Abstract

Clinical practice often treats higher brain disorders (e.g., Alzheimer's disease and prolonged disorders of consciousness) and pelvic floor dysfunction (e.g., stress urinary incontinence and overactive bladder) as unrelated problems, despite frequent co-occurrence and overlapping vulnerability contexts (e.g., aging, frailty, medications). Here, “axis” denotes a control-architecture mapping and phenotyping heuristic for LUT control and pelvic-floor outlet coordination, rather than a claim of new anatomy or shared etiology. Accordingly, we use a hypothesis-generating control-loop framing that links descending executive control with ascending interoceptive signaling to account for this clinicobiological mismatch. Within this framework, two provisional working failure-mode categories: top-down disintegration, in which impaired supraspinal control weakens volitional inhibition and shifts continence toward reflex-dominant regulation; and bottom-up disturbance, in which persistent peripheral salience-like signals may up-weight interoceptive processing and contribute to maladaptive central network adaptations. These categories are LUT-focused working categories and are not intended as a comprehensive taxonomy of all LUT phenotypes. We further introduce Coordinated Axis Neuromodulation (CAN) as a hypothesis-driven intervention concept that temporally couples cortical, spinal, and peripheral stimulation and may facilitate control-loop–level rebalancing compared with single-node modulation; this proposal requires direct empirical validation. This framework yields testable predictions, including directionally specific coupling between cortical biomarkers (e.g., executive/salience network metrics) and peripheral readouts (e.g., pelvic-floor EMG timing indices and/or diary-defined urgency/UUI burden; urodynamics as supportive phenotyping/secondary mechanistic data when included), and differential response profiles of CAN protocols across failure-mode–stratified cohorts. We outline a validation route spanning synchronized neurophysiology–pelvic physiology paradigms (e.g., EMG timing and diary endpoints; urodynamics as supportive phenotyping/secondary mechanistic data when included), proof-of-mechanism studies, and safety-monitored, mechanism-oriented RCTs designed to falsify or refine the CPA/CAN hypothesis.

1 Introduction

Against the backdrop of a global aging population and the escalating burden of chronic diseases, an increasingly recognized clinical and conceptual disconnect: the recurring co-occurrence of higher-brain dysfunction and pelvic-floor/LUT symptoms in some populations remains artificially compartmentalized within conceptual frameworks and clinical practice (Bartolone et al., 2021). Taking Alzheimer's disease (AD) as an example, as cognitive and memory networks gradually deteriorate, urinary control often declines simultaneously (Bartolone et al., 2021). However, within the current healthcare system, these two processes are assigned to different specialties. AD is regarded as a classic neurodegenerative disorder, while the urinary incontinence associated with AD is often downgraded to a common geriatric issue or a late-stage caregiving burden. Rarely are these two conditions viewed as different manifestations that may be mapped onto a shared control architecture for coordinated phenotyping and management planning, rather than as evidence of shared pathogenesis (Gill et al., 2005; de Codt et al., 2015). A similar distinction exists in the management of patients with prolonged disorders of consciousness (pDoC). While the clinical focus for pDoC primarily centers on promoting arousal within the cortical-thalamic network, a patient's ability to truly be discharged from hospital care largely depends on whether they can be weaned off urinary catheters and regain basic bladder and/or bowel autonomy (Pelizzari et al., 2023). The restoration of consciousness and pelvic floor control, two functions that collectively determine a patient's dignity and prognosis, remain independently addressed in both research and treatment pathway. The core contradiction lies in the fact that the prevalence of this co-occurrence raises a testable question about whether partially overlapping control-circuit vulnerability patterns may be identifiable at the level of control-loop phenotyping, yet current disciplinary barriers hinder direct testing of this connection. Current neurodegeneration-focused and pelvic-floor–focused literatures often discuss cognitive decline in the brain and disruption of urinary control in discipline-specific terms, effectively treating them as parallel pathological trajectories in practice; this separation can also extend to conditions often framed as seemingly localized problems (Jafarian et al., 2025; Szabo et al., 2025). For example, stress urinary incontinence (SUI) is classically defined as an outlet-support/mechanical failure. Beyond this primary mechanism, some patients—particularly those with mixed urinary incontinence, coexisting urgency, or high symptom-related distress—may experience recurrent leakage episodes and anticipatory fear associated with increased symptom vigilance and psychosocial burden (Li and Wang, 2024). In this paper, these central effects are treated as subgroup-dependent aggravation mechanisms rather than core mechanistic evidence for pure SUI pathogenesis.

Whether the presenting disorder is higher-brain dominant (e.g., AD/pDoC) or pelvic-floor dominant (e.g., SUI), the CPA hypothesis maps these conditions onto different nodes of a shared brain–spinal–pelvic control architecture. In this framing, the “continuity” refers to the organization of the control loop (and the possibility of coupled dysfunction across nodes), not to a claim of shared etiology or direct disease-to-disease causality. Scientifically, we possess extensive knowledge relating to how brain networks collapse or how urethral pressure changes, yet we rarely couple these processes within an operationally testable integrative control-loop model. Clinically, patients receive fragmented and multi-targeted interventions combining cognitive medications, nursing pads, and arousal therapy that is disconnected from urinary management. This approach lacks layered, coordinated intervention strategies informed by a shared control-architecture perspective, representing an underdeveloped area for mechanism-oriented translational research.

