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Parkinson’s disease is a movement disorder with cardinal signs of resting tremor, akinesia, and rigidity. These manifest after a progressive death of many dopaminergic neurons of the midbrain. Unfortunately, the progression of this neuronal death has proved difficult to slow and impossible to reverse despite an intense search for the specific causes and for treatments that address the causes. There is a corresponding need to develop approaches that regulate the self-repair mechanisms of neurons, independent of the specific causes of the damage that leads to their death. Red to infrared light therapy (λ=600–1,070 nm) is emerging as an effective, repair-oriented therapy that is capable of stabilizing dying neurons. Initially a space-age anecdote, light therapy has become a treatment for tissue stressed by the known causes of age-related diseases: hypoxia, toxic environments, and mitochondrial dysfunction. Here we focus on several issues relating to the use of light therapy for Parkinson’s disease: 1) What is the evidence that it is neuroprotective? We consider the basic science and clinical evidence; 2) What are the mechanisms of neuroprotection? We suggest a primary mechanism acting directly on the neuron’s mitochondria (direct effect) as well as a secondary, supportive mechanism acting indirectly through systemic systems (indirect effect); 3) Could this be effective in humans? We discuss the pros and cons of this treatment in humans, including the development of a new surgical method of delivery; and 4) What are the advantages of using light therapy? We explore the features that make this therapy a promising potential treatment. In summary, early evidence indicates that light regulates specific neuronal functions and is neuroprotective in animal models of Parkinson’s disease. The stage is set for detailed and rigorous explorations into its use on Parkinson’s disease patients, in particular, whether light slows the disease progression rather than simply mitigating signs.
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The potential of light therapy in Parkinson’s
Daniel M Johnstone1
Kristina Coleman2
Cécile Moro3
Napoleon Torres3
Janis T Eells4
Gary E Baker5,†
Keyoumars Ashkan6
Jonathan Stone1
Alim-Louis Benabid3
John Mitrofanis2
1Department of Physiology and Bosch
Institute, 2Department of Anatomy
and Histology, University of Sydney,
Sydney, NSW, Australia; 3Clinatec
LETI-DTBS, CEA Grenoble, France;
4Department of Biomedical Science,
University of Wisconsin, Madison,
WI, USA; 5Department of Optometry
and Visual Science, City University,
6Department of Neurosurgery, King’s
College Hospital, London, UK
Gar y E Baker passe d away on
15 November 2011.
Correspondence: John Mitrofanis
Department of Anatomy and Histology
F13, University of Sydney, Sydney,
NSW 2006, Australia
Tel +61 2 9351 2500
Fax +61 2 9351 2813
Abstract: Parkinson’s disease is a movement disorder with cardinal signs of resting tremor,
akinesia, and rigidity. These manifest after a progressive death of many dopaminergic neurons
of the midbrain. Unfortunately, the progression of this neuronal death has proved difficult to
slow and impossible to reverse despite an intense search for the specific causes and for treat-
ments that address the causes. There is a corresponding need to develop approaches that regulate
the self-repair mechanisms of neurons, independent of the specific causes of the damage that
leads to their death. Red to infrared light therapy (λ=600–1,070 nm) is emerging as an effec-
tive, repair-oriented therapy that is capable of stabilizing dying neurons. Initially a space-age
anecdote, light therapy has become a treatment for tissue stressed by the known causes of
age-related diseases: hypoxia, toxic environments, and mitochondrial dysfunction. Here we
focus on several issues relating to the use of light therapy for Parkinson’s disease: 1) What is
the evidence that it is neuroprotective? We consider the basic science and clinical evidence; 2)
What are the mechanisms of neuroprotection? We suggest a primary mechanism acting directly
on the neuron’s mitochondria (direct effect) as well as a secondary, supportive mechanism act-
ing indirectly through systemic systems (indirect effect); 3) Could this be effective in humans?
We discuss the pros and cons of this treatment in humans, including the development of a new
surgical method of delivery; and 4) What are the advantages of using light therapy? We explore
the features that make this therapy a promising potential treatment. In summary, early evidence
indicates that light regulates specific neuronal functions and is neuroprotective in animal models
of Parkinson’s disease. The stage is set for detailed and rigorous explorations into its use on
Parkinson’s disease patients, in particular, whether light slows the disease progression rather
than simply mitigating signs.
Keywords: infrared, near infrared, neuroprotection, photobiomodulation, substantia nigra
The current “gold standard” treatments for Parkinson’s disease are very effective at
attenuating the motor signs, at least initially. However, they do not reliably slow the
progression of the disease; neurons continue to die during the course of treatment.
The discovery of new therapeutic approaches that offer neuroprotection against
parkinsonian insult is therefore paramount. In this context, several recent studies in
animal models of Parkinson’s disease, as well as other models of disease (eg, retinal
degeneration, stroke, multiple sclerosis, Alzheimer’s disease), have reported that red
to infrared light therapy (λ=600–1,070 nm; referred to forthwith as light therapy) can
be neuroprotective. There is real potential for the development of light therapy as a
treatment option for Parkinson’s disease patients – one that slows the ongoing neuronal
death and progression of the disease.
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Overview of Parkinson’s disease
Parkinson’s disease is a slow, progressive disorder that affects
1% of people over the age of 55–60 years. It has distinct
cardinal signs of resting (pill-rolling) tremor, lead-pipe rigid-
ity (increased muscle tone), akinesia (difficulty in initiating
and stopping movement), and/or bradykinesia (slowness
of movement).1,2 These signs manifest as a consequence
of degeneration of pigmented dopaminergic neurons in the
substantia nigra pars compacta (SNc) of the basal ganglia;
there is also some limited dopaminergic neuronal loss in
other nuclei, including the ventral tegmental area and ret-
rorubral field.1,3–5 Degeneration of the SNc dopaminergic
neurons, thought to be in the range of 50%–85%,1,4 leads
to a substantial reduction in the levels of dopamine in other
regions of the basal ganglia, in particular the striatum. This,
in turn, leads to the generation of abnormal neuronal activity
in certain basal ganglia nuclei, for example, the subthalamic
nucleus and the globus pallidus, which then manifests as the
distinct signs of the disease.1,4,5
The disease has an insidious onset. There is evidence that
it may be caused by exposure to a neurotoxin, for example,
paraquat, rotenone, 6 hydroxydopamine, or methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP).6–8 This exposure may
have occurred well before the onset of clinical signs since
compensatory mechanisms such as sprouting of new dop-
aminergic branches in striatum have been shown to delay
clinical manifestation.9 Indeed, animal models that involve
exposure to these and other toxins reproduce many of the
parkinsonian signs and pathological features.6–8 There is
also evidence, in a small number of cases (10%–15%), that
defective genes (eg, parkin, PINK1, SNCA [that encodes
the synaptic protein alpha-synuclein]) contribute to the
development of Parkinson’s disease.10,11 Further, there are
several transgenic animal models of the disease which, as
with the toxin-induced models, display many Parkinson-like
The mechanisms underpinning the degeneration of
dopaminergic neurons, whether after toxic insult or genetic
defect, have come under much scrutiny in recent years. It is
clear that mitochondrial dysfunction plays a central role in the
process.14 Mitochondria are the “engine rooms” of neurons
they produce energy in the form of adenosine triphosphate
(ATP) that fuels neuronal function. Under certain conditions,
for example in ageing or after toxic insult/genetic defect,
there is a progressive accumulation of mutations in mito-
chondrial DNA that reduces mitochondrial efficiency and
ATP yield. This process leads to an increase in toxic reactive
oxygen species, generating oxidative stress and subsequent
neuronal degeneration.14,15 A rather common feature of
neurodegeneration is the development and accumulation of
abnormal proteins, such as alpha-synuclein within the neu-
rons. This protein is a major constituent of Lewy bodies, found
in particular in Parkinson’s disease.16 Further exacerbating
the degenerative process are glutamate excitotoxicity,17–20
inflammation,21 and glial cell activation.22 The glutamatergic
inputs to the dopaminergic neurons, particularly those from
the subthalamic nucleus, become overactive in Parkinson’s
disease, and the excessive glutamate promotes mitochondrial
defects within the dopaminergic neurons. Under normal
conditions, glial cells, both microglia and astrocytes, support
neuronal function, but in the adverse parkinsonian condi-
tion, they become reactive and toxic to neurons, generating
a sustained local inflammation within the SNc.21,22
Current therapies
for Parkinson’s disease
The current treatment option for most patients with
Parkinson’s disease is dopamine replacement drug therapy,
followed by surgery in selected patients. The basic strategy
of each treatment is simple: dopamine drug therapy aims to
replace the dopamine lost from the system, while surgery
aims to correct the abnormal function of the basal ganglia
circuitry caused by the loss of the dopamine. The surgical
option is usually recommended to patients after the efficacy
of drug treatment lessens (see Surgical treatment section
below) or when the disease has progressed sufficiently. Both
of these main treatments provide symptomatic relief (ie, treat
the signs that characterize the disease).23 They will each be
discussed briefly below.
