Colleen A. Hanlon - US grants

[unreadable] DESCRIPTION (provided by applicant): Movement disturbances, including tics, dystonia, and dyskinesias, are often overlooked yet disabling consequences of chronic cocaine abuse. The persistence of these motor control deficits implies that prolonged cocaine exposure has lasting effects on the nigrostriatal dopamine system, though this hypothesis has not been explicitly tested in humans. Accordingly, the overarching goal of this proposal is to translate basic science findings to human addicts through functional neuroimaging in order to characterize sensorimotor network changes which may underscore cocaine-related motor disturbances. This functional MRI investigation will examine the behavioral and neurofunctional changes that occur in chronic cocaine users relative to controls performing a visually-cued motor task (Aim #1) and a memory-cued motor task (Aim #2). Through these aims I seek to translate previous basic science research to a human model of sensorimotor disturbance in chronic cocaine addicts. As the average young user in the cocaine boom of the 1980s reaches the middle age, during which may movement disorders first become clinically detectable, the neurobiologic basis for movement dysfunction in these patients may be of increasing public priority. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is a request for 5 years of funding through the Mentored Research Scientist Development Award (K01) mechanism. The applicant, Dr. Colleen Hanlon, is a neurobiologist with experience using functional magnetic resonance imaging to examine neural networks affected in chronic cocaine users. To further characterize changes in cortical activity in cocaine users, this application proposes a program of training in diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS). The long- term goal of the applicant is to become an independent investigator, skilled in the application of multiple imaging modalities that may be used to guide treatment strategies in substance abusing populations. The training plan includes structured training courses in TMS acquisition and analysis, DTI image analysis, and multivariate statistics, as well as ongoing training by a team of mentors. Career development is also a strong component of this application with time devoted to Training in the Responsible Conduct of Research, manuscript and grant writing, mentoring students, attendance at scientific meetings, and interactions with the institutional review board. The research component of this award extends prior NIH-funded research complete by Dr. Hanlon, and has been carefully designed to parallel the training plan. The overarching goal of this proposal is to determine the extent to which changes in corpus callosum integrity (Specific Aim #1) and cortical inhibitory tone (Specific Aim #2) are related to atypical BOLD signal changes in the cortex of chronic cocaine users. In addition to extending investigations on sensorimotor laterality, the impact of loss of cortical laterality on cognitive function in cocaine users will also be addressed (Specific Aim #3). These experiments will reveal the extent to which changes in cortical inhibitory tone and corpus callosal integrity may contribute to neurofunctional and behavioral deficiencies in chronic cocaine users. The results of these experiments will be used to further the investigation and development of therapeutic treatment strategies in stimulant dependent individuals. PUBLIC HEALTH RELEVANCE: This is a request for 5 years of funding through the Mentored Research Scientist Development Award (K01) mechanism. The applicant, Dr. Colleen Hanlon, is a neurobiologist with experience using functional magnetic resonance imaging to examine neural networks affected in chronic cocaine users. To further characterize changes in cortical activity in cocaine users, this application proposes a program of training in diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS). The long- term goal of the applicant is to become an independent investigator, skilled in the application of multiple imaging modalities that may be used to guide treatment strategies in substance abusing populations. The training plan includes structured training courses in TMS acquisition and analysis, DTI image analysis, and multivariate statistics, as well as ongoing training by a team of mentors. Career development is also a strong component of this application with time devoted to Training in the Responsible Conduct of Research, manuscript and grant writing, mentoring students, attendance at scientific meetings, and interactions with the institutional review board. The research component of this award extends prior NIH-funded research complete by Dr. Hanlon, and has been carefully designed to parallel the training plan. The overarching goal of this proposal is to determine the extent to which changes in corpus callosum integrity (Specific Aim #1) and cortical inhibitory tone (Specific Aim #2) are related to atypical BOLD signal changes in the cortex of chronic cocaine users. In addition to extending investigations on sensorimotor laterality, the impact of loss of cortical laterality on cognitive function in cocaine users will also be addressed (Specific Aim #3). These experiments will reveal the extent to which changes in cortical inhibitory tone and corpus callosal integrity may contribute to neurofunctional and behavioral deficiencies in chronic cocaine users. The results of these experiments will be used to further the investigation and development of therapeutic treatment strategies in stimulant dependent individuals.