To address this integrative gap, we draw conceptually on established “axis” models (e.g., the brain–gut axis) as an analogy and precedent for systems-level thinking, while recognizing that mechanistic mapping in the brain–gut research literature is more mature and that the CPA remains hypothesis-driven. This framework is used to describe the complex bidirectional communication between the brain and pelvic system through neural, endocrine, and immune pathways. This strategy has helped organize and interpret comorbid conditions such as anxiety disorders and irritable bowel syndrome, driven interdisciplinary research and fostering novel therapeutic approaches (Carabotti et al., 2015). Drawing upon this model, we have re-examined existing explorations in the pelvic-floor medicine literature. In a previous study, Professor Derek Griffiths demonstrated that urination is a complex decision-making process that is dependent on prefrontal inhibition and an emotional state, rather than a local reflex (Griffiths, 2015). Furthermore, the emerging clinical subspecialty of neuropelveology has enhanced our understanding of peripheral neuropathology in the pelvic floor, particularly in conditions of chronic pain (Cho, 2017). However, the former's research scope is typically confined to lower urinary tract control and is rarely integrated with the systemic collapse of higher cognitive networks. The latter approach primarily originated from the pelvic region and focuses on peripheral neuropathy and surgical reconstruction, without incorporating higher-level cognitive functions, emotions, and consciousness as equal components within its core framework. Consequently, an operationally useful integrative mapping framework for cross-level control-loop phenotyping across this spectrum remains underdeveloped.

Prior frameworks have described brain–bladder communication and supraspinal control circuits in substantial detail (e.g., the bladder–brain axis perspective). Our proposal does not redefine these canonical neurourological pathways. Instead, CPA is introduced as an explicit control-loop framing that: (i) broadens the mapping scope from “bladder” to the broader pelvic effector set (pelvic floor, outlet control, bowel/sexual functions when relevant); (ii) uses two directional working failure-mode categories (top-down disintegration vs. bottom-up disturbance) as a phenotyping language across neurologic and pelvic-floor–dominant conditions; and (iii) links this phenotyping to mechanism-oriented, falsifiable predictions and intervention design logic (CAN). Accordingly, CPA should be read as a hypothesis-generating synthesis layer built on established brain–bladder circuitry, rather than a replacement of existing neurourology models.

Importantly, CPA is proposed as a control-architecture and phenotyping framework, not a nosological claim. It does not assume a shared etiology or deterministic disease coupling between AD/pDoC and pelvic-floor disorders but instead provides a testable way to map how dysfunction at different nodes may produce partially coupled phenotypes in well-phenotyped cohorts.

In this Hypothesis and Theory article, we use the term “cerebro-pelvic axis” (CPA) as a hypothesis-generating, working control-loop mapping framework for organizing bidirectional brain-pelvic observations relevant to lower urinary tract control and pelvic-floor outlet coordination. Within this framework, interactions between higher brain functions (cognition, emotion, and consciousness) and pelvic organ/pelvic-floor functions (including urinary storage and voiding, and potentially bowel/sexual functions in broader applications) are organized as components of a brain-spinal-pelvic control loop. Based on this CPA framing, we outline an interdisciplinary research agenda (here termed “neuro-pelviology” as a provisional working label) for integrative, mechanism-oriented, and translational studies across brain-pelvis interactions. The core aim of the CPA framework is not to redefine disease entities, but to provide a control-architecture mapping for phenotyping how dysfunction may arise at different nodes of the brain–spinal–pelvic loop. Within this mapping, higher-brain–dominant and selected pelvic-floor–dominant presentations can be described as different failure-mode expressions, without implying shared etiology or disease-to-disease coupling. The present framework provisionally uses two working failure-mode categories, top-down disintegration (impaired descending control over storage–voiding coordination) and bottom-up disturbance (aberrant or over-weighted pelvic afferent/interoceptive signaling with potential central consequences in selected phenotypes). Here, “top-down disintegration” refers to impaired executive/brainstem command over storage–voiding coordination, whereas “bottom-up disturbance” refers to excessive or distorted bladder/pelvic afferent signaling that drives maladaptive central processing. This framework is intended to support integrated phenotyping and to generate testable hypotheses for diagnostic and intervention development.

2 CPA as a working control-loop mapping framework

The current medical system routinely treats higher brain dysfunction (such as AD and chronic altered states of consciousness) and pelvic floor dysfunction (such as SUI) as two distinct and unrelated conditions. However, in current care pathways, cognitive/neurobehavioral syndromes and lower urinary tract/pelvic floor symptoms are typically assessed and managed in separate clinical silos, often with non-overlapping outcomes and limited cross-referral; this separation can obscure shared control-circuit vulnerabilities and hinder mechanism-oriented phenotyping across conditions. To adequately describe this coupled phenomenon, we must first explore a working descriptive and analytic vocabulary. To this end, we introduce two linked working terms: the CPA and neuro-pelviology. The specific framework is detailed in Figure 1.

