Introduction

Neurological disorders cause the majority of disability and are the second leading cause of death worldwide. Over the last three decades, the total number of deaths and disabilities caused by neurological diseases has increased significantly, particularly in low- and middle-income countries [1]. Congenital defects, epigenetic changes, aging, and environmental health issues are the primary causes of the onset and progression of various neurological disorders, which affect both the central and peripheral nervous systems (CNS and PNS) [2,3,4].

Photobiomodulation (PBM) is a non-invasive physical treatment modality that uses low-level lasers (from the red to near-infrared spectrum, with intensities ranging from 1–500 mW) and/or light-emitting diodes (LEDs) [5]. Evidence suggests that PBM could boost mitochondrial function by improving the electron transfer chain and increasing adenosine triphosphate (ATP) synthesis, as well as lowering oxidative stress biomarkers and inhibiting neuroinflammation [6]. PBM has been used to treat a variety of CNS and PNS disorders, including traumatic brain injury [7], stroke [8], Parkinson’s disease (PD) [9], Alzheimer’s disease (AD) [10], depression, anxiety, cognitive impairments [11, 12], spinal cord injury [13], and carpal tunnel syndrome (CTS) [14]. Both preclinical and clinical studies have shown that PBM therapy improves CNS function [15, 16] and effectively inhibits inflammation in peripheral nerves [17].

Currently, numerous PBM clinics and medical device manufacturers are actively working to improve the parameters that influence PBM effectiveness in the treatment of neurological disorders [18]. The safety of this technique was evaluated in three large randomized clinical trials on acute stroke, known as the "NeuroThera Effectiveness and Safety Trials" (NEST-1, NEST-2, and NEST-3), which found no adverse effects [19,20,21]. While there have been numerous peer-reviewed articles on PBM, there are few standard RCTs to definitively determine the clinical efficacy of this therapeutic approach [22].

There are some important gaps in the field of PBM therapy that must be addressed. Optimizing neural tissue stimulation with this technique is one of the most difficult challenges, due to the diverse types and severity of neuropathologies, as well as the rapid attenuation of light transmission in tissue [23, 24]. Combination therapies have been proposed as a way to increase treatment efficacy while avoiding severe side effects. As a result, current experimental and clinical studies concentrate on combination therapy rather than single therapy, indicating potential future clinical combination treatment schedules.

Although several systematic reviews have examined the effects of PBM on various neurological disorders [13, 14, 24, 25], we were unable to locate a comprehensive systematic review on PBM combination therapy in neurologic and neuropsychiatric disorders. This review aims to provide an overview of published procedures for determining whether combination therapies for CNS and PNS disorders are more effective than monotherapies. To that end, PBM-based methodologies were tested for detecting and treating neurologic and neuropsychiatric disorders such as depression, anxiety, Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, neuropathic pain, spinal cord injury, sciatic nerve crush, paresis, and facial nerve injury. Furthermore, the parameters involved in these procedures were evaluated.

Methods

Search strategy

According to the PRISMA (Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the findings of this review were reported. The Google Scholar, PubMed, and Scopus databases, as international electronic databases, were independently searched up to January 2024 to retrieve all types of studies primarily focused on the synergistic and complementary effects of PBM-combined strategies in the treatment of neurologic and neuropsychiatric disorders. The following keyword combinations based on MeSH terms were used: Photobiomodulation; PBM; Low-Level Laser Therapy; LLLT; Low-Level Light Therapy; Light-Emitting Diode; LED; Combine; Central Nervous System; CNS; Peripheral Nervous System; PNS; Neuropsychiatric; Neurodegenerative; Paresis; Neuropathy; Ischemia; Nerve Injury; pain. The search strategy is presented in Appendix 1. Before selection, duplicate citations were eliminated using the Endnote software. Two independent investigators scrutinized all titles, abstracts, and full texts of potentially qualified articles based on the eligibility criteria, and any discrepancies were resolved by the analysis of a third independent author and the majority consent was taken. Moreover, the reference lists from each article were checked through hand searching to find articles that the search strategy could not have found.

