July 2012
Volume 53, Issue 8
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Physiology and Pharmacology  |   July 2012
Comparison of Choroidal and Optic Nerve Head Blood Flow Regulation during Changes in Ocular Perfusion Pressure
Author Affiliations & Notes
  • Doreen Schmidl
    From the Department of Clinical Pharmacology and the
  • Agnes Boltz
    From the Department of Clinical Pharmacology and the
    Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
  • Semira Kaya
    From the Department of Clinical Pharmacology and the
  • Rene Werkmeister
    Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
  • Nikolaus Dragostinoff
    Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
  • Michael Lasta
    From the Department of Clinical Pharmacology and the
  • Elzbieta Polska
    From the Department of Clinical Pharmacology and the
  • Gerhard Garhöfer
    From the Department of Clinical Pharmacology and the
  • Leopold Schmetterer
    From the Department of Clinical Pharmacology and the
    Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
Investigative Ophthalmology & Visual Science July 2012, Vol.53, 4337-4346. doi:10.1167/iovs.11-9055
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      Doreen Schmidl, Agnes Boltz, Semira Kaya, Rene Werkmeister, Nikolaus Dragostinoff, Michael Lasta, Elzbieta Polska, Gerhard Garhöfer, Leopold Schmetterer; Comparison of Choroidal and Optic Nerve Head Blood Flow Regulation during Changes in Ocular Perfusion Pressure. Invest. Ophthalmol. Vis. Sci. 2012;53(8):4337-4346. doi: 10.1167/iovs.11-9055.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: We compared the response of choroidal and optic nerve head blood flow (ChBF, ONHBF) in response to an increase in ocular perfusion pressure (OPP) during isometric exercise and during a decrease in OPP during an artificial increase in intraocular pressure (IOP).

Methods.: We included 96 healthy subjects in our study. In 48 subjects OPP was increased by 6 minutes of squatting, and either ONHBF (n = 24) or ChBF (n = 24) was measured continuously. In 48 other healthy subjects either ONHBF (n = 24) or ChBF (n = 24) was measured continuously during a period of artificial increase in IOP using a suction cup. All blood flow measurements were done using laser Doppler flowmetry.

Results.: During all experiments the response in blood flow was less pronounced than the response in OPP, indicating for flow regulation. During isometric exercise ChBF regulated better than ONHBF (P = 0.023). During artificial IOP increase ONHBF regulated better than ChBF (P = 0.001). Inter-individual variability in blood flow responses was high. During squatting ONHBF decreased considerably below baseline ONHBF when OPP fluctuated in 3 subjects, although OPP still was much higher than at baseline. This phenomenon was not observed in the choroid.

Conclusions.: Our data indicate that regulation of ChBF and ONHBF during changes in OPP is different and complex. In some subjects performing squatting, considerable ONHBF reductions were observed during OPP fluctuations, although OPP still was high. Whether this predisposes to ocular disease remains unclear.

