Neuromodulation of Cortical Control in Freezing of Gait

Neuromodulation of Cortical Control in Freezing of Gait | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL European Journal of Neuroscience This is a preprint and has not been peer reviewed. Data may be preliminary. 9 September 2025 V1 Latest version Share on Neuromodulation of Cortical Control in Freezing of Gait Authors : Gonzalo Revuelta 0000-0003-3917-8634 [email protected] , Daniel Lench , Carla Batista 0000-0003-0244-6535 , Marian Dale , and Martina Mancini Authors Info & Affiliations https://doi.org/10.22541/au.175744822.24326032/v1 288 views 160 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Freezing of gait (FOG) is a disabling feature of Parkinson’s Disease (PD) that results in a loss of automatic gait. Neuroimaging studies suggest that increased cortical involvement in gait is closely linked to a loss of automaticity. While non-invasive neuromodulation techniques, such as transcranial magnetic stimulation (TMS), show promise in targeting cortical control mechanisms involved in FOG, their effectiveness is limited by an incomplete understanding of the underlying interactions between cortical control of gait and FOG. Recent studies have brought into question whether increased cortical control of gait in people with FOG is adaptive or maladaptive. Here, we present evidence and literature supporting these two opposing frameworks. One perspective suggests increased cortical involvement serves a compensatory, adaptive role, helping to overcome the loss of automatic gait and mitigate FOG episodes. In contrast, the alternative view suggests that increased cortical control is maladaptive, resulting from a disruption of automatic motor processes that may exacerbate gait impairments. To review these conceptual models, we examine neuroimaging, non-invasive brain stimulation studies, pharmacological modulation, and physical therapy interventions in people with PD and FOG. We conclude that while the vast majority of studies have performed neuromodulation under the conceptual framework that increased cortical control is adaptive, there is limited evidence that this approach is in fact superior to the alternative framework. We encourage future studies to develop a causal, mechanistic understanding of how cortical control of gait impacts freezing behavior to advance the development of effective brain-based treatment strategies. Title : Neuromodulation of Cortical Control in Freezing of Gait Authors : Gonzalo J Revuelta, DO 1 , Daniel Lench, PhD 1 , Carla Silva-Batista, PhD 2 , Marian L. Dale, MD 2,3 , Martina Mancini, PhD 2 Author Affiliations: 1 Department of Neurology, Medical University of South Carolina, Charleston, SC, USA. 2 Oregon Health Sciences University, Portland, OR, USA. 3 Portland VA Medical Center PADRECC, Portland, OR, USA. Running Head or Short Title : Neuromodulation of Freezing of Gait Total Word Count: 2670 Citations: 68 not-yet-known not-yet-known not-yet-known unknown Abstract: 244 Keywords : Freezing of Gait, Parkinson’s Disease, Neuromodulation, Cortical Control, Volitional Control Funding : NIH NINDS R00NS131447, 1R01NS131396 Conflict of Interest Statement: The authors do not report any conflicts of interest relevant to the research or topics covered in the manuscript. math_shortcuts Corresponding Author: Gonzalo J. Reuvuelta, DO Email: [email protected] List of abbreviations: Freezing of Gait (FOG), Transcranial Magnetic Stimulation (TMS), Parkinson’s Diseaes (PD), Prefrontal Cortex (PFC), supplementary motor area (SMA), peduncolopontine nucleus (PPN), mesencephalic locomotor region (MLR), functional magnetic resonance imaging (fMRI), functiona near infrared spectroscopy (fNIRS), transcranial direct current stimulation (tDCS), new freezing of gait questionnaire (nFOGQ), continuous theta burst stimulation (cTBS), interittent theta burst stimulation (iTBS), subthalamic nucleus (STN), deep brain stimulation (DBS), cingulate motor area (CMA), subthalamic locomotor region (SLR), cerebellar locomotor region (CLR), resting motor threshold (RMT), anterior cingulate cortex (ACC). not-yet-known not-yet-known not-yet-known unknown Abstract: Freezing of gait (FOG) is a disabling feature of Parkinson’s Disease (PD) that results in a loss of automatic gait. Neuroimaging studies suggest that increased cortical involvement in gait is closely linked to a loss of automaticity. While non-invasive neuromodulation techniques, such as transcranial magnetic stimulation (TMS), show promise in targeting cortical control mechanisms involved in FOG, their effectiveness is limited by an incomplete understanding of the underlying interactions between cortical control of gait and FOG. Recent studies have brought into question whether increased cortical control of gait in people with FOG is adaptive or maladaptive. Here, we present evidence and literature supporting these two opposing frameworks. One perspective suggests increased cortical involvement serves a compensatory, adaptive role, helping to overcome the loss of automatic gait and mitigate FOG episodes. In contrast, the alternative view suggests that increased cortical control is maladaptive, resulting from a disruption of automatic motor processes that