Pharmacologically modulating the noradrenergic arousal system to reduce freezing of gait in Parkinson’s disease: study protocol of the international AnTi-FREEZE study

Pharmacologically modulating the noradrenergic arousal system to reduce freezing of gait in Parkinson’s disease: study protocol of the international AnTi-FREEZE study | 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 Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 9 January 2026 V1 Latest version Share on Pharmacologically modulating the noradrenergic arousal system to reduce freezing of gait in Parkinson’s disease: study protocol of the international AnTi-FREEZE study Authors : Franka Goossens 0009-0004-7876-1018 [email protected] , Kaylena A. Ehgoetz Martens , Bastiaan Bloem , Rick C. Helmich , Erika Howe 0000-0002-4476-9431 , Melvyn Roerdink , James Shine , Anouk Tosserams , Simon J. G. Lewis , and Jorik Nonnekes Authors Info & Affiliations https://doi.org/10.22541/au.176796918.82151521/v1 296 views 126 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Freezing of gait (FOG) is a burdensome Parkinson’s disease (PD) symptom. Gait control in people with PD relies on compensation from cognitive, sensory, and limbic networks. Their integration is influenced by the noradrenergic ascending arousal system, modulated by the locus coeruleus. In PD, locus coeruleus degeneration has been linked to increased FOG severity. Atomoxetine, a selective noradrenaline reuptake inhibitor, may provide a novel therapeutic approach for FOG. However, to date, studies on atomoxetine’s effect on FOG have been underpowered and inconsistent. This study will evaluate the effects of atomoxetine on FOG severity, both in the dopaminergic OFF- and ON-states. Moreover, we will assess its mode of action by examining its influence on brain network topology. Additionally, we will examine clinical and imaging markers to predict an individual’s treatment response. Sixty patients with frequent FOG will be recruited for a multi-centre, single-dose, double-blind, placebo-controlled, cross-over clinical trial. Assessments include clinimetrics, MDS-UPDRS III, gait assessments, pupillometry, and neuroimaging, conducted in the dopaminergic OFF- and ON-states. The primary outcome is FOG severity in the dopaminergic OFF-state, quantified based on the percentage of time spent frozen during gait assessments. Resting-state fMRI is conducted to assess network integration and segregation across brain regions and task-fMRI for revealing neural circuitry changes during FOG. Lastly, locus coeruleus and substantia nigra integrity will be assessed using structural MRI. This study will provide insights into the role of the noradrenergic ascending arousal system and potentially identify a novel pharmaceutical treatment pipeline for FOG in PD. \articletype Original Articles Pharmacologically modulating the noradrenergic arousal system to reduce freezing of gait in Parkinson’s disease: study protocol of the international AnTi-FREEZE study Franka M. Goossens 1,2 , Kaylena A. Ehgoetz Martens 3 , Bastiaan R. Bloem 4 , Rick C. Helmich 2,4 , Erika E. Howe 3 , Melvyn Roerdink 5,6 , James M. Shine 7 , Anouk Tosserams 1,4 , Simon J. G. Lewis 8 , Jorik Nonnekes 1 1 Department of Rehabilitation, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands 2 Donders Institute for Brain, Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, The Netherlands 3 Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada 4 Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands 5 Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands 6 Department of Nutrition and Movement Sciences, NUTRIM Institute of Nutrition and Translational Research in Metabolism & MHeNs Institute of Mental Health and Neurosciences, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands 7 Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia 8 Parkinson’s Disease Research Clinic, Macquarie Medical School, Macquarie University, Sydney, Australia \articletype Original Articles Corresponding Author Information: Franka Goossens Radboud University Medical Centre PO Box 9101, 6500 HB Nijmegen The Netherlands E-mail: [email protected] Key words : Parkinson’s disease, Freezing of gait, Atomoxetine, Network connectivity \articletype Original Articles Abstract Freezing of gait (FOG) is a burdensome Parkinson’s disease (PD) symptom. Gait control in people with PD relies on compensation from cognitive, sensory, and limbic networks. Their integration is influenced by the noradrenergic ascending arousal system, modulated by the locus coeruleus. In PD, locus coeruleus degeneration has been linked to increased FOG severity. Atomoxetine, a selective noradrenaline reuptake inhibitor, may provide a novel therapeutic approach for FOG. However, to date, studies on atomoxetine’s effect on FOG have been underpowered and inconsistent. This study will evaluate the effects of atomoxetine on FOG severity, both in the dopaminergic OFF- and ON-states. Moreover, we will assess its mode of action by examining its influence on brain network topology. Additionally, we will examine clinical and imaging markers to predict an individual’s treatment response. Sixty patients with frequent FOG will be recruited for a multi-centre, single-dose, double-blind, placebo-controlled, cross-over clinical trial. Assessments include clinimetrics, MDS-UPDRS III, gait assessments, pupillometry, and neuroimaging, conducted in the dopaminergic OFF- and ON-states. The primary outcome is FOG severity in the dopaminergic OFF-state, quantified based on the percentage of time spent frozen during gait assessments. Resting-state fMRI is conducted to assess network integration and segregation across brain regions and task-fMRI for revealing neural circuitry changes during FOG. Lastly, locus coeruleus and