Introduction
Autoregulation is defined as the ability of a vascular bed to keep blood flow constant when perfusion pressure is changed. The classic theory of autoregulation assumes that the vascular bed changes its resistance via vasoconstriction or vasodilatation when perfusion pressure either increases or decreases. 1 This model, however, applies to isolated organs and ocular blood flow regulation in vivo appears to be more complex. 15  
Several studies over the recent years have investigated the regulation of choroidal blood flow (ChBF) using laser Doppler flowmetry (LDF) in humans. During changes in ocular perfusion pressure (OPP) some regulatory capacity has been observed during an increase and decrease in OPP. 516 Alterations of the response in ChBF have been observed in smokers 17 and vasospastics, 18 as was well as in patients with diabetic retinopathy, 19 central serous chorioretinopathy, 20 age-related macular degeneration, 21 and glaucoma. 22  
By contrast only few studies have investigated optic nerve head blood flow (ONHBF) during changes in OPP. 2328 The aim of our study was to extend our understanding of ONHBF regulation during changes in OPP. Accordingly, we studied blood flow in the optic nerve head (ONH) during an increase in OPP as induced by isometric exercise, as well as during a decrease in OPP as induced by an artificial increase in intraocular pressure (IOP). In addition, we investigated ChBF during the same procedures and compared the response in the two vascular beds. This was done in an effort to characterize the full regulatory range of the ONH and the choroid when OPP is manipulated. 
Materials and Methods
Our study was performed in adherence with the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines. The study protocol was approved by the Ethics Committee of the Medical University of Vienna. A total of 96 healthy subjects aged 19–35 years participated in this study. The nature of the study was explained to all subjects and they gave written consent to participate. Each subject passed a screening examination, including medical history and physical examination as well as 12-lead electrocardiogram. Subjects were excluded if any abnormality was found as part of the pretreatment screening unless the investigators considered the abnormality to be clinically irrelevant. Moreover, an ophthalmic examination, including slit-lamp biomicroscopy, indirect funduscopy, and applanation tonometry, was performed. Inclusion criteria were normal ophthalmic findings, ametropia of less than 3 diopters, anisometropia of less than 1 diopter and IOP <20 mm Hg. 
Experimental Design
Of the 96 volunteers included in these studies 24 participated in the experiments on ONHBF during isometric exercise, 24 participated in the experiments on ChBF during isometric exercise, 24 participated in the experiments on ONHBF during IOP increase, and 24 participated in the experiments on ChBF during IOP increase. The time course of the experiments was identical for ChBF and ONHBF studies. All measurements were performed after a resting period of at least 20 minutes in a sitting position. Stability of blood pressure and pulse rate was verified by repeated measurements before the actual experiments were started. 
During the isometric exercise experiments a 3-minute continuous baseline recording of either ChBF or ONHBF was scheduled. Thereafter, the isometric exercise stimulation period was started and subjects had to squat for 6 minutes. This period of isometric exercise consisted of squatting in a position where the upper and the lower legs formed approximately a right angle to increase mean arterial blood pressure. Subjects were first sitting on a chair for baseline measurement. When the squatting period was started the chair was removed carefully and the subject under study was asked not to change her/his position. The investigator who removed the chair was standing behind the subject who performed squatting for security reasons. During this squatting period continuous measurement of either ChBF or ONHBF was performed. At the end of the squatting period IOP was measured again. Blood pressure and pulse rate were assessed every minute throughout these experiments. 
