Motor–Behavioral Phenotypes in the RBD-PD Continuum: Neurophysiological Mechanisms and Rehabilitative Implications

Abstract

REM sleep behavior disorder (RBD) represents a prodromal manifestation of Parkinson’s disease (PD), reflecting the breakdown of inhibitory networks extending from the brainstem to the cortex. This review synthesizes pathological, physiological, and behavioral evidence to illustrate how early α-synuclein pathology disrupts REM-sleep atonia and motor automaticity through degeneration of pontomedullary and cholinergic–inhibitory circuits. The resulting failure of inhibitory precision links nocturnal REM sleep without atonia to daytime gait and postural abnormalities, framing RBD as a dynamic systems disorder rather than a purely sleep-related phenomenon. By examining this continuum across neurophysiological, behavioral, and clinical domains, the review highlights current knowledge gaps, particularly regarding the temporal dynamics of degeneration and compensation. It further integrates multimodal biomarkers that capture these transitions in vivo and discusses therapeutic strategies aimed at preserving inhibitory network integrity and delaying phenoconversion to overt Parkinsonian syndromes.

1. Introduction

Parkinson’s disease (PD) is now recognized as a multisystem neurodegenerative movement disorder characterized by abnormal aggregation of α-synuclein and a prolonged prodromal stage before the onset of classical motor symptoms [1,2,3,4]. Based on the Braak staging hypothesis, α-synuclein pathology originates in the dorsal motor nucleus of the vagus and the olfactory bulb, before propagating rostrally through the locus coeruleus, pontomedullary reticular formation, and substantia nigra to limbic and neocortical areas [1,2,5,6,7]. This caudo-rostral progression explains why non-motor symptoms such as constipation, hyposmia, and REM sleep behavior disorder (RBD) frequently appear years before motor symptoms become evident [2,8,9,10]. Consequently, PD is increasingly understood not as a focal dopaminergic disorder but as a multisystem degeneration involving inhibitory, cholinergic, and motor regulatory circuits.

Among prodromal markers, idiopathic RBD (iRBD) is considered one of the most reliable clinical phenotype and serves as an in vivo window into early synuclein-related dysfunction. RBD is characterized by loss of the normal muscle atonia that accompanies REM sleep, which can lead to dream-enactment behaviors such as talking, shouting, or striking movements [11,12,13]. Longitudinal multicenter studies suggest that about six percent of individuals with iRBD convert each year to a synucleinopathy such as Parkinson’s disease, and that roughly seventy to eighty percent develop one within a decade [2,8,14]. Findings from the North American Prodromal Synucleinopathy (NAPS) cohort, a prospective study of REM sleep physiology, indicate that individuals with iRBD carry a substantial risk of phenoconversion [9]. Long-term follow-up studies from Barcelona report conversion rates approaching 90% over 14 years, reinforcing the view that RBD represents an early stage of synucleinopathy [8,15].

Current evidence indicates that iRBD originates from dysfunction within pontomedullary inhibitory circuits, including the sublaterodorsal nucleus (SLD) and ventromedial medulla (VMM), which normally produce REM atonia via descending GABAergic and glycinergic projections to spinal motoneurons. The pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei provide cholinergic input that modulates SLD and medullary networks and contributes to REM-state transitions, including the maintenance of REM atonia [16,17]. When α-synuclein pathology disrupts this circuitry, inhibitory drive is reduced and REM sleep without atonia (RSWA) appears, permitting motor activity during dreaming [18]. Importantly, these same cholinergic–inhibitory pathways help regulate postural tone and gait during wakefulness [19], and degeneration within this shared network may contribute to gait and postural instability in PD [20,21,22]. Consistent with this, longitudinal studies report that PD patients with comorbid RBD show faster motor worsening and greater cognitive decline, especially within the postural instability/gait dysfunction (PIGD) subtype [12,23]. These observations are consistent with the view that RBD-positive PD corresponds to a body-first phenotype, typically presenting with akinetic-rigid features, postural instability, freezing of gait, and autonomic involvement [24,25].

In this review, we integrate findings across these domains to clarify how early inhibitory deficits relate to later-emerging motor and non-motor features in Parkinsonian disorders. Most previous reviews have examined RBD and PD separately, with an emphasis on either REM sleep physiology or dopaminergic loss. Only a few have considered how tonic (RSWA) and phasic (REM density) REM abnormalities relate to early changes in motor automaticity. This separation has made it difficult to view sleep and motor findings within a single framework. In this review, we bring these areas together and describe how early disturbances in inhibitory control may contribute to later motor and non-motor features across the RBD-PD continuum, as summarized in Figure 1.

2. Neurophysiological Mechanisms of Inhibitory Network Breakdown

The link between iRBD and Parkinson’s disease is thought to involve early degeneration of pontomedullary circuits responsible for REM sleep atonia, with subsequent involvement of cholinergic and dopaminergic pathways as disease progresses. Selective α-synuclein deposition disrupts inhibitory circuits governing REM atonia, postural regulation, and fine motor control progressively converting physiological inhibition into pathological disinhibition. This hierarchical process, beginning within the pontomedullary reticular formation and extending to cortical motor areas, forms the biological substrate linking RSWA to waking motor dysfunction [16,26].