may exacerbate gait impairments. To review these conceptual models, we examine neuroimaging, non-invasive brain stimulation studies, pharmacological modulation, and physical therapy interventions in people with PD and FOG. We conclude that while the vast majority of studies have performed neuromodulation under the conceptual framework that increased cortical control is adaptive, there is limited evidence that this approach is in fact superior to the alternative framework. We encourage future studies to develop a causal, mechanistic understanding of how cortical control of gait impacts freezing behavior to advance the development of effective brain-based treatment strategies. not-yet-known not-yet-known not-yet-known unknown Background: Under the current pathophysiological model of Parkinson’s disease (PD), dopaminergic cell loss in the substantia nigra pars compacta leads to dopaminergic denervation of the posterior putamen, which in turn leads to a loss of habitual control of movement or a loss of automaticity1. Imaging studies supporting this notion have demonstrated activation of the posterior putamen during automatic movements in healthy controls, while individuals with PD activate more rostral striatum and cortical regions when performing the same automatic movements, demonstrating a loss of automatic or habitual control2. Gait automaticity refers to the ability of the central nervous system to control walking with minimal use of executive control (which demands attention) 3. People with PD have difficulty controlling automatic movements and thus shift to more voluntary control of gait, which requires more executive resources2. Following this model, freezing of gait (FOG) can be viewed as a loss of automatic control of locomotion compensated by volitional control until the system is overwhelmed (for example, when competing cognitive tasks occur). Some proxies of loss of gait automaticity in PD include increased prefrontal cortex (PFC) activity during walking, higher dual-task cost of gait, and greater gait variability. In fact, people with FOG usually show higher PFC activity4 5, higher dual-task cost of walking6, 7, and greater gait variability, 4, 8, 9 compared to people without FOG. Despite evidence that there is an increase in cortical control associated with loss of automaticity, it remains unclear whether this represents an ineffective compensatory mechanism (adaptation) or a maladaptive response. Based on this conceptual framework, cortical neuromodulation strategies have been developed with opposing goals: to either enhance automatic locomotion by reducing cortical involvement, or to improve goal-directed walking by increasing cortical engagement. Here we present both conceptual models and critically review the current evidence from neuromodulation interventions supporting each approach. math_shortcuts Increased Cortical Control in FOG: ineffective adaptation or maladaptive response? Highly automatized motor skills which have been learned over time require little to no volitional control. In fact, volitional control may be disruptive in the context of such behaviors. For example, skilled athletes often have suggested that overthinking a motor skill can have detrimental effects on performance. Perhaps one of the most universal motor skills humans develop over their lifetime is the ability to walk with a high degree of automaticity in an environment that contains an almost infinite number of distractions. In people with PD and FOG this learned automatic walking behavior increasingly requires attention and cognitive resources. While this may appear to be a beneficial adaptation, it is possible that excessive attention to gait may in fact be maladaptive as described in the example of the skilled athlete. From a circuit-level perspective, overreliance on cortical structures that mediate volitional control of gait may interfere with automatic locomotor centers in people with PD and FOG. Indeed, there is evidence from tract tracing studies that the premotor and supplementary motor area (SMA) cortices have direct anatomical projections to subcortical locomotor centers involved in automatic gait control. Electrophysiological recordings in humans have also suggested that the pedunculopontine nucleus (PPN) within the mesencephalic locomotor region (MLR) interacts with the SMA as evidenced by changes in beta coherence prior to movement initiation 10 . While connectivity between the cortex and automatic locomotor centers may be a part of normal locomotor control to adapt to specific contexts, the strength of this connection appears to be excessive in PwF 11-13 . Several neuroimaging studies (fMRI) point to alterations in frontal and fronto-striatal networks as key potential mechanisms for FOG 14-17 . Specifically, the interplay between automaticity of movement and controlled cognitive process may be crucial in understanding FOG 18 through impaired integration of cognitive control networks (e.g., executive and attentional networks) 16, 19 . In fact, findings of studies with fMRI using a virtual-reality gait paradigm have demonstrated a consistent increase in activity of frontal and parietal cortical regions and decreased subcortical activity during motor arrests (FOG