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- SPIE
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- 2329-423X
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- 2329-4248
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- 10.1117/1.NPh.5.1.011004
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Abstract
Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation measured by broadband near-infrared spectroscopy Xinlong Wang Divya D. Reddy Sahil S. Nalawade Suvra Pal F. Gonzalez-Lima Hanli Liu Xinlong Wang, Divya D. Reddy, Sahil S. Nalawade, Suvra Pal, F. Gonzalez-Lima, Hanli Liu, “Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation measured by broadband near-infrared spectroscopy,” Neurophoton. 5(1), 011004 (2017), doi: 10.1117/1.NPh.5.1.011004. Neurophotonics 5(1), 011004 (Jan–Mar 2018) Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation measured by broadband near-infrared spectroscopy a,† a,† a,† b c a, Xinlong Wang, Divya D. Reddy, Sahil S. Nalawade, Suvra Pal, F. Gonzalez-Lima, and Hanli Liu * University of Texas at Arlington, Department of Bioengineering, Arlington, Texas, United States University of Texas at Arlington, Department of Mathematics, Arlington, Texas, United States University of Texas at Austin, Department of Psychology and Institute for Neuroscience, Austin, Texas, United States Abstract. Transcranial infrared laser stimulation (TILS) has shown effectiveness in improving human cognition and was investigated using broadband near-infrared spectroscopy (bb-NIRS) in our previous study, but the effect of laser heating on the actual bb-NIRS measurements was not investigated. To address this potential confounding factor, 11 human participants were studied. First, we measured time-dependent temperature increases on forehead skin using clinical-grade thermometers following the TILS experimental protocol used in our previous study. Second, a subject-averaged, time-dependent temperature alteration curve was obtained, based on which a heat generator was controlled to induce the same temperature increase at the same forehead location that TILS was delivered on each participant. Third, the same bb-NIRS system was employed to monitor hemodynamic and metabolic changes of forehead tissue near the thermal stimu- lation site before, during, and after the heat stimulation. The results showed that cytochrome-c-oxidase of forehead tissue was not significantly modified by this heat stimulation. Significant differences in oxyhemoglo- bin, total hemoglobin, and differential hemoglobin concentrations were observed during the heat stimulation period versus the laser stimulation. The study demonstrated a transient hemodynamic effect of heat-based stimulation distinct to that of TILS. We concluded that the observed effects of TILS on cerebral hemodynamics and metabolism are not induced by heating the skin. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. [DOI: 10.1117/1.NPh.5.1.011004] Keywords: transcranial infrared laser stimulation; photobiomodulation; near-infrared spectroscopy; heat. Paper 17089SSR received Apr. 8, 2017; accepted for publication Aug. 10, 2017; published online Sep. 19, 2017. However, besides metabolic and hemodynamic effects on 1 Introduction cerebral tissues, TILS may generate non-negligible thermal The concept of using near-infrared or infrared light to modulate 9,10 effects that may confound the results of previous studies biological functions, also known as photobiomodulation (PBM), due to laser heating on the tissue. Up to now, while several has recently gained rising attention since it may serve as an beneficial effects of PBM have been reported for its therapeutic effective, noninvasive, interventional tool for multiple neural 15,16 1–4 use, the contribution of heat generated from near-infrared applications in the future. For example, transcranial infrared or infrared light toward any of the studied positive effects laser stimulation (TILS) with 1064-nm laser applied to the fore- has never been tested. In principle, continuous irradiance with head has served as a particular approach of brain PBM for laser or light-emitting diodes over a period of time at a particular improving human neurocognitive functions, such as attention, 4–8 region of interest would result in an accumulated thermal effect memory, and executive functions. A couple of mechanistic 9,10 and thus lead to an increase of skin or local temperature at studies on TILS were recently reported by Wang et al., sup- the stimulated region. Such a thermal effect could lead to porting the hypothesis that photons at 1064 nm oxidize local increases of blood flow and tissue oxygenation, which cytochrome c oxidase (CCO), the terminal enzyme in the could confound the association or interplay between metabolic mitochondrial respiratory chain. Light absorption of CCO 5,6 and hemodynamic effects induced by TILS. Specifically, it effectively contributes to oxygen and energy metabolism in was unclear whether our measured changes of oxyhemoglobin, neurons. TILS leads to upregulation of cerebral CCO and deoxyhemoglobin, and total-hemoglobin concentration (i.e., hemodynamics as well as increases in cerebral oxygen con- 9,10,13 Δ½HbO, Δ½HHb, and Δ½HbT) under TILS were induced sumption. The mechanism of TILS supported/discussed by the enhanced metabolism (i.e., increased oxidized CCO in Refs. 9 and 10 helps us understand the relationship between metabolic and hemodynamic changes, and provides a mecha- concentration, Δ½CCO) or by the TILS-produced thermal nistic explanation for beneficial neural effects of