Marian L. Dale
Carla Silva-Batista
Filipe Oliveira de Almeida3
Fay B. Horak- 1Balance Disorders Laboratory, Department of Neurology, Oregon Health and Science University, Portland, OR, United States
- 2Neurology Section, VA Portland Health Care System, Veterans Health Administration, Portland, OR, United States
- 3Exercise Neuroscience Research Group, University of São Paulo, São Paulo, Brazil
Background: The use of objective gait and balance metrics is rapidly expanding for evaluation of atypical parkinsonism, and these measures add to clinical observations. Evidence for rehabilitation interventions to improve objective measures of balance and gait in atypical parkinsonism is needed.
Aim: Our aim is to review, with a narrative approach, current evidence on objective metrics for gait and balance and exercise interventions in progressive supranuclear palsy (PSP).
Methods: Literature searches were conducted in four computerized databases from the earliest record up to April 2023: PubMed, ISI’s Web of Knowledge, Cochrane’s Library, and Embase. Data were extracted for study type (cross-sectional, longitudinal, and rehabilitation interventions), study design (e.g., experimental design and case series), sample characteristics, and gait and balance measurements.
Results: Eighteen gait and balance (16 cross-sectional and 4 longitudinal) and 14 rehabilitation intervention studies were included. Cross-sectional studies showed that people with PSP have impairments in gait initiation and steady-state gait using wearable sensors, and in static and dynamic balance assessed by posturography when compared to Parkinson’s disease (PD) and healthy controls. Two longitudinal studies observed that wearable sensors can serve as objective measures of PSP progression, using relevant variables of change in turn velocity, stride length variability, toe off angle, cadence, and cycle duration. Rehabilitation studies investigated the effect of different interventions (e.g., balance training, body-weight supported treadmill gait, sensorimotor training, and cerebellar transcranial magnetic stimulation) on gait, clinical balance, and static and dynamic balance assessed by posturography measurements. No rehabilitation study in PSP used wearable sensors to evaluate gait and balance impairments. Although clinical balance was assessed in 6 rehabilitation studies, 3 of these studies used a quasi-experimental design, 2 used a case series, only 1 study used an experimental design, and sample sizes were relatively small.
Conclusion: Wearable sensors to quantify balance and gait impairments are emerging as a means of documenting progression of PSP. Robust evidence for improving balance and gait in PSP was not found for rehabilitation studies. Future powered, prospective and robust clinical trials are needed to investigate the effects of rehabilitation interventions on objective gait and balance outcomes in people with PSP.
Introduction
Progressive supranuclear palsy (PSP) is a relatively rare and rapidly progressive neurodegenerative disease classified among atypical Parkinsonisms (1, 2), but evidence suggests that the clinical spectrum of PSP is larger than originally described. The most frequent form of the disease, PSP-RS (PSP Richardson syndrome), is characterized by vertical supranuclear gaze palsy and backward postural instability with early falls (2), while the second most common form of disease is characterized by a parkinsonian syndrome resembling Parkinson’s disease (PD) especially in the earliest stages (3). The 2017 Movement Disorder Society criteria recognize multiple subtypes of PSP (4), and these subtypes encompass a spectrum of degree of gait and balance deficits. PSP-RS, PSP-P, and PSP-progressive gait freezing (PSP-PGF) display prominent gait and balance abnormalities, while other subtypes and stages of PSP, such as probable PSP frontal presentation (probable PSP-F) and possible PSP speech and language (possible PSP-SL), are characterized primarily by deficits other than gait and balance impairment.
It has long been recognized that particular clinical exam findings and history questions serve as a red flag for gait and balance in atypical parkinsonism disorders, such as PSP and multiple system atrophy (MSA). For example, Nonnekes et al. (5) highlighted the tandem gait sign and bicycle sign as indicative of atypical parkinsonism versus idiopathic PD (iPD): if a patient has impaired tandem gait or states that early in their disease course that they were no longer able to ride a bicycle, one should be concerned for possible atypical parkinsonism. This reflects the clinical observation of a wider-based gait and earlier balance troubles as reflective of atypical parkinsonism.
The use of objective gait and balance metrics is rapidly expanding for evaluation of atypical parkinsonism, and these measures add to clinical observations. For example, Raccagni et al. (6) used inertial sensors on the feet to compare a group of subjects with PSP and MSA to a group with iPD and found reduced gait speed and stride length in the atypical parkinsonism subjects compared to subjects with iPD.
