Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05687773 |
| Other study ID # |
ParkinsonVR22 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2021 |
| Est. completion date |
September 14, 2023 |
Study information
| Verified date |
January 2023 |
| Source |
Federal University of Health Science of Porto Alegre |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction: Parkinson's Disease (PD) is characterized as a neurodegenerative disorder
associated with the progressive loss of dopamine in the basal ganglia region, resulting in
classic motor symptoms such as bradykinesia, rigidity, postural instability and tremor. Such
symptoms end up affecting the functionality of the upper limbs (ULM) in this population. In
recent years, therapy based on Virtual Reality (VR) has been gaining popularity, but studies
in the area are still lacking. Objective: To verify the benefits of immersive and
non-immersive virtual reality in the functionality of the upper limbs in individuals with PD,
and to identify possible differences between them. Methodology: This is a randomized clinical
trial, in which the evaluators will be separate from the experimental groups (single-blind).
Subjects with PD will be randomized into two groups: Immersive group (IVR), which will
receive treatment with virtual reality games in an immersive environment through Leap Motion
Controller (LMC) devices together with image projection on a Head-mounted -display (Oculus
Quest) and the non-immersive group (RVnI) in which they will receive treatment with the CML
on a flat screen. Both treatments will focus on broad and fine upper limb tasks, in a
protocol with 4 activities and duration of 27 minutes, twice a week, for eight weeks. The two
groups will be evaluated in three moments: before the intervention, immediately after 8 weeks
and 60 days after the end of the interventions. They will be analyzed in terms of ADLs,
through the TEMPA test and part II of the unified assessment of PD (MDS-UPDRS II); motor
assessment (part III) of the MDS-UPDRS and motor staging of PD (Hoehn & Yahr); manual
dexterity through the Box and Block test and through the Nine Hole Peg Test; cognition by
Montreal Cognitive Assessment (MoCA); quality of life through the PD questionnaire (PDQ-39);
the usability of the system (SUS); and possible side effects (Simulator Sickness
Questionnaire). This study is expected to show that treatment with immersive VR has greater
positive effects than non-immersive VR on the functionality of the upper limbs of individuals
with PD.
Description:
Parkinson's disease (PD) is characterized as a complex neurological disorder, with classic
motor symptoms that are mainly associated with the development of Lewy bodies within nerve
cells and with the loss of dopaminergic neurons in the substantia nigra. Among the most
characteristic motor symptoms of the disease, tremor, rigidity, bradykinesia, postural
instability and gait difficulty are included. Consequently, such motor comorbidities directly
impact the patient's life, affecting quality of life, increasing the risk of falls, and
decreasing independence in general. PD is currently the second most prevalent
neurodegenerative disease (after Alzheimer's disease), with a rate of 14 affected per 100,000
inhabitants; when considering the population over 65 years old, the values rise to 160
affected per 100,000 inhabitants. Approximately 60,000 new cases of PD are diagnosed each
year in the United States, in addition to the more than one million cases already diagnosed.
In Brazil, it is estimated that 200,000 individuals have PD in the general population, with a
high prevalence in people aged between 60 and 79 years. About 36,000 new cases arise in the
country each year. The incidence rate of Men-Women varies between 1.3 and 2.0 in most of the
recorded data. In 2012, Noyce et al. analyzed 30 environmental factors that could be related
to the development of PD, among which those that were highly significant: exposure to
pesticides, previous injury to the skull region, living in a rural area, use of
beta-blockers. , workers in rural areas and consumption of water from wells. Among the
protective factors found are: smoking, use of non-steroidal anti-inflammatory drugs, caffeine
consumption, use of calcium channel blockers and alcohol consumption. Among the genetic
factors best described in the literature are the SNCA genes, which encode the alpha-synuclein
protein; mutations in LRRK2; mutations in the GBA gene, which encodes the
beta-Glucocerebrosidase enzyme, which is the main genetic risk factor found until then for
the development of PD.
Lewy bodies were first described in 1912 by Friedrich Henrich Lewy, becoming a major
pathological marker of PD. They are found inside neurons and are made up of neurofilaments
with aggregates of alpha-synuclein and ubiquitin. In 2007, through the study by Wakabayashi,
he showed that Lewy bodies were not directly related to the causes of PD, but to its
symptoms.
