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Transcranial Low-Level Laser Therapy for Depression and Alzheimer’s Disease

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There is no effective therapy in patients with depression and Alzheimer’s disease (AD). The need for novel treatments offers researchers the opportunity to explore new technology for these disorders. Transcranial low-level laser therapy (LLLT) is a novel therapeutic approach based on laser irradiation to biological tissue, and it has been used to treat brain disorders. Although there are certain therapeutic options for depression and AD, there is little treatment available as non-invasive physical therapy. In this mini-review, we focus on a growing body of evidence surrounding the therapeutic effects of LLLT for depression and AD. Transcranial LLLT can enhance ATP biosynthesis, regulate mitochondrial homeostasis, and facilitate neurogenesis and/or neuroplasticity. However, the cellular and molecular mechanisms underlying the treatment of LLLT on these disorders are still at early stages. Clinical trials on depression and AD by transcranial LLLT are critical for future studies.
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10.4172/Neuropsychiatry.1000369 © 2018 p- ISSN 1758-2008
e- ISSN 1758-2016
Neuropsychiatry (London) (2018) 8(2), 477–483 477
Transcranial Low-Level Laser Therapy for Depression and
Alzheimer’s Disease
Jinlong Chang1, Yandong Ren1, Rui Wang1, Chengchong Li1, Yuhua Wang1, Xiang-Ping Chu1,2,†
1Neuroscience Laboratory for Translational Medicine, School of Mental Health, Qiqihar Medical University, Qiqihar 161006, China
2Departments of Biomedical Sciences and Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri
64108, USA
Author for correspondence: Xiang- Ping Chu, Departments of Biomedical Sciences and Anesthesiology, University of Missouri-Kansas City
School of Medicine 2411 Holmes Street, Kansas City, MO 64108 USA, Tel:816-235-2248; Fax: +1 816-235-6517; email: chux@umkc.edu
Abstract
There is no eective therapy in patients with depression and Alzheimer’s disease (AD). The
need for novel treatments oers researchers the opportunity to explore new technology for
these disorders. Transcranial low-level laser therapy (LLLT) is a novel therapeutic approach
based on laser irradiation to biological tissue, and it has been used to treat brain disorders.
Although there are certain therapeutic options for depression and AD, there is little treatment
available as non-invasive physical therapy. In this mini-review, we focus on a growing body of
evidence surrounding the therapeutic eects of LLLT for depression and AD. Transcranial LLLT
can enhance ATP biosynthesis, regulate mitochondrial homeostasis, and facilitate neurogen-
esis and/or neuroplasticity. However, the cellular and molecular mechanisms underlying the
treatment of LLLT on these disorders are still at early stages. Clinical trials on depression and
AD by transcranial LLLT are critical for future studies.
Keywords
Low-level infrared laser, Depression, Alzheimer’s disease, Mitochondrion
Introduction
Low-level laser therapy (LLLT) was discovered
50 years ago and has been used to treat wounds,
pain, inammation and cancer [1]. LLLT applies
low-powered red or near-infrared (NIR) laser
light (1-500 mW of power levels and 600-1100
nm of wavelengths) to stimulate a biological
response [1]. ese lasers generate a thermal
eect without heating, sound, or vibration
[1]. It belongs to class 3 of laser classication.
Recently, researchers have shifted the focus of
research to the application of LLLT on brain
disorders [1-3]. During the past decade, LLLT
has been widely used to study neurological and
psychological diseases [3] such as depression-
like behaviors [4-8], Alzheimer’s disease
(AD) [9-20], Parkinson’s disease [21], stroke
[22,23] and traumatic brain injury (TBI) [24-
32]. Because red or NIR light can eectively
penetrate into brain tissues [33,34], it can
be noninvasive and play a benecial role in
increasing ATP biosynthesis and neurogenesis
[1,2]. A number of excellent reviews have
focused on LLLT for TBI [1-3,35], depression
[36] and AD [35,37].
Increasing evidence supports roles for LLLT
in rodent models of TBI [1,35]. Transcranial
LLLT improved neuromuscular performance,
increased brain derived neurotrophic factor
(BDNF), reduced brain lesion volume, enhanced
learning and memory, and overall improved
the neurological severity score in mouse model
of TBI [24,25,28-32]. In addition, the clinical
studies found that LLLT could improve
cognition and decrease depression, anxiety,
headache and insomnia in patients with chronic
Neuropsychiatry (London) (2018) 8(2)
478
Review Xiang- Ping Chu
and long-term spatial and recognition memory
impairments in rats that were injected bilaterally
with Aβ 1-42 to the hippocampus CA1
region [9]. Moreover, LLLT also inhibited
Aβ 25-35-induced pheochromocytoma
(PC12) cell apoptosis [20]. Furthermore, laser
irradiation with moderate levels of 670-nm
light and epigallocatechin gallate (EGCG)
supplementation complementarily decreased
Aβ aggregates in human neuroblastoma (SH-
EP) cells [18]. More detailed information was
summarized in Table 2. Taken together, LLLT
plays benecial roles in AD.
e mechanisms of LLLT in depression LLLT
might increase the levels of brain monoamine
neurotransmitters
Depression is a common mental disorder.
