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Pre- and unplanned walking turns in Parkinson’s disease – Effects of dopaminergic medication
Neuroscience 341 (2017) 18–26
PRE- AND UNPLANNED WALKING TURNS IN PARKINSON’S DISEASE – EFFECTS OF DOPAMINERGIC MEDICATION DAVID CONRADSSON, a,b* CAROLINE PAQUETTE, c JOHAN LO¨KK d,e AND ERIKA FRANZE´N a,b
pattern. Specifically, subjects with PD turned with narrower cross-over steps, i.e. when the external foot crossed over the line of progression of the internal leg. We conclude that turning impairments remained even after dopaminergic medication and problems modulating step width appears to be a critical feature for turning in PD. Ó 2016 Published by Elsevier Ltd on behalf of IBRO.
a
Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Alfred Nobels Alle 23, 141 83 Huddinge, Sweden b Functional Area Occupational Therapy & Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden c Department of Kinesiology and Physical Education, McGill University, and Interdisciplinary Research Center in Rehabilitation (CRIR), 475 Pine Avenue West, Montreal, Quebec H2W 1S4, Canada
Keywords: Parkinson’s disease, levodopa, gait, turning.
d Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Novum Pl 5, Blickaga˚ngen 6/Ha¨lsova¨gen 7 14157 Huddinge, Sweden
INTRODUCTION For individuals with Parkinson’s disease (PD), turning impairments are common features of gait disturbance which is, for many, a trigger to freezing of gait, falls and declined level of societal participation (Stack and Ashburn, 1999; Bloem et al., 2001; Ashburn et al., 2008). Even if turning difficulties increase with disease progression, more than 50% of people in mild-tomoderate stages of PD report turning problems (Nieuwboer et al., 1998; Bloem et al., 2001). Turning in PD is characterized by impaired axial coordination (Crenna et al., 2007; Huxham et al., 2008b; Spildooren et al., 2013), excessive reduction of spatial gait parameters (Huxham et al., 2008a; Mak et al., 2008) and a greater number of steps required for turning (Stack and Ashburn, 2005, 2008; Crenna et al., 2007; Huxham et al., 2008b). Although the aforementioned studies provided a detailed description of turning impairments in PD, this knowledge predominantly reflects preplanned turns, where the walking direction is known in advance. However, the need to turn in response to a given stimuli, such as turning to circumvent an unexpected obstacle, is a common unpredictable condition occurring on a daily basis. Contrasting preplanned turns, unplanned turning limits the time for planning and execution of motor commands (Cao et al., 1997; Patla et al., 1999), which have shown to induce delayed turning onset and degraded performance in individuals with PD compared to controls (Mak et al., 2008). Dopaminergic medication has a dramatic clinical effect on motor impairments in PD (Connolly and Lang, 2014); however the effects of medication on balance and gait remain uncertain (Bohnen and Cham, 2006; Curtze et al., 2015). For instance, positive effects of medication on global measures of balance (Franzen et al., 2009; McNeely et al., 2012) and gait in individuals with PD is well documented (O’Sullivan et al., 1998; Shan
e
Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden
Abstract—Although dopaminergic medication improves functional mobility in individuals with Parkinson’s disease (PD), its effects on walking turns are uncertain. Our goals was to determine whether dopaminergic medication improves preplanned and unplanned walking turns in individuals with PD, compared to healthy controls. Nineteen older adults with mild-to-moderate PD and 17 healthy controls performed one of the following three tasks, presented randomly: walking straight, or walking and turning 180° to the right or left. The walking direction was visually cued before starting to walk (preplanned) or after (unplanned, i.e., 0.6 m before reaching the turning point). Subjects with PD were assessed off dopaminergic medication (OFF) and on dopaminergic medication (ON) medication. Turning strategy (step and spin turns), turning performance (turning distance and body rotation) and walking pattern were analyzed for three turning steps. Irrespective of medication state and turning condition, step and spin turns followed a nearly 50:50 distribution. After intake of dopaminergic medication, subjects with PD increased their turning distance but not the amount of body rotation or their walking pattern. Compared to controls, turning impairments in subjects with PD remained while ON medication and problems regulating step width were the most prominent features of their walking *Correspondence to: D. Conradsson, Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Alfred Nobels Alle 23, 141 83 Huddinge, Sweden E-mail addresses: [email protected] (D. Conradsson), [email protected] (C. Paquette), Johan.lokk@karolinska. se (J. Lo¨kk), [email protected] (E. Franze´n). Abbreviations: ANOVA, analysis of variance; C7, seventh cervical vertebrae; CI, confidence interval; ES, effect size; OFF, off dopaminergic medication; ON, on dopaminergic medication; PD, Parkinson’s disease; UPDRS, unified Parkinson’s disease rating scale; SD, standard deviation. http://dx.doi.org/10.1016/j.neuroscience.2016.11.016 0306-4522/Ó 2016 Published by Elsevier Ltd on behalf of IBRO. 18
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et al., 2001; Morris et al., 2005; McNeely et al., 2012; McNeely and Earhart, 2013; Curtze et al., 2015); but negative effects on postural adjustments (Horak et al., 1996; Hall et al., 2013) and postural sway have also been reported (Bronte-Stewart et al., 2002; Rocchi et al., 2002; Franzen et al., 2012; Curtze et al., 2015). Turning while walking is a complex task incorporating gait and balance skills, such as deceleration of the forward progression and maintenance of dynamic body stability while continuing the step cycle (Patla et al., 1991, 1999). Unfortunately, information about the effects of medication on walking turns in PD is limited to a few studies focusing on global performance measures (e.g. turning duration) only (Akram et al., 2013; Curtze et al., 2015). These studies revealed inconsistent results that vary from no improvement (Akram et al., 2013) to moderate improvements (Curtze et al., 2015). Consequently, little remains known about the effects of dopaminergic medication on walking turns (e.g. turning strategies, performance and regulation of the walking pattern) in individuals with PD. Thus, the overarching aim of this study was to determine whether dopaminergic medication improves pre- and unplanned turning in individuals with PD. Specifically, we sought to assess the effects of medication on turning initiation (i.e. turning strategy and onset), turning performance (i.e. body rotation, turning distance, trajectory and velocity) and the walking pattern (i.e. step length and width). We hypothesized that medication would improve turning performance for both turning conditions, with smaller effects expected for unplanned turns due to its reactive features requiring quick modification of the walking pattern (Cao et al., 1997; Mak et al., 2008).
EXPERIMENTAL PROCEDURES Subjects Nineteen individuals with a clinical diagnosis of idiopathic PD were recruited from a randomized controlled trial
(Conradsson et al., 2012). We also recruited 17 healthy individuals, matched for age and gender, as a control group (Table 1). The sample size of approximately 20 individuals with PD and controls, respectively, was based on a previous study assessing the effects of dopaminergic medication on turning (McNeely and Earhart, 2011). The inclusion criteria for both groups were: age 60 years; Mini Mental State Examination score of 24 (Folstein et al., 1975); no visual impairments; and no medical condition or recent injury affecting gait or balance. Specific inclusion criteria for PD participants were: currently being treated with stable oral levodopa therapy; Hoehn and Yahr stage 2–3; ability to walk indoors without assistance or a walking aid; and no prior brain surgery, severe dyskinesia or freezing of gait. There were no significant differences for any characteristics between the PD group and the controls (see Table 1). This study was approved by the Regional Board of Ethics in Stockholm, and all participants provided written informed consent prior to their enrollment in the study.