In general, the pathophysiology of PD is characterized by a progressive neuronal loss of the
compact part of the substantia nigra of the midbrain, requiring a loss of more than 60% for
the main symptoms of the disease to appear. However, in addition to the deficit in the
dopaminergic pathway, other neurotransmitters may also be involved in the pathophysiology of
PD. In the noradrenergic system, the locus coeruleus, presents the loss of 50 to 80% of
pigmented neurons, in addition to the reduction of neurons in the dorsal vagus nucleus and in
the supraoptic and paraventricular hypothalamic nuclei, accompanied by a decrease in the
function of the noradrenergic projections; In the serotonergic system, a reduction of 57.8%
of neurons in the dorsal raphe nucleus is observed; And in the cholinergic system, a
reduction of 50 to 60% of cholinergic neurons in the dorsal raphe nucleus was observed.
In 2003, a study developed by Braak et al. showed that PD begins in Meissner's gastric
autonomic plexus and in the olfactory neural endings, propagating to the brainstem
(midbrain), precisely in the dorsal vagus nuclei, glossopharyngeal nucleus, olfactory and in
the intermediate area. From there, evolution is divided into 5 more stages, namely: 1 - raphe
nuclei, gigantocellular nucleus and locus coeruleus; 2 - compact part of the substantia
nigra; 3 - forebrain areas of the temporal mesocortex; 4 - areas of association of the
frontal neocortex; 5 - neocortex association areas, premotor and motor areas.
The main motor symptoms of PD are bradykinesia, hypokinesia, akinesia, tremor and rigidity,
as well as balance and gait deficits. In addition, cognitive disorders, memory deficits,
problems related to visuospatial dysfunction, difficulties in performing sequential and
repetitive movements, freezing and slow psychological responses are often present. Decreased
writing and problems in the voice and swallowing of individuals can also be observed. Among
the main clinical symptoms of PD is tremor, which in about 50% of cases begins in the distal
extremities. In rest situations, the decrease or disappearance of this symptom is noticeable,
which returns if the individual maintains a more prolonged action or posture. Bradykinesia
(slowness of movement) is due to an imbalance between the inhibitory and excitatory systems,
resulting from the absence of dopamine in the striatum, affecting mainly automatic movements,
generating a general poverty of movement and frequent complaint of weakness. Patients with PD
have a high chance of acquiring a posture with their center of gravity forward, generating a
bent or flexed posture. There is also a decrease in postural reflexes, such as protective
extension, balance, and righting reactions. The gait presents itself as a slow, shuffling
gait with a shortened stride length.
Pharmacological treatment consists of drugs that increase intracerebral concentrations of
dopamine or stimulate its receptors. In the first line of treatment are Levodopa, which
corresponds to an immediate precursor of dopamine, which, unlike it, can cross the
blood-brain barrier. Bromocriptine, Lissuride, Pergolide and Paramixepol are dopamine
receptor (D-2) agonist drugs, being dopaminomimetics, used alone or in association with
Levodopa. Cardidopa is usually associated with Levodopa to facilitate the drug's action on
the central nervous system, thus decreasing its side effects, such as nausea, vomiting, loss
of appetite, and accelerated heart rate, in addition to increasing its therapeutic
effectiveness. In the second line of treatment are central anticholinergics, which exert
their therapeutic effects by blocking the central cholinergic transmission of acetylcholine,
restoring balance with dopamine. In the third line of treatment are the catechol-o-methyl
transferase (COMT) inhibitors, which act by blocking the conversion of levodopa to
3-O-methyldopa, thus increasing the half-life in plasma and the fraction of the dose that
reaches the brain. Also in the third line of treatment are irreversible inhibitors of the MAO
enzyme type B, which also inhibit the reuptake of dopamine from the synaptic space.
However, even with an adequate pharmacological treatment for the management of PD, the
patient can still present significant functional losses, which will directly affect their
activities of daily living and their participation in society. The physiotherapeutic
treatment aims to enable the individual with PD to maintain their maximum level of activity
and mobility, being an adjunct therapy to the isolated pharmacological treatment.
