Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and the fastest growing neurodegenerative disease, due to an ageing population, a longer duration of the disease and possibly the increase in environmental contributors such as xenotoxins and environmental pollutants [
1]. It is also possible that the current COVID-19 pandemic may result in an increased incidence of PD in the future [
2,
3]. Deterioration in symptoms in sufferers of PD is the norm due to the progressive spread of α-synuclein mediated neuroinflammation, the loss of neurons in the substantia nigra and subsequent reduction in dopamine levels and the decrease in mitochondrial function [
4]. To date there is no effective treatment that can cure or slow the progression of PD [
5], although medications and deep brain stimulation can control some motor symptoms. The increasing recognition of the importance of the gut-brain axis in PD and the early presentation of gut symptoms [
6], suggests the possibility of the gut as a target for PD therapies [
7].
Photobiomodulation (PBM) therapy is the use of narrow-wavelength bands of non-thermal light (LED or laser) to modulate cellular responses. The main target of PBM is thought to be cytochrome-C-oxidase, which absorbs red and near-infrared light [
8]. This is thought to release reactive oxygen species (ROS) from the complex, promoting increased mitochondrial membrane potential, to increase ATP production and to regulate downstream cellular signalling pathways via ATP, cAMP, ROS, Ca
2+ and nitric oxide (NO) to influences gene transcription [
8,
9]. PBM therapy has a decades-long safety record [
10‐
12] with a safety profile equating to that of ultrasound tests. Unlike much pharmaceutical therapy, PBM therapy is free of serious deleterious side-effects and is non-invasive.
Because PBM acts at a cellular and mitochondrial level, the therapy has been shown to have a multitude of beneficial effects in the body and on various disorders, such as wound and diabetic ulcer healing, pain reduction, treating inflammatory disorders such as lung inflammation, osteoarthritis, tendinopathies and other musculoskeletal conditions [
13,
14]. In addition to the local effect of PBM on target cells, PBM also has a systemic effect [
14‐
18] and a delayed effect due to activation of DNA transcription factors [
8,
9]. One of the primary downstream effects of PBM is on immune cells, producing an anti-inflammatory effect, which has profound consequences for many body processes [
14]. Recently there has been a great deal of interest in the use of transcranial PBM therapy to address symptoms of neurological and neuropsychiatric disorders [
13].
Several studies have reported encouraging results for the application of PBM therapy in animal models of PD, and a recent review of animal evidence concluded that human trials are justified [
19]. PBM has been shown to precondition and protect animals (including non-human primates) from a toxin (MPTP)-induced PD model, both in the signs of the induced PD and protection of the neurons in the substantia nigra [
20‐
22]. This preconditioning effect was also observed when PBM was delivered to areas remote from the brain [
15,
23‐
25], including when the head was shielded from light [
26]. Several small trials and case studies are currently being undertaken with transcranial PBM [
27‐
29]. The application of remote PBM has not so far been investigated. In the current study, treatment consisted of combination of transcranial PBM and remote PBM treatment to the abdomen and to the neck. These locations were selected based on the importance of the gut-brain axis in PD, the richness of the enteric nervous system, the proximity of the vagus nerve in the neck and both the success of these targets in animal models as well as clinical experience.
The aim of this proof-of-concept prospective clinical study was to assess the effectiveness of PBM to mitigate the clinical signs of PD in humans and to inform on treatment regimens and outcome measures for a future randomized placebo-controlled study (RCT). The primary outcome measure was improvement in timed up-and-go (TUG) as a measure of mobility. Secondary outcome measures were mobility, cognition, fine motor skill, micrographia and static balance. Quality of life outcome measures and patient reported symptomatic changes, including depression are the subject of a separate report.
Discussion
We have shown that PBM treatment is capable of improving a number of clinical signs of Parkinson’s disease, including the primary outcome measure of TUG, which assesses functional mobility, and also other mobility related signs, some fine motor skills and cognition. These improvements persisted for up to one year with continued PBM treatment. Importantly, there was no significant decline in any outcome measure over one year, although there were small (non-significant) declines in the NHPT and in micrography. To the best of our knowledge, the study described herein represents the first clinical trial in PD patients using PBM treatment to a combination of anatomical targets, although several small trials and case studies using transcranial PBM for PD are currently underway with [
27‐
29]. Although the study reported here was not sufficiently powered to detect irrefutable changes in clinical signs of PD, the results build on results from animal studies and demonstrate the potential clinical relevance of the PBM treatment in mitigating clinical signs of PD. Importantly the treatment presented no safety concerns and the participants reported no adverse side-effects, confirming the safety of PBM as has been seen in numerous other studies of PBM treatment.
