Optical method and device for determining blood glucose levels

Description Submit all comments and votes

FIELD OF THE INVENTION

This invention relates generally to the field of optics and more specifically to a method and device for analyzing a patient's perception of a light pattern having a plurality of different visual characteristics, and relating such to the patient's blood glucose level.

BACKGROUND OF THE INVENTION

More than ten million people in the United States of America suffer from diabetes, a deficiency in the ability to regulate blood glucose levels. Individuals afflicted with the disease must control their blood glucose levels by measuring their blood glucose levels as frequently as possible and adjusting their food intake, level of physical activity and insulin dosage to regulate the glucose level. Blood glucose level is measured using one of several available invasive techniques.

Invasive techniques require a blood sample from the patient each time an analysis is to be performed. An accurate laboratory blood analysis requires about 5 to 10 ml of blood, and analysis using a laboratory instrument designed for performing such a biochemical analysis. However, the results of the test often are not available for several hours, and sometimes days. In addition, the instruments necessary to perform such an analysis are expensive and require that the blood samples be taken and analyzed by trained technicians.

Another invasive technique, referred to as a "finger stick" uses an integrated, self-contained instrument that evaluates a much smaller blood sample (approximately 0.25 ml). The small blood sample is obtained by puncturing a finger with a small lancet. The sample is then placed on a chemically treated carrier and inserted into the instrument. The finger stick devices normally provide the glucose concentration results in a few moments. However, they are still costly, and require that patient puncture a finger several times per day.

More recently, portable finger stick instruments have become available which require the use of single use, disposable, chemically treated carrier "strips". Although the portable instruments have a relatively low cost (about $100 to $300), the cumulative cost to diabetics for the normal supply of disposable carrier strips is considerable.

Invasive techniques for glucose analysis are problematic and suffer from poor compliance. Although diabetics can forestall the debilitating and often fatal complications of diabetes by frequent monitoring and control, only a small fraction of diabetics monitor their glucose levels as regularly as recommended. Diabetics find the current invasive methods of blood glucose monitoring painful, inconvenient and costly. To encourage frequent monitoring and control there is a clear need for a glucose monitor that requires no blood samples, is easy and convenient to use, is portable, and costs less than current methods.

Non-invasive methods for measuring blood glucose have been described. These methods include measurement of the optical polarization of light in the eye; the absorption, transmission, or scatter of infrared light in body tissue; or the chemical analysis of interstitial fluid removed through the skin by reverse iontophoresis (see, e.g., Rosenthal et al., U.S. Pat. Nos. 5,086,229; 5,279,543; Cote et al., IEEE Trans. of Biomed. Engineer. (1992) 39:752-56). However, to date none of these techniques has resulted in a commercially useful instrument. All of these methods have serious technical problems due to the small signals available and the inherent variability of measurements in live tissue. Furthermore, due to the complexity of the implementation, these methods are not likely to lead to small, low-cost instruments that will encourage frequent testing by diabetics.

SUMMARY OF THE INVENTION

We have found that the sensitivity of the visual system to alternating changes in luminance, or luminance contrast, changes with blood glucose concentration in a predictable and precise manner. This property can be used to determine blood glucose non-invasively: one can measure the sensitivity of the visual system to luminance contrast, and from this measurement one can determine the existing blood glucose concentration via calibration data that relates the blood glucose levels that correspond to different values of luminance contrast sensitivity.

One aspect of the invention is a method for determining the concentration of glucose in a subject's blood, by providing a light stimulus having two or more visual characteristics (e.g., a luminance contrast pattern), allowing the subject to observe the stimulus, and correlating the subject's observations with a previously determined calibration curve. In one embodiment of the invention, the subject varies a parameter of the pattern until a subjective change in the pattern appears, and the threshold or crossover point is compared with a calibration curve.

Another aspect of the invention is a device for determining the concentration of glucose in a subject's blood, by providing a variable-parameter light stimulus (e.g., a luminance contrast pattern), which comprises a body member, a display means for generating a light stimulus, and optionally actuator means for initiating the display and/or for indicating when a crossover or change is observed.