During IOP increase experiments ChBF or ONHBF also was measured continuously for three minutes at baseline. Then, the suction cup was applied using a suction force of 50 mm Hg. When the suction cup was applied, the subject was not able to fixate the laser beam for approximately 10–15 seconds. The investigator who fixed the suction cup was standing next to the subject during the whole experiment to control the adequate position of the cup of the sclera. The suction force was increased in three consecutive steps to 75, 100, and 125 mm Hg. Each suction level was maintained for 1 minute during which ChBF or ONHBF was measured continuously. After a resting period of at least 30 minutes, another identical suction cup period was scheduled that exactly followed the time course of the first suction cup period. However, instead of blood flow measurements, IOP was assessed at each suction cup level using applanation tonometry. 
In 1 subject the measurements of ONH blood flow during isometric exercise were repeated on 3 different study days to assess the reproducibility of the measurements. 
Measurements
Systemic Hemodynamics
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP) were monitored on the upper arm by an automated oscillometric device. Pulse rate (PR) was recorded automatically from a finger pulse-oximetric device (HP-CMS patient monitor; Hewlett Packard, Palo Alto, CA). The performance of this system has been reported previously. 29  
Laser Doppler Flowmetry
Continuous measurements of ChBF and ONHBF were performed by laser Doppler flowmetry as described previously. 3032 With this technique, the vascularized tissue is illuminated by coherent laser light. Light scattered by the moving red blood cells undergoes a frequency shift. In contrast, static tissue scatterers do not change the light frequency, but lead to randomization of light directions impinging on red blood cells. Hence, red blood cells receive light from numerous random directions. As the frequency shift is dependent not only on the velocity of the moving red blood cells, but also on the angle between the incident and the scattered light, scattering of the light in tissue broadens the Doppler shift power spectrum. From this spectrum hemodynamic parameters can be determined based on a theory of light scattering in tissue. Blood flow parameters obtained included blood flow, velocity, and volume. Velocity is the mean velocity of the red blood cells moving in the sampled tissue proportional to the mean Doppler frequency shift. Volume is the number of moving red blood cells in the sampled tissue proportional to the amount of Doppler shifted light. Blood flow was calculated as the product of velocity and volume. Only data with a direct current (DC) value of ±15% to the baseline value were included for analysis. 
In our study, a compact laser Doppler flowmeter, which has been described in detail previously, 33,34 was used for the ChBF measurements. Measurements were performed in the fovea by asking the subject to fixate directly at the beam. The fovea was chosen, because the retina is avascular in this region. For the measurements of ONHBF a fundus-camera based system was used. 30 The laser beam was directed towards the temporal neurovascular rim. Care was taken to avoid that any visible vessels were within the scattering volume. During all experiments LDF measurements were done by 2 investigators. One investigator controlled the relative position of the instrument to the subjects' eye and adequate fixation. The second investigator controlled the signal on the computer. 
Intraocular Pressure
A slit-lamp mounted Goldmann applanation tonometer was used to measure IOP. Before each measurement, one drop of 0.4% benoxinate hydrochloride combined with 0.25% sodium fluorescein was used for local anesthesia of the cornea. 
Suction Cup Method
The IOP was raised applying a method described by Ulrich and Ulrich. 35 In our study we used an automatic suction pump that is connected by plastic tubing to a rigid plastic suction cup. After topically applied local anesthesia, a standardized 11 mm diameter suction cup was placed on the temporal sclera with the anterior edge at least 1 mm from the limbus. The vacuum was increased incrementally from 50 to 125 mm Hg. 
Data Analysis
Ocular perfusion pressure was calculated as OPP = 2/3 × MAP – IOP. 36 All blood flow values measured at OPP below 10 mm Hg were excluded from statistical analysis because of problems in LDF signal analysis at very low flow rates as discussed in detail by Riva et al. 23 During the IOP elevation experiments OPP was calculated using the IOP data that were measured during the second suction cup period. This was done because it is impossible to measure IOP and blood flow concomitantly. However, we have shown, in a pilot experiment (unpublished data, n = 8), that after a resting period of 30 minutes IOP data during application of a suction cup are well reproducible and have returned to baseline. During isometric exercise we obtained IOP levels at the beginning and end of each squatting period. From these data the IOP values during every single minute of squatting were calculated using linear regression analysis. We have shown in pilot experiments that this approach estimates actual IOP during isometric exercise with errors of less than 1 mm Hg (unpublished data, n = 8). 