Conceptual framework of the cerebro-pelvic axis (CPA) and the neuro-pelviology interdisciplinary research agenda. This diagram establishes a conceptual framework for the cerebro-pelvic axis (CPA), a bidirectional system connecting the brain to the pelvic floor via “descending control” pathways (originating from the PFC) and “ascending interoceptive” pathways (projecting to the insula/ACC). This framework reframes clinical issues into two working failure-mode categories: “downstream pathway disruption” (central dysfunction, such as in Alzheimer's disease) and “bottom-up disturbance” (peripheral signals interfering with the central nervous system, such as OAB and selected SUI/mixed UI phenotypes). Finally, the diagram positions neuro-pelviology as an interdisciplinary research agenda integrating neuroscience, urology/pelvic-floor medicine, and rehabilitation medicine, aiming to support integrative phenotyping and mechanism-oriented translational study designs for CPA-relevant dysfunction patterns. The diagram is intended as a control-architecture mapping and does not imply shared etiology between the illustrated conditions.

2.1 The cerebro-pelvic axis (CPA)2.1.1 Definitions

We define the CPA as a control-loop mapping framework that integrates neuromodulation, endocrine signaling, somatosensory input and psycho-emotional processing. Functionally, the CPA connects the cerebral cortex with subcortical networks (including the frontal-parietal executive network, limbic system and the insula), the integration centers of the brainstem and thalamus, the autonomic and somatic motor centers of the spinal cord (particularly the thoracolumbar and sacral nuclei), and ultimately the effectors in the pelvic floor region that execute physiological behaviors (bladder, urethra, pelvic floor muscles, anal sphincter and genital-related neuromuscular structures) (Jang et al., 2018; Schellino et al., 2020). This axis comprises two fundamental functional limbs. The first functional limb is the descending (output) control pathway, which governs top-down regulation. Higher brain centers integrate commands related to urination, urinary control, pelvic floor stability, and sexual behavior into actionable directives such as “permit/inhibit” or “immediate/delayed” commands that incorporate precise timing and contextual considerations before transmitting these signals downward (Tish and Geerling, 2020). The second functional limb is the ascending (afferent) interoceptive pathway, which coordinates bottom-up feedback signals. Multimodal interoceptive signals from the pelvic region, such as bladder fullness, urethral pressure, perineal tension, pain, or leakage awareness, are continuously transmitted to interoceptive centers in the brain such as the insula and anterior cingulate cortex. This process shapes subjective experiences such as urgency, safety or the perception of threat (Pang et al., 2022; Santoso et al., 2025).

Scope statement (CPA in this paper). In this hypothesis paper, we discuss the CPA primarily in the context of lower urinary tract (LUT) control and pelvic-floor outlet coordination—i.e., bladder storage–voiding regulation and urethral/pelvic-floor muscle synergies, indexed by urodynamics and pelvic-floor EMG. We adopt this restricted scope because human evidence and measurable brain–pelvis coupling paradigms are currently most mature for LUT phenotypes (e.g., AD/pDoC-associated incontinence, OAB, and SUI/mixed UI). Other pelvic phenotypes that may also map onto a broader brain–pelvis control loop—including dysfunctional voiding/functional outlet obstruction, bowel dysfunction, sexual dysfunction, and postpartum pelvic-floor syndromes are acknowledged as important extensions but are not systematically analyzed here due to limited mechanistic evidence and space constraints. The failure-mode framework (top-down disintegration vs. bottom-up disturbance) is therefore operationalized for urinary continence/voiding control, with the intent to extend it to other pelvic phenotypes as standardized biomarkers and synchronized paradigms become available.

We explicitly exclude common LUT phenotypes such as bladder outlet obstruction (BOO), including BPH-related obstruction, and urinary retention/underactive bladder from the current framework. These phenotypes, which involve increased outlet resistance, impaired detrusor contractility, attenuated afferent signaling, or mixed mechanisms, are not included in the present “top-down disintegration” and “bottom-up disturbance” failure-mode scheme, as they do not align clearly with the definitions of these categories. In this paper, they are treated as important extension cases for future refinement of CPA phenotyping rather than fully specified CPA categories.

2.1.2 The CPA as a dynamic feedback loop

The CPA does not represent a unidirectional relationship in which the brain controls the pelvic floor but represents a real-time dynamic feedback loop that encodes peripheral physiological states into subjective experiences and translates these experiences into behavioral decisions. For instance, the mechanical stimulus created by “bladder fullness” is translated within the CPA framework into the behavioral command “I need to find a restroom,” which carries cognitive priority and the assessment of social consequence. Conversely, “holding urine” is not merely a simple contraction of the sphincter muscles, but rather a sustained inhibitory command issued by the prefrontal executive network to the spinal micturition reflex. At its core, the CPA represents a higher-order cognitive control strategy (Michels et al., 2015; Schott et al., 2023). This formulation implies measurable coupling (and decoupling) between central decision networks and peripheral physiology, enabling falsifiable biomarkers of control-loop integrity.

