Abnormal Resting-State Network Presence in Females with Overactive Bladder.

Overactive bladder (OAB) is a global problem reducing the quality of life of patients and increasing the costs of any healthcare system. The etiology of OAB is understudied but likely involves supraspinal network alterations. Here, we characterized supraspinal resting-state functional connectivity in 12 OAB patients and 12 healthy controls (HC) who were younger than 60 years. Independent component analysis showed that OAB patients had a weaker presence of the salience (Cohen's d = 0.9) and default mode network (Cohen's d = 1.1) and weaker directed connectivity between the fronto-parietal network and salience network with a longer lag time compared to HC. A region of interest analysis demonstrated weaker connectivity in OAB compared to HC (Cohen's d > 1.6 or < -1.6), particularly within the frontal and prefrontal cortices. In addition, weaker seed (insula, ventrolateral prefrontal cortex) to voxel (anterior cingulate cortex, frontal gyrus, superior parietal lobe, cerebellum) connectivity was found in OAB compared to HC (Cohen's d > 1.9). The degree of deviation in supraspinal connectivity in OAB patients (relative to HC) appears to be an indicator of the severity of the lower urinary tract symptoms and an indication that such symptoms are directly related to functional supraspinal alterations. Thus, future OAB therapy options should also consider supraspinal targets, while neuroimaging techniques should be given more consideration in the quest for better phenotyping of OAB.

High-level motor planning allows flexible walking at different gait patterns in a neuromechanical model.

Humans can freely adopt gait parameters like walking speed, step length, or cadence on the fly when walking. Planned movement that can be updated online to account for changes in the environment rather than having to rely on habitual, reflexive control that is adapted over long timescales. Here we present a neuromechanical model that accounts for this flexibility by combining movement goals and motor plans on a kinematic task level with low-level spinal feedback loops. We show that the model can walk at a wide range of different gait patterns by choosing a small number of high-level control parameters representing a movement goal. A larger number of parameters governing the low-level reflex loops in the spinal cord, on the other hand, remain fixed. We also show that the model can generalize the learned behavior by recombining the high-level control parameters and walk with gait patterns that it had not encountered before. Furthermore, the model can transition between different gaits without the loss of balance by switching to a new set of control parameters in real time.

OAB supraspinal control network, transition with age, and effect of treatment: A systematic review.

OBJECTIVE: In light of a better understanding of supraspinal control of nonneurogenic overactive bladder (OAB), the prevalence of which increases with age, functional imaging has gained significant momentum. The objective of this study was to perform a systematic review on the transition of supraspinal control of OAB with age, the effect of therapeutic modalities, and a coordinate-based meta-analysis of all neuroimaging evidence on supraspinal OAB control in response to bladder filling. METHODOLOGY: We performed a systematic literature search of all relevant libraries in November 2021. The coordinates of brain activity were extracted from eligible neuroimaging studies to perform an activation likelihood estimation (ALE) meta-analysis. RESULTS: A total of 16 studies out of 241 were selected for our systematic review. Coordinates were extracted from five experiments involving 70 patients. ALE meta-analysis showed activation of the insula, supplementary motor area, dorsolateral prefrontal cortex, anterior cingulate gyrus, and temporal gyrus with a transition of activation patterns with age, using a threshold of uncorrected p < 0.001. Among young patients, neuroplasticity allows the activation of accessory circuits to maintain continence, as in the cerebellum and temporoparietal lobes. Anticholinergics, pelvic floor muscle training, sacral neuromodulation, and hypnotherapy are correlated with supraspinal changes attributed to adaptability and possibly a substratum of an intrinsic supraspinal component. The latter is better demonstrated by a resting-state functional connectivity analysis, a promising tool to phenotype OAB with recent successful models of predicting severity and response to behavioral treatments. CONCLUSION: Future neuroimaging studies are necessary to better define an OAB neurosignature to allocate patients to successful treatments.

Considering non-bladder aetiologies of overactive bladder: a functional neuroimaging study.