substantia nigra integrity will be assessed using structural MRI. This study will provide insights into the role of the noradrenergic ascending arousal system and potentially identify a novel pharmaceutical treatment pipeline for FOG in PD. Introduction Freezing of gait (FOG) is a burdensome symptom of Parkinson’s disease (PD), frequently associated with falls, hospital admissions, and a need for long-term care (Aarsland et al. , 2000; Moore et al. , 2007). In early stages of PD, approximately one in four patients report FOG, which increases to four in five patients as the disease progresses (Macht et al. , 2007; Nutt et al. , 2011; Zhang et al. , 2021). FOG has been studied widely, but its pathophysiology remains incompletely understood (Tosserams et al. , 2025). Although dopaminergic medication can alleviate FOG symptoms for some patients, they are ineffective for others, presenting a clinical challenge for people with FOG, caregivers, and clinicians. Gait control relies in part on a basic ‘locomotor network’, which includes corticostriatal projections to the primary motor cortex, brainstem mesencephalic and cerebellar locomotor regions and spinal central pattern generators (Jahn et al. , 2008; Takakusaki, 2017). Furthermore, distributed cortical areas, especially the frontoparietal and supplementary motor regions, contribute to the fine-tuning and adaptive control of walking (Takakusaki, 2013). When walking in an automated manner, without paying conscious attention to it, people with PD often have difficulties engaging cortical motor areas (Gilat et al. , 2019). Consequently, effective gait control in PD not only depends on the integrity and function of corticostriatal motor loops, but also on compensation from cognitive, sensory, and limbic systems (Lewis & Barker, 2009; Gilat et al. , 2021; Tosserams et al. , 2022). Current evidence suggests that the pathophysiology of FOG involves a phasic overload of cortico-striatal circuits and dysfunctional network-level integration, leading to inhibition of mesencephalic locomotor regions in the brainstem (Lewis & Barker, 2009; Ehgoetz Martens et al. , 2018a). Emerging research indicates that arousal and its influence on the functional integration of distributed brain networks play a role in the occurrence of FOG (Maidan et al. , 2010; Economou et al. , 2021; Taylor et al. , 2022; Tosserams et al. , 2023). To effectively integrate distinct and segregated compensatory brain networks, the noradrenergic ascending arousal system is essential, yet impaired to varying degrees in patients with FOG (Shine et al. , 2018; Taylor et al. , 2022; McKay et al. , 2023; Wang et al. , 2023). A U-shaped correlation between FOG and arousal has been proposed (Tosserams et al. , 2023). For example, when arousal is low, compensatory brain networks may remain too segregated to support effective gait, whereas heightened arousal can increase cross-talk between competing networks, potentially disrupting their balance and contributing to dysfunctional integration, as observed in anxiety-induced FOG (Ehgoetz Martens et al. , 2014; Taylor et al. , 2022). A study conducted over twenty years ago reported that individuals with PD had lower cerebrospinal fluid concentrations of dopamine and noradrenaline, which was related to the severity of posture and gait impairments (Tohgi et al. , 1997). More recent work has extended these findings, showing that dopa-responsive freezers had significantly reduced whole-brain noradrenaline transporter binding compared to non-freezers, with reductions in thalamic noradrenaline transporter binding being significantly associated with FOG severity (McKay et al. , 2023). Another study found a decreased volume and surface area in the locus coeruleus, which also correlated with FOG severity (Betts et al. , 2019; Doppler et al. , 2021; Wang et al. , 2023). No differences between freezers and non-freezers in the substantia nigra volume or surface area have been observed (Wang et al. , 2023). Taken together, freezers exhibit widespread noradrenergic denervation, particularly in the locus coeruleus and the thalamic noradrenergic system, which are closely linked to the limbic circuits that have been implicated in the pathophysiology of FOG (McKay et al. , 2023). Given that FOG involves both dopaminergic and non-dopaminergic contributions, addressing noradrenergic deficits may represent a relevant and important therapeutic approach (Grimbergen et al. , 2009). Work examining the effects noradrenergic drugs on FOG have shown some initial promise. However, studies to date have been underpowered and inconsistent . A multicentre, parallel, double-blind, placebo-controlled randomized trial in 65 PD patients with FOG and subthalamic deep brain stimulation found that 33 participants receiving methylphenidate (a noradrenaline and dopamine reuptake inhibitor) showed a significant reduction in FOG episodes compared to placebo (Moreau et al. , 2012). Two further trials also reported improvements in gait and freezing with methylphenidate, although these involved small samples (N=5 and N=17) and were not placebo-controlled (Auriel et al. , 2006; Pollak et al. , 2007). Moreover, a placebo-controlled, double-blind study of methylphenidate for gait impairments found a trend toward reduced FOG frequency but overall worsened motor function and no significant changes in gait (Espay et al. , 2011). Two uncontrolled studies of L-DOPS, a prodrug to noradrenaline, reported a dose-dependent increase in cerebrospinal noradrenaline concentrations, which was associated with FOG improvement in half of the participating patients with advanced PD (Tohgi et al. , 1990; Tohgi et al. , 1993). One caveat to using L-DOPS is that, while it increases noradrenaline, it may also reduce dopamine levels, as observed in rat studies