Address; Age; base; Basic Science; Brain; Brain imaging; Brain region; cardiovascular risk factor; Chronic; chronic stroke; Clinical; clinically relevant; Contralateral; Corpus Callosum; Data; Equilibrium; Fiber; Ficial compensation; Foundations; gamma-Aminobutyric Acid; Glutamates; Goals; Hand; Handedness; Impairment; Individual; interest; Investigation; kinematics; Left; Lesion; Magnetic Resoce Imaging; Magnetic Resoce Spectroscopy; Measures; Middle Cerebral Artery Infarction; Motor Cortex; motor disorder; motor rehabilitation; Movement; neuroimaging; Neurons; Neurophysiology - biologic function; Outcome; Patients; Pattern; Performance; Physiologic pulse; Process; Rehabilitation Outcome; relating to nervous system; Research; Side; Signal Transduction; South Carolina; stroke; stroke recovery; Task Performances; Testing; Time; Transcranial magnetic stimulation; Treatment outcome; Upper Extremity;

DESCRIPTION (provided by applicant): Chronic cocaine use is among the most difficult substance-use disorders to treat. High relapse rates are likely due to a combination of limbic and cognitive factors, including vulnerability to salient limbic cues and loss of executive control This may be due to elevated functional connectivity in limbic neural circuitry (e.g. between the medial prefrontal cortex (MPFC) and ventral striatum) and/or lower functional connectivity in executive control circuitry (e.g. between the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum). The overarching goal of this longitudinal imaging study is to use the novel TMS/fMRI probe to determine the relationship between executive and limbic circuit integrity as it relates to immediate and extended outcomes after an intensive outpatient treatment program. This will be achieved by assessing functional connectivity in treatment-seeking cocaine users and non-drug using controls at baseline (Aim1) and the change in functional connectivity after a 28-day cognitive- behavioral treatment program (users only)(Aim 2). We will also determine the relationship between the integrity of these circuits and clinically meaningful outcome measures 60 days and 90 days after baseline (Aim 3). The fundamental neuroscience knowledge resulting from these aims regarding the importance of executive (e.g. DLPFC) and limbic (e.g. MPFC) circuit connectivity to addiction treatment outcomes. These data will provide a critical foundation from which the field can develop evidence-based brain stimulation treatment strategies (such as repetitive TMS) to amplify DLPFC connectivity among treatment-seeking individuals.

PROJECT SUMMARY Alcohol Use Disorder (AUD) is prevalent, devastating, and difficult to treat. High relapse rates are likely due to factors that affect neural circuits that govern craving and cognitive control. There is growing interest in the utilization of prefrontal cortex repetitive transcranial magnetic stimulation (TMS) as a novel, non-invasive, non- pharmacologic approach to decreasing craving among individuals with alcohol use disorder (AUD). At this early stage of development, however, it is unclear if the best TMS strategy is to (1) attenuate activity in the medial prefrontal cortex (mPFC, which is involved in craving), or (2) amplify activity in the dorsolateral prefrontal cortex (dlPFC, which is involved in cognitive control). Several laboratories have demonstrated that a single session of 10 Hz TMS over the dlPFC leads to a decrease in craving for alcohol, nicotine, and cocaine. We have demonstrated that a single session of continuous theta burst (cTBS) TMS over the mPFC can also decrease craving, as well as the brain response to drug cues in cocaine users and alcohol users. The overarching goal of this proposal is to determine which of these brain stimulation strategies is more effective in decreasing functional activity (measured by BOLD signal) in limbic regions involved in alcohol craving (Aim 1), and decreasing self-reported craving (Aim 2). This will be achieved through a double-blind, sham-TMS controlled within-subject crossover study of individuals with AUD. Using functional MRI, the neural response to alcohol-cues (a task identical to that used in Research Project #2- Anton/Schacht) will be measured within 10 minutes after the participant receives a dose of continuous theta burst TMS to the mPFC, 10 Hz TMS to the dlPFC, or sham rTMS. Additionally, the effects of these TMS strategies on cortical neurochemistry will be measured using magnetic resonance spectroscopy (exploratory Aim 3), enabling us to relate the outcomes of these aims with complementary neurochemical information. The outcomes of this project will provide an evidence-based foundation for cortical target selection in future clinical trials of TMS as an innovative treatment strategy for individuals with AUD.