A repeated measures ANOVA model was used to analyze data. Data during the IOP increase and squatting were analyzed separately. For both analyses the ONHBF and the ChBF data were included in one model. Accordingly, the repeated measures ANOVA model during IOP increase included 10 values for each dependent variable (n = 48), and the model during squatting included 14 values for each dependent variable (n = 48). Differences between the subjects undergoing the ONHBF and ChBF experiments were calculated based on the interaction between time and treatment. Post hoc analyses were done using planned comparisons. For this purpose the time effect was used to characterize the effect of IOP increase and squatting on the outcome parameters. 
In addition, pressure-flow relationships were calculated. For this purpose the data were expressed as percentage change in OPP and flow values over baseline. The OPP values then were sorted according to ascending values and grouped into 6 groups. Therefore, for the squatting experiments 24 values were considered in each group. As such, the first group consisted of those pressure-flow data with the smallest OPP increase, whereas the sixth groups consisted of the pressure-flow data with the largest OPP increase. For the IOP experiments, the number of values was slightly different for the ONH and choroidal experiments, because values with an OPP <10 mm Hg were not included. Accordingly the number of values obtained for ChBF was 14 in the first 2 groups and 13 in groups 3–6. The number of values obtained for ONHBF was 14 in the first 5 groups and 13 in group 6. Again, the first data point consisted of those pressure-flow data with the smallest OPP decrease, whereas the sixth groups consisted of the pressure-flow data with the largest OPP decrease. A statistically significant deviation from baseline flow was defined when the 95% confidence interval (CI) did not overlap with the baseline value any more. 
For data description percentage changes over baseline were calculated. A P value < 0.05 was considered the level of significance. Statistical analysis was performed using CSS Statistica for Windows (Version 6.0; Statsoft Inc., Tulsa, CA). 
Results
Isometric Exercise Data
The baseline characteristics of the subjects are presented in Table 1. No significant differences were found between the groups. No statistical comparison was done between ONHBF and ChBF values, because laser Doppler flowmetry measures blood flow in arbitrary units only. 32 All participating subjects finished the study as scheduled and no adverse reactions were observed. 
Table 1. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Isometric Exercise Experiments (n = 48, mean ± SD)
Table 1. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Isometric Exercise Experiments (n = 48, mean ± SD)
Choroidal Blood Flow Experiments (N = 24) ONH Blood Flow Experiments (N = 24) P Value
Age (y) 23.6 ± 3.1 24.7 ± 2.9 0.20
Sex (M/F) 12/12 12/12 1.00
SBP (mm Hg) 118.2 ± 6.1 119.4 ± 8.0 0.61
DBP (mm Hg) 58.2 ± 4.8 59.1 ± 6.5 0.51
MAP (mm Hg) 77.0 ± 5.0 78.5 ± 7.0 0.43
PR (beats per minute) 67.2 ± 6.4 71.7 ± 10.1 0.07
IOP (mm Hg) 14.0 ± 2.4 14.0 ± 2.3 1.00
OPP (mm Hg) 37.3 ± 3.6 38.3 ± 5.2 0.47
Flow (arbitrary units) 28.5 ± 5.8 20.4 ± 3.7 *
The effect of isometric exercise on MAP and PR is shown in Figure 1. As expected, a highly significant increase in MAP and PR was seen during the ONH and choroidal experiments (P < 0.001 versus baseline each). However, the response was not significantly different between the 2 groups (MAP P = 0.60, PR P = 0.062). No effect of isometric exercise on IOP was observed (P = 0.99, data not shown). Figure 2 shows a sample measurement of ChBF during isometric exercise. Figure 3 depicts the response in OPP as well as the response in flow during isometric exercise. As expected, OPP increased significantly during squatting (P < 0.001 versus baseline each). The response in flow was significantly different between the choroid and ONH (P = 0.023) with a less pronounced increase in the choroid. 
Figure 1. 
 
