How to Choose Low Level Laser Therapy For Hyperviscosity?

We note that there are very few publications published on the topic outside of Russia. Russian scientists, as always, are ahead of world science and low-level laser therapy practice.

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In this brief review, only some part of studies is given as an example; pediatrics issues are almost not discussed. However, the review clearly demonstrates that various methods of laser illumination (specific techniques are given) make it possible to influence almost all the known pathogenesis of the disease, and low-level laser therapy is a truly effective method of treatment.

At the same time, the experts have ignored more than 50 years of successful experience of low-level laser therapy, the results of hundreds of studies proving the effectiveness of the method in treating patients with all forms of bronchial asthma. It is proved that therapeutic and periodic (2&#;4 per year) courses of low-level laser therapy can significantly decrease the frequency and severity of attacks, reduce or cancel the reception of medicines, as well as negative consequences.

Bronchial asthma is an autoimmune disease, one of the most common and practically non-treatable by standard methods. At present, the used drugs only maintain a state of temporary remission, simultaneously having a negative effect on various organs and structures and causing side effects.

Bronchial asthma (BA) is one of the most common diseases of the respiratory system in children and adults. The life-long progression, the high rate of aggravation and the often serious condition at the height of an asthma attack, the limited occupational aptitude and other characteristics increase the social significance of the disease. According to the latest epidemiological studies, more than 339 million people in the world suffer from BA [1]; 7.5% of the population in the USA is afflicted with it, of which 1.8 million people are hospitalized annually [2]. In Russia, according to epidemiological studies, asthma affects about 7 million people (5&#;7% of adults and 10&#;15% of children) [3]. Many patients have pronounced hormone dependence and/or various hormone-related disorders. Reduced levels of cortisol, testosterone, DHEA-s and estrogen in patients with asthma below the normal range are prognostic criteria for the deterioration of their quality of life [4,5].

Regardless of the severity, BA is a chronic inflammatory disease of the respiratory passages (RPs), occurring with the participation of mast cells, eosinophils and T-lymphocytes, the release of a large number of inflammatory mediators ( ). Inflammation of the RPs causes their hyperreactivity, bronchial obstruction, and respiratory symptoms. With hyperactivity RPs narrow too easily and/ or strongly in response to the influence of provoking factors. Bronchial obstruction is caused by the following mechanisms: acute bronchospasm, edema of the bronchial wall, obstruction by mucus and remodeling of the bronchial wall. Recurrent exacerbations of asthma are based on inflammation of the bronchi, their remodeling and impaired neurogenic control. An exacerbation of BA is associated with increased inflammation of the RPs and can be induced by a respiratory infection, exposure to allergens, or occupational sensitizing factors. Atopy, the production of excess IgE in response to exposure to exogenous allergens, is an important factor predisposing to the development of BA [3].

According to most experts, for successful treatment of patients with asthma, it is sufficient to properly divide patients according to the disease severity and adjust drug dosages and prescribed regimens for β2-agonists and systemic or inhaled glucocorticosteroids (GCS) that have remained for decades [2]. However, there has only been an increase in the number of patients throughout the world, and so far not a single patient has really been cured, i.e., no asthma attacks have been cured permanently. The task is only to provide emergency care [3]. The situation is complicated by the side effects that all drugs have. Even the use of inhaled corticosteroids comes with side effects, especially when consuming high dosages. The resulting systemic absorption often leads to a blockade of the hypothalamic-pituitary-adrenal system and the development of complications such as glaucoma, cataracts, osteoporosis and various skin lesions [6&#;11].

The development of intoxication and hypoxia, which impede the normal functioning of the immune system, is of great importance in BA pathogenesis. The effect of endotoxins on neutrophils is determined by the severity of all bronchopulmonary diseases, including bronchial asthma. The greatest changes concern molecules of average weight, circulating immune complexes (CIC), lipid peroxidation (LPO) and the toxicity index [12,13]. The increased content of endotoxins in the blood of asthma patients leads to a violation of the albumin-binding capacity and increased intoxication, as evidenced by a sharp increase in the albumin toxicity index [12]. The involvement of histamine and serotonin in BA pathogenesis is generally recognized [14]. The asthma exacerbation phase is characterized by increased histamine and serotonin levels in the blood and plasma, which is accompanied by the development of an intense allergic reaction, reduced phagocytic ability (both in phagocytic number and phagocytic index) and an increased number of NBT-positive neutrophils [12].

A ramified chain of events plays a significant role in the pathogenesis of asthma, depending on the functioning of almost all cellular elements of peripheral blood. The number of normal discocytes decreases; the abnormal shapes of erythrocytes with high cholesterol content on the membrane predominate; their deformability decreases, and their aggregation ability increases [15,16]. The percentage of abnormal shapes of erythrocytes (echinocytes, teardrop-shaped and target cells, ovalocytes and spherocytes) grows against the background of a decrease in the number of discocytes and an increase in the total number of immature reticulocytes, resulting in the impaired oxygen transport function of the blood and increased hypoxia [17].

According to our data, the main links of the mechanism of therapeutic action in comprehensive low-level laser therapy (LLLT) include the reduction of side effects in the form of local or systemic reactions, the improvement in the indicators of external respiratory function (ERF) and central hemodynamics, positive immune changes, the improvement in adrenal cortex function and the reduction in allergen-specific sensitivity and nonspecific hyperreactivity [18,19].

The therapeutic effect of low-intensity laser illumination (LILI) on BA, according to some authors, begins with the response of immunocompetent cells. The mechanism of formation of the cellular response to laser screening finds its manifestation in the initial phase of the development process, is associated with changes in the activity of enzymes and the structure of plasma membranes, and includes the following steps: molecular membrane rearrangements &#; reducing cholesterol and fatty acid saturation factor, increasing the proportion of phospholipids and reducing microviscosity; functional modification of membranes &#; changes in lipid-protein interactions and increased trans-membrane potential; and functional modification of cells &#; an increase in the phagocytic index and neutrophil count [12,13].

As our studies have shown, exposure to LILI in various modes allows for extremely effective increase in the deformability of erythrocyte membranes through their structural rearrangement. At the same time, more than 90% of erythrocytes with dysfunctional morphology restore their normal discoid shape, which enables reduction of the level of hypoxia [20].

The pathogenetic validity of various methods of LLLT in the comprehensive treatment of patients with asthma was confirmed by numerous studies [21&#;26]. Some national standards and clinical practice guidelines include almost all known methods: exposure to LILI in the projection of the thymus, adrenal glands, carotid sinus and Zakharyin-Ged zones, laser acupuncture, as well as intravenous laser blood illumination (ILBI) with red (635 nm wavelength) spectrum, and extracorporeal ultraviolet blood illumination (UVBI) [27,28].

Laser therapy should be considered as a multi-component and pathogenetically substantiated treatment of asthma patients, enabling the reversal of the main symptoms of the disease more quickly with an earlier cancellation or reduction of the drug dosage. These measures contribute to the complete recovery of electrophoregrams, rapid reduction of the elevated sialic acid, seromucoid and ceruloplasmin level and enhanced kinin-kallikrein system activity. After the LLLT course, a more pronounced positive dynamics is observed in the external respiration function (a decrease in the phenomena of bronchial obstruction). In addition to a faster onset and lengthening of remission periods, LLLT allows the body resistance to colds and meteorological factors to increase [26].

The exposure to pulsed IR LILI also has an immunomodulatory effect, along with a positive clinical effect. The latter is manifested by increased metabolic and mitotic activity of lymphocytes, changes in the expression and affinity of E-lymphocyte receptors and the serum concentrations of IgM. Neutrophil phagocytosis was significantly enhanced in the immune status of patients after the treatment. From to 15,526 patients with various immunopathologies, including adults and 12,651 children, were treated in several medical clinics in Smolensk and Moscow (Russia) [29].

We do not significantly address the topic of treating asthma in children; it deserves a detailed study in a special review, since treatment approaches differ significantly. In this article we only cite several publications from different Russian scientific schools as an example [30&#;41].

It should be noted that in the English-language publications, and there are very few of them, only laser acupuncture is used and only in the treatment of children [42&#;49]. In Russia, laser acupuncture is also in active use [50,51], however, most frequently as part of the comprehensive treatment with the adjustment of techniques [52], which is more logical and effective.

A systematic review (search on Cochrane Library, Medline, EMBASE, AMED, CINAHL, CNKI, VIP electronic databases through February ), gives 13 randomized placebo-controlled trials (RCTs), the results of which do not prove or disprove the effectiveness of laser acupuncture for the treatment of bronchial asthma in children (the data are very contradictory) [53]. However, this is not surprising, since none of the publications describe the use of optimal parameters of laser illumination for laser acupuncture: 635 nm wavelength, power of 2&#;3 mW, exposure for 20&#;40 s per one corporal point, and the maximum permissible values are exceeded manifold, both in terms of laser power and exposure time.

Experimental English-language publications are also few in numbers [54&#;59], but they are extremely important for understanding the mechanisms of the biological action of LILI.

There are hundreds of times more studies and publications of Russian scholars that not only prove the highest efficiency of laser therapy, but also substantiate the optimal parameters of laser illumination techniques, the principles of drawing up optimal therapeutic schemes, based on many factors. There is nothing similar elsewhere in the world.

Many experts believe that ILBI is the most universal and effective method of laser therapy for asthma patients. The main advantage of ILBI is a significant reduction in the amount of medications taken and a decrease in the number of asthma attacks after treatment [60&#;62], which is closely related to the severity of the disease and the applied option of the LLLT technique [63].

presents the treatment outcomes for three groups of patients after 10 daily laser therapy procedures for such daily average indicators (what fold decrease was shown), as the frequency of asthma attacks and the daily dose of β2-agonists. With regard to the GCS, the data is only qualitative: &#;significant&#; dose reduction and the ability to make a &#;soft&#; transition from systemic to inhaled medications [63; 64].

Table 1

Methods of treatment/indicatorsLight Medium Strong AAβ2-agonistsAAβ2-agonistsAAβ2-agonistsGroup 14,22,32,52,5&#;&#;Group 23,63,54,21,71,52,5Group 3&#;&#;2,01,42,52,9Open in a separate window

Group 1. Patients with mild and moderate-severe atopic BA and allergic rhinitis were exposed to continuous LILI (633 nm wavelength, power of 6 mW) endonasally for 5 min per each nasal passage.

Group 2. Patients with mild, moderate-severe and severe atopic and mixed BA were exposed percutaneously to pulsed IR LILI (890 nm wavelength, power of 5 W, pulse repetition frequency of 150&#; Hz): in the thoracic area, in the areas of projection of the adrenal glands (the lumbar area at the level of Th12 &#; L2), of the thymus (the sternum area at the level of the second rib attachment) and the vascular bundle (the left supraclavicular area).

Group 3. Patients with moderate-severe and severe mixed and atopic BA were exposed to ILBI-635 (635 nm wavelength, power of 3 mW, 45 min exposure time).

Patients demonstrated positive dynamics in the course of the disease: the number of nocturnal asthma and dyspnea symptoms was reduced, the non-productive cough disappeared, and lung auscultation was normalized. The clinical efficacy of LLLT was confirmed by the ERF studies, and the sputum leukocyte and eosinophil counts also decreased in the patients [64].

Comparative evaluation of the clinical efficacy of LLLT in the comprehensive treatment of asthma patients indicates the need for a differentiated use of various methods depending on the form and severity of the disease [63]. In our opinion, it is always better to apply combined and combinative techniques.