Procedures and setup The PD group was assessed twice, first after overnight withdrawal of medication (OFF, average off time = 16 h, range: 12–22 h) and then approximately one hour after taking their usual morning dose of dopaminergic medication (ON). Both test sessions were performed on the same day, since assessments over two days were not possible for many of the participants. One trained physical therapist assessed motor impairments of all participants before each test session (OFF and ON) by means of the motor section of the unified Parkinson’s disease rating scale (UPDRS). The control group also underwent a protocol covering two sessions. In the first session, controls performed the task at comfortable walking velocity. The same protocol was then repeated (2nd session) with controls walking at a pace that matched the comfortable pace of the subjects with PD.
Table 1. Participant characteristics
Age (y) Gender, males/females Body weight (kg) Body height (cm) Disease duration (y) Levodopa dose equivalencya
UPDRS motor PIGDb,*
*
Straight walking Velocity (m/s) *y Step length (m) *y Step width (m)
Parkinson’s disease (n = 19)
Control (n = 17)
72 (4) 12/7 74.7 (10.7) 172.9 (6.4) 5.2 (4.2) 636 (228)
72 (5) 10/7 76.1 (8.8) 175.8 (8.8) – –
OFF
ON
44.8 (7.2) 3.8 (1.5)
35.0 (7.5) 3.0 (1.4)
– –
1.17 (0.18) 0.60 (0.07) 0.08 (0.03)
1.24 (0.14) 0.63 (0.08) 0.08 (0.03)
1.46 (0.15) 0.76 (0.06) 0.08 (0.02)
Values are mean (standard deviation) for all variables except gender that was presented as proportion. UPDRS, unified Parkinson’s disease rating scale; PIGD, Postural Instability and Gait Difficulty. a Daily levodopa dose equivalency calculated in accordance with Tomlinson et al. (2010). b The PIGD score is a four-item sub-score (arising from a chair, standing posture, gait and postural stability) calculated from the UPDRS motor assessment. * Significant differences (p 6 0.025) between the OFF and ON medicated states (Wilcoxon signed-rank test). y Significant differences (p 6 0.025) between the PD ON and the control group (Mann–Whitney U test).
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For most control subjects, the matched velocity was achieved by instructing controls to walk slower than their comfortable speed. To achieve a matched turning speed, walking speed was assessed with a handheld stopwatch and by counting the number of steps over a distance of two meters prior to the turn. In cases where control subjects deviated from the targeted speed, they were instructed to change their walking speed (i.e. to walk faster or slower). Subsequently, trials from the control group were included if their walking velocity (prior to the intersection positon) was within one
standard deviation (SD) of the mean velocity of the PD ON. By using this approach turning characteristics could be compared between PD and the control group without potential velocity bias (Akram et al., 2010; Spildooren et al., 2013). Before the start of data collection, practice sessions were performed to familiarize participants with the procedure. The PD and control groups performed two different turning conditions (preplanned and unplanned) in a randomized order. For both turning conditions, participants walked at their comfortable velocity along a 9-meter walking lane where the turning position was indicated by two poles (see circles in Fig. 1A). For both preplanned and unplanned turns, one of the following three tasks was performed in a randomized order: walking straight, or walking and turning 180° to the right or to the left. Subjects were instructed to walk and turn to the indicated direction without stopping, taking the closest path to the target (see squares in Fig 1A). Subjects started each trial 4.65 m from the turning intersection, which provided sufficient distance to reach a steady-state straight walking velocity before initiating the turn (Lindemann et al., 2008). For the preplanned condition, the walking direction was provided by a visual signal before they started to walk whereas for the unplanned condition, the same visual signal returned approximately one step length (0.6 m) prior to the intersection point (i.e. during steady-state walking). The pre- and unplanned turning condition each contained a total of 15 trials per subject (i.e. five trials – in randomized order – for straight walking, right and left turning). The participants were allowed to rest when needed during testing.
Measurements An eight-camera motion analysis system (Elite 2002, version 2.8.4380; BTS, Milano, Italy) was used to record at 100 Hz the position of 11 spherical retro-reflective markers located on the spinous process of the seventh cervical vertebrae (C7) and bilaterally on the head, acromion, posterior superior iliac spine and heel. Two markers were also positioned on the two poles forming the intersection (see Fig. 1A). Three-dimensional trajectories of the markers were reconstructed using a tracking system (Tracklab-BTS, Milan, Italy) (Fig. 1A). Data were processed and filtered (Butterworth low-pass filter: 7-Hz cut-off frequency) using MATLAB software (MATLAB, 7.4.0, MathWorks, Natick, MA, USA).
Fig. 1. (A) Schematic drawing of the walking alley. The walking direction (straight, right or left) was indicated with a visual signal before walking initiation during preplanned turns and 0.6 m prior to the intersection point during unplanned turns. For the three dimensional motion analysis, reflective markers were attached to 11 anatomical landmarks to represent the segments of head, trunk, pelvis and feet. (B) Gray foot prints indicate the two pre-turning steps and black foot prints represent footstep adjustments for the three turning steps during a step turn (i.e. first turning step equal the turning direction) and a spin turn (i.e. first turning step opposite to the turning direction). The first turning step was identified as the first heel strike that exceeded two standard deviations in medio-lateral displacement of straight walking (i.e. gray area in figure). (C) Calculation of step width and step length for a right stride.
Data analysis The outcome variables retained for analysis focused on turning initiation (i.e. turning strategy and onset), turning performance (i.e. body rotation, turning distance, trajectory and velocity) and spatial gait parameters (i.e. step length and width). We focused our analysis on the first three turning steps since about 75% of the subjects with PD reached an 80–120° turn over the first three steps. This turning magnitude is common in daily life activities (Mancini et al., 2015) and is challenging for PD (Huxham et al., 2008a).
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0.169 <0.001* <0.001* 0.763* 0.726* Values are mean values (95% confidence interval). PD, Parkinson’s disease; ES, effect size; CON; control. a Positive effect sizes denote changes that are considered improvement (i.e. toward the control group). * Significant main effect for turning condition.
