Salience network functional connectivity is spatially heterogeneous across sensorimotor cortex in healthy humans.

The salience network is responsive during a range of conditions requiring immediate behavioral responses, including pain processing. Resting-state functional connectivity of the salience network to the sensorimotor cortex is altered in chronic pain. However, little is understood about their fundamental communication in the absence of pain. In this study, we mapped salience network resting-state functional connectivity across sensorimotor cortex in healthy individuals. Using electromyography and task-based functional magnetic resonance imaging (fMRI), we first localized distinct regions-of-interest across sensorimotor cortex in medial (gluteal), intermediate (shoulder), and lateral (hand) areas. We then used resting-state fMRI for two cohorts (primary and replication) of healthy individuals from public repositories to map salience network resting-state functional connectivity across sensorimotor cortex. Both the primary and replication cohorts exhibited significant heterogeneity in salience network resting-state functional connectivity across the sensorimotor regions-of-interest. Using a cortical flatmap to visualize the entire sensorimotor surface, we observed similar heterogeneity in both cohorts. In general, the somatotopic representation of proximal body regions (trunk/face) had higher salience network resting-state functional connectivity compared to distal body regions (upper/lower limbs). We conclude that sensorimotor cortex is spatially heterogeneous in its interaction with the salience network in healthy individuals.

Motor cortical neuromodulation of pelvic floor muscle tone: Potential implications for the treatment of urologic conditions.

AIMS: In the human brain, supplementary motor area (SMA) is involved in the control of pelvic floor muscles (PFMs). SMA dysfunction has been implicated in several disorders involving PFMs, including urinary incontinence and urologic pain. Here, we aimed to provide a proof-of-concept study to demonstrate the feasibility of modulating resting PFM activity (tone) as well as SMA activity with noninvasive stimulation of SMA. METHODS: We studied six patients (3 women + 3 men) with Urologic Chronic Pelvic Pain Syndrome. Repetitive transcranial magnetic stimulation (rTMS) was applied to SMA immediately after voiding. We tested two rTMS protocols: high-frequency (HF-rTMS) which is generally excitatory, and low-frequency (LF-rTMS) which is generally inhibitory. PFM activity was measured during rTMS using electromyography. Brain activity was measured immediately before and after rTMS using functional magnetic resonance imaging. RESULTS: The rTMS protocols had significantly different effects on resting activity in PFMs (P = 0.03): HF-rTMS decreased and LF-rTMS increased pelvic floor tone. SMA activity showed a clear trend ( P = 0.06) toward the expected differential changes: HF-rTMS increased and LF-rTMS decreased SMA activity. CONCLUSIONS: We interpret the differential effects of rTMS at the brain and muscle level as novel support for an important inhibitory influence of SMA activity on pelvic floor tone after voiding. This preliminary study provides a framework for designing future studies to determine if neuromodulation of SMA could augment therapy for chronic urologic conditions.

Brain Connectivity Associated with Muscle Synergies in Humans.