Laser blood illumination (LBI) and most often its intravenous option (ILBI) is the most common method of laser therapy, which is used to treat BA patients. The first successful intravenous laser blood illumination with continuous LILI of the red spectrum (633 nm wavelength, ILBI-635) was performed in patients with bronchial asthma in the early s, that is, immediately after the technique had appeared [65,66].

ILBI-635 is most effective in patients with the atopic variant of bronchial asthma, who show no effect from specific hyposensitization therapy. In steroid-dependent patients, ILBI makes it possible to reduce the dose of glucocorticosteroids or to discontinue them at all, increasing sensitivity to other medications. Laser therapy can be carried out in any phase of the disease and as the prophylactic treatment in BA patients who have sensitization to plant pollen (prior to the pollination period). LLLT has an immunomodulatory effect, adjusts the ratio between the oxidant and antioxidant systems, and normalizes the indicators of the respiratory function. The application of ILBI in the comprehensive treatment of BA patients can reduce the number of days of disability and lengthen remission periods by 2.4 times [66].

A hyperviscosity syndrome has been reported to occur in BA patients: increased whole blood viscosity at low shear rates, reduced deformability and suspension stability of erythrocytes, their increased ability to hyperaggregate, echinocytosis, the tendency of platelets to slow and weakly reversible aggregation [61]. Since the possibilities of exposure to LILI that normalize blood rheology are well known, S.A. Borzenkov () [61] used ILBI-635 (wavelength 633 nm, power of 2 mW, 30 min exposure time, 10 procedures per a treatment course daily) in the comprehensive treatment of BA patients with positive clinical outcomes that correlated with normalized rheological parameters. The minimum shear stress decreased by 14%, whole blood viscosity reduced (at a shear rate of 1 cP - by 17%, at a shear rate of 9 cP - by 12%, at a shear rate of 25 cP -by 21%, at a shear rate of 100 cP - by 22%, and at a shear rate of 256 cP - by 28%), single-unit RBC count decreased by 47%, and the echinocyte count reduced by 49% as well, the RBC deformability increased by 1.2% and the non-aggregated RBC count increased by 1.18%.

But at the same time, no effect on platelet aggregating properties was found in BA patients. The application of ILBI in the comprehensive treatment of asthma patients also enables decrease in the drug dosage taken by more than 20% and reduction of hospital lengths of patients&#; stay on average by 2.91 days.

The use of ILBI-635 (633 nm wavelength, 1&#;1.5 mW, 30 min exposure time, 10 procedures per a treatment course daily) to treat asthma enables to obtain a more pronounced normalizing effect on bronchial patency, reduce the degree of hypoxemia, contribute to the improvement of the clinical picture of the disease [17].

The synergistic effect of medication and laser therapies on central hemodynamics, microcirculation and blood rheological properties makes it possible to cancel prolonged β2-agonists and reduce doses of systemic GCS [67], when prescribing ILBI sessions, which is essential to compensate for the negative effect of glucocorticoid therapy on the morphofunctional state of endobronchial microhemocirculation [68].

ILBI-635 is known to have pronounced immunomodulatory properties associated with the effect of illumination on the lymphoid elements of peripheral blood, which is also indicated for BA patients. In addition, the content of physiologically active substances, including glucocorticoid hormones, is also changed in these patients. The level of total 11-oxycorticosteroids (11-OCS) increases from (2&#;20). 10&#;5 g/l to (10&#;50)·10&#;5 g/l in the patients' serum after five procedures of ILBI [69].

In patients with asthma in the acute phase, the balance between LPO and the antioxidant system (AOS) is disturbed, and the antioxidant activity of blood significantly decreases [12]. There is an oxidative stress, which is expressed in significant (exceeding the average in healthy people by 12 times) hyperproduction of free-radical metabolites against the background of 20% decreased activity of intracellular antioxidant enzymes. The use of inhaled GCS with the standard treatment of BA patients leads to the positive dynamics of clinical and functional parameters, but does not have an appreciable impact on LPO and AOC parameters. In standard therapy using systemic GCS patients show a significant decrease in LPO (by 33% of baseline values) with simultaneous inhibition of AOC parameters (by 12% of baseline values). When combining systemic and inhaled GCS, LPO parameters decrease less (by 25%), but the extent of inhibition of AOS parameters is greater (a decrease by 16%) [70]. Therefore, it is required to additionally adjust LPO and AOS parameters against the background of GCS use in BA patients, at the same time the ability of ILBI to normalize LPO processes is well enough confirmed [71].

The most significant AOS disorders are observed in hormone-dependent BA patients, but these patients show the best treatment outcomes after a course of ILBI-635 (633 nm wavelength, power of 3 mW, 20 min exposure time, 8&#;10 procedures per a treatment course daily). These results are correlated with a significant increase in the activity of antioxidant enzymes and a decrease in LPO intensity in RBC. Against the background of ILBI, a decrease in the average dosage of systemic GCS and a more relaxed transition to inhaled drugs have been observed. Patients who received ILBI against the background of traditional therapy as opposed to patients, who were traditionally treated, experienced faster clinical dynamics of the disease: decrease in the number of asthma attacks, replacement of full-scale attacks of asphyxiation with symptoms of dynamic bronchial obstruction, and decrease in cough intensity. Against the background of low-level laser therapy, there was a significant reduction in the need for bronchodilators and GCS doses. The average bed-occupancy rate was 10.7% less in such patients than in those who received only traditional therapy. The most pronounced improvement in respiratory function was observed in the group of patients with newly developed asthma [72&#;74].

Research by V.I. Korzhov et al. () [75] showed that ILBI-635 in the comprehensive treatment of BA patients enables to achieve remission in 92.1% of cases and the phase of unstable remission in 7.9% of cases (in the control group 73.8 and 26.2%, respectively). At the same time, in patients of the main group (ILBI), the disappearance or decrease in the number of asthma attacks occurred in 5&#;6 days, while in the control group this result was achieved in 8&#;10 days. A reliable decrease (by 15.8%) was established in the concentration of molecules with average weight as compared to the initial level, and after treatment this parameter practically becomes equal to that in healthy donors &#; 238 ± 10.5 units. Analysis of the dynamics of accumulation of LPO products revealed an increase in their level in the studied patients; however, as a result of the treatment provided, the degree of normalization of both intermediate and final compounds is very significant. Thus, the content of lipid hydroperoxides decreased by 12.8% from the initial level, the decrease in the concentration of malondialdehyde (MDA) was even more significant - by 34%.

An increase in the conjugated diene concentrations is registered in all patients with moderate-severe asthma during exacerbation of the disease. These changes directly depend on asthma duration [73,74,76]. Comprehensive treatment, including ILBI procedures (633 nm wavelength, power of 2&#;3 mW, 20 min exposure time, 8&#;10 procedures per a treatment course daily), to a greater extent contributes to reducing the intensity of LPO processes as compared to traditional treatment.

The content of antioxidants in erythrocytes and plasma increases in the exacerbation phase in BA patients with short duration of the disease. In patients with the disease duration of more than 10 years against the background of an exacerbation, a decrease is registered in the concentration of antioxidants in the studied media, respectively. The application of ILBI-635 demonstrates a more pronounced tendency to normalize the studied parameters, i.e. this method is a powerful corrective tool for affecting patients' AOS as well [77&#;79]. Other authors also confirmed the best efficacy of laser therapy with disease duration of more than 10 years and a more severe course than with newly diagnosed BA [80].

All BA patients have changes in the cytokine profile, cellular and humoral immunity, the nature of which depends on the severity of the disease and on the available allergic reactions. With an increase in the severity of the disease, serum immunoglobulin (IgA) levels increase, while IgG and IgE decrease, which is accompanied by an increase in the number of granulocytes with the phenotype CD45 + CD66b + CD11b+ and enhanced phagocytic activity of neutrophils: the phagocytic number increases by 3&#;16 times, and the phagocytic index grows by 3.5&#;4 times as compared to healthy donors. Peripheral blood mononuclear cells isolated in the exacerbation phase of bronchial asthma are characterized by increased production of IL-4 (spontaneous production is 6.3 times as high, induced one is 4.8 times as high), IL-6 (spontaneous production is 2.4 times as high, induced one is 4.3 times as high) and IL-17 (spontaneous production increases by 23%, induced one - by 19%). The level of spontaneous production of IL-8 is reduced by 7%, while that of the induced one is increased by 7.5%. In this connection, recently, special importance has been attached to immunomodulatory therapy [81]. Low-level laser therapy has also fairly powerful capabilities in this component of the physiological regulation.

It has been shown that in patients with an infectious-dependent form of BA ILBI-635 contributes to the normalization of the number of E-rosetting cells, a decrease in the content of theophylline-resistant subpopulation of T-cells enhanced upon admission and an increase in the number of theophylline-sensitive subpopulation of T-cells, which leads to the normalization of theophylline-resistant-to-theophylline-sensitive T-cell ratio: Eth-r-ROS/Eth-s-ROS [82]. After a course of ILBI-635, dyspnea is reduced, the external respiratory function improves, a more rapid recovery of alveolar blood flow is observed, a distinct stimulating effect on the cell level parameters of phagocytic activity of neutrophils is reported [83,84].

It is most effective to administer ILBI-635 (633 nm wavelength, 1&#;2 mW, 30 min exposure time, 5&#;7 procedures per a treatment course daily) for patients with moderate depression of the T-cell immunity. ILBI can be successfully used as monotherapy in BA patients with mild disease and drug polyallergy. The distinct positive dynamics in the T-cell immunity naturally manifests itself in an accelerated and pronounced regression of the clinical implications of the disease [85].

The inclusion of ILBI -635 in the comprehensive therapy of infection-dependent BA increases the effectiveness of treatment: it accelerates the time for remission onset and increases its duration, reduces the frequency of exacerbations and enables to decrease the amount of drug therapy. Under the influence of ILBI, the inflammatory process subsides, which is reflected in ERF improvement (VC increases by 39.9%, FVC - by 27.9%, FEV1 - by 41.6%, MEF50 - by 42.0%, MEF75 - by 47.4%, MEF25 - by 58.3%), with marked fall in peripheral blood eosinophils and positive general clinical dynamics [86].

L.V. Vasilieva () [87] showed the following effects of ILBI-635 in bronchial asthma:

• &#; stimulation of β-adrenergic receptors;

• &#; increase in the functional activity of lymphocytes and leukocytes, and phagocytic activity of neutrophils and monocytes;

• &#; normalization of immunoglobulin levels and CIC;

• &#; restoration of the aggregative state of blood.

The use of intravenous laser blood illumination in the comprehensive treatment of BA patients reliably improves bronchial patency compared with the results of conventional therapy. ILBI-635 has a corrective effect on the hemostatic system, mainly optimizes Hageman-kallikrein-dependent fibrinolysis, which determines an additional mechanism of its action. In addition, ILBI has anti-aggregation properties, reduces the coagulation potential, increases the antioxidant activity of the blood and decreases pre-beta cholesterol and beta cholesterol levels [88]. RBC morphometry and electrophoretic mobility measurement in BA patients after ILBI procedures show that the proportion of discocytes in the blood recovers almost to the norm [89].

Many experts are sure that the combination of plasmapheresis (PA) or enterosorption + laser blood illumination is one of the most effective options of therapy, including for BA patients [28,60,62,90&#;93].