Although advances in technology of small, body-worn, inertial sensors have objectively quantified balance and gait impairments in the clinic for research trials and clinical practice in people with PD (7–9), this approach has not been explored in PSP. Objective balance and gait metrics may eventually provide useful biomarkers for PSP, clinical efficacy of new treatments, in place of counting falls from diaries or clinical balance rating scales. Objective balance and gait biomarkers also may be helpful in clinical practice to monitor effects of interventions and prognosis. Biomarkers of balance control could be especially useful to monitor PSP progression and fall risk as well as to differentiate PSP subtypes.
In this narrative review, we examine current evidence for objective metrics of gait and balance in people with PSP. We summarize cross-sectional studies examining gait initiation, steady state gait, and balance in PSP, as well as studies that use gait and balance data mining approaches for classification of PSP, and studies examining radiological correlations with gait and balance metrics in PSP. We then discuss the emerging use of objective gait and balance measures for longitudinal monitoring in PSP and objective gait and balance measures as endpoints for rehabilitation intervention trials in PSP.
Methods
Literature searches were conducted in the following four computerized databases from the earliest record up to April 2023: PubMed, ISI’s Web of Knowledge, Cochrane’s Library, and Embase. Inclusion criteria were: any study design (cross-sectional, longitudinal, and rehabilitation interventions) published in peer-reviewed journal, published in English, available in full text, with or without rehabilitation interventions [e.g., physical exercise, virtual reality, and repetitive transcranial magnetic stimulation (rTMS)], population with diagnosis of PSP, mixed PSP subtypes, gait and/or balance assessment. Exclusion criteria were: no gait and/or balance assessment and invasive brain stimulation.
The search was limited to English language. All the identified and retrieved electronic search titles, selected abstracts, and full-text articles were independently evaluated by two of the authors (FOA and CSB) to assess their eligibility. In case of disagreements, a consensus was adopted or, if necessary, a third reviewer evaluated the article (MD). The search process is depicted in Figure 1.
Figure 1. PRISMA flowchart for inclusion into the review.
Results
Gait and balance as a diagnostic tool: cross-sectional studies
Sixteen cross-sectional studies were included in this review (Table 1). These studies compared gait initiation, steady state gait, and balance between people with and without PSP. In addition, some studies used radiological correlations with gait and balance measures in PSP and mixed PSP phenotypes. We have separated the following discussion of cross-sectional studies according the type of gait and balance assessment.
Table 1. Summary characteristics of the cross-sectional included studies.
Gait initiation in PSP
In an elegant 2015 study Amano and colleagues examined the mechanics of gait initiation in PSP using a combination of force platforms embedded in a walkway and a 3D motion capture system (11). Twelve subjects with PSP-Richardson syndrome (PSP-RS), 12 subjects with PD, and 12 age- and gender-matched healthy controls (HC) performed 5 gait initiation trials at a self-selected speed, and their anticipatory postural adjustments (APAs) were examined in detail. Whereas subjects with Parkinson’s disease and HCs displayed the normal APA with an initial backward and lateral center of pressure shift to initiate gait, subjects with PSP could not tolerate the initial destabilization of the APA imbalance phase. In other words, subjects with PSP displayed an inefficient gait initiation strategy because they were unable to initially shift their center of pressure to generate momentum for forward movement, but rather moved their swing foot forward more robotically without the normal, anticipatory weight shift that moves the center of body mass forward and over the stance leg.
The authors proposed that gait initiation in PSP prioritizes stability over mobility, and suggested possible strategies for rehabilitation including focusing on medio-lateral balance to overcome the minimal lateral weight shift and staggering the initial swing foot posteriorly to try to promote the physiological weight shift of a normal APA. Limitations of this study include a lack of accounting for baseline anthropometric measurements and width of the initial base of support, and the fact that all subjects were evaluated on levodopa, likely preferentially improving APAs in the iPD group (25). The study was also conducted prior to the 2017 Movement Disorder PSP Criteria (4), and thus only included subjects with the Richardson syndrome variant of PSP (PSP-RS).
Steady state gait in PSP-RS
In the same Amano study discussed above, PSP, iPD, and HC subjects also performed 10 steady state gait trials at a self-selected speed, and gait analysis revealed a slower, and more variable, gait in PSP-RS compared to iPD (11). Hatanaka et al. also compared steady state gait in 20 PSP-Richardson syndrome, 124 PD, and 24 HC subjects, using triaxial accelerometers for 10-meter, self-selected straight walking (15). Their study replicated the finding of slower gait in PSP, showing an overall hypokinetic gait pattern with decreased velocity, step length, cadence, and mean acceleration in PSP. They additionally found that the subjects with PSP demonstrated an especially small vertical displacement but larger vertical acceleration than PD patients when comparing subjects with the same cadence.
