Mark S. George - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): Deep Brain Stimulation (DBS) of the thalamus, globus pallidus (GPi) or subthalamic nucleus (STN) is a new treatment for essential tremor and bradykinesia in Parkinson's Disease (PD). The neuropsychological and mood effects of stimulation at these sites are poorly categorized and understood. Major depression (MD) occurs in up to 40% of PD patients. The functional neuroanatomy of normal mood regulation in health and the pathological changes in MD are becoming better understood but still lag behind the neuroanatomical knowledge of motor dysfunction in PD. A key concept developed by the PI and others is that mood is regulated through changes in activity in the anterior paralimbic circuit (APLC) (amygdala, septum, anterior cingulate cortex, anterior temporal poles and orbitofrontal cortex) and that this system functions abnormally in MD. The PI and others have pioneered new treatments for MD JMS, VNS) that have indirectly stimulated this brain circuit. In modem research, no one has used DBS for the primary treatment of MD, although mood effects of DBS have been observed. Based on functional imaging, case report and animal model data, we hypothesize that DBS will cause acute mood changes in PD patients only when DBS affects the APLC. To test this theory that APLC activation is necessary for mood-altering and perhaps antidepressant effects of DBS, we propose to recruit 32 PD patients over a three year period who would fulfill PD clinical indications for DBS (e.g. resistant akinesia, postural rigidity). We will randomly assign these subjects to bilateral DBS at one of two sites either the STN or the GPi. Two days following implantation we will use interleaved DBS/fMRI and intermittently stimulate at the 4 sites on each electrode (bilaterally coordinated), examining changes in self rated mood, psychophysiological measures (HR, BP, GSR, Oxygen saturation), and most importantly, rCBF changes locally and in secondary limbic regions (APLQ. In a masked clinical trial, we will then examine the effects of 4 weeks of a fixed dose of clinically indicated DBS at the implanted site (GPi, STN) on movement, mood and cognition. Subjects with depression symptoms following the 'standard' care will be treated for 4 weeks at the electrode site that on fMRI had the most APLC involvement. The goals of this study are to test this APLC hypothesis of mood regulation and to develop a better working knowledge of the effects of DBS on mood in PD. Thus, we plan to use interleaved fMRI and DBS to directly examine the effects of DBS on hypothesized brain circuits and to correlate this with immediate and longer-term (4 week) behavioral outcomes (mood and cognition).

transcranial magnetic stimulation; portable biomedical equipment; evaluation /testing; sleep deprivation; behavioral medicine; biomedical equipment development; performance; war /peace; biomedical equipment safety; longitudinal human study; military personnel; functional magnetic resonance imaging; field study; bioengineering /biomedical engineering; behavioral /social science research tag; clinical research;

human therapy evaluation; performance; piperidine; dosage; drug screening /evaluation; sleep deprivation; 1,3 benzodioxole; psychic activity level; fatigue; quinoxalines; clinical research; human subject; neuropsychological tests;

DESCRIPTION (provided by applicant): This resubmission requests support for a 4-year, 4-site, randomized sham-controlled trial of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depression, rTMS has shown an antidepressant effect in 20 small sample randomized controlled comparisons, five separate meta analyses of these studies, and in randomized trials with electroconvulsive therapy. However, the sample sizes of these studies have been small and the rTMS stimulus administered may not have been of an adequate dose in terms of the intensity of stimulation or length of treatment in order to demonstrate an optimal antidepressant effect. Considerable skepticism and many questions remain concerning the ultimate clinical meaningfulness of these studies. Recent scientific evidence and pilot data from our groups support the fact that the antidepressant response to rTMS is dose-dependent. The present protocol uses rTMS parameters that maximize the stimulation duration and intensity within the published safety guidelines to treat 240 unipolar depressed adults with moderate levels of treatment resistance. We will investigate the safety and efficacy of repeated daily left prefrontal 5Hz rTMS at 120% of motor threshold (MT) in a 3 week fixed dose trial. In subjects showing an antidepressant response after 3 weeks, rTMS will be administered for up to 6 weeks to achieve remission of clinical symptoms of depression. Patients who do not remit with the initial fixed dose trial will be administered 1Hz rTMS in an open trial over the right prefrontal cortex. Baseline magnetic resonance images will be used to determine the optimal stimulus intensity by adjusting for individual differences in cortical to skull distances. Safety measures will include the most comprehensive neuropsychological testing and adverse event profile used to date. We will also determine the long-term antidepressant effect of TMS in remitters, using a standardized continuation medication protocol over 6 months. Finally, we will evaluate whether neuroanatomic findings on magnetic resonance images, stimulus location, demographic, and/or clinical variables affect clinical response to TMS. [This clinical site grant (CSG) proposal is one of four scientifically identical proposals resubmitted under a CSMD mechanism.]

