Ocular impedance-based system for brain health monitoring

Abstract

To provide methods and systems for monitoring and assessing brain bioimpedance through the use of an ocular window that assesses dynamic changes in the cerebral blood volume (CBV).SOLUTION: The ocular window is implemented through an ocular bioimpedance device that, in a non-invasive manner, measures numerous different brain health indicators using the bioimpedance measurements collected through regions around eyes. The ocular bioimpedance device may be goggles with localized measurement electrodes that include cathodes and anodes.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 506,971, filed May 16, 2017, entitled “Ocular Impedance Based System for Brain Health Monitoring,” which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to techniques for monitoring and assessing brain health, and more particularly to techniques for monitoring and assessing brain health using ocular impedance measurements. [Background technology]

[0003] The description of the background art provided herein is for the purpose of generally presenting the context of the present disclosure. The work of the presently named inventors to the extent described in this Background section, and aspects of the description that may not otherwise be considered prior art at the time of filing, are not admitted, expressly or impliedly, as prior art to the present disclosure.

[0004] Traumatic brain injury (TBI) plays a significant role in approximately 30% of injury-related deaths in the United States and is often referred to as a "silent epidemic" due to associated complications that remain undiagnosed and unnoticed but may have lasting effects on health. Management strategies in the treatment of severe TBI are usually aimed at preventing secondary brain injury, which manifests primarily as inflammation and cerebral ischemia. Monitoring intracranial pressure (ICP) and optimizing cerebral perfusion pressure (CPP) to target levels have been proposed in the past as primary methods to prevent secondary injury and are central to current practice. However, recent trials have not demonstrated a clear benefit of ICP monitoring, or targeting CPP to guide management.

[0005] Recent management approaches have attempted to utilize more dynamic, individualized precision optimization of CPP based on cerebrovascular autoregulation (CAR) using methods such as the pressure reactivity index (PRx). Autoregulation is the ability of blood vessels to adjust vascular tone in response to changes in CPP and, in so doing, maintain a constant level of cerebral blood flow (CBF) to match the metabolic demands of the brain. CAR may be considered one of the most important central nervous system self-protection mechanisms against secondary brain injury. CAR is often impaired after severe TBI and has been shown to be a predictor of outcome in patients with severe TBI, as well as various acute neurological diseases and ischemic injuries such as stroke, subarachnoid hemorrhage, brain tumors, cardiac arrest, hypertensive crisis, and others.

[0006] However, current assessment methods for CAR lack the ability to directly monitor and track relative changes in cerebral blood volume, and are not available in out-of-hospital settings. For example, current techniques using PRx require invasive monitoring.

[0007] There is a need for technology that can be used to monitor dynamic changes in cerebral blood volume (CBV) as a reflection of CAR. There is a need for a portable, non-invasive sensor to measure CBV changes in injured individuals with traumatic brain injury and other cerebrovascular emergencies that is suitable for use in a variety of settings (e.g., civilian and military pre-hospital settings, emergency trauma centers, intensive care units, etc.). This would allow for early, accurate monitoring and treatment to prevent secondary brain injury. Summary of the Invention

[0008] The present technology includes a method and system for monitoring and evaluating cerebral bioimpedance through an ocular window as a way to assess dynamic changes in cerebral blood volume (CBV). The technology can be accomplished in a non-invasive and continuous manner. The technology monitors cerebral impedance to track changes in CBF, ICP, and CPP associated with changes in cerebral blood volume. In this way, the technology can be further used to assess CAR impairment.

[0009] The present technology provides a non-invasive method of measuring a number of different brain health indicators using impedance measurements collected through a subject's eye(s). An ocular bioimpedance device is used to specifically localize measurement electrodes, which may include a combination of cathodes and anodes.

[0010] In one example, an apparatus for assessing brain health of a subject comprises one or more electrodes, one or more processors, and computer readable memory storing non-transitory instructions that, when executed by the one or more processors, cause the apparatus to: supply an electric current to an ocular region of the subject using the one or more electrodes; sense an electrical signal obtained from the ocular region of the subject using the one or more electrodes and determine a bioimpedance value of the subject from the electrical signal, wherein the bioimpedance value represents the bioimpedance of a conductive pathway that includes at least a portion of the ocular and brain region of the subject; and determine a brain health indicator from the bioimpedance information.

