Positive effects of auditory cue in locomotor pattern of people with Parkinson ’ s disease ( off and on medication )

 e dysfunctions in spatial, temporal, kinetic and electromyographic parameters in the gait of people with Parkinson’s disease (PD) have been widely described in literature. Dopaminergic medication has a positive e ect on the length and velocity of the stride and on the ability to produce muscle strength, however, cadence and double support does not alter in response to medication. Moreover, therapy with auditory cues is also used as a sensory reinforcement for improving gait kinematic parameters of people with PD. Recently, Rochester et al. found that auditory cues have a positive role in gait kinematic parameters, which are resistant to dopaminergic treatment people with PD. However, it is important to analyze the e ect of auditory cues on electromyographic and kinetic parameters in di erent gait phases in people with PD.  us, these variables could identify changes in the pattern of muscle activation during di erent gait phases and a better understanding of how the movements are controlled under an external sensory stimulation. From this analysis, it would be possible to understand more comprehensively the associative e ects between medication and auditory cue in the gait of people with PD. Thus, we ask: Could auditory cues associated with levodopa make people with PD improve the locomotor parameters?  e aim of this study was to investigate the e ect of auditory cues and medication on kinematic, kinetic and EMG parameters, during di erent gait phases of people with PD and healthy elderly. Abstract


Introduction
Positive effects of auditory cue in locomotor pattern of people with Parkinson's disease (off and on medication) Method Participants 30 subjects participated in this study: Group 1 -15 people with and Group 2 -15 healthy elderly (control group).PD patients presented the UK Parkinson's disease Society Brain Bank Diagnostic Criteria.Both groups were matched in relation to age, gender, height and weight (TABLE 1).e patients were diagnosed with idiopathic PD by a neurologist and they did not su er from severe dyskinesia or freezing that would impair their ability to walk.e inclusion criteria were: a) they should be diagnosed in the stages which varied from 1 to 3 as assessed by the Hoehn and Yahr Scale 14; b) they should receive regular pharmacological treatment with levodopa; c) they should not present indication of dementia according to the Mini-Mental State Examination (MMSE).Besides that, the disease severity was measured by the Uni ed Parkinson's Disease Rating Scale Section III (motor subscale) (UPDRS-III) 15 .
It was confirmed that participants had no other neurological disease, including hearing and musculoskeletal disorders that would in uence walking tasks with the metronome (auditory cue). is study was approved by the Local Ethics Committee (Protocol # 2635).All participants signed a Free Informed Consent Form.The clinical scales were done only in the on medication state 16 .Data collection of people with PD was performed in the morning and in two stages: rst, patients were without medication (12 hours) -o medication state; in the second stage, one hour after taking the medication -on medication state, the same experimental task was done.Subjects were asked to walk on a pathway 8 m long by 1.4 m wide in all experimental conditions.ey realized two experimental conditions, non-cued and cued condition.For the cue condition, an auditory cue was provided by a metronome (software Metronome plus).e instruction given to the subjects was to synchronize each footstep in time to the metronome.e frequency of auditory cues was administered at 10% above the baseline stride 11 .Before the data collection, some practice trials were provided

Procedures
for the subjects.It was realized 3 trials for each condition and it was completely randomized.
For the kinematic analysis, four infra-red emitting diode (IREDs) were placed on each subject's lower limbs at the following locations: head of the fth right and of the rst left metatarsal and lateral face of the right calcaneous and medial face of the left calcaneous.e surface electromyographic data were collected from tibialis anterior, gastrocnemius medialis and lateralis, vastus lateralis and medialis and biceps femoris in the lower right limb.e electrodes were positioned according to the recommendation made by the project SENIAM 17 .

Equipment
One Optotrak Certus System (Northern Digital Inc., Waterloo, Canada) was positioned in the Va l u e s r e p r e s e n t means with SDs in parentheses.