DESCRIPTION (provided by applicant): This application requests support for a 4 year, 4 site randomized sham-controlled trial of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depression. TMS has shown an antidepressant effect in 20 small sample randomized controlled comparisons, five separate meta-analyses of these studies, and in randomized trials with electroconvulsive therapy. However, the sample sizes of these studies have been small and the TMS stimulus administered may not have been optimal for antidepressant effect. Considerable skepticism and many questions remain concerning the ultimate clinical meaningfulness of these studies. Recent scientific evidence and pilot data from our groups support the fact that the antidepressant response to rTMS is dose-dependent. The present protocol uses TMS parameters that maximize the stimulation duration and intensity within the published safety guidelines to treat 240 unipolar depressed adults with moderate levels of treatment resistance. We will investigate the safety and efficacy of repeated daily left prefrontal TMS at 120% of motor threshold (MT) in a 3 week fixed dose trial. In subjects showing an antidepressant response after 3 weeks, rTMS will be administered for up to 6 weeks to achieve remission of clinical symptoms of depression. Patients who do not remit with the initial fixed dose trial will be administered rTMS in an open dose escalation trial with the intensity of rTMS increased to a maximum of 140% MT. Baseline magnetic resonance images will be used to determine the optimal stimulus intensity by adjusting for individual variations in cortical to skull distances. Safety measures will include the most comprehensive neuropsychological testing and adverse event profile used to date. We will also determine the long-term antidepressant affect of TMS in remitters, using a standardized continuation medication protocol over 6 months. Finally, we will evaluate whether neuroanatomic findings on magnetic resonance image, stimulus location, demographic, and/or clinical variables affect clinical response to TMS. (This coordinating Center Grant (CCG) application is submitted under a CSMD mechanism, linked to 4 clinical site grants (CSG).

Nicotine dependence is the leading preventable cause of mortality in the world today. Cue-induced craving is likely to play an important role in relapse. The neural correlates of smoking cue-induced craving and extinction have been elucidated using fMRI. Recent advances make it possible to utilize real-time fMRI (rtfMRI) feedback to modify behavior, cognitions and regional brain activity. The purpose of this proposal is to develop the imaging parameters, brain-computer interface and standardized procedures for using rtfMRI with visual feedback to help nicotine-dependent individuals decrease craving when presented with smoking cues. The exploratory nature of this study requires a phased approach. Phase 1 will focus on the development of the technology and study paradigm. In order to proceed to Phase 2, there must be convincing evidence that a substantial proportion of nicotine-dependent individuals can manipulate brain activity in critical brain regions associated with smoking cue-induced craving based on rtfMRI visual feedback. If this is established, a controlled comparison and duration of effect will be explored in Phase 2. This project will set the stage for clinical trials investigating a very innovative approach to the treatment of nicotine dependence and other substance use disorders. The study will provide critical information about optimal techniques, durability and transferability of the effects to situations outside of the scanner. The findings of this study can be used to inform the design of a clinical trial to investigate the use of rtfMRI neuromodulation training in smoking cessation.