2.1. Brainstem Origins of REM Atonia and Postural Tone Regulation

REM sleep atonia is produced by a well-defined inhibitory circuit in the pontomedullary reticular formation. Neurons in the sublaterodorsal (SLD) region activate GABAergic and glycinergic cells in the ventromedial medulla, including ventral gigantocellular areas, which project to spinal motoneurons and suppress muscle tone during REM sleep [16,17,27]. Recent circuit-tracing work confirms that this SLD-medullary pathway provides the primary inhibitory drive responsible for REM atonia [17]. This inhibitory network is influenced by cholinergic input from the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei, which regulate REM state transitions but do not directly generate spinal inhibition. Disruption of the SLD or its medullary targets in animal models reliably produces REM sleep without atonia, underscoring their causal role in maintaining REM atonia [26]. Several of these pontomedullary structures also contribute to waking motor regulation. Degeneration within these shared inhibitory–cholinergic pathways may also influence posture and gait as Parkinsonian disorders evolve.

2.2. Cortical Inhibition and Maladaptive Plasticity

At the cortical level, reduced inhibitory control is reflected in changes in excitability and in the capacity to modulate synaptic strength. These features are commonly assessed with transcranial magnetic stimulation (TMS) and paired-associative stimulation (PAS), which provide complementary indices of GABAergic inhibition and Hebbian-like plasticity in vivo [28,29,30]. In this framework, short-interval intracortical inhibition (SICI) and cortical silent period (CSP) reflect GABA_A- and GABA_B-receptor-mediated inhibition in the motor cortex, whereas PAS induces long-term potentiation (LTP)- or depression (LTD)-like changes that serve as measures of cortical neuroplasticity.

Neurophysiological studies in early, drug-naïve Parkinson’s disease consistently demonstrate both reduced inhibition and altered plasticity. SICI and CSP are diminished and shortened, indicating weakened GABAergic inhibition [31,32]. Under TMS-PAS protocols, the less-affected hemisphere shows relatively greater, facilitation, whereas the more-affected hemisphere shows little or no PAS-induced potentiation [32]. This asymmetry has been interpreted as relative hyperexcitability in the less-affected hemisphere, possibly reflecting an attempt to sustain motor output despite subcortical dysfunction. Longitudinal observations indicate that this compensatory response diminishes over time and parallels the loss of hemispheric asymmetry and clinical progression [31].

Bologna and colleagues proposed that these physiological abnormalities reflect a broader disturbance of homeostatic plasticity, in which dopaminergic loss disrupts the balance between inhibitory and excitatory mechanisms within the motor cortex [33]. Their later study showed that reduced PAS responsiveness and diminished GABAergic inhibition correlate with bradykinesia and increased movement variability, linking cortical inhibitory deficits to impaired motor scaling and precision [34].

Overall, these previous studies suggest that cortical inhibitory regulation becomes increasingly difficult to sustain as the disease progresses. Early dysfunction within pontomedullary inhibitory pathways may contribute to cortical disinhibition, and the subsequent loss of homeostatic plasticity and cholinergic modulation may further limit the ability to regulate cortical excitability. Although TMS-PAS paradigms have not been systematically applied in iRBD or in PD defined by RSWA status, the hemispheric asymmetry observed in early PD suggests that related changes may already be present in the prodromal phase. Altered fronto-striatal connectivity in iRBD supports this possibility and raises the question of whether cortical inhibitory imbalance begins before dopaminergic degeneration becomes clinically evident [35].

2.3. Cholinergic and GABAergic Imbalance

Imaging and pathological studies show that cholinergic degeneration emerges in Parkinson’s disease [22,36,37,38,39]. Positron emission tomography (PET) using [18F]-FEOBV demonstrates widespread cortical and thalamic cholinergic denervation in PD and related synucleinopathies, with additional alterations reported in individuals exhibiting RBD or RSWA features [37]. This cholinergic loss is associated with both cognitive and motor dysfunction, suggesting that acetylcholine-dependent modulation contributes to impaired inhibitory regulation across domains.

Preclinical studies demonstrate that GABA- and glycine- mediated neurons in the pontomedullary reticular formation are essential for REM-atonia, and their disruption can reproduce REM sleep without atonia in animal models [16,17]. Together, these findings are consistent with the broader inhibitory–cholinergic framework outlined earlier, indicating that both neurotransmitter systems contribute to the emergence of impaired automaticity in later disease stages.

Although inhibitory and cholinergic pathways form the core of this model, other early mechanisms also contribute to sleep–wake disruption in prodomal synucleinopathy. Dopaminergic and noradrenergic degeneration, particularly within the substantia nigra and locus coeruleus, as well as emerging neuroinflammatory changes and autonomic dysregulation, have each been implicated in early REM sleep instability. These processes likely interact with inhibitory network dysfunction and may shape the heterogeneity of clinical progression.

2.4. An Integrative Model of Dynamic Degeneration and Compensation

Current evidence indicates that inhibitory network dysfunction in the RBD-PD continuum emerges in a stepwise manner across different levels of the motor system rather than as a single abrupt transition. The earliest abnormalities are seen in pontomedullary circuits that generate REM atonia, and impairment in these pathways is expressed clinically as REM sleep without atonia. With increasing disease burden, cholinergic regions such as the pedunculopontine nucleus and basal forebrain show evidence of involvement, changes that often coincide with reduced postural stability and a decline in automatic control of movement [19,40]. Alterations in cortical physiology generally appear later, including reduced inhibitory tone and changes in plasticity, which may initially compensate for subcortical dysfunction but gradually lose effectiveness as the disease advances. Taken together, longitudinal cohort data, Braak-stage neuropathology, and neurophysiological and imaging findings support a gradual progression from iRBD to Parkinsonian syndromes rather than an abrupt categorical shift [2,8,14]. The progressive brainstem-to-cortex spread of α-synuclein pathology is accompanied by stage-specific changes in neural circuits and inhibitory mechanisms, as summarized in

Table 1. Summary of underlying neural mechanisms and supporting basic research evidence across the proposed brainstem-to-cortex continuum of PD.

