Variability and effect sizes of intracranial current source density estimations during pain: Systematic review, experimental findings, and future perspectives.

Pain arises from the integration of sensory and cognitive processes in the brain, resulting in specific patterns of neural oscillations that can be characterized by measuring electrical brain activity. Current source density (CSD) estimation from low-resolution brain electromagnetic tomography (LORETA) and its standardized (sLORETA) and exact (eLORETA) variants, is a common approach to identify the spatiotemporal dynamics of the brain sources in physiological and pathological pain-related conditions. However, there is no consensus on the magnitude and variability of clinically or experimentally relevant effects for CSD estimations. Here, we systematically examined reports of sample size calculations and effect size estimations in all studies that included the keywords pain, and LORETA, sLORETA, or eLORETA in Scopus and PubMed. We also assessed the reliability of LORETA CSD estimations during non-painful and painful conditions to estimate hypothetical sample sizes for future experiments using CSD estimations. We found that none of the studies included in the systematic review reported sample size calculations, and less than 20% reported measures of central tendency and dispersion, which are necessary to estimate effect sizes. Based on these data and our experimental results, we determined that sample sizes commonly used in pain studies using CSD estimations are suitable to detect medium and large effect sizes in crossover designs and only large effects in parallel designs. These results provide a comprehensive summary of the effect sizes observed using LORETA in pain research, and this information can be used by clinicians and researchers to improve settings and designs of future pain studies.

Artificial Intelligence in Multiphoton Tomography: Atopic Dermatitis Diagnosis.

The diagnostic possibilities of multiphoton tomography (MPT) in dermatology have already been demonstrated. Nevertheless, the analysis of MPT data is still time-consuming and operator dependent. We propose a fully automatic approach based on convolutional neural networks (CNNs) to fully realize the potential of MPT. In total, 3,663 MPT images combining both morphological and metabolic information were acquired from atopic dermatitis (AD) patients and healthy volunteers. These were used to train and tune CNNs to detect the presence of living cells, and if so, to diagnose AD, independently of imaged layer or position. The proposed algorithm correctly diagnosed AD in 97.0 ± 0.2% of all images presenting living cells. The diagnosis was obtained with a sensitivity of 0.966 ± 0.003, specificity of 0.977 ± 0.003 and F-score of 0.964 ± 0.002. Relevance propagation by deep Taylor decomposition was used to enhance the algorithm's interpretability. Obtained heatmaps show what aspects of the images are important for a given classification. We showed that MPT imaging can be combined with artificial intelligence to successfully diagnose AD. The proposed approach serves as a framework for the automatic diagnosis of skin disorders using MPT.

Comparison of electrical impedance tomography and intracranial pressure during dehydration treatment of cerebral edema.

Cerebral edema after brain injury can lead to brain damage and death if diagnosis and treatment are delayed. This study investigates the feasibility of employing electrical impedance tomography (EIT) as a non-invasive imaging tool for monitoring the development of cerebral edema, in which impedance imaging of the brain related to brain water content is compared with intracranial pressure (ICP). We enrolled forty patients with cerebral hemorrhage who underwent lateral external ventricular drain with intraventricular ICP and EIT monitoring for 3 h after initiation of dehydration treatment. The average reconstructed impedance value (ARV) calculated from EIT images was compared with ICP. Dehydration effects induced changes in ARV and ICP showed a close negative correlation in all patients, and the mean correlation reached R2 = 0.78 ±â€¯0.16 (p < .001). A regression equation (R2 = 0.62, p < .001) was formulated from the total of measurement data. The 95% limits of agreement were - 6.13 to 6.13 mmHg. Adaptive clustering and variance analysis of normalized changes in ARV and ICP showed 92.5% similarity and no statistically significant differences (p > .05). Moreover, the sensitivity, specificity and area under the curve of changes in ICP >10 mmHg were 0.65, 0.73 and 0.70 respectively. The findings show that EIT can monitor changes in brain water content associated with cerebral edema, which could provide a real-time and non-invasive imaging tool for early identification of cerebral edema and the evaluation of mannitol dehydration.

The effects of chiropractic spinal manipulation on central processing of tonic pain - a pilot study using standardized low-resolution brain electromagnetic tomography (sLORETA).

