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Exploring the Use of Intracranial and Extracranial (Remote) Photobiomodulation Devices in Parkinson’s Disease: A Comparison of Direct and Indirect Systemic Stimulations
Abstract
In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson’s disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson’s disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson’s disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson’s disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.
... More recently (2021), TPBM has been shown to be beneficial in animal models of Parkinson's disease as it improves movement behavior and is neuroprotective. Early observations in people with Parkinson's disease have also been positive, with improvements seen most consistently in the non-motor symptoms of the disease [23]. Although the exact mechanisms behind these improvements are not clear, two procedures have been proposed: direct stimulation, in which light reaches and acts directly on neurons, and remote stimulation, in which light affects cells and/or molecules that provide systemic protection and thereby acts indirectly on disturbed neurons. ...
... For indirect systemic stimulation, PBM could be applied either to the head using a transcranial helmet or via a more remote body part (e.g., abdomen, leg). However, currently, the evidence for both the direct and indirect neuroprotective effects of PBM in Parkinson's disease is discussed, and it is also stated that at present both types of treatment modalities, when combined with intracranial and extracranial devices, represent the best possible therapeutic option of the PBM [23]. ...
... rect and indirect neuroprotective effects of PBM in Parkinson's disease is discussed, and it is also stated that at present both types of treatment modalities, when combined with intracranial and extracranial devices, represent the best possible therapeutic option of the PBM [23]. ...
Helmet designs have not only been used successfully in integrative medicine for decades in acupuncture research, but they are also increasingly being used in the field of transcranial photobiomodulation (TPBM), primarily in so-called mental diseases. The author of this article has been dealing with developed helmet constructions for neuromonitoring for over 25 years and not only gives an overview of the development of these methods, but also shows new methods and perspectives. The future of this branch of research certainly lies in the development of so-called sensor-controlled therapy helmets for TPBM.
... Finally, in animal studies and clinical trials, almost all studies performed PBM directly at the target tissue. However, increasing studies over the past several years demonstrated that the beneficial effects of PBM therapy are not limited to irradiated tissue [150,151]. However, the indirect or remote PBM therapy mechanisms remain to be understood. ...
... However, the indirect or remote PBM therapy mechanisms remain to be understood. More studies on the remote PBM therapy have far-reaching implications on the therapeutic application of PBM in AD as the brain is a difficult-to-irradiate organ [150,151]. ...
... Ethics approval and consent to participate Not applicable. [96] • There are still have conflicting data doubting whether it is the primary acceptor or target of PBM therapy [148,149] • The precise mechanisms of PBM treatment, especially the exact mechanisms of pulsed-wave PBM therapy in AD, remain elusive [69,70] • The effects and mechanisms of indirect or remote PBM therapy remain to be understood [150,151] rTMS • Evidence regarding long-term efficacy and exact underlying mechanisms is still limited [153] • More advanced clinical trials are still needed to find the therapeutic window [153] • No agreement on the parameters and protocols of rTMS therapy at which a medication appeared to be effective in the clinical application of AD [153] • More studies on the regulation of mitochondria and glial cells' transformation are needed • The safety of rTMS treatment needs to be clarified [234] tDCS • No standard protocols regarding the clinical use of tDCS [278] • Finds ways to extend the after-effect of the tDCS [247] • The effect of anodal and cathodal tDCS needs to be clarified [234] • More studies are required to investigate the specific target of tDCS Exercise • No agreement on the optimal dosages, the best types of exercise, and the optimal timing of initiation of physical exercise for prevention or slowing down AD • The effects of exercise in different types of memory tasks are variable [9,44,282,342] • The gender difference is one of the major factors that need to be considered [343] • More animal and human studies are still required to elucidate the underlying molecular mechanism of physical activity in AD (for instance, the effectiveness of exercise on BBB) [310,344] ...
Alzheimer’s disease (AD) is one of the major neurodegenerative diseases and the most common form of dementia. Characterized by the loss of learning, memory, problem-solving, language, and other thinking abilities, AD exerts a detrimental effect on both patients’ and families’ quality of life. Although there have been significant advances in understanding the mechanism underlying the pathogenesis and progression of AD, there is no cure for AD. The failure of numerous molecular targeted pharmacologic clinical trials leads to an emerging research shift toward non-invasive therapies, especially multiple targeted non-invasive treatments. In this paper, we reviewed the advances of the most widely studied non-invasive therapies, including photobiomodulation (PBM), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and exercise therapy. Firstly, we reviewed the pathological changes of AD and the challenges for AD studies. We then introduced these non-invasive therapies and discussed the factors that may affect the effects of these therapies. Additionally, we review the effects of these therapies and the possible mechanisms underlying these effects. Finally, we summarized the challenges of the non-invasive treatments in future AD studies and clinical applications. We concluded that it would be critical to understand the exact underlying mechanisms and find the optimal treatment parameters to improve the translational value of these non-invasive therapies. Moreover, the combined use of non-invasive treatments is also a promising research direction for future studies and sheds light on the future treatment or prevention of AD.
... Overall risk of bias for animal studies was high across most studies, as illustrated in Figure 4. benefits to those observed with transcranial delivery 29 . In animal models however, direct stimulation appears to carry greater benefit 66,67 . The mechanism for this is not known, but has been proposed as activation of remote immune and stem cells which become systemically active after PBM 66 . ...
... In animal models however, direct stimulation appears to carry greater benefit 66,67 . The mechanism for this is not known, but has been proposed as activation of remote immune and stem cells which become systemically active after PBM 66 . It is noteworthy here that the deep brain target in Parkinson's disease (substantia nigra) receives significantly attenuated doses in humans, even with transcranial application. ...
Photobiomodulation (PBM) is a therapeutic modality which has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include anti-apoptotic and anti-inflammatory effects. This systematic review summarises the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models; and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favour intervention versus control. Sub-group analysis based on PBM parameter variables for these outcomes was performed. Favourable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤ 4 hours; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic sub-studies within included in vivo studies are presented and were found to support hypotheses of anti-apoptotic, anti-inflammatory and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Consideration of study design and PBM parameters should be closely considered for future human clinical studies.
... There is an agreement that apoptotic mechanisms are the main leading cause of DA neuron death in PD. The apoptotic process, a slow breakdown of cellular components, is mediated by two major mechanisms including Lewy body accumulation and mitochondrial dysfunction [264,265]. Photobiomodulation, which refers to the application of red to infrared wavelength (λ = 600-1070 nm) on body tissues through influences of mitochondrial activity, exerts beneficial effects in PD studies. For that reason, photobiomodulation has been reported as a potential therapeutic option for neurodegenerative diseases such as PD [266][267][268]. ...
Parkinson's disease (PD) is a common age-related neurodegenerative disorder whose pathogenesis is not completely understood. Mitochondrial dysfunction and increased oxidative stress have been considered as major cause and central event responsible for the progressive degeneration of dopaminergic (DA) neurons in PD. Therefore, investigating mitochondrial disorders plays a role in understanding the pathogenesis of PD and can be an important therapeutic target for this disease. This study discusses the effect of environmental, genetic and biological factors on mitochondrial dysfunction and also focuseson the mitochondrial molecular mechanisms underlying neurodegeneration, and its possible therapeutic targets in PD, including reactive oxygen species generation, calcium overload, inflammasome activation, apoptosis, mitophagy, mitochondrial biogenesis, and mitochondrial dynamics. Other potential therapeutic strategies such as mitochondrial transfer/transplantation, targeting microRNAs, using stem cells, photobiomodulation, diet, and exercise were also discussed in this review, which may provide valuable insights into clinical aspects. A better understanding of the roles of mitochondria in the pathophysiology of PD may provide a rationale design of novel therapeutic interventions in our fight against PD.
