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Abstract 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.

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.

Abstract 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.

Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.

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.

We developed a new approach to investigate how the nervous system activates multiple redundant muscles by studying the endpoint force fluctuations during isometric force generation at a multi-degree-of-freedom joint. We hypothesized that, due to signal-dependent muscle force noise, endpoint force fluctuations would depend on the target direction of index finger force and that this dependence could be used to distinguish flexible from synergistic activation of the musculature. We made high-gain measurements of isometric forces generated to different target magnitudes and directions, in the plane of index finger metacarpophalangeal joint abduction–adduction/flexion–extension. Force fluctuations from each target were used to calculate a covariance ellipse, the shape of which varied as a function of target direction. Directions with narrow ellipses were approximately aligned with the estimated mechanical actions of key muscles. For example, targets directed along the mechanical action of the first dorsal interosseous (FDI) yielded narrow ellipses, with 88% of the variance directed along those target directions. It follows the FDI is likely a prime mover in this target direction and that, at most, 12% of the force variance could be explained by synergistic coupling with other muscles. In contrast, other target directions exhibited broader covariance ellipses with as little as 30% of force variance directed along those target directions. This is the result of cooperation among multiple muscles, based on independent electromyographic recordings. However, the pattern of cooperation across target directions indicates that muscles are recruited flexibly in accordance with their mechanical action, rather than in fixed groupings. [ABSTRACT FROM AUTHOR]

Resistance training is a promising strategy to promote healthy cognitive aging; however, the brain mechanisms by which resistance training benefits cognition have yet to be determined. Here, we examined the effects of a 12-week resistance training program on resting brain activity and cerebrovascular function in 20 healthy older adults (14 females, mean age 69.1 years). In this single group clinical trial, multimodal 3 T magnetic resonance imaging was performed at 3 time points: baseline (preceding a 12-week control period), pre-intervention, and post-intervention. Along with significant improvements in fluid cognition ( d = 1.27), 4 significant voxelwise clusters were identified for decreases in resting brain activity after the intervention (Cerebellum, Right Middle Temporal Gyrus, Left Inferior Parietal Lobule, and Right Inferior Parietal Lobule), but none were identified for changes in resting cerebral blood flow. Using a separate region of interest approach, we provide estimates for improved cerebral blood flow, compared with declines over the initial control period, in regions associated with cognitive impairment, such as hippocampal blood flow ( d = 0.40), and posterior cingulate blood flow ( d = 0.61). Finally, resistance training had a small countermeasure effect on the age-related progression of white matter lesion volume (rank-biserial = −0.22), a biomarker of cerebrovascular disease. These proof-of-concept data support larger trials to determine whether resistance training can attenuate or even reverse salient neurodegenerative processes.

ObjectivesResistance training (RT) is a promising strategy to slow or prevent fluid cognitive decline during aging. However, the effects of strength-specific RT programs have received little attention. The purpose of this single-group proof of concept clinical trial was to determine whether a 12-week strength training (ST) program could improve fluid cognition in healthy older adults 60 to 80 years of age, and to explore concomitant physiological and psychological changes.MethodsTwenty participants (69.1 ± 5.8 years, 14 women) completed this study with no drop-outs or severe adverse events. Baseline assessments were completed before an initial 12-week control period, then participants were re-tested at pre-intervention and after the 12-week ST intervention. The NIH Toolbox Cognition Battery and standard physical and psychological measures were administered at all three time points. During the 36 sessions of periodized ST (3 sessions per week), participants were supervised by an exercise specialist and challenged via autoregulatory load progression.ResultsTest-retest reliability over the control period was good for fluid cognition and excellent for crystallized cognition. Fluid composite scores significantly increased from pre- to post-intervention (8.2 ± 6.1%, p < 0.01, d = 1.27), while crystallized composite scores did not (-0.5 ± 2.8%, p = 0.46, d = -0.34). Performance on individual fluid instruments, including executive function, attention, working memory, and processing speed, also significantly improved. Surprisingly, changes in fluid composite scores had small negative correlations with changes in muscular strength and sleep quality, but a small positive correlation with changes in muscular power.ConclusionsThus, improvements in fluid cognition can be safely achieved in older adults using a 12-week high-intensity ST program, but further controlled studies are needed to confirm these findings. Furthermore, the relationship with other widespread physiological and psychological benefits remains unclear.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

