTBS per day, as per principles of spaced learning theory (optimized intersession-intervals), within a functional connectivity derived target (L-DLPFC-sgACC). In TRD, we have observed dramatic changes in mood and associated explicit suicidal cognition using SAINT. We propose utilizing SAINT to modulate the neural circuitry that underlies explicit and implicit suicidal cognition along with moderators/mediators (hopelessness, anhedonia, and depression). We will conduct a randomized, controlled trial of SAINT applied to the L-DLPFC-sgACC to assess efficacy of the approach in reducing suicidal cognition in hospitalized psychiatric inpatients.