Pathological Stage	iRBD (Brainstem-Dominant Stage)	Early PD (Subcortical Involvement)	Advanced PD (Cortical Spread)
Dominant neural structures	Pontomedullary brainstem (SLD, VMM)	Brainstem–basal ganglia–PPN network	Motor cortex and distributed cortical networks
Key neural mechanisms	Disruption of REM-atonia circuitry Reduced inhibitory transmission within SLD-VMM pathways	Degeneration of PPN/LDT cholinergic projections Impaired inhibitory integration across brainstem–basal ganglia circuits	Cortical inhibitory dysfunction Breakdown of large-scale inhibitory network coordination
Supporting basic research evidence	Animal models: Disruption of pontomedullary inhibitory circuits induces REM sleep without atonia Human tissue: Early synuclein pathology in pontomedullary regions	Animal models: PPN lesions reduce gait automaticity and postural control Human studies: Imaging and neuropathology reveal early cholinergic deficits	Human neurophysiology: TMS studies demonstrate altered SICI and CSP Human tissue: Widespread cortical α-synuclein pathology
Functional/clinical implications	REM sleep without atonia and dream enactment behaviors Largely preserved daytime motor function via compensation	Early emergence of gait/balance deficits Increasing reliance on compensatory motor strategies	Failure of compensation with persistent motor instability Reduced adaptability and higher fall risk

Note: This table aligns pathological stages illustrated in Figure 2 with dominant neural structures, key inhibitory and cholinergic mechanisms, and representative supporting evidence from animal models and human tissue studies, together with their functional and clinical implications across the clinical timeline.

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Figure 2. A neurodegenerative trajectory across the RBD-PD continuum. Note: Figure 2 describes a pathological cascade in which α-synuclein pathology arises within brainstem inhibitory circuits and then spreads stepwise to cholinergic, basal ganglia, and cortical networks, ultimately progressing to global network collapse as compensatory plasticity is lost.

Figure 2. A neurodegenerative trajectory across the RBD-PD continuum. Note: Figure 2 describes a pathological cascade in which α-synuclein pathology arises within brainstem inhibitory circuits and then spreads stepwise to cholinergic, basal ganglia, and cortical networks, ultimately progressing to global network collapse as compensatory plasticity is lost.

3. Behavioral and Motor Signatures of the RBD-PD Continuum

Clinically, most people with idiopathic RBD first come to attention because of dream enactment and other REM sleep–related behaviors, whereas patients with Parkinson’s disease are usually referred for motor complaints such as slowness, stiffness, or gait change. In this section, we focus on waking motor features that emerge across the RBD-PD continuum, from subtle irregularities in force control and gait to more overt bradykinesia and postural instability [41,42,43,44,45]. These waking motor features can be viewed as intermediate expressions between the predominantly sleep-related presentation of iRBD and the motor-dominant phenotype that characterizes Parkinson’s disease [46,47], as summarized in

Table 2. Multisystem progression across the RBD–PD continuum: From prodromal inhibitory dysfunction to motor and cognitive decline.

Domain	iRBD (Prodromal Stage)	PD − RSWA (Mild/Intermediate)	PD + RSWA (Advanced/Non-Motor Dominant)
Behavioral/Motor	Increased force variability during constant force tasks Normal movement speed and relaxation Mild gait deficits compared to PD + RSWA	Decrement in movement amplitude and speed (sequence effect) Markedly asymmetric rigidity Gait deficits milder than PD + RSWA	More symmetric and higher rigidity Significant gait impairment Increased freezing of gait (FOG)
Neurophysiological	No systematic TMS studies Possible early inhibitory instability, but no direct data in iRBD	Reduced SICI and PAS variability No subgroup-specific analysis	No TMS studies directly comparing PD + RSWA vs. PD − RSWA Widespread inhibitory loss inferred from behavioral and imaging findings, but not directly tested with TMS
Sleep Physiology	Presence of RSWA Elevation of Phasic and tonic muscle activity during REM sleep	Low/subthreshold RSWA Tonic and phasic EMG levels comparable to controls	Significant elevation of tonic and phasic RSWA RSWA highly associated with FOG
Neuroimaging	Reduced BOLD activity in motor cortex and basal ganglia regions Elevated free water in putamen No change in putamen and pSN free-water compared to control	Higher free-water and lower RD across tracts	Reduced compensatory responses

Note: Table 2 summarizes the major behavioral, neurophysiological, sleep, imaging, cognitive, and neurochemical characteristics observed along the RBD-PD continuum. Idiopathic RBD (iRBD) represents the earliest prodromal stage of α-synucleinopathy, marked by inhibitory network dysfunction within pontomedullary circuits and subtle motor variability. PD without RSWA (PD − RSWA) shows mild asymmetrical motor symptoms and emerging cortical disinhibition, whereas PD with RSWA (PD + RSWA) exhibits widespread loss of inhibition, reduced white-matter integrity, prominent RSWA, and significant cognitive–executive decline. Representative references highlight key studies supporting these stage-dependent transitions across behavioral, physiological, and neurobiological domains.

