Publications scientifiques
Les équipes de recherche de Clinatec publient très régulièrement leurs travaux dans des revues internationales. Retrouvez ci-dessous leurs dernières publications.
Exploring current and future technologies to make sense of the biophoton phenomenon: a narrative review (2024)
Hoh Kam J; Billères M; Hérault L; Cali C; Sarmiento B; Cassano P; Magistretti P; Mitrofanis J
Advanced Technology in Neuroscience 1(2):p 201-210, December 2024. | DOI: 10.4103/ATN.ATN-D-24-00019
Biophotons is the very weak light generated by cells. This light has been shown to change with different states of cell activity and/or cell health. Although their precise significance is still not clear, biophotons are thought to function as a means of cell-to-cell communication and cell repair. In this narrative review, we consider first, the current technology available that detects biophotons. These include (1) photomultipliers: these devices have advantages of giving real-time outputs, cover a relatively large detection area and have a low dark-noise per unit detection ability; their quantum efficiency is not great however and they do not have the ability to capture images; (2) image detectors: can capture images with an ultra-sensitive camera, together with count photons from living tissue; their process of acquiring an image can take a long time however, and their photon counts are less accurate than those obtained with photomultipliers and (3) histological methods: that relies on the reduction of silver (Ag)+ to Ag that is thought to mark sites of photon activation and can be identified with a light microscope; there are however, some issues on how this reduction process affects the tissue and whether it can influence biophoton count. Next, we consider prospects for future methods that may determine both the functional significance of biophotons, together with how their detection can be used clinically. The development of better technology in the field of biophoton research can reveal a better understanding of how the brain functions under both normal and pathological conditions.
Trace Toxins: The Key Component of a Healthful Diet (2024)
Stone, J., Mason, R., Mitrofanis, J., & Johnstone, D. M. J
Dose-response : a publication of International Hormesis Society, 22(3), 15593258241271692. https://doi.org/10.1177/15593258241271692
Although it is well established that a vegetable-rich (Mediterranean) diet is associated with health benefits in later life, the mechanisms and biological origins of this benefit are not well established. This review seeks to identify the components a healthful diet that reduce the individual’s suffering from non-communicable disease and extend longevity. We note the difference between the claims made for an essential diet (that prevents deficiency syndromes) and those argued for a diet that also prevents or delays non-communicable diseases and ask: what chemicals in our food induce this added resilience, which is effective against cardiovascular and neurodegenerative diseases, diabetes and even cancer? Working in the framework of acquired resilience (tissue resilience induced by a range of stresses), we arguethat the toxins evolved by plants as part of allelopathy (the competition between plant species) are key in making the ‘healthful difference’. We further suggest the recognition of a category of micronutrients additional to the established ‘micro’ categories of vitamins and trace elements and suggest also that the new category be called ‘trace toxins’. Implications of these suggestions are discussed.
A spotlight on dosage and subject selection for effective neuroprotection: exploring the central role of mitochondria (2024)
Mitrofanis, J., Stone, J., Hamblin, M., Magistretti, P., Benabid, AL., Jeffery, G.
Neural regeneration research, ():10.4103/NRR.NRR-D-24-00222, June 03, 2024. | DOI: 10.4103/NRR.NRR-D-24-00222
Neurons are notoriously vulnerable cell types. Even the slightest change in their internal and/or external environments will cause much distress and dysfunction, leading often to their death. A range of pathological conditions, including stroke, head trauma, and neurodegenerative disease, can generate stress in neurons, affecting their survival and proper function. In most neural pathologies, mitochondria become dysfunctional and this plays a pivotal role in the process of cell death. The challenge over the last few decades has been to develop effective interventions that improve neuronal homeostasis under pathological conditions. Such interventions, often referred to as disease-modifying or neuroprotective, have, however, proved frustratingly elusive, at both preclinical and, in particular, clinical levels. In this perspective, we highlight two factors that we feel are key to the development of effective neuroprotective treatments. These are: firstly, the choice of dose of intervention and method of application, and secondly, the selection of subjects, whether they be patients or the animal model. We use the method of red to near-infrared light (λ = 600–1300 nm) treatment as our prime example of why these factors are so important. We then suggest that mitochondria within the distressed neurons form central players in the process and that these organelles, already known to be able to induce cell death, can be the targets for successful neuroprotective intervention.
Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice (2024)
Lau, A. A., Jin, K., Beard, H., Windram, T., Xie, K., O’Brien, J. A., Neumann, D., King, B. M., Snel, M. F., Trim, P. J., Mitrofanis, J., Hemsley, K. M., & Austin, P. J.
Journal of neurochemistry, 10.1111/jnc.16145. Advance online publication. https://doi.org/10.1111/jnc.16145
Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10–14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.
Does photobiomodulation require glucose to work effectively? (2024)
Hoh Kam, J., & Mitrofanis, J.
Neural regeneration research, 19(5), 945–946. https://doi.org/10.4103/1673-5374.385290
A main requirement for cells to function normally is the availability of glucose. Glucose, available either direct from circulation or storage, is converted to the essential energy that cells need to drive critical intrinsic functions. If cells are deprived of glucose, they become dysfunctional and suffer distress. Photobiomodulation, the use of specific wavelengths of light on body tissues, has been shown to promote, through small organelles called mitochondria, the metabolism of glucose to make energy for cells; this energy can be used to improve cell function and survival. In this perspective, we hypothesize that the availability of glucose is central to the core mechanism of photobiomodulation; that photobiomodulation is at its most efficient in stimulating mitochondrial activity and improving cell function when there is glucose readily available.
Photobiomodulation promotes the functionality and viability of human pancreatic islets in basal conditions and under cytokine stress conditions (2024)
Perrier, Q., Tubbs, E., Benhamou, P. Y., Moro, C., & Lablanche, S.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 24(3), 506–508. https://doi.org/10.1016/j.ajt.2023.10.014
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) corresponds to low-level laser therapy with selective absorption of wavelengths using chromophores, mainly at the mitochondrial level,3 with demonstrated effects in neurologic stimulation and wound healing. Few data are available on insulin-secreting cells: Liebman et al4 showed a significant increase in insulin secretion of BT6 cells exposed to PBM, and Huang et al5 reported a weak increase in insulin secretion in low glucose after PBM on porcine pancreatic islets. The aim of this study was to evaluate the effects of PBM on viability and insulin secretion in human islets.
The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer’s Disease (2024)
Stone, J., Mitrofanis, J., Johnstone, D. M., & Robinson, S. R.
Journal of Alzheimer’s disease : JAD, 97(3), 1069–1081. https://doi.org/10.3233/JAD-231202
This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.
Twelve protections evolved for the brain, and their roles in extending its functional life (2023)
Stone, J., Mitrofanis, J., Johnstone, D. M., & Robinson, S. R.
Frontiers in neuroanatomy, 17, 1280275. https://doi.org/10.3389/fnana.2023.1280275
As human longevity has increased, we have come to understand the ability of the brain to function into advanced age, but also its vulnerability with age, apparent in the age-related dementias. Against that background of success and vulnerability, this essay reviews how the brain is protected by (by our count) 12 mechanisms, including: the cranium, a bony helmet; the hydraulic support given by the cerebrospinal fluid; the strategically located carotid body and sinus, which provide input to reflexes that protect the brain from blood-gas imbalance and extremes of blood pressure; the blood brain barrier, an essential sealing of cerebral vessels; the secretion of molecules such as haemopexin and (we argue) the peptide Aβ to detoxify haemoglobin, at sites of a bleed; autoregulation of the capillary bed, which stabilises metabolites in extracellular fluid; fuel storage in the brain, as glycogen; oxygen storage, in the haemoprotein neuroglobin; the generation of new neurones, in the adult, to replace cells lost; acquired resilience, the stress-induced strengthening of cell membranes and energy production found in all body tissues; and cognitive reserve, the ability of the brain to maintain function despite damage. Of these 12 protections, we identify 5 as unique to the brain, 3 as protections shared with all body tissues, and another 4 as protections shared with other tissues but specialised for the brain. These protections are a measure of the brain’s vulnerability, of its need for protection. They have evolved, we argue, to maintain cognitive function, the ability of the brain to function despite damage that accumulates during life. Several can be tools in the hands of the individual, and of the medical health professional, for the lifelong care of our brains.
Do astrocytes respond to light, sound, or electrical stimulation? (2023)
Naour, A. L., Beziat, E., Kam, J. H., Magistretti, P., Benabid, A. L., & Mitrofanis, J.
