Device description and analysis

Although it does not seem to exist a clear tendency towards the use of a particular device for a particular application, some advantages and disadvantages from each category can be described.

Laser handpiece

Laser handpieces were the most featured devices across all records. These devices are simple and easy to handle by the operator, which can quickly and conveniently place the device in any area of the head. The small actuation area of these devices also allows a more precise treatment in the target location. On the downside, in most situations, the assistance of the operator is expected to correctly identify the desired site of actuation, as well as to position the handpiece in the correct place and to hold it during treatment, changing locations whenever needed. This implies that the assistance of a specialized third party is always required, which may affect the patient’s ability to perform treatments as needed, and the operator will be completely occupied by the task since they have to hold the handpiece.

Overall, the results of the studies using these devices showed an improvement of the symptoms for various diseases and positive findings in physiological characterization and cognitive function studies, except for two studies targeting stroke, that used NeuroThera® Laser System, in which there were no significant improvements in patients’ condition [55, 57]. The most used device was the Model CG-5000 Laser, with 19 reports, which was mostly used in physiological characterization and cognitive function studies. This device works on the highest range of wavelength covered in this review, 1064 nm, and it was used in continuous mode with a power output up to 3.5 W. Studies that use these parameters showed safety, negligible heat, and no physical damage [20, 29]. One study reported that the neuromodulation caused by PBM was not due to the heat generated during treatments [48]. Nonetheless, further studies are warranted to corroborate this finding. The reason why this device was frequently employed could be due to its wavelength, since reduced light scattering in the head tissues was demonstrated with this wavelength [10, 41, 51, 58].

LED clusters

LED clusters were the second most recurrent devices in the revised records, relating to six different devices. Generally, the actuation area of these devices is larger, which is useful for stimulating a greater area, being also more forgiving in placement. However, this can also be perceived as an issue when the stimulation of a smaller area is required. Usually, these devices use more than one LED cluster simultaneously, meaning that several regions of the brain can be stimulated at the same time.

Although these devices presuppose the assistance of an operator to hold them in place, several articles report the use of mechanisms, such as fabric covers, to keep the clusters in position during treatment and, thus, freeing the operator during the stimulation session, as opposed to the laser handpieces [18, 19, 30]. These devices were used for different health conditions, such as TBI, stroke, depression, Gulf War illness, and cognitive function deficits, showing positive improvements in cognitive function, as well as antidepressant effects, neuromodulation, and overall improvement of neurological symptoms. The most used LED cluster was the MedX Health Model 1100, relating to 6 reports. The most distinctive feature of this device is its versatility since it encompasses two or three LED clusters that can be applied simultaneously in different locations (e.g., its use for ear stimulation). It uses red (633 nm) and NIR (870 nm) light, broadening the possible stimulatory effects since articles report the efficiency of both wavelengths [3, 33].

Helmets

The helmet configuration presents another advantage that is lacking in the previous categories of devices; since the placement of the helmet is straightforward, it enables home use and autonomy of the patient. However, the device may fit differently in different patients, missing the intended areas for stimulation. One other advantage that may arise from this type of device is that distinct areas of the helmet can be turned on, at different times, to enable customized treatments. Nevertheless, only one article referenced the use of this feature, meaning that, although a possibility, it is not considered of significance in the use of such devices [14].

The application of helmet devices is associated with great power output values, which may cause overheating of the head tissues. Most articles report the use of a cooling system, usually with fans, to prevent this situation [39, 73, 80, 96]. For LED helmets, all articles showed improvements in many health conditions. Regarding the laser helmet, its use was not conveniently justified, and it does not appear to provide any advantage compared to LED helmets. Furthermore, the article in which this device was used investigated schizophrenia and showed no significant improvements in this condition [71]. The Cognitolite Transcranial Photomodulation System—a modular helmet comprised of several LED clusters, and the Thor photomedicine LED lined helmet, which is a metal structure encrusted with LEDs, were the most commonly reported LED helmets.