The objectives of the study were to investigate changes in pain perception and neural activity during tonic pain due to altered sensory input from the spine following chiropractic spinal adjustments. Fifteen participants with subclinical pain (recurrent spinal dysfunction such as mild pain, ache or stiffness but with no pain on the day of the experiment) participated in this randomized cross-over study involving a chiropractic spinal adjustment and a sham session, separated by 4.0 ± 4.2 days. Before and after each intervention, 61-channel electroencephalography (EEG) was recorded at rest and during 80 seconds of tonic pain evoked by the cold-pressor test (left hand immersed in 2 °C water). Participants rated the pain and unpleasantness to the cold-pressor test on two separate numerical rating scales. To study brain sources, sLORETA was performed on four EEG frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (12-32 Hz). The pain scores decreased by 9% after the sham intervention (p < 0.05), whereas the unpleasantness scores decreased by 7% after both interventions (p < 0.05). sLORETA showed decreased brain activity following tonic pain in all frequency bands after the sham intervention, whereas no change in activity was seen after the chiropractic spinal adjustment session. This study showed habituation to pain following the sham intervention, with no habituation occurring following the chiropractic intervention. This suggests that the chiropractic spinal adjustments may alter central processing of pain and unpleasantness.

Intravenous administration of normal saline may be misinterpreted as a change of end-expiratory lung volume when using electrical impedance tomography.

Electrical impedance tomography (EIT) is a noninvasive imaging modality that allows real-time monitoring of regional lung ventilation. The aim of the study is to investigate whether fast saline infusion causes changes in lung impedance that could affect the interpretation of EIT data. Eleven pigs were anaesthetized and mechanically ventilated. A bolus of 500 mL of normal saline was administered rapidly. Two PEEP steps were performed to allow quantification of the effect of normal saline on lung impedance. The mean change of end-expiratory lung impedance (EELI) caused by the saline bolus was equivalent to a virtual decrease of end-expiratory lung volume (EELV) by 227 (188-250) mL and decremental PEEP step of 4.40 (3.95-4.59) cmH2O (median and interquartile range). In contrast to the changes of PEEP, the administration of normal saline did not cause any significant differences in measured EELV, regional distribution of lung ventilation determined by EIT or in extravascular lung water and intrathoracic blood volume. In conclusion, EELI can be affected by the changes of EELV as well as by the administration of normal saline. These two phenomena can be distinguished by analysis of regional distribution of lung ventilation.

Electrode fabrication and interface optimization for imaging of evoked peripheral nervous system activity with electrical impedance tomography (EIT).

OBJECTIVE: Non-invasive imaging techniques are undoubtedly the ideal methods for continuous monitoring of neural activity. One such method, fast neural electrical impedance tomography (EIT) has been developed over the past decade in order to image neural action potentials with non-penetrating electrode arrays. APPROACH: The goal of this study is two-fold. First, we present a detailed fabrication method for silicone-based multiple electrode arrays which can be used for epicortical or neural cuff applications. Secondly, we optimize electrode material coatings in order to achieve the best accuracy in EIT reconstructions. MAIN RESULTS: The testing of nanostructured electrode interface materials consisting of platinum, iridium oxide, and PEDOT:pTS in saline tank experiments demonstrated that the PEDOT:pTS coating used in this study leads to more accurate reconstruction dimensions along with reduced phase separation between recording channels. The PEDOT:pTS electrodes were then used in vivo to successfully image and localize the evoked activity of the recurrent laryngeal fascicle from within the cervical vagus nerve. SIGNIFICANCE: These results alongside the simple fabrication method presented here position EIT as an effective method to image neural activity.

Regional expiratory time constants in severe respiratory failure estimated by electrical impedance tomography: a feasibility study.

