Photobiomodulation (PBM) utilizes light within the red-to-near-infrared range (lambda = 600-1000 nm) to modulate cellular activity and enhance tissue resilience. Over the past fifteen years, our group has demonstrated, in several preclinical models of Parkinson's disease (PD), that PBM can significantly reduce dopaminergic neurodegeneration. These ef fects appear to arise from the activation of intrinsic self-protective and repair mechanisms, promoting neuronal survival in conditions of stress or injury. Building upon this robust preclinical foundation, we initiated a first-in-human proof-of-concept clinical trial (NCT04261569) involving fourteen patients with early-stage PD. Seven participants received intracranial PBM treatment through a dedicated implantable light-delivery device. All participants are followed for four years with standardized motor and neurological assessments, as well as dopaminergic imaging, to monitor disease progression. After one year, no adverse events have been reported, confirming the safety and tolerability of the intracranial PBM approach. Preliminary one-year outcomes suggest stabilization of motor symptoms in the PBM-treated group, contrasting with the expected decline in untreated PD patients. Although early, these findings indicate that PBM may offer a novel disease-modifying therapeutic strategy. This work highlights the translational potential of light-based neuromodulation and its promise as a safe, non-pharmacological intervention for neurodegenerative diseases, paving the way for larger-scale clinical validation.

Photobiomodulation (PBM) has been shown to protect pancreatic islets under inflammatory or metabolic stress, but its effects during hypoxia-reperfusion remain unclear. We evaluated PBM applied as preconditioning or during hypoxia-reperfusion in MIN6 cells and rodent islets. Hypoxia significantly reduced viability and glucose-stimulated insulin secretion, while PBM failed to prevent these alterations and did not modify mitochondrial parameters. These findings indicate that PBM efficacy is stress-dependent and suggest limited benefit in the context of hypoxia-reperfusion, where mitochondrial dysfunction appears minimal in islet cells.

Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common neurodegenerative diseases, characterized by the progressive loss of synapses and neurons, leading to cognitive and motor decline. Their pathophysiology includes cerebral lesions, oxidative stress, neuroinflammation as well as brain-gut axis microbiota dysbiosis. Preclinical investigations demonstrated that brain photobiomodulation (bPBM) reduces oxidative stress and inflammation, increases cerebral blood flow and enhance neurogenesis and synaptogenesis, which makes bPBM a promising treatment in AD and PD. This review focuses on the clinical application of bPBM in AD and PD. It aims to provide a scientific overview of the current clinical knowledge, review recent clinical studies findings, and describe future directions and upcoming clinical studies. So far, several clinical studies investigated bPBM therapy, at various parameters, both in patients with AD and related dementia, and PD. All demonstrate bPBM safety and bring valuable clinical information regarding efficacy, with particularly promising results in AD. However, their exploratory design and inconsistent quality lead to a low level of evidence, which currently does not support the widespread use of bPBM in clinical practice. Future clinical research should address two gaps: the need for robust double-blinded RCTs vs sham with a higher number of patients and a longer follow-up, and the need for research focusing on dosimetry to determine which bPBM parameters are optimal. The ongoing or unpublished clinical studies on bPBM should fill in this gap.