2.1.3 Disease reconstruction under the CPA framework

The CPA provides a working integrative mapping framework that enables us to map different clinical conditions onto a shared control architecture for phenotyping purposes. Urinary incontinence in AD or pDOC may be mapped as a failure of the upstream control layer of the CPA (the cortico-thalamic-brainstem integration circuit). When the brain loses its capacity to inhibit, plan and time pelvic floor actions, voiding behavior regresses to a lower-level automated reflex (Sugimoto et al., 2017; Qin et al., 2021). Conversely, SUI is primarily an outlet/continence-mechanism failure at the effector level (Aoki et al., 2017). Within the CPA framework, it may be mapped as a pelvic-floor–dominant phenotype at the output end of the control loop. In selected subgroups (e.g., mixed UI or SUI with prominent urgency/distress), recurrent leakage and anticipatory fear may also be associated with secondary ascending salience-like signaling and cognitive-affective burden, which should not be generalized as a primary mechanism in pure SUI. In other words, the CPA framework is intended to complement, rather than replace the established mechanical model of SUI in phenotyped subgroups where symptom burden and psychosocial distress may contribute to clinical severity (Dutta and Pathak, 2024).

Rather than arguing for disease-level coupling, the CPA offers a control-architecture mapping in which AD/pDoC-related urinary dysfunction and pelvic-floor/LUT–dominant phenotypes (e.g., OAB and selected SUI/mixed UI presentations) may be mapped to dysfunction at different nodes of a shared brain–spinal–pelvic control loop. More specifically, the hypothesis concerns a reproducible control-loop mapping pattern—i.e., partially coupled clinical presentations that may reflect dysfunction in shared control nodes, computations, or vulnerability contexts—rather than a claim of shared pathology. For hypothesis generation and phenotyping, the CPA emphasizes three mapping dimensions that may be partially shared across otherwise distinct conditions: (i) control nodes (e.g., mPFC/ACC–PAG–PMC); (ii) control computations (e.g., executive inhibition and interoceptive/salience weighting); and (iii) overlapping vulnerability contexts (e.g., aging, cerebrovascular burden, medication effects, frailty). This is not a claim of mutual causality or shared pathology. Rather, it is a node-level mapping claim in which dysfunction at different levels of the same control loop may generate partially coupled phenotypic patterns, which should be treated as distinct failure-mode expressions within the CPA framework.

2.2 Neuro-pelviology2.2.1 Definition

In this work, we use “neuro-pelviology” to refer to a provisional interdisciplinary research agenda grounded in the CPA framework, which allows the systematic investigation of physiological structure, information flow, plasticity, and patterns of pathological dysregulation to develop diagnostic and interventional strategies. The knowledge system encapsulated by neuro-pelviology spans neuroscience, urology, gynecology, rehabilitation medicine, and bioengineering, but it is not limited to these specific fields. It is necessary to distinguish this broad and system-centered concept from the existing and more surgery-focused field of “neuropelveology” to avoid conceptual overlap (Fowler et al., 2008; Possover, 2011). Here, “neuropelveology” is used in its established sense as a clinically oriented discipline focusing on peripheral pelvic nerve pathology, often leveraging surgical exploration/reconstruction and pain-centric phenotyping. In contrast, we use “neuro-pelviology” to denote a systems-neuroscience and rehabilitation-facing research program in which the unit of analysis is the brain–spinal–pelvic control loop, the primary outputs are mechanism-oriented phenotypes (failure modes), and the core measurable readouts include synchronized neurophysiology/neuroimaging with urodynamics/EMG. The intent is not terminological novelty, but to define a translational scope that connects circuit models to falsifiable biomarkers and trial designs.

2.2.2 The paradigm shifts in neuro-pelviology

Compared with conventional single-specialty perspectives, the CPA-guided neuro-pelviology research agenda offers three practical shifts in perspective. First, this concept adopts the central axis as the unit of measurement, treating the brain and pelvic floor as a single and malleable physiological entity. Second, by using failure modes as the unit of analysis, clinical dilemmas are redefined as classifiable faults at different levels of the CPA (e.g., upstream control breakdown vs. downstream execution instability). This provides a universal language for diagnosis and research targeting cross-disease mechanisms. These two approaches have precedent in other axis-oriented frameworks (e.g., the gut–brain–microbiome axis), where bidirectional dysregulation has been used to organize heterogeneous clinical syndromes. Bidirectional dysregulation within the same axis can simultaneously explain clinical syndromes that were previously categorized as distinct gastrointestinal disorders and neurological disorders. This suggests that problems should be described based on the specific dysfunctional pattern within the axis (i.e., identifying which segment is failing) rather than traditional disease labels. Consequently, this approach enables the investigation of common pathological mechanisms and therapeutic targets across diseases (Zhao et al., 2018). Ultimately, this working concept guided by a multi-level interventional approach that inherently supports an engineering-oriented objective: establishing a CPA-referenced, tiered and targeted individualized testable individualized intervention strategies (Panicker et al., 2015), Furthermore, different levels can be targeted by distinct neuromodulation tools, such as cortical networks (rTMS), spinal cord centers (rTSMS), and peripheral afferents (SNM) (Chen A. et al., 2024; Dequirez et al., 2025).