[0011] In another example, a method of assessing brain health of a subject, the method comprising: determining an eye-brain region bioimpedance value of the subject in response to providing an electrical signal to an ocular region of the subject and detecting the electrical signal on a conductive pathway including at least a portion of an ocular region and a brain region; determining from the eye-brain region bioimpedance value changes in intracranial pressure over a sample period, which changes correspond to changes in cerebral blood volume (CBV); determining an effect of the subject's arterial pressure on CBV over the sample period; determining an effect of mean intracranial pressure over the sample period and mean arterial pressure over the sample period on CBV; and determining a pressure responsiveness index value from a correlation of the mean intracranial pressure and the mean arterial pressure, wherein the pressure responsiveness index relative to CBV is indicative of brain health of the subject.

[0012] In another example, a method of assessing brain health of a subject, the method including receiving mean intracranial pressure data of the subject over a sample period; receiving mean arterial pressure data of the subject over the sample period; receiving a pressure responsiveness index value determined from a correlation of the mean intracranial pressure and the mean arterial pressure, where the pressure responsiveness index is indicative of brain health of the subject; determining the subject's eye-brain region bioimpedance over the sample period in response to providing an electrical signal to an ocular region of the subject and detecting the electrical signal on a conductive pathway including at least a portion of the ocular region and the brain region; and combining the bioimpedance with the pressure responsiveness index to generate a brain health index, where the index has positive values ​​indicative of a healthy brain state of the subject and negative values ​​indicative of an unhealthy brain state of the subject.

[0013] In another example, a method of treating a brain condition in a subject, the method comprising administering to an ocular region of the subject a treatment that affects a brain state to the subject, the treatment that affects the brain state being transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), biophotonic stimulation, and / or acoustic stimulation.

[0014] In another example, a device for treating a brain condition of a subject, the device comprising: a housing configured to engage an ocular region of the subject, the housing having one or more electrodes configured to deliver electrical signals to the ocular region of the subject; one or more processors; and computer-readable memory storing non-transitory instructions that, when executed by the one or more processors, cause the device to deliver electrical signals in the form of transcranial direct current stimulation (tDCS) and / or transcranial alternating current stimulation (tACS) to the ocular region of the subject using the one or more electrodes to treat the brain condition. [Brief description of the drawings]

[0015] The drawings described below depict various aspects of the systems and methods disclosed herein. It should be understood that each figure depicts an example of an aspect of the systems and methods.

[0016] [Figure 1] Shown is the placement on a test subject of a Foley catheter balloon (1), an ICP probe (2), an LDF probe (3), and an ocular impedance electrode (which may include a combination of cathode and anode) (4). [Diagram 2] 1 is a plot of impedance waveforms showing changes in respiration and cardiac cycle measured using ocular impedance electrodes in one example. [Diagram 3] A: During hyperventilation, plot A1) dz vs. MAP, plot A2) dz vs. ICP, plot A3) dz vs. CPP, plot A4) change in dz vs. CBF, and plot A5) dz vs. PetCO2. B: During vasopressor infusion, plot B1) dz vs. MAP, plot B2) dz vs. ICP, plot B3) dz vs. CPP, and plot B4) change in dz vs. CBF. C: During epidural hematoma, plot C1) dz vs. ICP, plot C2) dz D: Scatter plots and correlation coefficients of dz vs MAP, plot D2) dz vs ICP, plot D3) dz vs CPP, and plot D4) change in dz vs CBF during systemic hemorrhage, where dz is the measured cerebral bioimpedance, MAP is the mean arterial pressure, ICP is the intracranial pressure, CPP is the cerebral perfusion pressure, and CBF is the cerebral blood flow. [Figure 4] 1 shows plots of impedance waveforms obtained with ocular impedance electrodes (cathode and anode) placed at various locations, i.e., plot A1) on the eyelid and plot A2) on the scalp, as well as the power spectral density of plots B1) ocular impedance and B2) scalp impedance. The plots are to the same scale. [Diagram 5]5A) shows plots of brain-ocular impedance measurements obtained from ocular impedance electrodes. FIG. 5A) shows an exemplary measured impedance response during normal breathing. FIG. 5B) shows an exemplary measured impedance response during deep breathing. FIG. 5C) shows an exemplary measured impedance response during the Valsalva maneuver. FIG. 5D) shows an exemplary measured impedance response during breath holding. The scale of the images is varied to allow visual inspection of changes. [Figure 6] Changes in ICP, CBF, MAP, and impedance during induction of epidural hematoma (IN) and removal of the hematoma (OUT) are shown. [Figure 7] 1 illustrates an ocular bioimpedance measuring device according to one embodiment. [Figure 8] 1 shows an ocular bioimpedance measuring device according to another embodiment. [Figure 9] 1 shows an ocular bioimpedance measuring device according to another embodiment. [Figure 10] 1 illustrates an ocular bioimpedance assessment system according to one embodiment of the present disclosure. [Figure 11] 1 shows an ocular bioimpedance measuring device according to another embodiment. [Figure 12] 1 shows an ocular bioimpedance measuring device according to another embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Although the following text describes detailed descriptions of many different embodiments, it should be understood that the legal scope of the present invention is defined by the language of the claims set forth at the end of this patent. The detailed description should be construed as merely exemplary and does not describe all possible embodiments, as describing all possible embodiments would be impractical, if not impossible. Many alternative embodiments may be implemented using either current technology or technology developed after the filing date of this patent, and still be within the scope of the claims.

