Parkinson's disease (PD) may be the fastest growing neurodegenerative disease in the
world (Bloem et al., 2021). Pathologically, it is characterised by the loss of the
dopaminergic neurons within the substantia nigra pars compacta (SNc) and other pigmented
nuclei of the brainstem. At present, the cost of healthcare for the estimated 145,000
people living with PD in the United Kingdom is over £728 million per year rising to a
total economic impact of £3.6 billion (Weir et al. 2018). If current projections are
correct of people with PD, this will double by 2040 (Dorsey et al. 2018), consequently
the figure may exceed £7.2 billion. Most people affected are 60 years or above. However,
there are many people who are diagnosed at a younger age. Common clinical manifestations
of PD include a range of both motor (e.g., bradykinesia, rigidity, tremor, and postural
instability) and non-motor (e.g., fatigue, psychiatric and behavioural disturbances,
autonomic dysfunction, cognitive impairment, sleep dysfunction and olfactory loss)
features.
The motor features can be present anywhere in the body. Some of the common features are
lack of facial expression, low volume speech, stiffness and slowness of movements.
Further, gait and balance are often affected. People with PD tend to have a festinating
gait, and/or experience postural instability with or without freezing of gait (FOG) which
may occur when initiating walking, standing from sitting, turning, and passing through
narrow passages or certain circumstances such as approaching a destination (Nutt et al.,
2011) or dual tasking (DT) (Bloem et al., 2000; Jacobs et al., 2014; Isaacson et al.,
2018). Postural instability, gait problems and FOG may significantly affect a person's
ability to perform ADL, increase their falls risk (Muslimovic et al., 2008; Lamont et
al., 2017) and reduce their quality of life (QoL). Approximately 70% of people with PD
will fall in a year period which can often result in serious consequences including
injuries (e.g., fractures and traumatic brain injury) which further increase morbidity,
mortality, and healthcare and personal costs (Farombi et al., 2016).
Currently, there is no cure for PD or treatment options available that can slow down the
progression of this condition. However, all people with PD are provided options to treat
the signs and symptoms of the condition to support their ability to participate in ADL
that are meaningful to them (Huber et al., 2011). First line therapy, the dopaminergic
medications, have some impact on motor symptoms in PD but rarely get people back to a
"normal" state (Killane et al., 2015). People often remain significantly limited in their
ADL during 'OFF' state but even during 'ON' state, many features of PD do not respond
adequately despite optimal pharmacotherapy (Shukla et al., 2012). Moreover, the usage of
medication often has serious side effects, particularly in older adults. The average
person living with PD may be taking nine doses of medication a day (Grosset et al.,
2007). Thus, drug resistance is another concern and dose limiting side effects is a
barrier to successful deployment of pharmacotherapy (Killane et al., 2015). This issue
increases with disease progression because neurodegeneration progressively involves
non-dopaminergic brain areas. As a result, various non-pharmacological, non-invasive
interventions have been developed to manage sensory dysfunction, a major problem in
people with PD, associated with PD symptoms (Conte et al., 2013). Cueing and vibrotactile
sensory stimulation are two such examples that have been used to modulate sensory
dysfunction in people with PD, especially the sensorimotor integration problems.
Cueing is a mechanism of applying an external temporal or spatial stimulus to facilitate
movement initiation and continuation and it can be somatosensory, auditory, attentional
or visual (Nieuwboer et al., 2007; Muthukrishnan et al., 2019). It is reported to work by
shifting habitual motor control to goal directed motor control (Redgrave et al., 2010).
Many studies have demonstrated that cueing helps to improve postural control, balance,
FOG (van Wegen et al., 2006; Nieuwboer et al., 2007; Munoz-Hellin et al., 2013; Spaulding
et al., 2013; Muthukrishnan et al., 2019), as well as DT performance in activities
involving the upper (Heremans et al., 2016; Park & Kim, 2021) and lower (Rochester et
al., 2007; 2009; 2010 (a); 2010(b); Fok et al., 2010; Mak et al., 2013; Beck et al.,
2015; Chomiak et al., 2017; Mancini et al., 2018; Stuart & Mancini, 2020) limbs in people
with PD. However, many cueing modalities used for the research purposes in the laboratory
environments cannot be easily replicated in people's homes. Thus, a recent narrative
review recommends the development of cueing wearable systems that can be used at home or
in the community to improve gait and posture in PD (Muthukrishnan et al., 2019).