In this article, neuro-pelviology is used to outline a provisional interdisciplinary research framework and translational agenda for the interdisciplinary research agenda of functional interactions between the brain and pelvis.

3 The biological basis of the CPA: from concept to circuitry

In this section, we outline circuit-level mechanisms that render the CPA a measurable and testable control-loop mapping, with intervention-eligible nodes across cortical, brainstem, spinal, and peripheral levels. These circuits provide a mechanistic scaffold for interpreting clinical syndromes as directional failure modes of a single control loop. Much of the circuit-level evidence summarized here derives from animal, translational, and neuroimaging studies; therefore, species differences and inferential gaps should be considered when extrapolating to human clinical phenotypes.

3.1 The downstream control pathway: the command chain from intent to execution

For humans, urinary control is a quintessential goal-directed behavior that requires the simultaneous fulfillment of both physiological and social imperatives. This implies that the brain must coordinate decision-making across multiple higher-level modules and relay results to the pelvic floor. This multi-tiered and intricate chain of command ensures that functionality of the pelvic floor evolves from primitive reflexes into complex behaviors that are regulated by both conscious intent and situational context.

The starting point of the descending control pathway in the CPA is located in the cerebral cortex, specifically the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). The PFC is responsible for executive control and situational judgment and inhibits inappropriate urges to urinate (Kuhtz-Buschbeck et al., 2005). The latter integrates a sense of urgency–risk perception to assess whether an individual can endure the sensation any longer (Gao et al., 2015). The insula translates signals from the pelvic region into subjective urinary urgency intensity, while emotional structures such as the amygdala assign emotional connotations of “threat” or “safety,” collectively determining whether to initiate the process of urination (Pang et al., 2022).

The integrated output from these cortical and subcortical regions first converges in the periaqueductal gray (PAG) of the brainstem (de Groat et al., 2015), which serves as a critical relay and gating hub to integrate ascending inputs and descending cortical commands (Kitta et al., 2015). When this integrated assessment yields a “permit urination” outcome, the PAG activates the pontine micturition center (PMC), which functions as a master switch and pattern generator for urination. The PMC translates abstract behavioral decisions into a precisely choreographed sequence of neural discharge patterns (de Groat and Wickens, 2013). Subsequently, this pattern projects via brainstem-spinal descending pathways to the thoracolumbar (T11–L2) and sacral (S2–S4) spinal nuclei. On one hand, the PMC inhibits sympathetic output mediating urine storage and the activity of the pudendal nerves originating from the Onuf nucleus, thereby releasing the urethral and pelvic floor sphincter defenses. In contrast, the PMC activates sacral parasympathetic nerves to drive detrusor contraction, achieving efficient and coordinated micturition at the peripheral level (Stoffel, 2016; Kim et al., 2020).

This descending pathway is not merely a simple regulatory mechanism, but rather a central dispatch system that compresses social judgments, emotional appraisals, autonomic outputs and striated muscle precision contractions into a single behavioral scheme. This may help interpret why urinary dysfunction in AD or pDoC often co-presents with cognitive or consciousness impairments, potentially representing systemic damage to the upstream control layers of the CPA.

3.2 The ascending sensory pathway: constructing perception from signals

The ascending pathways of the CPA transmit real-time physiological signals from the pelvic floor to the brain and contribute to subjective sensation and behavioral responses.

Mechanoreceptors, chemoreceptors, and nociceptors in the pelvic region encode a range of signals, including distension, stretching and pain. These signals are transmitted via the pelvic nerves and pudendal nerves to the dorsal horn of the sacral spinal cord (de Groat and Yoshimura, 2009). Subsequently, the signal ascends along pathways such as the spinothalamic tract, relays through the parabrachial nucleus, and projects to the thalamus, the gateway through which sensory information enters the cerebral cortex (Pang et al., 2022). Ultimately, the signal reaches the insular cortex and ACC, the two core components of the interoceptive hub (Ketai et al., 2016). Here, the original neural signals are translated into subjective experiences we can perceive, such as “a slight urge to urinate,” “a strong sense of urgency” or “discomfort in the pelvic floor.”

The function of this pathway extends beyond the mere conveyance of physiological states. Persistent abnormal sensory input is most clearly established in pain-dominant conditions such as chronic pelvic pain (Till et al., 2019). In LUT disorders such as OAB and in selected SUI/mixed UI subgroups with prominent urgency or leakage-related distress, symptom monitoring and anticipatory vigilance may also increase cognitive and emotional burden. The magnitude and mechanisms of these effects likely differ across phenotypes and should not be assumed equivalent. Such interference may consume executive resources, including attention and working memory, that are managed by prefrontal control systems, thereby contributing to impaired performance in other cognitive tasks (Steiner et al., 2020).