following L-threo-DOPS administration (Mizoguchi et al. , 1992). Atomoxetine is a drug with noradrenergic and dopaminergic properties, and has been shown to be safe and well tolerated in PD (Weintraub et al. , 2010; Revuelta et al. , 2015). It is a selective noradrenaline reuptake inhibitor (SNRI), which prevents cellular reuptake of noradrenaline, thereby increasing its free synaptic concentrations. Atomoxetine is approved and commonly used for the treatment of attention deficit hyperactivity disorder (ADHD), a condition in which, similar to FOG, dysregulation of noradrenergic and dopaminergic pathways appears to play a critical role in suboptimal executive functioning within the prefrontal regions (Del Campo et al. , 2011). This therapeutic compound has a complex pharmacological profile with two novel targets relevant for FOG. A tomoxetine increases both noradrenaline and dopamine within the prefrontal cortex but not within the nucleus accumbens or striatum (Bymaster et al. , 2002). This is likely to be advantageous as it reduces the associated side effects and abuse potential commonly seen with other medications (such as methylphenidate, dextroampetamine and lidexamfetamine). A study in healthy adults showed that atomoxetine alters network topology in resting-state and task-based functional magnetic resonance imaging (fMRI), reorganizing the functional connectome in a manner sensitive to cognitive demands (Shine et al. , 2018). This effect involves restoring the neural systems supporting executive functions by improving the coordination of functionally connected networks, including enhancing prefrontal activation and frontostriatal connectivity (Ye et al. , 2015; Rae et al. , 2016; Borchert et al. , 2019; O’Callaghan et al. , 2021). In PD, atomoxetine improves attention, response inhibition, executive functions and anxiety (Weintraub et al. , 2010), which are all clinical features that have been associated with FOG severity (Ehgoetz Martens et al. , 2020). However, to date only inconsistent reports of improvements in FOG upon atomoxetine treatment have been reported in small samples (Jankovic, 2009; Revuelta et al. , 2015). The first study enrolled 5 PD patients with dopa-unresponsive FOG into a double-blind randomized trial and found that the gait and balance scale score improved, albeit not significantly, compared to a worsening in the placebo group (Jankovic, 2009). A second study, consisting of a pilot open label experiment on 10 PD patients with FOG, reported no significant change in the primary outcome (i.e. self-reported FOG-questionnaire) from pre- to post test (Revuelta et al. , 2015). Both studies noted the challenge of detecting genuine treatment effects, largely due to difficulties in reliably determining FOG severity with the currently available tools (Hulzinga et al. , 2020). In addition, neither study incorporated standardized gait assessments specifically designed to provoke FOG, further limiting the interpretability of their findings. This present study aims to examine the therapeutic potential of atomoxetine for the treatment of FOG. In addition, it seeks to mechanistically understand the influence of atomoxetine on network topology in PD and how this relates to FOG severity. We hypothesize that atomoxetine will reduce FOG severity, restore functional network segregation, and enhance frontostriatal pathways. Furthermore, we hypothesize that a lower LC integrity may predict a better treatment response.(O’Callaghan et al. , 2021) These hypotheses will be tested by examining the effects of atomoxetine on: (a) FOG severity in the dopaminergic OFF-state; (b) FOG severity in the dopaminergic ON-state; (c) brain network topology and its relationship to FOG; (d) FOG under heightened arousal. Moreover, this study will examine (e) individual factors and imaging markers predicting the response to atomoxetine. Methods Participating centres include the Radboud University Medical Center (Nijmegen, the Netherlands), Donders Centre for Cognitive Neuroimaging (Nijmegen, the Netherlands), Macquarie University (Sydney, Australia) and University of Waterloo (Waterloo, Canada). The AnTi-FREEZE study is preregistered on ClinicalTrials.gov under Identifier: NCT07316296. Study design and setting AnTi-FREEZE is a multi-centre, single dose, counterbalanced, double-blind, placebo-controlled, cross-over clinical trial to determine the effect of atomoxetine on FOG severity and brain network topology. The protocol comprises three on site visits over the span of three weeks. Measurements will be done at the Donders Centre for Cognitive Neuroimaging, Macquarie University, and the University of Waterloo. Recruitment Participants for the Dutch arm of the study will be recruited through the outpatient clinic of Radboudumc Nijmegen, the Parkinson Vereniging Nederland, ParkinsonNL and ParkinsonNet. In Australia, recruitment will be through the Parkinson’s Disease Research Clinic, Macquarie University Medical School facilitated via established connections with local and national patient representative bodies, including Parkinson’s NSW and Parkinson’s Australia, with outreach supported by public forums and newsletters. In Canada, participants will be recruited using the UW-Parkinson Database for the Waterloo region, as well as through collaborations with local and national patient organizations, including Parkinson Society Southwestern Ontario, Living Better with Parkinson’s, Parkinson Canada, and the Canadian Open Parkinson Network. Eligibility \articletype Original Articles We will include sixty adult participants, twenty per centre. Inclusion criteria: Eligible participants are adults (≥18 years) with PD diagnosed according to MDS criteria, stabilised on optimal dopaminergic treatment for at least four weeks prior to baseline and for