episodes) in people with FOG 14-16 . In addition, FOG episodes off medication have been characterized by an overall loss of synchrony between cortico-striatal pathways 17 . A major limitation of fMRI studies in investigating cortical contributions to gait is that subjects cannot ambulate in the scanner environment. More recent studies using mobile imaging (e.g., functional near infrared spectroscopy, fNIRS) have allowed investigation of the cortical control, specifically PFC control of gait and turning in people with PD with and without FOG 4, 20-25 . Gait during dual-task conditions and turning in place have been the main triggers for evoking FOG in the laboratory setting 26 . Using fNIRS, increased PFC activity has been reported in the following situations: 1) immediately before and during FOG episodes when turning 180° while walking 27 , 2) during 360 degrees turning-in-place 25 , and 3) during single and dual-task walking 4 in people with PD and FOG compared to those without FOG. In addition, higher PFC activity while turning in place is moderately associated with worse FOG severity 25 . Taken together, these fMRI and fNIRS findings suggest that people with FOG may increase cortical activity in fronto-parietal regions in an attempt to compensate for the striatal dysfunction leading to reduced automaticity of gait and increased stride-to-stride variability 28-30 . Attention and executive function are recruited through the frontoparietal areas, likely to compensate for the loss of automatic gait control. This is in keeping with previous work highlighting how people with PD become increasingly reliant on cognitive control and external sensory input for their gait, switching to goal-directed behavior 1, 31 . However, the integration of cerebral compensatory regions in an attempt to adjust for the loss of automatic gait control through goal-directed motor control may lack efficiency in two cases: 1) during challenging conditions that further rely on PFC, such as when multi-tasking or during turns, when the load on the frontal networks may become not sustainable (overload), thus leading to FOG 16, 18, 19 or 2) the degeneration of the compensatory cortical areas that occurs with disease progression. A recent review suggests that the reliance on compensatory networks (e.g., cognitive and sensory) may contribute to the “occasional” breakdown of gait and FOG. However, as the disease progresses, these compensatory mechanisms, although necessary, become increasingly impaired. This degradation may result in more severe loss of gait automaticity and frequent FOG 32 . While studies show correlations between worsening FOG and greater cortical control over gait 25, 27, 33 , it remains unclear if this is due to worsening FOG, which engages greater cortical control, or truly a maladaptive process that contributes to worsening FOG severity. To truly understand this relationship, manipulating cortical control systematically via neuromodulation approaches can be highly informative . Neuromodulation interventions designed to increase cortical control in FOG: A comparative analysis of the available evidence on neuromodulation of cortical control is challenging given the high number of variables, including neuromodulation modality, study design, target, and choice of FOG outcome measures. We sought to represent neuromodulation modalities that addressed FOG specifically in idiopathic PD and excluded open-label studies as it is difficult to draw conclusions from these findings. The objective of this summary was not to evaluate clinical evidence towards efficacy, but rather, to elucidate the effects of experimental manipulation of cortical control on FOG severity. Overall, improvements reported from excitatory repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) approaches were modest, with up to 2 points improvement in the Freezing of Gait Questionnaire (FOGQ), reduction of two FOG episodes, 4% reduction of percent time frozen in FOG provoking tasks, and one study showed up to a 15-second reduction in TUG time in the active group but no significant improvement in FOGQ. Several excitatory studies did not show any efficacy or were equivocal (see Table 1). Neuromodulation interventions designed to decrease cortical control in FOG: While the vast majority neuromodulation studies for FOG have been performed to increase cortical control, only two studies used rTMS to reduce cortical control of gait 12 . One comparative study of cTBS and iTBS reported a small improvement in the iTBS (excitatory) group (2 freezing episodes or 4% reduction) and no improvement in the inhibitory group 36 . The other study 12 (conducted by DL and GJR) tested the framework that hyper-connectivity of cortical brain regions to automatic gait centers could be dampened by using an inhibitory form of stimulation. In this study 20 participants with FOG were randomized into either a sham or active TMS treatment over 10 days. 1Hz rTMS was administered at a suprathreshold level (110% rMT) over the supplementary motor area (SMA) and combined with daily gait training sessions. These 20-minute training sessions were used to promote gait automaticity by having participants focus on a cognitive task while maintaining a constant