Interventions utilising vibrotactile sensory stimulation in PD can be split into two main
groups: a) whole body vibrotactile stimulation and b) focused (e.g., targeted)
vibrotactile stimulation. The results on the effectiveness of whole body vibrotactile
stimulation on sensory dysfunction and motor symptoms are mixed with a large variation
being reported from none to small improvement on motor symptoms, balance, gait and
mobility (Dincher et al., 2019). On the other side, focused vibrotactile stimulation
which is a non-invasive neuromodulation technique used by somatosensory cues (e.g.,
tactile/somatosensory cueing) to apply gentle vibrations to focal joints in the body may
have a more positive and consistent effect (Basta et al., 2011; Pfeifer et al., 2021).
Trials which include cylindrical vibration devices on the triceps (Pereira et al., 2016),
a vibrotactile waistband around the abdomen in FOG (Goncalves et al., 2018), vibrotactile
insoles to reduce falls (Otis et al., 2016) and a proprioceptive stabiliser on postural
instability (Volpe et al., 2014) show promising results. The CUE1 is a non-invasive
medical device which utilises a metronome-like pulsed vibration which represents both
auditory and somatosensory low frequency cueing and high frequency focused vibrotactile
stimulation to help improve motor task performance in people with PD (Tan et al., 2021;
Ong et al., 2022; Wilhelm et al., 2022). It is a CE marked and an MHRA registered
non-invasive medical device.
Like other cueing and vibrotactile stimulation devices, the CUE1 stands out as a
non-invasive medical instrument. It employs a metronome-like pulsed vibration,
incorporating both auditory and somatosensory low-frequency cueing, along with
high-frequency targeted vibrotactile stimulation. This design aims to enhance motor task
performance in individuals with PD (Tan et al., 2021; Ong et al., 2022; Wilhelm et al.,
2022). Preliminary assessments of employing the CUE1 indicated an overall enhancement of
16.75% in motor symptoms, as evidenced in the White Paper on Proof of Concept from 2019.
This improvement was observed not only in the MDS-UPDRS Part III Motor test
score-considered the benchmark for evaluating motor symptoms in individuals with PD-but
also in various assessments such as the TUG test, TTT, and diverse gait features, as
detailed in the White Papers on Proof of Concept from 2020. Moreover, users reported that
donning the CUE1 device contributed to enhanced fatigue levels and increased subjective
balance confidence.
Subsequent investigations from smaller-scale studies revealed notable advancements linked
to CUE1 usage. Specifically, the device was shown to significantly boost gait speed in
the TUG test (Tan et al., 2021) and improve MDS-UPDRS performance scores while reducing
falls by an impressive 85% (Ong et al., 2022). Furthermore, a study design acceptance
paper authored by Wilhelm et al. in 2022 showcased a reduction in Freezing of Gait (FOG)
and an augmentation in walking speed, accompanied by positive feedback from individuals
with PD regarding their experience with the CUE1.
This feasibility study will test primarily the feasibility, safety and tolerability and
secondary the effect of the CUE1 and the CUE1+ (e.g., updated version of the CUE1 which
has better motor and longer battery life but same treatment settings) device in people
with PD and related disorders. This clinical study aims to identify whether the results
seen in the prototype testing and previous small studies (Tan et al., 2021; Ong et al.,
2022; Wilhelm et al., 2022) can be reproduced in a controlled clinical setting. Overall
the risk assessment related to the use of the CUE1 and CUE1+ device has been previously
tested on people with PD and has shown to have a minimal chance for error or adverse
effect to the patient. Based on real world data, the CUE1 has shown to be effective in
significantly improving motor symptoms such as rigidity, stiffness, tremor and slowness
of movement in people with PD (White Paper-Proof of Concept, 2019; 2020). The CUE1 has
also shown to improve fatigue (White Paper-Proof of Concept, 2020), walking speed,
balance and FOG and decrease falls in people with PD (Tan et al., 2021; Ong et al., 2022;
Wilhelm et al., 2022). The potential harm for the people with PD was very low, the
acceptance of using the CUE1 and its renamed/rebranded model with longer battery life and
better motor function, the CUE1+ device was very good, and positive user feedback was
received (Wilhelm et al., 2022). The device also utilised medical grade established
silicone-based skin adhesives. The product is water resistant and designed to CE
standards hence product and electrical malfunction risk will be low.
Positive results arising from this feasibility study will strengthen the evidence that
the CUE1+ device is feasible to be used, tolerated, safe and help to improve movement and
mobility in people living with PD and related disorders. It may also assist in selecting
the most appropriate outcome measures to test the effectiveness of the CUE1+ and
contribute to the growing academic interest in the application of peripheral stimulation
in other neurological disorders with movement, gait and balance problems such as various
types of dystonias and tremors, multiple sclerosis, stroke and vestibular disorders.