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3.1. Upper-Limb Inhibitory Dysfunction: From Force Variability to Rigidity and Fine-Motor Bradykinesia

In precision hand isometric-force tasks, individuals with iRBD show greater variability in steady-force output than healthy controls, while maintaining normal rates of force relaxation [48]. PD participants, however, showed not only elevated hand force variability but also slower force relaxation, indicating a transition from unstable inhibition to bradykinetic slowness. These results suggest that the primary abnormality is increased motor noise rather than a loss of strength, consistent with disinhibition within corticospinal and brainstem pathways.

A custom-made robotic manipulandum was used to quantify upper-limb rigidity [49]. Using this device, Linn-Evans and colleagues reported that PD patients with RSWA (PD + RSWA) showed greater and more symmetric rigidity than those without RSWA (PD − RSWA). The robotic system measured passive resistance to externally imposed joint motion, and the more bilateral rigidity pattern in the RSWA group was viewed as consistent with dysfunction in brainstem inhibitory pathways [50].

Automated motion-tracking analyses have revealed early deterioration of fine-motor automaticity. High-resolution video analysis of repetitive finger-tapping and hand-rotation movements showed that bradykinesia and hypokinesia were significant only in PD, whereas both PD and iRBD displayed a progressive decrement in amplitude and speed across movement sequences [51]. These quantitative kinematic markers reliably distinguished iRBD and PD from controls, indicating that fine-motor automaticity declines before clinically measurable bradykinesia emerges.

3.2. Lower-Limb Inhibitory Dysfunction

Lower-limb findings show a pattern similar to that observed in the upper limbs, suggesting that inhibitory control of ankle torque regulation is affected across multiple levels of the motor system. To test whether this extends to locomotor muscles, both steady-force and goal-directed ankle-torque tasks were administered to individuals with iRBD, PD, and healthy controls [48]. In the steady-force task, participants were instructed to produce ankle dorsiflexion at 15% of maximal voluntary contraction with visual feedback. Relative to controls, iRBD participants showed greater ankle torque variability but normal ramp-up and relaxation slopes of ankle. PD participants showed increased ankle force variability as well as slower relaxation, findings that point to early inhibitory disorganization—first through elevated motor noise and later through impaired termination of muscle activity. Force amplitude did not differ across groups, which suggests that these abnormalities are linked to reduced inhibitory precision rather than to weakness [48].

In the goal-directed task, participants rapidly generated and released ankle torque toward a visual target. Individuals with iRBD showed normal peak ankle dorsiflexion force production and relaxation times. By contrast, participants with PD demonstrated delayed relaxation of force production [48]. The progression from efficient ankle force release in iRBD to slowed relaxation in PD indicates declining temporal precision in inhibitory motor control, a process that appears to precede the emergence of slowness movement.

Findings from both the upper and lower limbs point toward a shared mechanism. The descending inhibitory pathways may already show instability in the iRBD stage, before gait abnormalities become clinically observable. Reduced inhibitory stability in limb control at rest and during goal-directed movement may represent an early step toward the later breakdown of rhythmic locomotor coordination.

3.3. Gait and Locomotor Regulation

Gait provides a macroscopic index of inhibitory network integrity across pontomedullary, basal ganglia, and cortical systems. PD patients with RSWA walk more slowly, take shorter steps, and show greater stride-to-stride variability than both PD − RSWA and healthy controls, indicating reduced rhythmic control within locomotor circuits that govern REM muscle tone and gait initiation [21,52]. The magnitude of RSWA correlates with gait irregularity, linking impaired REM atonia to diminished inhibitory precision during locomotion [52].

Longitudinally, PD + RSWA participants exhibit an approximately three-fold faster decline in step length over three years (−7.9% vs. −2.6%) and greater deterioration in gait variability and postural stability, identifying RSWA as a biomarker of accelerated motor-network degeneration and a measurable daytime expression of tonic inhibitory failure [53].

Reduced REM density, defined as the number of rapid eye movements per minute of REM sleep, has been linked to higher dual-task gait cost, slower turning, and poorer executive performance [54]. These findings suggest reduced phasic cholinergic modulation and a weakening of the connections between motor and cognitive control during walking [55].

Taken together, these findings demonstrate two complementary pathways of locomotor impairment in synucleinopathies: (1) tonic disinhibition (RSWA) indicative of destabilizing rhythmic motor output, and (2) phasic modulation loss (low REM density) indicative of disrupting adaptive and cognitive aspects of gait. Both mechanisms arise from progressive dysfunction of inhibitory and cholinergic circuits originally engaged in REM atonia, providing a physiological window into the gradual failure of gait control.

3.4. Integrated Physiological-Behavioral Continuum

Behavioral and polysomnographic (PSG) findings together suggest a continuum linking REM-related inhibitory loss with daytime motor impairment. Increased tonic RSWA may signal reduced inhibitory control in pontomedullary pathways and is often accompanied by gait variability and greater rigidity [21,50]. Quantitative analyses of REM sleep show that a higher level of RSWA is significantly associated with the duration of disease and the severity of motor symptoms, suggesting that REM muscle activity may provide critical information of motor network degeneration [52]. Furthermore, data from longitudinal observations indicate that individuals with PD + RSWA show a faster decline in step length [53], while reduced phasic REM density corresponds to greater dual-task interference and executive deficits [55].

