Analysis of Normal Retinal Nerve Fiber Layer Thickness by Age, Sex, and Race Using Spectral Domain Optical Coherence Tomography
Alasil T, Wang K, Keane PA, Lee H, Baniasadi N, Boer de JF, and Chen TC
Abstract:
Purpose: To determine the effects of age, sex, and race on the retinal nerve fiber layer (RNFL) in the normal human eye as measured by the spectral domain optical coherence tomography (SD-OCT) Spectralis machine (Heidelberg Engineering).
Methods: Peripapillary SD-OCT RNFL thickness measurements were determined in normal subjects seen at a university-based clinic. One randomly selected eye per subject was used for analysis in this cross-sectional study. Multiple regression analysis was applied to assess the effects of age, sex, ethnicity, and mean refractive error on peripapillary RNFL thickness. Results are expressed as means±SD wherever applicable.
Results: The study population consisted of 190 healthy participants from 9 to 86 years of age. Of the 190 participants, 62 (33%) were men, 125 (66%) Caucasians, 26 (14%) African Americans, 14 (7%) Hispanics, 16 (8%) Asians, and 9 (5%) other races. The mean RNFL thickness for the normal population studied was 97.3±9.6 µm. Normal RNFL thickness values follow the ISNT rule with decreasing RNFL thickness values starting from the thickest quadrant inferiorly to the thinnest quadrant temporally: inferior quadrant (126±15.8), superior quadrant (117.2±16.13), nasal quadrant (75±13.9), and temporal quadrant (70.6±10.8 µm). Thinner RNFL measurements were associated with older age (P<0.001); being Caucasian, versus being either Hispanic or Asian (P=0.02 and 0.009, respectively); or being more myopic (P<0.001). For every decade of increased age, mean RNFL thickness measured thinner by approximately 1.5 µm (95% confidence interval, 0.24-0.07). Comparisons between ethnic groups revealed that Caucasians had mean RNFL values (96±9.2 µm) slightly thinner than those of Hispanics (102.9±11 µm; P=0.02) or Asians (100.7±8.5 µm; P=0.009). African Americans RNFL values (99.2±10.2 µm) were not significantly different when compared with Caucasians. There was no relationship between RNFL thickness and sex.
Conclusions: The thickest RNFL measurements were found in the inferior quadrant, followed by the superior, nasal, and temporal quadrants (ISNT rule applied to the RNFL). Thinner RNFL measurements were associated with older age and increasing myopia. Caucasians tend to have thinner RNFL values when compared with Hispanics and Asians. SD-OCT analysis of the normal RNFL showed results similar to time domain OCT studies.
Abstract:
Purpose: To determine the effects of age, sex, and race on the retinal nerve fiber layer (RNFL) in the normal human eye as measured by the spectral domain optical coherence tomography (SD-OCT) Spectralis machine (Heidelberg Engineering).
Methods: Peripapillary SD-OCT RNFL thickness measurements were determined in normal subjects seen at a university-based clinic. One randomly selected eye per subject was used for analysis in this cross-sectional study. Multiple regression analysis was applied to assess the effects of age, sex, ethnicity, and mean refractive error on peripapillary RNFL thickness. Results are expressed as means±SD wherever applicable.
Results: The study population consisted of 190 healthy participants from 9 to 86 years of age. Of the 190 participants, 62 (33%) were men, 125 (66%) Caucasians, 26 (14%) African Americans, 14 (7%) Hispanics, 16 (8%) Asians, and 9 (5%) other races. The mean RNFL thickness for the normal population studied was 97.3±9.6 µm. Normal RNFL thickness values follow the ISNT rule with decreasing RNFL thickness values starting from the thickest quadrant inferiorly to the thinnest quadrant temporally: inferior quadrant (126±15.8), superior quadrant (117.2±16.13), nasal quadrant (75±13.9), and temporal quadrant (70.6±10.8 µm). Thinner RNFL measurements were associated with older age (P<0.001); being Caucasian, versus being either Hispanic or Asian (P=0.02 and 0.009, respectively); or being more myopic (P<0.001). For every decade of increased age, mean RNFL thickness measured thinner by approximately 1.5 µm (95% confidence interval, 0.24-0.07). Comparisons between ethnic groups revealed that Caucasians had mean RNFL values (96±9.2 µm) slightly thinner than those of Hispanics (102.9±11 µm; P=0.02) or Asians (100.7±8.5 µm; P=0.009). African Americans RNFL values (99.2±10.2 µm) were not significantly different when compared with Caucasians. There was no relationship between RNFL thickness and sex.