Study selection and data extraction

Following the search, all English-language published original articles on animal studies and clinical trials were included. The exclusion criteria were in vitro (i.e., cell culture) studies, literature reviews, case reports, protocol studies, conference abstracts, non-English articles, duplicate studies with the same ethical approval number, studies on a combination of two or more lasers at different wavelengths, and acupuncture lasers.

To clarify the relevant details from each included article, data and information from each study were extracted and tabulated as follows: author name and publication year, disease category, species (sex and age), type of combination therapy, laser properties (wavelength, energy density), duration of treatment, and key outcomes. Due to the high variability in the type of disease and treatment meta-analysis was not performed.

Study quality

The Cochrane Collaboration tool was utilized to evaluate the risk of bias (RoB) in randomized controlled clinical trials. This tool consists of several components including selection bias, performance bias, detection bias, attrition bias, and reporting bias. Animal studies were scored based on a modified version of the CAMARADES’ study quality checklist. The CAMARADES checklist is a reliable and commonly used tool that offers mentoring to those who conduct systematic reviews and meta-analyses of data from preclinical literature [26, 27]. The questions in this tool covers information about publication in a peer-reviewed journal, control of temperature, random allocation to treatment or control, blinded induction, blinding of outcome assessment, use of anesthetic without significant intrinsic neuroprotective activity, animal model, sample-size calculation, compliance with animal welfare regulations, and a statement regarding possible conflicts of interest.

The assessment was conducted by two independent authors. The authors were familiar with both the methodological issues and the topic area. They also had previous experience of working with the tools. There was an explicit procedure for resolving disagreements among authors. All disagreements were resolved by comparing supporting information from each study report, which was divided into two parts of the data collection process (rechecking the document) and a difference in interpretation (resolved via discussion). Unresolved discrepancies were resolved after consulting with a third senior author [28, 29].

Result

Literature search

The electronic search of the mentioned databases (Google Scholar (n = 200), PubMed (8475) and Scopus (10273)), resulted in a total of (18948) studies. After removing duplicated papers (n = 8382) and conducting the appraisal process, 117 studies remained for full-text reading. Among these studies, three were excluded because they were conducted in cell culture. Studies that used combined lasers at different wavelengths were also excluded (n = 7). Additionally, eight case reports and four protocol studies were excluded. The PRISMA flowchart of the review selection process is illustrated in Fig. 1.

Fig. 1
figure 1

The PRISMA flowchart of the review selection process

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The results yielded 95 studies, which assessed the efficacy of strategies on behavioral and molecular changes in neurological disorders.

The included studies in the first step were divided into two major categories: clinical (human, n = 66) and pre-clinical (animal, n = 29) studies. Clinical studies were further classified into two main groups including CNS and PNS disorders. The first group was re-classified into neuropsychiatric disorders (n = 6), neurodegenerative diseases (n = 5), ischemia (n = 7), and nerve injury (n = 19). The second group contained pain (n = 48), paresis (n = 3), and neuropathy (n = 7). Tables 1 and 2 provide the main characteristics of the included studies outcomes, light source parameters and combination treatments, in central and peripheral nervous system disorders in clinical studies. Since the re-categorizing preclinical studies was not possible due to limitations in the number of articles in each possible section, they were reported in a holistic manner. Table 3 represents the similar data from experimental studies. All included articles addressed the impacts of laser therapy combined with other therapies on neurological disorders.