Localized helmets

Localized LED helmets relate to a specific type of device by the company Vielight®. The advantages of using these devices are their home use and simple positioning, similar to other helmets, but with the addition of a simple and lightweight design, and an intranasal LED. Even though this device was designed and is commercially available to enhance mental performance, it was used in 12 reports for eight different purposes, namely AD [105, 106], autism [99], cognitive function improvements [100, 104], dementia [26], Gulf War illness [101], PD [23], physiological characterisation [102], and TBI [103]. Overall, all articles showed clinical improvements, except one for cortical excitability, where the lack of success was attributed to the use of healthy and young subjects, as opposed to other similar studies which showed positive findings in older or neurological diseased subjects [102]. Also, another study focused on the improvement of TBI symptoms showed positive outcomes in only one subject, however, the authors state that it may be due to a placebo effect [103].

A downside of using these devices may be the specific locations of the LEDs and the inability to move the actuators as desired, which can limit their use for certain health conditions if the affected area of the brain to be stimulated does not coincide with the location of the LEDs.

LED headband

The LED headbands, which were used in a study dedicated to the improvement of cognitive function [93] and another for the improvement of anxiety symptoms [92], may be useful to stimulate wider areas. However, their design appears to be more focused on the forehead. Furthermore, one of the devices, the OEG-SpO2, was designed to be portable and can be placed by the user, which allows home use. Both reports showed positive findings in the scope of their studies [93].

Laser needles

The laser needles device by Weber Medical comprises four laser needles, each with a very small actuation area. In theory, this system allows the simultaneous stimulation of different locations, according to the placement of the needles. Nevertheless, the study that reported using this device placed the needles close together. This device encompasses a fixation system that frees the operator during the stimulation session, but it is a complex system to be applied at home by the patient alone. Also, the setup of this device is one of the most complex, as it requires the placement and fixation of each needle individually. Changing the stimulation site, for instance, will require more time compared to the other devices, which are simply placed in the actuation site. The study that used this device found neuroplastic changes after its use [72].

Intranasal

There were seven reports of intranasal devices used for brain PBM. One report relates to a light penetration study that used a laser intranasal device [37]. A study with demented patients used a Vielight® intranasal device as a complementary home treatment after sessions of PBM therapy in the clinic [26]. Regarding intranasal devices used individually, a study of blood conditions [32] used the BLOODCARE Medical Laser Device, and a PBM study with PD patients [33] used an intranasal LED. The remaining three reports concern simultaneous use of intranasal and transcranial devices for the treatment of Gulf War illness [14] and AD [25].

The main advantage of this type of device is the stimulation of the inner parts of the brain. These devices are portable and easy to use, however, they can be considered invasive. The Vielight® devices Neuro Alpha and Neuro Gamma include an intranasal LED, which was used in all 12 reports of these devices. The results of the studies which combined intranasal devices with transcranial devices cannot clearly be related to the use of intranasal devices solely, since studies for the same pathologies with only transcranial stimulation showed similar results, namely for the treatment of dementia [94], AD [24], and Gulf War illness [101]. However, solo intranasal devices led to improvements in signs of PD [33] and blood hemorheology behaviour [32].

From the 15 articles that described the simultaneous stimulation of transcranial and intranasal, eye, or ear stimulation, there is no clear difference arising from their combination, since similar studies also showed positive results when stimuli were applied individually. Thus, further studies which directly compare the sole use of intranasal, ear, and eye stimulation with their concomitant utilization with transcranial devices are warranted to determine its efficiency and necessity.

Moreover, there was no significant trend toward the use of LEDs or lasers since they were used in similar numbers, and there is no consensus if either one is preferable to the other. Cost may be a decisive factor as lasers are generally more expensive [107].

Table 3 presents an overview of the design, advantages, and disadvantages of each category of device, along with the most used device in each category.