gait velocity. This study found a 4.8-point reduction on the New Freezing of Gait Questionnaire FOG-Q (nFOG-Q) following the active TMS intervention and a modest 1.8-point reduction following sham TMS intervention. Although pre- to post-changes in the active group were significant, between-group differences were not significant in this small sample. Reductions in SMA connectivity were found with several brain regions, including the anterior cingulate cortex (ACC), medial PFC, and angular gyrus in the active group. This study provides direct evidence that a reduction in cortical control of gait can lead to an improvement in FOG. Aside from non-invasive forms of stimulation, subthalamic nucleus deep brain stimulation (STN-DBS) is effective in improving FOG in a subgroup of people with PD 48 . Evidence from the DBS literature supports the notion that improvements in FOG may be the result of reduced cortical influence on subcortical regions responsible for locomotor control. While DBS has direct effects on attenuating pathological beta frequency in the STN, modulation of hyperdirect pathway signaling likely contributes to therapeutic effects. Stimulation of fibers which are connected to SMA, (pre-SMA and PPN for example) have been associated with improved FOG 49 . While the precise mechanisms of STN-DBS are being actively investigated there is evidence that high frequency stimulation abolishes the excitatory influence of the cortex on STN 50 . Thus, cortical influence over downstream locomotor centers may be reduced when the proper target is stimulated. Taken together, there is reasonable evidence that reducing cortical control of gait through both invasive and non-invasive forms of stimulation may in fact alleviate FOG. Future studies that compare stimulation protocols and perform more standardized interventions to facilitate gait automaticity will be needed to provide more conclusive evidence. Non-Neuromodulation Approaches designed to Improve Automaticity of Gait in FOG: Dopamine replacement therapy may restore the appropriate corticostriatal connectivity 14, 51 and improve gait automaticity (decreased step time variability) in people with and without FOG 52 , especially in the early to moderate stages of the disease 14 . Preliminary findings in a small group of people with PD show that levodopa may decrease PFC activity during walking 53 , although levodopa combined with cholinesterase inhibitor (donepezil) improves walking more than levodopa alone 53 . Although levodopa seems to have an important effect on proxies of gait automaticity in PD 14 , FOG progressively may become a dopamine-resistant phenomenon 54 , thus, rehabilitation approaches aiming to improve gait automaticity have been studied to alleviate subjective FOG severity 31 . Exercise interventions have demonstrated some positive effects on improving gait automaticity in people with FOG, specifically if the intervention targets motor- and/or non-motor correlates of FOG 55, 56 . For example, 18 sessions of challenging motor-cognitive exercises improved dual-task cost on stride length and gait speed in people with PD and FOG 55 ; such improvement was more evident in individuals with FOG compared to those without FOG 57 . In addition, visual and frontoparietal cortical thicknesses at baseline are associated with exercise-induced improvements in dual-task cost on gait speed in PwF 57 . Another type of exercise intervention, mixing complex and challenging exercises that involved sensorimotor integration, dual task, balance, and resistance exercises, 58 resulted in significant improvements in dual-task cost on gait speed and stride length 56 . Interestingly, increased cerebellar locomotor region (a controlled locomotion center) activity was associated with improved gait automaticity (decreased dual-task cost on stride length) after the complex and challenging exercise interventions in freezers 56 . These results suggest that challenging exercises may restore gait automaticity in people with PD and FOG by recruitment of cerebellar networks. Due to the positive impacts of exercise intervention on gait automaticity, studies have used the combination of aerobic exercise, which has a positive impact on the gait function of PD, with neuromodulation, for example with transcranial direct current stimulation to modulate cortical excitability 59 . Facilitation of dorsolateral PFC with bilateral tDCS reduces dual-task cost on gait speed in people with PD 60 . We have also observed improvements in gait automaticity with gait training combined with cortical inhibition 12 , raising the question of whether maladaptive increases in cortical control can prevent effective rehabilitation of gait automaticity, and therefore cortical inhibition would facilitate recovery. Non-Neuromodulation Approaches designed to Improve Cortical Control in FOG: Another commonly used strategy in physical therapy introduces goal-directed movements by providing a reference or target, commonly known as external cueing. Cueing, either open- or closed-loop, and in the form of auditory, tactile, or visual stimuli 61 , generally shows an immediate correction of gait, with limited carry‐over or training effects to un-cued gait performance 61-64 . The