Effect of squatting on MAP and PR. Data are shown separately for the squatting periods during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 1. 
 
Effect of squatting on MAP and PR. Data are shown separately for the squatting periods during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 2. 
 
Measurements of ChBF (FLOW) during an increase in ocular perfusion pressure during squatting and an artificial IOP increase. The DC signal also is shown. For better visibility the first 100 seconds of baseline recordings are not shown.
Figure 2. 
 
Measurements of ChBF (FLOW) during an increase in ocular perfusion pressure during squatting and an artificial IOP increase. The DC signal also is shown. For better visibility the first 100 seconds of baseline recordings are not shown.
Figure 3. 
 
Effect of squatting on OPP and flow. Squatting periods are shown separately for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 3. 
 
Effect of squatting on OPP and flow. Squatting periods are shown separately for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 4 depicts the pressure-flow relationship during isometric exercise for the ONH. At OPP values of 66% above baseline, ONHBF values were not significantly different from baseline. Thereafter, ONHBF values increased almost linearly. Figure 5 shows the pressure-flow relationship during isometric exercise for the choroid. At OPP values of 70% above baseline, ChBF values were not significantly different from baseline. An almost linear increase in ChBF was found thereafter. 
Figure 4. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 4. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 5. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 5. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figures 35 also show that the error bars for ONHBF generally are larger than for ChBF data. This becomes clear when looking into individual OPP and flow data during the experiments. Figure 6 shows 3 data sets from individual subjects participating in the ONHBF experiments. In these subjects OPP did not rise continuously during the 6-minute squatting period, but showed some fluctuations. This was not an unusual behavior in the experiments because subjects get exhausted and change their position slightly, associated with a temporary reduction in blood pressure. In the graphs in Figures 6A and 6B, this was the case at minute 6 of isometric exercise, whereas in Figure 6C this was the case at minutes 2 and 3. Although during these transient periods OPP still was higher than at baseline, ONHBF values decreased below baseline values. This drop in ONHBF was pronounced and as high as −33% in one subject (Fig. 6C). Figure 7 shows 3 individual traces (Figs. 7A–C) obtained in the ChBF experiments where fluctuations in OPP also were visible. In the graph in Figure 7A, this was the case at minutes 5 and 6 of isometric exercise, in Figure 7B this was the case at minute 4, and in Figure 7C this phenomenon was seen at minutes 3 and 4. Unlike in the cases presented for ONHBF in Figure 6, ChBF did not decrease below baseline in any case during the temporal decrease in OPP. In Figure 8 the ONHBF response is shown for 1 subject presented in Figure 6, when experiments were repeated on 3 study days. On the second study day there was no temporal drop in OPP and, accordingly, no drop in ONHBF. On the third study day, however, OPP decreased slightly at minute 6, which again was associated with a decrease in ONH blood flow below baseline. 
Figure 6. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 3 healthy subjects (A, B, C). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 6. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 3 healthy subjects (A, B, C). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 7. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during isometric exercise in 3 healthy subjects (top, middle, bottom). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 7. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during isometric exercise in 3 healthy subjects (top, middle, bottom). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 8. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 1 healthy subject on 3 study days (day 1 also is presented in Fig. 6). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 8. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 1 healthy subject on 3 study days (day 1 also is presented in Fig. 6). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Data during Artificial IOP Increase
The baseline characteristics of the subjects are presented in Table 2. No significant differences were found between the groups. All participating subjects finished the study as scheduled and only mild conjunctival redness was seen in the subjects after the application of the suction cup. 
Table 2. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Experiments during IOP Elevation (n = 48, mean ± SD)
Table 2. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Experiments during IOP Elevation (n = 48, mean ± SD)
Choroidal Blood Flow Experiments (N = 24) ONH Blood Flow Experiments (N = 24) P Value
Age (y) 22.5 ± 3.0 23.5 ± 3.1 0.13
Sex (M/F) 12/12 12/12 1.00
SBP (mm Hg) 116.7 ± 7.5 117.7 ± 8.0 0.61
DBP (mm Hg) 56.3 ± 6.2 57.2 ± 7.1 0.43
MAP (mm Hg) 76.2 ± 6.2 77.5 ± 7.2 0.54
PR (beats per minute) 68.6 ± 9.7 65.3 ± 11.6 0.40
IOP (mm Hg) 14.6 ± 2.1 13.4 ± 2.3 0.80
OPP (mm Hg) 36.6 ± 4.0 38.3 ± 5.2 0.12
Flow (arbitrary units) 26.3 ± 4.5 21.0 ± 4.1 *
Figure 9 presents the change in IOP and MAP during application of the suction cup. As expected, IOP increased significantly (P < 0.001 versus baseline each), but the response was comparable during ChBF and ONHBF experiments (P = 0.94). Application of the suction cup neither changed MAP (P = 0.16 between groups) nor PR (data not shown, P = 0.93). A sample measurement of ChBF during the increase in IOP is shown in Figure 2. Changes in OPP and flow during artificial IOP increase are shown in Figure 10. The response of OPP to an artificial increase in IOP was comparable between subjects participating in ChBF and ONHBF experiments (P = 0.716). By contrast, the response in ONHBF was significantly less pronounced than the decrease in ChBF when IOP was elevated (P = 0.001). Looking into the results presented in Figure 10, this difference is due mainly to a different behavior at moderate OPP reductions. Whereas at the lowest level of IOP elevation ONHBF almost remained constant versus baseline, ChBF showed a decline already. This also is reflected in the pressure-flow curves presented for ONHBF and ChBF in Figures 11 and 12, respectively. Whereas ONHBF was not different from baseline at an OPP decrease of 29%, ChBF was constant only until an OPP decrease of 15%. Nevertheless ChBF also showed some degree of blood flow regulation during an IOP increase, because the percentage change in flow was less pronounced than the percentage change in OPP. 
Figure 9. 
 
Effect of an artificial IOP increase on IOP and MAP. Data are shown separately for the artificial IOP increase during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 9. 
 
Effect of an artificial IOP increase on IOP and MAP. Data are shown separately for the artificial IOP increase during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 10. 
 
Effect of an IOP increase on OPP and flow. Data are shown separately for the artificial IOP increase for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 10. 
 