Neural regeneration research, 18(11), 2343–2347. https://doi.org/10.4103/1673-5374.371343
Astrocytes are not only the most populous cell type in the human brain, but they also have the most extensive and diverse sets of connections, across synapses, axons, blood vessels, as well as having their own internal network. Unsurprisingly, they are associated with many brain functions; from the synaptic transmission to energy metabolism and fluid homeostasis, and from cerebral blood flow and blood-brain barrier maintenance to neuroprotection, memory, immune defenses and detoxification, sleep, and early development. And yet, notwithstanding these key roles, so many current therapeutic approaches to a range of brain disorders have largely neglected their potential involvement. In this review, we consider the role of astrocytes in three brain therapies; two are emerging treatments (photobiomodulation and ultrasound), while the other is well-established (deep brain stimulation). In essence, we explore the issue of whether external sources, such as light, sound, or electricity, can influence the function of astrocytes, as they do neurons. We find that, when taken all together, each of these external sources can influence many, if not, all of the functions associated with astrocytes. These include influencing neuronal activity, prompting neuroprotection, reducing inflammation (astrogliosis) and potentially increasing cerebral blood flow and stimulating the glymphatic system. We suggest that astrocytes, just like neurons, can respond positively to each of these external applications and that their activation could each impart many beneficial outcomes on brain function; they are likely to be key players underpinning the mechanisms behind many therapeutic strategies.
Glucose Improves the Efficacy of Photobiomodulation in Changing ATP and ROS Levels in Mouse Fibroblast Cell Cultures (2023)
Hoh Kam, J., & Mitrofanis, J.
Cells, 12(21), 2533. https://doi.org/10.3390/cells12212533
In this study, we tested the idea that photobiomodulation—the application of red to near infrared light (~λ = 600–1300 nm) to body tissues—is more effective in influencing cell metabolism when glucose is readily available. To this end, we used a mouse fibroblast (L-929) cell culture model and had two sets of conditions: non-stressed (10% FBS (foetal bovine serum)) and stressed (1% FBS), both either with or without glucose. We treated (or not) cells with photobiomodulation using an 810 nm laser at 15 mW/cm2 (~7.2 J/cm2). Our results showed that photobiomodulation was neither cytotoxic nor effective in enhancing measures of cell viability and proliferation, together with protein levels in any of the cell cultures. Photobiomodulation was, however, effective in increasing adenosine triphosphate (ATP) and decreasing reactive oxygen species (ROS) levels and this was—most importantly—only in conditions where glucose was present; corresponding cultures that did not contain glucose did not show these changes. In summary, we found that the benefits of photobiomodulation, in particular in changing ATP and ROS levels, were induced only when there was glucose available. Our findings lay a template for further explorations into the mechanisms of photobiomodulation, together with having considerable experimental and clinical implications.
A shared-control framework for BCI control of various effectors: towards home-used BCIs (2023)
L. Struber, S. Karakas, A. Bellicha, L. Devigne, F. Pasteau, F. Martel, V. Juillard, A. Castillejo, S. Chabardes, T. Aksenova, G. Charvet & M. Babel
BCI Meeting,
Abstract Book of the 10th International Brain-Computer Interface Meeting 2023, DOI: 103217/978-3-85125-962-9-43
Despite promising progress in ongoing clinical research in BCI, very few systems allow daily use outside the laboratory. Several shortcomings, in terms of device reliability, safety, portability and ease of use, still need to be addressed to enable home-use. In this context, an implantable BCI technology was developed, aiming to enable a person with quadriplegia to control various effectors in a semi-assisted shared-control framework based on proximity sensors.
Remote photobiomodulation targeted at the abdomen or legs provides effective neuroprotection against parkinsonian MPTP insult (2023)
Gordon, L. C., Martin, K. L., Torres, N., Benabid, A. L., Mitrofanis, J., Stone, J., Moro, C., & Johnstone, D. M.
The European journal of neuroscience, 57(9), 1611–1624. https://doi.org/10.1111/ejn.15973
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.
The brain’s weakness in the face of trauma: How head trauma causes the destruction of the brain (2023)
Johnstone, D. M., Mitrofanis, J. & Stone, J.