An object of the invention is to provide a non-invasive optical means of determining a patient's blood glucose level. Another object is to provide the non-invasive means for determining glucose levels by using images or light patterns which provide visual stimulation to the retina and determining with such images or light patterns changes that take place in a patient's retina in response to changes in blood glucose levels.

These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the structure, methodology and usage as more fully set forth below with reference being made to the accompanying figures forming a part hereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which shows the relationship between luminance, mean luminance, and amplitude of modulation for a flickering light source.

FIG. 2 is a graph showing the crossover point for a flickering source as a function of contrast and flicker frequency.

FIG. 3 is a graph which shows how the crossover point changes as blood glucose level changes.

FIG. 4 is a graph illustrating the difference in crossover point at different blood glucose concentrations.

FIG. 5 is a graph showing the measured crossover point in correlation with blood glucose concentration for a first subject.

FIG. 6 is a graph showing the measured crossover point in correlation with blood glucose concentration for a second subject.

FIG. 7 is a graph showing the measured crossover point in correlation with blood glucose concentration for a third subject.

FIG. 8 is a graph showing the measured crossover point in correlation with blood glucose concentration for a fourth subject.

FIG. 9 is a black and white schematic view of a radial vane (windmill) light stimulus in a first position;

FIG. 10 is a graph showing the measured crossover point in correlation with blood glucose concentration for an observer, obtained using a windmill pattern.

FIG. 11 is a graph showing the correlation between windmill reversal and glucose concentration.

FIG. 12 shows an embodiment of the device;

FIG. 13 is a schematic block diagram showing principal functional sections of the device of FIG. 12;

FIG. 14 is a schematic flow diagram showing steps of a diagnostic sequence; and

FIG. 15 is a graph demonstrating compensation for reaction time.

DETAILED DESCRIPTION OF THE INVENTION

Before the present optical method and device for determining blood glucose levels is described, it is to be understood that this invention is not limited to the particular process steps, light changing, light stimulus or other steps and components described as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.

The singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a changing light stimulus" refers to one or more changing light stimuli, reference to "an actuation means" refers to one or more means and so forth.

Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned hereunder are incorporated herein by reference.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention claimed herein is not entitled to antedate such publications by virtue of prior invention.

It is well understood that glucose is present in blood and can migrate to all tissues via the circulatory system. In particular glucose is an important metabolite for the retina. The retina possesses a high rate of metabolic and electrical activity which is almost exclusively fueled via the oxidative breakdown of glucose (W. K. Noell, Am. J. Physiol. (1959) 48:347; B. S. Winkler, Exp. Eye Res. (1975) 21:545). The retina obtains the required glucose from an abundant blood supply provided to the retina via the retinal choroid capillaries. Not only does the retina utilize glucose for its metabolic and electrical activity, but the retina is able to consume glucose in proportion to the amount of glucose available over a wide range of glucose levels (A. Ames III et al., J. Neurophysiol. (1963) 26:617; B. S. Winkler, Vision Res. (1972) 12:1183; B. S. Winkler, J. Gen. Physiol. (1981) 77:667).

In view of the above it can be anticipated that changes in the blood glucose concentration will have noticeable effects on the visual system. Such effects have been demonstrated by others in areas unrelated to the subject of this invention. Specifically, glucose concentration affects rod-mediated responses in the perfused cat eye (C. Macaluso, et al., Invest. Ophthalmol. & Visual Science, Supp. (1991) 32:903); high blood glucose concentration decreases the detection thresholds with respect to low-contrast patterns and increases the ERG amplitude in humans (R. B. Barlow, Jr., et al., Invest. Ophthalmol. & Visual Science, Supp. (1993) 34:785); and lastly, low blood glucose concentrations increase dark-adapted detection thresholds in humans (R. A. McFarland et al., J. Gen. Physiol. (1940) 24:69).

This demonstrates that the ability of an individual to perceive certain types of visual stimuli changes with fluctuations in blood glucose level. Based on this it can be understood that the appearance of some images can change with changes in blood glucose level. The present invention utilizes this basic principle to provide a method and device which calculates blood glucose levels based on changes in the appearance of a specially designed visual stimulus.

