Authors: Minsub Cho (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea), Jin Whan Cho (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea), Dallah Yoo (Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, South Korea), Jinse Park (Haeundae Paik Hospital, Inje University, Busan, South Korea), Do‐Young Kwon (Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan‐si, South Korea), Seong‐Beom Koh (Department of Neurology, South Korea University Guro Hospital, Seoul, South Korea), Jeong‐Ho Park (Department of Neurology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea), Jinyoung Youn (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea)
Categories: SPECIAL ISSUE REVIEW, choline, dopamine, freezing, GABA, glutamate, neurotransmitter, norepinephrine, Parkinson, serotonin
Source: The European Journal of Neuroscience
Doi: 10.1111/ejn.70590
Authors: Minsub Cho, Jin Whan Cho, Dallah Yoo, Jinse Park, Do‐Young Kwon, Seong‐Beom Koh, Jeong‐Ho Park, Jinyoung Youn
Freezing of gait (FOG) is a common and debilitating symptom of Parkinson's disease (PD). Despite its significant clinical impact, the underlying pathophysiological mechanisms of FOG remain poorly understood. Given the clinical heterogeneity of FOG and its occurrence in various disorders, not only dopaminergic dysfunction but also multiple nondopaminergic neurotransmitter systems play a role in this phenomenon. In this review, we offer a comprehensive overview of current evidence regarding the contributions of various neurotransmitters to FOG, including dopamine, acetylcholine, norepinephrine, serotonin, glutamate, and gamma‐aminobutyric acid (GABA). While dopaminergic dysfunction is particularly relevant in levodopa‐responsive forms of FOG, the occurrence of paradoxical ON‐state freezing and levodopa‐unresponsive FOG underscores dopamine's limited and nonlinear role in gait control. Degeneration of the cholinergic system has been linked to impaired gait automaticity, attentional control, and postural stability, thereby exacerbating freezing, especially in cognitively triggered and levodopa‐unresponsive FOG. Additionally, noradrenergic dysfunction may impair attentional and adaptive control of gait, making locomotor networks more susceptible to freezing under stress or cognitive load. Although evidence is limited, the serotonergic system is also thought to be involved in FOG. An imbalance between glutamatergic excitation and GABAergic inhibition within cortico–basal ganglia–brainstem circuits may destabilize locomotor network dynamics and contribute to freezing, as supported by neuroimaging and pharmacological studies. The ways in which these neurotransmitter systems contribute to FOG are multifactorial and involve complex interactions within distributed locomotor networks.
Freezing of gait (FOG) is a gait disturbance characterized by brief episodes of gait arrest, which result in an inability to start or continue walking, especially while turning (Nutt et al. 2011). FOG in Parkinson's disease (PD) is linked to a higher risk of falls, loss of independence, and a decline in quality of life, becoming more problematic as the disease advances (Walton et al. 2015; Youn et al. 2017). Despite its significant clinical impact, the precise pathophysiological mechanisms behind FOG are still not fully understood.
A key challenge in comprehending FOG lies in its considerable heterogeneity. While FOG can respond to levodopa treatment, in some cases, dopaminergic medications are ineffective and may even worsen the condition. This clinical heterogeneity indicates that, although dopaminergic deficiency is a contributing factor for FOG in certain patients, other nondopaminergic and network‐level mechanisms are crucial in cases resistant to levodopa (Nutt et al. 2011). Additionally, FOG can be observed in various movement disorders beyond PD, such as progressive supranuclear palsy (PSP), vascular parkinsonism (VaP), and normal pressure hydrocephalus (NPH), where the benefits of levodopa treatment are limited (Zijlmans et al. 2004; Williams and Lees 2009; Youn et al. 2012; Youn et al. 2022; Bluett et al. 2023). In these conditions, FOG is thought to reflect dysfunction in higher‐level gait control rather than primary basal ganglia pathology (Schaafsma et al. 2003). The presence of FOG across these diverse disorders supports the idea that freezing is indicative of a failure in distributed locomotor networks, rather than a mechanism unique to nigrostriatal dopaminergic degeneration in PD (Nutt et al. 2011).