Frontiers in neuroscience, 17, 1141568. https://doi.org/10.3389/fnins.2023.1141568
Of all our organs, the brain is perhaps the best protected from trauma. The skull has evolved to enclose it and, within the skull, the brain floats in a protective bath of cerebrospinal fluid. It is becoming evident, however, that head trauma experienced in young adult life can cause a dementia that appears decades later. The level of trauma that induces such destruction is still being assessed but includes levels well below that which cracks the skull or causes unconsciousness or concussion. Clinically this damage appears as dementia, in people who played body-contact sports in their youth or have survived accidents or the blasts of combat; and appears also, we argue, in old age, without a history of head trauma. The dementias have been given different names, including dementia pugilistica (affecting boxers), chronic traumatic encephalopathy (following certain sports, particularly football), traumatic brain injury (following accidents, combat) and Alzheimer’s (following decades of life). They share common features of clinical presentation and neuropathology, and this conceptual analysis seeks to identify features common to these forms of brain injury and to identify where in the brain the damage common to them occurs; and how it occurs, despite the protection provided by the skull and cerebrospinal fluid. The analysis suggests that the brain’s weak point in the face of trauma is its capillary bed, which is torn by the shock of trauma. This identification in turn allows discussion of ways of delaying, avoiding and even treating these trauma-induced degenerations.
A systematic review of the effects of transcranial photobiomodulation on brain activity in humans (2023)
Dole, M., Auboiroux, V., Langar, L., & Mitrofanis, J.
Reviews in the neurosciences, 34(6), 671–693. https://doi.org/10.1515/revneuro-2023-0003
In recent years, transcranial photobiomodulation (tPBM) has been developing as a promising method to protect and repair brain tissues against damages. The aim of our systematic review is to examine the results available in the literature concerning the efficacy of tPBM in changing brain activity in humans, either in healthy individuals, or in patients with neurological diseases. Four databases were screened for references containing terms encompassing photobiomodulation, brain activity, brain imaging, and human. We also analysed the quality of the included studies using validated tools. Results in healthy subjects showed that even after a single session, tPBM can be effective in influencing brain activity. In particular, the different transcranial approaches – using a focal stimulation or helmet for global brain stimulation – seemed to act at both the vascular level by increasing regional cerebral blood flow (rCBF) and at the neural level by changing the activity of the neurons. In addition, studies also showed that even a focal stimulation was sufficient to induce a global change in functional connectivity across brain networks. Results in patients with neurological disease were sparser; nevertheless, they indicated that tPBM could improve rCBF and functional connectivity in several regions. Our systematic review also highlighted the heterogeneity in the methods and results generated, together with the need for more randomised controlled trials in patients with neurological diseases. In summary, tPBM could be a promising method to act on brain function, but more consistency is needed in order appreciate fully the underlying mechanisms and the precise outcomes.
Lights at night: does photobiomodulation improve sleep? (2023)
Valverde, A., Hamilton, C., Moro, C., Billeres, M., Magistretti, P., & Mitrofanis, J.
Neural regeneration research, 18(3), 474–477. https://doi.org/10.4103/1673-5374.350191
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.
Online adaptive group-wise sparse Penalized Recursive Exponentially Weighted N-way Partial Least Square for epidural intracranial BCI (2023)
Moly, A., Aksenov, A., Martel, F. & Aksenova, T.
Frontiers in human neuroscience, 17, 1075666. https://doi.org/10.3389/fnhum.2023.1075666
Motor Brain–Computer Interfaces (BCIs) create new communication pathways between the brain and external effectors for patients with severe motor impairments. Control of complex effectors such as robotic arms or exoskeletons is generally based on the real-time decoding of high-resolution neural signals. However, high-dimensional and noisy brain signals pose challenges, such as limitations in the generalization ability of the decoding model and increased computational demands.
Impact of dataset size and long-term ECoG-based BCI usage on deep learning decoders performance (2023)
Śliwowski, M., Martin, M., Souloumiac, A., Blanchart, P., & Aksenova, T.
Frontiers in human neuroscience, 17, 1111645. https://doi.org/10.3389/fnhum.2023.1111645
In brain-computer interfaces (BCI) research, recording data is time-consuming and expensive, which limits access to big datasets. This may influence the BCI system performance as machine learning methods depend strongly on the training dataset size. Important questions arise: taking into account neuronal signal characteristics (e.g., non-stationarity), can we achieve higher decoding performance with more data to train decoders? What is the perspective for further improvement with time in the case of long-term BCI studies? In this study, we investigated the impact of long-term recordings on motor imagery decoding from two main perspectives: model requirements regarding dataset size and potential for patient adaptation.