Data analysis Statistical analysis
Kinematic data was ltered using a 2 th order Butterworth lter with 6 Hz cuto frequency.For kinetic analysis, it was used a 4 th order Butterworth lter with 4 Hz cuto frequency.For EMG analysis, it was used a 4 th order Butterworth lter with 10 Hz cuto frequency.e following dependent variables were calculated on the central stride (from one heel contact to the next heel contact), removing e ects of acceleration and deceleration: -Kinematic variables: stride length and velocity, cadence, double and single support time; -Kinetic variables: extracted from the force-time curves: braking and propulsive impulses in two directions (vertical and anterior-posterior [AP]).ese variables were calculated for the central stride ( rst heel contact [force plate 1] and second heel contact [force plate 2]); -Electromyographic variables: each gait cycle was normalized in 100%.en, ve selected phases of The Kolmogorov-Smirnov and Levene tests showed that the data were not normally distributed and homogenous.For each analysis (kinematic, kinetic and EMG), Mann-Whitney tests were performed to investigate possible di erence between groups ([control group x PD o ], [control group x PD on]) in cued and non-cued conditions.Besides, Wilcoxon tests were performed for possible di erences between conditions (with and without auditory cue) for all groups (control, PD o and PD on).Furthermore, to investigate the interaction between medication and auditory cue e ects on gait of PD patients ([PD on x PD o ] in cued and non-cued conditions), paired tests of Friedman with repeated measures were performed for each analysis.When necessary, "post hoc" tests with Bonferroni adjustments were performed.e signi cance level for all analyses was kept at 0.05.sagittal plane to track all IREDs at a sampling rate of 100 Hz.Two force plates (AccuGait, Advanced Mechanical Technologies, Boston, MA) -50 cm x 50 cm -, embedded in the pathway (covered with the black rubber carpet), were positioned approximately in the middle of the walkway to record ground reaction forces during task execution at a frequency of 200 Hz.At the beginning of each data collection, subjects were weighed on both force platforms.is weight (BW) was used to normalize kinetic variables 18 .
The EMG signals were recorded using electromyography (EMG System of Brazil), which was linked to a computer for conversion of analog data into digital data with a sampling frequency of 2000 Hz.All data acquisition was electronically synchronized.gait cycle were computed: loading (0-10% of the gait cycle), mid-stance (11-30%), terminal-stance (31-60%), initial swing (61-86%) and terminal swing (87-100%) 19 .The muscles analyzed for each phase of gait cycle were: tibials anterior, medial gastrocnemius, lateral gastrocnemius, vastus lateralis, vasus medial, biceps femoris.In all these phases, Root Mean Square (RMS) and Linear Envelope were calculated to determine the co-activation index and the level of activation of each analyzed muscle (de ned as the area under the curve), respectively.e co-contraction index was calculated between the agonist and antagonist muscles, taken in pairs (tibials anterior vs. lateral gastrocnemius) and (vastus lateralis vs biceps femoris) 20 .

Changes in PD locomotor pattern in cued and non-cued condition before the medication intake
In cued and non-cued conditions, Mann Whitney test indicated that people with PD o medication showed shorter gait length (U = 47, p = 0.010), velocity (U = 37, p = 0.003) and double support (U = 48.5, p = 0.013) than the control group (FIGURE 1).Regarding the first heel contact in the first force plate, Mann Whitney test revealed for both conditions (cued and non-cued) that people with PD o medication showed lower braking and propulsive impulse (U = 37, p = 0.05) than control group.For the second heel contact on the second force plate without auditory cue, people with PD o medication showed lower propulsive impulse (U = 26, p = 0.04) than control group.However, with auditory cue, this e ect was only observed for vertical braking impulse (U = 24, p = 0.01) (FIGURE 2).