Studies have shown that the specic symptoms
of depression in adults are closely related to
three major monoamine neurotransmitters in
the brain circuits including dopamine, serotonin
and norepinephrine [38]. e pathogenesis
of depression is largely neurotransmitter-
dependent. Serotonin is a messenger that
produces pleasure and aects almost every
aspect of brain activity from regulating emotion,
energy, and memory to shaping life [38].
erefore, antidepressants generally play a role
by increasing brain serotonin [40]. In addition,
dopamine is also an important neurotransmitter
which is closely related to depression, mainly
used to transmit excitement and happiness
[40]. Both serotonin and dopamine levels in the
TBI [26,27]. us, LLLT could be an alternative
approach for treatment of TBI.
Depression is a common mental disorder
characterized by depressed mood, slow thought,
diminished volitional activity, cognitive decline
and somatic symptoms [38]. Recently, Xu et
al. investigated that LLLT eectively decreased
depression-like behaviors; it also increased ATP
biosynthesis and the level of mitochondrial
complex IV expression and activity in two
depressive-related mice models [4]. e two mice
models were space restriction and Abelson helper
integration site-1 (Ahi1) knockout (KO) mice
[4]. In another study using forced swimming
test (FST) and electrocorticography (ECoG)
spectral analysis, transcranial LLLT was shown
to successfully ameliorate depressive-related
behavior induced by reserpine in rats [5]. Further,
LLLT could enhance outcomes for treatment of
depression in clinical studies [6-8]. ese results
were summarized in Table 1. Collectively, this data
suggest that transcranial LLLT has a benecial role
in depressive–related behaviors.
AD, which is a chronic neurodegenerative disease,
is characterized by a progressive decline in many
cognitive functions, resulting in memory loss and
dementia [39]. Extracellular accumulation of
amyloid β (Aβ) peptide aggregates, which results
in the formation of senile plaques, indicates
one of the neuropathological markers of AD
[39]. In recent years, accumulating evidence
has suggested that transcranial LLLT suppresses
Aβ-induced hippocampal neurodegeneration
Table 1: Summary of studies on LLLT for treatment of depression.
Subjects Wavelength of
laser
Power output density
of
laser
Duration of laser
irradiation LLI treatment eects References
Male adult ICR mice 808 nm 23 mW/cm2
30 min per
day for 28 days
Improved depression-like behaviors;
elevated ATP biosynthesis and the level of
mitochondrial complex IV expression and
activity in PFC [4]
Adult male albino rats 804 nm
approximately 0.64,
1.60, and
3.18 W/cm21 min
Signicantly decreased
animal’s immobility in the FST; increased
signicantly delta frequency band in ECoG
spectral analyses [5]
10 patients with
major depression 810 nm 250 mW/cm24 min Reductions in both HAM-D and HAM-A
scores; No side eects. [6]
39 sequential patients
with depression 810/980 nm 55-81 J/cm29–12 min Deduction of QIDS total score [7]
51 adults with de-
pression 1064nm 250 mW/cm24 min
Greater symptom improvement among
participants whose attention
was responsive to ABM [8]
ABM: attention bias modication; ATP: adenosine triphosphate; ECoG: electroencephalographic; FST: forced swimming test; HAM-A: a Hamilton
Anxiety Rating Scale; HAM-D: a Hamilton Depression Rating Scale; ICR: Institute of Cancer Research; LLI: low-level laser irradiation. PFC: prefrontal
cortex; QIDS: the Quick Inventory of Depression Symptomatology-Self Report;
479
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Transcranial Low-Level Laser Therapy for Depression and Alzheimer’s Disease
Table 2: Summary of studies on LLLT for treatment of Alzheimer’s disease.
Subjects Wavelength
of laser
Power output
density of laser
Duration of
laser irradiation LLI treatment eects References
Male Sprague-
Dawley rats 808 nm
25 mW/cm2 (cerebral
cortex tissue );
8.33±0.27mW/cm2
(hippocampus tissue )
Two-minute daily
for 5 consecutive days
Suppress Aβ-induced hippocampal
neurodegeneration and long-term spatial
and recognition memory impairments
[9]
The Aβ PP
transgenic
mouse model
of Aβ peptide
amyloidosis
808±10 nm ~10 mW/cm2
1 min
An increase in soluble AβPP; an increase
in ATP levels , mitochondrial function
and c- fos; reduction in expression of
inammatory markers
[10]
Male and
female
TASTPM mice
1072 nm 5 mW/cm26 min Reduction in Aβ 1-42 plaques in the cerebral
cortex [11]
APP/PS I
and K3 tau
transgenic
mouse
670 nm 2m W/cm290 s Mitigating degeneration in many regions of
the mouse brain [12]
30 femalemice
from CDl mice
1072 nm Not found 6 min Improved cognitive performance [13]
PC12 cells 0.52
mW/cm2
632.8 nm 0.52 mW/cm2From 5 to 40 mins Inhibited A Aβ 25-35 induced PC 12 cell
apoptosis
[20]
PC12 cells 632.8 nm 12.74 mW/cm2Not found
Increased the nuclear translocation of
-catenin and enhanced its T cell factor/
lymphocyte enhancer factor-dependent
transcriptional activity
[17,18]
hippocampus were signicantly down-regulated
in Ahi1 KO mice, which reveals depressive-like
behaviors [4]. Transcranial LLLT attenuated
depressive-like behaviors in Ahi1 KO mice,
which could be involved in the enhancement of
serotonin and dopamine levels in the brain [4].
us, the therapeutic mechanism of LLLT on
depression is closely associated with monoamine
neurotransmitters (Figure 1).