BACKGROUND: Electrical impedance tomography (EIT) has been used to guide mechanical ventilation in ICU patients with lung collapse. Its use in patients with obstructive pulmonary diseases has been rare since obstructions could not be monitored on a regional level at the bedside. The current study therefore determines breath-by-breath regional expiratory time constants in intubated patients with chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). METHODS: Expiratory time constants calculated from the global impedance EIT signal were compared to the pneumatic volume signals measured with an electronic pneumotachograph. EIT-derived expiratory time constants were additionally determined on a regional and pixelwise level. However, regional EIT signals on a single pixel level could in principle not be compared with similar pneumatic changes since these measurements cannot be obtained in patients. For this study, EIT measurements were conducted in 14 intubated patients (mean Simplified Acute Physiology Score II (SAPS II) 35 ± 10, mean time on invasive mechanical ventilation 36 ± 26 days) under four different positive end-expiratory pressure (PEEP) levels ranging from 10 to 17 cmH2O. Only patients with moderate-severe ARDS or COPD exacerbation were included into the study, preferentally within the first days following intubation. RESULTS: Spearman's correlation coefficient for comparison between EIT-derived time constants and those from flow/volume curves was between 0.78 for tau (τ) calculated from the global impedance signal up to 0.83 for the mean of all pixelwise calculated regional impedance changes over the entire PEEP range. Furthermore, Bland-Altman analysis revealed a corresponding bias of 0.02 and 0.14 s within the limits of agreement ranging from - 0.50 to 0.65 s for the aforementioned calculation methods. In addition, exemplarily in patients with moderate-severe ARDS or COPD exacerbation, different PEEP levels were shown to have an influence on the distribution pattern of regional time constants. CONCLUSIONS: EIT-based determination of breath-by-breath regional expiratory time constants is technically feasible, reliable and valid in invasively ventilated patients with severe respiratory failure and provides a promising tool to individually adjust mechanical ventilation in response to the patterns of regional airflow obstruction. TRIAL REGISTRATION: German Trial Register DRKS 00011650 , registered 01/31/17.

Feasibility of imaging evoked activity throughout the rat brain using electrical impedance tomography.

Electrical Impedance Tomography (EIT) is an emerging technique which has been used to image evoked activity during whisker displacement in the cortex of an anaesthetised rat with a spatiotemporal resolution of 200 µm and 2 ms. The aim of this work was to extend EIT to image not only from the cortex but also from deeper structures active in somatosensory processing, specifically the ventral posterolateral (VPL) nucleus of the thalamus. The direct response in the cortex and VPL following 2 Hz forepaw stimulation were quantified using a 57-channel epicortical electrode array and a 16-channel depth electrode. Impedance changes of -0.16 ±â€¯0.08% at 12.9 ±â€¯1.4 ms and -0.41 ±â€¯0.14% at 8.8±1.9 ms were recorded from the cortex and VPL respectively. For imaging purposes, two 57-channel epicortical electrode arrays were used with one placed on each hemisphere of the rat brain. Despite using parameters optimised toward measuring thalamic activity and undertaking extensive averaging, reconstructed activity was constrained to the cortical somatosensory forepaw region and no significant activity at a depth greater than 1.6 mm below the surface of the cortex could be reconstructed. An evaluation of the depth sensitivity of EIT was investigated in simulations using estimates of the conductivity change and noise levels derived from experiments. These indicate that EIT imaging with epicortical electrodes is limited to activity occurring 2.5 mm below the surface of the cortex. This depth includes the hippocampus and so EIT has the potential to image activity, such as epilepsy, originating from this structure. To image deeper activity, however, alternative methods such as the additional implementation of depth electrodes will be required to gain the necessary depth resolution.

Two-layer heterogeneous breast phantom for photoacoustic imaging.

Photoacoustic tomography (PAT) is emerging as a potentially important aid for breast cancer detection. Well-validated tissue-simulating phantoms are needed for objective, quantitative, and physically realistic testing for system development. Prior reported PAT phantoms with homogenous structures do not incorporate the irregular layered structure of breast tissue. To assess the impact of this simplification, we design and construct two-layer breast phantoms incorporating vessel-simulating inclusions and realistic undulations at the fat/fibroglandular tissue interface. The phantoms are composed of custom poly(vinyl chloride) plastisol formulations mimicking the acoustic properties of two breast tissue types and tissue-relevant similar optical properties. Resulting PAT images demonstrate that in tissue with acoustic heterogeneity, lateral size of imaging targets is sensitive to the choice of sound speed in image reconstruction. The undulating boundary can further degrade a target's lateral size due to sound speed variation in tissue and refraction of sound waves at the interface. The extent of this degradation is also influenced by the geometric relationship between an absorber and the boundary. Results indicate that homogeneous phantom matrixes may underestimate the degradation of PAT image quality in breast tissue, whereas heterogeneous phantoms can provide more realistic testing through improved reproduction of spatial variations in physical properties.

A Versatile Noise Performance Metric for Electrical Impedance Tomography Algorithms.