Plasmapheresis combined with ILBI-635 allows for significant (by 60%) improvement of performance in patients with the most severe clinical course of asthma and concomitant autoimmune thyroiditis. Comprehensive therapy not only contributes to obtaining stable long-term remission, control over the BA symptoms, but also significantly reduces the antibody titer to the thyroid microsomal fraction [90].

Against the background of comprehensive therapy applying PA, UVBI and ILBI, in most cases, it is possible to achieve clinical remission in BA patients with a pronounced reduction in the amount of drug therapy, up to the discontinuation of hormonal drugs. It was shown that the therapeutic effect of the extracorporeal and laser therapy techniques is implemented by enhancing the therapeutic efficacy of sympathomimetic agents [94], and increasing the immunosorption and insulin-binding capacity of erythrocyte membranes [94,95].

Combining drug therapy of BA patients with PA and ILBI-635 it is possible to accelerate the onset of the disease remission through more rapid reverse development of asthma attacks, which results in the considerable increase in exercise tolerance and ERF normalization. With a significant reduction in the volume of drugs, the periods of remission are simultaneously extended. Combined treatment can prevent the development of complications by reducing the total doses of hormonal drugs or their discontinuation. LLLT contributes to more rapid stabilization of the bronchial receptor apparatus, in particular of β-adrenoreceptors, increasing their sensitivity to sympathomimetics and glucocorticoid drugs. Combination of ILBI and PA to treat patients with various forms of asthma corrects immune disorders and phagocytosis dysfunction, which is one of the main pathogenetic mechanisms causing a pronounced clinical effect and improving the course of the disease [60].

These outcomes are confirmed by other authors. Against the background of PA and ILBI-635, cough disappears in earlier periods and lung auscultation is normalized, while the dose of oral GCS is reduced, doubling the remission duration. After the course of LLLT, respiratory indicators that characterize the bronchial patency are normalized by the end of the 3rd week of treatment, providing rapid functional activation of the oxygen-dependent bactericidal system of blood neutrophils (NBT-test), which is associated with an additional increase in the T-lymphocyte suppressor potential, normalized immunoregulatory index and increased phagocytic activity of neutrophils [96&#;98].

According to A.S. Kuno () [99], it is necessary to include immunomodulators in the treatment regimen in addition to PA and UVBI, which enable to prolong remission by stabilizing humoral immunity.

Along with ILBI, laser acupuncture is quite actively used to treat BA patients; more often, as we have noted above, as part of the comprehensive therapy with other methods of low-level laser therapy applied [52,93,100,101].

It was shown that the optimal time for local exposure in treating patients with allergic BA by pulsed IR LILI (890 nm wavelength, 5&#;7 W, 700&#; Hz) is 60 s (paravertebrally), 300 s &#; supraclavicular region, by illuminating APs for 30 s (stimulation) and 60&#;90 s (suppression). The following acupuncture points were used: V10 (Tianzhu), V11 (Dazhu), V13 (Feishu), V12 (Fengmen), V15 (Xinshu), V17 (Geshu), CV22 (Tiantu), VC21 (Xuanji), V&#;20 (Huagai), VC17 (Shanchung).), VC16 (Zhongting), VC15 (Jiuwei), RP6 (Sanyinjiao), &#;14 (Kufang), &#;15 (Wuyi), &#;36 (Zusanli), GI4 (Hegu), &#;7 (Lieque), P11 (Shaoshang). Auricular points: AAP55 (Shen Men point, having general strengthening effect), AAP31 (Ping Chuan, Asthma point, relieving symptoms of asthma, calming panting, etc.), AAP13 (Adrenal Control point). Against the background of combined laser therapy, a positive ERF dynamics is observed, rhinocytogram indices are normalized, there is reduction in general and local eosinophilia), cutaneous and, especially, local sensitivity to specific allergens. The positive clinical effect of the therapy is accompanied by the immune normalization: T-lymphocyte and T-helper cell counts significantly increase, the level of serum immunoglobulins (IgA and IgG) raises, and the percentage of degranulated mast cells decreases [103].

Considerably worse results were obtained by M.A. Borodina () [104], either because of a different acupuncture prescription, or because of the multifactorial effect on APs (simultaneous exposure to LILI, magnet and heat). An alternative prescription is given by foreign authors: P5 (Chize), &#;7 (Lieque), P9 (Taiyuan), GI4 (Hegu), V13 (Feishu), V23 (Shenshu), &#;36 (Zusanli), RP6 (Sanyinjiao), VG14 (Dazhui), VC17 (Shanchung). However, as is often the case, they use completely unacceptable LILI parameters [42], and perhaps for this reason their results are not the best ones.

I.E Yesaulenko et al. () [105] recommended a simplified prescription to treat BA patients with concomitant chronic rhinosinusitis: GI4 (Hegu), &#;7 (Lieque), GI20 (Yingxiang) and &#;5 (Chize), ZP15 (Jiabi), VG23 (Shangxing), &#;A&#;22 symmetrically on alternate days, 10 procedures per a treatment course daily.

Laser acupuncture can significantly improve the results of outpatient treatment and rehabilitation of patients with light and moderate-severe asthma statistically significantly earlier than with conventional drug therapy.

Patients with severe BA demonstrate the best result with comprehensive therapy. The clinical course improves, bronchial sensitivity to sympathomimetics is restored, the need for β2-agonists, inhaled and systemic GCS is reduced, Short-Term Disability periods decrease by 5&#;7 days, remission duration is prolonged to 3 years, there is reduction in frequency of hospitalization by 1.3 times, emergency call incidence by 23%, and disability retirement rate to 12%.

The restoration of impaired histochematic barrier and systemic changes in the synthesis and utilization of biogenic amines by the blood cells that stimulate the production of mature heparin, which binds inflammatory mediators &#; histamine and serotonin, as well as an excess of catecholamines is the basic mechanism of therapeutic action of LILI. Heparin has anti-inflammatory value and removes the blockade of β2-adrenergic receptors, and catecholamines produce bronchodilation, by binding to β2-adrenergic receptors [51].

Summing up some intermediate result of the brief review, we have systematized the results of various studies ( ), which clearly demonstrate the normalizing effect of laser illumination on virtually all known pathogenetic mechanisms of asthma development, therefore, there is no doubt that laser therapy can and should be used as the basic method of therapy. However, there is still a very important issue about the optimization of laser therapy parameters; the answer to this question helps gain knowledge of the mechanism of therapeutic action of LILI and some rules. Sometimes it is hindered by incorrect description of materials and research methods [16], which raises doubts about the reliability of their results, but there are so many publications ( gives only a small part of them as an example) that it is easy to draw conclusions about the optimal techniques.