Conclusions: The thickest RNFL measurements were found in the inferior quadrant, followed by the superior, nasal, and temporal quadrants (ISNT rule applied to the RNFL). Thinner RNFL measurements were associated with older age and increasing myopia. Caucasians tend to have thinner RNFL values when compared with Hispanics and Asians. SD-OCT analysis of the normal RNFL showed results similar to time domain OCT studies.
Biomechanical Characterization of Keratoconus Corneas Ex Vivo with Brillouin Microscopy
Scarcelli G, Besner S, Pineda R, and Yun SH
Abstract:
PURPOSE:
Loss of corneal strength is a central feature of keratoconus progression. However, it is currently difficult to measure corneal mechanical changes noninvasively. The objective of this study is to evaluate if Brillouin optical microscopy can differentiate the mechanical properties of keratoconic corneas versus healthy corneas ex vivo.
METHODS:
We obtained eight tissue samples from healthy donor corneas used in Descemet's stripping endothelial keratoplasty (DSEK) and 10 advanced keratoconic corneas from patients undergoing deep anterior lamellar keratoplasty (DALK). Within 2 hours after surgery, a confocal Brillouin microscope using a monochromatic laser at 532 nm was used to map the Brillouin frequency shifts of the corneas.
RESULTS:
The mean Brillouin shift in the anterior 200 μm of the keratoconic corneas at the cone was measured to be 7.99 ± 0.10 GHz, significantly lower than 8.17 ± 0.06 GHz of the healthy corneas (P < 0.001). The Brillouin shift in the keratoconic corneas decreased with depth from the anterior toward posterior regions with a steeper slope than in the healthy corneas (P < 0.001). Within keratoconic corneas, the Brillouin shift in regions away from the apex of the cone was significantly higher than within the cone region (P < 0.001).
CONCLUSIONS:
Brillouin measurements revealed notable differences between healthy and keratoconic corneas. Importantly, Brillouin imaging showed that the mechanical loss is primarily concentrated within the area of the keratoconic cone. Outside the cone, the Brillouin shift was comparable with that of healthy corneas. The results demonstrate the potential of Brillouin microscopy for diagnosis and treatment monitoring of keratoconus.
Abstract:
PURPOSE:
Loss of corneal strength is a central feature of keratoconus progression. However, it is currently difficult to measure corneal mechanical changes noninvasively. The objective of this study is to evaluate if Brillouin optical microscopy can differentiate the mechanical properties of keratoconic corneas versus healthy corneas ex vivo.
METHODS:
We obtained eight tissue samples from healthy donor corneas used in Descemet's stripping endothelial keratoplasty (DSEK) and 10 advanced keratoconic corneas from patients undergoing deep anterior lamellar keratoplasty (DALK). Within 2 hours after surgery, a confocal Brillouin microscope using a monochromatic laser at 532 nm was used to map the Brillouin frequency shifts of the corneas.
RESULTS:
The mean Brillouin shift in the anterior 200 μm of the keratoconic corneas at the cone was measured to be 7.99 ± 0.10 GHz, significantly lower than 8.17 ± 0.06 GHz of the healthy corneas (P < 0.001). The Brillouin shift in the keratoconic corneas decreased with depth from the anterior toward posterior regions with a steeper slope than in the healthy corneas (P < 0.001). Within keratoconic corneas, the Brillouin shift in regions away from the apex of the cone was significantly higher than within the cone region (P < 0.001).
CONCLUSIONS:
Brillouin measurements revealed notable differences between healthy and keratoconic corneas. Importantly, Brillouin imaging showed that the mechanical loss is primarily concentrated within the area of the keratoconic cone. Outside the cone, the Brillouin shift was comparable with that of healthy corneas. The results demonstrate the potential of Brillouin microscopy for diagnosis and treatment monitoring of keratoconus.
Brillouin Microscopy of Collagen Crosslinking: Noncontact Depth-Dependent Analysis of Corneal Elastic Modulus
Scarcelli G, Kling S, Quijano E, Pineda R, Marcos S, and Yun SH
Abstract:
PURPOSE:
Corneal collagen crosslinking (CXL) is designed to halt the progression of keratoconus and corneal ectasia by inducing corneal stiffening. However, it currently is difficult to monitor and evaluate CXL outcome objectively due to the lack of suitable methods to characterize corneal mechanical properties. We validated noncontact Brillouin microscopy to quantify corneal mechanical properties before and after CXL.