PBM and/or effect. The objective of this study was to quantitatively assess 5–8 TILS-induced thermal effects on metabolic and hemodynamic TILS in a number of medical conditions. changes of forehead tissue measured by broadband near-infrared spectroscopy (bb-NIRS), as well as to confirm/demonstrate the *Address all correspondence to: Hanli Liu, E-mail: hanli@uta.edu potential role of such thermal effects on hemodynamic changes of forehead tissue determined by bb-NIRS. Equal contribution Neurophotonics 011004-1 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . The experimental setup of a bb-NIRS system used for the 2 Materials and Methods previous TILS study is shown in Fig. 1; it was also utilized 2.1 Brief Review of Previous TILS Setup and in the current heat-effect study. Section 2.3 below will provide Measurements detailed information on the bb-NIRS setup and related param- eters chosen for bb-NIRS measurements. We recently reported that TILS could result in upregulation of cerebral CCO and hemodynamics as well as increases in cer- 9,10,13 2.2 Human Subjects Participated in TILS and ebral oxygen consumption. While details on TILS setup Thermal Experiments and experimental protocols were given in Refs. 9, 10, and 13, we briefly review related information on the TILS experi- Eleven healthy human subjects were recruited from the local mental setup and protocols here for the reader’s convenience. community of The University of Texas at Arlington (UTA) The laser used in our previous TILS studies was a 1064-nm with 31 13.7 years of age (i.e., average standard deviation) continuous wave laser device (HD Laser Model CG-5000, Cell in TILS and thermal experiments. The two sets of experiments Gen Therapeutics LLC, Dallas, Texas), which has been Food were carried out by two independent experimental designs with and Drug Administration (FDA) cleared for various uses in three visits (one visit for the TILS-induced effect and two visits 17,18 humans. The laser light was delivered from a handpiece for the heat-induced effects) of the same human participants. with a beam area of 13.6 cm . Since the laser was collimated, Prestudy screening was taken for each human participant during the laser beam’s size was kept approximately the same from each visit prior to the stimulation/data acquisition. The inclusion the laser aperture to the stimulation spot on the participant’s criteria included either sex, any ethnic background, and in an forehead. The laser power during TILS was kept ∼3.4 W with age range of 18 to 50 years old. The exclusion criteria included: a power density in the beam area of 0.25 W∕cm , the same as (1) diagnosed with a psychiatric disorder; (2) had history of a 4,5,9,10,13 that reported in previous studies. For the sham experi- neurological condition, or any brain injury, or violent behavior; ment, the laser power was reduced close to zero (i.e., 0.1 W) (3) had ever been institutionalized/imprisoned; (4) took any with a black cap covering the laser aperture. In this way, the long-term or short-term medicine; (5) was currently pregnant; sham stimulation seemed similar to the actual TILS but without and (6) was a smoker or had diabetes. any light delivered to the subject’s forehead. TILS-induced metabolic and hemodynamic responses were 4,5,10,13 Specifically, following previously successful studies, measured and reported earlier. The current study focused on heat-induced changes of metabolic and hemodynamic signals our safe laser stimulation parameters were as follows: on the forehead to determine whether thermal effects of TILS total laser power ¼ 3.4 W; area of laser beam radiation ¼ 2 2 2 would potentially confound PBM effects that we observed 13.6 cm ; power density ¼ 3.4 W∕13.6 cm ¼ 0.25 W∕cm ; previously. Specifically for the current thermal-effect study, time radiated per cycle ¼ 55 s; total laser energy per cycle ¼ the chosen individuals were assigned to participate in two sep- 3.4 W × 55 s ¼ 187 J∕cycle; total laser energy density 2 2 arate experiments done on the forehead: (1) skin-temperature per cycle ¼ 0.25 W∕cm ×55 s ¼ 13.75 J∕cm ∕cycle. The TILS recording under TILS and (2) thermal stimulation done at stimulation and measurement consisted of a 2-min baseline the same forehead location as that of TILS, together with bb- period, an 8-min laser stimulation period, followed by a 5-min 5,6 NIRS measures as in our previous studies. These two experi- recovery period. The stimulation site was on the right frontal ments were performed during two separate visits. Specifically, forehead above the eye brow (see Fig. 1). Within each minute, skin-temperature-recording experiments were performed for all the stimulation was on for 55 s and off for 5 s, when the participants within 1 week. After the subject-averaged time-de- bb-NIRS data acquisition was performed. pendent temperature curve was acquired, all subjects underwent thermal stimulation experiments on their foreheads in the following week. The experimental protocols adhered to National Institutes of Health (NIH) guidelines and were approved by the institutional review board (IRB) at UTA for ethical guidelines, which govern human experiments. Each participant received explanations of the instruments and procedures of the experiment. A written consent was taken from participants before the start of every experiment. 