Changes in PD locomotor pattern in cued and non-cued condition after the medication intake
Mann-Whitney test revealed that people with PD o medication showed shorter length (U = 49, p = 0.08) and velocity (U = 60, p = 0.029) stride (FIGURE 1), smaller braking impulse (kinetic analysis) of the rst (U = 61.5, p = 0.05) and second heel contact on the force plate (U = 32.5, p = 0.02) than control group (FIGURE 2) without auditory cue.Provided with auditory cue, people PD o medication overstayed in double support when compared with control group (U = 60.5, p = 0.05) (FIGURE 1).As there was no signi cant di erence between groups with auditory cue, it can be assumed that auditory cue caused some changes in the kinetic parameters of gait in people with PD on medication, since their locomotor pattern was similar to the control group.For electromyographic analysis, Mann-Whitney test revealed that PD on medication showed higher co-contraction index between vastus lateralis and biceps femoris (terminal swing) (U = 59, p = 0.02) than control group, without auditory cue.However, with auditory cue, Mann-Whitney test showed that PD on medication showed lower biceps femoris activation (loading phase) (U =

Positive effect of cued condition in PD locomotor pattern
When people with PD were o medication, the bene cial e ect of auditory cue was observed due to the reduction in double support time (Z = -2.42,p = 0.015) and an increased in vastus medial (swing phase) (Z = -2.49,p = 0.012) and tibialis anterior activation (terminal swing phase) (Z = -2.44,p = 0.015).However, after taking the medication, reduction was observed in co-contraction index between vastus lateralis and biceps femoris (terminal swing phase) (Z = -2.41,p = 0.016) and co-contraction index between vastus lateralis and biceps femoris (swing phase) (Z = -1.98,p = 0, 02) (FIGURES 1, 3 and TABLE 2).

Association effects between medication and cue conditions for people with PD
In order to investigate the e ects of medication and auditory cue on the gait of people with PD, Friedman test revealed an increase in length (X 2 (2) = 11.08,p = 0.01) and velocity (X 2 (2) = 11.08,p = 0.01) stride after medication intake with auditory cues.Besides, it was observed an increase of biceps femoris activation in the loading phase of gait cycle (X 2 (2) = 13.64,p = 0.003).Wilcoxon "post hoc" tests showed that with auditory cue, after intake the medication, people with PD had increased length (p = 0.001) and velocity (p = 0.01) stride.Furthermore, people with PD showed greater biceps femoris activation (p = 0.01) after medication intake.Also, biceps femoris showed higher activation when patients were in the o state medication (with auditory cue) compared to the on state medication (without auditory cue) (FIGURES 1 and 3, TABLE 2).49, p = 0.01) and higher co-contraction index between vastus lateralis and biceps femoris (terminal swing) (U = 58.5, p = 0.04) than control group (FIGURE 3 and TABLE 2).