METHODS:
CXL was performed on fresh porcine eyes using various presoaking times and light doses, with or without epithelial debridement. From Brillouin maps of corneal elastic modulus, stiffness and average modulus of anterior, middle, and posterior stroma were analyzed. Corneal stiffening index (CSI) was introduced as a metric to compare the mechanical efficacy of a given CXL protocol with respect to the standard protocol (30-minute riboflavin presoak, 3 mW/cm² ultraviolet illumination for 30 minutes).
RESULTS:
Brillouin corneal stiffness increased significantly (P < 0.001) by epi-off and epi-on CXL. The increase of Brillouin modulus was depth-dependent, indicating that anterior stromal stiffening contributes the most to mechanical outcome. The increase of anterior Brillouin modulus was linearly proportional to the light dose (R² > 0.98). Compared to the standard epi-off procedure, a typical epi-on procedure resulted in a third of stiffness increase in porcine corneas (CSI = 33).
CONCLUSIONS:
Brillouin microscopy allowed imaging and quantifying CXL-induced mechanical changes without contact in a depth-dependent manner at high spatial resolution. This technique may be useful to evaluate the mechanical outcomes of CXL procedures, to compare different crosslinking agents, and for real-time monitoring of CXL in clinical and experimental settings.
Abstract:
PURPOSE:
Corneal collagen crosslinking (CXL) is designed to halt the progression of keratoconus and corneal ectasia by inducing corneal stiffening. However, it currently is difficult to monitor and evaluate CXL outcome objectively due to the lack of suitable methods to characterize corneal mechanical properties. We validated noncontact Brillouin microscopy to quantify corneal mechanical properties before and after CXL.
METHODS:
CXL was performed on fresh porcine eyes using various presoaking times and light doses, with or without epithelial debridement. From Brillouin maps of corneal elastic modulus, stiffness and average modulus of anterior, middle, and posterior stroma were analyzed. Corneal stiffening index (CSI) was introduced as a metric to compare the mechanical efficacy of a given CXL protocol with respect to the standard protocol (30-minute riboflavin presoak, 3 mW/cm² ultraviolet illumination for 30 minutes).
RESULTS:
Brillouin corneal stiffness increased significantly (P < 0.001) by epi-off and epi-on CXL. The increase of Brillouin modulus was depth-dependent, indicating that anterior stromal stiffening contributes the most to mechanical outcome. The increase of anterior Brillouin modulus was linearly proportional to the light dose (R² > 0.98). Compared to the standard epi-off procedure, a typical epi-on procedure resulted in a third of stiffness increase in porcine corneas (CSI = 33).
CONCLUSIONS:
Brillouin microscopy allowed imaging and quantifying CXL-induced mechanical changes without contact in a depth-dependent manner at high spatial resolution. This technique may be useful to evaluate the mechanical outcomes of CXL procedures, to compare different crosslinking agents, and for real-time monitoring of CXL in clinical and experimental settings.
Correlation of Retinal Nerve Fiber Layer Thickness and Visual Fields in Glaucoma: A Broken Stick Model
Alasil T, Wang K, Yu F, Field MG, Lee H, Baniasadi N, Boer de JF, Coleman AL, and Chen TC
Abstract:
PURPOSE:
To determine the retinal nerve fiber layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss.
DESIGN:
Retrospective cross-sectional study.
METHODS:
Eighty-seven healthy and 108 glaucoma subjects (1 eye per subject) were recruited from an academic institution. All patients had VF examinations (Swedish Interactive Threshold Algorithm 24-2 test of the Humphrey Visual Field Analyzer 750i) and spectral-domain optical coherence tomography RNFL scans. Comparison of RNFL thickness values with VF threshold values showed a plateau of VF threshold values at high RNFL thickness values and then a sharp decrease at lower RNFL thickness values. A broken stick statistical analysis was used to estimate the tipping point at which RNFL thickness values are associated with VF defects. The slope for the association between structure and function was computed for data above and below the tipping point.
RESULTS:
The mean RNFL thickness value that was associated with initial VF loss was 89 μm. The superior RNFL thickness value that was associated with initial corresponding inferior VF loss was 100 μm. The inferior RNFL thickness value that was associated with initial corresponding superior VF loss was 73 μm. The differences between all the slopes above and below the aforementioned tipping points were statistically significant (P < .001).
CONCLUSIONS:
In open-angle glaucoma, substantial RNFL thinning or structural loss appears to be necessary before functional visual field defects become detectable.
Abstract:
PURPOSE:
To determine the retinal nerve fiber layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss.