Group Medication
0.212 0.099* 0.003* 0.931* 0.594* 48 (41–55) 113 (108–118) 1.74 (1.67–1.82) 0.72 (0.67–0.78) 0.22 (0.20–0.25)
CON ES
0.46 0.33 0.70 0.17 0.17 54 (47–61) 103 (97–109) 1.46 (1.36–1.55) 0.74 (0.69–0.81) 0.19 (0.17–0.22)
PD ON PD OFF
47 (40–54) 100 (94–107) 1.39 (1.29–1.49) 0.72 (0.67–0.77) 0.18 (0.16–0.20) 47 (39–54) 99 (92–105) 1.82 (1.74–1.89) 0.60 (0.56–0.63) 0.45 (0.40–0.49)
CON ES
0.09 0.30 0.75 0.29 0.08 50 (41–59) 80 (72–88) 1.55 (1.46–1.63) 0.59 (0.55–0.64) 0.47 (0.43–0.50)
PD ON PD OFF
48 (39–57) 77 (68–86) 1.47 (1.37–1.57) 0.61 (0.57–0.66) 0.46 (0.40–0.52) Step turns (%) Body rotation (°) Distance (m) Trajectory (m) Velocity (m/s)
a
Unplanned turning
a
Preplanned turning
All statistical analyses were performed using the STATISTICA software (Statsoft, version 12, Tulsa, OK). Responsiveness of turning performance (body rotation, turning distance, trajectory and velocity) to dopaminergic medication was expressed as Cohen’s d effect sizes (ES) (Cohen, 1988). Positive ES denote changes that are considered an improvement (i.e. toward the control group). A two-way repeated measures analysis of vari-
Variable
Statistical analysis
Table 2. Preplanned and unplanned turning in PD OFF and ON and controls
The turning steps were identified as the first heel strike exceeding two SD in medio-lateral displacement of five straight walking trials (computed for each participant) in the designated turning direction (see Fig. 1B) (Akram et al., 2010). Heel strike events were determined based on the velocity profiles of the heel markers (verticalaxis). Similar to Akram et al. (2010) capturing of the first heel strike event for the right and left foot (i.e. three to four steps prior to the intersection point for most subjects) was used as baseline in determining the onset of the first turning step. To discriminate between preparatory turning steps and the actual turning step, the succeeding turning step also needed to exceed 2 SD from the straight walking trial average. As shown by Hase and Stein (1999), we observed two distinct stepping strategies during turning. As illustrated in Fig. 1B, a turn was defined as a step turn if the first turning step was performed in the direction of turning or as a spin turn if the first turning step was in the opposite direction of turning. The proportion of turning trials using the step strategy was used as an outcome measure. Turning onset latency was calculated relative to the intersection point (i.e. time when the trunk [C7 marker] crossed the intersection point). Therefore, negative onsets for this outcome measure indicates that turning was initiated before reaching the intersection point while positive values reflect turns initiated after passing the intersection. The magnitude of pelvis rotation at the third turning step was retained for analysis. For the first three turning steps, the turning distance (i.e. the cumulative linear displacements of the C7 marker in the horizontal plane), mean turning velocity (i.e. the first derivative of the tangential displacement of the C7 marker) and mean turning trajectory (i.e. distance in meters between C7 and the markers positioned at the turning pole) were calculated. In accordance with Huxham et al. (2006) the step width and length were calculated by assessing the spatial position of the heel marker at each heel strikes. Step width was calculated in relation to the line of progression for each stride (corresponding to a straight line connecting the heel marker between each heel strike) and measured as the distance between the opposite foot and the perpendicular line from the line of progression (see Fig. 1C). Therefore, a negative step width was obtained when the heel strike of the external foot (e.g. right foot during a turn to the left) crossed over and landed medial to the line of progression of the internal leg. As step length during straight walking was shorter for subjects with PD compared to controls (P = 0.012), the step length during turning trials were normalized by subtracting the mean step length of the straight walking trials.
Main Effects (P)
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ance (ANOVA) was used to evaluate the effects of medication (PD OFF and PD ON) and turning condition (preplanned and unplanned) on turning initiation (turning strategy and onset) and turning performance. A two-way ANOVA was also used to evaluate the difference between groups (PD ON and controls) and turning condition (preplanned and unplanned). No differences were found between turns to the right or left or turning strategy (spin or step turn) for turning onset and performance. Hoehn and Yahr stages (2–3) were also similar in these outcomes. Thus, Fig. 2. Mean turning onsets (seconds) during pre- and unplanned turning for PD-OFF, PD-ON and these trials/stages were collapsed control group. Negative and positive onset values indicate that turning was initiated before and crossing the intersection, respectively. Error bars represent 95% confidence interval. together for further analysis. Further- after * p 6 0.025. more, as the amplitude of step width and length was differently regulated for step and spin turns, both step occurred earlier for PD ON (0.16 sec), in contrast to length and width were analyzed separately for turning control subjects in the preplanned condition strategies (step and spin turns) and turning conditions (group condition: P < 0.001); however, no difference in (preplanned and unplanned). A two-way repeated meaonset between groups for the unplanned turns was found. sures ANOVA was used to evaluate the effects of medication (PD OFF and PD ON) and steps (turning step 1, 2 & Turning performance 3) on step width and length. A two-way ANOVA was used to evaluate the difference between groups (PD ON and In both PD and controls, mean turning velocity was at controls) and steps (turning step 1, 2 & 3). The Greenleast twice as high during preplanned turns (0.45– house–Geisser correction was applied in the event of vio0.47 m/s), compared to unplanned turns (0.18–0.22 m/s) lations of sphericity and Tukey’s HSD test whenever a (P < 0.001, Table 2). In contrast, the slower unplanned significant interaction effect occurred. Corrections for multurns led to a larger degree of body rotation at the third tiple statistical testing were not used due to the light of turning step (100–113°) compared to preplanned turns criticism of such corrections (e.g. Bonferroni) to minimize (77–99°) (P < 0.001, Table 2). the incidence of false negative when examining hypotheMedication increased turning distance by 5% for preses (Perneger, 1998). Instead, the significance level was and unplanned turns (p = 0.003), still controls set at p 6 0.025. Data are presented as mean and 95% demonstrated 17–19% greater turning distance confidence intervals (95% CI). compared to PD ON (P < 0.001, Table 2). Medication did not have any effect on body rotation (P = 0.099), and controls obtained 10–24% higher body rotation RESULTS compared with PD ON (group: P < 0.001). There were ON medication, participants with PD improved 22% in no effects of medication or differences between PD ON their UPDRS motor score and 21% in their Postural and controls on turning trajectory and velocity Instability and Gait Difficulty score as compared to OFF (P > 0.559). The effects of medication or group (PD ON medication (Table 1, P < 0.010). As illustrated in table and controls) were independent of the type of turn 1, the mean straight walking velocity improved by performed (medication/group turning condition: 0.07 m/s after medication intake along with a 0.03 m P > 0.132). increase in step length (Table 1, P < 0.010). Still, individuals with PD ON medication walked slower with Regulation of step width shorter steps as compared to controls (P < 0.001). For PDs and controls, a general pattern of alternating step width amplitude was observed, i.e. widening – crossingTurning initiation over – widening the base of support for step turns and crossing-over – widening – crossing-over the base of Overall, we found a nearly 50:50 distribution between step support for spin turns (Fig. 3A, B). and spins during both pre- and unplanned conditions When using the step strategy during pre- and (Table 2). The strategies used for turning did not change unplanned turns, significant interaction effects were with medication (PD OFF vs. ON) and were similar found for step width (medication step interaction: between PD ON and controls. Preplanned turns were P = 0.024 and P = 0.003, respectively), still post-hoc initiated prior to the intersection while unplanned turns testing did not reveal any significant differences were initiated after crossing the intersection point (Fig. 2). between PD OFF and ON. There were no effects of Whether OFF or ON medication, subjects with PD initiated their turns with similar latency. Turning onset medication on step width for the spin strategy.
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Regulation of step length As illustrated in Fig. 4A, B, both PDs and controls consistently reduced their step length in all conditions during turning, compared to straight walking. Irrespective of medication state, subjects with PD demonstrated a similar reduction of step length while performing step and spin turns. Compared to controls however, PD ON further reduced their step length by 33–36% using step turns during the pre- (group: P = 0.006) and unplanned condition (group: P = 0.019, Fig. 4A). PD ON also demonstrated 33% higher step length reduction for the second turning step during the unplanned condition while using spin turns compared to controls (group step interaction: P = 0.004, Fig. 3B). There were no group differences for step length reduction using spin turns during the preplanned condition.