Accumulating evidence from neuroimaging, neuropathology, and electrophysiology implicates a distributed locomotor network that involves the frontal cortex, basal ganglia, thalamus, brainstem, and cerebellum (Takakusaki 2017). Disruption of fronto‐striatal circuits, especially those involving the supplementary motor area and prefrontal cortex, may impair gait initiation and diminish automatic control of walking (Shine et al. 2013). Degeneration of brainstem locomotor regions, including the pedunculopontine nucleus (PPN) and the broader mesencephalic locomotor region, is associated with axial gait dysfunction, postural instability, and freezing, particularly in cases resistant to levodopa (Youn et al. 2015; Lucas McKay et al. 2019). Additional involvement of thalamic and cerebellar pathways may further impair the sensorimotor integration necessary for rhythmic and adaptive gait (Espay et al. 2012). White matter lesions affecting frontal‐subcortical connections, commonly observed in VaP and NPH, further support the role of network disconnection in freezing phenomena (Stolze et al. 2000; Williams and Lees 2009; Youn et al. 2012).
The cross‐talk hypothesis suggests that FOG results from abnormal interactions among parallel neural circuits involved in motor, cognitive, and limbic processing. Excessive cross‐talk within fronto‐basal ganglia networks, particularly under conditions of heightened cognitive load or emotional stress, may disrupt the normal selection and execution of gait‐related motor programs. This disruption helps explain the episodic nature of freezing and its sensitivity to anxiety, dual‐tasking, and environmental complexity (Nieuwboer and Giladi 2013). FOG is increasingly recognized as a heterogeneous phenomenon due to the varied clinical responses to pharmacological treatments, the involvement of multiple neural structures, and the range of proposed pathophysiological mechanisms. This diversity likely indicates the influence of several neurotransmitter systems beyond dopamine. In this review, we examine the current evidence regarding the roles of different neurotransmitters in the pathophysiology of FOG.
It should be noted that much of the current evidence linking neurotransmitter dysfunction to FOG is largely correlative and derived from clinical and neuroimaging studies. Therefore, many of the proposed mechanisms remain hypothetical, and the relationships described in this review should be interpreted as potential contributors rather than definitive causes of FOG.
Dopamine is regarded as the main neurotransmitter involved in PD. Clinically, FOG in PD can be subdivided into phenotypes based on responsiveness to dopaminergic therapy (Schaafsma et al. 2003; Amboni et al. 2015). The most common subtype is OFF‐FOG, which occurs in the dopaminergic “off” state and typically improves, at least partially, with levodopa administration. In contrast, ON‐FOG is a paradoxical phenomenon where freezing occurs or worsens during the dopaminergic “on” state, sometimes in a dose‐dependent manner, despite improvements in other parkinsonian motor features (Espay et al. 2012; Amboni et al. 2015). A third category, commonly known as ONOFF‐FOG or levodopa‐unresponsive FOG, persists regardless of dopaminergic state and is often observed in more advanced stages of the disease (Amboni et al. 2015; Lucas McKay et al. 2019). However, levodopa should still be the first medication tried, as the majority of FOG cases are responsive to it. Thus, dopaminergic dysfunction is likely the most important mechanism underlying FOG. Table 1 summarizes key clinical and imaging studies that investigate the role of the dopaminergic system in FOG. Although levodopa should still be the first medication tried, as the majority of FOG cases are responsive to it, these levodopa‐resistant phenotypes suggest that nondopaminergic mechanisms also contribute to FOG. Therefore, while dopaminergic dysfunction remains a major contributor to FOG, nondopaminergic systems such as the cholinergic system likely play an important complementary role, particularly in levodopa‐resistant or paradoxical FOG phenotypes.
Presynaptic degeneration of nigrostriatal dopaminergic neurons has been linked to the development of FOG, particularly in its early and levodopa‐responsive forms. In a large cohort of newly diagnosed PD patients, lower baseline DAT uptake in both the caudate nucleus and putamen was found to predict subsequent development of FOG during follow‐up (Kim et al. 2018; Yang et al. 2023). This finding supports the role of presynaptic striatal dopaminergic denervation in increasing vulnerability to FOG. Consistent with this, a recent systematic review and meta‐analysis of predictors for incident FOG identified lower DAT uptake in the caudate and putamen as a significant risk factor for future FOG (Herman et al. 2023).