Selge et al. applied straight walking on a gait mat, with and without cognitive and motor dual tasks, to differentiate PSP-RS from normal pressure hydrocephalus (NPH) (20). Clinically, gait in NPH is considered to be even wider-based and slower than in PSP with an additional “magnetic” quality, but in certain cases the gait patterns of the two diseases approximate each other and contribute to a differential diagnosis that includes both NPH and PSP. In the Selge study, 27 subjects with idiopathic NPH and 38 subjects with PSP performed straight walking at their preferred speed, at a slow speed, and at their maximum speed, as well as dual-task walking at their preferred speed with the serial 7 s cognitive task or while carrying a tray as a motor dual task. Importantly, the PSP and NPH subjects were initially matched on a clinical, functional gait assessment scale. The authors found that gait was slower and more broad-based in NPH, and gait in PSP was more variable and more sensitive to dual-task conditions. They interpreted the increased sensitivity to dual- task conditions in PSP to increased cortical attention for walking. A limitation of this (and many other dual-task studies) was that prioritization of the dual-task was not assessed, so it was not known to what degree the subjects were focused on walking versus on the cognitive task during the assessments.
Steady state gait in mixed PSP phenotypes
After establishment of the 2017 Movement Disorder Society Criteria for PSP (4), several groups examined steady state gait in multiple phenotypic variants of PSP. Amboni et al. (12) included variants of PSP to compare with iPD specifically in early diagnostic stages. The iPD subjects were enrolled less than a year from symptom onset and had confirmed positive DAT scans. The subjects with PSP met MDS PSP diagnostic criteria and included 11 with PSP-RS, 5 with PSP-parkinsonism (PSP-P), and 4 with PSP-progressive gait freezing (PSP-PGF). Objective gait analysis revealed a longer stance phase in all PSP variants compared to iPD.
While some groups have compared the gait characteristics of PSP-RS, PSP-P, and PSP-PGF to each other and to iPD, other groups have pooled the variant subtypes to compare as a group to the traditional PSP-RS type, leading to slightly different conclusions. Takamatsu et al. compared gait mat measurements in 27 patients with PSP (including PSP-RS, PSP-PGF, and PSP-P variants) to patients with iPD and to healthy controls (24). They found an overall longer gait cycle time and a larger step width in PSP compared to iPD and HC. They also found a trend toward a faster walking speed in PSP-PGF compared to PSP-RS, and a trend toward a slower walking speed in PSP-P compared to PSP-RS. Low subgroup numbers did not allow for full statistical analysis. Picillo et al. performed a gait analysis in 19 patients with PSP in single and dual tasks (21) and compared the PSP-RS group to a pooled variant group of PSP-P and PSP-PGF (vPSP). Ten of the 19 PSP subjects had the PSP-RS subtype, 5 had PSP-P, and 4 had PSP-PGF. The authors found reduced cadence and increased cycle duration with a longer stance duration in PSP-RS compared to vPSP. With the dual task condition, they found an additional increase in stance phase in PSP-RS compared to the vPSP group. In addition to different methodologies for comparison groups, another important limitation of these studies is that straight walking on a gait mat may not elicit freezing episodes that are fully representative of real-world mobility impairments.
Balance in PSP-RS
Despite the fact that postural instability and falls are classic features of PSP, fewer studies have focused on static and dynamic balance compared to the number of studies of gait in PSP. Early studies focused on the contribution of vestibular dysfunction to balance impairment in PSP. In 2008 Liao et al. combined otolith-ocular reflexes (VORs) and vestibular-evoked myogenic potentials (VEMPs) while subjects with PSP-RS were seated on a dynamic chair capable of translations and rotation and found smaller translational VORs and smaller VEMPs in PSP compared to control subjects (16). The authors concluded that abnormal otolith reflexes may contribute to frequent falls in PSP. Using the sensory organization test (SOT), during which subjects stand in 6 conditions on a moveable force plate (Neurocom) platform (1. eyes open with stationary platform, 2. eyes closed with stationary platform, 3. eyes open with visual background movement, 4. eyes open with platform movement, 5. eyes closed with platform movement, and 6. eyes open with both background and platform movement), Ondo et al. showed that subject with PSP-RS performed worse than subjects with iPD on the total SOT score (17).They also found that subjects with PSP-RS had specific impairments in a pattern that they concluded suggested vestibular dysfunction (conditions 3, 4, 5, and 6 of the SOT). However, these are also the most challenging balance conditions in the SOT, nonspecific for vestibular loss.
Our group subsequently compared the sensory and motor responses of 12 subjects with PSP-RS, 12 postural instability and gait disturbance (PIGD)-matched subjects with iPD, and 12 healthy controls while sitting and standing on the same Neurocom moveable force plate platform system (13). We specifically examined subjects’ reactions to forward platform translations and toes-up platform tilts that resulted in backward sway. Compared to subjects with iPD, we found that subjects with PSP accurately perceived gravity when standing on a tilting surface, but could not accurately perceive toes-up platform tilts, and furthermore exerted less postural corrective motor responses in response to forward platform translations and toes up surface tilts. Taken together, we postulated that balance dysfunction in PSP is the result of abnormal central sensory integration, rather than a result of a primary vestibular deficit.