Table 2

Form of BA; clinical outcomeIndicatorLLLT technique (number of daily procedures)ReferenceAntioxidant SystemABA, children; reduction of bronchospasm attacks and dyspnea, up to the complete disappearanceActivation of AOS, reduction of the level of primary and final LPO productsILBI-635 (3&#;5)[106]MBA; earlier normalization of the main clinical and laboratory signs, reduction of the dose of GCSReduction of MDA, lipid hydroperoxides, increase in SODILBI-635, external pulsed IR LILI: paravertebrally Th3&#;Th5, at the II and III intercostal space, symmetrically, projection of the adrenal glands (14)[87]IABA; a significant decrease in the amount of medications taken and a reduction of the number of asthma attacksNormalization of the work of AOS for all studied parameters (DC, MDA, Schiff bases, SOD, catalase, glutathione peroxidase, glutathione reductase)Enterosorption and ILBI -635 (10)[62]ABA, IABA, MBA; reduction of doses of hormonal drugs and cancellation, reduction of the days of disability, lengthening the terms of remission 2.4 timesDecrease in the content of LPO products (DC, MDA), increase in enzyme activity (SOD, catalase), stabilization of cell membranesILBI-635 (5&#;12)[66]In vivo, miceReduction of ROS content, decrease in activity of NO-synthase in bronchoalveolar lavage fluid, increase in catalase activity, SOD, glutathione peroxidase, NADPH oxidase, and Nrf2 transcription factor660 nm, 30 mW, 5 min (1)[55]In vitro, U937 cellsSuppression of glucocorticoid resistance induced by oxidative stress, inhibition of TNF-α and IL-8 secretion through an increase in cAMP and inhibition of the PI3K signaling pathway660 nm, 17,85 mW/cm2, 60 s (1)[58]Immune systemNot indicatedDecrease in eosinophil countLaser acupuncture (10&#;20)[107]ABA, children; reduction of bronchospasm attacks and dyspnea, up to the complete disappearanceNormalization of the ratio of T-and B-lymphocytesILBI-635 (3&#;5)[106]IABA; decrease in skin and, especially, local sensitivity to specific allergensReduction of general and local eosinophilia is accompanied by normalization of immunity: the content of T-lymphocytes, T-helpers increases, the level of serum immunoglobulins A and G increases, the percentage of degranulated mast cells decreasesLaser acupuncture (10&#;15)[103]ABANormalization of IgA, IgG and IgM levelsLBI, laser acupuncture, in the projection (10)[18]MBA; a significant decrease in the amount of medications taken and a reduction of the number of asthma attacks after LLLT courseNormalization IgA, IgG, IgM, IgE levels, activation of phagocytosisPA and ILBI-635 (4&#;7)[60]ABA, IABA with concomitant autoimmune thyroiditis; increase in the duration of remissionReduction of antibody titer to the microsomal fraction of the thyroid glandPA and ILBI-635 (3&#;5)[90]In vitroChanges in the morphofunctional state of lymphocyte membranes633 nm (1)[108]ABA, MBA; decrease in the frequency of attacksDecrease in eosinophil countEndonasal, topical, ILBI (10)[63,64]ABA, childrenReduction of IgE levelLaser acupuncture (10)[52]MBA and COB; rapid regression of clinical symptomsActivation of T-cellular component of immune systemILBI-635 (5&#;7)[85]MBA, children; clinical symptoms are reduced 3&#;6 days fasterReduction of IgE, VEGF, IL8, IL4 levels, CD4+ lymphocytes, increase in CD8+ lymphocytesLaser acupuncture (10)[32]IABANormalization of the ratio of Eth-r-ROS/Eth-s-ROSILBI-635 (5&#;8 on alternate days)[82]IABA; remission occurs one week faster, its duration increases; the severity of the disease decreases and the frequency of exacerbations is reduced 2 times; the dose of oral corticosteroids is reducedActivation of neutrophils of peripheral bloodPA and ILBI-635 (8&#;10)[96]Not indicatedReduction of IgG, CIC levels, increase in phagocytosis and normalization of the immunoregulatory index of the T-system of immunityPA and ILBI-635 (3&#;4)[98]ABA, children; absence of severe asthma attacks and the frequency of attacks of moderate and mild severity are 1.8&#;2.5 times lessNormalization of levels of immunoglobulins of the main classes and reduction of the initially high level of IgE, normalization of phagocytosis and levels of proinflammatory cytokines in blood serumExternal pulsed IR LILI (10)[36]ABA, adults and childrenIncrease in metabolic and mitotic activity of lymphocytes, neutrophil phagocytosis, changes in the expression and affinity of E-receptors of lymphocytes, a decrease in IgM concentration in blood serumExternal pulsed IR LILI (5&#;8)[29]ABA, children; decrease in the number of asthma attacks 4 &#;6 times, reduction of the severity of the diseaseNormalization of IgA, IgG, IgM, IgE, IL-1β and TNF-α levelsExternal pulsed IR (890 mm) LILI (10)[38]ABA, HBADecrease in the number of eosinophils, normalization of IgA, IgG and IgM levelsLaser acupuncture (10&#;15)[51]Not indicatedNormalization of T-cell immunityILBI-635 (5)[69]ABA, IABA, MBA; normalization of sensitivity and reactivity of the bronchiNormalization of T-lymphocyte differentiation, increase in T-suppressor activity, decrease in IgE productionILBI-635 (5&#;12)[66]Illumination of the blood of patients with MBA in vitroIncrease in phagocytic index and neutrophil count633 nm, 20 mW[13]Not indicated, children; the number of exacerbations decreased 3 times, the need for antibiotics decreased 3.7 timesNormalization of almost all investigated parameters of the immune status (CD3+, CD4+, CD8+, CD16+, CD20 +,IgA, IgG, IgM)Externally on several areas by continuous LILI of red spectrum (633 nm) and pulsed IR (890 nm) LILI (7-10)[41]In vivo, miceReduction of IgE level660 nm, 30 mW, 5 min (1)[55]In vivo, miceDecrease in the number of eosinophils and bronchial hyperactivity through the expression of the RhoA gene, reduction of allergic lung inflammation through the expression of the STAT6 gene660 nm, 30 mW, 5 min (1)[57]In vivo, ratsDecrease in the number of eosinophils, IL-4 and IgE levels, increase in the production of IFN-γ, the ratio of T-helpers Th1/Th2 is normalized810 nm, 20 mW/cm2, 20 min (21)[59]Muscle toneIn vivo, ratsRelaxation of the inflammatory smooth muscle of the trachea, TNF-α inhibition, cAMP accumulation650 nm, 31,25 mW/cm2, 42 and 300 s (1)[54]In vivo, ratsDecrease in cholinergic hyperactivity, elimination of bronchial smooth muscle spasm, reduction of the expression of mRNA TNF-α655 nm, 31,25 mW/cm2, 42 s and 5 min (1)[56]Neuroendocrine systemABAInitial low blood cortisol increasesLBI, laser acupuncture, in the projection (10)[18]MBA; a significant decrease in the amount of medications taken and a reduction of the number of asthma attacks after LLLT courseThe sensitivity of β-adrenoreceptors to sympathomimetics and glucocorticoid drugs is increasedPA and ILBI-635 (4&#;7)[60]MBAIncrease in testosterone levels in men and estradiol in womenPulsed IR LILI in the projection of the adrenal glands and NLBI (10)[4,5]Aspirin BA; 2 times lower doses of GCS and 2&#;2.5 times of β2-agonistsIncrease in ACTH and cortisol levels in the bloodHemosorption and ILBI-635 (8)[91]Not indicated; reduction of GCS dosesNormalization of aldosterone levels, increase in steroid hormones levels in the bloodPulsed IR in the projection of the upper respiratory tract (10&#;15)[6,109,110]ABA, HBAInitially reduced levels of cortisol and catecholamines in the blood increase, initially increased levels of histamine and serotonin are reducedLaser acupuncture (10&#;15)[51]Not indicatedIncrease in mineralcorticoid function of the adrenal cortex, normalization of the ionic composition of blood (potassium, sodium)Laser acupuncture (15&#;20)[111]Not indicatedIncrease in levels of 11-oxycorticosteroids (11-OCS) in the bloodILBI-635 (5)[69]Vascular system, hemorheologyABA, children; reduction of bronchospasm attacks and dyspnea, up to the complete disappearanceImprovement of the structure of erythrocyte membranesILBI-635 (3&#;5)[106]Not indicatedLengthening the blood clotting time, reduction of fibrinogen concentration and increase in fibrinolytic activity of bloodLaser acupuncture (10&#;20)[112]Not indicated; a significant decrease in the amount of medications taken and a reduction of the number of asthma attacks after LLLT courseImprovement of the rheological properties of blood, increase in the deformability of erythrocyte membranes, decrease in the content of echinocytesILBI-635 (10)[61]ABAChanges of indicators of central hemodynamicsLBI, laser acupuncture, in the projection (10)[18]MBA, childrenNormalization of erythrocyte and platelet parameters, restoration of endothelium-dependent characteristics (endothelin-1 and circulating endotheliocytes)Pulsed IR LILI in the projection of lungs (10)[30,31]MBA + hypertensive diseaseNormalization of blood lipid spectrumILBI-635 (&#;)[77]IABA; remission occurs one week faster, its duration increases; the severity of the disease decreases and the frequency of exacerbations is reduced 2 times; the dose of oral GCS is reducedImprovement of central and peripheral hemodynamicsPA and ILBI-635 (8&#;10)[96]Not indicated, combination with MSNormalization of blood lipid spectrumILBI-635 (8&#;10)[113&#;115]IABA; improvement of bronchial patencyHageman-kallikrein-dependent fibrinolysis is optimized, anti-aggregation effect appears, coagulation potential decreases, blood antioxidant activity increases, pre-beta cholesterol and beta cholesterol levels decreaseILBI-635 (5)[88]Not indicatedNormalization of blood lipid spectrumLaser acupuncture (10&#;20)[116]IABARestoration of the form of erythrocytes, an increase in the proportion of discocytes in the bloodILBI-635 (10)[89]HBA, IABA; reduction in the amount of drug therapy up to cancellation of hormonal drugsIncrease in immunosorption and insulin binding ability of erythrocyte membranesPA, UVBI and ILBI-635 (10)[94]ABA, IABA; broncholytic effect, cancellation of prolonged β2-agonists and reduction of doses of systemic GCSFavorable effect on central hemodynamics, microcirculation and rheological properties of bloodILBI-635 (&#;)[67]IABA; the main symptoms of the disease are stopped more quickly with an earlier cancellation or reduction of the dose of drugsLLLT contributes to a more complete recovery of foregrams, a rapid decrease in elevated levels of sialic acids, seromucoids, ceruloplasmin, and the activity of the kinin-kallikrein systemLaser acupuncture, continuous LILI (633 nm) on reflex zones (10&#;19 depending on the severity)[26]Respiratory function (normalization of indicators)IABAVC, FVCLaser acupuncture (10&#;15)[103]ABAVC, FVC, MEF25-75, FEV1, FEV1/FVCLBI, laser acupuncture, in the projection (10)[18]MBA; earlier normalization of the main clinical and laboratory signs, reduction of the dose of glucocorticoids takenVC, FVC, MEF25-75, FEV1, FEV1/FVCILBI-635, external pulsed IR LILI: paravertebrally Th3&#;Th5, at the II and III intercostal space symmetrically, the projection of the adrenal glands (14)[87]MBAFVC, FEV1, FEV1/FVCPulsed IR LILI in the projection of the adrenal glands and NLBI (10)[4]ABA, childrenPEF, FEV1Laser acupuncture (10)[52]ABA; elimination of bronchospasmVC, FVC, FEV1, FEV1/FVC, PEF, etc.Laser acupuncture (10&#;20)[100]MBA, childrenFVC, PEFPulsed IR LILI in the projection of lungs (10)[30,31]ABA, MBA; decrease in the frequency of attacksVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFEndonasal, topical, ILBI (10)[63]MBA and COB; rapid regression of clinical symptomsVC, FVC, MEF25-75, FEV1, FEV1/FVCILBI-635 (5&#;7)[85]MBA, children; clinical symptoms are reduced 3&#;6 days fasterVC, FVC, MEF25-75, FEV1, FEV1/FVCLaser acupuncture (10)[32]ABA, children; absence of severe asthma attacks and the frequency of attacks of moderate and mild severity are 1.8&#;2.5 times lessVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFExternal pulsed IR LILI (10)[36]BA and hypertensive diseaseMEF75, FEV1, PEF25-75, normalization of blood pressureExternal, NLBI (10)[117]MBAFEV1, PEF, reduction of endogenous intoxicationNLBI, laser acupuncture (12&#;14)[118]ABA, IABA, MBAVC, FVC, MEF25-75, FEV1, FEV1/FVCNLBI, ILBI-635 (8)[80]ABA, IABA, MBA; elimination of bronchial obstruction syndromeVC, FVC, FEV1, FEV1/FVC, PEFILBI-635 (5&#;12)[66]ABA, HBA; the need for β2-agonists, inhalation and systemic GCS decreases, the period of temporary disability decreases by 5&#;7 days, the duration of remission increases up to 3 yearsVC, FVC, FEV1, MEF50,75Laser acupuncture (10&#;15)[50,51]ABA, children; absence of severe asthma attacks and reduction of the frequency of attacks of moderate and mild severityVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFExternal pulsed IR LILI (10)[40]IABAVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFILBI-635 (5)[86]MBA; improvement of bronchial patency of large, medium and small bronchi due to a pronounced anti-inflammatory, bronchodilator, anti-edematous, antioxidant actionVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFNLBI (10)[119,120]MBA with rhinosinusitisVC, FVC, MEF25-75, FEV1, FEV1/FVC, PEFPulsed IR LILI endonasally[121]Not indicated, children; improvement according to GINA criteria in 91.7% of patients, reduction of doses of medicationsVC, FEV1, FEV1/FVCLaser acupuncture (10)[42]Not indicated, childrenVC, FEV1, FEV1/FVC, PEFLaser acupuncture (10)[43]Not indicated, childrenFEV1, MEF25Laser acupuncture (10)[44]Not indicated, childrenPEFLaser acupuncture (10)[46]Not indicated, childrenVC, FVC, MEF25-75, FEV1Laser acupuncture (10)[48]Not indicated, children; improvement of the quality of lifePEF, FEV1Laser acupuncture (10)[49]Open in a separate window

Laser blood illumination, as we said above, is the most commonly used method for treating BA. While the issue with the optimal power for the &#;classical&#; ILBI-635 technique (633 nm wavelength) can be considered solved (it should be 1&#;3 mW), the issue with the exposure time is more complicated. Previously, laser illumination was performed by many authors for 30 min or even more [17,61,85], although it has long been unequivocally proven that the exposure time for this mode of ILBI should not exceed 15&#;20 min. Moreover, this conclusion was made not only for bronchial asthma [76], but also for other pathological processes and diseases [20].

It is known that in order to get the best treatment outcome it is necessary to combine various methods of LLLT for topical and systemic action [20], but this is especially important if the patient has several diseases.

Comparative evaluation of the clinical efficacy of laser therapy in the comprehensive treatment of BA patients against the background of hormonal disorders confirmed that precisely the combined methods are most optimal when using laser illumination techniques of both primarily topical and systemic action on the entire body as a whole [110; 122; 123]. Combining ILBI-635 and external LILI for patients with various hormonal disorders characteristic of asthma improves the quality of patients' life [5]. Long-term treatment of BA patients using systemic GCS increases the risk of developing osteoporosis. Low-level laser therapy (ILBI-635) is an effective means of preventing complications and helps normalize testosterone and estradiol levels [124]. Combining ILBI-635 and external LILI is most effective for osteoporosis prevention in patients taking GCS [44].

The availability of BA determines the peculiarities of hypertension progression, since a sharp rise in blood pressure often occurs at the time of a suffocation attack or an increase in bronchial obstruction, leading to negative consequences. Laser therapy in this case acts as a non-specific therapeutic factor, providing a pronounced double effect, promoting the improvement of the bronchial patency of the large, medium and small bronchi due to a pronounced anti-inflammatory, bronchodilatory, anti-edematous, antioxidant action, simultaneously normalizing blood pressure and preventing its sharp jumps [117,119,120].