Muscle coordination studies repeatedly show low-dimensionality of muscle activations for a wide variety of motor tasks. The basis vectors of this low-dimensional subspace, termed muscle synergies, are hypothesized to reflect neurally-established functional muscle groupings that simplify body control. However, the muscle synergy hypothesis has been notoriously difficult to prove or falsify. We use cadaveric experiments and computational models to perform a crucial thought experiment and develop an alternative explanation of how muscle synergies could be observed without the nervous system having controlled muscles in groups. We first show that the biomechanics of the limb constrains musculotendon length changes to a low-dimensional subspace across all possible movement directions. We then show that a modest assumption--that each muscle is independently instructed to resist length change--leads to the result that electromyographic (EMG) synergies will arise without the need to conclude that they are a product of neural coupling among muscles. Finally, we show that there are dimensionality-reducing constraints in the isometric production of force in a variety of directions, but that these constraints are more easily controlled for, suggesting new experimental directions. These counter-examples to current thinking clearly show how experimenters could adequately control for the constraints described here when designing experiments to test for muscle synergies--but, to the best of our knowledge, this has not yet been done.

Background: Non-invasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused upon protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than M1 itself. While previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes., Objective: The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations., Methods: A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13trials, n = 565 participants) were appraised using PEDro and GRADE and a random effects model was used to meta-analyse outcomes where possible., Results: A small number of studies found that NIBS applied to DLPFC may improve pain modulation in patients with fibromyalgia, and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied between studies and there remains a paucity of primary research., Conclusion: This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Background: Low peak alpha frequency (PAF) is an electroencephalography (EEG) outcome associated reliably with high acute pain sensitivity. However, existing research suggests that the relationship between PAF and chronic pain is more variable. This variability could be attributable to chronic pain groups typically being examined as homogenous populations, without consideration being given to potential diagnosis-specific differences. Indeed, while emerging work has compared individuals with chronic pain to healthy controls, no previous studies have examined differences in PAF between diagnoses or across chronic pain subtypes., Methods: To address this gap, we reanalysed a dataset of resting state EEG previously used to demonstrate a lack of difference in PAF between individuals with chronic pain and healthy controls. In this new analysis, we separated patients by diagnosis before comparing PAF across three subgroups: chronic widespread pain (n = 30), chronic back pain (n = 38), and healthy controls (n = 87)., Results: We replicate the original finding of no significant difference between chronic pain groups and controls, but also find that individuals with widespread pain had significantly higher global average PAF values than those of people with chronic back pain [p = 0.028, β = 0.25 Hz] after controlling for age, sex, and depression., Conclusions: These novel findings reveal PAF values in individuals with chronic pain may be diagnosis-specific and not uniformly shifted from the values of healthy controls. Future studies should account for diagnosis and be cautious with exploring homogenous 'chronic pain' classifications during investigations of PAF., Significance: Our work suggests that, contrary to previous hypotheses, inter-individual differences in PAF reflect diagnosis-specific mechanisms rather than the general presence of chronic pain, and therefore may have important implications for future work regarding individually-tailored pain management strategies., (© 2024 European Pain Federation ‐ EFIC ®.)

Purpose: Of women with interstitial cystitis/bladder pain syndrome and men with chronic prostatitis/chronic pelvic pain syndrome 85% have concomitant pelvic floor muscle tenderness (PFT). The significance of this finding is incompletely understood. This study examines PFT among participants in the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network and its relationship with urologic chronic pelvic pain syndrome (UCPPS) symptom severity in order to determine whether this is a phenotypic predictor in UCPPS., Materials and Methods: Participants in the MAPP Network Symptom Patterns Study underwent a standardized pelvic examination (PEX). Trained examiners palpated 6 locations evaluating the pelvic musculature for PFT. Participants were assigned a 0 to 6 PEX score based on the number of areas with tenderness on PEX. Using regression tree models, PEX scores were divided into low (0, 1), mid (2, 3, 4, 5) and high (6). The relationship between PFT and UCPPS symptoms was examined using several validated questionnaires., Results: The study cohort consisted of 562 UCCPS participants (375 females and 187 males) and 69 controls. Diagnoses included interstitial cystitis/bladder pain syndrome (397), chronic prostatitis/chronic pelvic pain syndrome (122), both (34) or no diagnosis (9). Of UCPPS participants 81% had PFT on PEX compared to 9% of controls: 107 (19%) low, 312 (56%) mid and 143 (25%) high. Participants with higher PFT scores had more severe disease burden (worse pelvic pain and urinary symptoms), worse quality of life and more widespread distribution of nonpelvic pain., Conclusions: UCPPS patients with more widespread PFT have severe pain and urinary symptoms, worse quality of life and a more centralized pain phenotype.