DISCUSSION This is the first study to evaluate the effects of dopaminergic medication on pre- and unplanned turns while walking in individuals with PD. After intake of dopaminergic medication, subjects with PD increased the turning distance but not the amount of body rotation. Regardless, dopaminergic medication did not Fig. 3. Step width (meter) of three turning steps for PD-OFF, PD-ON and control group while improve turning performance of using (A) step and (B) spin turns during the pre- and unplanned condition. Positive values reflect widening of the base of support whereas negative values reflect crossing-over of the base of individuals with PD to the level of the support (i.e. when the external foot crossed over and landed medial compared to the line of control group. These residual turning * progression of the internal foot). Error bars represent 95% confidence interval. p 6 0.025; impairments were accompanied by ** p 6 0.01. narrower, cross-over steps during turning, which should be considered and addressed during rehabilitation and in fall prevention programs of During step turns control subjects crossed their individuals with PD. external foot further away from the line of progression of Consistent with previous studies (McNeely and the internal foot compared to PD ON (group step Earhart, 2011; Curtze et al., 2015), turning performance interaction: P < 0.001). Specifically, for the second while on medication did not reach that of the control group. turning step using step turns, the step width of controls Our results indicate that these persisting impairments are was 0.07 m (48–82%) greater (i.e. increased negative related to poor effects of medication on step width and step width) compared to PD ON for both turning length. Furthermore, problems regulating step width, not conditions (preplanned: P = 0.016, unplanned: step length as previously been emphasized in PD P = 0.006). For spin turns, the comparison between PD (Hulbert et al., 2014), were the most prominent differences ON and controls revealed a different result for pre- and between PD and controls in their walking pattern. In particunplanned turns. For the unplanned condition, PD ON ular, individuals with PD turned with narrower steps while did not cross-over as much as controls (group step using a crossing step (i.e. step width closer to a value of interaction: P < 0.001), which was evident in the 0.07– zero). Crossing steps while turning is not only a complex 0.08 m (67%) greater negative step width in controls for motor task that could induce instability due to the drastic the first (P = 0.001) and third turning step (P < 0.001). change of the base of support, but is also an important conIn contrast, there were no group differences for the tributor to body rotation (Huxham et al., 2008a). Consepreplanned condition. quently, problems modulating step width in PD
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medication for the linear component compared to the angular component of turning. Although previous findings reporting similar effects of dopaminergic medication on the performance of turning-in-place (Franzen et al., 2009; McNeely and Earhart, 2011) and walking turns in individuals with PD (Curtze et al., 2015), the divergent effect of medication on linear and angular components of walking is a novel finding. Increased functional connectivity between cortical and sub-cortical brain areas has been demonstrated during turning compared to straight walking in PD (Gilat et al., 2015). Our current findings imply that the linear and angular component of locomotion likely involve distinct brain networks with potential varying sensitivity to dopaminergic medication. This notion is also supported by a recent study of Curtze et al. (2015) reporting smaller effects of dopaminergic medication on walking turns (ES = 0.20–0.50) compared to straight walking (ES > 0.50). In contradiction to our hypothesis, the effects of medication on turning performance were not influenced by the availability of time for planning the turn (i.e. pre- vs. unplanned condition). Less effects of medication were expected for the unplanned turns because of their more reactive nature requiring quick modification of the walking pattern (Cao et al., Fig. 4. Mean normalized step length for three turning steps using (A) step and (B) spin turns 1997), which adds stress to impaired during the pre- and unplanned condition for PD-OFF, PD-ON and control group. Step length data executive functioning in PD (i.e. rapid represent the absolute difference between straight walking and turning, i.e. negative values reflect information processing to regulate the shorter steps length while turning compared to straight walking. Error bars represent 95% confidence interval. motor commands) (Dirnberger and Jahanshahi, 2013). Impaired executive functioning has shown to be inefcompromise medio-lateral stability (Horak et al., 2005; King fectively treated with dopaminergic and Horak, 2008) and force production necessary to accelmedication in individuals with PD (Michely et al., 2012). erate the center of mass toward the turn direction (Mak On the other hand, the unplanned turn was triggered et al., 2008). In line with our findings, narrower step width and guided by a visual cue, which by itself could have in PD has been observed during postural reactions facilitated turning as previously reported for other tasks (Horak et al., 2005; King and Horak, 2008) and walking (Mak and Hui-Chan, 2005; Nieuwboer et al., 2009). turns (Huxham et al., 2008a; Mak et al., 2008). It is likely We aimed to capture realistic turning behavior without that problems modulating step width restrict the perforspatial restrictions and found a nearly 50:50 distribution mance of turning, as seen in our data, and lead to instability between step and spin turns. This finding is in contrast and falls in individuals with PD during everyday living. As to previous studies of healthy adults in that spin turns previously suggested by King and Horak (2008), this findwere more common during preplanned turns (Akram ing highlights the importance of targeting medio-lateral staet al., 2010), while step turns have shown to be more bility during rehabilitation sessions in individuals with PD. common during challenging turns (e.g. unplanned turns) Walking turns involve an interaction between the (Patla et al., 1991; Akram et al., 2010). Instead, the linear component (i.e. forward progression of the body) overall mixed pRef. between step and spin turns found and the angular component (i.e. rotation in relation to in the present study could represent a sustained flexible the longitudinal axis) (Goodworth et al., 2012). Our results repertoire of movement strategies. Furthermore, turning showed better responsiveness to dopaminergic was initiated in a similar manner whether OFF or ON
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medication; however, the control group initiated their turn 64% later during preplanned turns compared to PD ON. This finding may be a compensatory strategy adopted by individuals with PD in accounting for the poor responsiveness of dopaminergic medication to turning we observed, or because of balance impairments or difficulties with modifying an ongoing motor command (Chong et al., 2000; Mak et al., 2008). This study aimed to determine whether dopaminergic medication improves turning in individuals with mild-tomoderate PD who do not present with freezing of gait. Therefore, these results can only be generalized to this specific population. Still, as turning is an important factor in triggering freezing of gait episodes, future studies should investigate the effects of medication on turning in individuals who report freezing of gait. All subjects with PD were tested on the same day and in a fixed order (OFF first), which may have led to an underestimation of the medication effect (e.g. fatigue) or to an overestimation induced by a practice effect from repeated testing. Thus, to address the potential risk of fatigue and a practice effect, brief resting sessions were allowed during testing and practice sessions were performed prior to testing, respectively. Further – contradicting a practice effect – turning performance did not systematically improve across the number of trials in PD OFF and ON (data not reported). Furthermore, while all subjects with PD were confirmed responders to dopaminergic medication (indicated by improved UPDRS-motor, PIGD score and straight line walking), the level of responsiveness to medication was not an inclusion criterion, as in other studies (McNeely and Earhart, 2011; McNeely et al., 2012). This may limit the generalization and interpretation of these results. Finally, in contrast to several previous studies of turning in PD (Mak et al., 2008; Akram et al., 2013; Curtze et al., 2015), the controls’ walking velocity was matched to that of the PD subjects. Thus, the differences we observed in turning with PD are attributed to the disease itself rather than walking speed.
CONCLUSIONS Dopaminergic medication appears to increase turning distance but not the amount of body rotation irrespective of performing preplanned or unplanned walking turns. Turning impairments in individuals with PD on dopaminergic medication did not reach the performance of the control group. These residual turning impairments in individuals with PD were accompanied by narrower cross-over steps during turning. These narrower steps reduce stability and are therefore considered as important targets of rehabilitation in individuals with PD. Acknowledgments—The authors would like to thank all the participants who contributed to this work. The authors acknowledge Niklas Lo¨fgren and Ha˚kan Nero for their support with data collection. This work was supported by the Swedish Research Council, the Swedish Parkinson Foundation, the Karolinska Institutet, the Loo and Hans Ostermans Foundation, the Gun and Bertil Stohnes Foundation, the Swedish NEURO Foundation and the Natural Sciences and Engineering Research Council of Canada.