DESIGN:
Retrospective cross-sectional study.
METHODS:
Eighty-seven healthy and 108 glaucoma subjects (1 eye per subject) were recruited from an academic institution. All patients had VF examinations (Swedish Interactive Threshold Algorithm 24-2 test of the Humphrey Visual Field Analyzer 750i) and spectral-domain optical coherence tomography RNFL scans. Comparison of RNFL thickness values with VF threshold values showed a plateau of VF threshold values at high RNFL thickness values and then a sharp decrease at lower RNFL thickness values. A broken stick statistical analysis was used to estimate the tipping point at which RNFL thickness values are associated with VF defects. The slope for the association between structure and function was computed for data above and below the tipping point.
RESULTS:
The mean RNFL thickness value that was associated with initial VF loss was 89 μm. The superior RNFL thickness value that was associated with initial corresponding inferior VF loss was 100 μm. The inferior RNFL thickness value that was associated with initial corresponding superior VF loss was 73 μm. The differences between all the slopes above and below the aforementioned tipping points were statistically significant (P < .001).
CONCLUSIONS:
In open-angle glaucoma, substantial RNFL thinning or structural loss appears to be necessary before functional visual field defects become detectable.
Design and Characterization of an Optimized Simultaneous Color and Near-Infrared Fluorescence Rigid Endoscopic Imaging System
Venugopal V, Park M, Ashitate Y, Neacsu F, Kettenring F, Frangioni JV, Gangadharan SP, and Gioux S
Abstract:
We report the design, characterization, and validation of an optimized simultaneous color and near-infrared (NIR) fluorescence rigid endoscopic imaging system for minimally invasive surgery. This system is optimized for illumination and collection of NIR wavelengths allowing the simultaneous acquisition of both color and NIR fluorescence at frame rates higher than 6.8 fps with high sensitivity. The system employs a custom 10-mm diameter rigid endoscope optimized for NIR transmission. A dual-channel light source compatible with the constraints of an endoscope was built and includes a plasma source for white light illumination and NIR laser diodes for fluorescence excitation. A prism-based 2-CCD camera was customized for simultaneous color and NIR detection with a highly efficient filtration scheme for fluorescence imaging of both 700- and 800-nm emission dyes. The performance characterization studies indicate that the endoscope can efficiently detect fluorescence signal from both indocyanine green and methylene blue in dimethyl sulfoxide at the concentrations of 100 to 185 nM depending on the background optical properties. Finally, we performed the validation of this imaging system in vivo during a minimally invasive procedure for thoracic sentinel lymph node mapping in a porcine model.
Abstract:
We report the design, characterization, and validation of an optimized simultaneous color and near-infrared (NIR) fluorescence rigid endoscopic imaging system for minimally invasive surgery. This system is optimized for illumination and collection of NIR wavelengths allowing the simultaneous acquisition of both color and NIR fluorescence at frame rates higher than 6.8 fps with high sensitivity. The system employs a custom 10-mm diameter rigid endoscope optimized for NIR transmission. A dual-channel light source compatible with the constraints of an endoscope was built and includes a plasma source for white light illumination and NIR laser diodes for fluorescence excitation. A prism-based 2-CCD camera was customized for simultaneous color and NIR detection with a highly efficient filtration scheme for fluorescence imaging of both 700- and 800-nm emission dyes. The performance characterization studies indicate that the endoscope can efficiently detect fluorescence signal from both indocyanine green and methylene blue in dimethyl sulfoxide at the concentrations of 100 to 185 nM depending on the background optical properties. Finally, we performed the validation of this imaging system in vivo during a minimally invasive procedure for thoracic sentinel lymph node mapping in a porcine model.
Diagnostic Capability of Peripapillary Retinal Thickness in Glaucoma using 3D Volume Scans
Simavli H, Que CJ, Akduman M, Rizzo JL, Tsikata E, Boer de JF, and Chen TC
Abstract:
PURPOSE:
To determine the diagnostic capability of spectral-domain optical coherence tomography (SD OCT) peripapillary retinal thickness (RT) measurements from 3-dimensional (3D) volume scans for primary open-angle glaucoma (POAG).
DESIGN:
Cross-sectional study.
METHODS:
setting: Institutional. study population: 156 patients (89 POAG and 67 normal subjects). observation procedures: One eye of each subject was included. SD OCT peripapillary RT values from 3D volume scans were calculated for 4 quadrants of 3 different sized annuli. Peripapillary retinal nerve fiber layer (RNFL) thickness values were also determined. main outcome measures: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios.