Combined gait and balance in mixed PSP phenotypes
More recently, Ali et al. combined gait and postural sway in a small number of PSP phenotypes versus age-matched controls using a 3D motion capture system (10). Sixteen patients with PSP (11 PSP-RS, 2 PSP-P, 2 PSP-SL, and 1 PSP-CBS) were compared with healthy controls using a 10-camera motion capture system and 41 body markers and ground-embedded force plates. They found a slower gait velocity, slower cadence, and longer double-support time in PSP that correlated with clinical disease severity on the PSP Rating Scale (PSPRS). They also noted larger antero-posterior sway, but there was no relationship between the clinical PSPRS scores and standing postural sway tasks. The findings suggest that static standing sway tasks may not fully capture dynamic balance impairments in PSP.
Data mining studies for classification of PSP versus PD
Machine learning approaches to classify gait in people with PSP from PD are the focus of two studies, one by Ricciardi (22) that uses data from a motion analysis system, and the other data from wearable Opal inertial sensors (APDM) by De Vos in 2020 (14). In the motion analysis study, straight walking data from 46 subjects with a mix of de novo PD, moderate PD, and unspecified PSP subtypes was compared. Freezing and turning data was excluded. In the initial machine learning classification attempt by Ricciardi, random forest and gradient boosted tree models correctly discriminated gait in those with PSP from iPD, with a sensitivity and specificity of 92.6 and 96.3 (random forest) and 96.3 and 92.6 (gradient boosted), respectively. However, because the disease duration differed largely between groups, the clinical utility of such classification is unclear. The subsequent machine learning study by deVos, 2020 used 6 wearable Opal sensors (placed on feet, wrists, sternum, and the lumbar region) to examine data from 4 PSP-RS subjects, 17 PSP-P subjects, 20 iPD subjects, and 30 healthy controls during a 2-min walk, sway on a firm surface with eyes closed, and a 3-m timed up and go task (14). The Opal triaxial sensors include accelerometers, gyroscopes, and a magnetometer. Subjects were tested on dopaminergic medication. The authors found that a random forest model with combined gait, sway, and timed up and go data predicted PSP versus PD with 86% sensitivity and 90% specificity. Sway, alone, did not discriminate the groups. This study was also limited by a variable disease duration in subjects. The average disease duration in the subjects with PD was 11.4 years, and only 2 years in the subjects with PSP. Additionally, machine learning approaches for classification of diseases can be of limited clinical utility when differences in the clinical features of the diseases under investigation are clinically apparent at baseline.
Radiological correlations with gait and balance measures in PSP
A 2016 study by Pasha et al. compared balance and radiological features in 17 PSP-RS and 12 PSP-P patients using a Biodex posturography system, which is a platform capable of tilting 20 degrees from the horizontal in all directions (19). They compared static limits of stability and dynamic stability in response to surface tilts with structural MRI features in PSP-RS and PSP-P and found that balance and radiological abnormalities were overall more severe in PSP-RS. This is consistent with evolution of the disease course, as we see that variants of PSP evolve with time and disease progression. In PSP-RS, they did not find any significant correlations between the PSPRS and specific areas of atrophy or between balance measures and imaging features. In PSP-P, the midbrain axial anterior–posterior diameter significantly correlated with the Tinetti Mobility Assessment total score and Gait subscore, but not with any dynamic posturography measures.
Palmisano et al. used a 3D motion capture system to examine anticipatory postural adjustments (APAs) for gait initiation in 26 subjects with PSP-RS and 14 age-matched controls and then correlates APA measures with metabolic activity on fluoro-D glucose (FGD) PET (18). Their study supported the findings of Amano and colleagues showing impaired APAs in people with PSP (11). Metabolic correlations were not significant after controlling for multiple comparisons, but the data suggested several trends toward significance such as an association between decreased regional caudate uptake and impaired APA control. The study was limited by a high rate of exclusion due to falls or total absence of the imbalance phase of the APA (8 out of 26 patients were excluded), and this highlights the major limitation of severity of disease in clinical trials in PSP.