The human brain is believed to simplify the control of the large number of muscles in the body by flexibly combining muscle coordination patterns, termed muscle synergies. However, the neural connectivity allowing the human brain to access and coordinate muscle synergies to accomplish functional tasks remains unknown. Here, we use a surprising pair of synergists in humans, the flexor hallucis longus (FHL, a toe flexor) and the anal sphincter, as a model that we show to be well suited in elucidating the neural connectivity underlying muscle synergy control. First, using electromyographic recordings, we demonstrate that voluntary FHL contraction is associated with synergistic anal sphincter contraction, but voluntary anal sphincter contraction occurs without FHL contraction. Second, using fMRI, we show that two important medial wall motor cortical regions emerge in relation to these tasks: one located more posteriorly that preferentially activates during voluntary FHL contraction and one located more anteriorly that activates during both voluntary FHL contraction as well as voluntary anal sphincter contraction. Third, using transcranial magnetic stimulation, we demonstrate that the anterior region is more likely to generate anal sphincter contraction than FHL contraction. Finally, using a repository resting-state fMRI dataset, we demonstrate that the anterior and posterior motor cortical regions have significantly different functional connectivity with distinct and distant brain regions. We conclude that specific motor cortical regions in humans provide access to different muscle synergies, which may allow distinct brain networks to coordinate muscle synergies during functional tasks. SIGNIFICANCE STATEMENT: How the human nervous system coordinates activity in a large number of muscles is a fundamental question. The brain and spinal cord are believed to simplify the control of muscles by grouping them into functional units called muscle synergies. Motor cortex is involved in activating muscle synergies; however, the motor cortical connections that regulate muscle synergy activation are unknown. Here, we studied pelvic floor muscle synergies to elucidate these connections in humans. Our experiments confirmed that distinct motor cortical regions activate different muscle synergies. These regions have different connectivity to distinct brain networks. Our results are an important step forward in understanding the cortical control of human muscles synergies, and may also have important clinical implications for understanding movement dysfunction.

Cortical activation associated with muscle synergies of the human male pelvic floor.

Human pelvic floor muscles have been shown to operate synergistically with a wide variety of muscles, which has been suggested to be an important contributor to continence and pelvic stability during functional tasks. However, the neural mechanism of pelvic floor muscle synergies remains unknown. Here, we test the hypothesis that activation in motor cortical regions associated with pelvic floor activation are part of the neural substrate for such synergies. We first use electromyographic recordings to extend previous findings and demonstrate that pelvic floor muscles activate synergistically during voluntary activation of gluteal muscles, but not during voluntary activation of finger muscles. We then show, using functional magnetic resonance imaging (fMRI), that a region of the medial wall of the precentral gyrus consistently activates during both voluntary pelvic floor muscle activation and voluntary gluteal activation, but not during voluntary finger activation. We finally confirm, using transcranial magnetic stimulation, that the fMRI-identified medial wall region is likely to generate pelvic floor muscle activation. Thus, muscle synergies of the human male pelvic floor appear to involve activation of motor cortical areas associated with pelvic floor control.

Reducing pain by improving brain and muscle activity with motor cortical neuromodulation in women with interstitial cystitis/bladder pain syndrome: a study protocol for a randomized controlled trial.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relates to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction. This study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam, and outcome measures and questionnaires to further study outcomes. ETHICS AND DISSEMINATION: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT04734847. Registered on February 1, 2021.

Analytic consistency and neural correlates of peak alpha frequency in the study of pain.

BACKGROUND: Several studies have found evidence of reduced resting-state peak alpha frequency (PAF) in populations with pain. However, the stability of PAF from different analytic pipelines used to study pain has not been determined and underlying neural correlates of PAF have not been validated in humans. NEW METHOD: For the first time we compare analytic pipelines and the relationship of PAF to activity in the whole brain and thalamus, a hypothesized generator of PAF. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data and subsequently 64 channel resting-state electroencephalographic (EEG) from 47 healthy men, controls from an ongoing study of chronic prostatitis (a pain condition affecting men). We identified important variations in EEG processing for PAF from a review of 17 papers investigating the relationship between pain and PAF. We tested three progressively complex pre-processing pipelines and varied four postprocessing variables (epoch length, alpha band, calculation method, and region-of-interest [ROI]) that were inconsistent across the literature. RESULTS: We found a single principal component, well-represented by the average PAF across all electrodes (grand-average PAF), explained > 95% of the variance across participants. We also found the grand-average PAF was highly correlated among the pre-processing pipelines and primarily impacted by calculation method and ROI. Across methods, interindividual differences in PAF were correlated with rs-fMRI-estimated activity in the thalamus, insula, cingulate, and sensory cortices. CONCLUSIONS: These results suggest PAF is a relatively stable marker with respect to common pre and post-processing methods used in pain research and reflects interindividual differences in thalamic and salience network function.