... There have been some studies that have explicitly resolved this exact issue. In a study of PBM for Parkinson's disease in a mouse model [43]. Mitrofanis et al., contrasted conveying light with the mouse head, and furthermore concealed the head with aluminium foil so they conveyed light to the rest of the mouse body. ...
Photobiomodulation (PBM) portrays the utilization of red or near infrared light to stimulate, heal, recover, and protect tissue that has either been harmed, is degenerating, or, else likely is in risk of dying. The brain experiences various issues that can be ordered into three general groupings: traumatic (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric (depression, anxiety, post-traumatic stress disorder). There is some proof that this multitude of apparently different circumstances can be advantageously impacted by applying light to the head. There is even the likelihood that PBM could be utilized for cognitive enhancement in normal healthy individuals. In this transcranial PBM (tPBM) application, near infrared (NIR) light is frequently applied to the forehead in view of the better entrance (no hair, longer wavelength). A few workers have utilized lasers, yet as of late the presentation of modest light emitting diode (LED) arrays has permitted the improvement of light radiating head helmets or "brain caps". This review will cover the mechanisms of action of photobiomodulation to the brain and sum up some of the key pre-clinical studies and clinical trials that have been embraced for different brain disorders.
... Most applications of PBM focus on the local effects on tissue that is directly exposed to far-red or NIR light. However, indirect systemic effects of PBM on wound-healing, lung inflammation, and Parkinson's disease have been demonstrated [18,[26][27][28]. The deeper skin penetration of NIR compared to other visible light (red or blue) might contribute to the broader beneficial responses [29]. ...
Modern urban human activities are largely restricted to the indoors, deprived of direct sunlight containing visible and near-infrared (NIR) wavelengths at high irradiance levels. Therapeutic exposure to doses of red and NIR, known as photobiomodulation (PBM), has been effective for a broad range of conditions. In a double-blind, randomized, placebo-controlled study, we aimed to assess the effects of a PBM home set-up on various aspects of well-being, health, sleep, and circadian rhythms in healthy human subjects with mild sleep complaints. The effects of three NIR light (850 nm) doses (1, 4, or 6.5 J·cm−2) were examined against the placebo. Exposure was presented five days per week between 9:30 am and 12:30 pm for four consecutive weeks. The study was conducted in both summer and winter to include seasonal variation. The results showed PBM treatment only at 6.5 J·cm−2 to have consistent positive benefits on well-being and health, specifically improving mood, reducing drowsiness, reducing IFN-γ, and resting heart rate. This was only observed in winter. No significant effects on sleep or circadian rhythms were noted. This study provides further evidence that adequate exposure to NIR, especially during low sunlight conditions, such as in the winter, can be beneficial for human health and wellness.
... PBM is known to improve tissue healing, promote cell survival, and reduce inflammation and oxidative stress [18][19][20]. In recent pilot clinical trials, PBM treatment has been shown to improve neuropathology and disease progression in mouse models of AD and to provide cognitive improvement trends in patients with dementia and AD [21][22][23][24][25]. PBM is considered to induce neuroprotection by direct stimulation into or onto the skull, but indirect (remote) PBM stimulation through targeting another part of the body (e.g., abdomen or leg) can also induce a neuroprotective effect [26][27][28][29][30]. While the mechanism by which this occurs remains unknown, some researchers hypothesize that it probably involves the stimulation of one or more circulating molecules or cell types. ...
Background:
Recent innovative non-pharmacological interventions and neurostimulation devices have shown potential for application in the treatment of Alzheimer's disease (AD). These include photobiomodulation (PBM) therapy.
Objective:
This pilot study assesses the safety, compliance with, and efficacy of a brain-gut PBM therapy for mild-to-moderate AD patients.
Methods:
This double-blind, randomized, monocentric sham-controlled study started in 2018 and ended prematurely in 2020 due to the COVID-19 pandemic. Fifty-three mild-to-moderate AD patients were randomized, 27 in the PBM group and 26 in the sham group. All patients had 40 treatment sessions lasting 25 min each over 8 weeks and were followed for 4 weeks afterwards. Compliance with the treatment was recorded. Safety was assessed by recording adverse events (AEs), and efficacy was evaluated using neuropsychological tests.
Results:
The PBM therapy proved to be safe in regard to the number of recorded AEs (44% of the patients), which were balanced between the PBM and sham groups. AEs were mainly mild, and no serious AEs were reported. The majority of the patients (92.5%) were highly compliant, which confirms the feasibility of the PBM treatment. Compared to the sham patients, the PBM patients showed higher ADAS-Cog comprehension sub-scores and forward verbal spans, and lower TMT-B execution times, which suggests an improvement in cognitive functions.
Conclusion:
This study demonstrates the tolerability of and patient compliance with a PBM-based treatment for mild-to-moderate AD patients. It highlights encouraging efficacy trends and provides insights for the design of the next phase trial in a larger AD patient sample.
... There are numerous examples of the benefits of indirect PBM application (that is PBM not specifically directed towards the site of the injury/disease) in both animal models and humans, including in cardiovascular disease [130,131], diabetic retinopathy [132], Alzheimer's disease [133], Parkinson's disease [134,135], in lung injury [104,136] and potentially depression [137]. Thus, there are arguments for combining direct (targeted) and indirect (remote) PBM for therapeutic benefit [138]. Clearly more studies are needed to understand the mechanistic basis of PBM to provide an opportunity to use this non-pharmacological therapy for CKD. ...
Chronic kidney disease (CKD) is a growing global public health problem. The implementation of evidence-based clinical practices only defers the development of kidney failure. Death, transplantation, or dialysis are the consequences of kidney failure, resulting in a significant burden on the health system. Hence, innovative therapeutic strategies are urgently needed due to the limitations of current interventions. Photobiomodulation (PBM), a form of non-thermal light therapy, effectively mitigates mitochondrial dysfunction, reactive oxidative stress, inflammation, and gut microbiota dysbiosis, all of which are inherent in CKD. Preliminary studies suggest the benefits of PBM in multiple diseases, including CKD. Hence, this review will provide a concise summary of the underlying action mechanisms of PBM and its potential therapeutic effects on CKD. Based on the findings, PBM may represent a novel, non-invasive and non-pharmacological therapy for CKD, although more studies are necessary before PBM can be widely recommended.
... Mechanistically, this results in enhanced mitochondrial electron transport capacity, reduced mitochondrial ROS formation and improved ATP-levels, as recently reviewed for muscle stem cells (Calabrese and Calabrese, 2022). A large body of research demonstrates the potential of this approach for PD (Johnstone et al., 2021;Salehpour and Hamblin, 2020). ...