The efficacy of combined LLLT for patients with asthma and stage 1 hypertensive disease is 80%, and for patients with asthma and stage 2 hypertensive disease is 70%, respectively. It is recommended to expose consistently the projection of the vasomotor center of the brain &#; the region of the posterior cranial fossa (1 min, 800&#; Hz frequency), the projection of kidneys (for 5 min per each, 80&#; Hz frequency), the projection of the lower lung lobes symmetrically (2 min, 80 Hz frequency) with pulsed IR LILI (904 nm wavelength, 100 ns light pulse duration, 8&#;10 W) paravertebrally at the C4&#;C6 level, at the Th2&#;Th6 level (for 1 min per each, 80&#;150 Hz), 10 procedures per a treatment course daily [117].

A special situation develops in BA patients with hormonal disorders and metabolic syndrome (MS). In case of bronchial disorders accompanied by bronchial obstruction, the leading role in the genesis of the impaired functional status of the adrenal glands is assigned to chronic hypoxia and hypoxemia (as a result of impaired bronchial patency and alveolar hypoventilation), which are the trigger mechanisms of stress. Rapid response activation of the hypothalamic-pituitary-adrenal system causes a standard non-specific reaction in the form of adrenocortical hypertrophy, lymph node atrophy, etc. In the conditions of pathology, the adaptive role of a number of hormones consists primarily in their influence on the development of inflammatory processes. The possibility of correcting the neuroendocrine system work after laser therapy is confirmed by the normalized serum aldosterone levels in such patients [6].

There are common key links in the pathogenesis of BA and MS: energy dependence of these processes, increased consumption of plastic material with involvement of the immune system in pathological reactions, activation of cytokine mechanisms, intense work of the endocrine system with active release of hormones and neurotransmitters into the blood. With this in mind, it can be assumed that a proper correction of MS contributes to the development of positive dynamics for the bronchial asthma progression. Laser therapy methods allow obtaining good treatment outcomes and are an effective means of preventing the development of complications [113&#;115]. The developed method of combined therapy for BA patients can increase the treatment efficacy and shorten the treatment duration, prevent side effects, correct hormone levels and reduce the dose of drugs used. Against the background of drug therapy, patients are exposed to NLBI and pulsed IR LILI in the projection of the adrenal glands. In this case, the NLBI is performed for 15 min at a wavelength of 635 nm. Before the 1st and 5th procedures of exposure to the pulsed IR LILI, the levels of cortisol and estradiol in women and testosterone in men are determined. At cortisol levels below 230 nmol/l and testosterone levels below 500 ng/dl in men and estradiol levels below 30 pg/ml in non-menopausal women and below 15 pg/ml in menopausal women, a pulse repetition frequency of 150 Hz is used. At the cortisol levels ranging from 230 to 750 nmol/l and estradiol levels ranging from 30 pg/ml to 160 pg/ml in women and testosterone ranging from 260 to ng/dl in men, a pulse repetition frequency of 80 Hz is used. The total time of the procedure is no more than 18 min. The treatment course consists of 10&#;12 daily procedures [125].

External illumination by pulsed IR LILI is carried out in BA patients either in the projection of the upper respiratory tract to stimulate β-adrenergic receptors, eliminate inflammation and bronchospasm, or in the projection of the adrenal cortex to stimulate the release of steroid hormones [26,109,110,114]. Most often, both variants are used with the aim of simultaneously affecting several mechanisms of the disease pathogenesis.

The possibility of using reflex zones in treating patients with allergic asthma for stimulation of blood circulation and trophism is noted. In this case laser illumination is performed paravertebrally in the C7&#;Th6 area in addition to exposing the projection of the inflammatory infiltrate and the adrenal cortex. When using this technique, persistent remission (no recurrence within 2&#;3 years) was observed in 14% of patients (with mild progression of the disease), who simultaneously stopped taking GCS. Relative remission, characterized by the absence of full-scale asphyxiation attacks during 1.5&#;2 years and occasional difficulties in breathing, occurred in 65% of patients [26].

We have shown the need to control the hormone content in the process of lasertherapy of BA patients. A method of exposure was proposed, consisting in illuminating two paravertebral and intercostal regions and two Krenig fields by pulsed IR LILI (890 nm wavelength, 8&#;10 W/cm2 power density, &#; Hz frequency, 5 min exposure time, 10 procedures per a treatment course daily). This technique is characterized by the use of additional modulation in the well-known &#;BIO&#; mode (synchronization of changes in the LILI power with patient's pulse and respiration frequency). In addition, after the 1st and 3rd LLLT procedures, the content of 11-oxicorticosteroids (11-OCS) is determined; in case of a decrease in their content further treatment continues. In the majority of patients (80%) with a good and satisfactory effect of LLLT, there was a significant decrease in the level of 11-OCS in the blood plasma and daily urine after the 1st procedure, and this trend continued until the end of the treatment. In patients with an unsatisfactory treatment outcome, the level of 11-ACS either did not change or tended to increase. The mode of illumination (power, frequency) was modified in a number of patients based on the change in the level of 11-OCS after the first procedure. In some cases, the dynamics of 11-OCS in the absence of a pronounced clinical effect suggested the indirect effect of LILI on metabolic processes in the lungs, which was confirmed later on by significantly better curability of patients when using drug therapy [126].

When treating BA patients with metabolic syndrome, Kryuchkova et al. () [127] recommended combining ILBI with external exposure to green light. Although in our opinion, this is hardly more effective than pulsed infrared LILI, even if we consider the situation only in terms of the depth of penetration, not to mention the special &#;healing properties&#; of coherence [128]. Light in the green region of the spectrum, regardless of the mono-chromaticity degree, is almost completely absorbed already in the upper layers of the skin, penetrating no more than a few millimeters, and therefore, it cannot directly affect the bronchi [20]. Although the issues of implementing the reflex mechanism and psychotherapeutic effects may well be discussed.

Endobronchial technique, which was used by some experts [129,130], did not find practical application due to the complexity of implementation with the worst treatment outcomes, which are achieved by using other methods of laser illumination.

Summing up the literature review, knowing the disorders that underlie the pathogenesis of the disease ( ), as well as the biomodulating mechanisms of the LLLT, we have drawn a scheme ( ) that clearly illustrates the basic mechanisms underlying the treatment of patients with bronchial asthma.

It seems promising to use low-intensity illumination of the extremely high-frequency range and laser light (EHF-laser therapy) [131], some progress has already been achieved in this direction [132,133], but the optimization of exposure parameters is clearly required.

Proceeding from the above data and an understanding of the methodology as a whole, we present laser therapy techniques with optimal parameters that are recommended for the treatment of patients with various forms of bronchial asthma, once again emphasizing the need for combination and variation.

ILBI-635 Technique: Matrix and Lasmik laser therapeutic devices, KL-ILBI-635-2 laser emitting head (635 nm wavelength, light guide output power of 1.5&#;2.5 mW, 15&#;20 min exposure time), 5&#;10 procedures per a treatment course daily [83,87]. Based on the well-known fact that the LLLT efficacy is observed with a disease duration exceeding 10 years and a more severe course than with newly diagnosed BA, it is recommended to reduce the exposure time for this category of patients down to 3&#;5 min for ILBI-635 [80].

It is also required to reduce the exposure time down to at least 7&#;10 min in all children (5&#;7 procedures per a treatment course daily) [106]. Although, in our opinion, in pediatrics, it is preferable to use a non-invasive option of the laser blood illumination technique &#; in the projection of the supraclavicular region on the left (the technique parameters depend on age).

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For the last 8&#;10 years such &#;classic&#; version of ILBI has been actively supplanted by a more effective combined technique, which allows both influencing the immune system and activating metabolism. It is highly recommended to combine laser blood illumination with plasmapheresis.

ILBI-635 + LUVBI® Technique: Matrix and Lasmik laser therapeutic devices, KL-ILBI-635-2 laser emitting head (red spectrum, 635 nm wavelength, light guide output power of 1.5&#;2 mW, 10&#;20 min exposure time) and KL-ILBI-365-2 laser emitting head 365&#;405 nm wavelength, light guide output power of 1.5&#;2 mW, 3&#;5 min exposure time). It is recommended to perform 10&#;12 procedures per a treatment course daily with mode alternation in a day [20].

ILBI-525 + LUVBI® Technique: Matrix and Lasmik laser therapeutic devices, KL-ILBI-525-2 laser emitting head (green spectrum, 525 nm wavelength, light guide output power of 1.5&#;2 mW, 7&#;10 min exposure time) and KL-ILBI-365-2 laser emitting head 365&#;405 nm wavelength, light guide output power of 1.5&#;2 mW, 3&#;5 min exposure time). It is recommended to perform 10&#;12 procedures per a treatment course daily with mode alternation in a day [20]. The most advanced version of ILBI, which has proven its effectiveness in many diseases; however, it is necessary to conduct appropriate clinical studies and test the applicability in bronchial asthma.

According to S.V. Papkov () [80], regardless of the LLLT technique used, in the overwhelming majority of cases, the course treatment of BA patients should be limited to 8 procedures daily for 10&#;15 min, since longer exposure has a stressful effect, leading to worsening of some autonomic parameters of the body. From this viewpoint, ILBI-525 + LUVBI® technique is also preferable to ILBI-635.

Non-invasive laser blood illumination (NLBI): The technique is not applied on the same day as ILBI. Wavelength of 635 nm, pulsed mode, ML-635-40 matrix laser emitting head (Matrix or Lasmik device, eight 4&#;5 W laser diodes), power of 50&#;80 W, power density of 4&#;5 W/cm2, frequency of 80 Hz (variation is not allowed).

Laser acupuncture: Wavelength of 635 nm, continuous or modulated operation mode, and the output power at a special acupuncture nozzle is 2&#;3 mW, to be exposed for 20&#;40 s on one corporal point, the prescription is selected individually or on the recommendation of specialists.

In the projection of the internal organs Wavelength of 904 nm, pulsed mode, ML-904-80 matrix laser emitting head (Matrix or Lasmik device, eight 10 W laser diodes), power of 50&#;80 W, power density of 8&#;10 W/cm2, frequency of 80 Hz (variation is allowed).

Localization (projection) and exposure time:

• &#; upper respiratory tract - 2 or 5 min, 1&#;2 areas;

• &#; thymus - 1 min;

• &#; adrenal cortex - 2 or 5 min per area symmetrically.

Paravertebrally: Wavelength of 904 nm, pulsed mode, LO-904-20 matrix laser emitting head with a mirror expender (Matrix or Lasmik device, one laser diode), power of 15&#;20 W, power density of 10&#;15 W/cm2, frequency of 80 Hz (variation is not allowed) at the level of C4&#;C6 and Th2&#;Th6 symmetrically, 1 min per each region.

Endonasal technique: The application of the technique is associated with the execution of certain mandatory rules. Continuous LILI of the red spectrum (635 nm wavelength, light guide output power of 3&#;5 mW) through the light guide or directly via the laser emitting head to expose for 2 min per one nasal passage. The efficacy and validity of the technique is beyond doubt [64; 134]; however, it is necessary to carefully consider its purpose, to control the technique parameters, especially the exposure time.