Discussion
e aim of this study was to investigate the e ect of auditory cues and medication on the kinematic, kinetics and EMG parameters, during di erent phases of gait in people with PD. e results of this study are in agreement with literature which has reduced kinematic, kinetic and electromyographic variables, for PD patients compared to elderly 5,[21][22] .
is is one of the rst studies to identify changes in muscle activation patterns in PD patients in di erent phases of gait with auditory cue.Del Olmo and Cudeiro showed that with auditory cue it was possible to observe positive changes on standard muscle (tibialis anterior and gastrocnemius) of PD patients, however, in this study it was not possible to identify in which gait phase this change took place 22 .
In the present study, patients with PD showed higher knee co-activation and lower muscle activation than control group, especially in the phases of balance and nal balance. is increase in the co-activation index of PD patients may indicate motor coordination problems, muscle function ine ciency and high energy expenditure 3 .e swing phase, since it generates imbalance, proves to be more challenging for patients with PD, regardless of the condition of the medication, when compared to healthy elderly. is result can be explained by loss of function of the basal ganglia, pushing the motor cortex to send motor commands with noise to the e ector system, so that agonists and antagonists are activated simultaneously and ine ciently.
In relation to medication intake, some studies have shown improvements in spatial and temporal parameters and in the ability to increase muscle activation pattern during gait in PD patients after ingestion of the medication [23][24][25] .e present study also found changes in gait parameters in PD patients after taking the medication, however, these changes were only observed with auditory cue, that indicated a better performance in the locomotor pattern of people with PD.Therefore, we observed an increase on the activation of eccentric biceps femoris muscle during single support when patients were in the o state medication and were provided with auditory cue.In this gait phase, the biceps femoris acts as a stabilizer of the knee to sustain body weight and propel the next step.is is an important nding because in a situation of freezing gait, where both feet are adhered to the ground, auditory cue may facilitate removal of the foot from the ground, freeing patients from this con icting situation.Another interesting nding is that people with PD o medication showed higher biceps femoris activation with auditory cue than without auditory cue.
ese results may help people with PD to use this sensory stimulation when they are o medication, e.g., during daily activities and motor intervention sessions.us, the auditory cue pulse makes that the motor impulses bypass the damaged circuitry in basal ganglia, and the medication acts in this damaged area, that even in this situation may not improve muscle activation.Besides that, these results can be explained by the demand for attentional and sensory resources stimulating the motor cortex, which subsequently sends commands to the spinal cord, without basal ganglia participation 26 .Therefore, in addition to medication therapy, patients with PD require a sensory reinforcement for improving some gait parameters.
When conditions were compared, improvements on kinematic, kinetic, and electromyographic parameters people with PD were evident.For patients with PD, signi cant di erence was found only for the double support.is study revealed a reduction in double support values, indicating a positive result for the dynamic stability.Moreover, provided with auditory cue, a similar behavior was observed in braking and propulsion impulses in the rst and second steps of the gait cycle in people with PD (on medication) and in healthy individuals.ese results can be explained by the increase in muscle activation of the vastus medialis (swing phase) and the tibialis anterior (terminal swing phase).As a consequence, in the swing phase, the greatest activation of the vastus medialis may have caused patients to elevate the leg over the ground, increasing the propulsion and reducing the double support.Subsequently, patients activated mostly the tibialis anterior muscle to perform ankle dorsi exion and ensure that the heel touches the ground.Yet, the rate of knee joint muscle co-activation decreased in the presence of auditory cue, indicating better motor coordination and even alleviating the problems of muscle sti ness.us, auditory cue resulted in greater consistency in the motor recruitment by means of motor neuron excitability through the reticulum spinal route 27 , de ecting circuit from the dopamine de cits basal ganglia 28 .
Besides these changes in the gait of people with PD in the presence of auditory cue, it seems that people with PD on medication state, adopted a
locomotor pattern similar to the control group.For example, without auditory cue, there was no signi cant di erence between the on and o medication state, but provided with auditory cue, this difference was observed, and people with PD on medication showed better locomotor performance.Besides medication therapy, people with PD require a sensory reinforcement to improve some gait parameters, such as reduction in coactivation rates.is is an important variable that indicates improvement in motor coordination.For rehabilitation, in addition to auditory cue, it is important that attentional cues synchronize movement with auditory cue 29 , which facilitates positioning of the foot on the ground.Finally, this study presents unprecedented results that auditory cue may help patients with PD in the most challenging phases of gait (initial and terminal swing phase), being an important factor for motor rehabilitation.Furthermore, it is important to emphasize that these stages patients with PD require greater sensory stimulus to overcome hypermetria, muscular rigidity and postural instability.
We can conclude that auditory cue resulted in improvements in muscle activity of people with PD patients that indicates a better locomotor pattern.Auditory cue can act as an external rhythmic generator and alleviate some PD symptoms such as bradykinesia and muscle rigidity.Moreover, this sensory stimulation caused changes in the motor system of these patients, such as increased recruitment of motor units, facilitating movement, especially in the most challenging phase of gait (swing).Consequently, we emphasize the use of auditory cue as a complementary therapy to levodopa to achieve improvement in the gait of patients with PD, since they can bene t from this sensory stimulation during daily activities and during motor interventions.

FIGURE 1 -
FIGURE 1 -Spatio-temporal parameters of gait (a,b,c,d,e) for healthy control and people with PD (on and o medication state) in noncued and cued condition.

FIGURE 3 -
FIGURE 3 -Muscular co-contraction index between vastus lateralis and biceps femoris (a,b,c,d) for healthy control and people with PD (on and off medication state) in noncued and cued condition.

TABLE 1 -
General characteristics of the healty control and PD patients.

TABLE 2 -
Mean and (± SD) for gait cycles phase for healthy control, PD off medication and PD on medication in cued and noncued conditions.