Physiotherapy applied to patients with PD ends up focusing mainly on: postural adjustments,
transfer maneuvers, improvement in upper limb function, balance, physical capacity, cognitive
capacity, and gait; always seeking patient independence and improving their quality of life.
Among some of the adjuvant therapies already studied in PD, we can mention: induced
containment therapy, dance, martial arts, Nordic walking, aquatic therapies, and music
therapy. Upper limb dysfunctions are frequently present in individuals with Parkinson's
disease. Among the first motor signs we can highlight micrograph and resting tremor. Resting
tremor is defined as a tremor of 4 to 6 Hertz in frequency in a limb that is fully at rest,
which temporarily disappears during movement and can be aggravated during situations of
emotional stress. Accompanied by a slowness and progressively smaller movements (hypokinesia)
characterizing bradykinesia, and an involuntary rigidity during a passive movement of a joint
(cogwheel phenomenon). A great loss of manual dexterity is also observed, which is
independent of the presence of bradykinesia or tremor. This phenomenon is coined as "Kinetic
apraxia of the limb", which is a loss of fine motor skills not explained by elementary motor
deficits, such as weakness or ataxia.
As the disease progresses, such dysfunctions end up impacting daily life tasks such as
getting dressed, brushing teeth, eating, buttoning buttons, using cell phones and, as a
consequence, we perceive a worsening in the quality of life of individuals with PD. In
addition, despite the known benefits of dopaminergic therapy for the management of PD
symptoms, it is shown to be ineffective in improving coordinated arm and hand movements,
which affect the individual's functional reach and grip movements.
Among the treatments presented in the literature for the management of upper limb deficits in
individuals with PD are techniques based on repetition training in single and dual tasks;
mirror therapy; restraint-induced therapy; and sensorimotor training. As well as several
publications in recent years have been portraying the use of VR for the treatment of upper
limb deficits in patients with PD, showing promising results in the area.
In recent years, interest in Virtual Reality (VR) has been growing exponentially, but the
technology has been used for some decades. VR was a term proposed and popularized in 1989 by
Jaron Laurier. VR is generated from computer graphics processing, in which simulations of
objects, spaces and events are offered to the user's visual field in order to mimic a real
experience. In addition to the visual offer, an auditory, tactile or even olfactory component
may be present in order to guarantee a greater multisensory stimulus together with the
possibility of real-time interaction between them. There is then a direct relationship
between the number of sensory channels generated by the computer that are offered to the user
and the level of immersion generated, which may vary according to the type of hardware used.
The virtual environment can be delivered to the user through traditional displays in two
dimensions (2D), projected through glasses in three dimensions (3D) or in devices called
Head-mounted display (HMD).
Among the elements in which VR is modeled, "Interactivity" represents the user's ability to
actively participate in the experience generated by VR. It is influenced by the
responsiveness of the system, graphics, sounds and degrees of freedom that are provided to
the user in the Virtual Environment (AV). "Presence" is the perception that the environment
and virtual objects are really there and that the user is inserted between them; In which
there is nothing that separates the "I" and the AV. Another feature is "Perceived Reality" in
which the AV is to some degree similar to the real world. Finally, immersion can also be
amplified when there is an emotional and/or cognitive affective component during the
experience, being related to intrinsic factors of the user, including physiological
parameters such as heart rate, skin conductance and psychological factors, such as
personality traits of the user.
Therefore, the term Virtual Reality can be more related to the user experience than to a
device itself.
In 1997, Mel Slater & Sylvia Wilbur also proposed five characteristics to which they
structure a virtual environment (VE): (a) Inclusive; refers to an AV that eliminates signals
that indicate the existence of a physical world separate from the virtual world (eg external
noise, joystick weight); (b) Extensive; refers to the number of sensory modalities stimulated
(eg, tactile, auditory.); (c) Surrounding; refers to the visual presentation of the AV,
including the ocular field of view (CVO) and the degree to which the real world is excluded
(eg, Head-mounted Display, computer screen). (d) Vivid; refers to the resolution and fidelity
of the image generated by the device (eg visual information); (e) Correspondent; refers to
how the VE is modified in response to the user's perspective and actions. The use of VR has
been used in several areas, in the scope of entertainment, professional training, military
area, among the most diverse applications. The first record of its use in the medical field
dates back to the early 1990s, and currently it has been widely used both for teaching in the
health area and for clinical practice, finding promising results in the area of physical and
intellectual rehabilitation.