LLLT enhances ATP biosynthesis
Depression, which is characterized by lack of
energy, impaired concentration and fatigue, is
believed to be closely related to mitochondrial
dysfunction [40-42]. ese clinical symptoms
may be partly attributed to reduced synthesis
of adenosine triphosphate (ATP) due to
mitochondrial dysfunction [41-43]. ATP,
which is produced by mitochondria, is the main
source of cellular energy. Energy is conserved via
the mitochondrial respiratory chain as the so-
called proton motive force. Transcranial LLLT
promotes ATP biosynthesis and increases the
expression level and activity of mitochondrial
complex IV in mice prefrontal cortex in
depressive mouse model [4]. To support this
idea, Ferraresi et al. illuminated that LLLT
increases mitochondrial membrane potential
and ATP synthesis in C2C12 myotubes [44].
erefore, the therapeutic mechanism of LLLT
on depression may be associated with an increase
of ATP-production caused by low-level laser
irradiation (LLLI) (Figure 2).
The mechanisms of LLLT in AD LLLT
contributes to mitochondrial homeostasis
in AD
Although the pathogenesis of AD remains
unclear, it has been widely recognized that
AD is characterized by extracellular Aβ plaque
and neurobrillary tangles within neurons
[39]. A large number of studies show that the
development process and the pathogenesis of
AD are closely related to a series of pathological
processes including intracellular neurobrillary
tangles, oxidative stress, nerve inammation
and mitochondrial dysfunction with consequent
neuronal dysfunction and cell death [39]. Lu
Y et al. illuminated that Aβ injection into the
hippocampus led to mitochondrial abnormalities
including impaired mitochondrial dynamics and
mitochondrial fragmentation [9]. In contrast,
transcranial LLLT is able to shift mitochondrial
dynamics toward fusion by balancing the
mitochondrial targeting ssion proteins and
Neuropsychiatry (London) (2018) 8(2)
480
Review Xiang- Ping Chu
Figure 1: The mechanisms of LLLT in depression.
Light passes through the scalp and the skull, whereupon it is absorbed by cytochrome c oxidase in the mitochondrial respiratory chain of the cortical
neurons. Adenosine triphosphate (ATP) biosynthesis is increased as a result of stimulated mitochondrial activity. LLLT might increase the secretion of
monoamine neurotransmitters in the brain of Ahi 1 knockout mice. These monoamine neurotransmitters include serotonin and dopamine.
Figure 2: The mechanisms of transcranial LLLT on Alzheimer’s disease.
Light passes through the scalp and the skull, whereupon transcranial LLLT shifts mitochondrial dynamics toward fusion by balancing the mitochondrial
targeting ssion and fusion proteins. LLLT regulates/modulates the mitochondrial targeting ration of active Bax/Bcl-2. LLLT colud inhibit Aβ 25-35- induced
cell apoptosis by Akt/YAP/p73/GSK3β/PKC.
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Transcranial Low-Level Laser Therapy for Depression and Alzheimer’s Disease
fusion proteins [9]. Simultaneously, LLLT
regulates the mitochondrial targeting ratio of
active Bax/Bcl-2 and antioxidant level, intimating
a vital role of LLLT in facilitating mitochondrial
homeostasis and protection in hippocampal
CA1 neurons [9]. Collectively, the mechanism
of LLLT in the treatment of AD is closely related
to mitochondrial homeostasis [42,45].
LLLT is involved in regulation of
oxidative stress and anti-inammation
Heat shock protein (HSP) signaling pathways are
involved in AD [46]. HSP reduction may lead to
insucient levels available to regulate abnormal
polypeptide folding and processing, resulting
in toxic accumulation which can initiate the
apoptotic pathway, and may contribute to the
progression of AD [47]. Consistent with idea,
Grillo et al examined whether LLLT upregulates
HSP and reduces the aggregation of Aβ in
TASTPM mice, a mouse model of AD [11].
ey found that LLLT treatment upregulates
HSP, which reduce Aβ protein aggregation and
neuronal apoptosis [11]. e data suggest that
LLLT treatment may regulate oxidative stress to
combat AD [11].
Inammation is responsible for the
pathophysiology of AD. De Taboada et al tested
whether LLLT plays an anti-inammation role
in an Aβ protein precursor (AβPP) transgenic
mouse model, a mouse model of AD [10]. ey
found that LLLT treatment decreases Aβ plaques
and the expression of inammatory markers in
the AβPP transgenic mice [10]. In addition,
LLLT treatment showed an increase in ATP
levels, mitochondrial function, and c-fos, which
result in an overall improvement in neurological
function [10]. e data suggest that LLLT is a
potential candidate for treatment of AD.
LLLT regulates/modulates multiple
intracellular down-stream signaling
pathways in AD
Although the molecular mechanism of LLLT
in the treatment of AD is highly complex,
increasing number of studies using LLLT was
found recently. Zhang et al. have reported
that Aβ 25-35 can induce pheochromocytoma
(PC12) cell apoptosis by increasing the level
of bax mRNA, and the anti-apoptotic eect of
LLLT is dependent on the up-regulation of bclxl
and down-regulation of bax via protein kinase C
(PKC) activation pathway [20]. Moreover, LLLT
increased the nuclear translocation of β-catenin
and enhanced its T cell factor/lymphocyte
enhancer factor-dependent transcriptional
activity via the Akt/GSK3β pathway to promote
cell survival upon treatment with Aβ 25-35 [19].