Islet transplantation has emerged as a therapeutic option for patients with unstable type 1 diabetes (T1D), but significant islet loss during the peri-transplant period—primarily due to inflammation and substrate deprivation stress—limits its efficacy. Photobiomodulation (PBM), a non-invasive therapy using red or near-infrared light to modulate cellular metabolism, has shown promise in enhancing cell survival under stress. However, its impact on pancreatic beta cells and islets under specific stress conditions remains insufficiently characterized. This study aimed to evaluate the protective and functional effects of PBM (670 nm LED light, 2.8 mW/cm²) when applied as a preconditioning or simultaneous treatment on pancreatic beta cells (MIN6) and rat islets exposed to two major types of stress encountered during islet transplantation: substrate deprivation and inflammatory cytokines. The hypothesis tested was that PBM could improve cell viability and insulin secretion under these stress conditions. A series of in vitro experiments were conducted using MIN6 cells and isolated rat islets. PBM was applied either for 24 h before or during stress exposure. Substrate deprivation stress (SDS) was induced by glucose and serum-free medium, while cytokine stress involved incubation with IL-1β, TNF-α, and IFN-γ. Outcomes assessed included cell viability (flow cytometry and confocal microscopy), insulin secretion (GSIS assay), mitochondrial function (mitochondrial membrane potential (MMp), superoxide content, oxygen consumption), and cellular energy metabolism (ATP/ADP content via HPLC). Statistical significance was evaluated using ANOVA and post-hoc tests, with p < 0.05 considered significant. PBM significantly preserved viability in both MIN6 cells and islets subjected to SDS and cytokine stress. Under SDS, PBM mitigated increases in superoxide production and declines in mitochondrial membrane potential and ATP content in MIN6 cells but did not restore insulin secretion or mitochondrial respiration. In cytokine-stressed cells and islets, PBM restored glucose-stimulated insulin secretion and reduced superoxide content but did not significantly impact MMP or ATP/ADP ratios. Protective effects varied by the timing of PBM application and the type of stress, with some differences observed between cell lines and intact islets. PBM exerts beneficial effects on pancreatic beta cell and islet viability and function under stress conditions relevant to islet transplantation, although its mechanisms appear to differ depending on the type of stress. These findings support further investigation into PBM as a preconditioning strategy to enhance islet survival and functionality, potentially improving outcomes in islet transplantation for patients with T1D.

Parkinson s disease (PD) is a progressive neurodegenerative disorder and current treatment options only tackle symptoms. We aimed to evaluate the effect of intracranial photobiomodulation (iPBM) on dopaminergic neurons and its consequences on motor symptoms in de novo PD patients. This randomised open label study included 6 de novo PD patients, 3 served as control and 3 were treated by chronic iPBM during 2 years. They were included from december 2020 to april 2022. Researcher analysing the PET data was unaware of patients iPBM status but clinical examinator was aware of it. Data analysis was performed on June 2024. De novo PD patients were recruited and randomized (1:1) to receive iPBM or medical treatment alone for 4 years. PD diagnosis was < 2 years, and no medication was allowed at inclusion. PET scan was performed at baseline and at 1 year This randomized clinical trial was performed in France, at Clinatec-CEA research center and University Hospital, Grenoble and in CERMEP, Lyon, France. Primary outcome was safety. The secondary outcome measure was the evolution at 2 years of motor scales using the MDS-UPDRS part III and the evolution of PET scan (using the [11C]-PE2I ligand) at 1 year. Six patients (1f, 5m) were recruited with a mean age (SD) of 55.3 years (7.6). We showed that iPBM was feasible and safe on the first 3 operated patients. The first novelty of the study was that iPBM improved motor scores in average at 2 years whereas the control group followed the natural clinical decline. Mean (SD) clinical outcome with iPBM was -6.2% (32.9%) improvement on the MDS-UPDRS (part III) compared to baseline versus +130% (143%) for control group. The second novelty was that in the iPBM group, [11C]-PE2I PET scans showed an unusual mean increase in tracer binding within the caudate +21.3%(15.9), nucleus accumbens +22.2%(23.7%), pallidum +89.7% (94.8%) and putamen +26.1%(34%). in the control group, as expected, tracer binding was decreased (SD) on average in the caudate -16.9%(-16.3%), nucleus accumbens -27.5%(-28.4%), and putamen -19.5%(-11.4%), but slightly increased in the pallidum +10.7%(+39.6%). Because of the small number of patients, no statistical test was performed at this stage. Conclusions: iPBM was feasible and safe in this small group of patients. It showed an unusual improvement of motor scores at 2 years that was associated with striking increase of dopamine transporter in the basal ganglia observed on the [11C]-PE2I PET. These preliminary data suggest a possible modifying disease effect related to iBPM. A larger number of patients with longer follow up is mandatory to validate our preliminary results. ### Competing Interest Statement SC is consultant for Medtronic and Boston Scientific ST has received consultant fees from Abbvie, Boston Scientific, Medtronic and payements for lectures from MERZ, Movement Disorders Society, NHC, Aguettant ### Clinical Trial NCT04261569 ### Funding Statement This study was funded by Boston Scientific and the Edmond J Safra Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The details of the Institutional Review Board (IRB) or oversight body that approved or provided exemption for the research described in this manuscript are outlined below: All analyses conducted as part of the present study were approved by the Comite de Protection des Personnes Phones Alpes Auvergne (2019-A02097-50) April 2020 and received additional authorization from the French National Agency for the Safety of Medicines and Health Products (ANSM) in January 2020. The treatment and handling of data adhered to all applicable ethical regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study will be available upon reasonable request to the authors, after completion of the study