OBJECTIVES: To better understand the neuropathophysiology of overactive bladder (OAB) in women by characterising supraspinal activity in response to bladder distention and cold stimulation. SUBJECTS/PATIENTS AND METHODS: We recruited 24 female participants, 12 with OAB (median [interquartile range, IQR] age 40 [32-42] years) and 12 healthy controls (HCs) without lower urinary tract (LUT) symptoms (median [IQR] age 34 [28-44] years), and assessed LUT and cognitive function through neuro-urological examination, 3-day bladder diary, urodynamic investigation, and questionnaires. Functional magnetic resonance (MR) imaging using a 3-T scanner was performed in all participants during automated, repetitive bladder filling and draining (block design) with 100 mL body temperature (37 °C) saline using a MR-compatible and MR-synchronised infusion-drainage device until strong desire to void (HIGH-FILLING/DRAINING) and bladder filling with cold saline (4 °C, i.e. COLD). Whole-brain and region-of-interest analyses were conducted using Statistical Parametric Mapping, version 12. RESULTS: Significant between-group differences were found for 3-day bladder diary variables (i.e. voiding frequency/24 h, P < 0.001; voided volume/void, P = 0.04; and urinary incontinence [UI] episodes/24 h, P = 0.007), questionnaire scores (International Consultation on Incontinence Questionnaire-Female LUT symptoms [overall, filling, and UI scores, all P < 0.001]; the Overactive Bladder Questionnaire short form [symptoms and quality-of-life scores, both P < 0.001]; the Hospital Anxiety and Depression Scale [anxiety P = 0.004 and depression P = 0.003 scores]), as well as urodynamic variables (strong desire to void, P = 0.02; maximum cystometric capacity, P = 0.007; and presence of detrusor overactivity, P = 0.002). Age, weight and cognitive function (i.e. Mini-Mental State Examination, P = 1.0) were similar between groups (P > 0.05). In patients with OAB, the HIGH task elicited activity in the superior temporal gyrus, ventrolateral prefrontal cortex (VLPFC), and mid-cingulate cortex; and the COLD task elicited activity in the VLPFC, cerebellum, and basal ganglia. Compared to HCs, patients with OAB showed significantly stronger cerebellar activity during HIGH-FILLING and significantly less activity in the insula and VLPFC during HIGH-DRAINING. CONCLUSIONS: The present findings suggest a sensory processing and modulation deficiency in our OAB group, probably as part of their underlying pathophysiology, as they lacked activity in essential sensory processing areas, such as the insula. Instead, accessory areas, such as the cerebellum, showed significantly stronger activation compared to HCs, presumably supporting pelvic-floor motor activity to prevent UI. The novel findings of the present study provide physiological evidence of the necessity to consider non-bladder aetiologies of bladder symptoms.

Neuroimaging in Neuro-Urology.

Neuroimaging allows in vivo visualization of neuronal structures/processes to assess their involvement in bodily functions. This is particularly valuable for the assessment of complex, multilevel neuronal controlled functions, such as urine storage and micturition. Using positron emission tomography or functional magnetic resonance imaging, significant alterations of supraspinal lower urinary tract (LUT) control have been described in patients with neurogenic LUT dysfunction due to spinal cord injury, Parkinson's disease, and multiple sclerosis. Severity of such alterations often correlates with symptom/dysfunction severity, both of which could be partly mitigated by therapeutic interventions. However, the overall evidence and study quality are presently very limited, and a multidisciplinary approach will be required to achieve clinical relevance in the long term. PATIENT SUMMARY: We reviewed the findings of neuroimaging studies in patients with bladder dysfunction due to neurological trauma/disease. Changes in the nervous systems of these patients alter bladder control, and neuroimaging may become a valuable tool for assessing these alterations.

Nervous mechanisms of locomotion in different directions.

Locomotion, that is active propulsive movement of the body in space, is a vital motor function. Intensive studies of the main, for the majority of living beings, form of locomotion, forward locomotion, have revealed essential features of the organization and operation of underlying neural mechanisms. However, animals and humans are capable to locomote not only forward but also in other directions in relation to the body axis, e.g. backward, sideways, etc. Single steps in different directions are also used for postural corrections during locomotion and during standing. Recent studies of mechanisms underlying control of locomotion in different directions have greatly expanded our knowledge about locomotor system and can contribute to improvement of rehabilitation strategies aimed at restoration of locomotion and balance control in patients. This review outlines recent advances in the studies of locomotion in different directions in lower and higher vertebrates, with special attention given to the neuronal locomotor mechanisms.

Decreased supraspinal control and neuromuscular function controlling the ankle joint in athletes with chronic ankle instability.