The motor rehabilitation process is influenced by three major factors: (a) early
intervention; (b) task-oriented training; (c) intensity and repetition. Tasks that include
various sensory processes (hearing, proprioception, vision, touch) are necessary in order to
promote an improvement in function. Another important factor for the success of the treatment
is based on the patient's engagement with the tasks oriented to him, and his motivation to
perform them. However, patient engagement in traditional neurological rehabilitation programs
seems to be low, and often the intensity dose used during sessions seems to be insufficient
to generate the greatest possible clinical improvement. Non-adherence to treatment can, in
addition to generating a low effectiveness in the result, have a high economic cost.
In this context, rehabilitation therapy using VR proves to be a viable alternative for the
neurological population, being in some cases more effective than the conventional therapy
widely used today. VR stands out for being a recommended technological approach to improve
movement learning, through visual, auditory or tactile feedback, the user is able to work
both motor and cognitive processes at the same time, through a challenging and motivating
environment. . Among the advantages of VR are the ability to modify the VE for scenarios of
real patient situations, and individualize treatment needs. In addition, an external observer
can activate the activity and record the entire performance of the task proposed to the user,
thus analyzing their progress. Also in the last decade, VR has been successfully used in the
scope of telerehabilitation, a modality that has been in constant demand in recent years.
Design systems designed in Head-Mounted Display were first conceived in the 1960s in the Utah
transformation by the then first of Ivan Sutherland's graphic transformation. It is defined
as a helmet in which, using two lenses, the images are seen by the individual wearing them,
making it possible to use them for immersive EVs in VR . In the last decades, with the cheap
technologies, the use of HMDs for VR has several applications for the general public, in
education, entertainment, and in the medical field. Among the HMD models that are available
for general public use, we can mention the HTC VIVE (HTC Corporation¸ Taiwan); Valve Index
(Valve Corporation¸ Washington, USA); and the Meta Quest 2 (Meta Inc.¸California,USA). Thanks
to the portability and low cost of the sensor, the LMC is suitable for performing exercises
in a therapeutic and home environment, without extensive supervision. Much of the current
literature focused on rehabilitation has been using non-immersive VR devices, and reviews in
the area point to a large gap in studies that use more immersive devices for the treatment of
such conditions. The use of a more immersive LV for treatment through HMD can be much more
intuitive to interact with than in environments projected on flat screens and generate better
results in the rehabilitation of the upper limbs, reducing external distractions, increasing
the focus of the immersed individual, and generating greater user motivation. Due to the lack
of studies in the area, the study in question aims to investigate the possible benefits that
a therapy based on an exposure protocol in different degrees of immersion in VR impacts on
the functional aspects of the upper limbs of individuals with PD.
PD is currently the second most prevalent neurodegenerative disease in the world , and
despite advances in disease control, upper limb motor disorders seem to show little response
to pharmacological treatment. In recent years, with the advancement of technology and its
increasingly easy access to the general population, the use of VR-based neurological
rehabilitation has been gaining more and more notoriety. The use of VR in rehabilitation has
already proved to be a viable, safe alternative, with similar or superior results to
conventional therapies adopted by Physiotherapists and/or Occupational Therapists . Among the
characteristics of VR in which the literature already proves its use, are the
individualization of the treatment, the ability to modify it to mimic everyday tasks, the use
in telerehabilitation and the ability to provide instant feedback to the patient and
therapist, characteristics essential for greater effectiveness in a rehabilitation protocol.
Despite the increasing progress in research, studies with a good methodological quality in
this area are still lacking. In addition, several reviews on the subject point to the lack of
studies comparing the different types of immersion in the treatment of neurological
conditions . In addition, more quality studies are needed to develop guidelines for clinical
practice using VR, generating more patient safety and an improvement in the cost and
effectiveness of treatment.
The general objective of the study will be to verify the effects of an intervention protocol
using a non-immersive Virtual Reality device (Leap Motion Controller and Flat Display) and
Immersive Virtual Reality (Leap Motion Controller and HMD) on the functionality of the upper
limbs of individuals with Parkinson's disease.