Dopamine drug therapy
Dopamine replacement drug therapy can work in one of three
ways. First, it can increase the amount of dopamine avail-
able in the brain. Levodopa (L-Dopa) is a precursor to dop-
amine and is often used as first line treatment.24 While highly
efficacious at reducing motor signs initially, its efficacy tapers
with prolonged use. For example, over time (ie, 5–8 years),
involuntary movements of the upper limbs (dyskinesias)
develop when plasma levels of L-Dopa are high (“on” time)
due to dysregulation of the striatal dopaminergic receptors.
Second, some drugs – dopamine agonists such as bromocrip-
tine and apomorphine mimic the action of dopamine,
activating dopamine receptors of neurons in the striatum
directly. While generally not as effective as L-Dopa, dopamine
agonists are associated with fewer motor complications
(ie, dyskinesias) and may be the first-line treatment choice in
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Light therapy in Parkinson’s disease
younger patients.24,25 Finally, other drugs – monoamine oxi-
dase type B inhibitors such as selegiline and rasagiline – help
stop the breakdown of dopamine at the synapse, increasing
its availability to the postsynaptic neurons.25
In general, these drug treatments have very good early
symptomatic effects, but their longer-term neuroprotective
or disease modifying effects are far from clear. For example,
although drugs such as selegiline and rasagiline have been
tested as putative neuroprotective agents in clinical trials,
their ability to actually stop neuronal death and slow the
pathology of the disease has yet to be demonstrated.26
Surgical treatment
Surgical intervention is reserved as a last-line treatment, after
the efficacy of the drug therapy diminishes and side effects
develop (eg, dyskinesias). The basic principle is to correct the
abnormal activity of certain basal ganglia nuclei and motor
thalamus, generated initially by the reduction of dopamine
levels in the striatum. The nuclei targeted most commonly for
intervention have been the motor nuclei of the thalamus, the
globus pallidus, and in particular, the subthalamic nucleus,
the efficacy of which extends to the “dopaminergic triad” of
signs: tremor, akinesia, rigidity. Surgeons have used either
destructive lesions or deep brain stimulation at high frequency
(creating a “functional” lesion) to dampen the abnormal activ-
ity in these nuclei.27,28 These methods have been very effective
in treating the motor signs of the disease in patients over long
periods.27,28 Although there is some evidence in animal mod-
els that lesion or deep brain stimulation of the subthalamic
nucleus is neuroprotective, by reducing glutamate excito-
toxicity to the SNc, the evidence available in Parkinson’s
disease patients is inconclusive.20,29 Due to its low morbidity,
deep brain stimulation at high frequency is often proposed to
patients earlier in their disease, when the medical treatment,
although still efficient, does not provide them with satisfactory
relief. The best time for surgery is before the patients have
finished their professional activity or before their social and
family life has been substantially altered.27,28
In summary, the primary limitation with the current
treatments for Parkinson’s disease in humans is that there is
little evidence for neuroprotection; the treatments seemingly
have little effect on slowing the pathology and preventing
the ongoing neuronal death. Thus, there is an aching gap in
the current management of Parkinson’s disease.
Putative neuroprotective treatments
In various animal models of the disease and in vitro, there
have been a large number of treatments too many to mention
in detail here – that have been shown to be neuroprotective
or “disease modifying.” Unfortunately such treatments have,
for the most part, not progressed well at the clinical level.
They are either presently at a very early phase of clinical trial,
with no clear outcome or they have yielded mixed results
after trial.30 These treatments vary greatly in approach, for
example, changing the phenotype of neurons (gene therapy,
introduction of viral vectors),31 introducing trophic factors
that increase neuronal survival (eg, glial cell line-derived
neurotrophic factor),32 stimulating neurogenesis,33 increasing
patient exercise programs,34 and finally, changing dietary
intake, for instance, using antioxidants (eg, coenzyme Q10),
fish oil, and vitamin E.35
Light therapy, specifically low-level laser therapy of red
to infrared light, is an emerging, putative neuroprotective
treatment that, as with the aforementioned treatments, is
showing promise at the basic science level. It awaits rigor-
ous exploration at the clinical level for Parkinson’s disease,
but given its novel mode of application (see below; “What
is light therapy and how does it offer neuroprotection”), we
are very hopeful of positive outcomes for many patients. In
the next section, we will explore in detail the basic science
and clinical evidence for neuroprotection by light therapy in
parkinsonian cases and consider its further use in Parkinson’s
disease patients using a new method of application.
It should be noted that we use the term “light therapy” to
refer specifically to red to infrared light (λ=600–1,070 nm).
Light that includes wavelengths outside this range may actu-
ally be detrimental to cell survival. A recent study in rats
has shown that continuous exposure to bright light, which
includes a peak wavelength of 440 nm, results in a reduction
in the number of dopaminergic neurons in the SNc.36 Indeed,
it has been suggested that excess bright light exposure (ie,
“polluted” light) may be a cause of Parkinson’s disease.36
What is light therapy and how does
it offer neuroprotection?
An intuitive reaction to the idea that light influences neu-
ronal function and survival in the mammalian brain is that
it is not possible, because the brain is encased in a cranium
and meninges, covered with skin and muscle. Further, why
would there be light-inducible protective mechanisms in
tissue that is encased in such layers and hence presum-
ably has little exposure to light? Perhaps the mechanisms
evolved in epithelial tissues and therefore remain induc-
ible in the neuroepithelium. In spite of these reservations,
there is a growing body of evidence suggesting that
neurons are in fact influenced by light and, in particular,
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Johnstone et al
that low-level laser therapy with red to infrared light
induces neuroprotective responses. The neuroprotective
efficacy of light has been demonstrated in animal models
of retinal disease,37–41 traumatic brain injury,42–44 experi-
mentally induced stroke,45–47 familial amyotrophic lateral
sclerosis,48 multiple sclerosis,49 Parkinson’s disease,50–54
and Alzheimer’s disease.55–57 In humans, light therapy has
been reported to improve cognition and emotional func-
tions,58 together with performance in a range of clinical
tests after ischemic stroke,59,60 brain trauma,61 depression,62
and in age-related macular degeneration.63 The fact that
light therapy has been reported to be effective in so many
different models of disease and in a range of neural sys-
tems suggests a common mechanism at play. Recent work
indicates that light is effective in reducing neuronal death
induced by apoptosis, but not necrosis.44 The pathway to
apoptosis is likely to involve a critical decline in cellular
energy production,64 which light may help to restore (see
below, in this section). This mechanism may be common
to all abovementioned conditions and is perhaps why light
therapy has such broad potential applications.