However, dopaminergic terminal loss shows variable relationships with freezing severity (Steidel et al. 2021). Additionally, treatment with rotigotine, a nonergot dopamine agonist with strong affinity for D1/D5 receptors, has been shown to improve FOG in a subset of patients, especially those experiencing OFF‐FOG (Ikeda et al. 2016). These findings suggest that receptor‐specific dopaminergic modulation, on top of global dopamine replacement, can be involved in levodopa‐responsive FOG. Dopamine receptor distribution differs between the neostriatum and extra‐striatal regions, with D2 receptors predominantly expressed in the striatum, whereas D1 receptors are more widely distributed in extra‐striatal regions such as the thalamus and cortex (Håkan Hall et al. 1994). Given that FOG is increasingly considered a disorder of distributed locomotor networks rather than a phenomenon explained solely by nigrostriatal dysfunction (Nutt et al. 2011), the beneficial effects of rotigotine in some patients may partly reflect modulation of extra‐striatal dopaminergic pathways involved in gait control (Ikeda et al. 2016).
Clinically, many patients experience improvement in FOG with levodopa, particularly in the OFF state. However, some patients may show incomplete, absent, or even paradoxical worsening of freezing despite receiving adequate dopaminergic replacement (Espay et al. 2012; Amboni et al. 2015). Dopaminergic dysfunction alone does not fully explain all subtypes of FOG, and levodopa‐unresponsive FOG or ON‐FOG highlights the complex and nonlinear relationship between dopaminergic stimulation and FOG.
Interestingly, recent data from levodopa‐naïve PD cohorts demonstrate a markedly lower prevalence of FOG compared with chronically levodopa‐treated patients with similar disease duration and severity (Jansen et al. 2023). However, this interpretation remains controversial, and alternative explanations should be considered. For example, patients who remain untreated with levodopa may represent a less severely affected subgroup despite similar disease duration, and overall disease progression and network degeneration may play a more important role in the development of FOG than levodopa exposure per se (N Giladi et al. 2001; Gilat et al. 2021). Furthermore, a substantial proportion of patients receiving long‐term levodopa therapy do not develop FOG, suggesting that the relationship between levodopa exposure and FOG is not necessarily causal (N Giladi et al. 2001). Taken together, current evidence suggests that while long‐term dopaminergic treatment may influence network plasticity and contribute to FOG in some patients, there is currently no consensus that levodopa exposure itself is a primary cause of FOG.
A significant number of patients experience levodopa‐unresponsive FOG, where freezing continues despite receiving adequate or even excessive dopaminergic treatment. Experimental studies involving levodopa challenges have shown that FOG can remain unchanged between OFF and ON states, a phenomenon referred to as levodopa‐unresponsive FOG (Amboni et al. 2015; Lucas McKay et al. 2019). Clinically, levodopa‐unresponsive FOG is more often associated with advanced disease, significant axial motor dysfunction, and cognitive or attentional impairment. Levodopa‐unresponsive FOG was reported after dopamine agonist withdrawal, so the role of postsynaptic changes can be important in levodopa‐unresponsive FOG (Salari et al. 2021). On the other hand, steady delivery of levodopa, not pulsatile stimulation, improved treatment‐resistant FOG with levodopa‐carbidopa intestinal gel (Shackleford et al. 2022). Therefore, postsynaptic dopaminergic changes from disease progression or pulsatile dopaminergic stimulation can be an important mechanism in levodopa‐unresponsive FOG. In addition, PD patients with levodopa‐unresponsive FOG are more prone to set‐switching errors than those with levodopa‐responsive FOG (OFF‐FOG), suggesting the role of nondopaminergic neurotransmitter systems beyond the loss of nigrostriatal dopamine in FOG (Turner et al. 2021). Similarly, dual lesion of dopaminergic and cholinergic systems can induce FOG‐like symptoms in animal models (Avila et al. 2020).