[0018] Bioimpedance is a measure of tissue resistance to an induced current or voltage. When a current is applied to the body, in whole or in part, bioimpedance represents the cumulative effect of the impedance of each of the components through which the current flows. These components include muscle tissue, bone, fat, intracellular and extracellular fluids, and blood. Blood, being a good conductor, affects impedance differently. Thus, physiological events or other induced events that regulate blood volume in the region of interest can be detected in the impedance. An example of this is the effect of ventilation, and even the cardiac cycle (Figure 5). Thus, electrical impedance across a segment of tissue increases when blood volume decreases and decreases when blood volume increases. For example, the Valsalva maneuver is expected to increase brain volume (and therefore decrease impedance) by increasing venous pressure and restricting venous return from the brain. Deep breathing is expected to show large variations in impedance because deep inspiration increases venous return from the brain, while breath holding is expected to minimize respiration-induced changes. The plots in Figures 5A-5D provide an example. Figure 6 shows the trends and changes over time in MAP, ICP, CBF, and impedance during the formation and subsequent removal of an epidural hematoma, a type of traumatic brain injury. As the plots in Figure 6 show, impedance (dz) increases with decreased blood volume (i.e., decreased CBF) and vice versa.

[0019] The present technology provides methods and systems for measuring brain bioimpedance through the eye or other parts of the ocular region using a bipolar array. Exemplary ocular bioimpedance devices are shown in Figures 7-9, 11, and 12. Due to the close proximity of the ocular bioimpedance device to the brain with a fluid interface and reduced intervening tissue (hair, scalp, muscle, bone), as well as the direct connection of the optic nerve to the brain, the present device is able to ensure that the brain is in contact with the majority of the current transmitted through the device. Because a small current can be applied through the eye, the resulting measured conductivity difference reflects the blood volume between the electrodes, which includes most of the brain.

[0020] As discussed further herein, we confirm the bioimpedance assessment through ocular measurements using various experimental techniques, such as increasing ICP using epidural balloon inflation, to demonstrate that changes in scalp or facial soft tissue blood flow are not responsible for the significant changes in impedance measured by the present technique. In this way, we demonstrate an entirely new bioimpedance pathway measurement that has not been recognized and isolated for measurement and evaluation heretofore, uncorrelated with traditional scalp-based measurement techniques. Furthermore, the present technique provides unexpected improvements in measuring bioimpedance and correlating the measurements with indices of brain health such as CBF, ICP, and CPP.