Overall, the data support the view that inhibitory dysfunction develops progressively along the RBD-PD spectrum. During the earliest stages of iRBD, small fluctuations in force steadiness and motor timing begin to appear, suggesting mild instability in inhibitory control even though overall strength is preserved. As degeneration extends into pontomedullary and cortical inhibitory pathways, this instability becomes more apparent and can develop into rigidity and slowing of fine movements in PD with RSWA (PD + RSWA). Later in the disease course, gait often becomes more irregular and more vulnerable to cognitive interference, which may signal reduced automaticity and increased dependence on executive control.

RSWA mainly reflects problems in the tonic inhibition of muscle tone, whereas REM density seems to relate more to cholinergic processes involved in phasic activity, rhythmic timing, and the interaction between cognitive and motor control. Taken together, these measures help illustrate how REM-related disinhibition connects to later loss of automatic movement during wakefulness. Consistent with this pattern, long-term population studies show that PD patients with features of RBD experience faster motor and cognitive decline, especially within the PIGD subtype [12,23,56]. In addition, these physiological and behavioral measures provide objective indicators of inhibitory network function for early neuro-rehabilitative intervention aimed at stabilizing motor automaticity and delaying phenoconversion.

4. Biomarkers and Neuroimaging Correlates of Inhibitory Network Breakdown

Using non-invasive electrophysiology and neuroimaging techniques, progressive loss of inhibitory regulation in the RBD-PD continuum can be measured. These modalities outline how early compensatory changes give way to cortical disinhibition, microstructural degeneration, and broader network alterations, offering objective markers that link physiological, structural, and functional changes.

4.1. Electrophysiological Markers of Cortical Inhibition

Cortical excitability and inhibitory balance in the RBD-PD continuum can be quantitatively assessed using transcranial magnetic stimulation (TMS) and paired-associative stimulation (PAS) paradigms. These techniques provide reproducible measures of GABAergic inhibition and synaptic plasticity through indices such as short-interval intracortical inhibition (SICI), cortical silent period (CSP), and PAS-induced facilitation. Longitudinal data in early, drug-naïve Parkinson’s disease consistently demonstrate reduced SICI with preserved PAS-induced facilitation, a combination indicative of cortical hyperexcitability with intact early-phase plasticity [32]. As the disease progresses, PAS responsiveness declines, SICI is further reduced, hemispheric asymmetry narrows, and CSP durations become progressively shorter, a pattern consistent with a gradual loss of homeostatic metaplastic control [31]. These neurophysiological markers relate directly to behavior. Reduced SICI, shortened CSP durations, and attenuated PAS responsiveness correlate with bradykinesia severity, increased movement variability, and impaired scaling during voluntary movement [33,34,57]. Together, these findings support the view that TMS-PAS derived indices provide a reproducible physiological framework for tracking inhibitory network dysfunction from prodromal stages (iRBD) through clinical Parkinsonism.

4.2. Diffusion MRI: Microstructural Adaptation and Degeneration

Diffusion MRI has provided key structural evidence for early-stage changes across the RBD-PD continuum. Using 7T MRI, Patriat and colleagues found that PD patients with normative RSWA levels (PD − RSWA) showed higher fractional anisotropy (FA) and lower radial diffusivity (RD) in the anterior corona radiata, superior longitudinal fasciculus, and thalamic radiations compared with healthy controls [58]. These findings were interpreted as potential early compensatory alterations in white-matter organization, although the underlying biological mechanisms remain uncertain. In contrast, PD participants with elevated RSWA (PD + RSWA) showed reduced FA across similar pathways, a pattern more consistent with microstructural degeneration. Diffusion metrics also showed meaningful behavioral associations in the same cohort, with FA in the anterior corona radiata associated with gait speed and step length, and FA in the superior corona radiata related to upper-limb movement velocity [58].

Tobin and colleagues used a bi tensor free-water model to separate the extracellular free-water signal from the tissue specific diffusion component, which makes it possible to distinguish early microstructural change from fluid related alterations linked to axonal degeneration [59]. The method rests on earlier work showing that free-water reflects relatively unrestricted diffusion in extracellular space [60]. With this approach, Tobin and colleagues observed that free-water in the putamen was higher in both iRBD and early Parkinson’s disease, while increases in free-water itself, particularly in the putamen and the posterior substantia nigra, were present only in Parkinson’s disease [59]. This pattern aligns with previous reports of elevated free-water in the posterior substantia nigra in Parkinson’s disease across both single site and multi-site cohorts [61,62]. Taken together, these findings indicate that iRBD shows early tissue level alterations without clear evidence of degeneration, and that increases in free-water appear later as the disease advances. Diffusion MRI measures derived from the bi tensor framework may therefore provide a sensitive way to detect subtle microstructural changes that precede the development of motor or sleep related symptoms.

4.3. Functional Imaging: Network Reorganization and Loss of Automaticity

Functional MRI studies consistently show that network-level changes appear early in the RBD-PD spectrum. Resting-state fMRI studies show that idiopathic RBD is marked by early disruption across multiple functional networks [35,63,64]. Rolinski and colleagues (2016) showed that the basal ganglia network connectivity is already reduced in idiopathic RBD and is nearly identical to the pattern seen in early Parkinson’s disease [63]. Notably, these network changes were present even though only some RBD participants showed dopaminergic loss on DaTscan. It suggested that functional alterations may precede presynaptic degeneration. Also, Seed-based analyses further demonstrate reduced substantia nigra–putamen connectivity and increased coupling with posterior cortical regions such as the precuneus and cuneus, a pattern interpreted as early compensatory recruitment [64]. Beyond motor pathways, fronto-striatal, attention, and executive networks also show reduced connectivity in idiopathic RBD, with these changes correlating with cognitive performance [35]. Importantly, these reductions were associated with poorer performance on attention and executive-function tasks, indicating that cognitive–motor network involvement is already present during the prodromal stage.