A subsequent, multimodal imaging study in 19 subjects with PSP analyzed 3 T MRI markers of atrophy and white matter integrity on diffusion tensor imaging (DTI) and fortaucipir-PET metabolic imaging with principal components analysis (23). Various subtypes of PSP were represented including PSP-RS, PSP-P, PSP-SL, and PSP-CBS. Gait features of decreased stride length, increased step width, and longer double-support time related to DTI measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum, and the sagittal striatum, to MRI volumes in frontal and precentral regions, and to flortaucipir-PET uptake in the precentral gyrus. Postural sway in standing, alone, did not correlate with imaging abnormalities, but this may be due to the mix of PSP phenotypes studied. In PSP-RS, alone, imaging and postural sway abnormalities did correlate. The authors note that a limitation of the study relates to the somewhat controversial use of flortaucipir PET in PSP, as it was optimized for the paired helical tau fragments in Alzheimer’s and is known to have off-target binding in PSP.
Gait and balance as a biomarker of progression: longitudinal studies
Four longitudinal studies were included in this review (Table 2). These studies evaluated longitudinal changes in gait, balance, and cognition up to 1.5 years. Two studies observed that wearable sensors can serve as sensitive measures of PSP progression.
Table 2. Summary characteristics of the longitudinal included studies.
An early study by Ghosh et al. (27) previously examined PSPRS and oculomotor function changes in 23 subjects with PSP Richardson syndrome over 14 months. They found significant changes on both the PSPRS and vertical eye movements via saccadometry during that period, but objective gait and balance outcomes were not used.
As part of a larger, longitudinal study in the United Kingdom, the “OxQuip” study, Pereira et al. examined longitudinal changes in motor and cognitive symptoms on clinical scales in PSP (28), and then Sotirakis et al. (29) built upon this background with longitudinal monitoring of PSP with 6 body-worn, inertial measurement units (IMU) sensors (“Opals,” by APDM). Pereira analyzed the PSPRS, MDS-UPDRS 3, MOCA, and MMSE in 28 subjects with possible or probable PSP by 2017 MDS criteria (with symptom onset at an average of 1.9 years prior to enrollment, but PSP subtypes were not specified) at visits every 3 months for 18 months. The gait and midline sub-score of the PSPRS was the earliest score to change and this change was observed at 6 months. This study experienced a drop-out rate of approximately 50% due to progression of illness, death, or change in diagnosis (the latter in only one subject). Other limitations of this study were the lack of pathological diagnoses and the fact that dopaminergic medication use was not accounted for at the time of assessments.
Sotirakis et al. then applied 6 wearable IMU Opal sensors to the wrists, feet, sternum, and lumbar region for longitudinal measurement in 27 subjects with PSP of the PSP-RS and PSP-P subtypes. The Opal sensors were applied for a 2-min walk with 180 degree turns and for a postural sway task for 30 s with eyes closed. Data from 17 participants was sufficient for analysis of visits at 3-month intervals for 12 months. Linear regression revealed that a model incorporating turn velocity, stride length standard deviation, and toe off angle detected statistically significant progression at visit 4, which was 3 months earlier than the clinical PSP Rating Scale, alone. This was an important first study to quantify disease progression in PSP using wearable sensors. An important limitation of this study is the lack of accounting for the potential influence of physical therapy interventions on progression.
A subsequent study by Abate et al. (26) also examined disease progression in PSP using Opal inertial sensors, and correlated kinematic data to the PSPRS. Twenty-three subjects were assessed for progression, and PSP phenotypes included in this study were PSP-RS (80%), PSP-P (14%), and PSP-PGF (6%). In this study Opals were applied to the feet and lumbar area only. At the 3-month follow-up, cadence and gait cycle duration from a two-minute walking task worsened significantly, although the total PSPRS did not worsen significantly, except for the specific “arising from chair” sub-item that did worsen significantly. A strength of this study is the use of fewer sensors, which improve ease of clinical use. An important limitation of this study is that only 29% of the subjects with PSP needed unilateral assistance for gait (i.e., a cane or a helper holding onto one limb), so the population only encompassed relatively mild disease presentations of PSP.
The Sotrirakis and Abate studies (26, 29) both suggest that wearable sensors may be important and more sensitive detectors of disease progression than the PSPRS. Both studies also found that dynamic gait parameters, rather than balance parameters, are related to disease progression. The authors hypothesize that dynamic instability outweighs static instability for assessment of progression, at least in the relatively early stages of the disease. It is important to acknowledge that more wearable sensor assessment of static balance is needed to better understand progression, particularly in more advanced stages of PSP.
Rehabilitation intervention studies
Fourteen rehabilitation intervention studies were included in this review (Table 3). These studies evaluated the effect of different interventions (balance training, home-gait exercise body-weight supported treadmill gait, virtual reality intervention, Robot-assisted walking, and cerebellar rTMS) on gait and balance outcomes in people with PSP. No study used wearable sensors to evaluate gait and balance impairments.
Table 3. Summary characteristics of the rehabilitation interventions included studies.