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(Accepted 10 November 2016) (Available online 17 November 2016)
PRE- AND UNPLANNED WALKING TURNS IN PARKINSON’S DISEASE – EFFECTS OF DOPAMINERGIC MEDICATION DAVID CONRADSSON, a,b* CAROLINE PAQUETTE, c JOHAN LO¨KK d,e AND ERIKA FRANZE´N a,b
pattern. Specifically, subjects with PD turned with narrower cross-over steps, i.e. when the external foot crossed over the line of progression of the internal leg. We conclude that turning impairments remained even after dopaminergic medication and problems modulating step width appears to be a critical feature for turning in PD. Ó 2016 Published by Elsevier Ltd on behalf of IBRO.
a
Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Alfred Nobels Alle 23, 141 83 Huddinge, Sweden b Functional Area Occupational Therapy & Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden c Department of Kinesiology and Physical Education, McGill University, and Interdisciplinary Research Center in Rehabilitation (CRIR), 475 Pine Avenue West, Montreal, Quebec H2W 1S4, Canada
Keywords: Parkinson’s disease, levodopa, gait, turning.
d Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Novum Pl 5, Blickaga˚ngen 6/Ha¨lsova¨gen 7 14157 Huddinge, Sweden
INTRODUCTION For individuals with Parkinson’s disease (PD), turning impairments are common features of gait disturbance which is, for many, a trigger to freezing of gait, falls and declined level of societal participation (Stack and Ashburn, 1999; Bloem et al., 2001; Ashburn et al., 2008). Even if turning difficulties increase with disease progression, more than 50% of people in mild-tomoderate stages of PD report turning problems (Nieuwboer et al., 1998; Bloem et al., 2001). Turning in PD is characterized by impaired axial coordination (Crenna et al., 2007; Huxham et al., 2008b; Spildooren et al., 2013), excessive reduction of spatial gait parameters (Huxham et al., 2008a; Mak et al., 2008) and a greater number of steps required for turning (Stack and Ashburn, 2005, 2008; Crenna et al., 2007; Huxham et al., 2008b). Although the aforementioned studies provided a detailed description of turning impairments in PD, this knowledge predominantly reflects preplanned turns, where the walking direction is known in advance. However, the need to turn in response to a given stimuli, such as turning to circumvent an unexpected obstacle, is a common unpredictable condition occurring on a daily basis. Contrasting preplanned turns, unplanned turning limits the time for planning and execution of motor commands (Cao et al., 1997; Patla et al., 1999), which have shown to induce delayed turning onset and degraded performance in individuals with PD compared to controls (Mak et al., 2008). Dopaminergic medication has a dramatic clinical effect on motor impairments in PD (Connolly and Lang, 2014); however the effects of medication on balance and gait remain uncertain (Bohnen and Cham, 2006; Curtze et al., 2015). For instance, positive effects of medication on global measures of balance (Franzen et al., 2009; McNeely et al., 2012) and gait in individuals with PD is well documented (O’Sullivan et al., 1998; Shan
e
Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden
Abstract—Although dopaminergic medication improves functional mobility in individuals with Parkinson’s disease (PD), its effects on walking turns are uncertain. Our goals was to determine whether dopaminergic medication improves preplanned and unplanned walking turns in individuals with PD, compared to healthy controls. Nineteen older adults with mild-to-moderate PD and 17 healthy controls performed one of the following three tasks, presented randomly: walking straight, or walking and turning 180° to the right or left. The walking direction was visually cued before starting to walk (preplanned) or after (unplanned, i.e., 0.6 m before reaching the turning point). Subjects with PD were assessed off dopaminergic medication (OFF) and on dopaminergic medication (ON) medication. Turning strategy (step and spin turns), turning performance (turning distance and body rotation) and walking pattern were analyzed for three turning steps. Irrespective of medication state and turning condition, step and spin turns followed a nearly 50:50 distribution. After intake of dopaminergic medication, subjects with PD increased their turning distance but not the amount of body rotation or their walking pattern. Compared to controls, turning impairments in subjects with PD remained while ON medication and problems regulating step width were the most prominent features of their walking *Correspondence to: D. Conradsson, Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Alfred Nobels Alle 23, 141 83 Huddinge, Sweden E-mail addresses: [email protected] (D. Conradsson), [email protected] (C. Paquette), Johan.lokk@karolinska. se (J. Lo¨kk), [email protected] (E. Franze´n). Abbreviations: ANOVA, analysis of variance; C7, seventh cervical vertebrae; CI, confidence interval; ES, effect size; OFF, off dopaminergic medication; ON, on dopaminergic medication; PD, Parkinson’s disease; UPDRS, unified Parkinson’s disease rating scale; SD, standard deviation. http://dx.doi.org/10.1016/j.neuroscience.2016.11.016 0306-4522/Ó 2016 Published by Elsevier Ltd on behalf of IBRO. 18
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et al., 2001; Morris et al., 2005; McNeely et al., 2012; McNeely and Earhart, 2013; Curtze et al., 2015); but negative effects on postural adjustments (Horak et al., 1996; Hall et al., 2013) and postural sway have also been reported (Bronte-Stewart et al., 2002; Rocchi et al., 2002; Franzen et al., 2012; Curtze et al., 2015). Turning while walking is a complex task incorporating gait and balance skills, such as deceleration of the forward progression and maintenance of dynamic body stability while continuing the step cycle (Patla et al., 1991, 1999). Unfortunately, information about the effects of medication on walking turns in PD is limited to a few studies focusing on global performance measures (e.g. turning duration) only (Akram et al., 2013; Curtze et al., 2015). These studies revealed inconsistent results that vary from no improvement (Akram et al., 2013) to moderate improvements (Curtze et al., 2015). Consequently, little remains known about the effects of dopaminergic medication on walking turns (e.g. turning strategies, performance and regulation of the walking pattern) in individuals with PD. Thus, the overarching aim of this study was to determine whether dopaminergic medication improves pre- and unplanned turning in individuals with PD. Specifically, we sought to assess the effects of medication on turning initiation (i.e. turning strategy and onset), turning performance (i.e. body rotation, turning distance, trajectory and velocity) and the walking pattern (i.e. step length and width). We hypothesized that medication would improve turning performance for both turning conditions, with smaller effects expected for unplanned turns due to its reactive features requiring quick modification of the walking pattern (Cao et al., 1997; Mak et al., 2008).
EXPERIMENTAL PROCEDURES Subjects Nineteen individuals with a clinical diagnosis of idiopathic PD were recruited from a randomized controlled trial
(Conradsson et al., 2012). We also recruited 17 healthy individuals, matched for age and gender, as a control group (Table 1). The sample size of approximately 20 individuals with PD and controls, respectively, was based on a previous study assessing the effects of dopaminergic medication on turning (McNeely and Earhart, 2011). The inclusion criteria for both groups were: age 60 years; Mini Mental State Examination score of 24 (Folstein et al., 1975); no visual impairments; and no medical condition or recent injury affecting gait or balance. Specific inclusion criteria for PD participants were: currently being treated with stable oral levodopa therapy; Hoehn and Yahr stage 2–3; ability to walk indoors without assistance or a walking aid; and no prior brain surgery, severe dyskinesia or freezing of gait. There were no significant differences for any characteristics between the PD group and the controls (see Table 1). This study was approved by the Regional Board of Ethics in Stockholm, and all participants provided written informed consent prior to their enrollment in the study.