[0021] A variety of experimental techniques (hyperventilation, vasopressor infusion, epidural hematoma, and systemic hemorrhage) were used to alter the level of cerebral blood volume through changes in ICP, CPP, and CBF to test the efficacy of the present technique. In each case, the ocular impedance measurement technique was capable of detecting changes in cerebral blood volume associated with the event. These studies demonstrated the ability of the present technique to provide an effective mechanism for evaluating CARs and other intracranial events by monitoring changes in cerebral blood volume through impedance. Thus, the techniques herein may be used to provide an early assessment of patients with TBI or other brain injuries prior to performing invasive monitoring procedures on the patient, or in conjunction with such invasive monitoring, as a mechanism for evaluating the effect of other therapies on CARs or changes in cerebral blood volume.

[0022] Additionally, the present technique may be combined with other monitoring techniques. For example, approaches such as calculation of pressure reactivity index (PRx) (moving Pearson correlation between mean arterial pressure MAP and ICP) have been shown to provide an independent predictor of brain health. The ocular measurement, bioimpedance technique herein may be used in conjunction with PRx, and the use of additional concurrent metrics such as cerebral impedance allows for improved use of PRx, which is otherwise a high noise measurement. While overall tissue impedance can change over time, vary from individual to individual, and be affected by the type and placement of electrodes (cathode and anode), the present technique may reduce these effects by normalizing the impedance wave to its base value, eliminating the need for an index to a baseline or normal value. Additionally, PRx-type metrics utilizing MAP and cerebral impedance (using moving Pearson correlation or other computational techniques) may be used as accurate metrics of CAR.

[0023] The techniques herein can be used more broadly with PRx and CAR in many ways. In some instances, the bioimpedance measurement techniques herein are used to determine ICP, which allows more accurate PRx values ​​to be determined, and more accurate assessment of CAR results. In other instances, PRx may be determined independently, for example through known techniques, and PRx values ​​may be correlated with bioimpedance for more accurate assessment of CAR.

[0024] As an exemplary embodiment, PRx is determined independently and then correlated with bioimpedance measured using the techniques described herein. For example, bioimpedance can be combined with pressure reactivity index to generate a brain health index, where, like the PRx value itself, a negative value of the index indicates a healthy brain state of the subject (i.e., intact autoregulation) and a positive value of the index indicates an unhealthy brain state of the subject (i.e., impaired autoregulation). This combination is a mathematical combination. For example, the two values ​​can be correlated over a sample period using a moving Pearson correlation. In addition, a moving Pearson correlation can be generated using the MAP and dz measured by bioimpedance, allowing both PRx and additional MAP and dz correlations to be compared and tracked together.

[0025] We describe an exemplary testing procedure below. In the first example, we measured cerebral bioimpedance using an eye-brain interface in a novel way to assess real-time changes in cerebral blood volume in response to a number of physiological challenges. Because blood is a good electrical conductor, we hypothesized that changes in cerebral bioimpedance (dz) would track changes in cerebral blood volume. Six anesthetized pigs were instrumented for invasive monitoring of ICP, mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF). Bioimpedance was continuously monitored through ECG electrodes placed on the eyelids. Low currents (0.1-1 mA, 50 kHz) were applied and potentials were sensed through the same electrodes. Interventions such as hyperventilation, vasopressor administration, epidural hematoma formation, and systemic hemorrhage were used to manipulate levels of ICP, CPP, and CBF.

[0026] The results of the study showed that bioimpedance (dz) was highly correlated with changes in ICP, CPP, and CBF (r=-0.72 to -0.88, p<0.0001). The receiver operating curve (ROC) of dz was plotted at different thresholds of CPP and percent change in CBF. Area under the curve (AUC), sensitivity, and specificity were calculated for each threshold. dz was shown to have high predictive power with area under the curve between (0.80-1.00, p<0.003), with sensitivity and specificity varying between (83%-100%) and (70%-100%), respectively, demonstrating the ability of dz to track changes in cerebral blood volume in real time.

[0027] Thus, these experiments confirm that cerebral bioimpedance measured through an eye-brain interface can be used to track changes in CPP and CBF with high precision and are worthwhile for assessing changes in cerebral blood volume and CAR.