Task-based fMRI findings are consistent with this broader pattern. During visual-guided precision-force production, both iRBD and PD groups show reduced blood-oxygen-level-dependent (BOLD) activation in the primary motor cortex, putamen, and thalamus compared to controls. These task-based BOLD signals correlate with fine-motor performance such as Purdue Pegboard Test [59]. These results indicate that as inhibitory networks degenerate, motor circuits become functionally hypoactive and increasingly reliant on prefrontal engagement. This reorganization parallels the behavioral shift from automatic to attention-dependent control, marking the systems-level manifestation of inhibitory network failure across the RBD-PD continuum.

4.4. Integrated Model of Compensatory Plasticity and Inhibitory Network Collapse

Multiple neurophysiological and imaging findings point to a broadly similar sequence of change across the RBD-PD continuum. Early in the disorder, several systems still appear capable of adapting to emerging subcortical dysfunction. Evidence for this comes from preserved or sometimes heightened associative plasticity, partial maintenance of intracortical inhibition, and diffusion profiles that have been interpreted as reflecting structural adjustment rather than loss. Functional MRI studies in iRBD and early PD also show greater engagement of premotor and parietal regions during tasks that would normally rely more heavily on automatic subcortical pathways, suggesting that additional cortical recruitment may help stabilize performance when inhibitory control begins to weaken [65].

As inhibitory circuits lose integrity, these adaptive responses become less reliable. Neurophysiological measures show a gradual reduction in intracortical inhibition and in the capacity for plasticity, while diffusion metrics shift from relative preservation toward patterns more consistent with declining white-matter organization. These changes mirror a reduced ability of the system to support automatic motor control.

With further progression, degeneration in brainstem, basal ganglia, and frontal pathways contributes to broader reorganization across motor and cognitive networks. Free-water imaging often reveals extracellular increases that are associated with axonal degeneration, and functional imaging studies show greater reliance on attention-based control strategies as automatic pathways deteriorate. When considered together, these observations outline a trajectory in which early compensatory responses gradually weaken, inhibitory regulation becomes less stable, and more extensive structural and functional changes emerge. This progression offers a useful way to understand how iRBD develops into clinically manifest Parkinson’s disease, as summarized in Table 2.

5. Rehabilitative and Translational Implications

Emerging data point to inhibitory network changes in the RBD-PD continuum that fluctuate between compensatory adjustment and subsequent loss of function. These shifts imply the presence of a phase in which residual plasticity can still be engaged, offering a potential opportunity for interventions aimed at stabilizing network performance before degeneration becomes less reversible.

In this section, we first outline rehabilitation and exercise strategies that have reasonably strong support in people with Parkinson’s disease and then turn to more mechanistic, as-yet untested ideas for prehabilitation in iRBD. There is only limited direct evidence that early training changes long-term progression or phenoconversion risk in iRBD, so the iRBD-focused suggestions below should be read as hypothesis-generating rather than as firm clinical recommendations. Figure 3 provides a conceptual overview of stage-specific network states along the PD continuum and illustrates how rehabilitative and translational strategies may be targeted according to the progression from brainstem-dominant pathology to advanced cortical involvement.

5.1. From Neurodegeneration to Network Preservation

The transition from iRBD to Parkinson’s disease (PD) involves progressive dysfunction of inhibitory circuits spanning the pontomedullary, basal ganglia, and cortical systems. In PD without REM sleep without atonia (PD − RSWA), diffusion MRI shows increased fractional anisotropy (FA) and reduced radial diffusivity (RD) in regions such as the anterior corona radiata and superior longitudinal fasciculus, findings that have been interpreted as possible early compensatory remodeling [58]. In contrast, individuals with PD + RSWA demonstrates reduced FA and increased free-water value, indicating brain structural degeneration and the loss of compensatory plasticity. This pattern parallels cortical neurophysiology, where PAS-induced facilitation is initially enhanced but declines with disease progression, reflecting impaired metaplastic regulation [31,32]. Taken together, these findings point to a period in which inhibitory circuits may retain some ability to adjust. This idea supports rehabilitation approaches that emphasize maintaining network integrity rather than only addressing clinical symptoms.

5.2. Rehabilitation Framework for the iRBD Stage

The iRBD stage may offer a chance to intervene before more fixed motor changes develop. At this point, neuroplastic capacity still seems relatively preserved, and training approaches such as aerobic exercise, balance work, and dual-task practice have been proposed as ways to support systems involved in inhibitory control and movement automaticity [66]. In this early phase, the emphasis is less on treating symptoms and more on helping maintain network function so that the decline in inhibitory tone and motor coordination seen in later PD may be postponed. However, these proposals are extrapolated from rehabilitation and exercise trials in PD [67,68,69,70], and there are currently no randomized studies showing that they delay phenoconversion or alter the clinical course in iRBD.