Procedures and setup The PD group was assessed twice, first after overnight withdrawal of medication (OFF, average off time = 16 h, range: 12–22 h) and then approximately one hour after taking their usual morning dose of dopaminergic medication (ON). Both test sessions were performed on the same day, since assessments over two days were not possible for many of the participants. One trained physical therapist assessed motor impairments of all participants before each test session (OFF and ON) by means of the motor section of the unified Parkinson’s disease rating scale (UPDRS). The control group also underwent a protocol covering two sessions. In the first session, controls performed the task at comfortable walking velocity. The same protocol was then repeated (2nd session) with controls walking at a pace that matched the comfortable pace of the subjects with PD.
Table 1. Participant characteristics
Age (y) Gender, males/females Body weight (kg) Body height (cm) Disease duration (y) Levodopa dose equivalencya
UPDRS motor PIGDb,*
*
Straight walking Velocity (m/s) *y Step length (m) *y Step width (m)
Parkinson’s disease (n = 19)
Control (n = 17)
72 (4) 12/7 74.7 (10.7) 172.9 (6.4) 5.2 (4.2) 636 (228)
72 (5) 10/7 76.1 (8.8) 175.8 (8.8) – –
OFF
ON
44.8 (7.2) 3.8 (1.5)
35.0 (7.5) 3.0 (1.4)
– –
1.17 (0.18) 0.60 (0.07) 0.08 (0.03)
1.24 (0.14) 0.63 (0.08) 0.08 (0.03)
1.46 (0.15) 0.76 (0.06) 0.08 (0.02)
Values are mean (standard deviation) for all variables except gender that was presented as proportion. UPDRS, unified Parkinson’s disease rating scale; PIGD, Postural Instability and Gait Difficulty. a Daily levodopa dose equivalency calculated in accordance with Tomlinson et al. (2010). b The PIGD score is a four-item sub-score (arising from a chair, standing posture, gait and postural stability) calculated from the UPDRS motor assessment. * Significant differences (p 6 0.025) between the OFF and ON medicated states (Wilcoxon signed-rank test). y Significant differences (p 6 0.025) between the PD ON and the control group (Mann–Whitney U test).
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For most control subjects, the matched velocity was achieved by instructing controls to walk slower than their comfortable speed. To achieve a matched turning speed, walking speed was assessed with a handheld stopwatch and by counting the number of steps over a distance of two meters prior to the turn. In cases where control subjects deviated from the targeted speed, they were instructed to change their walking speed (i.e. to walk faster or slower). Subsequently, trials from the control group were included if their walking velocity (prior to the intersection positon) was within one
standard deviation (SD) of the mean velocity of the PD ON. By using this approach turning characteristics could be compared between PD and the control group without potential velocity bias (Akram et al., 2010; Spildooren et al., 2013). Before the start of data collection, practice sessions were performed to familiarize participants with the procedure. The PD and control groups performed two different turning conditions (preplanned and unplanned) in a randomized order. For both turning conditions, participants walked at their comfortable velocity along a 9-meter walking lane where the turning position was indicated by two poles (see circles in Fig. 1A). For both preplanned and unplanned turns, one of the following three tasks was performed in a randomized order: walking straight, or walking and turning 180° to the right or to the left. Subjects were instructed to walk and turn to the indicated direction without stopping, taking the closest path to the target (see squares in Fig 1A). Subjects started each trial 4.65 m from the turning intersection, which provided sufficient distance to reach a steady-state straight walking velocity before initiating the turn (Lindemann et al., 2008). For the preplanned condition, the walking direction was provided by a visual signal before they started to walk whereas for the unplanned condition, the same visual signal returned approximately one step length (0.6 m) prior to the intersection point (i.e. during steady-state walking). The pre- and unplanned turning condition each contained a total of 15 trials per subject (i.e. five trials – in randomized order – for straight walking, right and left turning). The participants were allowed to rest when needed during testing.
Measurements An eight-camera motion analysis system (Elite 2002, version 2.8.4380; BTS, Milano, Italy) was used to record at 100 Hz the position of 11 spherical retro-reflective markers located on the spinous process of the seventh cervical vertebrae (C7) and bilaterally on the head, acromion, posterior superior iliac spine and heel. Two markers were also positioned on the two poles forming the intersection (see Fig. 1A). Three-dimensional trajectories of the markers were reconstructed using a tracking system (Tracklab-BTS, Milan, Italy) (Fig. 1A). Data were processed and filtered (Butterworth low-pass filter: 7-Hz cut-off frequency) using MATLAB software (MATLAB, 7.4.0, MathWorks, Natick, MA, USA).
Fig. 1. (A) Schematic drawing of the walking alley. The walking direction (straight, right or left) was indicated with a visual signal before walking initiation during preplanned turns and 0.6 m prior to the intersection point during unplanned turns. For the three dimensional motion analysis, reflective markers were attached to 11 anatomical landmarks to represent the segments of head, trunk, pelvis and feet. (B) Gray foot prints indicate the two pre-turning steps and black foot prints represent footstep adjustments for the three turning steps during a step turn (i.e. first turning step equal the turning direction) and a spin turn (i.e. first turning step opposite to the turning direction). The first turning step was identified as the first heel strike that exceeded two standard deviations in medio-lateral displacement of straight walking (i.e. gray area in figure). (C) Calculation of step width and step length for a right stride.
Data analysis The outcome variables retained for analysis focused on turning initiation (i.e. turning strategy and onset), turning performance (i.e. body rotation, turning distance, trajectory and velocity) and spatial gait parameters (i.e. step length and width). We focused our analysis on the first three turning steps since about 75% of the subjects with PD reached an 80–120° turn over the first three steps. This turning magnitude is common in daily life activities (Mancini et al., 2015) and is challenging for PD (Huxham et al., 2008a).
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0.169 <0.001* <0.001* 0.763* 0.726* Values are mean values (95% confidence interval). PD, Parkinson’s disease; ES, effect size; CON; control. a Positive effect sizes denote changes that are considered improvement (i.e. toward the control group). * Significant main effect for turning condition.