Effect of rehabilitation interventions on spatiotemporal gait metrics in PSP
Changes in spatiotemporal gait metrics were observed in six rehabilitation studies (31, 38, 39, 41–43). Of these studies, only one had a sample size of 19 people with PSP (43), the other studies were case report that investigated the effects of treadmill training and boxing (31), robot-assisted walking (38), virtual reality (39), treadmill training with body weight support (41), and cueing step-training (42) on spatiotemporal gait parameters such as gait speed, stride length, and cadence. Although these studies have shown changes in gait speed, stride length, and cadence after a short period of intervention, ranging from 8 (42) to 24 sessions (41), it is important to emphasize that the data from these case studies do not allow causal conclusions on the effects of these mode of rehabilitation in PSP. Therefore, caution should be exercised when interpreting these findings as they cannot be generalized to the entire PSP population. Thus, robust clinical trials are needed to investigate the effects of rehabilitation intervention on spatiotemporal gait parameters in people with PSP.
Zampieri et al. (43) assessed the effect of a rehabilitation intervention in PSP on kinematic gait parameters (stance time, swing time, and step length) by tracking foot motion using electromagnetic sensors. Nineteen people moderately affected by the PSP were assigned to either a treatment group (balance plus eye movement exercises, n = 10) or a comparison group (balance exercises only, n = 9). Although the authors did not find a difference between groups for any gait parameter, the within-group analysis revealed significant improvements in stance time and walking speed for the treatment group, whereas the comparison group showed improvements in step length only. These preliminary findings support the use of eye movement exercises as a complementary therapy for balance training in the rehabilitation of some gait parameters in people with PSP; however, future clinical trials powered at a higher level are needed to confirm these results.
Effect of rehabilitation interventions on clinical balance in PSP
Changes in clinical balance were observed in 6 rehabilitation studies (30, 32, 33, 35, 36, 40). These studies had a sample size ranging from 1 (40) to 24 (30). The number of sessions ranged from 10 (40) to 24 sessions (33). Most studies used the Berg Balance Scale (BBS) to assess clinical balance, while one study used the Mini-BESTest (40). Different interventions were used such as treadmill training (30), body-weight supported treadmill gait training (33), balance and resistance training (35), cueing balance-exercises (36), and backward gait training combined with gait-synchronized transcranial alternating current stimulation (tACS) (40).
Clerici et al. (30) observed that 20 sessions of treadmill training with visual cues and auditory feedback, both with (n = 12) and without (n = 12) the use of a robotic device, significantly improved the BBS scores in people with PSP. The authors concluded that both interventions have similar effects on clinical balance of this population, thus, the usefulness of an aerobic, sensory-feedback approach for the rehabilitation of patients suffering from PSP may be implemented in future clinical trials. Di Pancrazio et al. (33) tested the effect of 24 sessions of a rehabilitative program combining sensorimotor exercises (postural control, vibration, and cues) on postural instability of ten people with PSP. The authors observed that the combined rehabilitative program produced improvement in the BBS score and this clinical balance improvement persisted also in the follow-up phase after 30 days. Although the authors suggest that this specific rehabilitation program could improve postural instability in people with PSP due to intensive sensory stimulation involved in the intervention protocol, the failure to use a control group can make it impossible to draw meaningful conclusion from this study. Likewise, Matsuda et al. (35) applied 20 sessions of balance and resistance training in 20 people with PSP without the use of a control group. They also observed beneficial effects on the BBS score.
Although we do not know exactly the positive effects of progressive resistance strength training on people with PSP, there is strong evidence of benefit of this intervention in people with PD (44, 45). Two years of progressive resistance strength training were more effective than 2 years of non-progressive exercise in decreasing the motor symptoms of patients with mild-to-moderate PD (44). Our previous studies have demonstrated that combining balance exercises with progressive resistance strength training is more effective than progressive resistance strength training alone in decreasing motor symptoms of PD (46), as well improving clinical balance on the Balance Evaluation Systems Test (BESTest), mobility (timed-up-and-go test), and fear of falling in people with mild-to-moderate PD (47). Thus, a combined balance and progressive resistance training intervention would be more effective for people with PSP than progressive resistance training alone. Future controlled and randomized studies should test this intervention in PSP.
Nicolai et al. (36) tested the effects of 18 sessions of audio-biofeedback training on the BBS score in 8 people with PSP. This study used a new device that was well accepted for the participants and no adverse events occurred. Although the authors observed a significant improvement in the BBS score, which remained significant at the 4-week follow-up, the lack of a control group makes it difficult to be certain that the improvement in the BBS scores was caused by the audio-biofeedback training and not by other variables in the intervention. Thus, future powered and robust clinical trials are necessary to investigate the effects of sensory-feedback rehabilitation intervention on the clinical and objective balance of people with PSP.