2.3 Experimental Setup and Instruments for Thermal Stimulation Measurements The entire experiment was divided into two different phases. The first phase was to measure the skin temperature increase Fig. 1 Schematic diagram of the experimental setup for TILS, includ- 9,10 by the laser that was used in studies by Wang et al. As illus- ing a bb-NIRS spectroscopic system. This bb-NIRS unit consisted of a tungsten-halogen lamp as the light source and a miniature CCD trated in Fig. 2, the laser used for the setup was a FDA-cleared 9,10 spectrometer as the detector. TILS was administered underneath 1064-nm laser device and also used before for laser stimu- the “I” shaped probe holder. The narrow, middle section of the holder lation. The uniform laser beam with an area of 13.6 cm was was ∼8 mm in width. A laptop computer was used to acquire, display, emitted from a safe distance of 2 cm from the handpiece during and save the data from the spectrometer. A shutter controlled the on the experiment. Collimation of the laser facilitated the size of and off function for the white light from the tungsten–halogen lamp to the laser beam at the stimulation area to be maintained as that the subject’s forehead. A pair of protection goggles was worn during the whole experimental procedure. emitted from the laser aperture. The laser power was maintained Neurophotonics 011004-2 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . Fig. 3 Schematic diagram of the experimental setup for the second Fig. 2 Schematic diagram of the experimental setup for the skin- phase of the experiment using a bb-NIRS monitoring system. The temperature recording experiment that included a temperature spectroscopic system consisted of a tungsten–halogen lamp as the measurement system (TempTraq™, Blue Spark Technologies, Inc., light source and a high-sensitive CCD spectrometer as the detector. Westlake, Ohio). The TempTraq unit/patch includes a small thermal Thermal stimulation was administered above the I-shaped probe sensor (5 × 5 mm ), as shown in the figure, and a temperature circuit holder, which held two optodes with 3 cm apart. A shutter was to determine the temperature value induced by TILS on the forehead used for switching the light delivery on and off from the lamp to skin surface. TILS was delivered on the right side of the TempTraq the participant’s forehead. The data from the spectrometer were patch, which was connected via Bluetooth to a mobile device. collected, saved, and displayed using a laptop computer. Protection goggles were worn by the participants during the entire experimental procedure. The bb-NIRS system consisted of a broadband light source (i.e., a tungsten-halogen lamp) having a spectral range of 400 to at a constant value of 3.4 W and laser power density in 1500 nm (Model 3900, Illumination Technologies Inc., East the laser beam was 0.25 W∕cm . The values of laser power Syracuse, New York), a high-sensitivity CCD spectrometer with and power density were chosen to replicate the experimental a spectral range of 735 to 1100 nm (QE-Pro, Ocean Optics Inc., 9,10 procedure conducted in previous studies so as to acquire Dunedin, Florida), and a laptop computer for data acquisition. the same TILS-induced temperature changes as before. Specifically, the light emitted from the light source was directed A thermal patch, TempTraq (hands-free temperature moni- through a multimode fiber optode (diameter ¼ 3mm) to the toring system) was used for measuring thermal readings near subject’s forehead. The diffused light from the forehead was col- the TILS delivery site (right forehead) continuously during the lected by another fiber optode with the same size to the bb-NIRS spectrometer. The two fiber bundles were held by a 3D-printed entire experiment. This patch was made with safe, soft, flexible, I-shaped holder very closed to the stimulation site (see Fig. 3). durable, water-resistant, and nonlatex materials (TempTraq , Each acquired optical signal was sent to the QE-Pro spectrom- Blue Spark Technologies, Inc., Westlake, Ohio). In general, eter and then converted to a spectrum of 735 to 1100 nm for TempTraq is Bluetooth enabled to pair itself to any iOS or further spectroscopic analysis. The laptop computer would dis- Android device for continuous monitoring of body temperature play and store the results for offline analysis and interpretation. within a range of 40 feet. The patch was placed on the clean and Details of the bb-NIRS system can also be found in Refs. 9 dry skin surface; we ensured that no hair was trapped beneath and 10. the patch. The thermally sensitive area (5 × 5mm ) on the patch was located near the TILS location (marked by blue-shaded area in online Fig. 2). The rest of the patch included the embedded 2.4 Experimental Protocols for Thermal Stimulation thermal detection circuit and the Bluetooth device (marked by Measurements gray-shaded area in online Fig. 2). The second phase of experiments was the thermal-stimula- 2.4.1 Forehead skin temperature recording in response to tion measurements using a thermal stimulator (Pathway model TILS ATS, Pain and Sensory Evaluation system, Medoc Advanced During each experiment in both measurement phases, the sub- Medical Systems, Israel), which was employed to simulate jects were comfortably seated, and procedures of the experi- TILS-induced thermal effects at the same location of TILS. ments were well explained. They were also asked to wear The temperature output of the thermal stimulator was set accord- protective glasses for safety purpose and were instructed to close ing to the forehead skin-temperature experiment in response to their eyes during the entire experimental procedure. The 1064- TILS. The equipment has a dimension of 103 cm × 52 cm × nm laser was used to stimulate the right forehead of each 62 