Mitochondrial health is based on a delicate balance of specific mitochondrial functions (e.g. metabolism, signaling, dynamics) that are impaired in neurodegenerative diseases. Rescuing mitochondrial function by selectively targeting mitochondrial stressors, such as reactive oxygen species, inflammation or proteotoxic insults (“bottom-up” approaches) thus is a widely investigated therapeutic strategy. While successful in preclinical studies, these approaches have largely failed to show clear clinical benefits. Promoting the capacity of mitochondria - and other cellular components - to restore a healthy cellular environment is a promising complementary or alternative approach. Herein, we provide a non-technical overview for neurologists and scientists interested in brain metabolism on neuroprotective strategies targeting mitochondria and focus on top-down interventions such as metabolic modulators, exercise, dietary restriction, brain stimulation and conditioning. We highlight general conceptual differences to bottom-up approaches and provide hypotheses on how these mechanistically comparatively poorly characterized top-down therapies may work, discussing notably mitochondrial stress responses and mitohormesis.
... The aim of this Mini-Forum is to present the current state of the art in the application of photobiomodulation therapy for dementia, Alzheimer's disease, and other brain conditions. The first paper from the Mitrofanis group addresses the interesting question of whether direct PBM to the brain (either by a transcranial approach or an intracranial approach) is better than a systemic approach where the light delivered to the abdomen or leg to treat Parkinson's disease in animal models [9]. The next contribution from the Zhang group used transcranial PBM to treat the TgF344 rat model of Alzheimer's disease [10]. ...
This systematic review examines the effect of photobiomodulation (PBM), the application of red to near infrared light on body tissues, on the neuroinflammatory response and oxidative stress in animal models of neurodegenerative diseases. The research question and search protocol were prospectively registered on the PROSPERO database. Neurodegenerative diseases are becoming ever more prevalent in the ageing populations across the Western world, with no disease-modifying or neuroprotective treatment options being available. Hence there is a real need for the development of effective treatment options for patients. Inflammatory responses and oxidative stress within the central nervous system have a strong correlation with neuronal cell death. PBM is a non-invasive therapeutic option that has shown efficacy and promising effects in animal models of neurodegenerative disease; many studies have reported neuroprotection and improved behavioural outcomes. To the best of our knowledge, there has been no previous study that has reviewed the anti-inflammatory and the antioxidant effect of PBM in the context of neurodegeneration. This review has examined this relationship in animal models of a range of neurodegenerative diseases. We found that PBM can effectively reduce glial activation, pro-inflammatory cytokine expression and oxidative stress, whilst increasing anti-inflammatory glial responses and cytokines, and antioxidant capacity. These positive outcomes accompanied the neuroprotection evident after PBM treatment. Our review provides further indication that PBM can be developed into an effective non-pharmacological intervention for neurodegenerative diseases.
Background
This case-report explores the effects of photobiomodulation therapy (PBMT) on the healing of scar tissue. The patient was a 32-year old female two years post cholecystectomy resulting in a 15 cm linear scar that was causing severe pain.
Methods
Treatment was initiated using the BIOFLEX® therapist device which consists of LED arrays and laser probes of a specific wavelength, power and frequency applied directly on the skin overlying the scar. The frequency and duration of treatment was every other day for six weeks in a clinic setting, followed by three times a week for two months at home. Then the patient continued to use the BIOFLEX® therapist home device on an as-needed basis.
Findings
The final result of this patient's treatment was significant flattening and decreased redness of her scar. Her self-reported pain decreased to a 6/10. At the one year follow up, the patient reported that she stopped taking her opioids, antidepressant and sleeping pills and that her pain decreased to a 4/10. At the last review her pain score was 1/10; and she had returned to work and took Tylenol (acetaminophen) occasionally for breakthrough pain.
Conclusions
We attribute the patient's improvement in scar appearance and pain symptoms to PBMT. Since pain is often associated with depressed mood and sleep disturbances, it cannot be determined whether PBMT was the direct or indirect cause of this patient's improved mood. For future studies, we propose the use of control subjects with similar scars treated with sham treatment compared to those who will receive the PBMT and observed for the same duration of time and compare the overall results.
Lay Summary
Dermatological applications, especially wound healing; are accepted indications for photobiomodulation therapy (PBMT). The expansion into other clinical applications, particularly neurological ones show potential benefit. We present a case of a patient with a hypertrophic scar associated with severe neuropathic pain and concurrent depression, all of which improved directly or indirectly with PBMT. Although the original focus of treatment was dermatological the improvement in pain plus the discontinuation of therapy (opioids, antidepressants and benzodiazepines) were considered to be due to the PBMT.
In the last 25 years, helmet designs have made a significant contribution to the knowledge gained in acupuncture research and subsequently in photobiomodulation therapy. In principle, a distinction can be made between helmets that have diagnostic or monitoring functions and those that cause transcranial stimulating effects as part of therapeutic procedures. Both types are discussed in this article. The reporting is supplemented by current studies, which mainly refer to possible therapeutic effects of such helmet constructions. Future scenarios include research in the field of transcranial helmet functions, which include both variants, namely the development of sensor-controlled therapy helmets.
Parkinson's disease (PD) is a neurodegenerative disease with global burden. The mechanisms and therapeutic effects of photobiomodulation (PBM) correspond to main mechanisms in the pathogenesis of PD. Numerous research results applying PBM for PD were published during the past two decades. Although several systematic review or review articles provided complete introduction, they are either mainly basic research or clinical research, and the year of the article publication is up to 2020. Comprehensive systematic review or review articles containing basic and clinical studies including those articles published in 2021 and 2022 are lacking. Hence, this systematic review aimed to include both basic and clinical studies published up to 2022. Results were obtained by retrieving articles from PubMed with the intersection of the articles derived from the terms of PBM synonyms and Parkinson's disease followed by exclusion. Sixty-nine articles were included ultimately. Among them, 40 original articles were identified, which were composed of 31 basic research and 9 original articles of clinical research. Twenty-one review articles, a systematic review with focused content on PD, and 7 review articles with the term PD under general illustration of PBM were presented. Mechanisms regarding the therapeutic effects of PBM on the in vitro studies were reviewed. Positive outcomes on motor symptoms after PBM treatments were shown in most in vivo and clinical studies. The immunohistochemical examination of in vivo studies reflect the therapeutic effects of PBM on the preservation even reverse of the pathogenic insults of PD on the in vitro studies. The most frequently used wavelength among original articles included was 670nm. Considering the acceptability of PBM for patients with PD, noninvasive transcranial PBM (tPBM) had crucial roles in respect to invasive intracerebral PBM. To match the penetration depth reaching deep brain target, Substantia nigra pars compacta, in human brains of patients with PD, the wavelength 810nm might match the need in the clinical setting of tPBM. More future clinical studies were needed. In conclusion, therapeutic approaches applying PBM for PD are promising. Recent studies revealed positive outcomes. Future clinical practices containing PBM are to be expected.