the duration of the trial. They must have frequent FOG symptoms, quantified based on question two of the new freezing of gait questionnaire (NFOGQ) ; How frequently do you experience freezing episodes? Furthermore, they need to be able to walk ten meters unaided in the ON-state, provide written informed consent (ICH-GCP compliant), and be willing and able to undergo all study assessments. Exclusion criteria: Exclusion criteria include current or recent participation in another clinical trial (≤3 months), contraindications to magnetic resonance imaging (MRI) such as claustrophobia or implanted devices (e.g. pacemakers, infusion pumps, or other metallic implants) and deep brain stimulation. Further exclusions are co-morbidities affecting ambulation, severe cognitive impairment, active psychosis, or other protocol compliance barriers. Participants will also be excluded for medical conditions that can cause complications in combination with atomoxetine use, such as severe cardiovascular disorders (e.g. uncontrolled hypertension ≥180/110 mmHg, heart failure, significant arrhythmias, long QTc >500 ms), cerebrovascular disorders (e.g. aneurysm, recent stroke), hepatic or renal insufficiency, narrow-angle glaucoma, or (a history of) pheochromocytoma. Use of noradrenergic agents and other medication interacting or interfering with atomoxetine, such as CYP2D6 inhibitors, or high-dose β2-agonists is not permitted. Additional exclusions are pregnancy, breastfeeding, or known hypersensitivity to atomoxetine. Group allocation and blinding Blinding of the investigational medicinal product will be achieved through kit numbering. The contents of the kits will be randomized according to a randomization list generated by an independent party not involved in the study. The clinical trial pharmacist will have access to the allocation list and prepare the kits accordingly, while all study personnel involved in assessments will remain blinded to treatment allocation. Since the kit contents are randomized, the kits will be dispensed in consecutive numerical order. The randomization list will be kept under secured access. In the event of an emergency affecting participant safety, treatment allocation may be unblinded after consultation with the local principal investigator. Unblinding will be performed by personnel not involved in trial conduct or data analysis. Participant timeline After inclusion, participants will attend three on-site visits ( Figure 1 ). At visit one, participants complete clinimetrics, questionnaires, neuropsychological assessments, and the full gait protocol to minimize the learning effect between subsequent visits. Visits two and three will follow a cross-over design, with participants receiving atomoxetine at one visit and placebo at the other. Measurements are performed one hour post investigational medicinal product (IMP) ingestion, allowing the medication to reach peak plasma concentrations, and include the MDS-UPDRS part III, gait analysis including FOG-provoking tasks, pupillometry and (f)MRI. Assessments in visit two and three will first be conducted in the dopaminergic OFF-state, after withholding medication overnight, and then repeated in the dopaminergic ON-state 45 minutes after participants take their usual dopaminergic medication. During visits two and three blood pressure and heart rate will be measured upon arrival, one hour after IMP ingestion and 45 minutes after dopaminergic medication ingestion to monitor the participants safety and wellbeing throughout the trial. Procedures and assessments Clinimetrics and patient reported outcome measures At the first visit, conducted in the dopaminergic ON-state, we will collect extensive clinimetric data. Demographic and clinical data collected include date of birth, sex at birth, gender identity, sexual identity, height, weight, education (in years), disease duration (in years from diagnosis), race, ethnicity, descent, MDS-UPDRS score, Hoehn and Yahr stage, number of falls in the past six months and the Levodopa Equivalent Daily Dose. Cognitive function will be assessed using the following neuropsychological tests: Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005) - The MoCA is used to evaluate general cognitive function. Several cognitive domains, including language, executive function, attention, memory, orientation, and visuospatial ability, are tested in this assessment to determine the presence of mild cognitive impairments. The total score of the MoCA ranges from 0 to 30 points, with higher scores reflecting greater cognitive function. Frontal Assessment Battery (FAB) (Dubois et al., 2000) - The FAB is used to assess executive functions of the frontal lobe. The assessment consists of six subtests that evaluate conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The total score of the FAB ranges from 0 to 18 points, with higher scores indicating a better frontal lobe executive function. The Hayling and Brixton test (Burgess & Shallice, 1997) - The Hayling and Brixton test is used to assess executive functioning, by testing the ability to detect and adapt to rules or patterns. This is done by asking participants to predict the next position of a blue circle, which moves across a series of pages in a logical sequence. The total number of prediction errors is recorded, with fewer errors indicating better executive functioning. Additionally, participants will complete a series of patient-reported outcome measures (PROMs) to capture relevant psychological, behavioural, and gait-related characteristics. Parkinson Anxiety Scale (PAS) (Leentjens et al., 2014) - The PAS is a 12-item questionnaire, designed and validated to assess anxiety symptoms in individuals with Parkinson’s Disease. The questionnaire consists of three subscales that evaluate persistent