? DESCRIPTION (provided by applicant): Cortical thickness cocaine dependence is one of the most difficult substance-use disorders to treat and currently has no FDA- approved interventions. While current pharmacological strategies modulate neurochemistry in a spatially- unbiased manner, the development of non-invasive brain stimulation strategies would enable us to directly modulate neural activity in a circuit-specific manner. We recently demonstrated that direct attenuation of the medial prefrontal cortex (a cortical hub of frontal-striatal circuitry tht governs craving) through theta burst stimulation (MPFC cTBS) decreases baseline frontal-striatal activity, neural responses to cocaine uses, and craving in non-treatment seeking cocaine users. The effects of a single session however, erode over the first few hours after treatment. Sustainable effects require multiple days of treatment. GOAL: The primary goal of this proposal is to collect critical feasibility and effect size data which is necessary before moving forward wih multisite clinical trials. The questions that need to be addressed are: 1) Does MPFC cTBS improve retention and abstinence in treatment-engaged patients? and 2) Does it produce an acute and sustainable change in frontal-striatal connectivity among these patients? DESIGN: In this double-blind active sham controlled cohort study, cocaine users enrolled in a 4 week intensive outpatient treatment program will be randomized to receive 3 weeks of real or sham MPFC cTBS. Clinical assessments and neuroimaging data will be acquired four times: before the first cTBS session, after the last cTBS session, at the patient's 1 month follow-up visit, and at the 2 month follow-up visits. Aim 1 - Clinical effects. We will test the hypotheses that real cTBS treatment will enhance retention and decrease cocaine use during the treatment program (part A) and at the follow up visits (part B). Aim 2- Neurobiological effects. We will also test th hypotheses that real cTBS treatment will produce a selective decrease in MPFC-striatal functional connectivity (part A), and that this will be sustained in the individuals that return an have remained abstinent at the follow-up visits (part B). The scientific rationale of this study is an extension of optogenetic studies in animal models of addiction which have demonstrated a causal link between activity in this circuit and drug taking. The experimental design of this study is an extension of the initial clinical trials that led to FDA-approval of repetitive brain stimulaion as a treatment for major depression disorder. Taken together the results of this study may have a high impact and direct relevance to development of brain stimulation as a novel, innovative treatment option for cocaine dependent individuals.

ABSTRACT Effective control of chronic pain is a top priority in the United States, as approximately 10% of adults have severe chronic pain ? most of which is chronic lower back pain (CLBP). However, despite the advances in neuroscience over the past 20 years, we still largely treat chronic pain with opiate narcotics, much as was done in the Civil War. In addition to their high abuse liability and dependence potential (1), only 30?40% of chronic pain patients declare they receive satisfactory (>50%) relief from their pain through pharmacological treatment. Consequently there is a critical need for new, treatments that can treat pain and reduce reliance on opiates in individuals with chronic pain. The goal of this R21 proposal is to evaluate 2 novel non-invasive brain stimulation strategies to mitigate pain and the brain's response to pain in CLBP patients currently taking chronic opiates. Transcranial Magnetic Stimulation (TMS), can induce long term potentiation (LTP-like) and long term depression (LTD-like) effects on brain activity in a frequency dependent manner. Our group has previously demonstrated that LTP-like TMS to the dorsolateral prefrontal cortex (DLPFC, a node in the Executive Control Network (ECN)) can decrease perceived pain and corresponding BOLD signal in the ?Pain Network? (Strategy 1, Aim 1). An alternative strategy is to apply LTD-like stimulation to the medial prefrontal cortex (MPFC, a node in the Default Mode Network (DMN); Strategy 2, Aim 2). The proposed study will be the first to employ a randomized, double-blind, sham-controlled design to parametrically evaluate the longitudinal effects of 10 days of rTMS to the DLPFC (Aim 1) or the MPFC (Aim 2) on self-reported pain and the brain's response to pain. This will be done in a cohort of patients with chronic lower back pain that have been using prescription opiates for 3 or more months without adequate pain relief. Patients will be recruited from the comprehensive pain management clinic at MUSC (directed by Dr. Borckardt, Co-I) and MUSC General Medicine clinics. Quantitative Pain testing and Brain reactivity to pain will be measured immediately before and after 10 days of TMS as well as a 1 and 2 month follow-up (to evaluate durability).