Table 3 Comparison of device categoriesParameter analysis and condition relation

One of the purposes of this review was to understand if there were trends for the treatment of certain health conditions with brain PBM. It should be noted that the eight parameters initially established for the review were selected because they relate to a full characterisation of the stimulation, which is provided in 37 of the reviewed articles. However, it is possible to fully define the stimulation parameters with only the actuation site, area of actuation, power output, session time, mode of operation and wavelength. The purpose of comparing the reports for each of the eight parameters was to demonstrate the inconsistency of information, which often leaves the stimulation underdefined, and the need for standard methods of reporting PBM studies. Even though there are no clear indications for a standard treatment procedure for each condition, some trends can be pointed out.

Overall, the results of studies showed positive findings following the use of PBM, with no relevant difference due to the subjects’ sex, but a possible difference according to age and condition, a hypothesis raised from a study of cortical excitability in healthy volunteers [102].

Location of stimulation

Regarding stimulus location, the PFC is the most commonly stimulated region of the brain, with some articles mentioning the lack of hair in the forehead, and therefore, higher light penetration [39, 66, 76]. However, a substantial number of studies (e.g., those which used helmet devices) stimulated the scalp with hair and also showed beneficial outcomes, which means that the effect of hair in light penetration in head structures should be further investigated to understand if it has a significant effect. Furthermore, another advantage of the PFC as the PBM target location is that this region has a relevant role in the processing of simultaneous stimuli and thought, and in cognitive control, which explains its prevalent use in mental and physiological conditions [85, 108].

As previously mentioned, it was common for several regions of the brain to be stimulated simultaneously, especially in degenerative diseases and/or conditions, such as AD, PD, and dementia. For dementia and AD, which are associated with overall damage in cerebral structures and loss of neuronal communication, it appears reasonable that the whole head should be stimulated, since the damage is spread through the whole brain [109]. Regarding PD, deeper brain structures, such as the basal ganglia and hypothalamus, and back structures, such as the cerebellum and the brainstem, are affected, which justifies the broad placement of the stimulation since the aim is to reach deeper areas of the brain [110]. It is relevant to understand if the transcranial light can reach these depths, since a cadaver study demonstrated that light only penetrates up to 40 to 50 mm of the brain [38]. One study mentions the use of intraoral stimulation to better reach these internal structures, which may be a solution for this issue [28]. Additionally, Gulf War illness and schizophrenia also showed a trend in the stimulation of several regions, but the number of articles is reduced and, thus, this trend may be biased.

Wavelength

Concerning wavelength, 810 nm is the most widely used across all health conditions, with fluctuations from 808 to 850 nm. When red light is used, it is usually combined with NIR light, except in a LED helmet applied in PBM for PD patients [16], a LED device lacking a detailed description which was used to assess the effect of PBM in non-demented elderly women [79], and an intranasal LED device employed to treat generalized anxiety disorder [33], in which only red light was used for the stimulation.

The rationale behind the use of this wavelength is justified by its reduced absorption by the three major tissue chromophores (i.e., haemoglobin, melanin, and water), showing also effective absorption by the mitochondria, which is currently believed to be one of the mechanisms responsible for the effects of PBM on the brain [1,2,3, 77].

Nonetheless, a higher wavelength, namely 1064 nm, is more commonly used in physiological studies, specifically for cognitive function improvement and physiological characterisation, and in studies of fear and bipolar disorder. The use of this longer wavelength is associated to a deeper a penetration through the various head tissues. This characteristic is attributed to reduced scattering of photons in this wavelength. Studies show that even though this wavelength is not optimal for the known mitochondrial process behind the positive results of PBM, it still is produces this biological response [11, 111,112,113]. Additionally, there are some indications in literature that there is another mechanism activated by higher wavelengths, at light sensitive ion channels, but further research is required to establish the relevance and effectiveness of this mechanism [2]. Even so, the fact that this wavelength can reach deeper into the brain structures compensates for its lack of effect at the mitochondria, and some studies believe that this trade-off is actually beneficial and increases the positive results [10, 41, 51, 58].