PD currently has no cure and there are few options to arrest or slow the signs and symptoms of the disease and so treatment is based on symptomatic relief. The gold standard for treatment is dopamine replacement with levodopa, combined with carbidopa to prevent premature conversion to dopamine. These can improve motor symptoms but can also cause adverse side effects, such as dyskinesia and nausea, and become less effective with time. Other clinically useful medications for motor symptoms include dopamine agonists, ergot, MAO-B inhibitors, anticholinergics and Adenosine agonists, which can be used alone or as adjunct therapy [
5]. Because the signs and symptoms of PD are diverse, the pharmacological treatment of the mixture of symptoms is challenging and often necessitates a cocktail of pharmacologic interventions [
38], depending on individual patient needs [
39,
40].
Recent evidence-based review of treatment options for motor and non-motor signs and symptoms of PD, commissioned for the International Parkinson’s and Movement Disorder Society [
5,
41] concluded that there are few non-pharmaceutical options to control motor symptoms. Of these, exercise and physiotherapy are common interventions that are clinically useful, while supplements (e.g., coenzyme Q
10, creatine, Vitamin D), lack clinical evidence despite being popular with PD sufferers [
5]. Deep brain stimulation is an established surgical technique that controls some motor symptoms (stiffness, tremor) and can improve quality of life, but like all surgery carries some risk [
42]. For non-motor symptoms, it was concluded that “There were no clinically useful interventions identified to treat non-dementia-level cognitive impairment.” although there were some pharmacological options for dementia [
41]. A number of new interventions for PD are currently undergoing investigation, including high intensity focussed ultrasound [
43], immunotherapy [
44] and stem cell therapy [
45]. The current study provides early clinical evidence that PBM has the potential to be an effective treatment complimenting traditional pharmaco- and physical therapy in the management of the clinical signs of PD.
The primary outcome measure of the study was functional mobility as measured by TUG. Not only was this outcome measure significantly improved after the 12-week clinic-treatment period and the home-treatment period, but all participants showed this improvement. Motor symptoms of PD have a major impact on the quality of life of PD sufferers [
46] and are complex, being a combination of mobility, balance and cognition. All measures of mobility were improved in all participants, with significant improvements in walking speed, stride length, step test and TUG tests throughout the clinic-treatment and home-treatment periods. Both the 10MWT and the three TUG tests are validated for PD [
31,
47], show good reliability and a good relationship to mobility, falls risk and the progression of disease [
48]. Increased falls risk is also related to loss of balance, severity of PD and previous falls history [
49]. Although the step test was originally developed for stroke patients and includes a component of physical capacity, it is simple to perform and has found some utility for PD patients [
36,
50]. Participants in the current study showed significant improvement in the step test, with improvements being maintained through the home-treatment period. On the other hand, the TS and SLS tests of static balance, although somewhat improved with PBM, were also the most sensitive to dose down-titration. Mobility dysfunction is also related to cognition and the ability to integrate sensory information and motor planning [
51] as demonstrated by dual-task TUG (TUG motor and TUG cognitive) in PD [
52]. Improvement in these outcome measures has the potential to positively impact the mobility of individuals with PD and so reduce the risk of falls.
Another notable outcome of the study was the improvement in cognition as assessed by the MoCA, especially considering that up to 80% of PD patients develop dementia within 15–20 years of onset [
53]. The MoCA is considered a suitable cognitive assessment screening tool in PD [
54] and has excellent test-retest reliability with no significant learning effects, even when used within 1 month (
www.mocatest.org). Supporting the MoCA outcomes were anecdotal comments by study participants and carers who remarked on improvements in mood, engagement and socialisation (data not shown). There have been a number of previous reports of improved cognition using transcranial PBM [
55‐
57], often in conjunction with intranasal PBM [
58], including the VieLight device used in the current study [
59].