The first applications of light therapy were with
coherent-light sources (lasers), but effective therapy also
has been reported recently with noncoherent light sources
(light-emitting diodes [LED], eg, the WARP 10 LED;
Quantum Devices, Barneveld, WI, USA).65–68 The opti-
mal wavelengths required for therapeutic effects appear
to lie within the range of 600–1,070 nm, with the longer
wavelengths (eg, 810 nm, 830 nm, and 1,070 nm) having a
greater depth of penetration through body tissues than the
shorter ones within this range (eg, 670 nm),66,68 although
the shorter ones have been used most commonly. Hence,
unless stated otherwise, all the results below have been
obtained using a 670 nm external LED device. The energy
densities required for therapeutic effects vary greatly in the
literature, ranging between 1–60 joules/cm2 (and power
intensities between 1–750 mW/cm2), although the majority
of studies have used densities ,10 joules/cm2 and achieved
positive outcomes.65–68 The reviews by Rojas and Gonzalez-
Lima67 and Chung et al68 provide thorough outlines of light
stimulation protocols used by previous studies on brain
and peripheral tissues. There are also some guidelines set
by the World Association of Laser Therapy in April 2010,
but they apply to peripheral tissues, not brain. Some clear
guidelines for use in brain are very much needed; as noted
by Quirk et al,69 the sooner the “hodgepodge” of application
ceases the better.
The mechanisms that underpin the neuroprotective effects
of light therapy are not entirely clear, but there appear to
be two general modes of action (Figure 1). By far the most
commonly studied mode of action is light acting directly on
the neurons themselves, triggering intrinsic trophic factors.
The light “boosts” mitochondrial function by increasing
electron transfer in the respiratory chain and activating
photoacceptors, such as cytochrome oxidase, resulting in
increased ATP production65–68 and a reduction in apoptosis
(see above, in this section). A second, emerging hypothesis
relating to mode of action is that light may also trigger a more
indirect, systemic response. Several studies have reported
remote, often bilateral, effects on body tissues after local
light application to, for example, skin wounds.70 Intriguingly,
neuroprotection of the mouse brain has been demonstrated
after application of light to the dorsum of the animal, with
no direct irradiation of the head.71,72 While the mechanism
remains unknown, it could involve the stimulation of one or
more circulating molecules or cell types. One possibility is
the stimulation of immune cells, for example mast cells and
macrophages, could help neuroprotect cells in the brain.49,68,73
There may also be effects on inflammatory mediators, as light
therapy is associated with downregulation of proinflamma-
tory cytokines (γ-interferon, α-tumor necrosis factor) and
upregulation of anti-inflammatory cytokines (interleukin-4,
interleukin-10).49 In addition, bone marrow-derived stem cells
may also be involved; a series of studies has demonstrated that
light exposure increases proliferation of c-kit-positive cells
in the bone marrow and that, following myocardial infarction
in rats, these cells are mobilized and recruited specifically to
the site of damage where they contribute to a reduction in
myocardial infarct size and ventricular dilatation.74,75 These
cells, together with immune cells, may release trophic factors
such as nerve growth factor and vascular endothelial growth
factor that improve the function of dying (apoptotic) cells
and aid in their survival.74,76 Such an indirect mechanism is
similar to the so-called “abscopal” effect (Figure 1), where
localized treatment of a tumor leads to not only a shrinking
of the local tumor but also to shrinking of tumors far from the
treated area.77 Finally, several groups have suggested that light
promotes functional recovery by stimulating ventricular stem
cells, promoting neurogenesis and neuronal migration.47,60,68
It remains to be determined which of these mechanisms,
direct or indirect, offers the neuroprotection, but we note
that they are not mutually exclusive and that both may con-
tribute to the process.71,72,78 As a working hypothesis, direct
stimulation of the mitochondria, which is supported by the
most compelling evidence (as described above), is likely to
form the primary mechanism of protection by light therapy,
while the indirect stimulation of immune and/or stem cells
may form a secondary and supportive mechanism. Some early
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Light therapy in Parkinson’s disease
results in an animal model of Parkinson’s disease indicate
that, although there is some neuroprotection of the brain after
remote application of light therapy (eg, dorsum of body),
the neuroprotection is not as great as when light therapy is
applied directly to the head.71,72,78 In other words, neuropro-
tection is achieved with both direct and indirect irradiation,
but the direct irradiation is the more effective.
Basic science and clinical evidence
for neuroprotection by light therapy
in Parkinson’s disease
The view from the dish: the in vitro
The first studies to report the neuroprotective effects of light
treatment were in vitro. Light therapy was shown to reduce
Putative light protective mechanisms
Neural cell
Damaged neural cells saved
by direct NIr stimulation
Damaged neural cells
saved by immune
and/or stem cells
Stem cells
Immune cells
NIr stimulates circulating
immune and/or bone
marrow stem cells and
they swarm to site of damage
Bone marrow
A Direct
B Indirect (abscopal-like)
Figure 1 The putative light protective mechanisms in the brain.
Notes: (A) Direct stimulation of the mitochondria and (B) indirect stimulation via circulating immune cells and/or bone marrow stem cells. The latter is similar to the
so-called “abscopal” effect in the treatment of cancer metastatis. We suggest that the primary mechanism is the direct effect, while the indirect effect forms a secondary
supportive mechanism.
Abbreviations: LED, light emitting device; NIR, near infrared light; WARP, Warghter’s Accelerated Recovery by Photobiomodulation.
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Johnstone et al
neuronal death, increase ATP content, and decrease levels of
oxidative stress among rat striatal and cortical neurons after
exposure to the parkinsonian toxins rotenone and 1-methyl-
4-phenylpyridium (MPP+).45,51 In cultures of human neuro-
blastoma cells engineered to overexpress alpha-synuclein,
light therapy has been reported to increase mitochondrial
function and reduce oxidative stress after MPP+ exposure.79,80
Further, mitochondrial movement along axons in hybrid cells
bearing mitochondrial DNA from Parkinsons disease patients
improves substantially after light therapy (810 nm, laser),
with movement restored to near control levels.81
The view from the animal model:
the in vivo evidence
Cell survival
The pioneering in vitro findings led inevitably to in vivo
explorations. To date, the impact of light therapy on dopamin-
ergic neuronal survival has been examined in the well-known
MPTP mouse model as well as in a transgenic mouse model
(K369I) of Parkinson’s disease. In both acute53,62,71,78,79 and
chronic54 MPTP models, light therapy saves many dopamin-
ergic neurons from death; in many cases, the numbers of
neurons in the light-treated animals are near control levels.