Chronic pain is a debilitating neurological disorder which affects hundreds of millions of people worldwide. Neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are non-addictive alternatives for managing chronic neuropathic pain that is refractory to conventional medical management. SCS and DRGS apply sequences of brief electrical impulses to neural tissue. However, not all patients receiving these therapies obtain adequate pain relief, and patient outcomes are not improving despite decades of clinical experience and advancements in stimulation technology. This dissertation addresses two crucial knowledge gaps limiting the success of neurostimulation therapies: 1) we do not understand the physiological mechanisms of electrical stimulation-induced pain relief, and 2) we do not understand the sources of variability affecting the neural response to stimulation. The first portion of this thesis examined the mechanisms of action of DRGS. We developed statistical models of neural element (i.e., cell bodies, axons) locations in histological samples of human dorsal root ganglia (DRG) tissue. Next, we employed a histologically informed field-cable modeling approach to study the neural response to DRGS. We coupled a finite element method model of the potential distribution generated by DRGS to multi-compartment cable models of DRG neurons to simulate which types of sensory neurons are activated by therapeutic DRGS. Our data suggest that clinical DRGS directly activates the subset of sensory neurons that code nonpainful touch sensations, which may trigger pain-inhibition neural networks in the spinal cord dorsal horn. The second portion of this thesis investigated how biological variability at different scales (e.g., single cells, patient anatomy) affected the neural response to stimulation. We implemented a Markov Chain Monte Carlo (MCMC) method to parametrize populations of neurons with heterogeneous ion channel expression profiles. We incorporated this approach in our field-cable model of DRGS and showed that variability in ion channel expression can affect the stimulation amplitude required to generate activity in target neurons. We further applied this populationmodeling approach to investigate how pathology induced changes in ion channel expression can affect the behavior of neural circuits governing sensory transmission. Finally, we developed a framework for constructing patient-specific field-cable models of patients receiving SCS. This framework captured the effect of key anatomical details (e.g., the amount of cerebrospinal fluid between a patient’s SCS electrode array and the spinal cord) on neural activation during stimulation. Furthermore, this patient-specific modeling framework allows the comparison of model predictions of neural activation during SCS with clinical data, such as patient-reported outcomes (e.g., pain relief). The results of this dissertation suggest that DRGS may share mechanisms of action with other neurostimulation therapies for pain management, such as SCS. This dissertation also developed frameworks for studying the effect of biological variability on the nervous system’s response to electrical stimulation. To develop safe and effective therapies for neurological disorders, it is crucial to understand both the physiological mechanisms of symptom relief, and how the neural response to therapy may vary across cells, circuits, and patients. This dissertation provides novel insights on both aspects as they relate to neurostimulation for chronic pain.
Using fMRI (functional magnetic resonance imaging), we explored the effect of transcranial photobiomodulation on four major resting-state brain networks, namely the sensorimotor, salience, default mode and central executive networks, in normal young subjects. We used a vielight transcranial device (810 nm) and compared the scans in 20 subjects (mean age 30.0 ± 2.8 years) after active- and sham-photobiomodulation sessions. Four sets of analysis—independent components, network connectivity, infra-slow oscillatory power and arterial spin labelling—were undertaken. Our results showed that when comparing pre- with post-active and pre- with post-sham photobiomodulation scans, there were no substantial differences in activity across any of the four resting-state networks examined, indicating no clear photobiomodulation effect. When taken together with previous findings, we suggest that the impact of photobiomodulation becomes much clearer only after brain circuitry is altered, for example, after a neurone undergoes some change in its equilibrium or homeostasis, either during pathology or ageing, or during a change in functional activity when individuals are engaged in a specific task (e.g. evoked brain activity).
One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory research and medical practitioners who are not exposed to highly specialized journals. This review covers the literature on photobiomodulation therapy as a novel approach to prevent and treat Alzheimer's disease, aiming to bridge that gap by gathering together the terms and technical specifications into a single concise suggestion for a treatment protocol. In light of the predicted doubling in the number of people affected by dementia and Alzheimer's disease within the next 30 years, a treatment option which has already shown promising results in cell culture studies and animal models, and whose safety has already been proven in humans, must not be left in the dark. This review covers the mechanistic action of photobiomodulation therapy against Alzheimer's disease at a cellular level. Safe and effective doses have been found in animal models, and the first human case studies have provided reasons to undertake large-scale clinical trials. A brief discussion of the minimally effective and maximum tolerated dose concludes this review, and provides the basis for a successful translation from bench to bedside.
Photobiomodulation (PBM) might be an effective treatment for Parkinson’s disease (PD) in human patients. PBM of the brain uses red or near infrared light delivered from a laser or an LED at relatively low power densities, onto the head (or other body parts) to stimulate the brain and prevent degeneration of neurons. PD is a progressive neurodegenerative disease involving the loss of dopamine-producing neurons in the substantia nigra deep within the brain. PD is a movement disorder that also shows various other symptoms affecting the brain and other organs. Treatment involves dopamine replacement therapy or electrical deep brain stimulation. The present systematic review covers reports describing the use of PBM to treat laboratory animal models of PD, in an attempt to draw conclusions about the best choice of parameters and irradiation techniques. There have already been clinical trials of PBM reported in patients, and more are expected in the coming years. PBM is particularly attractive as it is a non-pharmacological treatment, without any major adverse effects (and very few minor ones).
Mitochondria are considered as the power-generating units of the cell due to their key role in energy metabolism and cell signaling. However, mitochondrial components could be found in the extracellular space, as fragments or encapsulated in vesicles. In addition, this intact organelle has been recently reported to be released by platelets exclusively in specific conditions. Here, we demonstrate for the first time, that blood preparation with resting platelets, contains whole functional mitochondria in normal physiological state. Likewise, we show, that normal and tumor cultured cells are able to secrete their mitochondria. Using serial centrifugation or filtration followed by polymerase chain reaction-based methods, and Whole Genome Sequencing, we detect extracellular full-length mitochondrial DNA in particles over 0.22 µm holding specific mitochondrial membrane proteins. We identify these particles as intact cell-free mitochondria using fluorescence-activated cell sorting analysis, fluorescence microscopy, and transmission electron microscopy. Oxygen consumption analysis revealed that these mitochondria are respiratory competent. In view of previously described mitochondrial potential in intercellular transfer, this discovery could greatly widen the scope of cell-cell communication biology. Further steps should be developed to investigate the potential role of mitochondria as a signaling organelle outside the cell and to determine whether these circulating units could be relevant for early detection and prognosis of various diseases.
Objective: The objective of this review is to consider the dual effects of microbiome and photobiomodulation (PBM) on human health and to suggest a relationship between these two as a novel mechanism. Background: PBM describes the use of low levels of visible or near-infrared (NIR) light to heal and stimulate tissue, and to relieve pain and inflammation. In recent years, PBM has been applied to the head as an investigative approach to treat diverse brain diseases such as stroke, traumatic brain injury (TBI), Alzheimer's and Parkinson's diseases, and psychiatric disorders. Also, in recent years, increasing attention has been paid to the total microbial population that colonizes the human body, chiefly in the gut and the mouth, called the microbiome. It is known that the composition and health of the gut microbiome affects many diseases related to metabolism, obesity, cardiovascular disorders, autoimmunity, and even brain disorders. Materials and methods: A literature search was conducted for published reports on the effect of light on the microbiome. Results: Recent work by our research group has demonstrated that PBM (red and NIR light) delivered to the abdomen in mice, can alter the gut microbiome in a potentially beneficial way. This has also now been demonstrated in human subjects. Conclusions: In consideration of the known effects of PBM on metabolomics, and the now demonstrated effects of PBM on the microbiome, as well as other effects of light on the microbiome, including modulating circadian rhythms, the present perspective introduces a new term "photobiomics" and looks forward to the application of PBM to influence the microbiome in humans. Some mechanisms by which this phenomenon might occur are considered.