Excessive daytime sleepiness in a model of Parkinson’s disease improved by low-frequency stimulation of the pedunculopontine nucleus (2023)
Davin A, Chabardès S, Devergnas A, Benstaali C, Gutekunst CN, David O, Torres-Martinez N, Piallat B
NPJ Parkinson’s disease, 9(1), 9. https://doi.org/10.1038/s41531-023-00455-7
Patients with Parkinson’s disease often complain of excessive daytime sleepiness which negatively impacts their quality of life. The pedunculopontine nucleus, proposed as a target for deep brain stimulation to improve freezing of gait in Parkinson’s disease, is also known to play a key role in the arousal system. Thus, the putative control of excessive daytime sleepiness by pedunculopontine nucleus area stimulation merits exploration for treating Parkinson’s disease patients. To this end, two adult nonhuman primates (macaca fascicularis) received a deep brain stimulation electrode implanted into the pedunculopontine nucleus area along with a polysomnographic equipment. Stimulation at low frequencies and high frequencies was studied, in healthy and then MPTP-treated nonhuman primates. Here, we observed that MPTP-treated nonhuman primates suffered from excessive daytime sleepiness and that low-frequency stimulation of the pedunculopontine nucleus area was effective in reducing daytime sleepiness. Indeed, low-frequency stimulation of the pedunculopontine nucleus area induced a significant increase in sleep onset latency, longer continuous periods of wakefulness and thus, a partially restored daytime wake architecture. These findings may contribute to the development of new therapeutic strategies in patients suffering from excessive daytime sleepiness.
Shifting patterns of cellular energy production (adenosine triphosphate) over the day and key timings for the effect of optical manipulation (2022)
Shinhmar, H., Hoh Kam, J., Mitrofanis, J., Hogg, C., & Jeffery, G.
Journal of biophotonics, 15(10), e202200093. https://doi.org/10.1002/jbio.202200093
Mitochondria are optically responsive organelles producing energy for cell function via adenosine triphosphate (ATP). But ATP production appears to vary over the day. Here we use Drosophila melanogaster to reveal daily shifts in whole animal ATP production in a tight 24 hours’ time series. We show a marked production peak in the morning that declines around midday and remains low through afternoon and night. ATP production can be improved with long wavelengths (>660 nm), but apparently not at all times. Hence, we treated flies with 670 nm light to reveal optimum times. Exposures at 670 nm resulted in a significant ATP increases and a shift in the ATP/adenosine diphosphate (ADP) ratio at 8.00 and 11.00, whilst application at other time points had no effect. Hence, light-induced ATP increases appear limited to periods when natural production is high. In summary, long wavelength influences on mitochondria are conserved across species from fly to human. Determining times for their administration to improve function in ageing and disease are of key importance. This study progresses this problem.
Lights on for Autism: Exploring Photobiomodulation as an Effective Therapeutic Option (2022)
Hamilton, C., Liebert, A., Pang, V., Magistretti, P., & Mitrofanis, J.
Neurology international, 14(4), 884–893. https://doi.org/10.3390/neurolint14040071
Autism is a neurodevelopmental condition that starts in childhood and continues into adulthood. The core characteristics include difficulties with social interaction and communication, together with restricted and repetitive behaviours. There are a number of key abnormalities of brain structure and function that trigger these behavioural patterns, including an imbalance of functional connectivity and synaptic transmission, neuronal death, gliosis and inflammation. In addition, autism has been linked to alterations in the gut microbiome. Unfortunately, as it stands, there are few treatment options available for patients. In this mini-review, we consider the effectiveness of a potential new treatment for autism, known as photobiomodulation, the therapeutic use of red to near infrared light on body tissues. This treatment has been shown in a range of pathological conditions-to improve the key changes that characterise autism, including the functional connectivity and survival patterns of neurones, the patterns of gliosis and inflammation and the composition of the microbiome. We highlight the idea that photobiomodulation may form an ideal treatment option for autism, one that is certainly worthy of further investigation.
The effect of photobiomodulation on the brain during wakefulness and sleep (2022)
Moro, C., Valverde, A., Dole, M., Hoh Kam, J., Hamilton, C., Liebert, A., Bicknell, B., Benabid, A. L., Magistretti, P., & Mitrofanis, J.
Frontiers in neuroscience, 16, 942536. https://doi.org/10.3389/fnins.2022.942536
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.
The code of light: do neurons generate light to communicate and repair? (2022)
Moro, C., Liebert, A., Hamilton, C., Pasqual, N., Jeffery, G., Stone, J., & Mitrofanis, J.