Further, results are similar whether the therapy is applied at
the same time or well after the insult, indicating that light
therapy both protects healthy neurons against an insult and
also rescues damaged neurons (self-repair) after the insult.54
The rescue of neurons is particularly relevant to the clinical
reality of the parkinsonian condition, where individuals first
suffer insult (and dopaminergic neuronal death) and then
receive therapeutic intervention. In terms of mechanism,
the protection and rescue of neurons by light is presumably
due to an increase in ATP production. The increase in ATP
before insult may help protect neurons from damage, while
reducing the decline in ATP after the insult may help to rescue
the dying neurons.65–68 In the K369I transgenic mouse model
of frontotemporal dementia, which also shows a chronic
and progressive degeneration of dopaminergic neurons in
the SNc and parkinsonian signs,13 light therapy decreases
oxidative stress and hyperphosphorylated tau and increases
dopaminergic neuronal survival in the SNc.80
Degree of neuroprotection
A common feature evident in most neuroprotection studies is
that beneficial outcomes are far greater when the therapy is
commenced earlier in the disease process.20,82 In other words,
there is greater capacity to save neurons when there is less
prior neuronal degeneration. This is certainly the case with
light therapy. In the acute MPTP model, there is a greater
proportion of neurons saved by light therapy following a
milder MPTP regime compared to a stronger one.53,72 There
may be a stage in the disease process, presumably at very
late stages (or after a very strong toxin dose) and extensive
neuronal death (eg, 70%–80%), when the neuroprotective
effect of light therapy, as well as other treatments, becomes
limited. Hence, the earlier the diagnosis and initiation of
treatment, the better the neuronal survival and likely clini-
cal outcome.
Neuroprotection among other dopaminergic
Other groups of dopaminergic neurons, for example those
in the retina, periaqueductal grey matter, and zona incerta-
hypothalamus, are not as likely to be saved by light therapy
after MPTP insult.53,54,83 The mechanisms that save dop-
aminergic neurons in the SNc from MPTP insult (see above;
“What is light therapy and how does it offer neuroprotection”)
are thus less effective in the other dopaminergic neurons.
Clinically, light therapy may be more effective in the treat-
ment of the central motor signs of the disease caused by SNc
neuronal loss (eg, akinesia) than the nonmotor symptoms
caused by a loss of other dopaminergic neurons (eg, sleep-
wakefulness and vision).83,84
Functional restoration
Not only does light therapy protect against the degeneration
of dopaminergic neurons, but it also appears to restore func-
tional activity to those neurons that are saved. For example,
light therapy has been shown to correct abnormal neuronal
activity generated by the parkinsonian condition.85 Using
Fos immunohistochemistry (a well-established measure of
neuronal activity), the overactivity of neuronal firing in the
subthalamic nucleus and zona incerta (two key basal ganglia
nuclei) characteristic of parkinsonian cases has been reported
to be reduced substantially after light therapy. This reduction
does not quite reach control levels, indicating that the restora-
tion is partial, and has been attributed to the surviving SNc
dopaminergic neurons being functionally active, continu-
ing to produce and release dopamine at their terminals in
the striatum.85 These early functional results could be built
upon by further electrophysiological and pharmacological
Behavioral improvements
The restoration of functional activity in the basal gan-
glia by the surviving dopaminergic neurons manifests in
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Light therapy in Parkinson’s disease
improved motor behavior. Previous studies have reported
that light therapy improves various parameters of loco-
motive behavior, for example mobility and velocity, after
MPTP treatment.52,86,79 It also delays disease progression
and reduces the severity of the disease phenotype in trans-
genic mice expressing the A53T human alpha-synuclein
mutation.87 In the MPTP-treated cases, the beneficial effects
of light therapy are not immediate, being seen only after
several doses of light over a period of 2–3 days.52,79 The mito-
chondria of the dopaminergic cells, after several treatments,
may have been stimulated further to increase their activity
and ATP production,65–68 thereby being better prepared to
protect against the MPTP toxicity.79
Does pigmentation limit benets of light therapy?
Moro et al79 have shown that the beneficial effects of light
therapy after MPTP insult were, somewhat surprisingly,
more evident in an albino mouse strain (Balb/c) than they
were in a pigmented mouse strain (C57BL/6).79 When
compared to albino mice, pigmented mice had a smaller
increase in dopaminergic neuronal number and no improve-
ment in locomotor activity in the light-treated compared to
the untreated MPTP cases. They found that there was less
penetration of light through fur overlying the cranium and
brain in the pigmented mice compared to the albinos. Hence,
they assumed that the melanin in the fur absorbed most
of the light before it reached the brain.79 However, unlike
the Moro et al study, DeSmet et al,86 and Whelan et al,52
reported improvements in mobility and velocity of move-
ment in MPTP-treated pigmented mice (C57BL/6) after light
treatment. One possible explanation for the differences in
these studies is the use of a greater total light energy in the
DeSmet et al and Whelan et al studies (8 and 30 joules/cm2,
respectively) relative to the Moro study (2 joules/cm2). The
greater energy presumably allowed for greater penetration
of light to the brain and hence neuroprotection. In summary,
pigmentation may limit penetration of light into the brain, but
this can be overcome by using high energy doses of light or
shaving the pigmented hair/fur before application.
Dose of light: how much does a neuron
need for self-repair or protection?
This issue has proved surprisingly difficult to define. At first
thought, one would give as much light as possible to the
neurons, so they can better resist the toxic insult or disease
process by increasing ATP production (see above; “What
is light therapy and how does it offer neuroprotection”).
However, empirical evidence suggests that this may not be
the optimal strategy.67 Using a new optical fiber device that
is implanted inside the brain to deliver light intracranially
(see below), neuronal survival against MPTP insult was just
as effective, if not marginally better, when light was applied
in short pulses (eg, 360 seconds) compared to continuously
(eg, 6 days). This phenomenon has been noted in other sys-
tems; light applied in short bursts (810 nm, laser) is more
effective in treating traumatic brain injury and stroke than if
applied continuously.41,43,60 Conversely, there are examples
of single doses of light not being sufficient to elicit a neu-
roprotective effect, and that several doses over a period of
2–3 days are needed.52,68,79 It appears that light therapy has
a threshold; the neurons need a certain level of exposure to
reap the beneficial effects, but after that level is reached these
benefits taper off.67,88 Its mechanism of action on mitochon-
drial activity, for example, has been likened to a “switch”,
but the mechanism of this switch is not known (Glen Jeffery,
University College London, personal communication May
2013). There is clearly much left to discover regarding the
mechanism of action of light therapy.
The view from the human:
the clinical evidence
Given these promising experimental results in animal models
of the disease, there have been surprisingly few reports on
the impact of light therapy in Parkinson’s disease patients.
In fact, there have been no major clinical trials published
to date, although two appear to be in progress through
the GAAD Medical Research Institute and Quietmind
Foundation. The Quietmind Foundation trial89 provides a
linked to a YouTube video showing a Parkinson’s disease
patient displaying improved movement and reduced tremor
after transcranially directed application of light therapy
(1,072 nm, laser), but few details are provided. There is a
recent noncontrolled and nonrandomized clinical report indi-
cating improvements in speech, cognition, freezing episodes,
and gait after transcranial light therapy in parkinsonian
patients.90 There are also some clinical reports suggesting
improvements in parkinsonian “symptoms” in the majority
of patients after light application utilizing an intranasal
device.91–93 Finally, there is a rather serendipitous finding
in one Parkinson’s disease patient who was treated with
light (660 nm, laser) for a dental problem; this patient was
reported to display a reduction in his parkinsonian signs fol-
lowing the light treatment.94 Hence, although these anecdotal
and casual clinical observations are encouraging, they lack
detail and rigor. Further, it remains far from clear whether
light therapy is neuroprotective (stopping neuronal death)
ChronoPhysiology and Therapy 2014:4
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Johnstone et al
and/or symptomatic (treating the motor signs) in humans.
If neuroprotective, the saving of neurons would ultimately
manifest in symptomatic improvements, yet it may turn out
that light therapy is symptomatic only, with no neuropro-
tective effects. (This issue is explored further in the next
section; “Could light therapy work in Parkinson’s disease
patients”). There is a need for a major, systematic, long-term
clinical trial on the neuroprotective and symptomatic effects
of light therapy on a large number of patients. Such a trial
is certainly warranted given the scientific findings gleaned
from experimental animals, together with the fact that light
therapy is safe and simple to use (see below; “What would
be the advantages of using light therapy”).