Effect of an IOP increase on OPP and flow. Data are shown separately for the artificial IOP increase for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 11. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 11. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 12. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 12. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Again, it is interesting to look into some individual data obtained as shown for the ONH in Figure 13 and the choroid in Figure 14. The data shown in Figure 13A indicate that, in this individual, ONHBF regulation during an IOP increase is almost absent, because the flow and OPP values are almost parallel. The individual data shown in Figures 13B and 13C show another pattern. ONHBF starts to decline at the third and second IOP step, respectively. Interestingly, subjects also were identified that showed very little regulation of ChBF during an increase in IOP, as shown in Figure 14B. Other subjects, however, showed a clear pattern of blood flow regulation and ChBF almost stayed constant until the third IOP elevation period (examples are presented in Figs. 14A, 14C). 
Figure 13. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 13. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 14. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 14. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Discussion
It has been suggested that open angle glaucoma may be associated with abnormal ONHBF and various excellent reviews on this topic have been published. 3739 A recent study, however, correctly pointed out that generally our knowledge on ONHBF regulation is limited. 40 Indeed, when looking into the literature, most of the published data arise from studies measuring either retinal or choroidal blood flow. 1,41 As such, we set out to investigate ONHBF during an increase and decrease in OPP, and compare data to those obtained in the choroid. 
Our study indicated significant differences between the regulatory behavior in ONHBF and ChBF when OPP was modified experimentally. When OPP was increased ChBF regulated better than ONHF. Our results are in good agreement with previous smaller scale studies in which the pressure-flow relationship was studied in humans. 6,25,42 To our knowledge, the only study that investigated ONHBF during exercise-induced changes in OPP did not report OPP values at which the upper level of autoregulation is reached, because the maximum increase that was achieved was 30% only. 25 Our results when IOP was increased also are in good agreement with previously reported data. 7,14,23,24 Generally both vascular beds showed some degree of regulation, which was more pronounced in the ONH than in the choroid, particularly at moderate IOP elevations. In the choroid no classic autoregulatory behavior was found, which assumes that there is an autoregulatory plateau until the lower limit of autoregulation and a linear decline thereafter. 1 Nevertheless our results are in good agreement with our previous studies 14 suggesting some degree of ChBF regulation during IOP increase, because the decline in OPP is more pronounced than the decline in flow. Previous studies 23, 24 in the ONH reported blood flow to be constant until IOP values of 40–45 mm Hg. In our study the lower limit of autoregulation already was reached at lower values of IOP (30–35 mm Hg), but the extremely wide inter-individual variability in this response must be taken into account (Fig. 13). 
When interpreting our results, the considerable differences between the vasculature of the ONH and the choroid must be considered. 4345 The anterior ONH is supplied from arterioles in the adjacent retina. The vasculature in this region is not under neural control and, as such, dominated by myogenic and metabolic mechanisms when OPP is changed. As discussed in more detail below, it appears that most of the laser Doppler signal from the ONH arises from these pre-laminar regions. 46 The post-laminar ONH is nourished by branches of the posterior ciliary arteries either directly or via the circle of Zinn-Haller. It has been hypothesized that astrocytes have a role in blood flow regulation in the ONH 44 as they do in other parts of the central nervous system. 47,48 However, the direct experimental evidence for a role of astrocytes in regulating blood flow in the ONH is weak. 
By contrast, the capillaries in the choroid are of relatively large diameter (20–40 μm) and fenestrated. The choroid shows rich parasympathetic, sympathetic, and sensory innervation. In addition, intrinsic choroidal neurons are present, which receive parasympathetic and sympathetic innervation. These intrinsic choroidal neurons are assumed to have a role in choroidal blood flow regulation, and stain positive for NADPH-diaphorase and/or neuronal nitric oxide synthase (nNOS). 49,50 This is well compatible with our previous results that NOS inhibition modulates the choroidal pressure-flow relationship during isometric exercise, 8 and that NO from endothelial and neuronal sources has a key role in choroidal blood flow regulation. 51,52  
Neuronal input also may explain the finding that ChBF regulates better than ONHBF during isometric exercise. Exercise induces activation of mechanically and chemically sensitive skeletal muscle receptors, which are responsible for adjusting sympathetic and parasympathetic nerve activity. This is assumed to regulate ChBF during isometric exercise via unknown pathways, although neither propranolol nor atropine modified the choroidal pressure-flow relationship during isometric exercise. 10  