The ascending interoceptive pathway may do more than report physiological states; in some phenotypes, persistent symptom-related input may shape emotional baseline, attentional allocation, and self-perception over time. Pelvic floor disorders may, in some phenotypes, be associated with changes in central processing and network organization via ascending pathways of the CPA.

3.3 Neurotransmitters: the chemical language of the CPA

The integrative function of the CPA relies not only on anatomical connections but also on a shared chemical language between the central and peripheral nervous systems. This language is mediated by norepinephrine (NE), 5-hydroxytryptamine (5-HT), dopamine (DA) and acetylcholine (ACh), which play characteristic dual roles at different levels of the CPA.

The noradrenergic system elevates urethral smooth muscle tone via sympathetic pathways in the spinal cord and periphery, serving as a crucial pharmacological basis for maintaining the threshold for urinary retention during the storage phase (Andersson and Uvelius, 2024). In the central nervous system, the noradrenergic system, originating from the locus coeruleus, regulates alertness and threat monitoring, playing a crucial role in the interoceptive vigilance state that determines whether maintaining pelvic floor closure must be prioritized (Ross and Van Bockstaele, 2020). Dysfunction of the noradrenergic system may couple stress-related hypervigilance with symptoms in the lower urinary tract, including urgency and frequency. The 5-HT system also exhibits central-peripheral parallel regulation. At the level of the spinal Onuf nucleus, 5-HT enhances excitability of the external urethral sphincter motoneurons, forming the primary pharmacological basis for the administration of duloxetine to treat SUI (Jost and Marsalek, 2004); At the brain level, 5-HT plays a critical role in regulating mood and impulse control (da Cunha-Bang and Knudsen, 2021). This imbalance may be associated with reduced emotional tolerance and altered sphincter-control thresholds; however, in most human data the relationship is bidirectional or associative. We therefore treat 5-HT as a candidate coupling mechanism within the CPA loop to be tested, rather than assuming a direct causal chain. As a key neurotransmitter in the basal ganglia-cortex motor and motivational circuitry, dopamine not only participates in general motor planning and behavioral selection but also modulates inhibition of the PMC via the striatum-thalamus-cortex circuit (Wang et al., 2020); In untreated patients with early-stage Parkinson's disease (PD), lower urinary tract symptoms are closely associated with dopaminergic degeneration in the substantia nigra-striatal pathway, thus indicating that dysfunction of the DA system can translate into a phenotype of detrusor overactivity and urgency/urge incontinence via the descending CPA pathway. Acetylcholine provides another key link between the CPA, consciousness and cognition. Peripherally, cholinergic parasympathetic efferents serve as the primary pathway driving detrusor contraction and initiating the micturition reflex (Fowler et al., 2008); In the central nervous system, the basal cholinergic systems in the forebrain and brainstem serve as pivotal hubs for maintaining wakefulness, attention and cortical activation. The functional decline of these systems aligns closely with key pathologies of AD and pDoC (Bekdash, 2021; Raciti et al., 2023) and offers a candidate control-loop coupling mechanism that may contribute to the co-presentation of cognitive/consciousness decline and urinary incontinence in some cohorts, although much of the current evidence is indirect and associative. Figure 2 provides an integrated overview of these descending/ascending neural circuits and their corresponding diffuse neurotransmitter systems to explore a structural foundation for considering the CPA as a measurable and intervention-eligible control-loop mapping.

Established brain–spinal–peripheral circuits and neuromodulatory systems supporting the cerebro-pelvic axis (CPA). This schematic summarizes established neurourological control pathways linking supraspinal networks with spinal autonomic and somatic outflow that coordinate lower urinary tract (LUT) storage and voiding. Ascending interoceptive signals originate from bladder mechanosensitive Aδ afferents and high-threshold C-fiber afferents, enter the spinal cord (including the sacral dorsal horn, S2–S4), and engage supraspinal relay and integration regions including the periaqueductal gray (PAG) and thalamus, with cortical processing in interoceptive–salience regions (e.g., insula, ACC) contributing to urgency/discomfort perception. Descending control is conveyed from cortical control regions (e.g., mPFC/ACC) to the PAG and the pontine micturition center (PMC/Barrington's nucleus), which in turn coordinates spinal outputs via the intermediolateral cell column (IML, T11–L2; sympathetic preganglionic), sacral parasympathetic nucleus (SPN, S2–S4; parasympathetic preganglionic), and Onuf's nucleus (S2–S4; somatic motor). Peripheral efferent pathways are indicated as the hypogastric nerve (predominantly sympathetic; storage), pelvic nerve (predominantly parasympathetic; voiding), and pudendal nerve (somatic; external urethral sphincter control). Diffuse neuromodulatory systems (e.g., 5-HT from raphe nuclei, NE from locus coeruleus, DA from VTA/SNc, and cholinergic systems) are shown as widespread modulators that shape arousal, affective state, and network excitability across these circuits. ACC, anterior cingulate cortex; mPFC, medial prefrontal cortex; PAG, periaqueductal gray; PMC, pontine micturition center; IML, intermediolateral cell column; SPN, sacral parasympathetic nucleus; EUS, external urethral sphincter.