PROJECT SUMMARY/ABSTRACT Smoking is the leading preventable cause of mortality and morbidity in the United States, each year contributing to approximately 443,000 deaths. Smoking and high relapse rates are likely due to factors that affect both limbic and executive circuits in the brain, including vulnerability to salient smoking-related cues and loss of cognitive control. Accumulating evidence indicates that in addiction, the frontal-striatal circuits involved in limbic reward and impulsive action are relatively hyperactive, while the executive control circuits are relatively hypoactive. Thus, intervention efforts should be directed at either decreasing the relative activity of the impulsive reward circuit or increasing the relative activity of the executive control circuits. Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-approved treatment for depression which is also being investigated for as a possible treatment for smoking cessation. The goal of this project is to use the novel theta burst stimulation (TBS) protocol to induce sustainable decreases and increases in the impulsive and executive control circuits, respectively. To do so, we will apply an attenuating form of TBS to the ventromedial prefrontal cortex to target the impulsive reward circuit and a potentiating form of TBS to the dorsolateral prefrontal cortex to target the executive control circuit. We will then investigate the efficacy of these protocols for reducing a range of smoking measures, including cigarette valuation, delay discounting, cigarette self-administration, and brain reactivity to smoking cues. The results from these investigations will pave a clear pathway for the systematic development of neural-circuit based strategies as treatments for tobacco use and dependence.

PROJECT SUMMARY - Overall The personal, social and criminal consequences of opioid and cocaine abuse are enormous problems in North America. This is most tragically seen in rising morbidity due to heroin, prescription opioids and fentanyl overdose in the USA. Addiction to drugs typically cycles between three phases, active drug use, withdrawal from drug use and relapse to drug use. A point in the cycle of addiction where pharmacological intervention can be particularly beneficial is to interfere with the overwhelming motivation by addicts to relapse to drug use, even after extended periods of abstinence when acute withdrawal symptoms have dissipated. However, the enduring state of relapse vulnerability arises from interdependent brain adaptations produced during all three phases of addiction. Thus, in order to develop biological rationales for treating relapse, it is necessary to understand not only the neurobiology of relapse itself, but to determine which changes produced by drug administration and drug withdrawal contribute to the final enduring state of relapse vulnerability. The overarching goal of the Center for Opioid and Cocaine Addiction (COCA) is to create and maintain mechanisms of scientific synergy that will facilitate discovering the neuropathologies that underpin the enduring and uncontrollable drive to seek opioids and cocaine, and thereby advance biological rationales needed to efficiently generate pharmacotherapies that inhibit drug relapse. This goal will be achieved through a bidirectional translational strategy that involves 3 Cores and 4 research Projects. In addition to the Administrative and Pilot Cores, the Animal & Validation Core makes available transgenic rodents that have been trained to self-administer heroin or cocaine, and have been instrumented with intracranial cannulae, fiber optics or GRIN lens. This Core will also validate all viral reagents and transgenic animals shared by the COCA Cores and Projects. The 4 Projects range from determining the epigenetic substrates of long- lasting drug-induced alterations to understanding the molecular and brain circuit mechanisms of cue-induced drug seeking in rodents and humans. The Projects are designed to be highly integrated and form a bidirectional translation strategy for providing biological rationales for new therapeutic approaches to relapse prevention.

PROJECT SUMMARY ? Project 4 In spite of substantial research effort, cocaine dependence is a particularly difficult substance use disorder to treat. Preclinical models in the Center demonstrate that decreasing neuronal activity in the ventromedial prefrontal cortex (vmPFC) and ventral striatum (i.e. nucleus accumbens core), henceforth corticostriatal circuit, block cocaine cue-induced reinstatement. The scientific and clinical premise of Project 4 is that targeted inhibition of the corticostriatal circuit will dampen cocaine cue-induced craving in cocaine users. Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation that induces long term depression-like (LTD-like) decreases in neural excitability in the area stimulated and downstream monosynaptic targets. A single dose of cTBS to the vmPFC selectively decreases activity in the ventral striatum and self-reported craving. Recently, we found that N- acetylcysteine (NAC) increases corticostriatal resting state functional connectivity (rsFC) in nicotine users concomitant with reducing craving. The overarching goals of Project 4 are to evaluate the efficacy of combined cTBS+NAC on addiction pathophysiology in corticostriatal circuitry, and to bidirectionally translate our findings with the preclinical COCA Projects. We will determine if LTD-like cTBS decreases cocaine cue reactivity in cocaine dependent individuals (Aim1), and if NAC strengthens corticostriatal rsFC (Aim 2). Then, we will examine the efficacy of cTBS+NAC to synergistically reduce drug cue reactivity and craving (Aim 3). These aims will be evaluated through a double blinded (TMS: TBS vs. SHAM; Medication: NAC vs. Placebo: PBO) study in 96 cocaine dependent individuals. All individuals will undergo an fMRI baseline scan and then randomized to one of 4 groups: 1) NAC + TBS, 2) NAC + Sham, 3) PBO + TBS, 4) PBO + Sham). As these data emerge, we will work closely with preclinical Projects 1-3 to provide these projects with human circuitry data that can help guide their studies. Conversely, we will receive data regarding corticostriatal mechanisms generated in rodent models of relapse that can inform the interpretations of our clinical data and guide our research through greater understanding of the underpinning molecular and circuit level neurobiology.