cm. The stimulation area of the ATS Thermode (probe) subject, and the laser hand piece was held by a well-trained that came in contact with the skin surface was 16 × 16 mm. research assistant to deliver TILS. A temperature sensor The temperature range that could be achieved was from 0°C patch, TempTraq, was placed on the right forehead, close to to 55°C with an accuracy of 0.1°C. The rate of increase or the TILS site (see Fig. 2). The protocol and timeline used for decrease of the temperature could be programmed up to 8°C/ TILS remained the same as those given in Refs. 9 and 10.In s. As it is shown in Fig. 3, the ATS thermode of the Medoc path- order to achieve accurate TILS-induced, skin-temperature read- way was placed on a clean surface of the right forehead for ings, the thermal recording was on continuously during the delivering thermal stimulation. The thermal stimulator was entire TILS experiment. Then, time-dependent (averaged over placed in close proximity of a 3D-printed, “I”-shaped, probe 1 min) temperatures across the pre-, during-, and poststimula- holder, which held the source and detector fibers to measure tion period were calculated and are plotted in Fig. 4, outlining the metabolic and hemodynamic responses to thermal heating estimated skin temperatures near the light delivery site during equivalent to that induced by TILS. and after TILS. This time-dependent, thermal profile then Neurophotonics 011004-3 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . Fig. 5 Experimental paradigm of bb-NIRS data acquisition pre-, dur- Fig. 4 Forehead skin temperature increases during and post-TILS. It ing-, and postthermal stimulation delivered to the right forehead of displays local skin temperatures of the forehead near the TILS site. each subject. Each experiment consisted of 2-min baseline, 8-min The red curve with solid diamonds displays measured temperatures thermal stimulation, and 5-min recovery. The shutter for the light of the skin near the laser delivery site from the first phase (skin-tem- source was switched on for only 5 s during bb-NIRS data acquisition perature-recording) measurement. Each red solid diamond displays a in each minute. The thermal stimulation consisted of a gradual single mean value with standard deviation, averaged over 1 min of the increase in temperature from 32°C to 41°C during 3 min and a con- thermal data (also over n ¼ 11 participants). The blue lines without stant temperature at 41°C for 5 min. any symbols shows the thermal setting values on the thermal stimu- lator used in the second phase of the experiment. Time zero marks the starting time of TILS delivery. format as that in our recent study. Also, potential heating caused by the white light during the measurement period was was used to set the temperature setting on the thermal stimulator reduced by a short-pass optical filter, passing only wavelengths (Medoc pathway) to simulate TILS-induced thermal effects. The shorter than 1000 nm. The temperature used for thermal stimu- blue (seen in online version) lines in Fig. 4 mark the thermal lation was initiated at 32°C and was varied according to the ther- temperature setting that was used to create thermal stimulations mal variation pattern obtained in the first phase measurement, as in the second phase of the experiments, namely to measure met- marked by the blue lines in Fig. 4. Namely, the thermode tem- abolic and hemodynamic responses to thermal effects. perature was set to increase steadily during the first 3 min to reach 41°C and then to maintain unchanged for 5 min as thermal stimulation, followed by a prompt stop to the baseline temper- 2.4.2 Metabolic and hemodynamic responses to thermal ature, 32°C. stimulation 2.5 Data Processing and Statistical Analysis For the second phase of measurements, each participant was asked to relax without moving the head while reduced light scat- Based on the modified Beer–Lambert law, a multilinear tering coefficient (μ ) and absorption coefficient (μ ) of the fore- s a regression model was applied to the acquired spectral data head were measured with a frequency-domain tissue oximeter for estimations of Δ½HbO, Δ½HHb, and Δ½CCO in response (OxiplexTS, ISS Inc., Champaign, Illinois), as described in to thermal effects. Mathematical details on both the modified Refs. 9 and 10. After this set of optical property measurements, Beer–Lambert law and multilinear regression model can be an “I”-shaped, optical probe holder was fixed on the right fore- found in Refs. 9 and 10. Additionally, concentration changes head near the TILS delivery site illuminated in the first phase of total hemoglobin (Δ½HbT) and differential hemoglobin (skin-temperature-recording) study (see Figs. 2 and 3). The dis- (Δ½HbD) were estimated by Δ½HbT¼ Δ½HbOþ Δ½HHb tance between the source and detector fiber bundles in the holder and Δ½HbD¼ Δ½HbO − Δ½HHb, respectively, for all the 13 remained 3 cm (see Figs. 1 and 3), the same as that in the first time points. The data for each time point across all 11 subjects phase and an earlier study. The thermode that delivered thermal were averaged. Also, the standard deviation and standard error stimulation was placed in good contact with the skin of the right of mean were computed. Statistical analysis was then carried forehead, just right above the probe holder (see Fig. 3). A hos- out to determine statistically significant differences between pital-graded, double-sided tape together with Velcro stripes was the thermally induced and TILS-induced effects on Δ½HbO, also used to securely hold the thermode and the “I”-shaped