anxiety, episodic anxiety, and avoidance behaviour. State-Trait Anxiety Inventory (STAI) (Spielberger, 1970) - The STAI is a two part questionnaire, distinguishing between state anxiety and trait anxiety, with each part containing 20 items. The state anxiety part of the questionnaire focuses on temporary anxiety, related to specific situations. The trait anxiety part of the questionnaire focuses on a general tendency to experience anxiety. Perceived Stress Scale (PSS) (Cohen et al., 1983) - The PSS is a 10-item questionnaire, designed to quantify the amount of stress experienced by a participant over the past month. Questions focus on the frequency of stress-related thoughts and feelings. Beck Depression Inventory-II (BDI-II) (Beck et al., 1961; Visser et al., 2006) - The BDI-II is a 21-item questionnaire, validated for use in Parkinson’s disease, designed to assess the severity of depressive symptoms. Participants rate the intensity of a specific mood or disorder symptoms (such as sadness, guilt, fatigue, and changes in appetite or sleep) over the past two weeks. Apathy Motivation Index (AMI) (Ang et al., 2017) - The AMI is an 18-item questionnaire, developed to assess apathy. It contains three subscales (behavioural, social, and emotional). Participants rate their motivation and engagement, providing insight into their levels of apathy. REM Sleep Behaviour Disorder Screening Questionnaire (RSBDSQ) (Stiasny-Kolster et al., 2007) - The RSBDSQ is a 13-item questionnaire, designed to assess symptoms of REM Sleep Behaviour Disorder. Participants report on dream-enactment behaviour, such as vocalizations, movements, and potential injuries during sleep. In addition, it examines associated aspects, including vivid or violent dreams. New Freezing of Gait Questionnaire (NFOGQ) (Nieuwboer et al., 2009) – The NFOGQ is a 9-item questionnaire designed to assess the severity, frequency, and impact of freezing episodes in individuals with Parkinson’s disease. Characterizing Freezing of Gait questionnaire (CFOGQ) (Ehgoetz Martens et al., 2018b) – The CFOGQ is a 30-item questionnaire to examine whether FOG is mainly triggered by motor, cognitive or affective triggers. \articletype Original Articles Gait protocol The primary outcome of the trial will be assessed using a standardised set of FOG-provoking tasks, based on the Giladi FOG test recommended by the International Consortium for FOG (IC-FOG) at the 2023 FOG Symposium (Ehgoetz Martens, 2025). The assessments will be video recorded and captured using five inertial measurement units (The Opal, APDM Wearable Technologies). In short, the Giladi FOG test involves the following standardized tasks: 1) walking including a 180-degrees turn, 2) dual-task walking including a 180-degrees turn, 3) six 360-degrees turns, 4) six dual-task 360-degrees turns, 5) walking with small, shuffling steps around a square taped on the floor and 6) stepping in all directions around a box, 7) walking while carrying, 8) doorway crossing. FOG will be quantified during these tasks by video annotation using Elan software. Furthermore, real-time Clinician-rated Outcome scores will be obtained using a standardised scoring metric. In addition to these FOG-provoking tasks, continuous gait will be assessed during two-minutes of continuous overground walking, performed with and without a concurrent dual-task. Participants will follow a nine-meter path marked by two pylons in a distraction-free environment and will be instructed to walk consistently in their one preferred direction around the pylons. The cognitive dual task consists of a recording of a random sequence of digits read aloud, with participants counting the number of occurrences of a target digit (Pieruccini-Faria et al. , 2014). The order of digits is randomized, with a stimulus presentation lasting 500 milliseconds and the inter-stimulus interval ranging from 100 to 1000 milliseconds. Spatiotemporal parameters, including gait speed, stride time, stride length and stride time variability, will be captured using the five inertial measurement units. Gait variability will be calculated based on these parameters as it is associated with fall risk in PD and other populations (Tinetti et al. , 1988; Hausdorff et al. , 2001; Schaafsma et al. , 2003). Gait variability will be defined as the coefficient of variation (CV) of stride time: \begin{equation} \text{Gait}\ \text{Variability}=\frac{\text{SD}_{\text{stride}\ \text{time}}\ }{\text{mean}_{\text{stride}\ \text{time}}}*100\%\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ (1)\nonumber \\ \end{equation} \articletype Original Articles Augmented reality paradigm To investigate the effects of atomoxetine on FOG and gait variability in the context of heightened arousal, participants will perform a two-minute continuous gait task, and six 360-degrees turns in a high-threat condition. This is achieved by performing the task on a raised plank or platform respectively within an augmented-reality (AR) environment developed by Strolll ( Figure 2 ), using the Meta Quest 3 head-mounted AR technology, similar to past work using VR (Ehgoetz Martens et al. , 2014). Gait variability in the context of heightened arousal will be determined based on the two-minute continuous gait task on a raised plank, using Equation 1. FOG in the context of heightened arousal will be assessed using video annotation of the turning task on a raised platform, to determine the percentage of time frozen. Arousal measures Physiological arousal levels during the gait tasks will be quantified using skin conductance with a 20Hz sampling rate (Shimmer3 GSR+ Unit) and ECG with a 250.14Hz sampling rate (Shimmer3 ECG Unit). ECG data will be used to determine the participants heart rate and heart rate variability as a measure for arousal. In addition, subjective