PURPOSE: Chronic ankle instability (CAI) alters lower extremity neuromuscular function, associated with a change in corticomotor excitability. The aim of this study was to compare corticomotor excitability and neuromuscular function of the muscles around the ankle between athletes with CAI and without CAI (non-CAI). METHODS: Nineteen CAI athletes (15 men and 4 women) and 19 non-CAI athletes (15 men and 4 women) participated (age- and sex-matched). Corticomotor excitability was measured by transcranial magnetic stimulation for the following muscles: the tibialis anterior (TA), peroneus longus (PL) and gastrocnemius medialis (GM). The resting motor threshold (rMT), motor evoked potential (MEP), and latency (Lat) were subsequently measured. Neuromuscular function was assessed with a jump test, using the EMG activity before foot contact, peak torque, and joint position sense. RESULTS: The corticomotor excitability in CAI showed a lower normalized MEP in the TA (p = 0.026) and PL (p = 0.003), and longer latency in the TA (p = 0.049) and GM (p = 0.027) compared with non-CAI. The neuromuscular assessment showed CAI had less EMG activity of the PL (p < 0.001), less peak torque of the dorsiflexor (p = 0.019) muscle compared with non-CAI. CONCLUSION: Athletes with CAI had lower corticomotor excitability in the TA and PL and a longer latency in the TA and GM muscles. Additionally, CAI demonstrated functional neuromuscular deficits by decreasing EMG activity of the PL muscle and strength of the dorsiflexor muscle. Our findings indicated maladaptation at both cortical and peripheral levels among athletes with CAI.

Reliability of supraspinal correlates to lower urinary tract stimulation in healthy participants - A fMRI study.

Previous functional neuroimaging studies provided evidence for a specific supraspinal network involved in lower urinary tract (LUT) control. However, data on the reliability of blood oxygenation level-dependent (BOLD) signal changes during LUT task-related functional magnetic resonance imaging (fMRI) across separate measurements are lacking. Proof of the latter is crucial to evaluate whether fMRI can be used to assess supraspinal responses to LUT treatments. Therefore, we prospectively assessed task-specific supraspinal responses from 20 healthy participants undergoing two fMRI measurements (test-retest) within 5-8 weeks. The fMRI measurements, conducted in a 3T magnetic resonance (MR) scanner, comprised a block design of repetitive bladder filling and drainage using an automated MR-compatible and MR-synchronized infusion-drainage device. Following transurethral catheterization and bladder pre-filling with body warm saline until participants perceived a persistent desire to void (START condition), fMRI was recorded during repetitive blocks (each 15 s) of INFUSION and WITHDRAWAL of 100 mL body warm saline into respectively from the bladder. BOLD signal changes were calculated for INFUSION minus START. In addition to whole brain analysis, we assessed BOLD signal changes within multiple 'a priori' region of interest (ROI), i.e. brain areas known to be involved in the LUT control from previous literature. To evaluate reliability of the fMRI results between visits, we applied different types of analyses: coefficient of variation (CV), intraclass correlation coefficient (ICC), Sørensen-Dice index, Bland-Altman method, and block-wise BOLD signal comparison. All participants completed the study without adverse events. The desire to void was rated significantly higher for INFUSION compared to START or WITHDRAWAL at both measurements without any effect of visit. At whole brain level, significant (p < 0.05, cluster corrected, k ≥ 41 voxels) BOLD signal changes were found for the contrast INFUSION compared to START in several brain areas. Overlap of activation maps from both measurements were observed in the orbitofrontal cortex, insula, ventrolateral prefrontal cortex (VLPFC), and inferior parietal lobe. The two highest ICCs, based on a ROI's mean beta weight, were 0.55 (right insular cortex) and 0.47 (VLPFC). Spatial congruency (Sørensen-Dice index) of all voxels within each ROI between measurements was highest in the insular cortex (left 0.55, right 0.44). In addition, the mean beta weight of the right insula and right VLPFC demonstrated the lowest CV and narrowest Bland and Altman 95% limits of agreement. In conclusion, the right insula and right VLPFC were revealed as the two most reliable task-specific ROIs using our automated, MR-synchronized protocol. Achieving high reliability using a viscero-sensory/interoceptive task such as repetitive bladder filling remains challenging and further endeavour is highly warranted to better understand which factors influence fMRI outcomes and finally to assess LUT treatment effects on the supraspinal level.

Motor Control of Human Spinal Cord Disconnected from the Brain and Under External Movement.

Motor control after spinal cord injury is strongly depending on residual ascending and descending pathways across the lesion. The individually altered neurophysiology is in general based on still intact sublesional control loops with afferent sensory inputs linked via interneuron networks to efferent motor outputs. Partial or total loss of translesional control inputs reduces and alters the ability to perform voluntary movements and results in motor incomplete (residual voluntary control of movement functions) or motor complete (no residual voluntary control) spinal cord injury classification. Of particular importance are intact functionally silent neural structures with residual brain influence but reduced state of excitability that inhibits execution of voluntary movements. The condition is described by the term discomplete spinal cord injury. There are strong evidences that artificial afferent input, e.g., by epidural or noninvasive electrical stimulation of the lumbar posterior roots, can elevate the state of excitability and thus re-enable or augment voluntary movement functions. This modality can serve as a powerful assessment technique for monitoring details of the residual function profile after spinal cord injury, as a therapeutic tool for support of restoration of movement programs and as a neuroprosthesis component augmenting and restoring movement functions, per se or in synergy with classical neuromuscular or muscular electrical stimulation.