In summary, the evidence from basic science, gathered
from a number of different laboratories, indicates that light
therapy is to a certain extent neuroprotective, restores func-
tional activity, and improves movement in various animal
models of Parkinson’s disease. However, the clinical evidence
is far sparser, prompting the need for a systematic, large-scale
clinical trial of light therapy in patients.
Could light therapy work
in Parkinson’s disease patients?
The big question that still remains is whether light therapy can
be effective (neuroprotective and/or symptomatic) in humans.
The answer is perhaps not simple. If the primary mechanism
of action of light is direct mitochondrial stimulation of the
damaged or diseased neurons (see above; “What is light
therapy and how does it offer neuroprotection”), then there
may be an issue with its therapeutic potential for Parkinson’s
disease patients. While light penetration and dissipation are
not a major consideration when there are few or no tissue
barriers, as in the culture dish,37,45,95,96 the retina,38–41 or even
in the mouse SNc (4–5 mm inside the skull),53,54 such issues
may become prohibitive when light is required to penetrate
a thick bony cranium, meninges, skin, and a large mass
of intervening brain parenchyma (80–100 mm inside the
skull) in order to reach the human SNc (Figure 2). Indeed,
almost all the current clinical studies reporting the beneficial
effects of light therapy in humans have been in cases where
the target region is in the cortex, lying only 8–10 mm below
the cranium,60 whether in patients suffering trauma (633 nm
and 870 nm, LED),61 stroke (810 nm, laser),59,60 or depres-
sion (810 nm, LED).62 Structures lying much deeper in the
human brain, such as the SNc, may be beyond the range of
the externally applied light therapy.
This issue has been examined by several previous studies.
It has been estimated that light reaches a depth of 20–30 mm
from the cortical surface in rabbits (810 nm, laser),45 monkeys
(670 nm, laser; personal observations), and humans (810 nm,
laser),97 while a similar distance of 30 mm has been reported
along the spinal cord in rats (810 nm, laser).73 However, there
would be considerable attenuation and loss of power intensity
from the bony surface and through the neural parenchyma.
It has been reported that there is 90% attenuation of light
signal inside the cranium of mice.53 Similar sets of values
have been reported recently for human cadaver specimens.98
Further, De Taboada et al46 estimated that there would be a
power density drop of .99% from the cortex to a depth of
18 mm in rats. In a recent report by Abdo et al99 in rats, the
authors noted significant attenuation of light signal, with a
power reduction of 90% at 1 mm depth from the cortex.
Moro et al78 have noted that, although a light signal is detect-
able from across 10 mm of brain tissue, its intensity at this
point is ,1% of that emitted from the source. They estimated
a 65% reduction of signal across each millimeter of brain.78
Hence, over a distance of 80–100 mm – the predicted dis-
tance between any externally applied light and the SNc in
humans – the light signal would be extremely weak, perhaps
Taken together, these data indicate that transcranial light,
even at the longer wavelengths and higher energy doses, may
not reach deeper brain regions in effective doses, particularly
regions deeper than 30 mm from cranial surface. This may
present a limitation in the use of light as a long-term and reli-
able neuroprotective treatment in humans, particularly those
suffering from Parkinson’s disease.60,78 While there may be
some neuroprotection by light therapy via the indirect sys-
temic effect, we suggest that it may not solely be enough to
have a substantial impact in the SNc. In order for the light to
have maximum neuroprotective effect, it may be necessary
to place the light source within 30 mm of the diseased SNc
neurons, within the brain itself, to stimulate the mitochondria
directly. This could potentially also stimulate an indirect sys-
temic effect; for example, by activating circulating immune
cells in nearby blood vessels, providing the secondary, sup-
portive neuroprotective mechanism of action.
Hence, there appears to be a need to develop effective
methods of delivering strong light signal to deeper brainstem
structures in humans. To this end, we are in the process of
developing a novel intracranial light-optical fiber device to
deliver light in regions near the SNc in order for diseased
neurons to receive sufficient signal and subsequent neuro-
protection (Figure 3). Our initial results in mice have shown
that the light does not cause any toxic damage around the
implant sites in the brain, and that the intracranially applied
ChronoPhysiology and Therapy 2014:4 submit your manuscript |
Light therapy in Parkinson’s disease
light is indeed neuroprotective to dopaminergic SNc neurons
against MPTP insult.78 We are currently using monkeys to
undertake our first implants within the third ventricle, a site
that lies close to the SNc (5–10 mm) and one that has been
used for deep brain stimulation.100 In addition, this site is ideal
because Parkinson’s disease is often a bilateral disease,1,2,4,5
and the placement of the optical fiber within the midline third
ventricle ensures that the SNc of both sides will be irradiated.
We are hopeful that our results in rodents and monkeys will
provide the template for future clinical trials using this device
in Parkinson’s disease patients.
Although light applied from an external source may not
reach the SNc in humans and hence, we argue, have a limited
neuroprotective effect, previous studies have reported that
light still reaches the cortex and has at least symptomatic
effects (Figure 2; see above in same section). If Parkinson’s
disease patients were to receive transcranial light therapy
from an external source, the abnormal activity of motor
cortex101–103 may be restored to normal (eg, by decreasing
overactivity and increasing underactivity in the different
areas), thereby leading to improvements in movement.
Further, if motor cortical activity is returned to normal, and
Penetration of light from external device
~5 mm
80–100 mm
20 mm
Figure 2 Penetration of light through brain and surrounding tissues.
Notes: It has been estimated that light applied from an external source will penetrate 20 mm through tissue, not nearly enough to reach deeper structures of the human
brain, such as the SNc. For the mouse brain, light has been shown to penetrate throughout its extent.
Abbreviations: LED, light emitting device; SNc, substantia nigra pars compacta; WARP, Warghter’s Accelerated Recovery by Photobiomodulation.
ChronoPhysiology and Therapy 2014:4
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Johnstone et al
the disease (see above; “What is light therapy and how does
it offer neuroprotection”), a feat not achieved by dopamine
drug therapy, the current mainstay of treatment. There are
some substances (eg, coenzyme Q10 and melatonin)104,105
or methods (eg, deep brain stimulation at high frequency)20
that have been shown to be neuroprotective in experimental
animals, and light therapy certainly fits into this category.
These are promising indications for a neuroprotective func-
tion in humans.
Second, light therapy is safe, and there are no reported
side effects. Previous studies using external (eg, WARP-LED)
or internal (eg, optical fiber device) methods to deliver light
therapy at power intensities ranging from 1–700 mW/cm2
have reported no adverse effect on brain tissue structure
and function (810 nm, laser and 670 nm, LED).61,68,69,78,106–108
While there is one report of some neuronal damage and
negative behavioral outcomes in mice subjected to exception-
ally high power intensity of 750 mW/cm2,106 approximately
one hundred times higher than the dose required to elicit
a therapeutic response (eg, ,10 mW/cm2), in general the
impact of light on all body tissues examined thus far has been
overwhelmingly positive.61,65–69,78,96,106–108 Hence, these data
indicate that when light is applied at therapeutic doses (and
even well above these doses) it has little or no adverse effect
on body tissues; there appears to be a large safety margin for
this treatment. Unlike many of the current therapies used for
Parkinson’s disease, particularly after prolonged use, light
therapy has been reported to have no major side effects, even
at doses well above the therapeutic window.61,68,97
Third, treatment with light therapy would be simple.
For effective neuroprotection of the SNc, the patient would
require a minimally invasive surgical stereotactic proce-
dure for the insertion of a light-optical device within the
brain. This device would be linked to a battery source and
pacemaker device (as with patients receiving deep brain
stimulation),28 applying the light to the SNc when required.