Animals; Assessment tool; base; Behavior; Brain; Centers of Research Excellence; Clinical; Clinical Trials; Complex; Computer Simulation; Computer software; Data; Data Analyses; Data Collection; design; Diagnostics Research; Educational workshop; Equipment; experience; Fiber; Fostering; Goals; Hand; Human; image guided; improved; Intervention; investigator training; Laboratories; Location; Magnetic Resonance Imaging; Measurement; Measures; Mentors; Methods; neurophysiology; novel; Protocols documentation; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Resources; Role; Scientist; South Carolina; Standardization; stroke; stroke recovery; Techniques; Time; tool; Transcranial magnetic stimulation; Translating; Translational Research; treatment effect;

PROJECT SUMMARY The overarching goal is for the National Center of Neuromodulation for Rehabilitation (NC NM4R) to exert a sustained, powerful influence on the research field of NM4R ? the mechanisms and use of brain stimulation and operant conditioning of brain and spinal cord networks integrated with rehabilitation principles. Thus, our overall mission will be ?fostering the success of the NM4R researcher?. NM4R researchers will not be successful if they do not have best resources available for studies. Thus, the overall objective of the Techniques Development component is to develop, adapt and/or validate core research techniques, tools and other resources designed to improve the accessibility, applicability, utility, validity and feasibility of these approaches for the NM4R research community. This also requires new scientific knowledge. Tech Development will act as a catalyst for NM4R research by addressing pressing questions in the field, such as understanding the proper location of stimulation, intensity needed to reach the nervous system as well as knowledge and technique to adjust that intensity individually, dosages of operant conditioning, and how to craft inclusion and exclusion criteria to maximize finding an effect. We accomplish objectives by carrying out two specific aims. 1. Advance the field of NM4R through a strategically targeted research and development program. The Tech Development component proposes to flexibly and responsively address a variety of small NM4R research and technology development questions that are critical for the advancement of neuromodulation technologies in the rehabilitation setting. These small, important studies are often not fundable as grants but without them the field would be slowed in its advancement. Thus, these studies will facilitate the NC NM4R impact on rehabilitation. Initial, example projects are included in proposal. Future projects will be developed from needs assessments in aim 2. 2. Optimize NC NM4R expertise and techniques in response to NM4R researcher feedback and needs. The main way the NC NM4R can advance expertise and technology is through the iterative process of assimilating feedback on the needs of the broader NM4R research community. The evaluation program of Admin Oversight component will assess the needs of NM4R researchers as well as the Center's initial performance in terms of current activities. The Executive Committee together with the External Advisory Board will review and set the Tech Development annual agenda for improving existing activities and develop new programs to best serve the rehabilitation research community. The success of the NC NM4R ultimately depends on the research community using the best technologies and strategies available. The Technology Development component is well positioned to accomplish that goal.

TECHNIQUES DEVELOPMENT ? PROJECT SUMMARY / ABSTRACT The overarching goal of the National Center of NM4R is to impact multiple RPR priorities by increasing rehabilitation research workforce access to NM4R approaches and supporting rigorous clinical research to translate them into effective, evidence-based rehabilitation interventions. A critical element to achieve this is to develop, test and share new techniques and enhanced technologies in neuromodulation for rehabilitation (NM4R ? the mechanisms and use of non-invasive brain stimulation and operant conditioning of brain and spinal cord networks integrated with rehabilitation principles). The Techniques Development component seeks to develop, adapt and/or validate core research techniques, tools and other resources designed to improve the accessibility, applicability, utility, validity and feasibility of these approaches for the NM4R research community. It is our primary research vehicle to translate promising NM4R approaches into effective, evidence-based rehabilitation interventions. The field of NM4R research is dynamic with methodology continually being refined. To advance techniques and technology in NM4R, we have the following Specific Aims. AIM 1.Increase rigor in NM4R design, methods and clinical trials through methods and technology development studies. Very important methods and technology development studies are rarely ?flashy? enough or large enough on their own for NIH funding. Yet they are crucial for the translation of neuroscience ideas into rehabilitation treatments, especially in the context of clinical trials. Tech Development currently acts as a catalyst for NM4R research by addressing pressing questions in the field such as how to develop TMS neurophysiological techniques most relevant to the leg when studying gait and balance. AIM 2. Perform key research to translate NM4R approaches into evidence-based interventions. Translating promising approaches into effective treatments usually requires key research studies to move beyond concepts. An example is the ongoing tech development project to determine how to individually dose tDCS studies, in the same way individual motor threshold is used to dose rTMS studies. AIM 3. Develop emerging NM techniques into NM4R tools. Currently rehabilitation lags behind psychiatry in developing new NM based tools. We propose to introduce emerging techniques into tools for NM4R much more quickly. Successful examples include taVNS and combined TMS-fMRI-EEG techniques.