In case of bronchial asthma with concomitant chronic rhinosinusitis, another technique is used, although the nasal area is exposed. Firstly, only pulsed IR LILI (890&#;904 nm, 5&#;10 W, 80 Hz) should be used, secondly, there is other localization: projections of maxillary sinuses and/or frontal sinuses and/or ethmoidal sinuses (depending on the localization of the inflammatory process according to x-ray or computed tomography data) on both sides, for 2 min each [121].

Most often, 10&#;15 daily procedures are recommended per a treatment course. Although there are other options, both upwards and downwards, we agree precisely with this approach. Fewer procedures will not allow obtaining a stable clinical effect, and more does not make sense according to the logic of the known patterns of chronobiology and chronomedicine.

The issue of alternating different techniques is also very important. In our opinion, if guided by the well-known rule of limiting the total procedure time to 20&#;25 min, then on one day 2-3-4 different options of laser illumination may and should be performed. The opinion of some experts that it is optimal to combine ILBI-635 with the exposure to pulsed IR LILI in the projection of the trachea region (supra-dorsal) and paravertebral every other day, 10&#;12 procedures per a treatment course daily [122], is most likely related to the wrong exposure time selected for ILBI.

Thus, low level laser therapy for BA patients with proper prescription and appropriate procedures, results in sustained remission throughout the patient's entire life. Moreover, drugs are not excluded from the treatment regimen, but are considered as part of the auxiliary treatment to provide emergency care in case of unforeseen and/or provoked exacerbation. Courses of prophylactic laser therapy are recommended: 3&#;5 procedures daily or every other day, at least 3&#;4 times a year [26,36,60,82,85,86]. It is preferable to use two techniques, most often ILBI and topical exposure. A course of prophylactic treatment is additionally prescribed for patients with allergic BA before the onset of seasonal exacerbation.

Abstract

This year marks the 50th anniversary of the discovery of the laser. The development of lasers for medical use, which became known as low-level laser therapy (LLLT) or photobiomodulation, followed in . In recent years, LLLT has become an increasingly mainstream modality, especially in the areas of physical medicine and rehabilitation. At first used mainly for wound healing and pain relief, the medical applications of LLLT have broadened to include diseases such as stroke, myocardial infarction, and degenerative or traumatic brain disorders. This review will cover the mechanisms of LLLT that operate both on a cellular and a tissue level. Mitochondria are thought to be the principal photoreceptors, and increased adenosine triphosphate, reactive oxygen species, intracellular calcium, and release of nitric oxide are the initial events. Activation of transcription factors then leads to expression of many protective, anti-apoptotic, anti-oxidant, and pro-proliferation gene products. Animal studies and human clinical trials of LLLT for indications with relevance to neurology, such as stroke, traumatic brain injury, degenerative brain disease, spinal cord injury, and peripheral nerve regeneration, will be covered.

INTRODUCTION

It was not long after the discovery of the first lasers (the ruby laser in and the helium-neon [HeNe] laser in ) that they began to be used in medical applications. In , Endre Mester in Hungary noticed the ability of the HeNe laser to increase hair growth [1] and stimulate wound healing in mice [2], and, shortly afterward, he began to use lasers to treat patients with nonhealing skin ulcers [3]. Since those early days, the use of low-power lasers (as opposed to high-power lasers that can destroy tissue by a photothermal effect) has steadily increased in diverse areas of medical practice that require healing, prevention of tissue death, pain relief, reduction of inflammation, and regenerative medicine. Some of the different organ systems, diseases, and injuries that have been effectively treated with low-level laser therapy (LLLT) are schematically shown in .

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Nevertheless, this modality, which is variously known as LLLT or photobiomodulation, remains controversial. The reasons for this lack of general acceptance among both the medical community and the general public at large are 2-fold. First, widespread uncertainty and confusion exists about the mechanisms of action of LLLT at the molecular, cellular, and tissue levels. Second, a large number of parameters (eg, wavelength, fluence, irradiance, treatment timing and repetition, pulsing, and polarization) can be chosen in designing LLLT protocols. Furthermore, a biphasic dose response exists in laser therapy [4], which describes the observation that increasing the overall &#;dose&#; of the laser either by increasing the power density or by increasing the illumination time may have a counter-productive effect compared with the benefit obtained with lower doses. Taken together, these considerations may explain why a number of negative studies have been published; however, this should not be taken to imply that LLLT in general does not work but rather that the laser parameters used in those particular studies were ineffective.

In recent years, the development of light-emitting diodes (LEDs) as alternative light sources for LLLT has added to the confusion. These devices produce light with wavelengths similar to those of lasers, but they have broader output peaks (ie, they are less monochromatic) and lack the coherence that is a particular feature of laser light. LEDs have the advantage of being significantly less expensive than laser diodes (by a factor of approximately 100 on a milliwatt basis), and the LLLT community is engaged in a vigorous ongoing debate about their respective benefits.

This review covers the mechanisms that are thought to operate at molecular and cellular levels in LLLT. Many of the most compelling applications of LLLT are in the field of neurology (both central and peripheral). Many serious brain diseases and injuries can be successfully treated with noninvasive transcranial laser therapy. Furthermore, in the peripheral nervous system, LLLT can be used effectively for nerve regeneration and pain relief.

STROKE

Transcranial LLLT (808 nm) has significantly improved recovery after ischemic stroke in rats when they received one treatment 24 hours after sustaining a stroke [21,22]. Stroke was induced in rats by 2 different methods: (1) permanent occlusion of the middle cerebral artery through a craniotomy or (2) insertion of a filament. The laser was used transcranially on the exposed (shaved skin) skull by placing the tip of the 4-mm diameter fiber optic onto the skin at 2 locations on the head (3 mm dorsal to the eye and 2 mm anterior to the ear) on the contralateral hemisphere to the stroke. These locations had been determined from prior measurements to be sufficient to illuminate 1 brain hemisphere as a result of dispersion of the laser beam by the skin and the skull. Results of previous studies had shown that LLLT of the contralateral, or both hemispheres, demonstrated no difference in functional outcome [23]. An NIR gallium arsenic diode laser was used transcranially to illuminate the hemisphere contralateral to the stroke at a power density of 7.5 mW/cm2 to the brain tissue [22]. In both models of stroke, the neurologic deficits at 3 weeks after stroke were significantly reduced (by 32%) (P < .01) in the laser-treated rats compared with control subjects.

In this study, the number of newly formed neuronal cells, assessed by double immunoreactivity to bromodeoxyuridine and tubulin isotype III, as well as migrating cells (double Cortin immunoreactivity), was significantly elevated in the subventricular zone of the hemisphere ipsilateral to the induction of stroke when treated by LLLT [21,22]. No significant difference in the stroke lesion area was found between control and laser-irradiated rats. The researchers suggested that an underlying mechanism for the functional benefit after LLLT in this study was possible induction of neurogenesis. Results of other studies also suggested that, because improvement in neurologic outcome may not be evident for 2-4 weeks in the poststroke rat model, delayed benefits may in part be due to induction of neurogenesis and migration of neurons [24,25]. In addition, transcranial LLLT may prevent apoptosis and improve outcomes by exerting a neuroprotective effect, although these exact mechanisms are poorly understood [26].

Other studies in rat and rabbit models also have observed that transcranial LLLT improves functional outcome after stroke [25,27,28]. A recent rabbit study combined transcranial LLLT with thrombolytic therapy by using tissue plasminogen activator, with no increase in bleeding and good safety [29].

In the aforementioned studies, it has long been hypothesized that increased mitochondrial function (ie, increased ATP production) in brain cells irradiated with NIR LLLT was one of the major mechanisms involved with the beneficial behavioral effects observed after LLLT treatment. A recent animal study with rabbits has shown a direct relationship between the level of cortical fluence (energy density) delivered (in J/cm2) and cortical ATP content in embolized rabbits [30]. Five minutes after embolization (right carotid), the rabbits were exposed to 2 minutes of NIR transcranial LLLT with use of an 808-nm laser source (continuous wave [CW] or pulsed wave [PW] at 100 Hz or at Hz on the skin surface, posterior to bregma at midline). Three hours after embolization, the cerebral cortex was excised and processed for measurement of ATP content. Embolization decreased cortical ATP content in ischemic cortex by 45% compared with naive rabbits.A linear relationship up to 4.5 J/cm2 in fluence delivered, was observed for the relationship between cortical fluence (in J/cm2) verus percent increase in cortical ATP content (over sham-treated embolized rabbits). This linear relationship was observed with a power density of 7.5 mW/cm2 CW (0.9 J/cm2), where an increase of 41% in cortical ATP was observed; and with a power density of 37.5 mW/cm2 PW (100 Hz, 4.5 J/cm2), where an increase of 157% in cortical ATP was observed. An increase in cortical ATP of 221% was observed with fluence of 31.5 J/cm2, delivered with a power density of 262.5 mW/cm2 PW, Hz. This suggests that a near-plateau effect was present regarding the fluence level delivered above 4.5 J/cm2. It was surprising, however, that the increased cortical ATP levels of 157% and 221%, were higher than those measured in naive rabbits that had never suffered stroke. Because the authors observed that the PW modes (100 Hz and Hz) were more effective than the CW mode to increase cortical ATP, they hypothesized that in future stroke studies in animals and in humans, even greater improvement in clinical rating scores might be achieved by optimizing the method of NIR transcranial LLLT delivery, including the length of treatment and the mode of treatment (PW).

Transcranial LLLT has been shown to significantly improve outcome in acute human stroke patients when applied approximately 18 hours after the stroke occurs over the entire surface of the head (20 points in the 10/20 electroencephalographic system), regardless of the stroke location [31]. Only one LLLT treatment was administered, and, 5 days later, significantly greater improvement was found in the real-treated group but not in the sham-treated group (P < .05, National Institutes of Health Stroke Severity Scale). This significantly greater improvement was still present 90 days after &#;the stroke occurred, at which time 70% of the patients treated with real LLLT had a successful outcome compared with only 51% of control subjects. An NIR (808 nm) laser was used, which delivered a fluence of 0.9 J/cm2 over the entire surface (2 minutes per each of the 20 points; power density of 7.5 mW/cm2).

In a second, similar study with the same transcranial LLLT protocol, an additional 658 acute stroke patients were randomly assigned to receive real or sham treatments of transcranial LLLT. Similar significant beneficial results (P < .04) were observed for the patients who had a moderate or moderate to severe stroke (n = 434) and received the real laser protocol but not for the patients who had a severe stroke [32]. When all 656 cases were included in the data analysis (including the severe stroke cases), no significant real versus sham LLLT effect was seen. When data for both stroke studies were pooled (n = 778 [120 plus 658]) [31,32], a highly significant beneficial effect was seen for the real transcranial LLLT group (P = .003) compared with those who received the sham laser treatment [33].

Lampl et al [31] wrote that &#;Although the mechanism of action of infrared laser therapy for stroke is not completely understood . . . infrared laser therapy is a physical process that can produce biochemical changes at the tissue level. The putative mechanism . . . involves stimulation of ATP formation by mitochondria and may also involve prevention of apoptosis in the ischemic penumbra and enhancement of neurorecovery mechanisms.&#;

To date, no studies have been conducted to examine transcranial LLLT treatment of chronic stroke patients. Naeser et al [34] studied the application of LLLT-laser acupuncture (instead of needles) to stimulate acupuncture points on the body in chronic stroke patients with paralysis. Seven stroke patients (range, 48-71 years; 5 men) were treated, 5 of whom had single left hemisphere stroke, and 2 of whom had single right hemisphere stroke. Five patients were treated for hemiplegia, including severely reduced or no voluntary isolated finger movement, and 2 patients had hand paresis only. Six of the 7 patients received laser acupuncture during the chronic phase after the stroke had occurred (10 months to 6.5 years after stroke onset), clearly beyond the spontaneous recovery phase, which is considered to be up to 6 months after the stroke occurs [35,36]. The patients served as their own controls; no sham LLLT was administered. One patient (who had hand paresis) received LLLT during the acute phase after the stroke occurred (1 month after the stroke occurred). The patients did not receive any physical therapy or occupational therapy treatments while participating in this study.