Neural regeneration research, 17(6), 1251–1252. https://doi.org/10.4103/1673-5374.327332
A great challenge in neuroscience has been to understand how neurons communicate. The neuroanatomists of the 19th 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. Over the ensuing two hundred years or so, we have come to understand that the circuity of the brain is not formed by a syncytium of neurons; rather, individual neurons communicate with each other with a range of biological signals. Neurons are highly active cells, with their activity being electrical and their communication being either chemical, electrical or gaseous.
Apport des techniques dans le domaine des déficits neurologiques : réalités et perspectives [What technologies bring in the field of neurological disorders: Current realities and future perspectives] (2022)
Benabid, A. L., Mitrofanis, J., Chabardes, S., & Garrec, P.
Medecine sciences : M/S, 38(3), 241–242. https://doi.org/10.1051/medsci/2022031
Depuis la lancette utilisée pour faire des saignées jusqu’à la radiothérapie pour traiter des tumeurs, la médecine et les sciences, notamment chimiques et physiques, ont toujours entretenu des liens étroits, tant pour le diagnostic que pour le traitement des maladies. Le cerveau, en particulier, en a bénéficié de plus en plus au cours du temps. Dans le domaine des neurosciences, la physique a ouvert des voies non seulement enthousiasmantes, mais aussi étonnamment productives, en permettant d’acquérir des données in vivo et d’en extraire des méthodes de compensation des déficits par le pilotage d’outils de plus en plus intelligents, telles les interfaces cerveau-machine, dont les premiers balbutiements ont conduit à la mise en forme d’un exosquelette.
Improvements in clinical signs of Parkinson’s disease using photobiomodulation: a prospective proof-of-concept study (2021)
Liebert, A., Bicknell, B., Laakso, E. L., Heller, G., Jalilitabaei, P., Tilley, S., Mitrofanis, J., & Kiat, H.
BMC neurology, 21(1), 256. https://doi.org/10.1186/s12883-021-02248-y
Parkinson’s disease (PD) is a progressive neurodegenerative disease with no cure and few treatment options. Its incidence is increasing due to aging populations, longer disease duration and potentially as a COVID-19 sequela. Photobiomodulation (PBM) has been successfully used in animal models to reduce the signs of PD and to protect dopaminergic neurons.
To assess the effectiveness of PBM to mitigate clinical signs of PD in a prospective proof-of-concept study, using a combination of transcranial and remote treatment, in order to inform on best practice for a larger randomized placebo-controlled trial (RCT).
Twelve participants with idiopathic PD were recruited. Six were randomly chosen to begin 12 weeks of transcranial, intranasal, neck and abdominal PBM. The remaining 6 were waitlisted for 14 weeks before commencing the same treatment. After the 12-week treatment period, all participants were supplied with PBM devices to continue home treatment. Participants were assessed for mobility, fine motor skills, balance and cognition before treatment began, after 4 weeks of treatment, after 12 weeks of treatment and the end of the home treatment period. A Wilcoxon Signed Ranks test was used to assess treatment effectiveness at a significance level of 5%.
Measures of mobility, cognition, dynamic balance and fine motor skill were significantly improved (p < 0.05) with PBM treatment for 12 weeks and up to one year. Many individual improvements were above the minimal clinically important difference, the threshold judged to be meaningful for participants. Individual improvements varied but many continued for up to one year with sustained home treatment. There was a demonstrable Hawthorne Effect that was below the treatment effect. No side effects of the treatment were observed.
PBM was shown to be a safe and potentially effective treatment for a range of clinical signs and symptoms of PD. Improvements were maintained for as long as treatment continued, for up to one year in a neurodegenerative disease where decline is typically expected. Home treatment of PD by the person themselves or with the help of a carer might be an effective therapy option. The results of this study indicate that a large RCT is warranted.
Exploring the Use of Intracranial and Extracranial (Remote) Photobiomodulation Devices in Parkinson’s Disease: A Comparison of Direct and Indirect Systemic Stimulations (2021)
Johnstone, D. M., Hamilton, C., Gordon, L. C., Moro, C., Torres, N., Nicklason, F., Stone, J., Benabid, A. L., & Mitrofanis, J.
Journal of Alzheimer’s disease : JAD, 83(4), 1399–1413. https://doi.org/10.3233/JAD-210052
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.