Group Medication
0.212 0.099* 0.003* 0.931* 0.594* 48 (41–55) 113 (108–118) 1.74 (1.67–1.82) 0.72 (0.67–0.78) 0.22 (0.20–0.25)
CON ES
0.46 0.33 0.70 0.17 0.17 54 (47–61) 103 (97–109) 1.46 (1.36–1.55) 0.74 (0.69–0.81) 0.19 (0.17–0.22)
PD ON PD OFF
47 (40–54) 100 (94–107) 1.39 (1.29–1.49) 0.72 (0.67–0.77) 0.18 (0.16–0.20) 47 (39–54) 99 (92–105) 1.82 (1.74–1.89) 0.60 (0.56–0.63) 0.45 (0.40–0.49)
CON ES
0.09 0.30 0.75 0.29 0.08 50 (41–59) 80 (72–88) 1.55 (1.46–1.63) 0.59 (0.55–0.64) 0.47 (0.43–0.50)
PD ON PD OFF
48 (39–57) 77 (68–86) 1.47 (1.37–1.57) 0.61 (0.57–0.66) 0.46 (0.40–0.52) Step turns (%) Body rotation (°) Distance (m) Trajectory (m) Velocity (m/s)
a
Unplanned turning
a
Preplanned turning
All statistical analyses were performed using the STATISTICA software (Statsoft, version 12, Tulsa, OK). Responsiveness of turning performance (body rotation, turning distance, trajectory and velocity) to dopaminergic medication was expressed as Cohen’s d effect sizes (ES) (Cohen, 1988). Positive ES denote changes that are considered an improvement (i.e. toward the control group). A two-way repeated measures analysis of vari-
Variable
Statistical analysis
Table 2. Preplanned and unplanned turning in PD OFF and ON and controls
The turning steps were identified as the first heel strike exceeding two SD in medio-lateral displacement of five straight walking trials (computed for each participant) in the designated turning direction (see Fig. 1B) (Akram et al., 2010). Heel strike events were determined based on the velocity profiles of the heel markers (verticalaxis). Similar to Akram et al. (2010) capturing of the first heel strike event for the right and left foot (i.e. three to four steps prior to the intersection point for most subjects) was used as baseline in determining the onset of the first turning step. To discriminate between preparatory turning steps and the actual turning step, the succeeding turning step also needed to exceed 2 SD from the straight walking trial average. As shown by Hase and Stein (1999), we observed two distinct stepping strategies during turning. As illustrated in Fig. 1B, a turn was defined as a step turn if the first turning step was performed in the direction of turning or as a spin turn if the first turning step was in the opposite direction of turning. The proportion of turning trials using the step strategy was used as an outcome measure. Turning onset latency was calculated relative to the intersection point (i.e. time when the trunk [C7 marker] crossed the intersection point). Therefore, negative onsets for this outcome measure indicates that turning was initiated before reaching the intersection point while positive values reflect turns initiated after passing the intersection. The magnitude of pelvis rotation at the third turning step was retained for analysis. For the first three turning steps, the turning distance (i.e. the cumulative linear displacements of the C7 marker in the horizontal plane), mean turning velocity (i.e. the first derivative of the tangential displacement of the C7 marker) and mean turning trajectory (i.e. distance in meters between C7 and the markers positioned at the turning pole) were calculated. In accordance with Huxham et al. (2006) the step width and length were calculated by assessing the spatial position of the heel marker at each heel strikes. Step width was calculated in relation to the line of progression for each stride (corresponding to a straight line connecting the heel marker between each heel strike) and measured as the distance between the opposite foot and the perpendicular line from the line of progression (see Fig. 1C). Therefore, a negative step width was obtained when the heel strike of the external foot (e.g. right foot during a turn to the left) crossed over and landed medial to the line of progression of the internal leg. As step length during straight walking was shorter for subjects with PD compared to controls (P = 0.012), the step length during turning trials were normalized by subtracting the mean step length of the straight walking trials.
Main Effects (P)
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ance (ANOVA) was used to evaluate the effects of medication (PD OFF and PD ON) and turning condition (preplanned and unplanned) on turning initiation (turning strategy and onset) and turning performance. A two-way ANOVA was also used to evaluate the difference between groups (PD ON and controls) and turning condition (preplanned and unplanned). No differences were found between turns to the right or left or turning strategy (spin or step turn) for turning onset and performance. Hoehn and Yahr stages (2–3) were also similar in these outcomes. Thus, Fig. 2. Mean turning onsets (seconds) during pre- and unplanned turning for PD-OFF, PD-ON and these trials/stages were collapsed control group. Negative and positive onset values indicate that turning was initiated before and crossing the intersection, respectively. Error bars represent 95% confidence interval. together for further analysis. Further- after * p 6 0.025. more, as the amplitude of step width and length was differently regulated for step and spin turns, both step occurred earlier for PD ON (0.16 sec), in contrast to length and width were analyzed separately for turning control subjects in the preplanned condition strategies (step and spin turns) and turning conditions (group condition: P < 0.001); however, no difference in (preplanned and unplanned). A two-way repeated meaonset between groups for the unplanned turns was found. sures ANOVA was used to evaluate the effects of medication (PD OFF and PD ON) and steps (turning step 1, 2 & Turning performance 3) on step width and length. A two-way ANOVA was used to evaluate the difference between groups (PD ON and In both PD and controls, mean turning velocity was at controls) and steps (turning step 1, 2 & 3). The Greenleast twice as high during preplanned turns (0.45– house–Geisser correction was applied in the event of vio0.47 m/s), compared to unplanned turns (0.18–0.22 m/s) lations of sphericity and Tukey’s HSD test whenever a (P < 0.001, Table 2). In contrast, the slower unplanned significant interaction effect occurred. Corrections for multurns led to a larger degree of body rotation at the third tiple statistical testing were not used due to the light of turning step (100–113°) compared to preplanned turns criticism of such corrections (e.g. Bonferroni) to minimize (77–99°) (P < 0.001, Table 2). the incidence of false negative when examining hypotheMedication increased turning distance by 5% for preses (Perneger, 1998). Instead, the significance level was and unplanned turns (p = 0.003), still controls set at p 6 0.025. Data are presented as mean and 95% demonstrated 17–19% greater turning distance confidence intervals (95% CI). compared to PD ON (P < 0.001, Table 2). Medication did not have any effect on body rotation (P = 0.099), and controls obtained 10–24% higher body rotation RESULTS compared with PD ON (group: P < 0.001). There were ON medication, participants with PD improved 22% in no effects of medication or differences between PD ON their UPDRS motor score and 21% in their Postural and controls on turning trajectory and velocity Instability and Gait Difficulty score as compared to OFF (P > 0.559). The effects of medication or group (PD ON medication (Table 1, P < 0.010). As illustrated in table and controls) were independent of the type of turn 1, the mean straight walking velocity improved by performed (medication/group turning condition: 0.07 m/s after medication intake along with a 0.03 m P > 0.132). increase in step length (Table 1, P < 0.010). Still, individuals with PD ON medication walked slower with Regulation of step width shorter steps as compared to controls (P < 0.001). For PDs and controls, a general pattern of alternating step width amplitude was observed, i.e. widening – crossingTurning initiation over – widening the base of support for step turns and crossing-over – widening – crossing-over the base of Overall, we found a nearly 50:50 distribution between step support for spin turns (Fig. 3A, B). and spins during both pre- and unplanned conditions When using the step strategy during pre- and (Table 2). The strategies used for turning did not change unplanned turns, significant interaction effects were with medication (PD OFF vs. ON) and were similar found for step width (medication step interaction: between PD ON and controls. Preplanned turns were P = 0.024 and P = 0.003, respectively), still post-hoc initiated prior to the intersection while unplanned turns testing did not reveal any significant differences were initiated after crossing the intersection point (Fig. 2). between PD OFF and ON. There were no effects of Whether OFF or ON medication, subjects with PD initiated their turns with similar latency. Turning onset medication on step width for the spin strategy.
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Regulation of step length As illustrated in Fig. 4A, B, both PDs and controls consistently reduced their step length in all conditions during turning, compared to straight walking. Irrespective of medication state, subjects with PD demonstrated a similar reduction of step length while performing step and spin turns. Compared to controls however, PD ON further reduced their step length by 33–36% using step turns during the pre- (group: P = 0.006) and unplanned condition (group: P = 0.019, Fig. 4A). PD ON also demonstrated 33% higher step length reduction for the second turning step during the unplanned condition while using spin turns compared to controls (group step interaction: P = 0.004, Fig. 3B). There were no group differences for step length reduction using spin turns during the preplanned condition.