The procedural risks would be comparable to those of single
electrode deep brain stimulation.
It should be noted that a potential disadvantage of light
therapy is that it may not be effective in treating the nonmo-
tor symptoms of the disease. As discussed, results in animal
models indicate that dopaminergic neurons in regions outside
of the SNc are less likely to be protected by light treatment
after parkinsonian insult. However, these symptoms are
minor compared to the striking motor signs of the disease.
In summary, light therapy compares favorably with,
and has notable advantages over, the current treatments of
Parkinson’s disease. It is fast developing into a treatment
Development of new intracranial device
for humans: light close to diseased cells
Figure 3 Development of new intracranial device for humans.
Notes: An optical bre linked to a LED or laser source has been developed recently,
one that can place the light very close to the diseased cells in the SNc. This would
presumably generate a maximum neuroprotective effect.
Abbreviations: LED, light emitting device; SNc, substantia nigra pars compacta.
because motor cortex projects heavily to the SNc, the activity
of SNc might also return to normal, leading ultimately to a
relief of motor signs. In this scenario, light therapy would be
symptomatic, but not necessarily neuroprotective; its impact
would be on part of the neural circuitry affected by the loss of
dopaminergic neurons, rather than on the diseased dopamin-
ergic neurons themselves. Hence, future clinical trials using
an external source must carefully consider, perhaps by fol-
lowing patients over a number of years and using functional
imaging methods, whether any improvements they observe
are purely symptomatic or indeed due to neuroprotection of
dopaminergic neurons.
In summary, although there may be symptomatic treat-
ment, it appears unlikely that light therapy, when applied
extracranially, can be neuroprotective to the human SNc. If,
however, applied intracranially, in regions very close to the
SNc, the diseased neurons may receive strong light signal
and hence be neuroprotected. These issues can be addressed
through carefully designed clinical trials.
What would be the advantages
of using light therapy?
There would be several key advantages for the use of light
therapy over current treatments for Parkinson’s disease.
First and foremost, light therapy has the potential to be
neuroprotective. A growing body of basic science evidence
indicates that light therapy slows or stops the pathology of
ChronoPhysiology and Therapy 2014:4 submit your manuscript |
Light therapy in Parkinson’s disease
option that is not only safe and simple but moreover helps
arrest the disease neuropathology.
Conclusions and implications
of future therapy
Although very much in its infancy, with the bulk of results
still at the basic science “proof of concept” stage, red to
infrared light therapy has the potential to develop into a
viable treatment option for patients with Parkinson’s disease
(and other neurodegenerative diseases). Light therapy would
offer patients the advantage of neuroprotection, something
that dopamine replacement drug therapy does not do. If
light therapy was applied at early stages, for example at
first diagnosis, it could potentially slow the progression of
the disease by rescuing the critical neurons from damage
and death. Consequently, over time, the greater survival of
neurons would lessen the clinical signs of tremor, akinesia,
and/or rigidity. Light therapy may not only be effective in
slowing the progression of the disease, but also in treating
the signs. Further, light therapy, because of its lack of side
effects, is amenable to use in conjunction with other treat-
ments. For example, patients may have light therapy with
a reduced dose of dopamine drug therapy as a first line
treatment. This would then prolong the efficacy of the drug
therapy and ultimately delay the use of surgery and deep brain
stimulation. There is so much to do in the further develop-
ment of this treatment, but the therapeutic (neuroprotective
and symptomatic) possibilities are many and the potential
outcomes very exciting.
We are forever grateful to Tenix corp, Salteri family, Sir Zelman
Cowen Universities Fund, Foundation Philanthropique Edmond
J Safra, France Parkinson, Michael J Fox Foundation, Fight
for Sight, International Retinal Research Foundation, and the
French National Research Agency (ANR Carnot Institute) for
funding our work. We thank Sharon Spana, Rat Venceslas,
Vincente Di Calogero, Christophe Gaude, Caroline Meunier,
and the Leti-DTBS staff for excellent technical assistance for
many of the experiments. Many thanks also to Glen Jeffery
(University College London) for his critical analysis of our
manuscript. We dedicate this work to our dear friend and
esteemed colleague, Gary Baker, who passed away during the
early stages of the preparation of this review.
The authors report no conflict of interest concerning the use
of light therapy. KC, CM, NT, DMJ, JTE, KA, JS, ALB, and
JM are members of staff at their respective institutions. DMJ
is supported by a National Health and Medical Research
Council of Australia (NHMRC) Early Career Fellowship.
JS is a director of Clear Sight Clear Mind (CSCM) Pty Ltd.
All authors contributed to the writing of the manuscript. The
authors report no other conflicts of interest in this work.
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... 16,17 In addition to the direct effect on the target cells, PBM also has a systemic 15,[18][19][20] and a delayed effect, likely due to the activation of DNA transcription factors. 13,14 Treatment of areas remote from the site of injury can be an effective strategy in animal models, 20 including models of PD and Alzheimer's disease 18,[21][22][23][24] even when the head of the animal is shielded from irradiation. 25 The mechanism of this systemic effect may be stimulation of stem cells, 20,26 immunomodulation, 27 stimulation of circulating cell-free mitochondria, 28 modulating circulating chemical messengers, 21 or a combination of these. ...
Objective: To assess whether remote application of photobiomodulation (PBM) is effective in reducing clinical signs of Parkinson's disease (PD). Background: PD is a progressive neurodegenerative disease for which there is no cure and few treatment options. There is a strong link between the microbiome-gut-brain axis and PD. PBM in animal models can reduce the signs of PD and protect the neurons from damage when applied directly to the head or to remote parts of the body. In a clinical study, PBM has been shown to improve clinical signs of PD for up to 1 year. Methods: Seven participants were treated with PBM to the abdomen and neck three times per week for 12 weeks. Participants were assessed for mobility, balance, cognition, fine motor skill, and sense of smell on enrolment, after 12 weeks of treatment in a clinic and after 33 weeks of home treatment. Results: A number of clinical signs of PD were shown to be improved by remote PBM treatment, including mobility, cognition, dynamic balance, spiral test, and sense of smell. Improvements were individual to the participant. Some improvements were lost for certain participants during at-home treatment, which coincided with a number of enforced coronavirus disease 2019 (COVID-19) pandemic lockdown periods. Conclusions: Remote application of PBM was shown to be an effective treatment for a number of clinical signs of PD, with some being maintained for 45 weeks, despite lockdown restrictions. Improvements in clinical signs were similar to those seen with the application of remote plus transcranial PBM treatment in a previous study. Clinical Trial Registration number: U1111-1205-2035.
... Although the majority of researchers have focused on the application of transcranial and intracranial illumination methods [72,73], light irradiation via the nasal cavity (intranasal method) and/or the oral cavity have also resulted in improvement in dementia and PD symptoms [74][75][76] (Fig. 3c, d). In the intranasal PBM method, the light source is located inside the nostril at the back of the nose and due to a thinner thickness of the ethmoid plate, it can directly irradiate subcortical (hypothalamus, thalamus, amygdala, hippocampus) and cortical (orbitofrontal cortex) structures of the limbic system in the brain which are related to AD and PD pathologies [77]. ...
Full-text available
Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca²⁺ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson’s disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.
... Hence, when an intervention is reported to offer neuroprotection to these vulnerable cells, particularly across a number of animal models of the disease, one has a sense of encouragement. Near-infrared light (NIr) therapy is one such intervention (λ = 600-1070 nm; Quirk et al. 2012;Johnstone et al. 2014aJohnstone et al. , 2016. ...
Full-text available
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.
