Jason J. Kutch, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The recruitment of motor units in a muscle is generally understood to progress in a fixed order from units that exert small forces to units that exert large forces. However, this understanding has been questioned in the literature as studies have shown that motor units in some muscles are recruited differently for different directions of joint force. However, the physiological basis for the differential activation of motor units has not been established. Using the first dorsal interosseous (FDI) as a model multifunctional muscle, we will determine if different motor units within the FDI exert twitch forces with different ratios of abduction to flexion force. If different motor units have a greater mechanical advantage for one direction over another, we will determine if the central nervous system (CMS) activates motor units so that units with the greatest mechanical advantage for the given task are preferentially activated. Loss of directional control in the affected hand after stroke may relate to a breakdown in the selective activation of motor units rendering some directions of index finger force either inaccessible or uncontrollable. Our study will determine the feasibility of this hypothesis by seeking to establish the physiological basis of differential motor unit activation in unimpaired human subjects. We will assess motor unit twitch force direction using spike- triggered averaging (STA). STA may accurately determine motor unit twitch force direction despite the fact that it can not accurately estimate the absolute amplitude of a twitch. We will examine the consistency of STA estimates for twitch direction across different directional tasks. By studying many motor units, we will assess the distribution of twitch directions that can be generated by FDI motor units. We will determine if a correlation exists between the twitch direction of a motor unit and its recruitment. Our study will both determine whether STA is a reliable indicator of motor unit twitch force direction, and determine whether different twitch force directions among motor units forms the physiological basis for differential motor unit activation. Relevance to Public Health: After suffering a stroke, many individuals lose the ability to move their joints in particular directions. Our study seeks both to develop methods to examine the direction of movement controlled by single cells in the spinal cord, and to determine how the undamaged brain activates these cells to control different directions of joint movement. Having this information will give us a baseline which we can then use to better understand how the damaged brain controls the spinal cord, and how specific interventions may improve motor control post-stroke. [unreadable] [unreadable] [unreadable]

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common and often debilitating condition. The underlying cause of CP/CPPS remains unknown. We recently published the first neuroimaging study comparing men with CP/CPPS to healthy men. We found that, most importantly, the functional connectivity between a brain motor region that activates pelvic floor muscles and a viscerosensory region in the right posterior insula was significantly reduced in men with CP/CPPS compared to healthy men. This prior work suggests that understanding this sensorimotor functional connection, which we term pelvic-motor/right- posterior-insula functional connectivity, may be critical to understanding the pathophysiology of CP/CPPS. However, we still do not fundamentally know how resting brain function influences active sensorimotor control. In the proposed work, we aim to fill this knowledge gap by relating pelvic-motor/right-posterior-insula functional connectivity to automatic pelvic floor muscle activation during voluntary activation of non-pelvic floor muscles in men with and without CP/CPPS. We will recruit 52 men with CP/CPPS and 52 healthy men. In each participant, we will use resting-state functional Magnetic Resonance Imaging (rs-fMRI) to quantify pelvic-motor/right- posterior-insula functional connectivity, surface EMG to quantify automatic pelvic floor muscle activation during voluntary gluteal muscle activation, and questionnaires to quantify CP/CPPS pain intensity. rs-fMRI, EMG, and pain measures will be analyzed with the following Aims. In Aim 1, we will study inter-individual differences in men and determine if reduced pelvic-motor/right-posterior-insula functional connectivity correlates with increases in the magnitude of automatic pelvic floor muscle activation during voluntary activation of non-pelvic floor muscles. In Aim 2, we will compare healthy men and men with CP/CPPS, whom we have shown to have a reduced value of resting state pelvic-motor/right-posterior-insula functional connectivity compared to healthy male controls. We will determine if men with CP/CPPS show corresponding increases in the magnitude of automatic pelvic floor muscle activation during voluntary activation of the gluteus maximus muscle, and if the magnitude of automatic pelvic floor muscle activation is correlated with the intensity of CP/CPPS pain. This work, to our knowledge, represents the first study relating resting brain function to the magnitude of automatic muscle activation during movement. This work is also the first study proposing to test a specific mechanism of altered pelvic floor muscle control in men with CP/CPPS. Our prior work defined a brain connection of interest in men with CP/CPPS. Our proposed work will determine if this brain connection is related to altered movement control. Our future work will be able to then examine modifying movement control as an approach to restoring normal brain function in men with CP/CPPS.