RESULTS:
The top 5 RT AUROCs for all glaucoma patients and for a subset of early glaucoma patients were for the inferior quadrant of outer circumpapillary annulus of circular grid (OCA) 1 (0.959, 0.939), inferior quadrant of OCA2 (0.945, 0.921), superior quadrant of OCA1 (0.890, 0.811), inferior quadrant of OCA3 (0.887, 0.854), and superior quadrant of OCA2 (0.879, 0.807). Smaller RT annuli OCA1 and OCA2 consistently showed better diagnostic performance than the larger RT annulus OCA3. For both RNFL and RT measurements, best AUROC values were found for inferior RT OCA1 and OCA2, followed by inferior and overall RNFL thickness.
CONCLUSION:
Peripapillary RT measurements from 3D volume scans showed excellent diagnostic performance for detecting both glaucoma and early glaucoma patients. Peripapillary RT values have the same or better diagnostic capability compared to peripapillary RNFL thickness measurements, while also having fewer algorithm errors.
Abstract:
PURPOSE:
To determine the diagnostic capability of spectral-domain optical coherence tomography (SD OCT) peripapillary retinal thickness (RT) measurements from 3-dimensional (3D) volume scans for primary open-angle glaucoma (POAG).
DESIGN:
Cross-sectional study.
METHODS:
setting: Institutional. study population: 156 patients (89 POAG and 67 normal subjects). observation procedures: One eye of each subject was included. SD OCT peripapillary RT values from 3D volume scans were calculated for 4 quadrants of 3 different sized annuli. Peripapillary retinal nerve fiber layer (RNFL) thickness values were also determined. main outcome measures: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios.
RESULTS:
The top 5 RT AUROCs for all glaucoma patients and for a subset of early glaucoma patients were for the inferior quadrant of outer circumpapillary annulus of circular grid (OCA) 1 (0.959, 0.939), inferior quadrant of OCA2 (0.945, 0.921), superior quadrant of OCA1 (0.890, 0.811), inferior quadrant of OCA3 (0.887, 0.854), and superior quadrant of OCA2 (0.879, 0.807). Smaller RT annuli OCA1 and OCA2 consistently showed better diagnostic performance than the larger RT annulus OCA3. For both RNFL and RT measurements, best AUROC values were found for inferior RT OCA1 and OCA2, followed by inferior and overall RNFL thickness.
CONCLUSION:
Peripapillary RT measurements from 3D volume scans showed excellent diagnostic performance for detecting both glaucoma and early glaucoma patients. Peripapillary RT values have the same or better diagnostic capability compared to peripapillary RNFL thickness measurements, while also having fewer algorithm errors.
Etalon Filters for Brillouin Microscopy of Highly scattering Tissues
Shao P, Besner S, Zhang J, Scarcelli G, and Yun SH
Abstract:
Brillouin imaging of turbid biological tissues requires an effective rejection of the background noise due to elastic scattering of probe laser light. We have developed a narrowband spectral notch filter based on a pair of a free-space Fabry-Perot etalon and a mirror. The etalon filter in a 4-pass configuration is able to suppress elastically-scattered laser light with a high extinction ratio of > 40 dB and transmit inelastically-scattered light in a frequency shift range of 2-14 GHz with only 2 dB insertion loss. We also describe a simple etalon that enables us to use semiconductor diode laser sources for Brillouin microscopy by removing spontaneous emission noise. Using a clinically-viable Brillouin microscope employing these filters, we demonstrate the first Brillouin confocal imaging of the sclera and conjunctiva of the porcine eye.
Abstract:
Brillouin imaging of turbid biological tissues requires an effective rejection of the background noise due to elastic scattering of probe laser light. We have developed a narrowband spectral notch filter based on a pair of a free-space Fabry-Perot etalon and a mirror. The etalon filter in a 4-pass configuration is able to suppress elastically-scattered laser light with a high extinction ratio of > 40 dB and transmit inelastically-scattered light in a frequency shift range of 2-14 GHz with only 2 dB insertion loss. We also describe a simple etalon that enables us to use semiconductor diode laser sources for Brillouin microscopy by removing spontaneous emission noise. Using a clinically-viable Brillouin microscope employing these filters, we demonstrate the first Brillouin confocal imaging of the sclera and conjunctiva of the porcine eye.
Evidence for Brain Glial Activation in Chronic Pain Patients
Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji RR, Riley M, Wasan AD, Zürcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, and Hooker JM
Abstract:
Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.
Abstract:
Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.