holder Δ½HHb, Δ½HbT, Δ½HbD, and Δ½CCO using a repeated-mea- in place to minimize motion artifacts. sure ANOVA, followed by one-way ANOVAs with the level of The phase-two (i.e., thermal-stimulation measurements Bonferroni corrected significance of p < 0.05 (to account for recording) experimental protocol is illustrated in Fig. 5.The ther- multiple-time measurements) in order to identify significant mal stimulation setting consisted of three different periods: base- differences at individual time points, for each of the five line (prestimulation) for 2 min, thermal stimulation for 8 min, chromophore concentrations. and recovery (poststimulation) for 5 min, which followed the protocol we used in phase-one measurements and previous 3 Results 9,10 studies. The white-light source for bb-NIRS was kept “on” during the entire experiment while the shutter was switched 3.1 TILS-Induced, Time-Dependent Changes in “on” only during the five-second data acquisition period and Concentrations of CCO, HbO, HHb, “off” for the rest of the experiment to avoid the confounding HbT, and HbD thermal effect caused by the bb-NIRS white light, as schemati- cally shown in Fig. 5. The optical broadband spectra were Figure 6 illustrates changes in concentrations of HbO, HHb, acquired from the right forehead of each subject in the same HbT, HbD, and CCO over the entire experiment of 15 min, Neurophotonics 011004-4 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . Fig. 6 Participant–averaged time courses of TILS (laser) and heat stimulation (thermal) effects on changes in (a) [HbO], (b) [HHb], (c) [HbT], (d) [HbD], and (e) [CCO], measured in vivo from each par- ticipant’s forehead (mean SE, n ¼ 11). The initial time at t ¼ 0 marked the onset of the TILS/thermal stimulation. The shaded region in each subplot displays the stimulation period. The unit for all concen- tration changes is in μM. In each panel, “*” symbols mark statistical significance with p < 0.05 (Bonferroni corrected) between TILS-induced and heat-induced chromophore concentration changes, based on repeated measure ANOVA followed by one-way ANOVAs. including 2-min baseline, 8-min TILS/thermal stimulation, and Next, one way ANOVAs with Bonferroni correction, performed 5-min recovery. Figure 6(a) displays two time-dependent curves at each individual time point for each of the chromophore con- of Δ½HbO in response to TILS and thermal (heat) stimulation. centrations, presented that significant differences between heat- Note that the TILS-induced Δ½HbO values were reported pre- induced and TILS-induced changes in [HbO], [HbD], [HbT], viously in Ref. 9, but they are reused and replotted in this section and [CCO] started to appear 1 min, 1 min, 2 min, and 3 min for easy comparison. For each respective case, each data point after the stimulation, respectively, as marked in each panel of was averaged over all the subjects; the shaded region indicates Fig. 6. However, the repeated-measure ANOVA given on the the time period under either TILS or thermal stimulation. The time-dependent changes in [CCO] values showed that there initial time at t ¼ 0 marked the onset of the TILS/thermal stimu- was no significant difference in [CCO] changes with respect lation. Since the laser energy density (E) delivered to the fore- to that at 1 min after the heat stimulation. Based on the published 19,20 21 22 head can be defined as a product of the exposure time (t ) work by Tsuji et al., Soul et al., and Hupert et al., exposure and the laser power density (P), namely, E ¼ t × P, changes in [HbT] are directly linked to changes in tissue blood exposure the delivered stimulation dose is in proportion to the exposure volume (ΔTBV) while changes in [HbD] are associated to time, as marked in Fig. 6. All five panels in Fig. 6 present changes in tissue blood flow (ΔTBF). Hence, Figs. 6(c) and dose–response curves, showing the dependence of metabolic/ 6(d) imply that the heat-based thermal stimulation on the hemodynamic response parameters (i.e., Δ½CCO, Δ½HbO, human forehead resulted in significant changes in ΔTBV and Δ½HHb, Δ½HbT, and Δ½HbD) on the TILS or heat stimulation ΔTBF during the thermal stimulation period. dose over the entire experiment time course. Two other findings are worthwhile to point out: (1) all of the The repeated-measure ANOVA showed that either time or heat-induced hemodynamic decreases in Δ½HbO, Δ½HbD, and stimulation (i.e., thermal and laser) could create overall statis- Δ½HbT returned toward baseline within 2 to 3 min as soon as tical significance for each of four chromophore concentration the termination of thermal heating while the TILS-induced changes, namely, Δ½HbO, Δ½HbT, Δ½HbD and Δ½CCO. increases in both hemodynamic and metabolic (i.e., Δ½CCO) Neurophotonics 011004-5 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . measures stayed constant, without any clear trend to quickly versus Δ½HbO, and Δ½CCO versus Δ½HHb under the thermal go back to baseline during the 5-min poststimulation period. stimulation given on the forehead surface, although the heating/ (2) Figure 6(b) illustrates that heat-induced Δ½HHb did not cre- stimulation temperature followed exactly the thermal response ate any significant difference at any time point from those to the TILS (determined by the first phase measurements). As caused by TILS. shown clearly in Fig. 7(a), all Δ½HbO and Δ½HHb values dur- ing thermal stimulation lie within a lower range of Δ½CCO (see the solid diamonds and squares, respectively, in the figure), as 3.2 Dependence of Tissue Hemodynamic compared to a strong linear