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain’s vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain’s vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.
Photobiomodulation (PBM) provides neuroprotection against dopaminergic cell death and associated motor deficits in rodent and primate models of Parkinson’s disease (PD). However, it has not yet been tested in the lipopolysaccharide (LPS) model of PD, which leads to dopaminergic cell death through microglia-evoked neuroinflammation. We investigated whether transcranial PBM could protect against dopaminergic cell death within the substantia nigra in male Sprague–Dawley rats following supranigral LPS injection. PBM fully protected rats from 10 µg LPS which would have otherwise caused 15% cell loss, but there was no significant neuroprotection at a 20 µg dose that led to a 50% lesion. Cell loss at this dose varied according to the precise site of injection and correlated with increased local numbers of highly inflammatory amoeboid microglia. Twenty microgram LPS caused motor deficits in the cylinder, adjusted stepping and rotarod tests that correlated with dopaminergic cell loss. While PBM caused no significant improvement at the group level, motor performance on all three tests no longer correlated with the lesion size caused by 20 µg LPS in PBM-treated rats, suggesting extranigral motor improvements in some animals. These results provide support for PBM as a successful neuroprotective therapy against the inflammatory component of early PD, provided inflammation has not reached a devastating level, as well as potential benefits in other motor circuitries.
Transcranial photobiomodulation (tPBM) is the application of low levels of red or near-infrared (NIR) light to stimulate neural tissues. Here, we administer tPBM in the form of NIR light (810 nm wavelength) pulsed at 40 Hz to the default mode network (DMN), and examine its effects on human neural oscillations, in a randomized, sham-controlled, double-blinded trial. Using electroencephalography (EEG), we found that a single session of tPBM significantly increases the power of the higher oscillatory frequencies of alpha, beta and gamma and reduces the power of the slower frequencies of delta and theta in subjects in resting state. Furthermore, the analysis of network properties using inter-regional synchrony via weighted phase lag index (wPLI) and graph theory measures, indicate the effect of tPBM on the integration and segregation of brain networks. These changes were significantly different when compared to sham stimulation. Our preliminary findings demonstrate for the first time that tPBM can be used to non-invasively modulate neural oscillations, and encourage further confirmatory clinical investigations.
Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670nm light (4J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.
This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the stresses that induce tissue resilience in mammals arise from everyday sources: sunlight, food, lack of food, hypoxia and physical stresses. At low levels, these stresses induce an organised protective response in probably all tissues; and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, we term this system ‘acquired resilience’. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life.
Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.
Introduction
Photobiomodulation was assessed as a novel treatment of Alzheimer’s disease (AD) by the use of a new device RGn500 combining photonic and magnetic emissions in a mouse model of AD.
Methods
Following the injection of amyloid β 25-35 peptide in male Swiss mice, RGn500 was applied once a day for 7 days either on the top of the head or the center of abdomen or both.
Results
RGn500 daily application for 10 min produced a neuroprotective effect on the neurotoxic effects of amyloid β 25-35 peptide injection when this type of photobiomodulation was applied both on the head and on the abdomen. Protection was demonstrated by memory restoration and on the normalization of key markers of AD (amyloid β 1-42, pTau), oxidative stress (lipid peroxidation), apoptosis (Bax/Bcl2) and neuroinflammation.
Discussion
RGn500 displays therapeutic efficacy similar to other pharmacological approaches evaluated in this model of AD.
Current treatments for Parkinson’s disease (PD) are primarily symptomatic, leaving a need for treatments that mitigate disease progression. One emerging neuroprotective strategy is remote tissue conditioning, in which mild stress in a peripheral tissue (e.g. a limb) induces protection of life-critical organs such as the brain. We evaluated the potential of two remote tissue conditioning interventions – mild ischemia and photobiomodulation – in protecting the brain against the parkinsonian neurotoxin MPTP. Further, we sought to determine whether combining these two interventions provided any added benefit.
Male C57BL/6 mice (n = 10/group) were pre-conditioned with either ischemia of the leg (4 × 5 min cycles of ischemia/reperfusion), or irradiation of the dorsum with 670 nm light (50 mW/cm², 3 min), or both interventions, immediately prior to receiving two MPTP injections 24 hours apart (50 mg/kg total). Mice were sacrificed 6 days later and brains processed for tyrosine hydroxylase immunohistochemistry.
Stereological counts of functional dopaminergic neurons in the substantia nigra pars compacta revealed that both remote ischemia and remote photobiomodulation rescued around half of the neurons that were compromised by MPTP (p < 0.001). Combining the two interventions provided no added benefit, rescuing only 40% of vulnerable neurons (p < 0.01).
The present results suggest that remote tissue conditioning, whether ischemia of a limb or photobiomodulation of the torso, induces protection of brain centers critical in PD. The lack of additional benefit when combining these two interventions suggests they may share common mechanistic pathways. Further research is needed to identify these pathways and determine the conditioning doses that yield optimal neuroprotection.
Transcranial infrared laser stimulation (TILS) at 1064 nm, 250 mW/cm² has been proven safe and effective for increasing neurocognitive functions in young adults in controlled studies using photobiomodulation of the right prefrontal cortex. The objective of this pilot study was to determine whether there is any effect from TILS on neurocognitive function in older adults with subjective memory complaint at risk for cognitive decline (e.g., increased carotid artery intima-media thickness or mild traumatic brain injury). We investigated the cognitive effects of TILS in older adults (ages 49–90, n = 12) using prefrontal cortex measures of attention (psychomotor vigilance task (PVT)) and memory (delayed match to sample (DMS)), carotid artery intima-media thickness (measured by ultrasound), and evaluated the potential neural mechanisms mediating the cognitive effects of TILS using exploratory brain studies of electroencephalography (EEG, n = 6) and functional magnetic resonance imaging (fMRI, n = 6). Cognitive performance, age, and carotid artery intima-media thickness were highly correlated, but all participants improved in all cognitive measures after TILS treatments. Baseline vs. chronic (five weekly sessions, 8 min each) comparisons of mean cognitive scores all showed improvements, significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). The neural studies also showed for the first time that TILS increases resting-state EEG alpha, beta, and gamma power and promotes more efficient prefrontal blood-oxygen-level-dependent (BOLD)-fMRI response. Importantly, no adverse effects were found. These preliminary findings support the use of TILS for larger randomized clinical trials with this non-invasive approach to augment neurocognitive function in older people to combat aging-related and vascular disease-related cognitive decline.
Intracranial application of red to infrared light, known also as photobiomodulation (PBM), has been shown to improve locomotor activity and to neuroprotect midbrain dopaminergic cells in rodent and monkey models of Parkinson’s disease. In this study, we explored whether PBM has any influence on the number of tyrosine hydroxylase (TH)+cells and the expression of GDNF (glial-derived neurotrophic factor) in the striatum. Striatal sections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice and monkeys and 6-hydroxydopamine (6OHDA)-lesioned rats that had PBM optical fibres implanted intracranially (or not) were processed for immunohistochemistry (all species) or western blot analysis (monkeys). In our MPTP monkey model, which showed a clear loss in striatal dopaminergic terminations, PBM generated a striking increase in striatal TH+ cell number, 60% higher compared to MPTP monkeys not treated with PBM and 80% higher than controls. This increase was not evident in our MPTP mouse and 6OHDA rat models, both of which showed minimal loss in striatal terminations. In monkeys, the increase in striatal TH+ cell number in MPTP-PBM cases was accompanied by similar increases in GDNF expression, as determined from western blots, from MPTP and control cases. In summary, these results offer insights into the mechanisms by which PBM generates its beneficial effects, potentially with the use of trophic factors, such as GDNF.