Table 1 Characteristics of the included studies outcomes, light source parameters and combination treatment, in central nervous system disorders in clinical studies
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Table 2 Characteristics of the included studies outcomes, light source parameters and combination treatment, in peripheral nervous system disorders in clinical studies
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Table 3 Characteristics of the included studies outcomes, light source parameters and combination treatment, in experimental studies
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Study characteristics

The wavelength, power/energy density (irradiance and fluence), mode of application (pulsed wave or continuous wave), and treatment frequency were the most important factors affecting the outcomes. Red to far-infrared lasers at a range of wavelengths from 630 to 1875 nm were widely used, as opposed to LEDs and CO2 lasers. The included protocols had an energy density of up to 983 J/cm2. According to the findings of this study, laser therapy was combined with other treatment approaches such as pharmacotherapy, exercise, environmental enrichment, exposure therapy, physiotherapy, ultrasound, mesenchymal stem cells, etc. The duration of treatment varied from 3 days to 18 months. Almost all studies showed positive effects of PBM-combined therapies on various neurological disorders.

Study quality and risk of bias

The Cochrane Collaboration’s tool showed that the majority of CNS studies were not blinded, and the allocation concealment rate was low in these studies. Accordingly, selection, and detection bias were apparent in these studies. The details of the quality assessment are presented in Figs. 2 and 3. The CAMARADES checklist was utilized in the quality assessment of animal studies which showed that almost all studies were qualified (Table 4). All of the articles had been published in peer-reviewed journals and reported details of the animal model, anesthetic use, compliance with animal welfare, and a statement of potential conflicts of interest. Random allocation to groups was reported in 18 (62%) studies. Nine (31%) studies reported blinded induction of the model. Only one study reported a sample size calculation and 10 (34%) studies reported blinded assessment of the outcome.

Fig. 2
figure 2

Risk of bias (RoB) assessment using Cochrane RoB tool (included CNS studies). Left panel shows RoB summary showing each RoB item for each included study. Right panel shows RoB graph showing each RoB item presented as percentages across all included studies. In this color-coded ranking, the green color represents a low RoB and red high RoB

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Fig. 3
figure 3

Risk of bias (RoB) assessment using Cochrane RoB tool (included PNS studies). Top panel shows RoB summary showing each RoB item for each included study. Bottom panel shows RoB graph showing each RoB item presented as percentages across all included studies. In this color-coded ranking, the green color represents a low RoB and red high RoB

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Table 4 The methodological quality of individual animal studies using the CAMARADES checklist
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Discussion

This systematic review sought to assess whether the integration of photobiomodulation (PBM) with other treatment strategies yielded additional advantages in the management of neurological and neuropsychological disorders, as compared to administering these treatments separately.

Central Nervous System (CNS)

Neuropsychiatric disorders

Zaizar et al. [30, 31] showed that the concurrent use of transcranial infrared laser and exposure therapy reduced fear in individuals with pathological fear. The study findings demonstrated that the combination of PBM with a static magnetic field and Pilates, a therapeutic approach for stress incontinence, resulted in enhanced muscle strength and reduced urinary loss [32]. In addition, certain studies have found that the concurrent use of transcranial PBM with pharmaceutical interventions, such as coenzyme Q10 and methylene blue, can reduce anxiety by counteracting oxidative stress, neuroinflammation, and neuronal apoptosis [96, 97]. Furthermore, the concurrent use of transcranial PBM and a stimulating environment has demonstrated a substantial elevation in hippocampal levels of BDNF, TrkB levels, and the p-CREB/CREB ratio, alongside a reduction in depressive behaviors [98].

Neurodegenerative diseases

Arakelyan et al. showed that the combination of low-level laser therapy (LLLT), magnetic field therapy, and light chromotherapy was more effective than using each therapy individually in reducing the deterioration associated with AD [33]. Nevertheless, Moges et al. observed no substantial enhancement in motor function or survival of motor neurons in the anterior horn of the lumbar spinal cord of a transgenic mouse model of familial amyotrophic lateral sclerosis when subjected to a combined laser therapy (810 nm) and riboflavin protocol [99]. Moreover, research has shown that the combination of PBM with exercise has a synergistic impact on mitigating the decline associated with AD [34]. Patients with PD have been found to benefit from combined treatments involving infrared laser and vacuum therapy, as well as molecular hydrogen water treatments. These treatments have been shown to effectively accelerate the relief of disease severity [35, 36].