LLLT has a prosurvival eect on Aβ-induced
apoptosis and may be an eective therapeutic
strategy in treating AD by targeting GSK3b
[17]. In addition, another study on EGCG has
also found that irradiation with moderate levels
of 670-nm light and EGCG supplementation
complementarily reduces Aβ aggregation
in human neuroblastoma SH-EP cells [18].
Further, Zhang et al. has uncovered evidence
that LLLT could inhibit Aβ 25-35-induced
cell apoptosis through activation of Akt/Yes-
associated protein (YAP)/p73 signaling pathway
[19]. Taken together, these results directly
point to a potential therapeutic strategy for
the treatment of AD through Akt/YAP/p73/
GSK3β/PKC signaling pathways with LLLT
(Fig. 2). Interesting, a recent study by Iaccarino
et al demonstrated that entraining gamma
oscillations (20 to 40 Hz), which is dierent
from LLLT, may provide systemic eects in the
brain to attenuate AD-related pathology through
modulation of microglia [48]. Further study in
gamma oscillations and LLLT is warranted to
examine whether it will have therapeutic eects
in human AD.
Conclusion and Perspective
As a noninvasive treatment, accumulating
evidence has shown that transcranial LLLT is
a benecial treatment for depression [4,5] and
AD [10-17] in rodent models. In addition,
transcranial LLLT has been carried out on
depression and chronic TBI patients in
preclinical trials [6-8,26,27]. With the increasing
enthusiasm for studies on LLLT, the cellular
and molecular mechanisms of LLLT are still at
early stages. LLLT might be related to factors
such as mitochondrial oxidative respiratory
chain, Akt/YAP/p73/GSK3β/PKC signaling
pathway, and neurogenesis, neuroplasticity, and
monoamine neurotransmitters as mentioned
above. However, the main mechanism of LLLT
is closely related to the function of mitochondria
in pathophysiological conditions [1,45].
Mitochondria might be the most important
organelle within cells governing the LLLT
responses [1,42].
Although the single and multiple applications
of LLLT at the surface of the cerebral cortex
appears to be safe within one year after
treatment in animal model [46], LLLT, as
Neuropsychiatry (London) (2018) 8(2)
482
Review Xiang- Ping Chu
a new therapeutic technology, needs more
studies to prove its safety. In addition, we need
to examine the eects of LLLT including laser
wavelength, energy intensity, irradiation mode,
and the duration of laser on physiological and
pathological conditions. Further, we should
explore other cellular and molecular mechanisms
responsible for its eect. Most importantly, it
is critical to test the eects of transcranial LLT
in treatment of depression and AD in clinical
trials. In conclusion, transcranial LLLT will shed
new light on the treatment of psychological and
neurological disorders.
Grants
is work was partly supported by grants from
the Qiqihar Medical University (QY2016-ZD1),
Heilongjiang Province, China and the University
of Missouri Research Board, Missouri, USA (XPC).
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... 15 There are also investigations demonstrating that this method affects the cognition abilities of Alzheimer's disease patients and causes improvement of executive performance and enhancement of cerebrovascular blood flow. [26][27][28] By considering the global increase in the prevalence of dementia in the future and attempting to develop a noninvasive and nonpharmaceutical approach for the treatment of dementia, this study investigated the possible effects of LLLT on the improvement of cognitive symptoms of dementia patients. ...
Article
Objective: To investigate the effects of low-level laser therapy (LLLT) as a new nonpharmaceutical approach to improve cognitive symptoms in patients with dementia. Background: Routine pharmacological treatment of dementia patients is inefficient and has considerable adverse effects. Recent attempts to develop nonpharmaceutical approaches are considered favorable for patients with dementia. Methods: Thirty-two patients with dementia were randomly divided into the same population of LLLT and sham groups. The LLLT group underwent transcranial LLLT, and the sham group received the same protocol with a zero-intensity laser. All patients in the two groups were evaluated using the minimental state examination (MMSE) and clinical dementia rating (CDR) tests at the time of admission as baseline at 2 and 6 weeks postintervention. Results: The rate of change of MMSE scores in sham and LLLT groups was 0.13 ± 0.96 and 2.31 ± 1.81 in week 2 (p = 0.00005) and also -0.25 ± 0.86 and 2.53 ± 1.73 in week 8 (p = 0.000003). In the LLLT group, the mean scores of CDR were 1.28 ± 0.71, 1.28 ± 0.71, and 1.25 ± 0.80 at baseline, week 2, and week 8 (p = 0.605 and p = 0.742), respectively. The mean scores of CDR in the sham group were 1.69 ± 0.73, 1.75 ± 0.68, and 1.72 ± 0.82 at baseline, week 2, and week 8, respectively. Conclusions: These findings suggest that laser therapy could be a promising treatment modality and an adjunct to pharmacotherapy in dementia patients. Clinical Trial Registration: IRCT20191018045148N1 was obtained from the Iranian Registry of Clinical Trials (IRCT.ir).
... Drug-free and noninvasive low level light therapy (LLLT), or photobiomodulation (PBM), is one promising approach allowing to stabilize cellular metabolism, primarily through the activation of the mitochondrial respiratory chain, resulting in an increased ATP production, and the stimulation of transcription factors [33][34][35][36]. LLLT uses low doses of light from red and near-infrared (NIR) lasers to achieve a therapeutic effect and has been applied for the treatments of various neurodegenerative diseases [37,38]. It has been shown in animal models that it can facilitate neurogenesis and neuroplasticity [39], improve spatial memory [40], preserve motor and cognitive skills [40][41][42]. ...