The present invention relies on the fact that subjectively observable phenomena vary depending on the concentration of glucose in the blood. It is currently believed that some visual subsystems are controlled by distinct groups of cells, and that some subsystems have different degrees of sensitivity to glucose concentration. However, the invention can be practiced without an understanding of the underlying causes: whatever the cause, subjective visual phenomena exist that vary with glucose concentration. In general, luminance contrast can be used to stimulate different visual subsystems to varying degrees, thus creating subjective visual effects.

The sensitivity of the visual system to luminance contrast can be measured using a number of methods. The following are three examples of suitable methods.

Method a) Threshold for Flicker

One can use a light pattern whose luminance changes over time, and can determine the minimum change in luminance that causes the subject to notice the luminance change. The ability of a subject to detect "flicker" in a fluctuating light source or image depends on the rate of fluctuation and the contrast (or depth of modulation): above a certain rate of change (typically around 48 Hz), one cannot detect flicker visually, a principle exploited by movies, television and computer monitors. A subject's sensitivity to flicker at a set frequency depends on the amount by which the luminance varies: above or below the optimal frequency, the contrast must be increased in order to detect flicker. One can plot a curve of the subject's detection of flicker as a function of contrast and frequency, as shown in FIG. 2. The position of the curve shifts, depending on the subject's glucose concentration.

The luminance changes can consist of regular alternations in luminance, such as shown in FIG. 1. The mean luminance of this pattern may be constant and the amplitude of modulation may be adjustable. The ratio of one-half the amplitude of modulation to the mean luminance is the temporal luminance contrast, or luminance contrast for short. One can use this pattern to measure the sensitivity of the visual system to luminance contrast by determining the minimum luminance contrast that makes the changes in luminance noticeable to the subject (contrast at threshold).

When one measures the threshold contrast at different frequencies of modulation one obtains a graph such as that shown in the upper plot of FIG. 2. These data were obtained for one subject at 4 frequencies, and show at each frequency the minimum contrast needed for the subject to see the luminance alternations, that is, to see flicker in the light pattern. In this plot, the vertical axis indicates the ratio of the amplitude of modulation to the mean luminance, or temporal luminance contrast of the light pattern at the point when the alternations in luminance become just visible. Thus the vertical axis is a convenient scale to measure the sensitivity of the visual system to the luminance alternations: the higher one goes on the vertical axis, the smaller the modulation needed to make the alternations just visible and thus the greater the sensitivity of the visual system to luminance alternations. The bottom end of the scale, shown as contrast value of 1, indicates the maximum modulation possible in the light pattern: the luminance of the pattern is alternating between a maximum of twice the mean luminance and a minimum of zero luminance. A data point at this level would indicate conditions of minimum sensitivity of the visual system to luminance alternations, since it would mean that under such conditions, it would take the maximum modulation possible to make the alternations visible. The horizontal axis is the frequency of the luminance alternations.

Thus, the upper plot of FIG. 2 represents the sensitivity of the visual system to luminance alternations of various frequencies. Of the 4 frequencies tested, sensitivity is maximum at 10 Hz and minimum at 40 Hz. The area of the graph above this plot indicates frequency-contrast combinations that produce the sensation of steady illumination, i.e. absence of flicker. Below this plot is a region where flicker is seen. Near 48 Hz the plot intersects the horizontal axis, indicating the maximum

frequency at which flicker can be seen under the conditions tested. The plot indicates that, under the test conditions used, the sensitivity of the visual system to luminance alternations decreases steadily for frequencies above 10 Hz, and that approximately 48 Hz is the maximum frequency at which flicker can be seen.

Different testing conditions yield a similar sensitivity plot but with slightly different shape. In particular, the height and the width of the plot change with the size of the pattern, the location of the retina where the pattern is imaged, and the mean luminance of the pattern. The data shown above was measured with a circular field 5 degrees in diameter, red in color, imaged in the central fovea, and with mean luminance of 30 cd/m.sup.2.