... [65]. When mice were dosed with 50 mg/kg of 1-methyl-4phenyl-1, 2, 3, 6-tetrhydropyridine results after stimulation with 670 nm NIR light on the body showed enough tyrosine hydroylasepositive cells to conclude that indirect NIR stimulation may lead to neuroprotection [66,67]. NIR LED therapy has been shown to restore axonal transport and NIR LLLT has increased axonal transport in model human dopaminergic neuronal cells [63]. ...
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Background: Since the discovery of laser for the use of clinical therapies in the early 1960s, light therapies has expanded vastly to accommodate light emitting diodes which the wavelength ranges from red to near infrared. Both laser and light emitting diode have shown to be effective with wound healing, inflammation, and neuroprotection where most lesions occur, with both medical and therapeutic qualities. The utility of NIR fluorescence allows for the ability to detect and give reference to the stability of carotid plaques and their microanatomy. Recently, research has begun to look into the therapeutic effects of NIR light on neurodegenerative diseases. Objective: To demonstrate that the laser and light emitting diode have shown to be effective and therapeutic for the control of wound healing metabolisms and modulation of inflammation. This article focuses on recent literature with new applications for wound healing, inflammation, as well as neurodegenerative diseases. Also discussed is a comparison of near infrared light emitting diodes and low level laser therapies. Materials and method: We analyzed medical and engineering books, journals, index medicus, PubMed, FDA recommendations, requirements, patents, social media, and anecdotal evidence related to near infrared light therapy, from 1976 through 2015. The manuscript contains 72 pertinent referenced articles after research of over 250articles. Conclusion: Light therapy has been shown to be an effective coadjutant therapy for many neurosurgical applications. The LED has had technological advancement in the last decade which makes it an excellent option for light therapy. Unlike the laser, LED devices are portable, cost effective, safer, easy to use and has shown to be effective in wound healing and inflammation on the central and peripheral nervous systems.
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Phototherapy has shown its effect on cell stimulation and inhibition based on Arndt-Schulz model. Even though this therapeutic method has apparent effect, but it has limitations for epithelial application due to limitations on light penetration. Hence, with the ideology of fully overcoming this limitation, phosphorescent powder (strontium aluminate) is proposed as the potential light source that emitting photon from inside the body for phototherapy purposes. The strontium aluminate powder used in the experiment has the highest peak absorption at wavelength around 650 nm and lowest at around 350 nm. According to FESEM images, the powder has the particle size varies from 10 to 50 μm at cubic phase. The assessment is done by studying the effect on erythrocyte after blood plasma is irradiated by strontium aluminate powder’s photon. The powder luminesces with a maximum at 491.5 nm when pumped with 473 nm laser at 100 mW in fixed amount of 0.005±0.001 g. Later, it is mixed with centrifuged blood plasma for a predetermined time period (5, 10, 15, and 20 minutes). From this study, it shows that 5 minutes irradiation is the optimum period for erythrocyte in term of morphology enhancement and increase of UV-visible absorption spectrum with at least 21% in comparing with control blood. While the significant increment located at wavelengths 340 nm and 414 nm with both increased by 54% and 41%, respectively. However, for 10 minutes and beyond, the irradiation leads to morphology deterioration while the UV-visible spectrum decrement starts at 15 minutes and beyond. In conjunction, a comparison between blood plasma that either interacted with powder emitting photon or powder with no emission shows that photon emission plays a role in the phototherapy effect.
Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used to dissect neural circuits in animal models of Alzheimer's disease, Parkinson's disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future.
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Mild traumatic brain injury (mTBI), including concussion syndromes, have been a subject of increasing interest both in and out of medicine. The 2014 World Health OraganizationTask Force-International Collaboration on Mild Traumatic Brain Injury Prognosis 2014 (ICoMP) report states it is now considered a " prominent public health problem ". J. David Cassidy, DC, PhD, DrMedSc , a Task Force member, and others are beginning to raise awareness of chiropractic's responsibility and its role in managing mTBI. The message is that chiropractic physicians are uniquely positioned to diagnose and treat mild traumatic brain injury (mTBI.) As neuromuscular specialists, chiropractors see a large percentage of a patient population with a history of traumatic head and neck injuries that result in mTBI. At is issue is that all post mTBI care is plagued by limited treatment modalities. Recent research has demonstrated LLLT delivered transcranially is both safe and effective in treatment of mTBI and other conditions of the central nervous system. Many chiropractic physicians recognize the effectiveness of low level laser therapy (LLLT) in neuromusculoskeletal treatment but have not realized its potential when utilized transcranially. It has largely gone unutilized at the clinical level. Current research is a wake-up call for chiropractic physicians to consider transcranial low level laser therapy (tLLLT) in mTBI cases and its beneficial effects. The Problem: Mild TBI often goes undiagnosed, untreated, or under treated. In cases of mild TBI, the term " mild " is used in reference to the severity of the initial physical trauma that caused the injury and does not indicate the degree of brain trauma or the severity of the consequences of the injury. These consequences are frequently manifested by impairment of working memory and information processing speed. Other secondary symptoms include chronic headaches, anxiety, depression, insomnia, social withdrawal, seizures and other indications of CNS dysfunction. These consequences may lead to long term impairment in the form of decreased ADL capacity or even employability. An additional concern is neurodegeneration which has become a serious concern in some subsets of mTBI patients. The WHO report recommends that DCs " facilitate a path to good recovery for MTBI patients through early education and positive reassurance as well as by providing treatments aimed at reducing associated spine and headache-related pain. " And goes on to warn about " excessive diagnostic testing or applying diagnostic labels " and " Integrating care with a patient's primary medical physician is
Working Paper
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Mild and moderate traumatic brain injury, including post concussion syndrome, (mTBI) have been a subject of increasing interest in medicine. It is now recognized that the severity of the initial physical trauma presentation may not indicate the extent of impact on neurons or the significance of both short and long term consequences of the injury. The initial injury and resulting cascade of neuronal responses to injury have consequences that can be manifested by overt symptoms such as chronic headaches, anxiety, depression, insomnia, social withdrawal, and seizures. Additionally, there often are more subtly manifested symptoms that may include impairment in working memory and information processing speed, dysautonomia, or other indications of CNS dysfunction. The unfortunate impact of unrecognized or undertreated mTBI is that it may lead to long term disability for the patient in the form of impaired ADL capacity or employability. There is also an additional concern of neurodegeneration in some subsets of mTBI patients.
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Myocardial ischemia reperfusion injury is a negative pathophysiological event that may result in cardiac cell apoptosis and is a result of coronary revascularization and cardiac intervention procedures. The resulting loss of cardiomyocyte cells and the formation of scar tissue, leads to impaired heart function, a major prognostic determinant of long-term cardiac outcomes. Photobiomodulation is a novel cardiac intervention that has displayed therapeutic effects in reducing myocardial ischemia reperfusion related myocardial injury in animal models. A growing body of evidence supporting the use of photobiomodulation in myocardial infarct models has implicated multiple molecular interactions. A systematic review was conducted to identify the strength of the evidence for the therapeutic effect of photobiomodulation and to summarise the current evidence as to its mechanisms. Photobiomodulation in animal models showed consistently positive effects over a range of wavelengths and application parameters, with reductions in total infarct size (up to 76%), decreases in inflammation and scarring, and increases in tissue repair. Multiple molecular pathways were identified, including modulation of inflammatory cytokines, signalling molecules, transcription factors, enzymes and antioxidants. Current evidence regarding the use of photobiomodulation in acute and planned cardiac intervention is at an early stage but is sufficient to inform on clinical trials.