Only one study investigated the effects of rehabilitation on freezing of gait (FOG) in people with PSP (34). We know FOG negatively impacts balance and functional gait in this population (48, 49). Irons et al. (34) observed that 24 sessions of a motor-assisted elliptical trainer with body weight support decreased FOG in a 67-year-old man with PSP. However, 1 month without training revealed worsening of his FOG, although the improved oxygen cost during training was sustained at 1-month follow-up. This case study is the first to document FOG improvement after a motor-assisted, elliptical training program for an individual with PSP, and future studies with a larger sample size are needed to investigate the possible benefits of this structured rehabilitation for people with PSP.
Interventions that involve cognitive and balance exercises should be applied to decrease FOG in people with PSP. People with PSP have more fear of falling, cognitive and balance impairments, and falls compared to people with PD (50). Our previous studies have demonstrated that 36 sessions (47, 51) or 18 sessions (52, 53) of challenging motor-cognitive balance training improved spatiotemporal gait parameters, anticipatory postural adjustments, postural stability, as well decreased FOG severity (51) and improved cognitive function in people with mild-to-severe PD. These interventions are challenging and need to be applied individually. As people with PSP are at higher risk of falling compared to those without PSP (49, 50), these exercises would be performed individually and with a body-weight support system (e.g., ZeroG) (54), in an attempt to significantly improve gait, cognition, FOG, and balance in a safe way. Thus, future, randomized, clinical trials are encouraged to implement this motor-cognitive rehabilitation strategy.
Using a different intervention approach, Shima et al. (40) assessed the effect of 10 sessions of rehabilitation (backward gait training) combined with gait-synchronized, cerebellar transcranial alternating current stimulation (tACS) on the MiniBESTest score in a 70-year-old woman with PSP-Richardson’s syndrome. Initially, the participant underwent short-term intervention with combined training of backward gait with synchronized cerebellar tACS, asynchronized, or sham stimulation according to the N-of-1 study design. Synchronized tACS training demonstrated an improvement in the MiniBESTest scores, whereas asynchronized or sham stimulation did not. The additional long-term interventions of combined backward gait training with synchronized cerebellar tACS demonstrated further improvement in MiniBESTest. Although this case study results can be difficult to replicate due to the sample size, it describes a novel approach for clinical balance in a patient with PSP-Richardson’s syndrome, as backward gait training with synchronized cerebellar tACS may be a promising therapeutic approach due to pathophysiology of disease involving cerebellar dysfunction (55, 56) and backward falls. Robust, prospective clinical trials are needed to test this new approach in people with PSP.
Although clinical balance was assessed in 6 rehabilitation studies (30, 33–36, 40), 3 of these studies used a quasi-experimental design (33, 35, 36), 2 used a case report (34, 40, 44–47), and only one study used an experimental design (30). Thus, the effects of balance- and gait-focused rehabilitation for people with PSP are still unknown due to small sample sizes. Future powered, prospective and robust clinical trials are needed to investigate the effects of rehabilitation interventions on clinical balance of the people with PSP.
Effect of rehabilitation interventions on objective balance measures in PSP
The effect of rehabilitation interventions on balance posturography has been investigated only in 2 studies, both of which used cerebellar transcranial magnetic stimulation (TMS) in people with PSP (32, 37). Neuroimaging and neuropathology studies have revealed a reduced volume of the cerebellum with tau accumulation (55, 56) that may be responsible for impaired balance and gait in patients with PSP. Thus, stimulatory cerebellar TMS may be a promising tool to improve balance and motor control in people with PSP.
Dale et al. showed that 10 sessions of cerebellar repetitive TMS (rTMS) improved backward postural stability when 2 subjects with PSP-RS stood on a force plate (Neurocom), as evidenced by reduction of the backward center of pressure excursion (less sway in the posterior direction) (32). The authors also observed that the 10 sessions of cerebellar rTMS increased cerebellar-brain inhibition by 50% in subject 1 and by 32% in subject 2. The rTMS protocol was well tolerated. Cerebellar rTMS may improve postural stability, but larger future studies are needed. One such study is currently enrolling (NCT04468932).
A recent study of cerebellar TMS compared theta burst TMS with sham cerebellar, single session stimulation in a randomized order in 2 different sessions in 20 people with PSP (37). Before and after stimulation, static balance was evaluated with instrumented (lower back accelerometer) 30-s trials in semi-tandem and tandem positions. In tandem and semi-tandem tasks, active stimulation was associated with increase in time without falls. In addition, postural sway area, velocity, acceleration, and jerkiness was improved only after theta burst TMS, compared to sham stimulation. These preliminary data suggest that cerebellar theta burst TMS has significant effect on postural stability in people with PSP, when assessed with mobile digital technology. The authors suggest that these results should motivate larger and longer trials using non-invasive brain stimulation for people with PSP. Future powered, prospective and robust clinical trials are needed to investigate the effects of cerebellar TMS on outcomes of this population.