arousal will be assessed using the arousal subscale of the Self-Assessment Manikin during the gait tasks with the AR paradigm (Gatti et al. , 2018). Furthermore, pupillometry (Pupil Labs Core, Capture and Player) will be measured in a seated position at rest for three minutes and during two cognitive-motor tasks. The cognitive-motor tasks will entail a Number switch task and Stroop task and will be conducted for 10 minutes (Rondeel et al. , 2015). Pupillometry is not measured during gait, because changes in light and eye movements while walking would influence the pupil dilation and constriction, hindering reliable arousal assessments. Imaging protocol MRI data will be acquired on Siemens Prisma (Nijmegen, Waterloo) and Siemens Vida (Macquarie) 3T MRI systems using harmonized acquisition protocols to ensure comparability across sites. All sites will use the same scanning sequences and a harmonization tool (e.g., ComBat) will be used for further harmonization. Moreover, site will be included as a covariate in subsequent analyses to account for potential inter-scanner variability. Full MRI sequence parameters and acquisition details are provided in Table 1 . Resting-state fMRI will be acquired in all four medication states to assess alterations in network integration and segregation (Shine et al. , 2018; Taylor et al. , 2022; Dirkx et al. , 2023). During the resting-state fMRI participants are instructed to look at a cross on the screen via a mirror mounted on the head coil and not to think about anything in particular. For analysis, BOLD time series will be extracted from 375 predefined regions of interest and analysed using graph theory to quantify whole-brain connectivity (Gaurav et al. , 2022). Task-based fMRI will be acquired during a validated virtual reality (VR) gait paradigm in the dopaminergic OFF state. Participants will lay supine in the MRI scanner, with foot pedals positioned at the end of the scanner bed, and view a previously validated VR task on the screen via a mirror mounted on the head coil (Shine et al. , 2011; Matar et al. , 2013; Shine et al. , 2013a). Alternating depression of foot pedals positioned at the end of the scanner bed allow forward movement through virtual corridors presented on the screen. Encoded binary inputs from the foot pedals, corresponding to left and right footsteps, are recorded on the computer. After turning a 90° degree corner the paradigm reveals either a normal corridor or a corridor with an elevated narrow plank to cross (Taylor et al. , 2022). Cognitive dual-tasking will also be assessed by participants responding to colour-word combinations presented on the screen according to a pre-trained rule (Shine et al. , 2013b). Freezing episodes are defined as footstep latencies exceeding twice the participant’s modal latency, calculated from the modal step interval. Structural imaging in this study comprises T1-weighted Magnetization Prepared Rapid Gradient Echo (MPRAGE) for detailed anatomical reference, two neuromelanin-sensitive sequences (i.e., turbo spin echo (TSE) and SandwichNM) to assess the integrity of the locus coeruleus (LC) and substantia nigra (SN) (Ji et al. , 2022; Nobileau et al. , 2023), diffusion-weighted imaging to quantify free-water content in the SN (Burciu et al. , 2017; Johansson et al. , 2025), and quantitative susceptibility mapping (QSM) to measure iron content in the SN and other regions of the basal ganglia (Chan et al. , 2025). LC integrity will be quantified from neuromelanin-sensitive imaging using established signal intensity ratio methods (Doppler et al. , 2021; Madelung et al. , 2022), while SN integrity will be assessed with NigraNet-based segmentation combined with free-water imaging (Gaurav et al. , 2022). QSM provides complementary information on iron accumulation relevant to Parkinson’s disease pathology (Pyatigorskaya & Santin, 2021; Johansson et al. , 2025). Primary outcome The primary objective of this clinical trial is to evaluate the effect of atomoxetine on FOG severity in the dopaminergic OFF-state. The primary endpoint represents the difference between atomoxetine and placebo in the percentage of time spent frozen during Giladi FOG test in the OFF-state, determined using video annotations. All video assessments will be annotated by certified assessors using Elan software (Gilat, 2019; Cockx et al. , 2022). Secondary and exploratory outcomes Secondary objectives of this clinical trial are to assess the effect of atomoxetine on FOG severity in the dopaminergic ON-state and to examine its effect on brain network topology. The corresponding endpoints are the difference between atomoxetine and placebo in the percentage of time frozen during FOG-provoking gait tasks in the ON-state, and the difference in brain network topology, quantified by the average integration/segregation coefficient, and its relationship with FOG severity. Exploratory objectives of this trial are to investigate the effect of atomoxetine on FOG in the context of heightened arousal and to identify individual clinical factors and imaging markers that may predict treatment response. Endpoints for these analyses include the difference between the effect of atomoxetine and placebo on FOG across varying arousal states (assessed using skin conductance, heart rate, heart rate variability and pupil diameter and performance on cognitive tasks), and across varying FOG subtypes (assessed by the CFOG questionnaire). As well as the influence of clinimetric and imaging markers on the effect of atomoxetine on the percentage of time frozen during FOG-provoking tasks and the average integration/segregation coefficient. Sample size and power calculation The power calculation was based on the primary outcome of this clinical trial and performed in G*Power 3.1.9.7. We used the difference