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Background Low-intensity light can decelerate neurodegenerative disease progression and reduce amyloid β (Aβ) levels in the cortex, though the cellular and molecular mechanisms by which photobiomodulation (PBM) protects against neurodegeneration are still in the early stages. Microglia cells play a key role in the pathology of Alzheimer’s disease by causing chronic inflammation. We present new results concerning the PBM of both oxidative stress and microglia metabolism associated with the activation of metabolic processes by 808 nm near-infrared light. Methods The studies were carried out using healthy male mice to obtain the microglial cell suspension from the hippocampus. Oligomeric β-amyloid (1-42) was prepared and used to treat microglia cells. Light irradiation of cells was performed using diode lasers emitting at 808 nm (30 mW/cm ² for 5 min, resulting in a dose of 10 J/cm ² ). Mitochondrial membrane potential, ROS level studies, cell viability, apoptosis, and necrosis assays were performed using epifluorescence microscopy. Phagocytosis, nitric oxide and H 2 O 2 production, arginase, and glucose 6-phosphate dehydrogenase activities were measured using standard assays. Cytokines, glucose, lactate, and ATP were measurements with ELISA. As our data were normally distributed, two-way ANOVA test was used. Results The light induces a metabolic shift from glycolysis to mitochondrial activity in pro-inflammatory microglia affected by oligomeric Aβ. Thereby, the level of anti-inflammatory microglia increases. This process is accompanied by a decrease in pro-inflammatory cytokines and an activation of phagocytosis. Light exposure decreases the Aβ-induced activity of glucose-6-phosphate dehydrogenase, an enzyme that regulates the rate of the pentose phosphate pathway, which activates nicotinamide adenine dinucleotide phosphate oxidases to further produce ROS. During co-cultivation of neurons with microglia, light prevents the death of neurons, which is caused by ROS produced by Aβ-altered microglia. Conclusions These original data clarify reasons for how PBM protects against neurodegeneration and support the use of light for therapeutic research in the treatment of Alzheimer’s disease. Graphical Abstract
... Therefore, the present investigation studies a crucial issue in the field due to its considerable effect on the experimental results. During the last decades, an increasing number of transcutaneous and transcranial photobiostimulation applications have been emerged [50,51]. Therefore, one of the most commonly used laser wavelength range (i.e., Infrared laser) in medical applications and the extensively studies tissue samples (skull and skin) have been utilized for the present investigation. ...
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Infrared (IR) lasers are extensively utilized as an effective tool in many medical practices. Nevertheless, light penetration into the inspected tissue, which is highly affected by tissue optical properties, is a crucial factor for successful optical procedures. Although the optical properties are highly wavelength-dependent, they can be affected by the power of the incident laser. The present study demonstrates a considerable change in the scattering and absorption coefficients as a result of varying the incident laser power probing into biological samples at a constant laser wavelength (808 nm). The optical parameters were investigated using an integrating sphere and Kubelka-Munk model. Additionally, fluence distribution at the sample’s surface was modeled using COMSOL-multiphysics software. The experimental results were validated using Receiver Operating Characteristic (ROC) curves and Monte-Carlo simulation. The results showed that tissue scattering coefficient decreases as the incident laser power increases while the absorption coefficient experienced a slight change. Moreover, the penetration depth increases with the optical parameters. The reduction in the scattering coefficients leads to wider and more diffusive fluence rate distribution at the tissue surface. The simulation results showed a good agreement with the experimental data and revealed that tissue anisotropy may be responsible for this scattering reduction. The present findings could be considered in order for the specialists to accurately specify the laser optical dose in various biomedical applications.
... Here, we investigated the effects of infrared PS (1267 nm) on the lymphatic removal of Aβ from healthy and AD mouse brains at night and during the day. An infrared light of 800-1100 nm was widely used for the PS therapy of brain diseases, including AD [22,50]. However, infrared PS has a significant limitation, such as limited penetration into the brain due to light scattering and heating effect [51]. ...
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The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aβ removal from the brain. There is increasing evidence that sleep plays an important role in Aβ clearance. Here, we tested our hypothesis that PS at night can stimulate Aβ clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aβ clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aβ accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aβ accumulation in the brain of people with disorder of Aβ metabolism, sleep deficit, elderly age, and jet lag.
... LLLT has also been applied to treatment of traumatic and degenerative brain disorder and psychiatric disease where is improvess mitochondrial function, inhibits neuronal apoptosis, reduces cell swelling (edema) and inflammation, and stimulates neurogenesis. [24][25][26][27] The mechanism of LLLT is hypothesized to be based on the principle that in the red -NIR spectral range, photons of light are able to deeply penetrate biological tissue and be absorbed by components of the cellular mitochondrial respiratory chain. This absorption of energy leads to an increase in adenosine triphosphate (ATP) production and modulates reactive oxygen species and nitic oxide content, thus leading to activation of signaling pathways and transcription factors to improve energy metabolism and mitochondrial function overall. ...