FOG can be observed in various other movement disorders, such as PSP, VaP, and NPH. FOG in these disorders shows little to no responsiveness to dopaminergic therapy, reflecting the dysfunction in fronto‐basal ganglia network. The presence of FOG in various disorders supports the idea that freezing is indicative of a failure in distributed locomotor networks, rather than a mechanism solely related to nigrostriatal dopaminergic degeneration in PD.
Several conceptual models have been proposed to explain FOG. One such model, the threshold model, posits that freezing occurs when the combined impact of motor, cognitive, and sensory impairments surpasses the functional capacity of the locomotor network (Nieuwboer and Giladi 2013). The interference model suggests that FOG arises from impaired integration of motor, cognitive, and limbic processes within fronto–basal ganglia circuits, leading to disruption in the selection and execution of effective stepping (Lewis and Barker 2009). The cognitive and attentional model emphasizes impaired executive control and reduced automaticity of gait, whereby increased cognitive load or environmental complexity precipitates FOG episodes (Vandenbossche et al. 2012). Crucially, this model suggests the involvement of neuromodulatory systems that underpin executive control, attention, and gait automaticity.
Cholinergic system is particularly important for modulating cortical attention, cognitive–motor integration, and the top–down control of locomotion. Thus, degeneration of cholinergic pathways may lower the threshold for FOG in response to cognitive load or environmental complexity, establishing a mechanistic link between cognitive models of FOG and dysfunction in nondopaminergic neurotransmitters (Albin et al. 2022). Various studies with neurophysiologic data suggested the role of cholinergic system in FOG. Although short‐latency afferent inhibition (SAI) was not reduced in PD patients with all subtypes of FOG (Picillo et al. 2015), SAI was reduced in PD patients with levodopa‐unresponsive FOG (Wang et al. 2022). Therefore, cholinergic system plays crucial role especially in levodopa‐unresponsive FOG, but executive function was correlated with FOG severity even in levodopa‐responsive FOG, suggesting the disruption of cognitive processes (Turner et al. 2021). A recent FEOBV PET study demonstrated distinct cholinergic topographical patterns between levodopa‐responsive and levodopa‐unresponsive freezers, suggesting that different patterns of cholinergic dysfunction in cortical and brainstem regions may contribute to different FOG subtypes (Chou et al. 2025). In addition, Hvingelby et al. (2025) found that cholinergic denervation patterns significantly correlated with the severity of ON‐FOG, whereas no such association was observed in the OFF‐FOG (Hvingelby et al. 2025). Together, these findings suggest that cholinergic dysfunction contributes to freezing through different anatomical and neurochemical mechanisms depending on the clinical subtype of FOG. Table 2 summarizes studies that investigate the role of cholinergic contributions to FOG.
Growing evidence suggests that the cholinergic system plays a significant role in the pathophysiology of FOG (Pasquini et al. 2021). Central cholinergic projections mainly originate from the basal forebrain, which extensively innervates the cerebral cortex, and from the PPN in the brainstem. The PPN is a crucial part of the mesencephalic locomotor region, sending projections to the thalamus, basal ganglia, cerebellum, and spinal locomotor circuits (Bohnen and Albin 2011; Bohnen et al. 2022). The degeneration of basal forebrain cholinergic neurons is linked to impaired attention, executive dysfunction, and decreased gait automaticity, all of which are known triggers of FOG (Bohnen et al. 2014; Zhang et al. 2024). Accordingly, gait disturbance in PD is closely related to cognitive dysfunction in previous studies (Choi et al. 2019; Na et al. 2019).