5.3. Decline of Automaticity and Sensory Recalibration

Evidence from both sleep and waking motor behavior suggests that REM-related inhibitory deficits may carry over into daytime movement. Reduced phasic REM density has been linked to higher dual-task gait cost and to poorer executive performance, findings that point to impaired cholinergic contributions to attention–motor coupling [55]. PD with RSWA (PD + RSWA) shows slower walk, shorter steps, and greater stride variability compared with PD − RSWA and healthy controls. The severity of RSWA is also associated with freezing of gait (FoG), consistent with shared involvement of cholinergic and reticulospinal pathways [19,20,40]. These observations have practical implications, as interventions such as rhythmic cueing, visual–auditory feedback, and dual-task gait practice may help stabilize temporal regularity and promote compensatory attentional engagement when automatic motor control becomes less reliable.

5.4. Upper-Limb Motor Control and Early Inhibitory Deficits

The findings regarding upper-limb movement closely align with observed locomotor patterns, thereby emphasizing the early manifestations of inhibitory imbalance. Specifically, PD with RSWA (PD + RSWA) shows greater bilateral rigidity and reduced interhemispheric asymmetry in tone regulation compared with PD − RSWA, reflecting pontomedullary inhibitory loss [50]. Furthermore, individuals with iRBD also show increased force variability during precision isometric-force tasks, suggesting less stable recruitment within the corticospinal pathways [48]. Given these insights, therapeutic approaches such as precision-based upper-limb training and visuomotor feedback may prove valuable for enhancing movement consistency during these prodromal stages.

5.5. An Integrated Prehabilitation Framework

REM sleep without atonia (RSWA), characterized by excessive muscle activity during REM sleep, is observed across multiple physiological and behavioral modalities and is generally interpreted as a marker of disinhibition within brainstem inhibitory circuits. It has also been linked to faster motor deterioration. For example, individuals with higher baseline RSWA (PD + RSWA) show roughly a threefold greater decline in step length and larger increases in gait variability over three years compared with PD − RSWA [53]. When considered alongside diffusion MRI measures and indices of cortical neuroplasticity, RSWA may help define a non-invasive multimodal neuroimaging biomarker set that can guide early, targeted intervention. If the shift from compensatory to more clearly degenerative phases can be identified, clinicians may be able to introduce exercise, cueing, or neuromodulation at a time when inhibitory and cholinergic systems are still responsive. In established PD, high intensity aerobic and balance focused exercise has been shown to improve gait, freezing of gait, and balance performance, and in some trials to alter task-related brain activity and dopaminergic markers [67,68,69,70,71,72,73]. This prehabilitation framework remains a conceptual proposal rather than an established disease-modifying strategy. Prospective trials will be required to test whether timing and targeting interventions in this way can meaningfully alter long-term outcomes in iRBD.

5.6. Digital Biomarkers and Precision Monitoring

Digital tools are beginning to make it feasible to monitor inhibitory network function in a more continuous and less intrusive way [74,75,76]. Automated video analysis, for instance, can capture very subtle signs of bradykinesia or sequence slowing in iRBD and PD changes that may not be obvious during routine clinical assessment [51]. Wearable gait sensors, combined with polysomnographic measures such as RSWA and REM density from cohorts like NAPS [9], offer another angle on how inhibitory and cholinergic circuits behave over time [77]. Together, these approaches suggest the possibility of adapting rehabilitation in real time, with feedback or training load adjusted according to the person’s physiological state instead of relying solely on scheduled sessions.

5.7. Ethical and Clinical Considerations

Importantly, not everyone with idiopathic RBD will develop a synucleinopathy, so any prehabilitation strategy needs to be grounded in biomarkers that have been carefully validated. In practice, decisions about who should receive early intervention will probably need to consider several indicators at once, including RSWA severity, neuroimaging findings, and newer physiological signals that might hint at emerging inhibitory network problems. Developing such an approach will require collaboration across sleep medicine, movement-disorders neurology, and rehabilitation science to work out appropriate dosing, monitor safety, and decide when to intervene. The broader aim is straightforward: to help people maintain independence and quality of life for as long as possible by supporting inhibitory and related neuromodulatory systems across the RBD-PD continuum.

6. Conclusions and Future Perspectives

6.1. Integrative Summary

Over the past two decades, work on RBD has substantially reshaped how we think about the early stages of Parkinson’s disease. What was once seen as a relatively benign parasomnia is now viewed as a prodromal α-synucleinopathy in which inhibitory networks fail in a selective and measurable way. Early disruption within the SLD and PPN appears to trigger a broader pattern of disinhibition that extends through basal ganglia-cortical loops. Clinically, this process is first reflected in REM sleep without atonia (RSWA) and subtle irregularities in force control, well before the emergence of bradykinesia, rigidity, or postural instability [16,21,50].

Evidence from neurophysiology, neuroimaging, and behavior studies points in a similar direction. Early loss of GABAergic inhibition, combined with changes in cholinergic modulation, appears to contribute to a state of cortical hyperexcitability that may offer some short-lived compensatory benefit but tends to become unstable over time [31,58]. Findings from TMS-PAS studies in early PD show reduced inhibition and diminished plastic potential [31,32,34], and diffusion MRI reveals progressive white-matter changes that differ depending on RBD status [58,59]. Behavioral measures, including greater force variability and gait irregularity, have been reported alongside these physiological and structural findings [48,51,53,55]. Collectively, these observations indicate that RBD provides an opportunity to examine prodromal synucleinopathy in vivo and to follow inhibitory dysfunction before dopaminergic loss becomes clinically apparent. Rather than a narrow transitional stage, RBD may represent a period during which meaningful neuroplastic capacity is still present.