Article
Treatment of traumatic brain injury, within a few minutes and even before transportation to the nearest medical facility, can significantly curtail injury severity and even prevent death. The primary aim of this study was to evaluate the effect of laser irradiation as a therapeutic intervention tool immediately following brain injury. To this end, a dual-wavelength laser speckle contrast imaging (DW-LSCI) system based on two laser sources at two wavelengths 532 and 660 nm was employed to monitor changes in cerebral blood flow, tissue saturation and rate of oxygen consumption in a mouse model of intact head injury. In addition, structural changes of tissue were evaluated using linear approximation to Rayleigh-MIE scattering in the range between the two laser wavelengths. Furthermore, cerebral tissue temperature was imaged by a thermal camera providing additional information on physiological brain tissue condition. Experiments were conducted on anesthetized mice (n = 6, female) subjected to a closed head weight-drop model of focal brain injury. After 5 min of baseline measurement, focal brain injury was induced and measurements were conducted for 10 min. Low-level laser therapy (LLLT) was than administrated for a duration of 15 min with uniform exposure of 45 J/cm² from a CW diode laser source (810 nm). Concurrently, measurements were carried out over the treatment time interval. Laser illumination was then blocked and measurements continued for another 20 min, followed by euthanasia. In comparison to baseline measurements, noticeable variations were revealed post-injury which indicate the severity of brain damage. The use of LLLT inhibited the development of complications in the injured mice by increasing blood flow and saturation and overall oxygen consumption level over the injured area which highlights its effectiveness as a neuroprotective agent immediately following brain injury. Different doses of low-level laser irradiation were also tested (n = 12) with less effectiveness on cerebral parameters. The results presented here support our hypothesis that a high dose of laser irradiation as a first aid can attenuate the injury and save the brain from further worse outcome. To the best of our knowledge, the implementation of the DW-LSCI system to monitor brain hemodynamic and metabolic response to LLLT shortly after head injury in intact mouse brain has not been previously reported.
... 23 The cognitive effect of transcranial LLLT on mice is reported by Salehpour et al and Chang et al have investigated the role of transcranial LLLT in depression. 24,25 It seems this field of investigation will experience more achievements in the near future. ...
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Introduction: Laser therapy has attracted experts’ attention in medical sciences. Many benefits of laser therapy are presented besides some complications. In the present study, it is tried to present a new perspective of laser therapy in the various fields of medicine. Methods: Laser therapy-related articles which are combined with regenerative medicine, cosmetic, dentistry, neurodegenerative diseases, kidney, bone fracture, and vaginal function in the English language were searched through the google scholar search engine in the range of 2000-2021. After title screening, the abstracts were evaluated to access the full texts. Results: Basic concepts and various kinds of lasers which are applied in medicine were explained. Applications of laser therapy in various fields of medicine such as pain reduction, wound healing, regenerative medicine, dentistry, and several other body organs were highlighted and some complications were pointed. Conclusion: High potential of laser therapy for application in medicine implies a reconsideration of the laser properties and also styles of laser applications to improve the treatment and prevention of its side effects.
... triphosphate and nitric oxide with an increase in energetic and metabolic capacities of the brain tissues [5]. A number of reviews have focused on application of tPBM for treatment of AD and depression [6,7], traumatic brain injuries and stroke [8]. tPBM can reduce Aβ-mediated hippocampal neurodegeneration, memory impairments in rodents, inhibits Aβ-induced brain cell apoptosis and causes a reduction in Aβ plaques in the cerebral cortex [9]. ...
Chapter
Here, we demonstrate the therapeutic effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm², a 9-day course) in mice with the injected model of Alzheimer’s disease (AD) associated with accumulation of beta-amyloid (Aβ) in the brain resulting in neurocognitive deficit vs. the control group (CG) (the neurological severity score (NNS), AD 3.67 ± 0.58 vs. CG 1.00 ± 0.26%, p < 0.05) and mild cerebral hypoxia (AD 72 ± 6% vs. CG 97 ± 2%, p < 0.001). The course of tPBM improved neurocognitive status of mice with AD (NNS, AD 2.03 ± 0.14 vs. CG 1.00 ± 0.26, vs. 2.03 ± 0.14, p < 0.05) due to stimulation of clearance of Aβ from the brain via the meningeal lymphatic vessels (the immunohistochemical and confocal data) and an increase in blood oxygen saturation of the brain tissues (the pulse oximetry data) till 85 ± 2%, p < 0.05. These results open breakthrough strategies for non-pharmacological therapy of AD and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying AD based on stimulation of oxygenation of the brain tissues and activation of clearance of toxic molecules via the cerebral lymphatics.
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Understanding the compartment fire behavior has a vital importance for fire protection engineers. For design purposes, whether to use a prescriptive code or performance based on design, life safety and property protection issues are required to be assessed. The use of design fires in computer modelling is the general method to determine fire safety. However, these computer models are generally limited to the input of one design fire, with consideration of the complex interaction between fuel packages and the compartment environment being simplified. Of particular interest is the Heat Release Rate, HRR, as this is the commonly prescribed design parameter for fire modelling. If the HRR is not accurate then it can be subsequently argued that the design scenario may be flawed. Therefore, the selection of the most appropriate fire design scenario is critical, and an increased level of understanding of compartment behavior is an invaluable aid to fire engineering assumptions. This thesis studies 3 types of pool fire geometry to enhance the understanding of the impact and interaction that the size and location of pool fires within an enclosure have upon the compartment fire behavior, also Ethanol pool fires were used. In this present work, we have carried out to analysis the effect of water to extinguish the fire and it and it's tested in 4 different ways with and without water. Also in the result, we can see the effect of water to visibility and also the concentration of air.