Electrical impedance tomography (EIT) is an emerging technology for real-time monitoring of patients under mechanical ventilation. EIT has the potential to offer continuous medical monitoring while being noninvasive, radiation free, and low cost. Due to their ill-posedness, image reconstruction typically uses regularization, which implies a hyperparameter controlling the tradeoff between noise rejection and resolution or other accuracies. In order to compare reconstruction algorithms, it is common to choose hyperparameter values such that the reconstructed images have equal noise performance (NP), i.e., the amount of measurement noise reflected in the images. For EIT many methods have been suggested, but none work well when the data originate from different measurement setups, such as for different electrode positions or measurement patterns. To address this issue, we propose a new NP metric based on the average signal-to-noise ratio in the image domain. The approach is validated for EIT using simulation experiments on a human thorax model and measurements on a resistor phantom. Results show that the approach is robust to the measurement configuration (i.e., number and position of electrodes, skip pattern) and the reconstruction algorithm used. We propose this novel approach as a way to select optimized measurement configurations and algorithms.

Problems and Possibilities of Passive Thermoacoustical Tomography.

The problems and possibilities of passive thermoacoustical tomography are discussed. Algorithms for reconstruction of internal temperature in the human body are proposed. These algorithms take into account heat transfer and blood circulation and the absorption factor, obtained previously. The results of reconstruction of deep temperature in the human hand in simulations with the medium with a heated object are reported. These results support the possibility of the correlation measurements of the thermal acoustic radiation. Such measurements allow the information on ultrasound absorption by the object under study to be obtained and open the way to the development of a passive acoustic tomography system using a priori information on the absorption factor.

Experimental validation of tangential resolution improvement in photoacoustic tomography using modified delay-and-sum reconstruction algorithm.

For a circular scanning geometry in photoacoustic tomography, the axial/radial resolution is spatially invariant and is not affected by the ultrasound transducer (UST, detector) aperture. However, the tangential resolution is dependent on the detector aperture size and it varies spatially. Many techniques were proposed to improve the tangential resolution, such as attaching a concave lens in front of the nonfocused transducer or using a virtual point detector. Both of these methods have difficulties. Therefore, a modified delay-and-sum reconstruction algorithm has been proposed which can be used together with a standard ultrasound detector (nonfocused) to improve the tangential resolution. In this work, we validate the modified delay-and-sum algorithm experimentally for both flat and cylindrically focused USTs. More than threefold improvement in tangential resolution is observed. It is also shown that the object shape is recovered with this modified algorithm, which is very helpful for diagnosis and treatment purposes.

High-energy proton imaging for biomedical applications.

The charged particle community is looking for techniques exploiting proton interactions instead of X-ray absorption for creating images of human tissue. Due to multiple Coulomb scattering inside the measured object it has shown to be highly non-trivial to achieve sufficient spatial resolution. We present imaging of biological tissue with a proton microscope. This device relies on magnetic optics, distinguishing it from most published proton imaging methods. For these methods reducing the data acquisition time to a clinically acceptable level has turned out to be challenging. In a proton microscope, data acquisition and processing are much simpler. This device even allows imaging in real time. The primary medical application will be image guidance in proton radiosurgery. Proton images demonstrating the potential for this application are presented. Tomographic reconstructions are included to raise awareness of the possibility of high-resolution proton tomography using magneto-optics.

Variance components in confocal scanning laser tomography measurements of neuro-retinal rim area and the effect of repeated measurements on the power to detect loss over time.

PURPOSE: To estimate the variation in measurements of neuro-retinal rim area (NRA) determined by confocal scanning laser tomography and consequences for clinical follow-up. METHODS: Altogether, 24 healthy subjects were randomized on -320 µm, Moorfields and Standard NRA plane strategies. Additionally, NRA was measured in 32 glaucoma subjects. Variance components for subjects, visits and measurements were estimated with analysis of variance. Sample sizes required to detect a 6.0 × 10-2  mm2 NRA change were estimated assuming a significance level of 0.05 and a power of 0.8. Consequences for independent group, and paired comparison design, respectively, were analysed. Further, precision in estimates within subjects over time was investigated. RESULTS: The variation of NRA among subjects was considerably larger than the variation among visits and measurements. For glaucoma subjects, the variation among visits and measurements were of the same order but larger than in healthy subjects. It was found that independent group comparisons require inconveniently large sample sizes. Within-subject paired comparisons over time require sample sizes of below 15 subjects. The estimated variations for glaucoma subjects imply that 54 months of follow-up is required for detection of change from baseline. CONCLUSIONS: The variance for subjects is substantial in relation to those for visits and measurements. Cross-sectional independent group comparisons of levels of NRA are unsuitable, due to considerable subject variation. Levels of NRA differences within subjects between visits can be estimated with acceptable precision. Neuro-retinal rim area (NRA) measurement can be used for long-term follow-up of glaucoma progression.