Ischemia

In their study, Lapchak et al. [100] found that the simultaneous use of transcranial near-infrared laser therapy and thrombolytic therapy did not have any impact on the occurrence or size of hemorrhages in a stroke model induced by embolism [100]. Another research conducted demonstrated that the use of red-light emitting diode irradiation in conjunction with bone marrow mesenchymal stem cell transplantation had a synergistic effect on enhancing the movement of stem cells towards damaged primary neurons. This approach also resulted in improved avoidance memory in a rat model of global cerebral ischemia [101]. Moreover, research has shown that the combined use of PBM and Coenzyme Q10 significantly reduced the negative effects of global cerebral ischemia on spatial and episodic memory, excessive production of reactive oxygen species (ROS), neuroinflammation, and impairments in mitochondrial function and biogenesis in a model of aging induced by d-galactose [102]. A clinical trial study demonstrated that the application of both PBM (comprising laser and LED) and static magnetic field treatment resulted in enhanced functional mobility outcomes in individuals who had experienced a stroke [37]. In a similar vein, Ashrafi et al. found that the concurrent use of pulsed LLLT and an extremely low-frequency electromagnetic field reduced the severity of stroke, enhanced cognitive function, alleviated depression, and mitigated the extent of disability in performing daily tasks among individuals who had suffered a stroke [38]. Other studies have shown that the co-administration of PBM with neuromuscular electrical stimulation or a static magnetic field to patients diagnosed with a stroke resulted in optimal improvements in cognitive function, pain relief, and kinematic variables of the hip in both paretic and non-paretic limbs [39, 40].

Nerve injury

Studies have shown that using a CO2 laser, along with three distinct suture materials and a bovine albumin protein solder, produces favorable initial histological outcomes and aids in the recovery process at the site of nerve repair [103].

Muniz et al. discovered that the combination of LLLT with natural latex protein reduces the severity of muscle wasting after a sciatic nerve injury (SCI) [108]. In addition, Yang et al. found that the combination of LLLT with mesenchymal stem cells had a more significant impact on the functional recovery of a crushed sciatic nerve compared to using either therapy alone [106]. In addition, the combination of PBM with dexamethasone and simvastatin demonstrated superior efficacy compared to individual therapies in enhancing SCI outcomes [109, 111]. In contrast, certain studies have suggested that the use of combination therapy does not result in a synergistic impact on the recovery from SCI [107, 125].

In their study, Souza et al. found that the concurrent application of transdermal monosialoganglioside (GM1) and laser did not result in any notable impact on the functional and neurological outcomes after SCI in rats [112]. Furthermore, the co-administration of PBM along with chondroitinase ABC or meloxicam has demonstrated enhanced functionality in the identical model [113, 114, 116]. Moreover, there have been reports indicating that the combination of LLLT with either human adipose-derived stem cells or human umbilical cord mesenchymal stem cells has proven to be successful in restoring motor function and promoting the regeneration of nerve fibers in rat models of SCI [115, 117]. A recent randomized clinical trial demonstrated that patients with incomplete spinal cord injury experienced improvements in sensory responses, muscle strength, and muscle contraction one month after receiving a combination of PBM and physiotherapy [41].

Peripheral Nervous System (PNS)

Pain

Prior research has shown that the amalgamation of LLLT with Q10 or oxytocin can elevate thresholds in models of neuropathic pain [121, 122]. Moreover, a randomized controlled clinical trial demonstrated that the combination of LLLT and carbamazepine reduced the intensity of pain in individuals suffering from trigeminal neuralgia [43]. Additionally, a separate study found that the combination of LLLT and Gasserian ganglion block can extend the duration of pain relief and decrease the amount of carbamazepine taken by patients with trigeminal neuralgia after treatment [42].