In this work, we introduce the design and fabrication of an innovative multi-sensor system integrated into a knee implant, aimed at the early detection of postoperative complications. This system incorporates pH and temperature sensors for infection detection, accelerometers for measuring flexion angles, and force and moment sensors to identify postoperative complications, particularly mechanical issues. A 13.56 MHz RFID-based system was employed for power and data transmission. Collaborative efforts with clinicians and project partners were crucial in designing, testing, and validating the prototype, with initial experiments conducted on cadaveric specimens.

This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm(2), from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM's protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy.

IntroductionDiabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation.MethodsThis review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database.ResultsThis review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM’s full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM’s impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance.ConclusionClinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

Sleep is a critical part of our daily routine. It impacts every organ and system of our body, from the brain to the heart and from cellular metabolism to immune function. A consistent daily schedule of quality of sleep makes a world of difference to our health and well-being. Despite its importance, so many individuals have trouble sleeping well. Poor quality sleep has such a detrimental impact on many aspects of our lives; it affects our thinking, learning, memory, and movements. Further, and most poignantly, poor quality sleep over time increases the risk of developing a serious medical condition, including neurodegenerative disease. In this review, we focus on a potentially new non-pharmacological treatment that improves the quality of sleep. This treatment, called photobiomodulation, involves the application of very specific wavelengths of light to body tissues. In animal models, these wavelengths, when applied at night, have been reported to stimulate the removal of fluid and toxic waste-products from the brain; that is, they improve the brain’s inbuilt house-keeping function. We suggest that transcranial nocturnal photobiomodulation, by improving brain function at night, will help improve the health and well-being of many individuals, by enhancing the quality of their sleep.