With advances in optogenetic stimulation techniques, preclinical studies have demonstrated that activity in frontal-striatal neural circuits has a causal influence on heavy drinking and alcohol reinstatement. Clinically, however, we have not yet translated this research into a neural circuit based therapeutic technique for patients with alcohol use disorder (AUD). The long term goal of our multidisciplinary research team is to determine the optimal parameters through which non- invasive transcranial magnetic stimulation can be used to improve alcohol drinking outcomes (abstinence, heavy drinking days) among individuals seeking behavioral treatment for AUD. Building on a foundation of several target identification studies and a small double-blinded clinical trial in treatment-engaged AUD patients performed by our group, here we propose a double-blind placebo controlled, randomized study to evaluate the relative efficacy of 2 potential TMS treatment strategies for AUD. Specifically, using the existing infrastructure of the MUSC Intensive Outpatient Treatment Program, consenting participants will be randomized to receive real or sham TMS delivered to the ventral medial prefrontal cortex (vmPFC), or dorsolateral prefrontal cortex (dlPFC) for 20 sessions (2x/day, 10 days) immediately before their daily intensive outpatient therapy sessions. The scientific premise of this 5 year R01 proposal is that, by modulating the neural circuits that regulate alcohol cue-reactivity (Strategy 1, Aim 1, vmPFC) or executive control (Strategy 2, Aim 2, dlPFC) it will be possible to increase alcohol abstinence rates and decrease heavy drinking days over a 4 month period. With our combined scientific expertise in brain stimulation (Hanlon, neuroimaging (Schacht and Hanlon), alcohol use disorder research (Schacht, Anton, Book), and clinical practice with AUD patients (Book, Smith) our research team at MUSC is uniquely suited to develop this critical line of research. The outcomes of the proposed Aims will provide an evidence-based foundation for a multisite clinical trial and will hasten progress towards developing a new neural circuit based treatment for patients with AUD.

DIDACTIC INTERACTIONS ? PROJECT SUMMARY / ABSTRACT The Didactic Interactions component of the National Center of Neuromodulation for Rehabilitation (NC NM4R) provides researchers the fundamental building blocks they need through a multi-layered and progressive program of didactic and experiential learning opportunities supported by complementary components in mentored collaborations and pilot funding. We offer interactions for researchers with no prior knowledge of neuromodulation, as well as advanced courses for those with some experience but who desire increased expertise. Building on the outstanding success of our workshops in the first phase of this grant, the NM4R Didactic Interactions leadership group have refined guidelines for all learning content for the new grant period. All sessions, regardless of level, must: 1) be rigorously evaluated for continuous improvement of future offerings; 2) include a hands-on, experiential learning component aimed to increase research rigor and reproducibility; 3) include a focus on underlying mechanisms of action so that investigators understand why to use a technique and not just how to do so; and 4) include promotion of synergistic research resources, pilot funding, and follow on mentored collaboration. Didactic Interactions has three Specific Aims. AIM 1. Provide foundational learning opportunities in NM4R techniques, methodology, safety, and rigor. Level 1 workshops are the primary tool for this aim. Adapting to NM4R community needs, we have evolved the curriculum and approach for Level 1 opportunities as new technologies and methods have emerged. The format combines lectures, laboratory experiences, case discussions centered on key rehabilitation problems, and skills testing leading to enhanced safety and rigor in research conduct. AIM 2. Develop in-depth and practical knowledge of NM4R approaches through advanced workshops that include extensive hands-on training based on the participants? research questions. Building on the knowledge gained from Level 1, Level 2 workshops will focus on in-depth topics in NM4R ? determined by the research interests of the national community. In addition to the advanced didactic content, participants will bring their own research questions and co-learn with leaders and colleagues to hone their hypotheses, skills, and methods to assist in translating their approach into an evidence-based neurorehabilitation intervention. AIM 3. Develop unique interdisciplinary training opportunities that stimulate the NM4R community?s technology development, creativity, and clinical translation. We will develop symposia, with didactic, and hands-on learning, to bring investigators from diverse fields together to explore novel and advanced applications of NM4R approaches to address priority areas identified in the RPR.