Objective:
This study investigated whether patients with mild to moderately severe dementia or possible Alzheimer's disease (AD) with Mini-Mental State Exam (MMSE) Baseline scores of 10-24 would improve when treated with near-infrared photobiomodulation (PBM) therapy.
Background:
Animal studies have presented the potential of PBM for AD. Dysregulation of the brain's default mode network (DMN) has been associated with AD, presenting the DMN as an identifiable target for PBM.
Materials and methods:
The study used 810 nm, 10 Hz pulsed, light-emitting diode devices combining transcranial plus intranasal PBM to treat the cortical nodes of the DMN (bilateral mesial prefrontal cortex, precuneus/posterior cingulate cortex, angular gyrus, and hippocampus). Five patients with mild to moderately severe cognitive impairment were entered into 12 weeks of active treatment as well as a follow-up no-treatment, 4-week period. Patients were assessed with the MMSE and Alzheimer's Disease Assessment Scale (ADAS-cog) tests. The protocol involved weekly, in-clinic use of a transcranial-intranasal PBM device; and daily at-home use of an intranasal-only device.
Results:
There was significant improvement after 12 weeks of PBM (MMSE, p < 0.003; ADAS-cog, p < 0.023). Increased function, better sleep, fewer angry outbursts, less anxiety, and wandering were reported post-PBM. There were no negative side effects. Precipitous declines were observed during the follow-up no-treatment, 4-week period. This is the first completed PBM case series to report significant, cognitive improvement in mild to moderately severe dementia and possible AD cases.
Conclusions:
Results suggest that larger, controlled studies are warranted. PBM shows potential for home treatment of patients with dementia and AD.
Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or “brain caps”. This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.
We have reported previously that intracranial application of near-infrared light (NIr) reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson’s disease. In this study, we explored whether NIr reduces the gliosis in this animal model. Sections of midbrain (containing the substantia nigra pars compacta; SNc) and striatum were processed for glial fibrillary acidic protein (to label astrocytes; GFAP) and ionised calcium-binding adaptor molecule 1 (to label microglia; IBA1) immunohistochemistry. Cell counts were undertaken using stereology, and cell body sizes were measured using ImageJ. Our results showed that NIr treatment reduced dramatically (~75 %) MPTP-induced astrogliosis in both the SNc and striatum. Among microglia, however, NIr had a more limited impact in both nuclei; although there was a reduction in overall cell size, there were no changes in the number of microglia in the MPTP-treated monkeys after NIr treatment. In summary, we showed that NIr treatment influenced the glial response, particularly that of the astrocytes, in our monkey MPTP model of Parkinson’s disease. Our findings raise the possibility of glial cells as a future therapeutic target using NIr.
Cardinal motor features of Parkinson’s disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.
We have shown previously that near-infrared light (NIr), when applied at the same time as a parkinsonian insult (e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP), reduces behavioural deficits and offers neuroprotection. Here, we explored whether the timing of NIr intervention-either before, at the same time or after the MPTP insult-was important. Mice received MPTP injections (total of 50 mg/kg) and, at various stages in relation to these injections, extracranial application of NIr. Locomotor activity was tested with an open-field test, and brains were processed for immunohistochemistry. Our results showed that regardless of when NIr was applied in relation to MPTP insult, behavioural impairment was reduced by a similar magnitude. The beneficial effect of NIr was fast-acting (within minutes) and long-lasting (for several days). There were more dopaminergic cells in the NIr-treated MPTP groups than in the MPTP group; there was no clear indication that a particular combination of NIr treatment and MPTP injection resulted in a higher cell number. In summary, irrespective of whether it was applied before, at the same time as or after MPTP insult, NIr reduced both behavioural and structural measures of damage by a similar magnitude. There was a broad therapeutic time window of NIr application in relation to the stage of toxic insult, and the NIr was fast-acting and long-lasting.
Alzheimer's and Parkinson's disease are the two most common neurodegenerative disorders. They develop after a progressive death of many neurons in the brain. Although therapies are available to treat the signs and symptoms of both diseases, the progression of neuronal death remains relentless, and it has proved difficult to slow or stop. Hence, there is a need to develop neuroprotective or disease-modifying treatments that stabilize this degeneration. Red to infrared light therapy (λ = 600–1070 nm), and in particular light in the near infrared (NIr) range, is emerging as a safe and effective therapy that is capable of arresting neuronal death. Previous studies have used NIr to treat tissue stressed by hypoxia, toxic insult, genetic mutation and mitochondrial dysfunction with much success. Here we propose NIr therapy as a neuroprotective or disease-modifying treatment for Alzheimer's and Parkinson's patients.
Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM), may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human α-synuclein (α-syn) in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD). In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated α-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies.
Objective:
To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease.
Methods:
We implanted an optical fibre device that delivered NIr (670nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a five to seven day period, during which time the NIr device was turned on. This was then followed by a three week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviourally (open field test) and their brains were processed for immunohistochemistry and stereology.
Results:
All monkeys in the MPTP group developed severe clinical and behavioural impairment (mean clinical scores, 21-34; n=11). By contrast, the MPTP-NIr group developed much less clinical and behavioural impairment (n=9); some monkeys developed moderate clinical signs (mean scores 11-15; n=3), while the majority - quite remarkably - developed few clinical signs (mean scores 1-6; n=6). The monkeys that developed moderate clinical signs had haematic fluid in their optical fibres at post-mortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs.
Interpretation:
Our findings indicated NIr as an effective therapeutic agent in a primate model of the disease and lay the template for translation into clinical trial. This article is protected by copyright. All rights reserved.
Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied.Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo.PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers.PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy.
Previous work assumed that ATP synthase, the smallest known rotary motor in nature, operates at 100% efficiency. Calculations which arrive to this result assume that the water viscosity inside mitochondria is constant and corresponds to that of bulk water. In our opinion this assumption is not satisfactory for two reasons: (1) There is evidence that the water in mitochondria prevails to 100% as interfacial water. (2) Laboratory experiments which explore the properties of interfacial water suggest viscosities which exceed those of bulk water, specifically at hydrophilic interfaces. Here, we wish to suggest a physicochemical mechanism which assumes intramitochondrial water viscosity gradients and consistently explains two cellular responses: The decrease and increase in ATP synthesis in response to reactive oxygen species and non-destructive levels of near-infrared (NIR) laser light, respectively. The mechanism is derived from the results of a new experimental method, which combines the technique of nanoindentation with the modulation of interfacial water layers by laser irradiation. Results, including the elucidation of the principle of light-induced ATP production, are expected to have broad implications in all fields of medicine.
The objective of this study was to investigate factors affecting health-related quality of life (HRQoL) among Estonian persons with Parkinson's disease (PD).