During islets transplantation 50% are destroyed at the time of transplantation due to several stresses (ischemia-reperfusion, IBMIR). Light absorption in the near infrared range, Photobiomodulation (PBM), was shown to have a positive impact on wound healing and cell regeneration in different pathologies (e.g., Parkinson’s disease) but few data on pancreatic islets. We studied the impact of PBM (670nm by LED, 2mw/cm²) on MIN6 and rat islets before or during stresses: 1) substrate deprivation (1.5 hours in glucose and serum-free medium for islets, 24 hours for MIN6), 2) cytokines cocktail (24-hour with IL1-β 600IU/mL, IFN-γ 6000IU/mL and TNF-α 6000IU/mL for both), or 3) hypoxia (16 hours, 1% O2 for both), in presence or not of PBM. Viability was checked (confocal microscopy or FACS) and glucose stimulated insulin secretion (GSIS) was performed (index insulin secretion = [insulin] in 16.7mM dextrose/ [insulin] in 2.8mM). For MIN6 the production of superoxide (Mitosox) and mitochondrial membrane potential (TMRM) were performed by FACS. Substrate deprivation-induced islet mortality (25.9 +/- 8.67%, n=12, p<0.001) was reduced if PBM was performed 24h before stress (15.7 +/- 8.34%, p<0.05) or during stress (16.0 +/- 9.19%, p<0.01), as for MIN6. No impact of PBM was observed regarding islets GSIS. Index of MIN6 insulin secretion exposed to substrate deprivation was decreased compared to control (1.07 +/- 0.52 vs. 2.00 +/- 0.55, n=8, p<0.05). If PBM was performed before or during the deprivation stress, MIN6 exhibited similar GSIS than control (p=0.55 and p=0.59). Cytokines-induced islet mortality (34.7 +/- 7.32%, n=5, p<0.05) is reduced if PBM is performed 24 hours before stress (26.9 +/- 4.27%, p<0.05) or during stress (26.7 +/- 4,59%, p<0.05), as for MIN6. Index of islets insulin secretion was decreased compared to control (0.82 +/- 0.22 vs 1.43 +/- 0.50, n=4, p<0.05) and restored only if PBM was applied during the stress (1.66 +/- 0.95, p<0.05). Protective effect of PBM was observed regarding the production of superoxide and restauration of mitochondrial membrane potential of MIN6 stressed by substrate deprivation or cytokines. Hypoxia-induced islet mortality (27.3 +/- 11.9%, n = 8, p<0.01) remained unchanged if PBM was performed during stress (24.2 +/- 11.5%, p=0.923); as for MIN6 cells. Index of islet insulin secretion was decreased by hypoxia compared to control (0.99 +/- 0.05 vs. 1.52 +/- 0.17, n=8, p<0.05) and no effect was observed with PBM; as for MIN6 cells. Exposure of islets to PBM prior or during cytokine exposure and substrate deprivation increase viability and improve functionality of MIN6 and pancreatic islets. Further experiments will be conducted on human islets to confirm these results. So far, our results suggest that islets exposure to PBM could be transposed in clinic as preconditioning of islet after isolation, before transplantation in order to improve their viability and functionality upon transplantation.

While several studies have demonstrated the metabolic benefits of islet transplantation in unstable diabetes,1 there are still major challenges to overcome. For example, over 50% of islets are destroyed at the time of transplantation due to the instant blood-mediated inflammation reaction and cytokine stress.2 The islets' resting period after isolation (24-72 hours) appears to be an opportune time to improve islet viability and possibly protect them from the consequences of instant blood-mediated inflammation reaction.

Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.

Over the last seventy years or so, many previous studies have shown that photobiomodulation, the use of red to near infrared light on body tissues, can improve central and peripheral neuronal function and survival in both health and in disease. These improvements are thought to arise principally from an impact of photobiomodulation on mitochondrial and non-mitochondrial mechanisms in a range of different cell types, including neurones. This impact has downstream effects on many stimulatory and protective genes. An often-neglected feature of nearly all of these improvements is that they have been induced during the state of wakefulness. Recent studies have shown that when applied during the state of sleep, photobiomodulation can also be of benefit, but in a different way, by improving the flow of cerebrospinal fluid and the clearance of toxic waste-products from the brain. In this review, we consider the potential differential effects of photobiomodulation dependent on the state of arousal. We speculate that the effects of photobiomodulation is on different cells and systems depending on whether it is applied during wakefulness or sleep, that it may follow a circadian rhythm. We speculate further that the arousal-dependent photobiomodulation effects are mediated principally through a biophoton – ultra-weak light emission – network of communication and repair across the brain.

>A great challenge in neuroscience has been to understand how neurons communicate. The neuroanatomists of the 19 th Century could see neurons stretching processes to contact other neurons, but could not see the detail of the contact. Many thought that neurons formed a syncytium, with continuity of membranes from one to the next.