If the sensitivity of the visual system to luminance contrast decreases, the resulting plot would be lower in the vertical scale, indicating that larger luminance contrasts are needed to detect flicker. FIG. 3 shows that at higher blood glucose levels, the luminance contrast sensitivity of a subject decreases at all frequencies between 10 and 40 Hz. To measure the sensitivity of the visual system to luminance alternations, one does not have to plot the entire luminance contrast sensitivity graph described above. It is sufficient to determine one point on the graph, that is, one combination of contrast-frequency that causes the flicker to just become visible. One can determine one point in the graph in a variety of ways. For example, one can keep the frequency constant and vary the luminance contrast of the light pattern until one finds the flicker-no flicker threshold. This is equivalent to seeking the flicker/no flicker boundary by moving in the sensitivity plot along a vertical line centered on the fixed frequency. Alternatively, one can fix the luminance contrast and vary the frequency, looking for the frequency that causes the flicker/no flicker transition. This is equivalent to moving in the sensitivity plot along a horizontal line corresponding to the fixed contrast until one finds the flicker-no flicker transition. A combination of the above two methods, that is, seeking the flicker/no flicker boundary by adjusting both contrast and frequency could also be used. Example 1 below shows a case in which the flicker threshold is measured by keeping the frequency constant while varying the luminance contrast. The thresholds so measured followed blood glucose levels.

Method b) Threshold for a Subjective Visual Effect

A second method of measuring the luminance contrast sensitivity is to determine the minimum luminance contrast that elicits a certain visual effect. For example, at higher luminance contrast levels than those needed to just see flicker, observers report subjective visual effects such as the appearance of geometric patterns, colors (i.e., colors other than a color that is actually displayed to the observer), radial movement, square or hexagonal grid patterns, etc.

The lower plot in FIG. 2 is an example of data taken on the same subject as the upper plot and shows, at each of a number of frequencies, the minimum contrast which elicited the subjective visual effect of a regular grid pattern. Thus, at a frequency of 10 Hz it was necessary to increase the contrast of the light pattern to 0.7 to elicit the sensation of a grid pattern, and near 20 Hz it was necessary to increase the contrast to 1.0, or its maximum level. At higher frequencies it was not possible to elicit the grid pattern effect. The resulting plot is another representation of the sensitivity of the visual system to luminance alternations of different frequencies. The area beneath the plot indicates contrast-frequency combinations that elicit the visual effect of a grid pattern. The occurrence of the visual effects associated with the fluctuations in luminance in the light pattern can be used to measure the sensitivity of the visual system to luminance alternations. As was the case with the flicker sensitivity, if the sensitivity of the visual system to luminance contrast were to decrease, as is the case when blood glucose rises, the lower plot in FIG. 2 would shift downward, indicating larger luminance contrast needed for the subject to perceive the visual effect. Also, as was the case with the flicker sensitivity, one can measure the visual effect threshold at one point in the graph, by approaching the visual effect/no visual effect boundary from a number of directions in the contrast-frequency space. Thus one can fix the frequency and vary the contrast, fix the contrast and vary the frequency, or use a combination of these methods. Example 2 shows a case in which the thresholds for the subjective visual effect of radial movement or appearance of a grid pattern were sought by keeping the luminance contrast constant at the maximum level of 1, while varying the frequency. The threshold values of frequency so measured followed blood glucose levels.

Method c) Comparison of Two Subsystems

The visual system contains parallel sub-systems or channels that process different aspects of a visual stimulus. It is possible to measure the sensitivity of one channel, for example the channel that processes the luminance contrast, by comparing its sensitivity relative to another channel. For example, one can stimulate the visual system with a light pattern that contains two parameters: temporal luminance contrast and color contrast. The pattern can be such that it causes a subjective visual effect that changes with the relative strength of the two parameters. Thus one can alter the value of one or both of the parameters until a desired subjective visual effect is noticed. The relative value of luminance contrast and color contrast when the visual effect occurred is a measure of the sensitivity of the luminance contrast channel relative to the color contrast channel.

The sensitivity of the luminance channel relative to other channels, such as the color contrast channel, changes when blood glucose level shifts. Thus the relative values of the luminance contrast and color contrast when the desired visual effect is noticed follows changes in blood glucose levels and can be used to determine blood glucose levels.