In addition to the neural control, regulation of blood flow during changes in perfusion pressure is assumed to be achieved via a complex interplay of myogenic and metabolic factors. 1 The myogenic response is activated when intraluminal pressure changes, resulting in pressure-dependent membrane depolarization associated with changes in lumen diameter. This effect is endothelium independent and involves the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) via the arachidonic acid pathway in the brain. 53 For a long time it has been assumed that the myogenic response is present in the ONH but not in the choroid. 41,54,55 More recently, this concept was challenged by animal experiments in the rabbit, which showed autoregulatory behavior compatible with myogenic control of choroidal perfusion during mechanical changes in OPP. 24,5658  
The contribution of metabolic and myogenic mechanisms in autoregulatory responses in the brain still is a matter of debate, 5961 and the situation is even more unclear for the eye. 1 Usually, it is assumed that the upper and lower levels of autoregulation are reached when maximum vasoconstriction and vasodilatation are achieved, respectively. This concept does, however, not apply to the ONH, because we have shown previously that, even below the lower level of autoregulation, the vasodilator response to flicker-stimulation is maintained fully. 28 Our results again indicated that ONHBF regulation during OPP modulation is complex and shows wide inter-individual variability (Figs. 6, 13). Indeed, autoregulation was almost absent in some subjects. 
An interesting observation of our study is that in some subjects ONHBF fell below baseline levels during OPP fluctuations, although absolute OPP was considerably higher than at baseline, a phenomenon that was not seen in the choroidal experiments (Figs. 6, 7). This points against a purely myogenic mechanism of blood flow regulation in the ONH during isometric exercise. The reason for this abnormal transient decrease in ONHBF is unknown. Data in 1 subject on 3 study days indicated that this effect is reproducible when OPP shows a temporal decrease, but further studies currently are designed to study this effect in more detail. Our previous results in the choroid showed considerably good intra-individual reproducibility, which allowed us to perform several double-masked, placebo-controlled studies on the mechanisms underlying this response. 8,10,1316 It is striking to speculate that subjects showing ONHBF reduction during OPP fluctuations as well as the subjects showing little evidence of ONH autoregulation in face of an IOP increase are predisposed for ischemic ocular disease. This also holds true for glaucoma, where low OPP has been identified as a risk factor, 62 and abnormal autoregulation may predispose for ischemic periods during fluctuations in MAP or IOP. Experimental data are required to test this hypothesis. 
A number of limitations must be considered when interpreting the results of our studies. Obviously different subjects start at different blood pressure and IOP levels during these studies. As such, pressure-flow relationships were drawn using the relative change over baseline. When looking into these figures, it also must be kept in mind that, particularly at higher OPPs, data often arrive from a few subjects only, because the degree of MAP increase during isometric exercise varies considerably. In addition, data arise from different time points after the initiation of the stimuli and, as such, do not consider adaption of flow to altered OPP with time constants in the order of minutes. This is an inherent limitation of all approaches investigating static autoregulation and highlights that in vivo not all aspects of autoregulation can be studied. 60 Other limitations apply to LDF as the method of assessing blood flow in the ONH and choroid, reflecting that a gold standard method of measuring blood flow in the human eye is not available. 32,6365 A complete discussion of this topic is beyond the scope of our article, but can be found in a recent review. 32 In the choroid, one must consider that only subfoveal blood flow was assessed. Given that the neural input as well as the distribution of intrinsic choroidal neurons shows considerable regional variability, 43 the data most likely are not representative for the entire choroid. In principle, such data may be obtained using peripheral LDF measurements in humans, 66 but to the best of our knowledge they have never been studied. In the ONH the signal appears to be dominated by the pre-laminar vasculature and cannot be applied to the deeper structures. However, a method for studying this important vascular bed has not been realized so far. 44 In addition, it is unclear to which degree re-distribution of blood flow has a role in ONH blood flow autoregulation. This question obviously cannot be answered by our study because single-point LDF was used at one position of the ONH only. 
In conclusion, our data indicated complex behavior of blood flow regulation in the ONH and the choroid that significantly deviated from our traditional view of autoregulation. During an isometric exercise-induced increase in OPP the choroid regulated better than the ONH, whereas during an IOP elevation-induced decrease in OPP the ONH regulated better than the choroid. These results may be related to the rich neural input into the choroid, but also to the complex interplay of myogenic and metabolic mechanisms when blood flow is regulated during OPP changes. In the ONH the inter-individual variability in responses was high. During IOP elevation some subjects showed almost no ONHBF regulation. During isometric exercise ONHBF fell below baseline values when OPP fluctuated, although OPP values at these time points still were considerably above baseline. It is striking to speculate that these subjects are at risk for ischemic ONH disease, but further studies are required to support this hypothesis. 
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Footnotes
 Supported by Austrian Science Fund (FWF), Projects P15970 and P21406, Christian Doppler Laboratory for Laser Development and their Application in Medicine.
Footnotes
 Disclosure: D. Schmidl, None; A. Boltz, None; S. Kaya, None; R. Werkmeister, None; N. Dragostinoff, None; M. Lasta, None; E. Polska, None; G. Garhöfer, None; L. Schmetterer, None
Figure 1. 
 