application of external cueing is thought to be a compensatory strategy that facilitates the shift from automatic to goal-directed control of gait, bypassing the most affected basal ganglia circuitries and increasing the recruitment of parieto-occipital cortical areas and not the prefrontal cortex 61 . In a recent systematic review 64 , Cosentino et al. emphasize overall the effectiveness of external cueing strategies in temporarily alleviating FOG episodes by facilitating motor initiation and bypassing impaired internal gait control mechanisms in PD. However, they also conclude that “one size does not fit all” due to the heterogeneity and variability in symptoms presentation. We recently observed that cortico-subcortical networks are the strongest predictors of responsiveness to tactile cueing in terms of decreased FOG severity during turning in place 65 . Overall, changes in cortical activity have not been directly investigated with cueing and the effects of cueing on FOG are mixed 62 . Future studies should investigate if long-term use of personalized cueing results in changes in cortico-subcortical circuits to improve gait automaticity. Pharmacologic interventions like stimulants 66 and cholinergic agents 53 have also been studied to improve attention and executive control in patients with FOG. In theory, these interventions aim to improve FOG severity by enhancing compensatory increases in volitional control of locomotion in patients with FOG. Thus far, these studies have yielded largely inconsistent results for the treatment of FOG specifically. math_shortcuts Conclusion: Here we explore the role of cortical or volitional control of locomotion and present a conceptual model whereby cortical input into subcortical locomotor centers can be modulated to improve FOG. Given the development of non-invasive neuromodulation for cortical targets, we propose that neuromodulation interventions for FOG can address two important knowledge gaps: 1) is cortical control an ineffective adaptation or a maladaptive response? and 2) should cortical control of gait be enhanced or inhibited to improve FOG? Currently, the vast majority of the literature in this field has aimed to increase cortical control of locomotion via neuromodulation and rehabilitation approaches with largely equivocal, negative, or subclinical effects. We propose that under this framework, cortical inhibition either in isolation or combined with strategies to improve gait automaticity should be further explored. Although it is difficult to compare efficacy across studies due to differences in modalities, targets, design, and particularly the lack of standardized outcome measures, the FOGQ and nFOGQ have been most widely used allowing for a more direct comparison of the magnitude of effects of multiple studies. The nFOGQ, however, has been criticized due to having a large minimum detectable change, 67 which is greater than any of the reported differences. It is important to note none the less, that the reported improvements in the limited number of inhibitory studies is at least as large or greater in magnitude than the excitatory studies. Another important factor when interpreting the results of neuromodulation studies is that inhibitory or excitatory strategies do not always result in the intended effect, particularly with more advanced or accelerated approaches like theta burst stimulation (TBS) 68 . As our understanding of the individual variability of FOG grows, and the variability of the effects of non-invasive neuromodulation interventions, future studies may pursue personalized interventions based on individual level findings that guide network specific interventions. not-yet-known not-yet-known not-yet-known unknown Acknowledgements: We would like to thank Niloufar Malakouti for her assistance with the table formatting. not-yet-known not-yet-known not-yet-known unknown Author Roles: Gonzalo Revuelta: design, execution, analysis, writing, editing Daniel Lench: design, execution, analysis, writing, editing Carla Batista-Silva: design, execution, analysis, writing, editing Marian Dale: design, execution, analysis, writing, editing Martina Mancini: design, execution, analysis, writing, editing References: 1. Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz MC, Lehericy S, Bergman H, Agid Y, DeLong MR, Obeso JA. 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Collection European Journal of Neuroscience Authors Affiliations Gonzalo Revuelta 0000-0003-3917-8634 [email protected] MUSC View all articles by this author Daniel Lench Medical University of South Carolina View all articles by this author Carla Batista 0000-0003-0244-6535 OHSU View all articles by this author Marian Dale OHSU View all articles by this author Martina Mancini Oregon Health & Science University View all articles by this author Metrics & Citations Metrics Article Usage 288 views 160 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Gonzalo Revuelta, Daniel Lench, Carla Batista, et al. Neuromodulation of Cortical Control in Freezing of Gait. Authorea . 09 September 2025. DOI: https://doi.org/10.22541/au.175744822.24326032/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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