DISCUSSION This is the first study to evaluate the effects of dopaminergic medication on pre- and unplanned turns while walking in individuals with PD. After intake of dopaminergic medication, subjects with PD increased the turning distance but not the amount of body rotation. Regardless, dopaminergic medication did not Fig. 3. Step width (meter) of three turning steps for PD-OFF, PD-ON and control group while improve turning performance of using (A) step and (B) spin turns during the pre- and unplanned condition. Positive values reflect widening of the base of support whereas negative values reflect crossing-over of the base of individuals with PD to the level of the support (i.e. when the external foot crossed over and landed medial compared to the line of control group. These residual turning * progression of the internal foot). Error bars represent 95% confidence interval. p 6 0.025; impairments were accompanied by ** p 6 0.01. narrower, cross-over steps during turning, which should be considered and addressed during rehabilitation and in fall prevention programs of During step turns control subjects crossed their individuals with PD. external foot further away from the line of progression of Consistent with previous studies (McNeely and the internal foot compared to PD ON (group step Earhart, 2011; Curtze et al., 2015), turning performance interaction: P < 0.001). Specifically, for the second while on medication did not reach that of the control group. turning step using step turns, the step width of controls Our results indicate that these persisting impairments are was 0.07 m (48–82%) greater (i.e. increased negative related to poor effects of medication on step width and step width) compared to PD ON for both turning length. Furthermore, problems regulating step width, not conditions (preplanned: P = 0.016, unplanned: step length as previously been emphasized in PD P = 0.006). For spin turns, the comparison between PD (Hulbert et al., 2014), were the most prominent differences ON and controls revealed a different result for pre- and between PD and controls in their walking pattern. In particunplanned turns. For the unplanned condition, PD ON ular, individuals with PD turned with narrower steps while did not cross-over as much as controls (group step using a crossing step (i.e. step width closer to a value of interaction: P < 0.001), which was evident in the 0.07– zero). Crossing steps while turning is not only a complex 0.08 m (67%) greater negative step width in controls for motor task that could induce instability due to the drastic the first (P = 0.001) and third turning step (P < 0.001). change of the base of support, but is also an important conIn contrast, there were no group differences for the tributor to body rotation (Huxham et al., 2008a). Consepreplanned condition. quently, problems modulating step width in PD
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medication for the linear component compared to the angular component of turning. Although previous findings reporting similar effects of dopaminergic medication on the performance of turning-in-place (Franzen et al., 2009; McNeely and Earhart, 2011) and walking turns in individuals with PD (Curtze et al., 2015), the divergent effect of medication on linear and angular components of walking is a novel finding. Increased functional connectivity between cortical and sub-cortical brain areas has been demonstrated during turning compared to straight walking in PD (Gilat et al., 2015). Our current findings imply that the linear and angular component of locomotion likely involve distinct brain networks with potential varying sensitivity to dopaminergic medication. This notion is also supported by a recent study of Curtze et al. (2015) reporting smaller effects of dopaminergic medication on walking turns (ES = 0.20–0.50) compared to straight walking (ES > 0.50). In contradiction to our hypothesis, the effects of medication on turning performance were not influenced by the availability of time for planning the turn (i.e. pre- vs. unplanned condition). Less effects of medication were expected for the unplanned turns because of their more reactive nature requiring quick modification of the walking pattern (Cao et al., Fig. 4. Mean normalized step length for three turning steps using (A) step and (B) spin turns 1997), which adds stress to impaired during the pre- and unplanned condition for PD-OFF, PD-ON and control group. Step length data executive functioning in PD (i.e. rapid represent the absolute difference between straight walking and turning, i.e. negative values reflect information processing to regulate the shorter steps length while turning compared to straight walking. Error bars represent 95% confidence interval. motor commands) (Dirnberger and Jahanshahi, 2013). Impaired executive functioning has shown to be inefcompromise medio-lateral stability (Horak et al., 2005; King fectively treated with dopaminergic and Horak, 2008) and force production necessary to accelmedication in individuals with PD (Michely et al., 2012). erate the center of mass toward the turn direction (Mak On the other hand, the unplanned turn was triggered et al., 2008). In line with our findings, narrower step width and guided by a visual cue, which by itself could have in PD has been observed during postural reactions facilitated turning as previously reported for other tasks (Horak et al., 2005; King and Horak, 2008) and walking (Mak and Hui-Chan, 2005; Nieuwboer et al., 2009). turns (Huxham et al., 2008a; Mak et al., 2008). It is likely We aimed to capture realistic turning behavior without that problems modulating step width restrict the perforspatial restrictions and found a nearly 50:50 distribution mance of turning, as seen in our data, and lead to instability between step and spin turns. This finding is in contrast and falls in individuals with PD during everyday living. As to previous studies of healthy adults in that spin turns previously suggested by King and Horak (2008), this findwere more common during preplanned turns (Akram ing highlights the importance of targeting medio-lateral staet al., 2010), while step turns have shown to be more bility during rehabilitation sessions in individuals with PD. common during challenging turns (e.g. unplanned turns) Walking turns involve an interaction between the (Patla et al., 1991; Akram et al., 2010). Instead, the linear component (i.e. forward progression of the body) overall mixed pRef. between step and spin turns found and the angular component (i.e. rotation in relation to in the present study could represent a sustained flexible the longitudinal axis) (Goodworth et al., 2012). Our results repertoire of movement strategies. Furthermore, turning showed better responsiveness to dopaminergic was initiated in a similar manner whether OFF or ON
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medication; however, the control group initiated their turn 64% later during preplanned turns compared to PD ON. This finding may be a compensatory strategy adopted by individuals with PD in accounting for the poor responsiveness of dopaminergic medication to turning we observed, or because of balance impairments or difficulties with modifying an ongoing motor command (Chong et al., 2000; Mak et al., 2008). This study aimed to determine whether dopaminergic medication improves turning in individuals with mild-tomoderate PD who do not present with freezing of gait. Therefore, these results can only be generalized to this specific population. Still, as turning is an important factor in triggering freezing of gait episodes, future studies should investigate the effects of medication on turning in individuals who report freezing of gait. All subjects with PD were tested on the same day and in a fixed order (OFF first), which may have led to an underestimation of the medication effect (e.g. fatigue) or to an overestimation induced by a practice effect from repeated testing. Thus, to address the potential risk of fatigue and a practice effect, brief resting sessions were allowed during testing and practice sessions were performed prior to testing, respectively. Further – contradicting a practice effect – turning performance did not systematically improve across the number of trials in PD OFF and ON (data not reported). Furthermore, while all subjects with PD were confirmed responders to dopaminergic medication (indicated by improved UPDRS-motor, PIGD score and straight line walking), the level of responsiveness to medication was not an inclusion criterion, as in other studies (McNeely and Earhart, 2011; McNeely et al., 2012). This may limit the generalization and interpretation of these results. Finally, in contrast to several previous studies of turning in PD (Mak et al., 2008; Akram et al., 2013; Curtze et al., 2015), the controls’ walking velocity was matched to that of the PD subjects. Thus, the differences we observed in turning with PD are attributed to the disease itself rather than walking speed.
CONCLUSIONS Dopaminergic medication appears to increase turning distance but not the amount of body rotation irrespective of performing preplanned or unplanned walking turns. Turning impairments in individuals with PD on dopaminergic medication did not reach the performance of the control group. These residual turning impairments in individuals with PD were accompanied by narrower cross-over steps during turning. These narrower steps reduce stability and are therefore considered as important targets of rehabilitation in individuals with PD. Acknowledgments—The authors would like to thank all the participants who contributed to this work. The authors acknowledge Niklas Lo¨fgren and Ha˚kan Nero for their support with data collection. This work was supported by the Swedish Research Council, the Swedish Parkinson Foundation, the Karolinska Institutet, the Loo and Hans Ostermans Foundation, the Gun and Bertil Stohnes Foundation, the Swedish NEURO Foundation and the Natural Sciences and Engineering Research Council of Canada.
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(Accepted 10 November 2016) (Available online 17 November 2016)