dependence of Δ½HbO on Δ½CCO Parameters on Thermal-Induced Metabolic under TILS (see the open diamonds in the figure). Figure 7(b) Changes also exhibits similar trends of no clear dependence of Δ½HbT and Δ½HbD on Δ½CCO (marked by solid circles and triangles, For better comparison, TILS- and heat-induced changes in respectively), during the entire thermal stimulation period. [HbO], [HHb], [HbT], and [HbD] were extracted, regrouped, and replotted in Fig. 7 to investigate/reveal the dependence of each hemodynamic parameter (i.e., Δ½HbO, Δ½HHb, 4 Discussion Δ½HbT, and Δ½HbD) of forehead tissue on the metabolic indi- cator (i.e., Δ½CCO) under the influence of TILS and/or thermal 4.1 Hemodynamic and Metabolic Responses of stimulation. The key observation is that distinct from the TILS Forehead Tissue to Thermal Stimulation case, no significant linear relationship existed between Δ½CCO In one of our recent studies, we clearly demonstrated that transcranial PBM by the 1064-nm laser gave rise to the upregu- lation of oxidized CCO concentrations and hemoglobin oxy- genation in vivo assessed/quantified by noninvasive bb-NIRS. However, it was not clear whether the measured signals were contaminated by potential thermal effects that could result from possible TILS-related laser heating on the human forehead. To address this concern, we designed a novel protocol that utilized the same bb-NIRS to quantify thermal effects caused by the laser heating. In this way, we were able to assess heat- generated metabolic and hemodynamic parameters in vivo for the first time. To simulate the same thermal effects created by the 1064-nm laser, a thermal sensor was calibrated and used to facilitate time-dependent, skin-temperature recording near the TILS delivery site (Fig. 2). Then, a computer-controlled thermal stimulator was carefully set to deliver the same thermal variation pattern as that during TILS (Fig. 3). By comparing the chromophore concentration changes caused by both TILS (as reported in Ref. 9) and heat stimulation, we successfully demonstrated the distinction between heat-induced and TILS- induced responses in the hemodynamic and metabolic signals, which enabled us to exclude the potential confounding effect due to laser heating to the subject’s forehead. Specifically, the experimental results shown in Fig. 6 clearly illustrated that transcranial Δ½HbO, Δ½HbT, and Δ½HbD dur- ing the 8-min heat stimulation decreased significantly, implying reduced blood oxygenation, blood flow, and blood volume at the measured site. All three of the altered hemodynamic parameters returned promptly to baseline after the heat stimulation was removed. The statistical analysis, based on a repeated measure ANOVA followed by one-way ANOVAs, revealed that TILS resulted in strong hemodynamic oxygenation and metabolism, whereas heat applied to the forehead, on the other hand, gener- Fig. 7 (a) Comparison of relationships between Δ½CCO versus ated cerebral hemodynamic effects distinct from those of TILS. Δ½HbO and Δ½CCO versus Δ½HHb across all subjects (n ¼ 11) Moreover, as shown in Fig. 7, no obvious linear interplay under TILS and thermal stimulation. The solid black diamonds and between hemodynamic and metabolic effects was observed solid tan squares show relationships of Δ½CCO versus Δ½HbO during and after pure thermal stimulation. and Δ½CCO versus Δ½HHb, respectively. Both open diamonds and While TILS-induced and thermally induced Δ½CCO squares symbolize TILS-induced Δ½CCO versus Δ½HbO and Δ½CCO versus Δ½HHb, respectively. (b) Comparison of relationships between changes showed significant differences, the statistical analysis Δ½CCO versus Δ½HbT and Δ½CCO versus Δ½HbD across all sub- revealed that heat stimulation could not make Δ½CCO signifi- jects (n ¼ 11) under thermal stimulation and TILS. The solid black cantly deviate from its initial onset value (i.e., 1 min after the circles and solid gray triangles illustrate the relationship of Δ½CCO heat stimulation) [Fig. 6(e)]. This observation implies that fore- versus Δ½HbT and Δ½CCO versus Δ½HbD, respectively. Both open head thermal stimulation over 8 min up to 41°C did not signifi- circles and triangles denote the TILS-induced relationships. Error cantly alter oxygen metabolism of forehead tissue, and thus bars were based on standard errors of means for each respective chromophore concentration. would not significantly affect/confound our previous results Neurophotonics 011004-6 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . and conclusions that TILS is able to upregulate CCO concen- thermal effects on hemodynamic and metabolic variations of trations and hemoglobin oxygenation in vivo in human forehead tissue. subjects. Another significant difference in forehead tissue Second, we were limited by the number of spectrometers (or responses to TILS and thermal stimulation is that both metabolic channels) used in this study, so we could not perform two-chan- and hemodynamic changes during post-TILS tended to stay for nel (for long- and short-separation) broadband NIRS measure- a longer duration of time while these respective parameters ments to simultaneously monitor hemodynamic and metabolic returned quickly back to their baselines as soon as the heat changes at different tissue depths on the human forehead. stimulation stopped (Fig. 6). This observation supports the state- Further upgrade on our instrumentation is needed for more ment that TILS is highly desirable for treating certain neurologi- comprehensive experiments to confirm our current findings. cal disorders because of its long-lasting