[0028] Hyperventilation: The ventilator was initially set to a baseline of 15-18 BPM to reach an end-tidal CO2 (PetCO2) of 35-40 mmHg. After the baseline reading, the respiratory rate (RR) was then increased 4-fold by 10 breaths until PetCO2 reached approximately 20 mmHg. PetCO2 was maintained at approximately 20 mmHg for 5-10 minutes. The RR was then decreased to the baseline level.

[0029] Vasopressor (norepinephrine) administration: Norepinephrine (4 μg / mL) was mixed with 500 mL of 5% dextrose and administered by continuous infusion, titrated to achieve a MAP of 160 mmHg or greater. MAP was maintained above 160 mmHg for 5 minutes, after which the infusion was stopped, allowing the animal's MAP to return to near baseline levels. Norepinephrine infusion was repeated three times.

[0030] Epidural hematoma: A simulated epidural hematoma was created using an 8F Foley catheter as described by Metzger and colleagues. The balloon was filled with 6-8 mL of saline at a rate of 0.5 mL / min. ICP was monitored as the balloon was inflated to reach an ICP of 35-45 mmHg. Pressure was maintained for up to 5 min, followed by deflating the balloon at the same rate to return the ICP to baseline levels.

[0031] Systemic bleeding: Finally, the animals were bled through the femoral artery at a rate of 50-100 mL / min. Bleeding continued without interruption for 16-20 min for a total volume of 800-1000 mL, corresponding to 30-40% of the animal's estimated total blood volume.

[0032] In a separate experiment, three human subjects consented and had electrodes placed on their closed eyelids for impedance monitoring using the same current and impedance monitoring parameters as described in the animal study. Volunteers were placed in supine position and then asked to perform the following maneuvers: normal breathing, deep breathing, breath holding, and Valsalva maneuver.

[0033] We examined and evaluated changes in oculo-cerebral impedance and cerebral and systemic hemodynamics (CBF, ICP, CPP, MAP, PetCO2) throughout baseline and during various maneuvers. Raw impedance signals were first smoothed and filtered using a repeated simple moving average (three passes through a 20-point moving average). Impedance change (dz) was calculated as dz = z max -z min ) / z max and transformed using the natural logarithm.

[0034] In two experiments, descriptive statistics were used to evaluate the effectiveness, showing the mean and standard deviation (SD) or median and interquartile range (IQR). A number of statistical analyses were utilized to compare the performance of dz with the invasive metrics of MAP, ICP, CBF, CPP, and PetCO2, as follows: Pearson correlation was used to allow visual inspection across a range of values. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) were constructed to evaluate the predictive value of dz across a certain range of CBF and CPP values. The ROC graph shows the relationship between true-positive and false-positive results, and the larger the AUC, the better the predictive value. The significance level was considered at α=0.05.

[0035] The results were as follows. In the first experiment, six animals with a mean (SD) body weight of 39.3 (0.75) kg were tested. Figure 2 shows baseline eye-brain bioimpedance recordings during mechanical ventilation, noting both respiration-induced changes as well as superimposed cardiac cycle changes. Table 1 shows the mean and (SD) values ​​of weight MAP, ICP, and CPP at baseline, as well as the range (minimum and maximum) and direction of changes during the various maneuvers. Pearson correlations showed high correlations between MAP, ICP, CPP, PetCO2, CBF changes and dz (r = 0.6-0.96, p < 0.0001) (see Table 1 and Figure 3).

[0036] The ROC of dz during manipulation was plotted at different thresholds of CPP and CBF change. The AUC, sensitivity, and specificity of dz during each manipulation were calculated, as shown in Table 2. dz showed high predictive ability with areas under the curve between (0.81-1.00, p<0.004). The sensitivity and specificity of the impedance method associated with the above thresholds varied between (0.75-1.00) and (0.80-1.00), respectively. Table 2 lists the various CPP and percent CBF change thresholds, as well as the corresponding AUC, sensitivity, and specificity of dz during manipulation.