MDS UPDRS was not used for assessment of outcomes in this study, due to the unavailability of the consulting neurologist at various stages of the study. While the MDS UPDRS is recognised as the “Gold Standard” for PD diagnosis, it may lack the sensitivity required to detect changes in the signs and symptoms in early PD and its progression [
60‐
62], especially for functional performance [
63] and cognition [
64]. It remains to be seen if the UPDRS would be suitable to detect the improvements in the clinical signs of PD that were seen with PBM treatment in the current study.
Many of the participants improved in multiple outcome measures as measured by improvement above an MCID value. MCID is interpreted as an improvement that is relevant to individual participants [
65] and is proposed as the “smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient’s management” [
66]. The use of a half standard deviation as a simple measure of MCID as proposed by Norman et al. [
37] is not universally accepted [
67] and its use in our study with its small number of participants has resulted in a standard deviation that is higher than would be expected with a larger cohort, leading to imprecision in detecting an MCID change, with an MCID change more difficult to achieve, and an underestimate of the numbers of participants that show a substantial improvement. This is most apparent in the measures of static balance (TS and SLS), where the high variance resulted in few participants achieving an MCID, despite some substantial improvements. While less than ideal, the categorizing of improvements in clinical signs as MCID provides a consistent although high benchmark against which to measure improvements. At a time when the consumer perspective is considered imperative in clinical research, especially in a disease with such diverse symptoms as PD, future studies using a measure of MCID would ideally be related to participant’s perceptions of what they themselves considered an ‘important difference’ to their own clinical signs and symptoms.
It was apparent that there was considerable variability among participants in response to the PBM treatment, which is important to consider at this early stage of clinical study. While all participants showed improvement in multiple clinical signs, the number and specific sign, as well as the extent of the improvement varied among participants. Many participants showed an improvement after PBM treatment for a range of outcome measures (e.g., A1, A4, B1, B2, B5, B6), while some participants showed an improvement in fewer outcome measures (e.g., A5).This is not unexpected due to the variability of signs and symptoms among PD patients and the heterogeneity of this small participant group. Variability in individual response to the PBM treatment may also be due to individual responses to light in general and to PBM in particular [
68]. A number of personal and unavoidable circumstances may also have adversely influenced performance of assessments after the clinic-treatment and home-treatment periods. Future studies will need to take account of the variability in the symptomology of PD participants and enrol sufficient numbers into the study to ensure statistical power to demonstrate improvements in clinical signs and symptoms.
The most noteworthy individual result was the maintenance of improvement in some outcome measures for up to one year with the continued self-administered home treatment. Indeed, some outcome measures such as the MoCA improved further during the home-treatment period and few of the outcome measures declined over this period. As a neurodegenerative disease in which motor and non-motor function would be expected to gradually decline, the improvement with PBM treatment in some of the clinical signs of PD and the preservation of this improvement over time is clinically relevant and worthy of further validation in longer term trials. Longer term treatment in the home setting also appears to be a practical and cost-effective strategy, with the treatment performed by the participant with or without the help of a carer. A second noteworthy result was the diminution of improvement with down-titration of the PBM dose, which resulted in a reversal of some of the most marked improvements at week 4 (such as TS). Dose down-titration is a common strategy in PBM therapy, developed by Chow (personal communication) among others, based on protocols for the relief of pain [
69]. This strategy can inform on the most effective dose of PBM and whether the therapy is able to be reduced or withdrawn, as is the case with pain management and wound healing with PBM. The reversal of the improvements with dose down-titration suggests that the PBM treatment needs to be maintained at a suitable level and that the dosing regimen is central to maximising treatment success. This observation informed on the dose regimen of the home-treatment (3 times per week). Despite the diminution of improvement after week 4, outcome measures remained significantly improved over baseline for the majority of outcome measures during the 12-week clinic-treatment period.
Micrographia is a common and often early sign of PD and can overlap with other signs and symptoms of PD [
70]. There was no significant change in participants’ handwriting during the PBM treatment period, which might indicate a stabilisation rather than the expected decline in participant’s micrographia. The stabilization of handwriting was also noted in a case series using transcranial PBM [
28], with 6 of 6 PD participants showing no decline over 24 months. Dopaminergic therapy and deep brain stimulation have not been shown to slow the decline in writing size [
71].