Various studies with neuroimaging showed that diminished integrity in specific cholinergic nuclei is linked to gait abnormalities, such as slower gait speed, increased variability, and impaired postural control (Bohnen et al. 2013; Wilson et al. 2021; Zhang et al. 2024). Notably, recent evidence indicates that both structural and functional changes in the PPN are associated with gait freezing and falls, independently of cortical cholinergic degeneration (Karachi et al. 2010; Thevathasan et al. 2012; Youn et al. 2012; Youn et al. 2015; Chambers et al. 2021). This supports the idea that the PPN plays a direct role in regulating gait initiation and locomotor rhythm. In addition, diffusion tensor imaging (DTI) studies have demonstrated asymmetric PPN connectivity in patients with FOG, with reduced connectivity particularly in the right PPN and its connections to the frontal cortex, thalamus, and cerebellum in patients with more severe FOG (Brett W Fling et al. 2013). Besides PPN, atrophy of cholinergic forebrain was also reported in PD patients with FOG (Gan et al. 2023). Additionally, reduced expression of the vesicular acetylcholine transporter in cortical and thalamic projection areas has been associated with the severity of freezing, underscoring the notion that combined cortical and brainstem cholinergic dysfunction contributes to FOG (Bohnen et al. 2014). It should be noted, however, that the PPN is a heterogeneous nucleus composed of cholinergic, GABAergic, and glutamatergic neuronal populations, and structural magnetic resonance imaging (MRI) findings alone cannot be interpreted as selective cholinergic degeneration (Juan Mena‐Segovia et al. 2004; Karachi et al. 2010). Experimental studies of the mesencephalic locomotor region have demonstrated that locomotion is regulated by cell‐type‐specific circuits, in which glutamatergic neurons facilitate locomotor initiation and GABAergic neurons suppress locomotor output, while cholinergic neurons appear to play a more modulatory role (Kiehn 2016; Roseberry et al. 2016). Nevertheless, converging evidence from PET imaging and neuropathological studies suggests that cholinergic degeneration within the PPN and related projection systems is particularly associated with gait dysfunction, postural instability, and FOG, supporting a prominent role of the cholinergic system within the mesencephalic locomotor region (Karachi et al. 2010; Bohnen and Albin 2011; Bohnen et al. 2013).
Clinical trials of acetylcholinesterase inhibitors further support the role of cholinergic systems in gait dysfunction and freezing. Treatment with rivastigmine and other acetylcholinesterase inhibitors has been shown to improve gait variability, reduce falls, and enhance attentional control in patients with PD. However, their effects on FOG have been modest and inconsistent (Henderson et al. 2016). Therefore, cholinergic dysfunction contributes to FOG primarily through impaired cognitive‐motor integration, rather than as a sole causative mechanism.
On the other hand, muscarinic receptor blockade from anticholinergic exposure has been associated with risk of FOG, supporting a functional role for muscarinic acetylcholine receptors signaling in locomotor control (Saeedi et al. 2021). Dysregulation of muscarinic receptor subtypes, particularly within cortical and striatal regions, can disrupt the balance between excitatory and inhibitory motor control required for stable gait (Hernandez‐Flores et al. 2015). Collectively, the available evidence indicates that cholinergic dysfunction plays an important nondopaminergic modifier of FOG (Ztaou et al. 2016) and may explain levodopa nonresponsive and cognitively triggered forms of FOG (Rochester et al. 2012).
Norepinephrine is a key neuromodulator that helps maintain adaptive control of gait by regulating arousal, vigilance, and cognitive flexibility. Because locomotion relies heavily on attentional resources and responsiveness to the environment, disruptions in noradrenergic signaling can compromise gait stability, even without any obvious motor impairment. In addition to its role in attention and arousal, the noradrenergic system is closely linked to emotional processing and limbic function. Anxiety and fear of falling are well‐known triggers of FOG, and anxiety has been proposed as an important underlying mechanism contributing to freezing episodes (Ehgoetz Martens et al. 2014).
Central noradrenergic projections primarily originate from the locus coeruleus in the brainstem, which extensively innervates the cerebral cortex, basal ganglia, thalamus, cerebellum, and spinal cord (Schwarz and Luo 2015). Degeneration of locus coeruleus neurons is linked to impaired attentional control, diminished adaptive responses to environmental demands, and increased gait instability (Yang et al. 2025). Although the mechanism is still not clearly elucidated, degeneration of the locus coeruleus may occur early in the disease course without immediately leading to FOG (Braak et al. 2003; Isaias et al. 2016). This may reflect the fact that the presence of noradrenergic changes alone is not sufficient to induce freezing, and that the severity or progression of these changes may be more critical for its clinical manifestation. In addition, neuromelanin‐related alterations in the locus coeruleus may interact with dopaminergic degeneration and other neurotransmitter system dysfunctions, collectively contributing to the development of FOG (K S Rommelfanger and Weinshenker 2007; Sara 2009). These findings support the concept that noradrenergic dysfunction may influence locomotor control through distributed network interactions rather than acting as an isolated deficit (Sara 2009; Nutt et al. 2011).
