Background

Parkinson’s disease (PD) is a common neurodegenerative disorder due to a dopaminergic deficiency in the basal ganglia.¹ The prevalence of PD rises as a growth of aging population. Approximately 0.5-1% of the population ranged from 65 to 69 years of age and rising to 1-3% among people who are older than 80 years of age.² Dysfunction of dopaminergic cells in basal ganglia leads to deficits in internal timing and automatic execution of movements^3,4 such as gait disturbances, which are the hallmark of PD.

Parkinsonian gait is characterized by small stride length, decreased gait speed, increased cadence, increased percentage of double leg support, absence of arm swing, and increased stride-to-stride variability.^5-8 Freezing of gait (FOG) is one of the disabling gait disturbances and defined as “brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk.”^9-11 Freezers exhibits more gait instability, which related to stride time variability,^12-15 than non-freezers.⁶

In order to ameliorate the impaired automatic motor performance, the pharmacological management is the primary way and has the capability to relieve certain symptoms; however, motor complications occur after long-term use of medicine, which should not be ignored. Rehabilitation such as physical therapies remains important for

patients with PD to gain function and decrease the rate of functional decline.

So far, overground gait training with external cues and treadmill training are the common interventions to improve gait disturbances attributed to dysfunction of motor automaticity. Auditory cues are widely applied in clinical studies or practice for PD.

Auditory cues provide an external rhythm that bypasses the internal rhythm deficits to prompt more appropriate gait pattern.^16,17 Abundant studies revealed the utilization of auditory cues facilitates the normalization of gait performances in PD such as reduced gait variability and increased stride length.^18,19 However, according to Willems et al.,⁷ different effects on improved step length were noted in freezers and non-freezers when they received different frequency of auditory cues. It seems that the freezers and non-freezers may exhibit the different responses in gait to the auditory cues. Insufficient studies investigate that the different responses to the auditory cues in freezers and non-freezers. We are still uncertain whether both types of patients can achieve equal favorable effects on gait performance from auditory cues.

Recently, there has been growing interest in combined auditory cues with treadmill training. Since treadmill training is another common and beneficial intervention to normalize the spatiotemporal gait parameter for PD, cues applied during treadmill walking may potentiate more positive effects on gait in PD compared to traditional intervention.^20,21 Despite this, we are still unclear these different effects of cued treadmill

training between freezers and non-freezers due to scarcer studies.

After having realized the effects of cueing-based training on gait pattern, it is necessary to dig into how these effects come from and what is the potential mechanism behind the auditory cues. According to the mechanism of learning-induced cortical plasticity in the primary motor cortex (M1), it hypothesized that synaptic plasticity could be modulated through long-term potentiation (LTP) and long-term depression (LTD) depend on different stimuli.²² An animal study had shown these neurophysiological changes after training is associated with improved motor performance.²³ Moreover, training-induced plasticity may be important to the rehabilitation.²⁴Based on the previous research, some neuroplastic changes in the brain might occur before the behavioral changes response to the auditory-cued training. One Positron Emission Tomography (PET) study²⁵ revealed significant metabolic increment in the cerebellum, parietal and temporal lobes after the patients with PD carried out the auditory cueing-based physical rehabilitation program. Nevertheless, gait parameters except for stride time variability after training did not differ from those obtained before training. It seems that neuroplasticity through cueing-based training plays a crucial role to improve gait disturbances for PD.

In order to explore the neuroplastic effects of cueing-based training in patients with PD, the application of the neuronal imaging techniques is needed. The common neuronal

imaging techniques for the human to demonstrate neuroplasticity include positron emission tomography (PET), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). Compared to PET and EEG, TMS parameters can be rapidly acquired and provide close monitoring of relatively short-duration neuroplastic changes following experimental manipulation. TMS explore the neuroplasticity as measured through the cortical excitability. Previous studies indicated the patients with PD exhibited abnormal cortical excitability including the reduced cortical silent period (CSP) and a failure of intracortical inhibition.²⁶ Therefore, it is worth for us to dig into whether auditory cued-based training has an impact on cortical excitability.

Based on our previous laboratory experiment,²⁷ for the cortical excitability, we investigated significantly lengthened CSP duration and reduced short intracortical inhibition (SICI) at 2ms after PD subjects received stepping-in-place (SIP) training with auditory cues (AC) but not without cues. Additionally, the freezers in comparison of the non-freezers achieved more plastic changes in CSP duration and SICI(2ms) after SIP training with AC. Concurrently, the freezers obtained significantly decreased walking step time CV after training. These findings suggested some changes in neuroplasticity and behavioral performance occurred after training with AC and the freezers and non-freezers may have different responses to the AC. Despite this, SIP is unlike walking, which needs to provide the forward propulsion. We cannot draw the firm conclusion that whether the

auditory-cued treadmill training could provide similar effects on the cortical excitability and gait performances in freezers.

In general, gait disturbances that related to the dysfunction of automatic motor execution is a major problem for the patients with PD, especially in freezers. Training-induced plasticity may play a crucial role in gait rehabilitation in PD. Therefore, it is worth for us to investigate whether the cortical excitability can be modulated through auditory-cued treadmill training and explore whether any improvement in gait performance after training.