Targeting Lumbar Spinal Neural Circuitry by Epidural Stimulation to Restore Motor Function After Spinal Cord Injury.

Epidural spinal cord stimulation has a long history of application for improving motor control in spinal cord injury. This review focuses on its resurgence following the progress made in understanding the underlying neurophysiological mechanisms and on recent reports of its augmentative effects upon otherwise subfunctional volitional motor control. Early work revealed that the spinal circuitry involved in lower-limb motor control can be accessed by stimulating through electrodes placed epidurally over the posterior aspect of the lumbar spinal cord below a paralyzing injury. Current understanding is that such stimulation activates large-to-medium-diameter sensory fibers within the posterior roots. Those fibers then trans-synaptically activate various spinal reflex circuits and plurisegmentally organized interneuronal networks that control more complex contraction and relaxation patterns involving multiple muscles. The induced change in responsiveness of this spinal motor circuitry to any residual supraspinal input via clinically silent translesional neural connections that have survived the injury may be a likely explanation for rudimentary volitional control enabled by epidural stimulation in otherwise paralyzed muscles. Technological developments that allow dynamic control of stimulation parameters and the potential for activity-dependent beneficial plasticity may further unveil the remarkable capacity of spinal motor processing that remains even after severe spinal cord injuries.

Segmental organization of vestibulospinal inputs to spinal interneurons mediating crossed activation of thoracolumbar motoneurons in the neonatal mouse.

Vestibulospinal pathways activate contralateral motoneurons (MNs) in the thoracolumbar spinal cord of the neonatal mouse exclusively via axons descending ipsilaterally from the vestibular nuclei via the lateral vestibulospinal tract (LVST; Kasumacic et al., 2010). Here we investigate how transmission from the LVST to contralateral MNs is mediated by descending commissural interneurons (dCINs) in different spinal segments. We test the polysynaptic nature of this crossed projection by assessing LVST-mediated ventral root (VR) response latencies, manipulating synaptic responses pharmacologically, and tracing the pathway transynaptically from hindlimb extensor muscles using rabies virus (RV). Longer response latencies in contralateral than ipsilateral VRs, near-complete abolition of LVST-mediated calcium responses in contralateral MNs by mephenesin, and the absence of transsynaptic RV labeling of contralateral LVST neurons within a monosynaptic time window all indicate an overwhelmingly polysynaptic pathway from the LVST to contralateral MNs. Optical recording of synaptically mediated calcium responses identifies LVST-responsive ipsilateral dCINs that exhibit segmental differences in proportion and dorsoventral distribution. In contrast to thoracic and lower lumbar segments, in which most dCINs are LVST responsive, upper lumbar segments stand out because they contain a much smaller and more ventrally restricted subpopulation of LVST-responsive dCINs. A large proportion of these upper lumbar LVST-responsive dCINs project to contralateral L5, which contains many of the hindlimb extensor MNs activated by the LVST. A selective channeling of LVST inputs through segmentally and dorsoventrally restricted subsets of dCINs provides a mechanism for targeting vestibulospinal signals differentially to contralateral trunk and hindlimb MNs in the mammalian spinal cord.

Supraspinal Control of Urine Storage and Micturition in Men--An fMRI Study.

Despite the crucial role of the brain in the control of the human lower urinary tract, little is known about the supraspinal mechanisms regulating micturition. To investigate the central regulatory mechanisms activated during micturition initiation and actual micturition, we used an alternating sequence of micturition imitation/imagination, micturition initiation, and actual micturition in 22 healthy males undergoing functional magnetic resonance imaging. Subjects able to micturate (voiders) showed the most prominent supraspinal activity during the final phase of micturition initiation whereas actual micturition was associated with significantly less such activity. Initiation of micturition in voiders induced significant activity in the brainstem (periaqueductal gray, pons), insula, thalamus, prefrontal cortex, parietal operculum and cingulate cortex with significant functional connectivity between the forebrain and parietal operculum. Subjects unable to micturate (nonvoiders) showed less robust activation during initiation of micturition, with activity in the forebrain and brainstem particularly lacking. Our findings suggest that micturition is controlled by a specific supraspinal network which is essential for the voluntary initiation of micturition. Once this network triggers the bulbospinal micturition reflex via brainstem centers, micturition continues automatically without further supraspinal input. Unsuccessful micturition is characterized by a failure to activate the periaqueductal gray and pons during initiation.