Neuroimaging studies reveal that a reduction in noradrenergic terminal integrity correlates with gait impairment and the severity of FOG, independent of nigrostriatal dopaminergic loss (Ono et al. 2016; Wang et al. 2023). Noradrenergic dysfunction lowers the resilience of locomotor networks, increasing the vulnerability of gait under conditions of cognitive load, stress, or environmental complexity (Tosserams et al. 2023). Importantly, noradrenergic dysfunction in FOG may not simply reflect a deficit state, but rather a dysregulation of noradrenergic tone. Both insufficient arousal and excessive arousal have been shown to precipitate freezing episodes, particularly in situations involving anxiety or increased cognitive demand (Ehgoetz Martens et al. 2014; Tosserams et al. 2023). These findings support a model in which stable gait performance depends on an optimal level of noradrenergic activity that maintains network stability under challenging conditions.
A recent norepinephrine transporter (NET) imaging study demonstrated reduced NET binding in patients with OFF‐FOG, particularly in the thalamus, where uptake was correlated with the severity of OFF‐FOG (McKay et al. 2023). Notably, however, NET binding was not significantly reduced in patients with levodopa‐unresponsive FOG, suggesting that noradrenergic dysfunction may contribute preferentially to specific FOG phenotypes rather than to all forms of FOG.
In addition to central noradrenergic dysfunction, peripheral noradrenergic denervation has also been associated with gait impairment in PD. A dual‐ligand PET study demonstrated that more extensive cardiac sympathetic denervation was associated with slower gait velocity and gait impairment in PD, and these associations remained significant even after controlling for nigrostriatal dopaminergic degeneration, age, disease severity, cognition, peripheral neuropathy, and autonomic symptoms (Carli et al. 2024). These findings suggest that noradrenergic dysfunction may influence gait through mechanisms that are at least partly independent of dopaminergic motor impairment, further supporting the concept that FOG is a multisystem disorder involving both central and peripheral noradrenergic pathways.
Pharmacological modulation of the noradrenergic system further underscores its role in the pathophysiology of FOG. The augmentation of noradrenergic transmission using droxidopa, a synthetic precursor of norepinephrine, has been shown to improve gait stability, reduce falls, and alleviate freezing in some patients, particularly those with levodopa‐resistant FOG (Hauser et al. 2016). However, considering droxidopa primarily acts through a peripheral mechanism by increasing norepinephrine levels and improving orthostatic hypotension and cerebral perfusion, rather than directly enhancing central noradrenergic transmission, the beneficial effects of droxidopa on gait may be mediated by improved blood pressure regulation and cerebral perfusion, which enhance overall gait stability and reduce falls.
Atomoxetine, a selective norepinephrine reuptake inhibitor, has been investigated as a potential treatment for levodopa‐unresponsive FOG, based on the role of the noradrenergic system in attention and executive control. However, early clinical studies and small pilot trials did not demonstrate significant improvement in freezing (Jankovic 2009; Revuelta et al. 2015). Despite these negative findings, interest in atomoxetine has recently been revived, as FOG is increasingly understood as a network disorder involving cognitive–motor integration and impaired neural network coordination. Ongoing studies are re‐evaluating atomoxetine using multimodal approaches, based on the hypothesis that enhancing noradrenergic transmission may reduce abnormal neural cross‐talk and improve gait control.
Serotonergic neurotransmission originating in the dorsal raphe nucleus projects widely to frontal, limbic, and brainstem regions associated with gait initiation, postural control, and the integration of cognitive‐emotional networks into motor output (Takakusaki 2017). Several studies suggested that serotonergic denervation observed in PD patients may underlie the phenomenon of FOG (Table 3). Analyses of cerebrospinal fluid have shown that total serotonin and related metabolites are reduced in PD, and lower serotonin levels correlate with the severity of FOG compared to other motor features (Tohgi et al. 1993). A recent study with resting‐state functional MRI revealed reduced functional connectivity between the dorsal raphe nucleus and several cortical regions, including the supplementary motor area, superior frontal gyrus, and cingulate cortex, in PD patients with FOG when compared with PD patients without FOG or healthy control (Lv et al. 2022).