268 persons with PD were evaluated using: the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS); the Hoehn and Yahr scale (HY); the Schwab and England Activities of Daily Living scale (SE-ADL); the Beck Depression Inventory (BDI); the Mini Mental State Examination (MMSE); the Parkinson's Disease Questionnaire (PDQ-39). Additional questions on clinical and socio-demographic variables were asked during a semi-structured interview. Predictors of HRQoL were tested using multiple regression analysis.
The main predictors of low HRQoL were depression and motor and non-motor aspects of daily living. 59.9 % of the variation in the PDQ-39 summary index (SI) score was explained by the predictive variables identified in this study. None of the socio-demographic variables (age, gender, urban/rural living, marital status, living alone/with others, education level) were significant predictors of HRQoL. Prevalence of non-motor Parkinson's symptoms were high (99.6 %); cognitive impairment, sleep and urinary problems were the most common. All non-motor symptoms correlated significantly with low HRQoL, except the features of impulse control disorders (ICDs).
Depression and motor and non-motor daily living experiences were found to be significant and independent factors of low HRQoL in persons with PD. Depression was the strongest determinant of low HRQoL. Our results highlight the importance of recognition and management of non-motor symptoms, as these features had more impact on patients' HRQoL than clinically assessed motor symptoms.
Cognitive impairment is a significant non-motor symptom of Parkinson's disease (PD). Longitudinal cohort studies have demonstrated that approximately 50% of those with PD develop dementia after 10 years, increasing to over 80% after 20 years. Deficits in cognition can be identified at the time of PD diagnosis in some patients and this mild cognitive impairment (PD-MCI) has been studied extensively over the last decade. Although PD-MCI is a risk factor for developing Parkinson's disease dementia there is evidence to suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses. The major pathological correlate of Parkinson's disease dementia is Lewy body deposition in the limbic system and neocortex although Alzheimer's related pathology is also an important contributor. Pathological damage causes alteration to neurotransmitter systems within the brain, producing behavioural change. Management of cognitive impairment in PD requires a multidisciplinary approach and accurate communication with patients and relatives is essential.
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We explore whether near infrared light can change patterns of resting (task-negative) and/or evoked (task-positive; eg finger-tapping) brain activity in normal, young human subjects using fMRI (functional magnetic resonance imaging). To this end, we used a vielight transcranial device (810nm) and compared the scans in subjects after active- and sham-light sessions. Our fMRI results showed that, while light had no effect on cerebral blood flow and global resting state brain activity (task-negative), there were clear differences between the active- and sham-light sessions in the patterns of evoked brain activity after finger-tapping (task-positive). The evoked brain regions included the putamen, primary somatosensory and parietal association cortex, and the overall effect of the light was to suppress or reduce their activity. We also found that while light had no effect on the resting functional connectivity of the putamen and primary somatosensory cortex and the rest of the brain, it did have an effect on the functional connectivity of parietal association cortex. In summary, our fMRI findings indicated that transcranially applied light did have a major impact on brain activity in normal subjects, but only when the brain region was itself functionally active, when undertaking a particular task. We suggest that these light-induced changes, particularly those in parietal association cortex, were associated with attention and novelty, and served to deactivate the so-called default mode network. Our results lay the template for our planned fMRI explorations into the effects of light in both Alzheimer's and Parkinson's disease patients.
Background and objective: Photobiomodulation (PBM) therapy is a promising and non-invasive approach to stimulate neuronal function and improve brain repair. The optimization of PBM parameters is important to maximize effectiveness and tolerability. Several studies have reported on the penetration of visible-to-near-infrared (NIR) light through various animal and human tissues. Scientific findings on the penetration of PBM light vary, likely due to use of different irradiation parameters and to different characteristics of the subject such as species, age, and gender.
Materials and methods: In this paper, we review published data on PBM penetration through the tissues of the head in both animal and human species. The patterns of visible-to-NIR light penetration are summarized based on the following study specifications: wavelength, coherence, operation mode, beam type and size, irradiation site, species, age, and gender.
Results: The average penetration of transcranial red/NIR (630-810 nm) light ranged 60-70% in C57BL/6 mouse (skull), 1-10% in BALB/c mouse (skull), 10-40% in Sprague-Dawley rats (scalp plus skull), 20% in Oryctolagus cuniculus rabbit (skull), 0.11% in pig (scalp plus skull), and 0.2-10% in humans (scalp plus skull). The observed variation in the reported values is due to the difference in factors (e.g., wavelengths, light coherence, tissue thickness, and anatomic irradiation site) employed by researchers. It seems that these data challenge the applicability of the animal models data on transcranial PBM to humans. Nevertheless, two animal models seem particularly promising, as they approximate penetration in humans: (I) Penetration of 808 nm laser through the scalp plus skull was 0.11% in the pig head; (II) Penetration of 810 nm laser through intact skull was 1.75% in BALB/c mouse.
Conclusions: In conclusion, it is worthwhile mentioning that since the effectiveness of brain PBM is closely dependent on the amount of light energy reaching the target neurons, further quantitative estimation of light penetration depth should be performed to validate the current findings.
Background:
Parkinson's disease is a well-known neurological disorder with distinct motor signs and non-motor symptoms.
Objective:
We report on six patients with Parkinson's disease that used in-house built photobiomodulation (PBM) helmets.
Methods:
We used "buckets" lined with light-emitting diodes (LEDs) of wavelengths across the red to near-infrared range (i.e., 670, 810, and 850 nm; n = 5) or an homemade intranasal LED device (660 nm; n = 1). Progress was assessed by the patients themselves, their spouse, or their attending medical practitioners.
Results:
We found that 55% of the initial signs and symptoms of the six patients showed overall improvement, whereas 43% stayed the same and only 2% got worse. We also found that PBM did not target a specific sign or symptom, with both motor and nonmotor ones being affected, depending on the patient.
Conclusions:
In summary, our early observations are the first to note the impact of PBM on patients' signs and symptoms over an extended period, up to 24 months, and lays the groundwork for further development to clinical trial.
Over the past few decades there has been a dramatic increase in scientific research into photobiomodulation (PBM) therapy, both to treat injury or illness and to enhance normal function or performance. More recently, substantial focus has been placed on PBM of the brain and nervous system, with a range of preclinical studies and some clinical trials yielding promising results. Naturally, almost all studies have reported on the effects of PBM when light is targeted directly at the tissue under investigation. However, a small number of studies over the years, increasing in frequency in recent times, have provided evidence that the beneficial effects of PBM are not confined to the irradiated tissue. Instead, it appears that PBM can elicit systemic effects that promote protection of remote tissues. While the mechanisms remain to be understood, this phenomenon of a body-wide response to localised PBM treatment has far-reaching implications, both for our understanding of basic biology as well as the therapeutic application of PBM, particularly for difficult-to-irradiate organs such as the brain.