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Transcranial photobiomodulation therapy (PBMT) also known as low-level laser therapy (LLLT) relies on the use of red/NIR light to stimulate, preserve and regenerate cells and tissues. In this review, we will present the most important laser types and sources used in the treatment of the brain, required energy densities to provide treatment, and laser delivery techniques to the brain through the cranium, eye, internal ear, and nostril. Various forms of light therapy have been practiced all over the world for many years. Among them, laser therapy has flourished in recent years. More and more laser equipment is being used in this area. The use of PBMT for neuronal stimulation has been studied in various animal and human models and has been shown to improve cerebral metabolic activity and blood flow and provide neuroprotection through anti-inflammatory and antioxidant pathways. In recent years, the concept of thermotherapy for the treatment of brain tumors has become more widespread. Traditionally, heat therapy is divided into hyperthermia, with a moderate increase in the temperature of the treated tissue above the physiological baseline level, and heat ablation, in which even higher temperatures are reached. Recently, intranasal light therapy, light delivery to the brain through the ear and other channels have become attractive and potential treatments for brain diseases. Here we summarize the various methods of delivering light through the nostrils and ear canals using lasers or light-emitting diodes (LEDs), which can be used alone or in combination with transcranial devices or (applied directly to the scalp) to treat a wide range of brain conditions such as the lungs cognitive impairment, Alzheimer's disease, Parkinson's disease, cerebrovascular disease, depression and anxiety, and insomnia. Evidence shows that low-intensity laser therapy improves blood rheology and cerebral blood flow, so there is no need to pierce blood vessels.
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Although there is plenty of evidence for the existence of the biofield, the evidence that DNA interacts with it is very limited. Therefore, the idea that the biofield is created by the mass of DNA in the organism remains a hypothesis. We will first briefly summarize the existing evidence and then briefly review our studies, in which we used computational genomics to reveal the traces of resonance signaling in the genome and provided statistical evidence for this resonance signaling.
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There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600–1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death in the brain. There is evidence that PBM can help the brain repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women), PBM has been shown to increase regional cerebral blood flow, tissue oxygenation, and improve memory, mood, and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports showing improvement in executive function, working memory, and sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).
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Background The treatment of depression has been hampered by low efficacy of antidepressant medications and safety concerns with alternative modalities. Recent work demonstrated that multi-Watt transcranial near-infrared light therapy (NILT) can effectively treat traumatic brain injury (TBI). The current objective is to explore multi-Watt NILT efficacy in a proof-of-concept study as a treatment for depression.Methods Thirty-nine sequential patients treated for TBI between March 2013 and May 2017 provided depression self-assessment data and/or were administered the Hamilton depression rating scale. Each completed the Quick Inventory of Depression Symptomatology-Self Report (QIDS) before and after treatment. Patients received multi-Watt NILT using near-infrared lasers (810/980 nm at 8–15 W) applied to forehead and temporal regions bilaterally for 9–12 min to each area. Pre- and posttreatment scores were analyzed by paired t-tests.ResultsAll met QIDS criteria for mild to severe depression and 69% had prior antidepressant trials. For 36 of the 39 patients, after 16.82 ± 6.26 treatments, QIDS scores indicated a robust response (decrease of QIDS total score by ≥50%). For 32 of 39 patients, posttreatment QIDS scores indicated a remission from depression (decrease of QIDS total score ≤5). Overall, the QIDS score fell from 14.10 ± 3.39 to 3.41 ± 3.30 SD (p = 6.29 × 10−19). With 12 or fewer treatments, QIDS score dropped from 14.83 ± 2.55 to 4.17 ± 3.93. Patients receiving ≥13 treatments showed a change in QIDS score from 13.67 ± 3.64 to 3.11 ± 3.14. Those (N = 15) who received the entire treatment course within ≤8 weeks (5.33 ± 1.72 weeks) showed a change in QIDS score from 13.86 ± 3.14 to 4.5 ± 3.94. Suicidal ideation resolved in all, but two patients. Patients remained in remission for up to 55 months after a single course of treatment.Conclusion This is the first report of high-powered NILT showing efficacy for depression. Multi-Watt NILT showed far greater efficacy and persistent benefit compared to low-power (<1 Watt) infrared light treatments. Patients saw benefit often within four treatments and resolution of depressive symptoms occurred within 4 weeks for some. These data raise an intriguing possibility—that multi-Watt NILT may be a safe, effective, and rapid treatment for depression comorbid with TBI and possibly primary major depression disorder. A double-blind, placebo controlled trial is warranted to verify these proof-of-concept data.
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Variants in mitochondrial DNA (mtDNA) and nuclear genes encoding mitochondrial proteins in bipolar disorder, depression, or other psychiatric disorders have been studied for decades, since mitochondrial dysfunction was first suggested in the brains of patients with these diseases. Candidate gene association studies initially resulted in findings compatible with the mitochondrial dysfunction hypothesis. Many of those studies, however, were conducted with a modest sample size (such as n < 1000), which could cause false positive findings. Furthermore, the DNA samples examined in these studies including GWAS were generally derived from peripheral tissues. One key unanswered question is whether there is an association between mood disorders and somatic mtDNA mutations (deletions and point mutations) in brain regions which accumulate a high amount of mtDNA mutations and/or are involved in the regulation of mood. Two lines of robust evidence supporting the importance of mtDNA mutations in the brain tissues for mood disorders have come from clinical observation of mitochondrial disease patients and an animal model study. More than half of them have comorbid mood disorders, and carry primary mtDNA mutations or accumulate secondary mtDNA mutations due to nuclear mutations. Mice carrying a neuron-specific expression of mutant mtDNA polymerase show spontaneous depression-like episodes. In this review, we first summarize current knowledge of mtDNA and its genetics and discuss what mtDNA analysis tells us about neuropsychiatric disorders based on an example of Parkinson's disease. We also discuss challenges and future directions beyond mtDNA analysis towards an understanding of the pathophysiology of "idiopathic" mood disorders.