A multicenter, open‐label, randomized trial with selective serotonin reuptake inhibitors (paroxetine or escitalopram) or serotonin‐norepinephrine reuptake inhibitor (duloxetine) in PD patients with depression demonstrated significant improvements in both depression and FOG (Takahashi et al. 2019). Although FOG was a secondary outcome and the sample size was modest, this finding emphasized the role of serotonergic dysfunction in FOG.
Glutamatergic and GABAergic neurotransmission is essential for maintaining the balance between excitation and inhibition in the motor and cognitive networks that control gait. Disruption of this balance can lead to increased network instability and diminish the effectiveness of motor program selection needed for smooth and adaptive walking. An altered balance between glutamatergic excitation and GABAergic inhibition in cortico‐basal ganglia‐brainstem circuits has been suggested as a factor contributing to gait network instability in PD (O'Gorman Tuura et al. 2018; Terkelsen et al. 2022). Previous studies indicated reduced GABAergic receptor availability in the thalamus or reduced GABA levels in the basal ganglia were associated with greater severity of axial motor symptoms, including FOG (Gong et al. 2018; Bohnen et al. 2023). These findings suggested that degeneration or dysfunction of basal ganglia excitatory–inhibitory balance (glutamatergic and GABAergic system) contributes to impaired regulation of locomotor output. In addition, magnetic resonance spectroscopy studies have demonstrated region‐specific alterations in GABA levels in PD. Elevated GABA levels have been reported in the pons and putamen in patients with mild‐to‐moderate PD, suggesting abnormal inhibitory modulation within brainstem locomotor regions and basal ganglia circuits (Uzay E. Emir et al. 2012). Furthermore, GABAergic changes within the thalamocortical circuit have been observed in PD, supporting the notion that impaired inhibitory control across distributed motor networks may contribute to gait and postural instability (van Nuland et al. 2020). Reduced GABA‐A receptor availability has been associated with falls and FOG in PD (Bohnen et al. 2023), leading to interest in flumazenil as a potential treatment aimed at restoring inhibitory network balance. Although clinical evidence remains limited, modulation of GABAergic transmission may represent a potential therapeutic strategy for FOG. Supporting this therapeutic rationale, a double‐blind, placebo‐controlled crossover study demonstrated that intravenous flumazenil may transiently improve motor symptoms in PD, suggesting a potential role for GABA‐A receptor modulation in restoring impaired inhibitory control (Ondo and Silay 2006). Together, these findings indicate that disruption of excitatory–inhibitory balance across the cortico‐basal ganglia‐thalamic‐brainstem network could possibly play an important role in the pathophysiology of FOG.
In line with the role of glutamatergic overactivity in FOG, NMDA receptor antagonists can modulate glutamatergic transmission and improve FOG. Several clinical studies have shown that amantadine can improve FOG, especially in patients who experience levodopa‐resistant or axial‐predominant FOG, highlighting the significance of glutamatergic mechanisms in this condition (Kim et al. 2012; Lee et al. 2013). However, therapeutic responses have been inconsistent, with benefits often being modest or transient. Some studies even show minimal effects on freezing severity. These variable outcomes suggest that glutamatergic overactivity is not only a unique driver of FOG, but rather acts as a state‐dependent modifier of gait network stability.