In summary, although the individual components of the CPA have been extensively investigated across various disciplines, the originality of the CPA framework lies in integrating these components into one system with a clear functional division of labor (downward control/upward interoception) and hierarchical structure, emphasizing the dynamic interactions of this axis as a unified system in both healthy and disease states. The clinical dysregulation described hereafter relates precisely to the manifestation of a system-level control-loop dysfunction.

4 Cross-disciplinary clinical evidence for CPA-relevant control-loop dysfunction patterns

We performed extensive literature reviews and have compiled clinical evidence from multiple research areas, including neurology, rehabilitation medicine, and urology, to demonstrate that multiple seemingly unrelated diseases can in fact be considered as functional impairments of the central nervous system at different levels and in different directions. For this hypothesis paper, we use two-category working classification (top-down disintegration and Bottom-Up Disturbance) to organize the currently most developed examples. We recognize that some LUT phenotypes, particularly urinary retention/underactive bladder and outlet-obstructive conditions may involve mixed, attenuated-signal, or reduced-drive mechanisms that are not fully captured by this provisional scheme.

4.1 Top-down disintegration: the pelvic floor phenotype in central nervous system disorders

The descending control pathways may also malfunction when lesions occur in the upstream control centers of the CPA (the cerebral cortex, subcortical structures and brainstem). Within the CPA framing, this dysfunction may be clinically informative as a manifestation of upstream control-loop decompensation, rather than being treated solely as a late-stage care complication. We describe this phenomenon as a descending CPA disconnection pattern that is characterized by disruption in the upstream command chain that initiates dysfunctionality in the pelvic floor execution system (Tish and Geerling, 2020).

4.1.1 AD and pDoC

The onset of urinary incontinence in AD is highly synchronized with declines in executive function and the capacity for behavioral inhibition (Sugimoto et al., 2017; Griebling, 2018). This aligns closely with disruption of the PMC control circuit within the CPA descending pathway. Similarly, in patients with pDoC, the widespread loss of urinary control may reflect a clinically relevant manifestation of concurrent disruption between the consciousness network and the CPA control network (Leboutte et al., 2023). In both scenarios, the loss of pelvic floor control is not merely a late-stage nursing detail or a simple decline in self-care abilities, but rather a core neurological symptom of dysfunction within the upstream integrative network of the central nervous system.

4.1.2 PD and stroke

Overactive bladder symptoms in PD are often multifactorial, reflecting varying contributions from dopaminergic–basal ganglia dysfunction, autonomic changes, medications, and comorbid peripheral factors. Within the CPA framework, PD can therefore express mixed failure modes, and phenotyping should prioritize axis-level readouts (urodynamics/EMG plus central biomarkers) over a single-node explanation (Sakakibara et al., 2010). In stroke, LUT dysfunction often shows temporal evolution (e.g., early hypocontractility/retention followed by later overactivity), which fits a control-loop view in which different CPA nodes recover or decompensate over time. Accordingly, CPA phenotyping should be time-stamped and ideally longitudinal, rather than purely lesion-location–based (Khan et al., 1990). Detrusor-sphincter dyssynergia is known to be caused by lesions in the brainstem (Sakakibara et al., 1996). Compared to traditional neurogenic bladder classifications, the CPA perspective places greater emphasis on the phenotypic differences corresponding to damage at different nodes along the descending pathways.

4.2 Bottom-up disturbance: putative central network adaptations in selected pelvic phenotypes with persistent symptom-related afferent burden

When primary dysfunction occurs downstream of the CPA, persistent symptom-related afferent signaling in selected phenotypes (most clearly pain-dominant or urgency-predominant conditions, and some mixed UI/urgency-distress SUI subgroups) may influence central processing via ascending pathways and has been associated with alterations in central neural networks. Recent rs-fMRI studies report group-level differences in interoceptive–salience networks (often centered on the insula/ACC) and their connectivity with frontoparietal executive networks in OAB. In some cohorts, these measures correlate with symptom severity (e.g., urgency/incontinence), supporting—but not proving—the hypothesis that persistent peripheral afferent input could contribute to central network adaptations (Mehnert et al., 2023). We describe this phenomenon as a putative axis-level maladaptive state (here provisionally referred to as “CPA circuitopathy” for descriptive convenience), referring to putative axis-level dysregulation in which aberrant ascending signaling is hypothesized to be linked with maladaptive central network plasticity. This concept does not aim to explore a new clinical syndrome, but rather to emphasize how peripheral dysfunction induces systemic alterations in central networks via maladaptive neuroplasticity.