Impaired Ability to Relax Pelvic Floor Muscles in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

OBJECTIVE: Excessive pelvic floor muscle activity has been suggested as a source of pain in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Our objective was to determine whether men with CP/CPPS have changes in neural drive that impair their ability to relax pelvic floor muscles. METHODS: We recruited 90 men (42 with CP/CPPS and 48 in the control group [without a history of pelvic pain]). All completed the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). We quantified the ability to relax by comparing resting pelvic floor muscle activity under 2 conditions: a "rest-only" condition, in which participants were instructed to simply relax, and a "rest-between-contraction" condition, in which participants were instructed to rest for several seconds between voluntary pelvic floor muscle contractions. We used multivariate mixed-effects models to examine differences between the groups (men with CP/CPPS and men in the control group) as well as the effect of 6 symptoms captured by the NIH-CPSI: pain related to location (perineum, testicles, penis, suprapubic region) and activity (urination, ejaculation). RESULTS: Men with CP/CPPS were significantly different from men in the control group; men with CP/CPPS had higher resting activity in the rest-between-contraction condition than in the rest-only condition, whereas men in the control group had similar resting activities in both conditions. This effect was strongest in men who reported ejaculation-related pain, which was 70% of the CP/CPPS group. CONCLUSION: Men without a history of pelvic pain were able to relax their pelvic floor muscles back to baseline after performing voluntary pelvic floor muscle contractions. In contrast, men with CP/CPPS, particularly those with ejaculation-related pain, had an impaired ability to relax their pelvic floor muscles. IMPACT: This study may support the investigation of more personalized physical therapist approaches for CP/CPPS that enhance the ability to relax pelvic floor muscles as a mechanism for pain reduction.

Distributed representation of pelvic floor muscles in human motor cortex.

Human motor cortex can activate pelvic floor muscles (PFM), but the motor cortical representation of the PFM is not well characterized. PFM representation is thought to be focused in the supplementary motor area (SMA). Here we examine the degree to which PFM representation is distributed between SMA and the primary motor cortex (M1), and how this representation is utilized to activate the PFM in different coordination patterns. We show that two types of coordination patterns involving PFM can be voluntarily accessed: one activates PFM independently of synergists and a second activates PFM prior to and in proportion with synergists (in this study, the gluteus maximus muscle - GMM). Functional magnetic resonance imaging (fMRI) showed that both coordination patterns involve overlapping activation in SMA and M1, suggesting the presence of intermingled but independent neural populations that access the different patterns. Transcranial magnetic stimulation (TMS) confirmed SMA and M1 representation for the PFM. TMS also showed that, equally for SMA and M1, PFM can be activated during rest but GMM can only be activated after voluntary drive to GMM, suggesting that these populations are distinguished by activation threshold. We conclude that PFM representation is broadly distributed in SMA and M1 in humans.

Reliability of superficial male pelvic floor structural measurements using linear-array transperineal sonography.

This study evaluated reliability of measures for superficial structures of the male pelvic floor (PF) obtained via transperineal sonography. Two embalmed cadavers were dissected to identify positioning of muscles on and around the bulb of the penis and to confirm the PF protocol. Cross-sectional area (CSA) and linear thickness of the bulb of the penis, urethra, bulbospongiosus (BS) muscles, and ischiocavernosus (IC) muscles were measured on 38 transverse images from 20 male patients by three raters with varied study knowledge and sonographic experience. Intra- and inter-rater reliability were calculated with two-way, mixed effects intra-class correlation coefficients. Measures of the bulb of the penis had the best reliability. CSA of all muscles and sagittal thickness of the BS near the central tendon had good reliability. Reliability varied for rater-identified thickest muscle region and measures of the urethra. Our study suggests that structures of the male PF can be reliably evaluated using a transperineal sonographic approach.

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study.

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.