Effect of squatting on MAP and PR. Data are shown separately for the squatting periods during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 1. 
 
Effect of squatting on MAP and PR. Data are shown separately for the squatting periods during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 2. 
 
Measurements of ChBF (FLOW) during an increase in ocular perfusion pressure during squatting and an artificial IOP increase. The DC signal also is shown. For better visibility the first 100 seconds of baseline recordings are not shown.
Figure 2. 
 
Measurements of ChBF (FLOW) during an increase in ocular perfusion pressure during squatting and an artificial IOP increase. The DC signal also is shown. For better visibility the first 100 seconds of baseline recordings are not shown.
Figure 3. 
 
Effect of squatting on OPP and flow. Squatting periods are shown separately for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 3. 
 
Effect of squatting on OPP and flow. Squatting periods are shown separately for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 4. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 4. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 5. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 5. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during isometric exercise. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 6. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 3 healthy subjects (A, B, C). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 6. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 3 healthy subjects (A, B, C). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 7. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during isometric exercise in 3 healthy subjects (top, middle, bottom). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 7. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during isometric exercise in 3 healthy subjects (top, middle, bottom). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 8. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 1 healthy subject on 3 study days (day 1 also is presented in Fig. 6). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 8. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during isometric exercise in 1 healthy subject on 3 study days (day 1 also is presented in Fig. 6). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 9. 
 
Effect of an artificial IOP increase on IOP and MAP. Data are shown separately for the artificial IOP increase during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 9. 
 
Effect of an artificial IOP increase on IOP and MAP. Data are shown separately for the artificial IOP increase during choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as absolute values (means ± SD).
Figure 10. 
 
Effect of an IOP increase on OPP and flow. Data are shown separately for the artificial IOP increase for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 10. 
 
Effect of an IOP increase on OPP and flow. Data are shown separately for the artificial IOP increase for choroidal (n = 24, solid up triangles) and ONH experiments (n = 24, open squares). Data are presented as percentage change from baseline (means ± SD). *Significant differences between the choroidal and ONH experiments.
Figure 11. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 11. 
 
Pressure-flow relationship for ONHBF (FLOW; n = 24, open squares) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ONHBF.
Figure 12. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 12. 
 
Pressure-flow relationship for ChBF (FLOW; n = 24, solid up triangles) during an increase in IOP. Data are sorted according to ascending OPP values, and the means as well as the 95% CIs are shown. *Significant changes from baseline ChBF.
Figure 13. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 13. 
 
Individual traces of OPP (solid circles) and ONHBF (FLOW, open squares) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ONHBF values.
Figure 14. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Figure 14. 
 
Individual traces of OPP (solid circles) and ChBF (FLOW, solid up triangles) during an increase in IOP in 3 healthy subjects (AC). The left y-axis scales OPP values and the right y-axis scales ChBF values.
Table 1. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Isometric Exercise Experiments (n = 48, mean ± SD)
Table 1. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Isometric Exercise Experiments (n = 48, mean ± SD)
Choroidal Blood Flow Experiments (N = 24) ONH Blood Flow Experiments (N = 24) P Value
Age (y) 23.6 ± 3.1 24.7 ± 2.9 0.20
Sex (M/F) 12/12 12/12 1.00
SBP (mm Hg) 118.2 ± 6.1 119.4 ± 8.0 0.61
DBP (mm Hg) 58.2 ± 4.8 59.1 ± 6.5 0.51
MAP (mm Hg) 77.0 ± 5.0 78.5 ± 7.0 0.43
PR (beats per minute) 67.2 ± 6.4 71.7 ± 10.1 0.07
IOP (mm Hg) 14.0 ± 2.4 14.0 ± 2.3 1.00
OPP (mm Hg) 37.3 ± 3.6 38.3 ± 5.2 0.47
Flow (arbitrary units) 28.5 ± 5.8 20.4 ± 3.7 *
Table 2. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Experiments during IOP Elevation (n = 48, mean ± SD)
Table 2. 
 
Demographic and Baseline Characteristics of the Subjects Participating in the Experiments during IOP Elevation (n = 48, mean ± SD)
Choroidal Blood Flow Experiments (N = 24) ONH Blood Flow Experiments (N = 24) P Value
Age (y) 22.5 ± 3.0 23.5 ± 3.1 0.13
Sex (M/F) 12/12 12/12 1.00
SBP (mm Hg) 116.7 ± 7.5 117.7 ± 8.0 0.61
DBP (mm Hg) 56.3 ± 6.2 57.2 ± 7.1 0.43
MAP (mm Hg) 76.2 ± 6.2 77.5 ± 7.2 0.54
PR (beats per minute) 68.6 ± 9.7 65.3 ± 11.6 0.40
IOP (mm Hg) 14.6 ± 2.1 13.4 ± 2.3 0.80
OPP (mm Hg) 36.6 ± 4.0 38.3 ± 5.2 0.12
Flow (arbitrary units) 26.3 ± 4.5 21.0 ± 4.1 *
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