A 20-mW gallium aluminum arsenide (780 nm) NIR CW laser with a 1-mm-diameter aperture was used (Unilaser, Copenhagen, Denmark). (At the time of this study, more powerful red or NIR lasers were not yet available.) Treatment consisted of stimulation of shallow acupuncture points (located on the hands and face) for 20 seconds per point (51 J/cm2). Deeper acupuncture points (located on the arms and legs) were treated for 40 seconds per point (103 J/cm2). Acupuncture points were treated on both the paralyzed side (arm, leg, and/or face) and on the nonparalyzed side by using primarily acupuncture meridians of the large intestine, triple warmer, gall bladder, liver, small intestine, and stomach [34]. The patients were treated 2-3 times per week for 3-4 months. They received a total of 20, 40, or 60 treatments (based on patient availability and transportation). Within a few days before the first treatment and a few days after the last treatment, physical therapy and/or occupational therapy testing was performed by therapists blinded to the acupuncture treatment program to which the patient had been assigned: LLLT, real or sham needle, or no acupuncture. Overall, 5 of 7 of the patients (71.4%) showed improvement.

The 2 patients who showed no improvement had severe paralysis. We have observed that severity of paralysis and potential for improvement after LLLT-laser acupuncture (or needle acupuncture) is related to lesion location on chronic computed tomography (CT) scan acquired at least 3 months poststroke onset. Patients with lesion in more than half of the &#;periventricular white matter area&#; (PVWM) (adjacent to the body of the lateral ventricle, superior to the posterior limb, internal capsule), an area containing multiple efferent and afferent pathways (eg, thalamocortical, occipitofrontal, pathways from SMA/cingulate gyrus to the body of caudate, medial subcallosal fasciculus, and others), had severe paralysis which did not improve following LLLT-laser acupuncture (or needle) acupuncture treatments [34,37,38]. This area is diagrammed in . The CT scan for a chronic stroke patient who had good response after LLLT-laser acupuncture treatments [34,37,38]. This area is diagrammed in .

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The 3 chronic stroke patients with hemiplegia who showed improvement after LLLT had an increase of 11%-28% in isolated, active range of motion for shoulder abduction, knee flexion, and/or knee extension (mean, 15.8%; SD, 7.1). This percentage increase after LLLT-laser acupuncture was similar to that observed after a series of 20 or 40 needle acupuncture treatments [37,38]. The person with hand paresis who was treated with LLLT at 33 months after stroke onset showed an increase of 2-6 lb in grip strength, 3-jaw chuck, tip pinch, and lateral pinch in the affected hand. These results are similar to those obtained with needle acupuncture [39]. These findings are intriguing and suggest that some recovery of motor function can occur with needle acupuncture or LLLT acupuncture applied to body acupuncture points in chronic stroke patients.

A reduction in hand spasticity also has been observed when chronic stroke patients are treated with a combination of red-beam laser applied to hand acupuncture points plus microamps transcutaneous electrical nerve stimulation (TENS). shows an immediate reduction in hand spasticity after the first hand treatment when LLLT-laser acupuncture and microamps TENS were used with 2 chronic stroke patients. This LLLT and microamps TENS hand treatment program also may be used with patients who have hand spasticity related to other etiologies, including, for example, traumatic brain injury (TBI), &#;stiff man syndrome,&#; and spinal cord injury (SCI) (personal observation, M.A.N., ). Similar to red and NIR LLLT, microamps TENS increases ATP levels when applied to the skin [40]. However, Cheng et al [40] observed that when stronger milliamps TENS was used (eg, similar to conventional TENS), the ATP levels were decreased. Hence when microamps TENS is used (as shown in ) [41], it is advisable to keep the sensation below threshold for the patient to increase ATP (not decrease ATP).

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TRAUMATIC BRAIN INJURY

Each year in the United States, more than 1.4 million new cases of TBI occur, and more than 80,000 persons are left with permanent disability [42]. Mild TBI (mTBI) from single and multiple events is the most frequent type of head injury experienced by military personnel deployed to Iraq and Afghanistan [43]. TBI is known to cause damage that ranges from observable to microscopic throughout the gray and white matter of the brain. Diffuse axonal injury [44] is often observed in the anterior corona radiata and frontotemporal regions [45]. Two regions highly susceptible to damage within the frontal lobes are the prefrontal cortex and the anterior cingulate gyrus. Cognitive processing problems result from tissue damage and inefficient cellular function in these brain regions. The prefrontal cortex is involved with maintaining, monitoring, and manipulating information in working memory [46] and particularly in sustained attention [47,48].

In the first reported study of the use of transcranial LLLT to treat traumatic brain injury, an animal model was used [49]. Mice were subjected to closed-head injury (CHI) by using a weight-drop procedure, and 4 hours after CHI, either sham or real NIR LLLT (808 nm) was administered transcranially. The control group received no laser therapy (n = 8); the laser-treated group (n = 16) received 1 transcranial LLLT treatment by using a 200-mW, 808-nm NIR laser with a 3-mm-diameter probe tip (Photothera Inc, Carlsbad, CA). Either 10 or 20 mW/cm2 was administered. A single point was treated on the skull (a skin incision was made) that was located 4 mm caudal to the coronal suture line on the midline. The point was treated for 2 minutes (1.2-2.4 J/cm2). At 24 and 48 hours after CHI, no significant difference in motor behavior was seen between mice in the laser-treated and control groups. After 5 days, the motor behavior was significantly better (P < .05) in the laser-treated group; in addition, the neurobehavioral scores were 26%-27% better (lower scores indicated better motor behavior). At 28 days after CHI, the brain-tissue volume was examined for mice in each group. The mean lesion size of 1.4% in the laser-treated group (SD 0.1) was significantly smaller (P < .001) than in the control group (12.1%, SD 1.3). No difference in lesion size or behavior was observed in the mice treated with 10 mW/cm2 and those treated with 20 mW/cm2. The researchers suggested various possible mechanisms, including an increase in ATP, total antioxidants, angiogenesis, neurogenesis, heat shock proteins content, and an antiapoptotic effect, similar to observations reported after LLLT treatment of ischemic heart skeletal muscles [50-54].

Moreira et al [55] conducted a study in using phototherapy with low-intensity lasers and observed the effect on local and systemic immunomodulation after cryogenic brain injury in rats. Brain and blood samples were analyzed by enzyme-linked immunosorbent assay for the production of cytokines interleukin (IL)-6 , IL-10, IL-1b, and tumor necrosis factor (TNF)-α. The study concluded that laser phototherapy could positively affect the balance of IL-1b, TNF-α, and IL-6 in rats and thereby prevent cell death after TBI.

Wu et al [56] reported another mouse study of LLLT mediated by transcranial laser therapy. A nonfocal (diffuse) TBI was produced by a CHI caused by a calibrated weight-drop device. A neurologic severity score for each mouse was determined based on 10 standardized performance tests (involving beam balancing and maze exiting) administered at specified times. Mice with a neurologic severity score of 7-8 (moderately severe brain injury) were used in the study. Mice were given a single treatment to the top of the head with 36 J/cm2 of a 665-nm, 810-nm, or 980-nm laser 4 hours after the closed head TBI. Both 665-nm and 810-nm lasers were highly effective in improving the neurologic performance of the mice during the succeeding 4 weeks. The 980-nm wavelength was ineffective (negative control). We believe that this difference in results can be explained by the absorption spectrum of the different chromophores; CCO has peaks at 660 nm and 810 nm, whereas water has a peak at 980 nm.

In humans, 2 persons with chronic mTBI recently have been reported to have improved cognition after a series of treatments with transcranial, red, and NIR LEDs [57,58]. The LED cluster heads were applied to the forehead and scalp areas (the hair was not shaved off but was parted underneath each 2-inch-diameter LED cluster head). Each cluster head had 61 diodes (9 red 633-nm diodes and 52 NIR 870-nm diodes). Each diode was 12-15 mW, and the total power output was 500 mW. The LED cluster heads were applied to bilateral frontal, parietal, and temporal areas and to the mid-sagittal suture line.

Each LED cluster head was applied for 10 minutes per placement. With the device used here (parameters described above), 1 joule per cm2 (J/cm2) energy density was produced during every 45 seconds of exposure time. The energy density dose at the forehead-scalp was 13.3 J/ cm2; the power density was 22.2 mW/cm2 (±20%). The power density refers to the mW of power applied per cm2. The ± refers to the range of fluctuation (plus or minus 20%) on the power density per cm2. This power density is well below that used in other transcranial laser or LED studies to treat acute stroke cases or severe depression cases (225 mW/cm2) [59]. It is estimated that only approximately 3% of the photons delivered to the forehead-scalp surface will reach 1 cm, to the cortex [60]. The dose of 13.3 J/cm2 per placement area was estimated to deliver only 0.4 J/cm2 to the brain cortex. No sensation of heat or pain was reported during the LED application to the skin or scalp. These LED cluster heads (MedX Health Corp, Mississauga, Ontario, Canada) are approved by the U.S. Food and Drug Administration for treatment of musculoskeletal pain; they were used off-label for treatment of cognition in the mTBI cases. No potential existed for ocular damage because the LEDs produce noncoherent light. These LED cluster heads also have been approved by the Food and Drug Administration for home treatment.

A 66-year-old woman (case 1) began transcranial LED treatments 7 years after a motor vehicle&#;related TBI. Before LED treatment, she could focus on her computer for only 20 minutes. After 8 weekly LED treatments, her focused computer time increased to 3 hours. She has treated herself nightly at home for 5.5 years, with transcranial LED. She maintains her improved cognition at age 72 years.

Case 2 involved a 52-year-old retired, high-ranking female military officer who had a history of multiple TBIs. Her brain MRI showed frontoparietal atrophy. She was medically disabled for 5 months before beginning nightly transcranial LED treatments at home (see ). After 4 months of nightly LED treatments, she returned to work full time as an executive consultant for an international technology consulting firm and discontinued medical disability. Neuropsychological tests performed after 9 months of transcranial LED showed significant improvement in cognition (see ). After LED treatments, she improved on tests of executive function (inhibition and inhibition accuracy, +2 SD) and on memory (immediate and delayed recall +1, +2 SD). The improvement of +1 or +2 standard deviations on her scores refers to the degree of improvement on her scores after 9 months of LED treatments (versus before LED treatments). The SDs are provided with the test materials, and they are based on the published norms for each test.

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Both patients with TBI reported that they needed to continue with home treatments. If they stop treatment for 1 or 2 weeks, then their cognitive problems started to return. Both patients with TBI reported improved sleep. The second patient with TBI reported a decrease in her posttraumatic stress disorder symptoms after a few months of using the transcranial LEDs, and Schiffer et al [59] also reported a reduction in posttraumatic stress disorder symptoms in 3 of 10 patients with major depression who were treated with transcranial LED.