Functional monitoring of peripheral nerves from electrical impedance measurements.

Medical electrical stimulators adapted to peripheral nerves use multicontact cuff electrodes (MCC) to provide selective neural interfaces. However, neuroprostheses are currently limited by their inability to locate the regions of interest to focus. Intended until now either for stimulation or recording, MCC can also be used as a means of transduction to characterize the nerve by impedancemetry. In this study, we investigate the feasibility of using electrical impedance (EI) measurements as an in vivo functional nerve monitoring technique. The monitoring paradigm includes the synchronized recording of both the evoked endogenous activity as compound action potentials (CAP) and the superimposed sine signal from the EI probe. Measurements were conducted on the sciatic nerve of rodents, chosen for its branchings towards the peroneal and tibial nerves, with both mono- and multi-contact per section electrodes. During stimulation phases, recordings showed CAP with consistent fiber conduction velocities. During coupled phases of both stimulation and sine perturbation, impedance variations were extracted using the mono-contact electrode type for certain frequencies, e.g. 2.941kHz, and were temporally coherent with the previous recorded CAP. Using a MCC, localized evoked CAP were also recorded but the signal to noise ratio (SNR) was too low to distinguish the expected associated impedance variation and deduce an image of impedance spatial changes within the nerve. The conducted in vivo measurements allowed to distinguish both evoked CAP and associated impedance variations with a strong temporal correlation. This indicates the feasibility of functional EI monitoring, aiming at detecting the impedance variations in relation to neural activity. Further work is needed to improve the in vivo system, namely in terms of SNR, and to integrate new multicontact devices in order to move towards EI tomography with the detection of spatially-localized impedance variations. Eventually, regions that are interesting to be targeted by stimulation could be identified through these means.

Can Visual Field Progression be Predicted by Confocal Scanning Laser Ophthalmoscopic Imaging of the Optic Nerve Head in Glaucoma? (An American Ophthalmological Society Thesis).

PURPOSE: To determine whether confocal scanning laser ophthalmoscopic imaging (Heidelberg retinal tomography [HRT]) can predict visual field change in glaucoma. METHODS: The study included 561 patients with glaucoma or ocular hypertension whose clinical course was followed at the Mount Sinai Faculty practice. Humphrey visual fields (HVFs) and HRT images were collected on one randomly selected eye per patient. Glaucoma progression was determined by the presence of two sequential statistically significant negative slopes in mean deviation (MD) or visual field index (VFI) at any point during the study period. Trend-based analysis on HRT parameters was used to determine progressive changes and whether these occurred before or after HVF change. Sensitivity and specificity of HRT to predict HVF change were calculated. HVF rate of change was correlated to the rate of change detected by HRT imaging. RESULTS: Approximately 17% of patients progressed by either MD or VFI criteria. MD and VFI correlated highly and identified overlapping sets of patients as progressing. HRT global parameters had poor sensitivity (∼42%) and moderate specificity (∼67%) to predict HVF progression. Regional stereometric parameters were more sensitive (69%-78%) but significantly less specific (24%-27%). Sensitivity of global stereometric parameters in detecting HVF change was not significantly affected by the level of visual field damage (P=.3, Fisher exact test). HVF rate of change did not correlate with rate of change of HRT parameters. CONCLUSIONS: Trend-based analysis of HRT parameters has poor sensitivity and specificity in predicting HVF change. This may be related specifically to HRT imaging or may reflect the fact that in some patients with glaucoma, functional changes precede structural alterations.

Detection of 'best' positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial.