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Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology.
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Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or “brain caps”. This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.
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Transcranial low-level infrared laser is a modality of therapy based on the principle of photons delivered in a non-invasive manner through the skull for the treatment of some neurological conditions such as psychological disorders, traumatic brain injuries, and neurodegenerative diseases among others. In the present study, effects of low-level infrared laser irradiation with different radiation powers (80, 200, and 400 mW, continuous wave) were investigated on normal animals subjected to forced swimming test (FST). Results indicated that there are changes in FST parameters in animals irradiated with laser; the lowest dose provoked a significant increase in animal activity (swimming and climbing) and a significant decrease in animal's immobility, while the highest laser dose resulted in a complete inverse action by significantly increasing animal immobility and significantly decreasing animal activity with respect to control animals. The lowest dose (80 mW) of transcranial laser irradiation has then utilized on animals injected with a chronic dose of reserpine (0.2 mg/kg i.p. for 14 days) served as an animal model of depression. Laser irradiation has successfully ameliorated depression induced by reserpine as indicated by FST parameters and electrocorticography (ECoG) spectral analysis in irradiated animals. The findings of the present study emphasized the beneficial effects of low-level infrared laser irradiation on normal and healthy animals. Additionally, it indicated the potential antidepressant activity of the low dose of infrared laser irradiation.
Article
This report examines the potential of low level laser therapy (LLLT) to alter brain cell function and neurometabolic pathways using red or near infrared (NIR) wavelengths transcranially for the prevention and treatment of cognitive impairment. Although laser therapy on human tissue has been used for a number of medical conditions since the late 1960s, it is only recently that several clinical studies have shown its value in raising neurometabolic energy levels that can improve cerebral hemodynamics and cognitive abilities in humans. The rationale for this approach, as indicated in this report, is supported by growing evidence that neurodegenerative damage and cognitive impairment during advanced aging is accelerated or triggered by a neuronal energy crisis generated by brain hypoperfusion. We have previously proposed that chronic brain hypoperfusion in the elderly can worsen in the presence of one or more vascular risk factors, including hypertension, cardiac disease, atherosclerosis and diabetes type 2. Although many unanswered questions remain, boosting neurometabolic activity through non-invasive transcranial laser biostimulation of neuronal mitochondria may be a valuable tool in preventing or delaying age-related cognitive decline that can lead to dementia, including its two major subtypes, Alzheimer's and vascular dementia. The technology to achieve significant improvement of cognitive dysfunction using LLLT or variations of this technique is moving fast and may signal a new chapter in the treatment and prevention of neurocognitive disorders.
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Transcranial photobiomodulation (PBM), also known as low level laser therapy (LLLT), relies on the use of red/NIR light to stimulate, preserve and regenerate cells and tissues. The mechanism of action involves photon absorption in the mitochondria (cytochrome c oxidase), and ion channels in cells leading to activation of signaling pathways, up-regulation of transcription factors and increased expression of protective genes. We have studied PBM for treating traumatic brain injury in mice using a NIR laser spot delivered to the head. Mice had improved memory and learning, increased neuroprogenitor cells in the dentate gyrus and subventricular zone, increased BDNF and more synaptogenesis in the cortex. These highly beneficial effects on the brain suggest that the applications of LLLT are much broader than first conceived. Other groups have studied stroke (animal models and clinical trials), Alzheimer's disease, Parkinson's disease, depression and cognitive enhancement in healthy subjects.
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Aβ is well accepted to play a central role in the pathogenesis of Alzheimer's disease (AD). The present work evaluated the therapeutic effects of Low-level Laser Irradiation (LLI) on Aβ-induced neurotoxicity in rat hippocampus. Aβ1-42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and two-minute daily LLI treatment was applied transcranially after Aβ injection for five consecutive days. LLI treatment suppressed Aβ-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: a) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aβ-induced extensive fragmentation; b) suppressed Aβ-induced collapse of mitochondrial membrane potential; c) reduced oxidized mtDNA and excessive mitophagy; d) facilitated mitochondrial homeostasis via modulation of the Bax/Bcl-2 ratio and of mitochondrial antioxidant expression; e) promoted cytochrome c oxidase activity and ATP synthesis; f) suppressed Aβ induced G6PDH and NADPH oxidase activity; g) enhanced the total antioxidant capacity of hippocampal CA1 neurons while reducing oxidative damage; and h) suppressed Aβ-induced reactive gliosis, inflammation and tau hyperphosphorylation. While development of AD treatments has focused on reducing cerebral Aβ levels, by the time the clinical diagnosis of AD or Mild Cognitive Impairment is made, the brain is likely to have already been exposed to years of elevated Aβ levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aβ induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis and tau pathology, LLI could represent a new promising therapeutic strategy for AD.