6.2. Conceptual Model of the RBD–PD Continuum

It can be helpful to think of the RBD to PD continuum in terms of two processes that unfold together. One concerns the gradual spread of alpha synuclein pathology from the brainstem toward cortical regions. The other relates to changes in the balance between excitation and inhibition within motor and cognitive systems. Early in RBD, partial loss of inhibitory control can produce a period of cortical hyperactivity that temporarily helps maintain performance, although this state usually does not last long. As pathology advances through the nervous system, this balance begins to give way, and features such as bilateral rigidity, reduced automaticity, and impaired integration of cognitive and motor control become more apparent [50,55].

This perspective also helps clarify individual differences in disease progression. Many people with RBD exhibit features consistent with a body-first form of pathology, marked by early involvement of autonomic and brainstem systems. In contrast, people with PD who do not have RBD often follow a brain first trajectory in which asymmetric loss of nigrostriatal dopamine is more prominent [78]. Longitudinal studies further show that PD patients with RBD features show decline more rapidly in both motor and cognitive domains, especially within the PIGD subtype [12,23,79]. These distinctions may allow early interventions to be matched more effectively to each person’s underlying neural vulnerabilities.

Within this framework, the brainstem-to-cortex spread of α-synuclein pathology helps explain why many individuals with idiopathic RBD later develop Parkinsonian syndromes [1,5,6]. Early involvement of pontomedullary REM-atonia and cholinergic nuclei can account for RSWA and subtle motor irregularities that remain compensable for years, whereas subsequent dysfunction in basal ganglia-cortical networks is consistent with the later emergence of bradykinesia, rigidity, and postural instability. Current evidence does not indicate that this pathological process can be reversed. Instead, additional cortical engagement and reorganization of white-matter connections may provide short-lived compensation, so that parkinsonian signs appear later or less clearly.

6.3. Translational and Rehabilitative Outlook

The mechanisms described above suggest a gradual shift from approaches that focus mainly on compensation toward those that aim to intervene earlier, when adaptation is still possible. The iRBD stage may offer such an opportunity, since inhibitory and cholinergic systems appear to retain some flexibility at this point. Exercise and skill-based practice could help support GABAergic function and white-matter organization, and sensory or rhythmic cueing may assist with timing and movement coordination. Non-invasive brain stimulation, including TMS and transcranial alternating current stimulation (tACS), may also be more effective when used early, at a time when PAS responsiveness is still detectable in PD [32,66,68]. If applied during this more adaptable phase, combining these approaches may help maintain stability within the broader motor system and slow functional decline. In this view, rehabilitation is not only a way to compensate for deficits that have already emerged but may also help preserve the neural processes that support automatic movement and cognitive control.

6.4. Future Directions

Several questions remain open. We still do not know how long the period of heightened plasticity lasts in idiopathic RBD or how much it varies from person to person. Identifying the shift from adaptive change to more permanent deterioration will be important for determining when intervention should begin. Current PSG studies show that the severity of RSWA relates to changes in motor networks and to the rate of progression [52], suggesting that quantitative EMG may serve as a useful marker for tracking these changes over time. Future work combining PSG measures such as RSWA and REM density with diffusion MRI and TMS-based physiology will help clarify how cortical inhibition evolves in relation to sleep physiology.

Although many individuals with iRBD eventually develop a Parkinsonian syndrome, some progress toward dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) [25,80,81]. Future research should therefore track both motor and cognitive trajectories, clarifying how early inhibitory and cholinergic dysfunction differentially shapes gait, coordination, and executive control.

Prospective work should also identify which gait metrics are most progression-sensitive, as some longitudinal cohorts report robust step-length decline accompanied by increased variability [53]. Further work is needed to clarify how GABAergic and cholinergic changes contribute to inhibitory failure will inform precision-targeted interventions across disease stages [12,20,23]. The optimal dose and combination of exercise, coordination training, and brain stimulation also remain unknown. Adaptive clinical trials integrating biomarker-guided timing could determine when prehabilitation is most effective.

Recent advances in wearable sensing and AI-based analytics now enable continuous, closed-loop monitoring of inhibitory network health, supporting individualized, mechanism-driven rehabilitation [9,51,77]. Large-scale initiatives such as the NAPS consortium and the Parkinson’s Progression Markers Initiative (PPMI)—an international biomarker study tracking multimodal progression across idiopathic RBD, de novo PD, and at-risk populations—should standardize multimodal biomarkers, validate predictive models, and establish evidence-based frameworks for mechanism-specific care.

6.5. Closing Perspective

Idiopathic RBD offers an opportunity to observe synuclein-related changes before parkinsonian features become evident. REM sleep without atonia, differences in REM density, and mild motor abnormalities are thought to indicate early involvement of brainstem inhibitory and cholinergic pathways. How much these physiological measures can improve individual risk prediction, however, remains uncertain. A key question moving forward is whether combining PSG features with quantitative motor and neuroimaging markers can improve prediction of phenoconversion and help identify clinically meaningful subtypes. Another challenge is to understand when compensatory processes begin to fade and how this shift is reflected in motor or sleep-related physiology, since this information will be important for timing early intervention.

Although early findings point to potential benefits of exercise, motor training, and neuromodulation, their specific effects in iRBD remain uncertain. Longitudinal studies will be important for testing whether biomarker-guided interventions can influence the course of the disease or help preserve function.