4.2.1 SUI and OAB

Pure SUI is primarily an outlet/continence-mechanism failure under increased abdominal pressure. In addition to peripheral mechanical defects, the persistent fear of urinary leakage experienced by a subset of patients with SUI—particularly those with mixed UI, coexisting urgency, or high symptom-related distress—may become a subgroup-specific salience-like signal. This signal may be associated with increased engagement of brain regions related to symptom monitoring, anxiety, and vigilance (such as the insula and ACC) via the ascending CPA pathway, potentially increasing executive control demands in the PFC (Di Gangi Herms et al., 2006). Neuroimaging studies suggest that a subset of OAB patients may exhibit altered salience-network processing consistent with “misinterpretation” and “amplification,” leading the brain to prematurely and excessively interpret these as urgent signals (Ketai et al., 2016, 2021). However, we note that rs-fMRI findings can be heterogeneous across cohorts and analytic pipelines; thus, these interpretations should be considered probabilistic rather than definitive. In summary, selected SUI phenotypes (especially mixed UI or urgency/distress-prominent subgroups) may be provisionally framed as bottom-up–disturbance–relevant presentations, whereas pure SUI remains primarily an outlet/mechanics phenotype. In pure SUI, any central changes should be interpreted cautiously as potential secondary correlates (if present) rather than core mechanisms. We acknowledge that some patients may exhibit mixed or shifting phenotypes (e.g., combined impaired inhibition and heightened afferent salience), and the CPA framework is intended to accommodate such cases as hybrid failure modes rather than forcing a binary classification.

4.2.2 Chronic pelvic pain (CPP)

CPP may provide one of the clearest clinical examples of central nervous system involvement associated with persistent ascending symptom input by dysfunction in the ascending pathways of the CPA. Long-term and persistent pelvic pain signals have been shown to induce significant structural and functional changes in the brain; this condition is known as central sensitization. Pain, emotion, and cognition-related networks (such as the default mode network) all exhibit abnormalities in functional connectivity, thus providing a plausible neurobiological basis for the frequent co-occurrence of CPP with depression, anxiety, and cognitive impairment (As-Sanie et al., 2016). Furthermore, compared to the interoceptive disturbances in SUI/OAB that are characterized by urgency and the fear of leakage, CPP manifests more as persistent pain-driven alterations in affective-cognitive networks.

Synthesizing the above evidence, we arrived at an interdisciplinary conclusion in that AD, pDoC and similar conditions represent disintegrative failures of the descending pathways of the CPA, while OAB, CPP, and selected SUI/mixed UI phenotypes with prominent urgency/distress may represent bottom-up disturbance patterns involving ascending CPA pathways. In many complex cases, particularly among the elderly or critically ill patients undergoing rehabilitation, these two failure modes often coexist to form a vicious cycle of bidirectional loss of control. Within the CPA framework, these failure modes are clearly defined as distinct dysregulation phenotypes along the same control architecture, as distinct dysregulation phenotypes mapped to different nodes (or mixed states) within a shared control architecture, rather than as an etiologic coupling claim. Table 1 systematically summarizes representative diseases, pelvic floor phenotypes, and hypothesized mechanisms under different CPA failure modes, thus providing a foundation for investigating integrated and mechanism-oriented interventional strategies.

CPA failure modeCohort contextPelvic floor functionRelevant CPA mechanismsReferencesDescending pathway disintegrationAlzheimer's disease (AD)Urge incontinence, frequent urination, nocturiaFrontal–limbic degeneration may reduce inhibitory control over brainstem micturition circuitry (PAG/PMC) and is associated with co-occurring LUT symptoms. Cholinergic deficits may be a plausible coupling mechanism, but current human evidence is predominantly associative.Panicker, 2020; Chang et al., 2021Descending pathway disintegrationTraumatic brain injury (TBI)Complete urinary incontinence often requires indwelling catheterizationDamage to rostral/corticothalamic–brainstem pathways may compromise supraspinal control and is associated with loss of voluntary continence in severe cases. The relative contribution of spinal reflex dominance vs. peripheral/iatrogenic factors is likely cohort- and phase-dependent.Albayram et al., 2019Descending pathway disintegrationParkinson's disease (PD)Detrusor overactivity → Urgency/Urge incontinenceNigrostriatal dopaminergic degeneration may reduce inhibitory modulation of brainstem micturition control (PAG/PMC) and is associated with DO/OAB-like phenotypes. Mechanistic contributions are multifactorial (autonomic changes, medications, comorbidities), supporting a phenotyping-first interpretation.Wang et al., 2020; Roy et al., 2018; Kim et al., 2024Descending pathway disintegrationStrokeMost cases involve urge or mixed urinary incontinence; some lesions may cause urinary retentionLesions affecting frontal–subcortical or brainstem pathways may disrupt descending inhibitory control and storage–voiding coordination. LUT phenotypes often evolve over time (including mixed UI or transient retention), supporting time-stamped control-loop phenotyping rather than single-mechanism attribution.Agapiou et al., 2024Bottom-up disturbance (selected pelvic phenotypes)Selected SUI/mixed UI phenotypes (urgency- or distress-prominent; not pure SUI broadly)Stress leakage (e.g., exertion/cough), often with coexisting urgency and/or high leakage-related distress in selected subgroupsPure SUI is primarily an outlet/mechanical phenotype. In carefully phenotyped mixed UI or urgency/distress-prominent SUI subgroups, recurrent leakage-related distress may increase symptom vigilance and psychosocial burden, with central changes interpreted cautiously as secondary correlates rather than core mechanisms of pure SUI. PFM-related cortical activation/plasticity is treated as compensatory or training-related rather than