ABSTRACT Urologic Chronic Pelvic Pain Syndrome (UCPPS) encompasses two highly prevalent chronic urologic pain disorders, interstitial cystitis/ bladder pain syndrome (IC/BPS) in men and women, and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men. Like many chronic pain disorders, UCPPS is poorly understood and characterized, and treatment is mostly empirical and unsatisfactory. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), to study the etiology and treated natural history of UCPPS, to inform better treatments and management of symptoms through improved designs of clinical trials, and to identify clinical factors and research measurements to define clinically relevant sub-groups of these patients. The MAPP Research Network is currently completing enrollment of participants into the Trans-MAPP Symptom Patterns Study (SPS), which involves integrated phenotyping of UCPPS participants at baseline and during a 36-month longitudinal, observational period. The SPS includes measures to refine UCPPS subgrouping, identify symptom trends, and discover associated risk factors and biological correlates to progression profiles. Integrated within the central protocol are studies to correlate clinical and biological profiles with response to selected UCPPS therapies (the Analysis of Therapies during Longitudinal Assessment of Symptoms [ATLAS] study). The current funding period ends in June 2019. We propose a three-year funding extension, through June 2022. During the proposed three-year extension, we aim to accomplish the following: SPECIFIC AIM 1: To Obtain an Additional 12 Months of Follow-up in the MAPP- II SPS. The MAPP-II SPS was designed to follow UCPPS participants for up to three years. By extending the timeframe for longitudinal follow-up from July 2019 to July 2020, the number of UCPPS participants followed for three years in the SPS will almost double (from 198 to 384). This additional data will substantially increase the ability of MAPP investigators to examine patterns and predictors of UCPPS symptoms over time. SPECIFIC AIM 2: To Observe Additional ATLAS Events in the MAPP-II SPS. A major focus of the MAPP-II SPS is to correlate individual participant phenotypes with UCPPS treatment response. To accomplish this, SPS participants complete a phenotyping assessment before and after starting new UCPPS treatments (ATLAS study). The additional year of follow-up will provide time for new treatment `events' to occur which can be included in this important analysis. SPECIFIC AIM 3: To Conduct Analyses of MAPP-II Data. The current funding period provides inadequate time for MAPP investigators to analyze the data collected as part of the SPS. Therefore, the final two years of the proposed three-year MAPP-II extension will be devoted exclusively to data analysis and manuscript preparation.

PROJECT SUMMARY Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a common, chronic, and debilitating condition in women. The underlying cause of IC/BPS remains unknown. We recently published the first functional magnetic resonance imaging (fMRI) study comparing brain function in women with IC/BPS to healthy women. We found that women with IC/BPS have altered resting activity in supplementary motor area (SMA). Specifically, these changes appear in a part of SMA that we have shown to control pelvic floor muscle activity (?pelvic-SMA?). Our results provide the first explanation for extensive published reports of increased pelvic floor muscle activity in women with IC/BPS. We hypothesize that we are observing evidence of an important theory of chronic pain: motor cortical changes occur that are initially beneficial to increase protective muscle activity but are ultimately maladaptive and perpetuate pain. Our goal is to reduce pain by improving brain activity and pelvic muscle activity (making them more similar to healthy individuals). Using non-invasive repetitive transcranial magnetic stimulation (rTMS) directed at pelvic-SMA, we aim to determine if we can reduce pain (Aim 1), improve resting brain activity (fMRI) and resting pelvic floor muscle electromyographic (EMG) activity in IC/BPS (Aim 2), and to link the pain reductions to fMRI/EMG improvements to develop a causal mediation model of IC/BPS symptoms (Aim 3). We will recruit 75 women with IC/BPS to participate in the study, and participants will be randomized to 3 groups of 25 to test different rTMS paradigms: high-frequency (to increase excitability), low-frequency (to decrease excitability), and sham (as a control). Our preliminary data suggest that high-frequency stimulation is the best protocol since it improves resting pelvic-SMA activity while reducing pain and pelvic muscle activity. These results are convergent with an independently-published preliminary study that suggests that 5 consecutive days of high-frequency stimulation can reduce IC/BPS pain relative to sham, even measured 3 weeks after the cessation of stimulation. We will extend these preliminary findings in the proposed work: in the high-frequency and sham rTMS groups, we will study 5 consecutive days of stimulation with both shorter-term outcome measures (associated with the first day of stimulation) and longer-term outcome measures (3 weeks after the cessation of stimulation). In the low-frequency rTMS group, we will only examine shorter-term outcome measures associated with a single session, since our preliminary data suggest that low-frequency stimulation is active but perturbs pelvic-SMA and resting pelvic floor muscle activity away from values associated with healthy controls and does not reduce pain. Our preliminary results agree with a large body of literature suggesting that high-frequency rTMS applied to motor cortex is the best rTMS paradigm to reduce pain. However, our proposed work has the potential to greatly innovate the field of brain stimulation for pain by using sham and active comparison groups, as well as objective fMRI/EMG outcome measures, to define the mechanism by which high-frequency stimulation can improve deficiencies in motor function in chronic pain.