after-effects. The heat intervention was observed to generate hemo- 5 Conclusion dynamic and metabolic changes in the distinct direction or trend with respect to TILS. Thus, it is possible that the actual In conclusion, we measured time-dependent temperature TILS-evoked changes in hemodynamic and metabolic enhance- increases on 11 subjects’ foreheads using clinical-grade ther- ment could be greater than being reported in Ref. 9 if appropri- mometers following the TILS experimental protocol used in ate calibrations were taken to compensate for the laser-heating our previous study. According to the broadband NIRS readings effect. on the same subjects, significant differences in hemodynamic and metabolic responses (i.e., ΔHbO, ΔHbT, ΔHbD, and ΔCCO) were observed between the heat-induced and laser- 4.2 Possible Explanation of Heat-Induced Changes induced effects on human foreheads. No obvious linear interplay in Hemodynamic Signals of Forehead Tissue between hemodynamic and metabolic effects was observed during and after pure thermal stimulation. The observations In principle, thermal heating on a subject’s forehead should indicated that the tissue–heat interaction exhibited distinct result in a temperature rise of forehead tissue, leading to the response patterns from those during the tissue–laser interac- dilation of blood vessels and increase of regional blood flow tion. This study overall demonstrated that the observed effects at the stimulation site. This would also give rise to increases of TILS on cerebral hemodynamics and metabolism are not of total hemoglobin concentrations in the local stimulation site. induced by heating the skin. However, the major temperature enhancement should happen only on the skin surface without affecting cerebral hemodynam- ics. Thus, any increase of tissue blood flow and blood volume Disclosures (i.e., ΔTBF and ΔTBV) would occur only at the heating site, The author(s) declared no potential conflicts of interest with driving more blood from nearby superficial layers and resulting respect to the research, authorship, and/or publication of this in decreases of ΔTBF and ΔTBV of nearby forehead tissue. article. Close inspection of Fig. 3 reveals that our bb-NIRS optodes interrogated a region of forehead tissue very adjacent to the heat-stimulation site. Thus, our observations on heat-induced References hemodynamic changes shown in Fig. 6 match well the afore- 1. F. Schiffer et al., “Psychological benefits 2 and 4 weeks after a single mentioned expectation. treatment with near infrared light to the forehead: a pilot study of While a 3-cm source–detector separation of bb-NIRS could 10 patients with major depression and anxiety,” Behav. Brain Funct. sense changes of hemodynamic signals in the cerebral regions, it 5, 46 (2009). measures all the signals coming from multiple layers below the 2. Y. Lampl et al., “Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety two optodes, including the scalp, skull, and cerebral regions. It is Trial-1 (NEST-1),” Stroke 38, 1843–1849 (2007). noted that bb-NIRS detects only changes with respect to a base- 3. J. C. Rojas and F. Gonzalez-Lima, “Neurological and psychological line. Thus, it is expected that contributions from the superficial applications of transcranial lasers and LEDs,” Biochem. Pharmacol. layers to the measured signals would become dominant if no or 86, 447–457 (2013). little change occured within the cerebral region. To confirm our 4. D. W. Barrett and F. Gonzalez-Lima, “Transcranial infrared laser stimu- expectation, a two-channel bb-NIRS system is needed with a lation produces beneficial cognitive and emotional effects in humans,” Neuroscience 230,13–23 (2013). short (1 cm) and long (>3cm) source–detector separation in 5. N. J. Blanco, W. T. Maddox, and F. Gonzalez-Lima, “Improving future studies, as pointed out in the following subsection. executive function using transcranial infrared laser stimulation,” J. Neuropsychol. 11(1), 14–25 (2017). 6. J. Hwang, D. M. Castelli, and F. Gonzalez-Lima, “Cognitive enhance- 4.3 Limitation of the Study and Future Work ment by transcranial laser stimulation and acute aerobic exercise,” Lasers Med. Sci. 31, 1151–1160 (2016). First, this heat-stimulation study did not include a placebo 7. S. G. Disner, C. G. Beevers, and F. Gonzalez-Lima, “Transcranial laser experiment with respect to thermal stimulation, assuming that stimulation as neuroenhancement for attention bias modification in there were no variations in any of the NIRS parameters over adults with elevated depression symptoms,” Brain Stimul. 9, 780–787 the baseline readings. This assumption may not be accurate (2016). 8. N. J. Blanco, C. L. Saucedo, and F. Gonzalez-Lima, “Transcranial infra- since cerebral hemodynamic signals (such as HbO, HHb, and red laser stimulation improves rule-based, but not information-integra- HbT) do fluctuate over time. Moreover, both bb-NIRS and ther- tion, category learning in humans,” Neurobiol. Learn. Mem. 139,69–75 mal probes placed on the subject’s forehead could give rise to (2017). time-dependent signal variations. All of these factors could 9. X. Wang et al., “Up-regulation of cerebral cytochrome-c-oxidase and confound the measured signals in the heat-stimulation group. hemodynamics by transcranial infrared laser stimulation: a broadband In our future studies, we will conduct placebo controlled experi- near-infrared spectroscopy study,” J. Cereb. Blood Flow Metab. ments in order to understand/reveal more rigorous/accurate 271678X17691783 (2017). Neurophotonics 011004-7 Jan–Mar 2018 Vol. 5(1) Wang