Photobiomodulation (PBM) therapy is based on the use of specific light parameters to promote tissue repair. Although demonstrated in different cell models and tissues, the mechanism by which photobiomodulation operates is not well understood. Previous studies suggested that the cell proliferation enhancement triggered by red and near-infrared PBM involves the activation of the mitochondrial respiratory chain enzyme cytochrome c oxidase (CCO). It was suggested that light in this range would displace inhibitory nitric oxide bound to CCO. To test this mechanism, we took advantage of cell lines lacking CCO, including a mouse line knockout for Cox10 (a gene required for the synthesis of heme a, the prosthetic group of CCO) and a human cell line with an mtDNA mutation in the tRNA Lysine gene, leading to mitochondrial protein synthesis impairment and the lack of three critical CCO subunits. In both models we showed the complete absence of assembled CCO. PBM (660 nm) was applied to these proliferating cells using various parameters. In most of the conditions tested, increased cell proliferation was associated with PBM in both control and CCO negative cells, demonstrating that CCO is not required for PBM enhancement of cellular proliferation. Additional experiments showed that PBM increased both ATP levels and citrate synthase activity and levels. These results showed that although metabolic changes are associated with PBM, CCO is not required for its cell proliferation enhancing effect.
Red‐light treatment is emerging as a novel therapy for promoting tissue recovery but data on red‐light penetration through human tissues are lacking. We aimed to: i) determine the effect of light irradiance, tissue thickness, skin tone, sex, and bone/muscle content on 660 nm light penetration through common sites of sports injuries, and ii) establish if cadaver tissues serve as a useful model for predicting red‐light penetration in live tissues. Live and cadaver human tissues were exposed to 660 nm light at locations across the skull, spinal cord and upper and lower limbs. Red‐light was produced by a light emitting diode array of various irradiances (15‐500 mW/cm²) and measured by a light‐probe positioned on the tissue surface opposite the LEDs. 100 mW/cm² successfully penetrated tissue < 50 mm thick; a disproportionate irradiance increase was required to achieve deeper penetration. Penetration was unaffected by skin tone, increased with irradiance and relative bone/muscle composition, and decreased with greater tissue thickness and in males. Live and cadaveric tissue penetration did not differ statistically for tissues < 50 mm but cadavers required more red‐light to penetrate > 50 mm. These results assist clinicians and researchers in determining red‐light treatment intensities for penetrating human tissues.
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Objective:
To examine the effects of transcranial and intranasal photobiomodulation (PBM) therapy, administered at home, in patients with dementia.
Background:
This study sought to replicate and build upon a previously published case series report describing improved cognitive function in five patients with mild-to-moderate dementia after 12 weeks of transcranial and intranasal near-infrared (NIR) PBM therapy.
Materials and methods:
Eight participants (mean age: 79.8 ± 5.8 years old) diagnosed with dementia by their physicians were randomized to 12 weeks of usual care (UC, n = 4) or home PBM treatments (n = 4). The NIR PBM treatments were administered by a study partner at home three times per week with the Vielight Neuro Gamma device. The participants were assessed with the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale and the Neuropsychiatric Inventory (NPI) at baseline and 6 and 12 weeks, and with arterial spin-labeled perfusion magnetic resonance imaging (MRI) and resting-state functional MRI at baseline and 12 weeks.
Results:
At baseline, the UC and PBM groups did not differ demographically or clinically. However, after 12 weeks, there were improvements in ADAS-cog (group × time interaction: F1,6 = 16.35, p = 0.007) and NPI (group × time interaction: F1,6 = 7.52, p = 0.03), increased cerebral perfusion (group × time interaction: F1,6 = 8.46, p < 0.03), and increased connectivity between the posterior cingulate cortex and lateral parietal nodes within the default-mode network in the PBM group.
Conclusions:
Because PBM was well tolerated and associated with no adverse side effects, these results support the potential of PBM therapy as a viable home treatment for individuals with dementia.
The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha‐synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD‐linked pathology creates translational opportunities for slowing or stopping disease progression. This article is protected by copyright. All rights reserved.
Parkinson disease is the second-most common neurodegenerative disorder that affects 2–3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.
We have shown previously that when applied separately, 670 nm and 810 nm near infrared light (NIr) reduces behavioural deficits and offers neuroprotection in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson’s disease. Here, we explored the beneficial outcomes when these NIr wavelengths were applied both together, either concurrently (at the same time) or sequentially (one after the other). Mice received MPTP injections (total of 50 mg/kg) and had extracranial application of 670 nm and/or 810 nm NIr. Behavioural activity was tested with an open-field test and brains were processed for tyrosine hydroxylase immunohistochemistry and stereology. Our results showed that when 670 nm and 810 nm NIr were applied both together and sequentially, there was a greater overall beneficial outcome − increased locomotor activity and number of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta − than when they were applied either separately, or in particular, both together and concurrently. In summary, our findings have important implications for future use of NIr therapy in humans, that there are some combinations of wavelengths that provide more beneficial outcome than others.
Photobiomodulation (PBM) using red or near-infrared (NIR) light has been used to stimulate the proliferation and differentiation of adipose-derived stem cells. The use of NIR wavelengths such as 810 nm is reasonably well accepted to stimulate mitochondrial activity and ATP production via absorption of photons by cytochrome c oxidase. However, the mechanism of action of 980 nm is less well understood. Here we study the effects of both wavelengths (810 nm and 980 nm) on adipose-derived stem cells in vitro. Both wavelengths showed a biphasic dose response, but 810 nm had a peak dose response at 3 J/cm² for stimulation of proliferation at 24 h, while the peak dose for 980 nm was 10–100 times lower at 0.03 or 0.3 J/cm². Moreover, 980 nm (but not 810 nm) increased cytosolic calcium while decreasing mitochondrial calcium. The effects of 980 nm could be blocked by calcium channel blockers (capsazepine for TRPV1 and SKF96365 for TRPC channels), which had no effect on 810 nm. To test the hypothesis that the chromophore for 980 nm was intracellular water, which could possibly form a microscopic temperature gradient upon laser irradiation, we added cold medium (4 °C) during the light exposure, or pre-incubated the cells at 42 °C, both of which abrogated the effect of 980 nm but not 810 nm. We conclude that 980 nm affects temperature-gated calcium ion channels, while 810 nm largely affects mitochondrial cytochrome c oxidase.
Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types. Furthermore, single nucleotide polymorphism (SNP)-specific changes in transcription factor binding are correlated with heritable alterations in chromatin state and considered a major mediator of sequence-dependent regulation of gene expression. Here we describe a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells. By generating a genetically precisely controlled experimental system, we identify a common Parkinson's disease associated risk variant in a non-coding distal enhancer element that regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson's disease. Our data suggest that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. This work establishes an experimental paradigm to functionally connect genetic variation with disease-relevant phenotypes.
OBJECT
The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6-hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson’s disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective.
METHODS
Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis.
RESULTS
The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other “symptomatic” elements contributing to behavioral improvements in these rats.
CONCLUSIONS
In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats.
Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer while in other cases the interactions are more distant and might be considered separate. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.
Copyright © 2015 Elsevier Ltd. All rights reserved.
We explored whether 810nm near-infrared light (NIr) offered neuroprotection and/or improvement in locomotor activity in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. Mice received MPTP and 810nm NIr treatments, or not, and were tested for locomotive activity in an open-field test. Thereafter, brains were aldehyde-fixed and processed for tyrosine hydroxylase immunohistochemistry. Our results showed that MPTP-treated mice that were irradiated with 810nm NIr had both greater locomotor activity (∼40%) and number of dopaminergic cells (∼20%) than those that were not. In summary, 810nm (as with 670nm) NIr offered neuroprotection and improved locomotor activity in MPTP-treated mice.
Copyright © 2014. Published by Elsevier Ireland Ltd.