between dependent means, and the a priori computation based on alpha, power, and effect size. The effect size was determined using the ‘From group parameters’ window. Based on two large clinical trials previously conducted (Barthel et al. , 2018; Walton et al. , 2018), we expect the time spent frozen in the placebo condition in the dopaminergic OFF-state to be 15% (SD: 5%). Considering the heterogeneity of FOG, it is assumed that atomoxetine will reduce FOG by 10% (SD: 5%) in approximately half of participants (Jankovic, 2009; Revuelta et al. , 2015), whereas no change compared to placebo is expected in the other half. This yields an expected average treatment effect of 5% with a within-participant SD of 10%. For the placebo group, we specified an expected treatment effect of 0%, with a standard deviation of 10%. A moderate correlation between conditions (r = 0.4) was assumed, resulting in an effect size of 0.456. Aiming for a power of 0.9 with alpha set at 0.05 and a two-tailed t-test, this corresponds to a total sample size of 53. With an expected dropout between 10–15%, the target sample size was set at 60 participants. Statistical analysis The primary analysis will assess changes in the clinical rated outcome measure of the Giladi FOG test and percentage of time spent frozen during FOG-provoking tasks in the dopaminergic OFF-state. Atomoxetine and placebo will be compared using a paired-samples t-test (or Wilcoxon signed-rank test if assumptions of normality are violated). Secondary outcomes will focus on fluctuations in network topology (segregation–integration). To this end, the average integration/segregation coefficient will be calculated and examined in relation to i) FOG severity, ii) changes as a function of noradrenergic and dopaminergic drug states, and iii) the individual’s locus coeruleus and substantia nigra integrity, and clinimetrics (i.e., phenotype of FOG). Additionally, secondary outcomes will include the change in the clinician-rated outcome measure of the Giladi FOG test and the percentage of time spent frozen during the FOG-provoking tasks in the dopaminergic ON-state. A linear mixed model with noradrenergic drug (atomoxetine, placebo) as within-participant factor will be performed. Exploratory outcomes will evaluate the effects of atomoxetine and dopaminergic medication on FOG severity. A linear mixed model with noradrenergic drug (atomoxetine, placebo) and dopaminergic drug (OFF, ON) as within-participant factors, and locus coeruleus integrity, substantia nigra integrity, and clinimetrics as covariates, will be fitted. Random participant effects will account for dependencies due to repeated measurements. The same analysis will be applied to gait variability measured during the continuous gait task. Finally, to explore the effect of atomoxetine on FOG under heightened arousal, a linear mixed model with noradrenergic drug (atomoxetine, placebo) and arousal (‘baseline’ and ‘heightened’) as within-participant factors, with locus coeruleus and substantia nigra integrity and clinimetrics (e.g., Parkinson Anxiety Scale) as covariates, will be fitted. Multiple testing will be corrected using FDR correction (Benjamini–Hochberg). Discussion Although several studies have investigated noradrenergic agents for the treatment of FOG, many were underpowered and lacked placebo-controlled designs (Tohgi et al. , 1990; Tohgi et al. , 1993; Auriel et al. , 2006; Pollak et al. , 2007; Espay et al. , 2011; Moreau et al. , 2012). To date, no adequately powered, placebo-controlled trial has specifically investigated the efficacy of atomoxetine in FOG (Jankovic, 2009; Revuelta et al. , 2015). Furthermore, previous studies on atomoxetine did not employ standardized or objective measures of FOG severity, limiting the interpretability of their finding (Jankovic, 2009; Revuelta et al. , 2015). The present study addresses these limitations by implementing a randomized, double-blind, placebo-controlled design with a sample size determined by an a priori power calculation. In addition, standardized FOG-provoking tasks will be used to objectively assess FOG severity; these tasks are currently being validated within an international consortium, these tasks are currently being validated within an international consortium (Mancini et al. , 2025). In addition to investigating the effectiveness of atomoxetine to reduce FOG, this study also focuses on its potential mechanism of action in FOG. Emerging research indicates that FOG possibly arises from failure to compensate for loss of automatic gait control (Tosserams et al. , 2025). Effective compensation most likely relies on the integration of distinct and segregated compensatory brain networks, which is modulated by the noradrenergic ascending arousal system (Shine et al. , 2018; Taylor et al. , 2022; McKay et al. , 2023; Wang et al. , 2023). By including structural MRI for assessing the resting-state functional MRI to study network connectivity and task-based fMRI to identify changes in neural circuitry during freezing-provoking tasks, this study aims to also elucidate the role of noradrenaline in FOG. It is well established that FOG occurs more frequently under conditions of heightened arousal (Ehgoetz Martens et al. , 2014). Given that atomoxetine acts on the noradrenergic arousal system, we aim to determine whether its effectiveness differs across contexts of normal and heightened arousal. To this end, arousal will be measured throughout the various walking conditions as well as experimentally manipulated by simulating walking under conditions of increased perceived height using an augmented reality environment, and by adding cognitive load (Ehgoetz Martens et al. , 2014; Dirkx et al. , 2020; van der Heide et al. , 2025). As FOG is highly heterogeneous, it is likely that the