et al.: Impact of heat on metabolic and hemodynamic changes in transcranial infrared laser stimulation. . . Divya D. Reddy received her bachelor of technology degree in 10. X. Wang et al., “Interplay between up-regulation of cytochrome-c- biomedical engineering from Dr. D. Y. Patil University, India, and pro- oxidase and hemoglobin oxygenation induced by near-infrared laser,” ceeded to work in a healthcare industry as an application specialist. Sci. Rep. 6, 30540 (2016). Being passionate about technology and research, she decided to pur- 11. D. Pastore, M. Greco, and S. Passarella, “Specific helium-neon laser sue further studies and graduated with MS degree in biomedical engi- sensitivity of the purified cytochrome c oxidase,” Int. J. Radiat. Biol. neering from the University of Texas, Arlington. Her research 76, 863–870 (2000). experience was in the field of near infrared spectroscopy, photobio- 12. M. T. Wong-Riley et al., “Photobiomodulation directly benefits primary modulation, tissue optics, signal and image processing. neurons functionally inactivated by toxins: role of cytochrome c oxidase,” J. Biol. Chem. 280, 4761–4771 (2005). Sahil S. Nalawade received his BE degree in biomedical engineering 13. F. Tian et al., “Transcranial laser stimulation improves human cerebral from Mumbai University, India, in May 2010. He received his MS oxygenation,” Lasers Surg. Med. 48, 343–349 (2016). degree in biomedical engineering from the University of Texas, 14. F. Gonzalez-Lima and A. Auchter, “Protection against neurodegener- Arlington. His research was focused on broadband near infrared ation with low-dose methylene blue and near-infrared light,” Front. spectroscopy and effects of thermal and laser stimulation on Cell Neurosci. 9, 179 (2015). human forehead. He has acquired skills in data acquisition, signal 15. P. Cassano et al., “Review of transcranial photobiomodulation for major processing, medical image processing, and data analysis. He was depressive disorder: targeting brain metabolism, inflammation, oxida- also the secretary of the Biomedical Engineering Student Society. tive stress, and neurogenesis,” Neurophotonics 3, 031404 (2016). 16. M. R. Hamblin, “Shining light on the head: photobiomodulation for Suvra Pal received his BSc and MSc degrees in statistics from the brain disorders,” BBA Clin. 6, 113–124 (2016). University of Calcutta, India, in 2006 and 2008, respectively, and his PhD in statistics from McMaster University, Ontario, Canada, in 2014. 17. R. T. Chow et al., “Efficacy of low-level laser therapy in the manage- He is currently an assistant professor in the Department of Mathe- ment of neck pain: a systematic review and meta-analysis of randomised matics at the University of Texas, Arlington, USA. He is a member placebo or active-treatment controlled trials,” Lancet 374, 1897–1908 of the American Statistical Association; his current research interests (2009). include survival analysis, cure rate modeling, and statistical inference. 18. J. D. Kingsley, T. Demchak, and R. Mathis, “Low-level laser therapy as a treatment for chronic pain,” Front. Physiol. 5, 306 (2014). F. Gonzalez-Lima is the George I. Sanchez Centennial Professor at 19. M. Tsuji et al., “Near infrared spectroscopy detects cerebral ischemia the University of Texas at Austin, and a leading researcher on brain during hypotension in piglets,” Pediatr. Res. 44, 591–595 (1998). energy metabolism, memory, and neurobehavioral disorders. He 20. M. Tsuji et al., “Cerebral intravascular oxygenation correlates with received his BS degree in biology, his BA degree in psychology from mean arterial pressure in critically ill premature infants,” Pediatrics Tulane University, New Orleans, and his PhD in anatomy and neuro- 106, 625–632 (2000). biology from the University of Puerto Rico School of Medicine. He 21. J. S. Soul et al., “Fluctuating pressure-passivity is common in the cer- received a Humboldt fellowship in neuroscience from Technical ebral circulation of sick premature infants,” Pediatr. Res 61, 467–473 University, Darmstadt, Germany. He is a fellow at the International (2007). Behavioral Neuroscience Society. In 2015, he received distinguished 22. T. J. Huppert et al., “A temporal comparison of BOLD, ASL, and Texas Scientist Award. His research has been funded for more NIRS hemodynamic responses to motor stimuli in adult humans,” than 30 years, and he has contributed more than 300 scientific Neuroimage 29, 368–382 (2006). publications. Hanli Liu received her MS and PhD degrees in physics from Wake Xinlong Wang received his BS degree in applied physics from Beijing Forest University, followed by postdoctoral training at the University of University of Technology, China. He received his PhD through BS Pennsylvania. She is a full professor of bioengineering and distin- to PhD program at the University of Texas (UT), Arlington, where guished university professor at the University of Texas, Arlington. he received the “Excellent Graduates” award. He is currently a post- She is also a fellow of American Institute for Medical and Biological doctoral fellow for a joint project among UT Arlington, UT Austin, Engineering. Her expertise lies in the field of near-infrared spectros- and UT Southwestern Medical Center at Dallas in the area of trans- copy of tissues, functional optical brain imaging, transcranial photo- cranial infrared photobiomodulation with multimode imaging and its biomodulation, and their clinical applications. applications. Neurophotonics 011004-8 Jan–Mar 2018 Vol. 5(1)
Journal
Neurophotonics – SPIE
Published: Jan 1, 2018