Example 3 below shows a case where luminance contrast and color contrast are made to cause motion in opposite directions in a windmill pattern, and the relative values of luminance contrast and color contrast at the point of no motion follows blood glucose levels.

Any of the luminance contrast sensitivity measurements described above can be made using one of several specific techniques known in vision psychophysics. For example, one technique involves presenting a predetermined number of contrast levels, several times each, and finding the fraction of times that the subject sees each stimulus level. The threshold is chosen as the contrast value that caused the stimulus to be seen, for example, 50% of the times.

A second technique is the staircase, which uses an interactive approach: the stimulus level on each trial is chosen on the basis of the observer's response to the previous trial. In this way, the observer "walks" the visual parameter to the level where the desired effect is found.

A third technique uses a continuous stimulus display rather than single-value presentations. With this technique, the observer uses a knob or keypad to change some aspect of the display (e.g. the contrast level). When the observer is satisfied that the stimulus parameter is at the appropriate level (e.g. the flicker is just visible), the device records the stimulus parameters at that instant.

The above three techniques are examples of sequential presentations. Alternatively, spatial presentations can be used advantageously in that the overall measurement time can be shortened relative to sequential presentations. In the spatial presentation technique, visual stimuli of different strengths are presented simultaneously side by side, for example lights or sections of a continuous light display modulated at different luminance contrast, or driven at different frequencies. The subject examines the array and chooses the location of the stimulus that has the desired characteristic, for example the light or segment of the display that just flickers, or the light or segment of the display that shows the desired characteristic.

Another useful technique involves a combination of the sequential and spatial techniques. An observer may determine which of a set of spatially distinct lights elicited an effect on the first trial. Then the lights or segments of the display are re-assigned parameter values and the trial repeated several times. This combination technique yields a more accurate and efficient measurement of the observer's sensitivity.

Other techniques for measuring sensitivity of visual mechanisms accurately involve presenting several alternatives to the subject and forcing the subject to respond which of the alternatives presented contained the desired visual characteristic. This technique avoids the subject's bias and yields very accurate sensitivity measurements.

Definitions

The term "light pattern" as used herein refers to an image which can produce two or more subjective visual impressions, or subjective characteristics, on an observer, where the subjective characteristic can be shifted from one to another by altering a controllable parameter. For example, a light pattern within the scope of this invention may be a light source that varies in luminance at a regular rate. Under certain frequencies of variation, and degrees of contrast between the "high" and "low" levels of luminance, an observer perceives a flicker in the image. By changing one or more parameters of the light pattern, for example by decreasing the luminance contrast and/or by increasing the rate of alternation (frequency), the subjective visual impression (flickering source) can be changed to a second visual impression (steady source): the flickering effect disappears. Note that either impression may constitute the "first subjective characteristic", i.e., either "flicker" or "no flicker" may be the first characteristic, and either may be the second characteristic. Examples of light patterns include, without limitation, a flickering source (a source which alternates between a high luminance level and a lower luminance level), a radial vane pattern (e.g., a windmill pattern, which produces the illusion of rotation), a checkerboard of alternating luminance levels and/or colors, and the like.

The term "crossover point" as used herein refers to the point at which a first subjective characteristic changes to a second subjective characteristic, for example, the point at which a flicker source appears to stop flickering (or at which a steady source appears to begin flickering), or the point at which a rotating image appears to stop and change direction.

The term "parameter" as used herein refers to any aspect of the light pattern that may be altered to produce a change in visual subjective characteristic. Examples of parameters within the scope of the invention include, without limitation, color, luminance level, contrast, shape, size, position, detail content, texture, speed of movement or rotation, direction of movement or rotation, rate of change, and the like. The parameter may vary in time or in space. For example, the luminance of the light pattern may be varied with time over all or part of the pattern, or the luminance may be smoothly varied from one part of the pattern to another. Alternatively, the pattern may be provided as a plurality of regions, with each region have a different value of the parameter. For example, a flickering source pattern may be provided having the same alternation rate throughout, but having a different degree of contrast in each of a plurality of regions. As another example, the light pattern may be a plurality of rotating vane images, having a different contrast between the vanes in each image, where the observer simply selects the image that does not appear to be rotating.

T