effectiveness of atomoxetine may vary across individuals. This trial incorporates a comprehensive set of clinical and imaging measures, enabling the exploration of individual biomarkers that may predict treatment response. We anticipate that the findings from this study will lay the groundwork for a novel treatment framework for FOG and open new avenues for pharmacological intervention. AMI Apathy Motivation Index BDI-II Beck Depression Inventory-II \articletype Original Articles CFOGQ Characterizing Freezing of Gait questionnaire ECG Electrocardiogram FA Flip Angle \articletype Original Articles FAB Frontal Assessment Battery (FAB) \articletype Original Articles FDR correction False Discovery Rate correction fMRI Functional Magnetic Resonance Imaging FOG Freezing of Gait FOV Field of View GRS Galvanic Skin Response IC-FOG International Consortium for freezing of gait LC Locus Coeruleus IMP Investigational Medicinal Product MDS Movement Disorder Society MDS-UPDRS Movement Disorder Society - Unified Parkinson’s Disease Rating Scale MoCA Montreal Cognitive Assessment MPRAGE Magnetization Prepared Rapid Gradient Echo MRI Magnetic Resonance Imaging NFOGQ Freezing of Gait Questionnaire PAS Parkinson Anxiety Scale PD Parkinson’s Disease \articletype Original Articles PROMs Patient-reported Outcome Measures \articletype Original Articles PSS Perceived Stress Scale \articletype Original Articles QSM Quantitative Susceptibility Mapping \articletype Original Articles RSBDSQ REM Sleep Behaviour Disorder Screening Questionnaire SN Substantia Nigra STAI State-Trait Anxiety Inventory TE Echo Time TI Inversion Time TR Repetition Time TSE Turbo Spin Echo \articletype Original Articles Declarations Ethics approval – Ethical approval was obtained by the institutional review board of the Radboud University Medical Center in Nijmegen and the AmsterdamUMC Medical Ethics Committee (CTIS: 2024-516756-18-00). Consent for publication – Not applicable. Availability of data and materials – Not applicable. Competing interests – The authors declare that they have no competing interests. Funding – This study is funded by the Michael J. Fox Foundation for Parkinson’s Research (Grant-ID: MJFF-024600). Acknowledgement – not applicable Author contributions – Franka M. Goossens: Writing - review & editing, Writing - original draft, Methodology, Validation, Project administration. Kaylena A. Ehgoetz Martens: Conceptualization, Funding acquisition, Methodology, Writing - review & editing, Supervision, Project administration. Bastiaan R. Bloem: Conceptualization, Funding acquisition, Writing - review & editing. Rick C. Helmich: Conceptualization, Funding acquisition, Methodology, Writing - review & editing. Erika E. Howe: Methodology, Writing - review & editing, Validation, Project administration. 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Figure Legends \articletype Original Articles Figure 1. Schematic overview of study procedures. Study timeline with three visits: baseline assessments (visit 1) and two cross-over visits (visits 2 and 3) with atomoxetine or placebo, each assessed in both dopaminergic OFF- and ON-states. \articletype Original Articles Figure 2: Low and high threat conditions of the AR environment. AR-paradigm showing the (A) neutral environment with a virtual plank at floor level, (B) the high threat environment presenting the plank at a virtual height, (C) neutral environment with a virtual platform at floor level and (D) the high threat environment presenting the platform at a virtual height. \articletype Original Articles Table 1: MRI acquisition parameters. Overview of MRI sequences used in the study, including anatomical, neuromelanin-sensitive, diffusion weighted, quantitative susceptibility mapping and functional scans. TR = repetition time; TE = echo time; FA = flip angle; TI = inversion time; FOV = field of view; accel. factor = acceleration factor. Voxel size refers to the spatial resolution of the acquired images. Acquisition times indicate the duration of each scan. Supplementary Material File (table_1.docx) Download 14.79 KB Information & Authors Information Version history V1 Version 1 09 January 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Franka Goossens 0009-0004-7876-1018 [email protected] Radboud universitair medisch centrum View all articles by this author Kaylena A. Ehgoetz Martens University of Waterloo Department of Kinesiology and Health Sciences View all articles by this author Bastiaan Bloem Radboud universitair medisch centrum View all articles by this author Rick C. Helmich Radboud universitair medisch centrum View all articles by this author Erika Howe 0000-0002-4476-9431 University of Waterloo Department of Kinesiology and Health Sciences View all articles by this author Melvyn Roerdink Vrije Universiteit Amsterdam Faculteit der Gedrags- en Bewegingswetenschappen View all articles by this author James Shine The University of Sydney Brain and Mind Centre View all articles by this author Anouk Tosserams Radboud universitair medisch centrum View all articles by this author Simon J. G. Lewis Macquarie University View all articles by this author Jorik Nonnekes Radboud universitair medisch centrum View all articles by this author Metrics & Citations Metrics Article Usage 296 views 126 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Franka Goossens, Kaylena A. Ehgoetz Martens, Bastiaan Bloem, et al. Pharmacologically modulating the noradrenergic arousal system to reduce freezing of gait in Parkinson’s disease: study protocol of the international AnTi-FREEZE study. Authorea . 09 January 2026. DOI: https://doi.org/10.22541/au.176796918.82151521/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. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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