Studies have shown that the use of PBM in conjunction with exercise or ultrasound therapy can alleviate pain, improve shoulder flexion, elbow extension, and handgrip strength in individuals suffering from lateral epicondylitis [44,45,46]. Amanat et al. demonstrated the effectiveness of combining laser therapy with pharmaceutical therapy, including tricyclic antidepressants, anxiolytics, muscle relaxants, and carbamazepine, for treating orofacial pain [47]. In addition, Martins et al. demonstrated that long-term combined therapy with PBM and B complex vitamins effectively reduced pain responses [126].

Administering infrared laser therapy in conjunction with exercise or conventional medical interventions (such as naproxen sodium, fluoxetine, and clonazepam) to individuals suffering from myofascial pain syndrome resulted in decreased pain levels and elevated excretion of serotonin metabolites [48, 49, 51]. Furthermore, the simultaneous application of LLLT and physiotherapy resulted in the alleviation of pain and enhancement of the quality of life in individuals suffering from myofascial pain syndrome [50].

Research has shown that the utilization of both infrared laser treatment and physical exercise can effectively alleviate pain in individuals suffering from chronic low back pain [52,53,54]. Moreover, a clinical trial demonstrated that the use of both hot-pack therapy and two specific wavelengths of low-level laser therapy (850 nm and 650 nm) effectively reduced pain severity and enhanced functionality and range of motion in this particular group [55]. Furthermore, a combined effect on the intensity of pain and the function of the shoulder has been observed when laser therapy is used in conjunction with exercise in individuals diagnosed with subacromial impingement syndrome [60,61,62].

Kolu et al. discovered that a combination of transcutaneous nerve stimulation (TENS), ultrasound, and exercise yielded superior results compared to high-intensity laser therapy combined with a hot pack and exercise. This combination was found to be more effective in reducing pain and improving functionality in patients with chronic lumbar radiculopathy [65]. Moreover, the concurrent use of PBM with a static magnetic field or active electrical stimulation has demonstrated synergistic effects in alleviating pain intensity in individuals suffering from chronic neck pain [127]. Similarly, the effectiveness of LLLT in combination with ultrasound, exercise, or physiotherapy has been reported to exhibit robust synergistic therapeutic effects in treating shoulder tendonitis [57, 58] and tendinopathy [66, 68, 128].

A combination of laser therapy, chiropractic joint manipulation, ozone therapy, or exercise has been shown to effectively improve cervical flexion, lateral flexion, rotation, and pain disability in patients with cervical facet dysfunction, cervical disc herniation, or spondylosis, when compared to using only one of these treatments [69,70,71,72]. Moreover, the application of LLLT and piroxicam has demonstrated favorable outcomes in reducing the intensity of pain in individuals afflicted with temporomandibular joint arthralgia [73].

The utilization of both PBM and manual therapy has been discovered to effectively alleviate pain and jaw impairments, while also enhancing mandibular function in individuals diagnosed with temporomandibular disorders (TMD) [75]. Moreover, multiple studies have utilized a fusion of PBM and ultrasound therapy for TMD treatment. These studies have documented decreases in physical pain and psychological constraints, along with enhancements in quality of life [76,77,78]. Furthermore, a combination therapy of laser therapy and vacuum therapy has been found to result in pain relief and improvement of TMD joint motion [78]. Combining orofacial myofunctional therapy with PBM has demonstrated favorable results, including decreased pain in patients with TMD [129].

Furthermore, recent findings indicate that individuals suffering from fibromyalgia can experience positive outcomes in terms of decreased pain and enhanced psychological well-being, functional ability, and overall quality of life through the use of adjunct PBM therapy and exercise, or a combination of PBM and ultrasound [80,81,82,83]. Furthermore, the combination of laser therapy and ultrasound has been proven to effectively alleviate pain and decrease disability in individuals suffering from osteoarthritis [84].

Gavish et al. found that the efficacy of a combined treatment of LLLT and physiotherapy was superior to physiotherapy alone in managing anterior knee pain in patients. Furthermore, this beneficial effect persisted for a duration of 3 months post-treatment [85].