In the context of organ shortage for transplantation, new criteria for better organ evaluation should be investigated. Ex-vivo lung perfusion (EVLP) allows extra-corporal lung re-conditioning and evaluation, under controlled parameters of the organ reperfusion and mechanical ventilation. This work reports on the interest of exhaled gas analysis during the EVLP procedure. After a 1 h cold ischemia, the endogenous gas production by an isolated lung of nitric oxide and carbon monoxide is simultaneously monitored in real time. The exhaled gas is analysed with two very sensitive and selective laser spectrometers developed upon the technique of optical-feedback cavity-enhanced absorption spectroscopy. Exhaled gas concentration measured for an ex-vivo lung is compared to the corresponding production by the whole living pig, measured before euthanasia. On-line measurements of the fraction of nitric oxide in exhaled gas (FENO) in isolated lungs are reported here for the first time, allowing to resolve the respiratory cycles. In this study, performed on 9 animals, FENO by isolated lungs range from 3.3 to 10.6 ppb with a median value of 4.4 ppb. Pairing ex-vivo lung and pig measurements allows to demonstrate a systematic increase of FENO in the ex-vivo lung as compared to the living animal, by a factor of 3 ± 1.2. Measurements of the fraction of carbon monoxide in exhaled gas (FECO) confirm levels recorded during previous studies driven to evaluate FECO as a potential marker of ischemia reperfusion injuries. FECO production by ex-vivo lungs ranges from 0.31 to 2.3 ppm with a median value of 0.8 ppm. As expected, these FECO values are lower than the production by the corresponding whole pig body, by a factor of 6.9 ± 2.7.

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.

Background Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. Methods We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18-45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4-C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. Findings Between June 12,2017, and July 21,2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-andtouch tasks and wrist rotations, using a virtual avatar at home (64.0% [SD 5.1] success) or an exoskeleton in the laboratory (70.9% [11.6] success). Compared with rnicroelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. Interpretation These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain-machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

In this study, we examined the cellular distribution of encephalopsin (opsin 3; OPN3) expression in the striatum of non-human primates. In addition, because of our long standing interest in Parkinson's disease and neuroprotection, we examined whether parkinsonian (MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) insult and/or photobiomodulation (670 nm) had any impact on encephalopsin expression in this key area of the basal ganglia. Striatal sections of control naïve monkeys, together with those that were either MPTP- and/or photobiomodulation-treated were processed for immunohistochemistry. Our results revealed two populations of striatal interneurones that expressed encephalopsin, one of which was the giant, choline acetyltransferase-containing, cholinergic interneurones. The other population had smaller somata and was not cholinergic. Neither cell group expressed the calcium-binding protein, parvalbumin. There was also rich encephalopsin expression in a set of terminals forming striosome-like patches across the striatum. Finally, we found that neither parkinsonian (MPTP) insult nor photobiomodulation had any effect on encephalopsin expression in the striatum. In summary, our results revealed an extensive network of encephalopsin containing structures throughout the striatum, indicating that external light is in a position to influence a range of striatal activities at both the interneurone and striosome level.

Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson’s disease (PD) patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI) using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF) administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials.

In this study, we explored the effects of a longer term application, up to 12 weeks, of photobiomodulation in normal, naïve macaque monkeys. Monkeys (n = 5) were implanted intracranially with an optical fibre device delivering photobiomodulation (red light, 670 nm) to a midline midbrain region. Animals were then aldehyde-fixed and their brains were processed for immunohistochemistry. In general, our results showed that longer term intracranial application of photobiomodulation had no adverse effects on the surrounding brain parenchyma or on the nearby dopaminergic cell system. We found no evidence for photobiomodulation generating an inflammatory glial response or neuronal degeneration near the implant site; further, photobiomodulation did not induce an abnormal activation or mitochondrial stress in nearby cells, nor did it cause an abnormal arrangement of the surrounding vasculature (endothelial basement membrane). Finally, because of our interest in Parkinson’s disease, we noted that photobiomodulation had no impact on the number of midbrain dopaminergic cells and the density of their terminations in the striatum. In summary, we found no histological basis for any major biosafety concerns associated with photobiomodulation delivered by our intracranial approach and our findings set a key template for progress onto clinical trial on patients with Parkinson’s disease.