Background: Parkinson's disease (PD) is depicted as the most prevailed neurodegenerative disease being secondary to the alzheimer's disease. PD is featured by severe dropping of dopamine related neurons present in substantia nigra as well as cytoplasmic inclusions. A number of therapeutic agents are available to treat initial as well as later complications of PD. However, transport of neurotherapeutics into the brain has been a consistent challenge for researchers, because of the existence of blood-brain barrier (BBB). In some last decades, nasal delivery pathway has gained extensive deliberations. Intranasal administration as a way to target neurotherapeutics to the central nervous system bypassing blood brain barrier, exhibit several advantages for treating neurodegenerative disorders. This route for transport of neurotherapeutics offers the merits of convenience of administration, avoidance of pre-systemic hepatic metabolism, and non- invasiveness. Objective: The present review explores the novel nano sized formulations of various actives researched for intranasal drug transport to be used in PD therapy. Feasibility of various nano-carriers systems such as nano-emulsions, lipid nanoparticles and polymeric micelles has been elaborated. The write up traces the pre-clinical and pharmacokinetic aspects of the nano-formulations. The neuroprotection and neurotoxicity aspects have also been furnished. Conclusion: Nano-formulations are the rising formulations in PD treatment as they offer targeted drug delivery, enhanced therapeutic efficacy and decreased systemic side effects of neurotherapeutics. These formulations provide effective intranasal transport by encapsulating drug, protecting it from biological/chemical degradation and extracellular transport through P-glycoprotein (P-gp) efflux thus, and enhancing CNS availability for drugs.
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Objective: To evaluate if LED Photobiomodulation (PBM) can affect vision in patients with dry Age- Related Macular Degeneration (AMD). Methods: Prospective interventional case series. Near Infra Red (NIR) and yellow wavelengths of low powered LED light were applied to eyes with AMD in serial consecutive treatments. Included were patients with dry AMD, 50 years or older and with visual acuity between 20/20-20/200. Primary outcome measures selected were change in visual acuity, contrast sensitivity and fixation stability. Results: The treatment protocol was completed in 18 eyes (9 patients). Changes in visual acuity (p<0.0001) and contrast sensitivity (p<0.0001 at 3 cycles/degree and p<0.0032 at 1.5 cycles/degree) were positive and significant. There were no significant changes in fixation stability parameters. Conclusions: LED PBM proves to be beneficial for improvement of vision and contrast sensitivity as well as a safe treatment for dry AMD in this pilot study. Larger studies are warranted to validate the findings from this study.
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The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage has been known for almost forty years since the invention of lasers. Originally thought to be a peculiar property of laser light (soft or cold lasers), the subject has now broadened to include photobiomodulation and photobiostimulation using non-coherent light. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial. This likely is due to two main reasons; firstly the biochemical mechanisms underlying the positive effects are incompletely understood, and secondly the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. In particular a biphasic dose response has been frequently observed where low levels of light have a much better effect than higher levels. This introductory review will cover some of the proposed cellular chromophores responsible for the effect of visible light on mammalian cells, including cytochrome c oxidase (with absorption peaks in the near infrared) and photoactive porphyrins. Mitochondria are thought to be a likely site for the initial effects of light, leading to increased ATP production, modulation of reactive oxygen species and induction of transcription factors. These effects in turn lead to increased cell proliferation and migration (particularly by fibroblasts), modulation in levels of cytokines, growth factors and inflammatory mediators, and increased tissue oxygenation. The results of these biochemical and cellular changes in animals and patients include such benefits as increased healing in chronic wounds, improvements in sports injuries and carpal tunnel syndrome, pain reduction in arthritis and neuropathies, and amelioration of damage after heart attacks, stroke, nerve injury and retinal toxicity.
Conference Paper
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A puzzling feature of reports of near infrared light (NIr) treatment of soft tissue wounds is the lack of laterality in the tissue response - it is typically bilateral after a unilateral exposure. This has led to the idea that NIr has an ‘indirect’ effect on non-irradiated tissues, mediated by circulating ‘factors’. We have recently reported that NIr protects midbrain dopaminergic cells of mice from parkinsonian insult. In those studies, NIr was directed to the head, on the assumption that it would penetrate the skull and brain to reach the midbrain; in practice the whole dorsum of the mouse was irradiated. In this study, we applied NIr to the body only, preventing the radiation reaching the head with a ‘helmet’ of aluminium foil. NIr radiation of the body only was effective in protecting these cells, although less protective than radiation of both body and head. The results suggest that the neuroprotective effect of NIr may be mediated at least partially by a systemic or indirect effect. The possibility of immune system involvement will be discussed.
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To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR). During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670nm light for 3 minutes a day (9J/cm(2)). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed. 670nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670nm light-exposed animals, and no adverse effects of exposure to 670nm light were detected. Low levels of exposure to 670nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity.
An impairment of energy metabolism may underlie slow excitotoxic neuronal death in neurodegenerative diseases. We therefore examined the effects of intrastriatal, subacute systemic, or chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. Following intrastriatal injection 3-NP produced dose-dependent striatal lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P, calbindin) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of 3-NP produced age-dependent bilateral striatal lesions with a similar neurochemical profile. However, in contrast to the intrastriatal injections, striatal dopaminergic afferent projections were spared. Both freeze-clamp measurements and chemical shift magnetic resonance spectroscopy showed that 3-NP impairs energy metabolism in the striatum in vivo. Microdialysis showed no increase in extracellular glutamate concentrations after systemic administration of 3-NP. The lesions produced by intrastriatal injection or systemic administration of 3-NP were blocked by prior decortication. However, the NMDA antagonist MK-801 did not block the effects of intrastriatal 3-NP, consistent with a non-NMDA excitotoxic mechanism. In contrast to subacute systemic administration of 3-NP, chronic (1 month) administration produced lesions confined to the striatum in which there was relative sparing of NADPH-diaphorase interneurons, consistent with an NMDA excitotoxic process. Chronic administration showed growth-related proliferative changes in dendrites of spiny neurons similar to changes in Huntington's disease (HD). These results are consistent with in vitro studies showing that mild metabolic compromise can selectively activate NMDA receptors while more severe compromise activates both NMDA and non-NMDA receptors. Chronic administration of 3-NP over 1 month produces selective striatal lesions that replicate many of the characteristic histologic and neurochemical features of HD.
We have previously shown near infrared light (NIr), directed transcranially, mitigates loss of dopaminergic cells in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a model of parkinsonism. These findings complement others suggesting NIr treatment protects against damage from various insults. However one puzzling feature of NIr treatment is that unilateral exposure can lead to a bilateral healing response, suggesting NIr may have 'indirect' protective effects. We investigated whether remote NIr treatment is neuroprotective by administering different MPTP doses (50, 75, 100 mg/kg) to mice and treating with 670 nm light directed specifically at either the head or body. Our results show that, despite no direct irradiation of the damaged tissue, remote NIr treatment produces a significant rescue of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta at the milder MPTP dose of 50 mg/kg (∼30% increase vs sham-treated MPTP mice, p<0.05). However this protection did not appear as robust as that achieved by direct irradiation of the head (∼50% increase vs sham-treated MPTP mice, p<0.001). There was no quantifiable protective effect of NIr at higher MPTP doses, irrespective of the delivery mode. Astrocyte and microglia cell numbers in substantia nigra pars compacta were not influenced by either mode of NIr treatment. In summary, the findings suggest that treatment of a remote tissue with NIr is sufficient to induce protection of the brain, reminiscent of the 'abscopal effect' sometimes observed in radiation treatment of metastatic cancer. This discovery has implications for the clinical translation of light-based therapies, providing an improved mode of delivery over transcranial irradiation.
Object: Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location. Methods: An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice. Results: The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated. Conclusions: In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective.
α-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.