Mode of operation

In the reported PBM studies for physiological characterization, light in continuous mode was the most used, whereas in studies of PBM in degenerative brain diseases, light in pulsed mode was more common. Among the included articles (n = 97), one study in AD patients compared both continuous and pulsed stimulation, observing that continuous stimulation caused a significant and large enhancement of neural activity in the gamma band [89]. One article assessing the effect of PBM in cortical excitability studied the use of pulsed NIR light in the 5 Hz, 10 Hz and 20 Hz frequencies, with a 50% duty cycle. This study noticed that not only low energy NIR stimulation changed the EEG signal when compared to the control group, but also that increasing frequency had a greater impact on brain activity, which may have a role in the improvement of memory [76].

Another article, which did not fit the initial inclusion criteria, compared the use of continuous or pulsed light in animal and human studies and concluded that pulsed light is more beneficial, especially for wound healing and post-stroke management [114]. Considering that there is no consensus on the mode of operation for the remaining health conditions, further studies are necessary to determine which mode of operation is more adequate for different circumstances.

Power density and power output

Power density was usually used at around 250 mW/cm2, especially in physiological conditions. Lower values were also applied, the lowest being 4 mW/cm2 for ear stimulation in a PBM study with Gulf War illness patients [14]. Studies investigating PBM in TBI, dementia, anxiety, severe disorder of consciousness and blood conditions explored power density values below 50 mW/cm2.

The highest recorded power density value was 800 mW/cm2, which was applied with a laser helmet, and a frequency of 75 Hz (20% duty cycle), in a study of PBM in schizophrenia patients [71]. Despite the high-power density values, no study reported negative side effects because of heat generated by light stimulation. As previously stated, helmet devices, which usually presented higher power values, were often combined with a cooling system to prevent this issue. High power values (10 to 13 W) were used in a PBM study with patients with TBI and related depression. This study utilized the laser handpieces LiteCure® LT1000 and Diowave 810 with a sweeping motion to avoid overheating, and patients reported a comfortable warm feeling during the sessions [59]. A study of the effects of PBM in AD patients used a laser handpiece Aspen diode laser, with power values between 5 and 25 W, oscillatory motion across the treatment site, fans, and pauses in treatment to maintain normal skin temperature [67]. These instances bring into discussion whether PBM treatments with higher power outputs can overheat the head tissues and cause damage. Even though these devices used cooling systems, it would be crucial to determine a safe threshold for power output per area (i.e., power density) to define a maximum power output value for future studies.

Table 4 presents a more detailed overview of the trends previously mentioned. The health conditions were subgrouped by category, namely degenerative, mental, physiological conditions, brain injury, or others, and the parameters provided are location, wavelength, mode of operation and power density, which are the most commonly reported, along with treatment time, which was already reported in Table 2. For each parameter and condition, the mode value is indicated. In cases where there were two modes or two values had close frequencies, both values are presented. NR refers to unreported values, which were considered in this analysis since, in several parameters, this was a significant number. When NR was the mode, the next value with greater frequency is also presented, when possible. When there was not a mode value, the whole range of values was presented. Energy density, energy per session and power output values were often not reported by the studies, and thus not considered.

Table 4 Target condition and parameter mode

Figure 4 depicts the brain regions stimulated, and thereby affected, by each type of condition. In some studies, the brain region being stimulated was not clear, and thus these cases were not included.

Fig. 4

Location of stimulation, condition, and device overview. Created with BioRender.com

Light penetration

Light penetration studies were focused on the wavelength and power values that enable more efficient light delivery to the targeted brain areas. One study detailed the use of continuous and pulsed light but did not show different results based on different modes of operation [38].

The wavelength used in studies assessing light penetration ranged between 633 and 970 nm, and power density between 35 and 700 mW/cm2. Light at 700 mW/cm2 and with 800 nm wavelength, can penetrate the skull, but with an attenuation greater than 95% [36]. Despite this power density value being higher than the values commonly reported in the articles under review, it has been proved to be safe for clinical use in major depressive disorder [22]. Furthermore, one study of PBM in schizophrenia patients used a higher power density value, namely 800 mW/cm2, and did not show significant improvement in cognitive impairment. However, the authors noted a declin