The placebo effect can be pronounced in clinical trials and is well known in PD therapy [
72]. The current study did not have a placebo arm to quantify the placebo effect, but the related Hawthorne Effect could be assessed. The Hawthorne Effect can occur in response to participation in research or being observed during a study [
73,
74] and has been recognised as a confounder to results in clinical trials of PD [
75], such as the evaluation of gait being affected (although not significantly) by whether the participant was observed overtly or covertly [
76]. The Hawthorne Effect appears to be transient, being short-lived during the treatment period [
75] and much diminished by 3 months [
77]. In the current study, the waitlisted participants (Group B) showed an improvement in outcome measures before treatment began, with some of these improvements being sufficient to qualify as an MCID, thus demonstrating a measurable Hawthorne Effect. The other possibility is that the participants have improved due to a practice effect with the repeated assessments. While possible, it is unlikely to completely explain the improvement during the 14-week period between enrolment and treatment. A practice effect cannot be entirely excluded for subsequent improvement at the 4-week assessment after treatment began and is a potential confounder for this assessment. PD patients have been shown to have a diminished ability for motor learning and require increased practice sessions for balance related tasks, compared to young healthy controls [
78].
While a placebo, Hawthorne or a practice effect as the sole explanation for all improvements seen in this study cannot be entirely ruled out, it appears quite unlikely. Most outcome measures showed continued and accelerated improvement once treatment began (Table
4) and the improvements in outcome measures were maintained throughout the home-treatment period (Table
3, Fig.
3b). The Hawthorne and placebo effects would be expected to be transitory and would, at the minimum, diminish during the home-treatment period when there was no continued interaction with study therapists and researchers. A more thorough randomized placebo-controlled trial is warranted to more fully explore the placebo effect in treatment of PD by PBM.
The mode of action of PBM treatment in PD merits further research. Transcranial PBM has recently been assessed for its effectiveness for a number of brain-related conditions and injuries including stroke [
79], traumatic brain injury [
55], post-traumatic stress disorder [
80], depression [
81] and Alzheimer’s disease [
59]. Transcranial devices have been shown to modulate neural oscillations [
82,
83]. A transcranial device has also been used as a treatment for PD in a series of case studies [
28,
84] with encouraging results, especially for non-motor symptoms. Evidence from experimental and animal models suggests that transcranial PBM could act via the cytochrome-C-oxidase target of near infrared light, to increase ATP and influence downstream cellular signalling to reduce oxidative stress and neuroinflammation and to upregulate synaptogenesis and neurogenesis [
85].
Treatment of areas remote from the injury/disease has been shown to be an effective therapy strategy. For example, targeting the tibia with PBM can help in the repair of cardiac tissue in an animal model [
17]. The mechanism of this systemic effect of PBM is likely to be pluralistic, through the stimulation of stem cells [
17,
24], an immune modulation response [
86], circulating cell-free functional mitochondria [
87], or by circulating chemical messengers [
23]. The use of the 904 nm laser PBM protocol was based on experimental models of remote PD treatment by various wavelengths of LED and laser in a mice model (unpublished data).
The study reported here is the first to use a combination of transcranial and remote abdominal PBM treatment for PD. The abdomen is an appropriate target for remote application of PBM for PD, given the strong gut-brain axis link for the disease and previous results of remote application in animal model studies [
23,
24]. The combination of PBM treatments used in the current study improved mobility and other clinical signs and symptoms of PD, including cognition, possibly by compensating for the loss of neuronal connections caused by the progressive lack of dopamine. Further study is required to ascertain the optimal sites of treatment, the optimal dose regimen and the precise mechanism of action.
Acknowledgements
The authors would like to thank
• Assoc Prof Geoffrey Herkes for support, discussions, assistance with study design and editing the manuscript
• Dr. Joanne Bullock-Saxton for assistance with study design
• Dr. John Tillet for the MDS UPDRS neurological assessment
• Dr. Vincent Pang for considerable help with editing the manuscript
• Ms. Angela Torrisi for assistance in conducting the assessments
• Dr. Dan Johnstone for many useful discussions
• Prof Jonathan Stone for continued encouragement and advice
• Ms. Olivia Nassaris for the ongoing support of Parkinson’s SA
• The participants in the study for their time and commitment
• Parkinson’s SA for financial support to conduct this trial
• Spectro Analytic Irradia AB for the supply of PBM devices used in the study