Conclusion
Objective measurement to quantify gait and balance and effects of rehabilitation on gait and balance in PSP is a rapidly growing field, with potential uses to classify of early parkinsonism, monitoring progression, and documenting effects of rehabilitation. A natural tension exists between lab-based, comprehensive 3D motion capture of gait and force plate measures of postural sway and wearable inertial sensors (57). The former yields laboratory, gold-standard data, but is impractical for clinical trials. Wearable sensors are currently being used in clinical trials of balance and gait and have the potential for home-based daily life monitoring of mobility (7–9).
In this narrative review we examined: (a) cross-sectional studies in PSP focused on quantifying step initiation and steady state gait and postural sway for standing balance that relate to disease progression and imaging features, and (b) the use of objective gait and balance metrics as endpoints for rehabilitation and brain stimulation intervention studies in PSP. This review suggests several potential practical applications: for example, abnormal anticipatory postural adjustments when initiating gait suggest medio-lateral tasks should be a focus in rehabilitation for PSP, not just backward postural instability, and body-worn sensors for longitudinal monitoring may detect relevant gait changes 3 months earlier than the PSP Rating Scale.
However, studies of objective measurement of gait and balance in PSP suffer from several limitations common to studies of rare diseases: small sample sizes, no pathological confirmation of diagnoses, lack of multi-center studies, lack of replication, lack of long-term follow-up, and unclear subtyping of PSP classification. A particular note of caution when interpreting PSP classification studies: it is important to consider what particular mix of PSP subtypes is being evaluated and if it is reasonable to lump such variants together for analysis. PSP-RS, PSP-P, and PSP-PGF are the most represented variants, and these variants can look rather different clinically. Little is known about any subtle gait or balance abnormalities that objective metrics may elucidate in other categories of PSP, such as possible PSP speech and language, possible PSP with predominant corticobasal syndrome, and other categories that are suggestive of early PSP. It is also important not to consider variant subtypes of PSP as static categories, but rather milestones along a progression to eventual development of probable PSP-RS.
Regarding rehabilitation interventions, due to small sample sizes, low statistical power and comparatively low methodological rigor (lack of a control group and case series) in the studies included in this review, the effectiveness of rehabilitation interventions on objective measures of gait and balance and clinical balance still needs to be confirmed. Although we still do not know the optimal content of exercise (dosage, frequency, intensity, time, and type) for people with PSP, the most of the studies included in this review have used gait training, balance training, and sensory feedback training of gait and balance. Thus, there is a need to understand if rehabilitation interventions may have positive impact in a large population with PSP in future randomized clinical trials.
Looking forward, longitudinal monitoring with objective gait and balance metrics from body-worn sensors should be incorporated into future clinical trials with PSP, complementing the PSPRS clinical scale that has traditionally been used as the primary endpoint. Studies of correlations between objective measures of gait and balance and imaging features in PSP are in early stages, but are likely to grow in the coming years. Exercise regimens in PSP are often modified from PD or stroke regimens, and development of rehabilitation targeted specifically to the balance and gait impairments in people with PSP are needed. Exercise and other intervention studies benefit from objective gait and balance endpoints, but need replication with multisite application and long-term follow-up.
Author contributions
MD conceived and designed the study. FA and CS-B collected and organized the data. MD and CS-B drafted the manuscript. FH critically revised the manuscript. All authors contributed to the article and approved the submitted version.
Funding
National Institute of Neurological Disorders and Stroke; 1K23NS121402-01A1 (MD).
Conflict of interest
FH is a part-time employee of Clario, that makes APDM Opals for clinical trials. This potential conflict has been managed by Oregon Health and Science University.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: progressive supranuclear palsy, balance, gait, objective measurements, rehabilitation
Citation: Dale ML, Silva-Batista C, de Almeida FO and Horak FB (2023) Balance and gait in progressive supranuclear palsy: a narrative review of objective metrics and exercise interventions. Front. Neurol. 14:1212185. doi: 10.3389/fneur.2023.1212185
Edited by:
Christopher D Stephen, Harvard Medical School, United StatesReviewed by:
Farwa Ali, Mayo Clinic, United StatesMaria Francesca De Pandis, Hospital San Raffaele Cassino, Italy
Nahid Olfati, University of California, San Diego, United States
Copyright © 2023 Dale, Silva-Batista, de Almeida and Horak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Marian L. Dale, ZGFsZW1Ab2hzdS5lZHU=