Paresis

The utilization of both LLLT and stellate ganglion block has demonstrated the ability to expedite the process of recuperation from facial paralysis[86]. Yamada et al. found that the use of both LLLT and corticosteroid therapy had a more significant impact on patients with facial palsy in the early stages of recovery compared to using either therapy alone [87]. The combined use of LLLT and facial exercise treatment has shown synergistic effects in patients with facial paralysis. This therapy has been found to enhance functional facial movements and reduce the time required for recovery [88].

Neuropathy

Combining LLLT with TENS has been shown to reduce pain scores and median nerve sensory latency, alleviate Phalen and Tinel signs, and enhance functionality in individuals with CTS [89]. Furthermore, a clinical trial validated that the utilization of a combination of a high-power laser (808 nm, 6.5 J/cm2) and TENS alleviated the intensity of pain and enhanced hand functionality in patients with CTS [93]. Dincer et al. found that the concurrent use of LLLT and splinting yielded superior results compared to individual therapies in terms of reducing pain scores and enhancing patient satisfaction [90]. Similarly, Fusakul et al. showed that the utilization of LLLT in conjunction with wrist splinting resulted in reduced pain scores, enhanced hand grip strength and pinch strength, and improved the functional status of individuals with CTS [92].

Nevertheless, a study indicated that the utilization of both kinesiotaping and LLLT in CTS did not exhibit superiority over LLLT alone in the immediate term (3 weeks). Over a period of 12 weeks, the combination of therapies yielded greater improvements in hand grip strength and finger pinch strength outcomes compared to individual therapy [94]. Bartkowiak et al. discovered that the use of LLLT at a wavelength of 830 nm and energy density of 9 J/cm2, along with nerve and tendon gliding exercises, significantly reduced sensory disturbances and pain scores in patients with CTS. Additionally, it improved hand grip strength and functionality. However, they found no additional advantage when comparing it to the combination of ultrasound with nerve and tendon gliding exercises [95].

Limitation

For this systematic review, some limitations should be highlighted. The lack of details about the parameters in some studies, hindered the possibility of meticulous evaluations. The heterogeneity in included disorders (CNS and PNS) exacerbated the exact focusing on each (made it difficult to focus on each specific disorder). Moreover, there was a limited number of CNS-related interventions in clinical studies. Also, the variation in combined treatment approaches resulted in a lack of uniformity in the data. The stimulation parameters used for performing PBM in the included disorders were not unified. Parameters such as wavelengths, frequency, pulse width, stimulation target, intensity, duration, and unilateral/bilateral treatment differed between the included studies. Due to these limitations, we could only assess the variety of combinations and the effect of key parameters on reported outcomes in the included studies. Another limitation was the moderate quality of the included studies, as assessed using a risk of bias assessment tool. The majority of studies had a pre-post design, were not randomized and blinded.

Despite the limitations of this systematic review, there were also several strengths that are important to mention. We conducted comprehensive research by including both animal and human studies that focused on PBM-combined methodologies which had not been previously mentioned.

Furthermore, we documented all potential combinations that were examined in prior investigations. Moreover, this systematic review covered a wide range of psychological and neurological disorders which is unique. Additionally, we considered multiple scientific databases, providing an overview that is as complete as possible.

Conclusion

This systematic review clearly demonstrates the therapeutic role of PBM combined therapies, as well as their potential to improve treatment efficacy and reduce side effects across a wide range of central and peripheral neurological disorders. This approach provides numerous research opportunities for studying the synergistic effects of combining PBM with other treatment modalities to optimize neural tissue stimulation by this technique. Also, this review listed the all-possible combinations that studied in previous preclinical and clinical researches. Given the significant heterogeneity in the combined treatment approaches and included disorders, additional studies are required to establish more consistent evidence of efficacy. These studies will provide guidance for the development of well-designed and successful clinical trials.