Freezing of gait (FOG) is unlikely to be explained by dysfunction of a single neurotransmitter system. Instead, growing evidence suggests that FOG represents a network disorder involving multiple neural circuits and interacting neurotransmitter systems that together regulate locomotion. While individual neurotransmitter systems contribute to different functional components of locomotion, dopaminergic dysfunction is primarily linked to movement initiation and motor execution, cholinergic dysfunction to gait automaticity and attentional modulation, noradrenergic dysfunction to adaptive regulation of gait under cognitive and emotional stress, and glutamatergic/GABAergic imbalance to the stability of motor program selection through excitatory–inhibitory control (Lewis and Barker 2009; Bohnen and Albin 2011; Nutt et al. 2011). Experimental models support this combined dopaminergic and cholinergic lesions produce more severe gait dysfunction and freezing‐like behavior than isolated lesions, suggesting synergistic contributions of multiple neurotransmitter deficits to locomotor failure (Kucinski et al. 2013). Likewise, interactions between dopaminergic and noradrenergic systems may also be relevant, as norepinephrine modulates dopaminergic transmission, and degeneration of the locus coeruleus has been associated with reduced levodopa responsiveness in PD, suggesting that noradrenergic dysfunction may compromise dopaminergic compensatory mechanisms (K S Rommelfanger and Weinshenker 2007; Zhou et al. 2021). Together, these findings suggest that FOG may emerge not simply from isolated neurotransmitter deficits, but from disrupted interactions between neurotransmitter systems and failure of distributed locomotor network connectivity. The heterogeneity of FOG may therefore reflect differences in which neurotransmitter interactions and network components are predominantly affected in individual patients.
Recent work has also proposed the somato‐cognitive action network (SCAN) as a large‐scale neural network integrating motor, cognitive, and sensory information for locomotion (Jianxun Ren et al. 2026). Disruption of this network has been implicated in Parkinsonian gait disorders, and neurotransmitter dysfunction across dopaminergic, cholinergic, noradrenergic, and GABAergic systems may contribute to impaired signaling within this network, ultimately leading to FOG. Together, these findings suggest that FOG should be understood as a disorder of distributed neural network function modulated by multiple neurotransmitter systems rather than as a deficit of a single neurotransmitter.
Compensatory interactions between neurotransmitter systems may transiently help preserve locomotor function and possibly prevent FOG. As dopaminergic dysfunction impairs automatic motor control, patients may increasingly rely on attentional and executive control to maintain gait, a shift thought to be supported by cortical and brainstem cholinergic systems (Wu and Hallett 2005). Likewise, preserved noradrenergic function may help maintain locomotor network resilience by supporting arousal, attention, and adaptive responses to cognitive and emotional stress (Sara 2009; Tosserams et al. 2023). These compensatory mechanisms could possibly temporarily buffer against progressive dopaminergic degeneration, but as cholinergic and noradrenergic dysfunction progresses, this compensatory capacity may fail, increasing the likelihood of FOG.
Furthermore, emerging evidence suggests that nondopaminergic pathologies may contribute to gait dysfunction in PD. For example, increased neocortical β‐amyloid deposition has been associated with greater postural instability and gait difficulty in PD patients at risk for dementia (Müller et al. 2013), suggesting that proteinopathy‐related network dysfunction may contribute to specific FOG phenotypes. Future studies are needed to determine whether different pathogenetic mechanisms of PD are associated with distinct neurotransmitter and network dysfunction profiles underlying FOG.
FOG represents a complex and heterogeneous manifestation of locomotor network failure rather than symptoms from single neurotransmitter dysfunction in PD. Although presynaptic dopaminergic denervation is linked to an increased vulnerability to freezing, dopaminergic mechanisms alone do not account for phenomena such as paradoxical ON‐FOG or levodopa‐unresponsive cases. Nondopaminergic neurotransmitter systems—including acetylcholine, norepinephrine, serotonin, glutamate, and GABA—play significant roles in modulating gait automaticity, attention, arousal, and the selection of motor programs through distributed networks involving the cortex, basal ganglia, and brainstem. Understanding FOG as a multineurotransmitter, network‐level disorder has important therapeutic implications, highlighting the necessity for individualized, multimodal treatment strategies and longitudinal investigations focused on specific neurotransmitters.
Minsub Cho: conceptualization, writing – original draft. Jin Whan Cho: writing – review and editing, supervision. Dallah Yoo: writing – review and editing, supervision. Jinse Park: writing – review and editing, supervision. Do‐Young Kwon: writing – review and editing, supervision. Seong‐Beom Koh: writing – review and editing, supervision. Jeong‐Ho Park: writing – review and editing, supervision. Jinyoung Youn: conceptualization, writing – review and editing, writing – original draft, supervision.
This study was supported by Korean Movement Disorders Society Gait Special Interest Group.
The authors declare no conflicts of interest.