Several possible mechanisms may be associated with the improved cognition in the mTBI cases treated with transcranial LEDs [58]. Mitochondria display a significant amount of dysfunction after TBI [61-63]. The primary mechanism for improvement posited in one study with human acute stroke patients was an increase in ATP, with photons being used by CCO in the mitochondria to increase ATP, especially in the cortex [64].

An increase in ATP after red and/or NIR LED treatments in patients with chronic TBI would have beneficial effects, including an increase in cellular respiration and oxygenation. Oxidative stress plays a role in the damage present after TBI [65]. One hypothesis is that LLLT produces low levels of ROS in mitochondria of illuminated cells and that these ROS cause NF-κB activation via the redox sensitive sensor enzyme protein kinase D1, which results in upregulation of the mitochondrial superoxide dismutase [66]. A single exposure of LLLT-LED in vitro with fibroblasts has been observed to increase NF-κB in the short term [67]. In stimulated dendritic cells in the longer term, however, NF-κB and pro-inflammatory cytokines were reduced [68]. Thus, in the long term, repeated LED treatments are hypothesized to decrease inflammation (less NF-κB) and upregulate gene products that are cytoprotective, such as superoxide dismutase, glutathione peroxidase, and heat shock protein 70 [54,69]. It is hypothesized that an overall protective response occurs with repeated LED treatments and that major ROS-mediated damage and chronic inflammation that occur in the brain after TBI may actually be reduced.

Acupuncture points located on the scalp were treated with the red-NIR LEDs [57]. This includes points along the Governing Vessel (GV) acupuncture meridian, located on the midline of the skull (including, in part, the mid-sagittal suture line). Some acupuncture points located on the GV meridian have been used historically to help treat patients in coma [70] and stroke [71], for example, GV 16 (inferior to occipital protuberance), GV 20 (vertex), and GV 24 (near center-front hairline); these points were treated in both patients with TBI reported in this study.

Transcranial red-NIR LED may have irradiated the blood via the valveless, emissary veins located on the scalp surface but interconnecting with veins in the superior sagittal sinus (M. Dyson, oral personal communication, June ). If red-NIR photons penetrate deeply enough to reach the cortex, then it also is possible they are entering small vessels located between the arachnoid and the pia mater, including those that supply arterial blood to superficial areas of the cortex. Direct in vitro blood irradiation with a red-beam laser has been observed to improve erythrocyte deformability (flexibility) and rheology [72,73]. A beneficial effect from direct-laser blood irradiation in vivo has been observed during stenting procedures where a low-level, red-beam laser (10 mW, 650 nm) was used, with the beam placed directly into a coronary artery [74]. The restenosis rate was reduced and no adverse effects or complications were noted. Thus blood irradiation at the scalp may have affected local intracerebral blood and circulation; however; whether this effect occurred is unknown and would require further study.

An increase in regional cerebral blood flow may have occurred, specifically to the frontal lobes. The second TBI case showed significant improvement on objective, neuro-psychological testing for executive function (inhibition) after administration of LED. These results suggest improved function in the prefrontal cortex and anterior cingulate gyrus regions. Significant improvement on &#;inhibition&#; on the Stroop test particularly suggests improved function of the medial prefrontal cortex, anterior cingulate gyrus area [75]. It is possible that this medial prefrontal cortex area could have been treated with NIR photons, especially when the LED cluster head was placed over the midline, front hairline area. The dorsolateral prefrontal cortex also was likely irradiated when the LEDs were placed on the left and right high-frontal areas of the scalp. Increased regional cerebral blood flow also could have occurred in frontal pole areas with the TBI cases, as was observed in the recent transcranial LED study to treat major depression [59]. Additional controlled studies with real and sham transcranial LLLT and LED are recommended to investigate whether these methods can be applied to improve cognition and reduce symptom severity in persons with acute and chronic TBI. The LED technology is not expensive ($ for a single LED cluster head and approximately $ to $ for a unit with 3 LED cluster heads). The transcranial LED treatment protocol can be used in the home.

DEGENERATIVE CENTRAL NERVOUS SYSTEM DISEASE

The positive effects of transcranial laser therapy on stroke and TBI have led to early investigations into whether LLLT may have benefits for persons with degenerative brain disorders, which are a rapidly growing affliction of the world's aging population. Moges et al [76] tested whether LLLT had a role to play in treating familial amyotrophic lateral sclerosis (FALS), which is a neurodegenerative disease characterized by progressive loss of motor neurons and death. Mitochondrial dysfunction and oxidative stress play an important role in motor neuron loss in ALS. The study combined LLLT (with use of an 810-nm diode laser with 140-mW output power targeting a 1.4-cm2 spot area for 120 seconds using 12 J/cm2 energy density) and riboflavin to test the survival of motor neurons in a mouse model of FALS. Motor function (determined with use of the Rota rod test) was significantly improved in the LLLT group in the early stage of the disease. Immunohistochemical expression of the astrocyte marker glial fibrillary acidic protein was significantly reduced in the cervical and lumbar enlargements of the spinal cord as a result of LLLT.

Trimmer et al [77] carried out preliminary studies that may have relevance to Parkinson disease (PD). Mitochondria supply the ATP needed to support axonal transport, which contributes to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. The researchers measured the velocity of mitochondrial movement in human transmitochondrial cybrid &#;cytoplasmic hybrid&#; neuronal cells with mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer control subjects (CNT). PD and CNT cybrid neuronal cells were exposed to NIR laser light (an 810-nm diode laser using 50 mW/cm2 for 40 seconds), and axonal transport of labeled mitochondria was measured. The velocity of mitochondrial movement in PD cybrid neuronal cells was significantly reduced compared with mitochondrial movement in disease-free CNT cybrid neuronal cells, and 2 hours after LLLT, the average velocity of mitochondrial movement in PD cybrid neurites was significantly increased and restored to levels comparable with those of CNT. Mitochondrial movement in CNT hybrids was unaltered by LLLT. PD cybrid neuronal cell lines with the most dysfunctional mtETC assembly and oxygen utilization profiles were least responsive to LLLT.

Zhang et al [78] likewise did preliminary experiments with relevance to Alzheimer disease. They showed that LLLT (0.156 -0.624 J/cm2 from a 5-mW HeNe laser) could protect rat pheochromocytoma PC12 cells (a model of cortical neurons) from apoptosis caused by amyloid β peptide (Aβ25-35). This protection was mediated by protein kinase C activation caused by an increase in the cell survival protein bcl-xl and a decrease in cell death protein bax. Although no peer-reviewed publications have been published to date, it is known that transcranial LLLT has been applied to patients with moderate Alzheimer disease.

Michalikova et al [79] treated middle-aged (12&#;month-old) female CD-1 mice with a daily 6-minute exposure to -nm LED light for 10 days and found that LLLT yielded a number of significant behavioral effects upon testing in a 3-dimensional maze. Middle-aged mice showed significant deficits in a working memory test, and LLLT reversed this deficit. LLLT-treated middle-aged mice were more considerate in their decision making, which resulted in an overall improved cognitive performance comparable with that of young (3-month-old) CD-1 mice. These results suggest that LLLT could be applied in cases of general cognitive impairment in elderly persons.

SPINAL CORD INJURY

SCI is a severe central nervous system trauma with no effective restorative therapies. Light therapy has biomodulatory effects on central and peripheral nervous tissue. Several groups investigated the effectiveness of LLLT on SCI. Roch-kind et al [80] demonstrated that LLLT applied simultaneously to the injured sciatic nerve and the corresponding segment of the spinal cord accelerates the process of regeneration of the injured peripheral nerve.

Light therapy (810 nm, 150 mW) significantly increased the axonal number and distance of regrowth in 2 SCI models: a contusion model and a dorsal hemisection model [81,82]. In addition, LLLT returned aspects of function to baseline levels and significantly suppressed immune cell activation and cytokine-chemokine expression [81].

Moreover, light therapy significantly improved the average length of axonal regrowth and increased the total axon number for both injury models. A statistically significant lower angle of rotation of the feet was observed during a walking test in the hemisection model and a statistically significant overall functional recovery in contusion model was seen in the LLLT groups. These results suggest that light may be a promising therapy for human SCI [82].

PERIPHERAL NERVE

The use of new therapeutic instruments such as electric stimulation, ultrasound, and LLLT for peripheral nervous system regeneration is currently being investigated in an attempt to achieve early functional recovery. LLLT has been used in several clinical and experimental research studies on peripheral nerves injuries.

In a pilot double-blind randomized study, Rochkind et al showed that postoperative 780-nm laser phototherapy enhances the regenerative process of the peripheral nerve after reconnection of the nerve defect by using a PGA neurotube. Morphologically, the laser-treated group showed an increased total number of myelinated axons [83]. These researchers also reported that, in patients with long-term peripheral nerve injury, 780-nm laser therapy (250 mW) can progressively improve nerve motor function, which leads to significant functional recovery [84].

Barbosa et al [85] observed that, compared with the 830-nm laser group and the sham group, rats in the 660-nm laser group had the best sciatic functional index scores on average, which indicates that the use of these parameters was more efficient. Differences in sciatic functional index were found among the 660-nm laser group and the other ones at the 14th day [85]. However, Gigo-Benato et al [86] found that pulsed (905 nm) continuous (808 nm) combined laser biostimulation showed the best effectiveness in promoting peripheral nerve regeneration.

CONCLUSION

LLLT is steadily moving into mainstream medical practice. As the Western populations continue to age, the incidence of the degenerative diseases of old age will only continue to increase and produce an evermore severe financial and societal burden. Moreover, despite the best efforts of &#;big pharma,&#; distrust of pharmaceuticals is growing in general because of uncertain efficacy and troublesome adverse effects. LLLT has no reported adverse effects, and no reports of adverse events can be directly attributed to laser or light therapy. We believe that the high benefit:risk ratio of LLLT should be better appreciated by medical professionals in the rehabilitation and physical medicine specialties. The introduction of affordable LED devices powered by rechargeable batteries will lead to many home-use applications of LLLT. The concept of &#;wearable&#; light sources is not far off. Moreover, the particular benefits of LLLT to both the central and peripheral nervous systems suggest that much wider use of LLLT could or should be made in cases of both brain diseases and injuries.

Acknowledgments

Disclosure: research in the Hamblin laboratory supported by NIH grant R01AI, Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-), CDMRP Program in TBI (W81XWH-09-1-), and Air Force Office of Scientific Research (FA-04-1-)

Footnotes

Disclosure key can be found on the Table of contents and at www.pmrjournal.org

Contributor Information

Javad T. Hashmi, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA; Department of Dermatology, Harvard Medical School, Boston, MA Disclosure: nothing to disclose.

Ying-Ying Huang, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA; Department of Dermatology, Harvard Medical School, Boston, MA; Aesthetic and Plastic Center, Guangxi Medical University, Nanning, PR China Disclosure: nothing to disclose.

Bushra Z. Osmani, Aga Khan Medical College, Karachi, Pakistan Disclosure: nothing to disclose.

Sulbha K. Sharma, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA Disclosure: nothing to disclose.

Margaret A. Naeser, VA Boston Healthcare System, Boston, MA; Department of Neurology, Boston University School of Medicine, Boston, MA Disclosure: nothing to disclose.

Michael R. Hamblin, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA; Department of Dermatology, Harvard Medical School, 40 Blossom St BAR414, Boston, MA ; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA. Address correspondence to: M.R.H.; ude.dravrah.hgm.xileh@nilbmah.

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