INTRODUCTION: This study compares different parameters derived from electrical impedance tomography (EIT) data to define 'best' positive end-expiratory pressure (PEEP) during a decremental PEEP trial in mechanically-ventilated patients. 'Best' PEEP is regarded as minimal lung collapse and overdistention in order to prevent ventilator-induced lung injury. METHODS: A decremental PEEP trial (from 15 to 0 cm H2O PEEP in 4 steps) was performed in 12 post-cardiac surgery patients on the ICU. At each PEEP step, EIT measurements were performed and from this data the following were calculated: tidal impedance variation (TIV), regional compliance, ventilation surface area (VSA), center of ventilation (COV), regional ventilation delay (RVD index), global inhomogeneity (GI index), and intratidal gas distribution. From the latter parameter we developed the ITV index as a new homogeneity parameter. The EIT parameters were compared with dynamic compliance and the PaO2/FiO2 ratio. RESULTS: Dynamic compliance and the PaO2/FiO2 ratio had the highest value at 10 and 15 cm H2O PEEP, respectively. TIV, regional compliance and VSA had a maximum value at 5 cm H2O PEEP for the non-dependent lung region and a maximal value at 15 cm H2O PEEP for the dependent lung region. GI index showed the lowest value at 10 cm H2O PEEP, whereas for COV and the RVD index this was at 15 cm H2O PEEP. The intratidal gas distribution showed an equal contribution of both lung regions at a specific PEEP level in each patient. CONCLUSION: In post-cardiac surgery patients, the ITV index was comparable with dynamic compliance to indicate 'best' PEEP. The ITV index can visualize the PEEP level at which ventilation of the non-dependent region is diminished, indicating overdistention. Additional studies should test whether application of this specific PEEP level leads to better outcome and also confirm these results in patients with acute respiratory distress syndrome.

Multi-frequency electrical impedance tomography system with automatic self-calibration for long-term monitoring.

Electrical Impedance Tomography (EIT) is a safe medical imaging technology, requiring no ionizing or heating radiation, as opposed to most other imaging modalities. This has led to a clinical interest in its use for long-term monitoring, possibly at the bedside, for ventilation monitoring, bleeding detection, gastric emptying and epilepsy foci diagnosis. These long-term applications demand auto-calibration and high stability over long time periods. To address this need we have developed a new multi-frequency EIT system called the KHU Mark2.5 with automatic self-calibration and cooperation with other devices via a timing signal for synchronization with other medical instruments. The impedance measurement module (IMM) for flexible configuration as a key component includes an independent constant current source, an independent differential voltmeter, and a current source calibrator, which allows automatic self-calibration of the current source within each IMM. We installed a resistor phantom inside the KHU Mark2.5 EIT system for intra-channel and inter-channel calibrations of all voltmeters in multiple IMMs. We show the deterioration of performance of an EIT system over time and the improvement due to automatic self-calibration. The system is able to maintain SNR of 80 dB for frequencies up to 250 kHz and below 0.5% reciprocity error over continuous operation for 24 hours. Automatic calibration at least every 3 days is shown to maintain SNR above 75 dB and reciprocity error below 0.7% over 7 days at 1 kHz. A clear degradation in performance results with increasing time between automatic calibrations allowing the tailoring of calibration to suit the performance requirements of each application.

Heidelberg Retina Tomograph (HRT3) in population-based epidemiology: normative values and criteria for glaucomatous optic neuropathy.

PURPOSE: To establish normative values for Heidelberg Retina Tomograph (HRT3) variables and to develop HRT3-based criteria for glaucomatous optic neuropathy for epidemiological research in a white population. METHODS: Consecutive participants in the Rotterdam Study were examined with HRT and simultaneous stereoscopic fundus photography (ImageNet) in addition to other ophthalmic examinations including intraocular pressure (IOP) measurements and perimetry. Normative values for all HRT3 variables were determined in participants who met all the following criteria: no glaucomatous visual field loss (GVFL), an IOP of 21mmHg or less, no IOP lowering treatment, and a negative family history of glaucoma. Sensitivity was determined in participants with glaucomatous visual field loss at a fixed high specificity of 97.5% - a value commonly used in population-based epidemiology. RESULTS: A total of 2516 participants were included in this study of whom 66 had glaucomatous visual field loss in at least one eye and 1680 fulfilled the criteria for contributing to the normative values. The HRT3 linear cup-disc ratio (LCDR) variable, adjusted for disc area, showed the highest sensitivity, 35%, at the required specificity of 97.5%. The 97.5th percentile of the LCDR was 0.67 for small discs (up to 1.5 mm(2)), 0.71 [corrected] for medium-sized discs and 0.76 [corrected] for large discs (above 2.0 mm(2)).The HRT3 Glaucoma Probability Score and previously published linear discriminant functions showed a lower sensitivity than LCDR at this specificity. CONCLUSIONS: At the high specificity of 97.5% as is commonly used in population-based epidemiology, the sensitivity of the HRT3 is low - albeit not lower than that of the vertical cup-disc ratio as assessed with simultaneous stereoscopic fundus photography and analyzed with the ImageNet software. The LCDR variable, stratified for disc area, seems to be the most suitable variable to develop criteria for glaucomatous optic neuropathy for epidemiological purposes.