[0037] To better understand and quantify the ability of the ocular route technique to capture or capture signals from the brain compared to the scalp, we performed another experiment in one additional animal. The effectiveness of ocular current injection was compared to injecting the same amount of current through the scalp by placing one pair of electrodes on the eyelid and another pair near the animal's ear at the same distance as the first pair. First, the resistance between the ocular and scalp electrodes was measured. Injecting current through the ocular route resulted in a resistance of 0.5 MΩ compared to 3 MΩ when current was injected through the scalp, indicating significantly superior conductance with ocular injection of current. Next, the power spectral density was used to compare the amplitude of the respiratory component of the dz (see Figure 4). Periodic breathing was controlled by a ventilator at a rate of 16 breaths per minute. The power of the respiratory component was 6.5 times greater when current was injected through the ocular route compared to the scalp route. When the animal was hyperventilated, the ratio increased 46 times (RR=56).

[0038] The voltage gradient was then measured in the brain by creating two burr holes in the skull equidistant between the ocular and scalp electrodes. The voltage gradient caused by the current was measured by periodically interrupting the current injection. This was repeated 20 times and averaged using each pair of electrodes. The results showed that the voltage gradient in the brain was 40% higher when the current was injected through the ocular pathway compared to the scalp pathway, indicating that a larger portion of the current passes through the brain when the current is injected through the ocular pathway. Finally, the animals were euthanized and the resistance between the two eyelids was measured in the absence of electrical fluctuations caused by changes in brain activity and blood flow. This was repeated after a craniotomy was performed and the brain was removed, followed by replacing the removed skull and scalp and suturing them back in place. The resistance was measured using the R T = 10kΩ, and then R S = 30 kΩ. Assuming a parallel model of the resistance of the brain and the remaining tissue between the eyelids, skin, and bone, the brain resistance was set to R B =R T R S / R S -R T) = 300 / 20 kΩ = 15 kΩ. As a result, the ratio of the current passing through the brain to the total current is I B / I T =R T / R B = 10 / 15. Thus, about two-thirds of the current injected through the ocular pathway passes through the brain. Although the current value of the electrical signal varies from subject to subject, using the improved techniques herein, bioimpedance can be measured from current values ​​less than about 10 mA, including less than 5 mA, such as 4 mA or less or 2 mA or less. The lower limit of the current value varies, but in some instances may be 1 mA, and in other instances may be even lower.

[0039] In the second experiment, impedance data collected from volunteer subjects showed similar impedance waveforms noted from the animal studies. Clear respiratory and cardiac cycle induced changes in the impedance waveform were observed. Deep inspiration and the Valsalva maneuver produced changes in impedance that would be expected from changes in cerebral blood volume produced by these respiratory maneuvers (see Figure 5).

[0040] 7-9 (as well as FIGS. 11 and 12) show different exemplary ocular bio-impedance devices and configurations.

[0041] FIG. 7 shows an exemplary ocular bio-impedance device 100 in the form of goggles having a first lens 102 formed from a cap that may be transparent, partially transparent, or opaque. In the illustrated example, the first lens 102 further includes one or more electrodes 104, shown in FIG. 8, at an interior ocular region engaging portion of the lens 102. The engaging portion is configured such that the one or more electrodes 104 are in conductive contact with the epidermis of the subject when the lens 102 is placed in place on the subject. The one or more electrodes 104 provide a conductive path to the skin for injecting an electric current into the subject at a contact point within, and thus through, the skin of the subject's ocular region. That conductive contact may be in direct contact with the skin (such as a closed eyelid), such that the contact point with the electrode 104 is direct, or that contact point may be through another electrical conductor positioned between the electrode 104 and the skin, for example, through a conductive film positioned on or around the ocular region to distribute the electric current more evenly to the patient. The device 100 includes a second lens 106 that may be similar or identical to the first lens 102, except that an electrode of the second lens 106 may be configured to sense the injected current from the first lens, thereby being used as a bioimpedance sensor. The electrode 108 of the second lens 106 may be in direct or indirect contact with the skin, similar to the electrode of the electrode 104. Additionally, although the current path is described as starting at the lens 102 and ending at the lens 106, such an orientation may be imposed by a control circuit coupled thereto (see, for example, FIG. 10). The control circuit may reverse the current flow direction and the operation would be the same. In some examples, the electrodes 104 and 108 are not identical, but the electrode pattern and / or positioning may differ. In such examples, the particular direction of current injection and sensing may be established based at least in part on the differences in those electrodes. The lenses 102 and 106 are physically connected by a bridge 110 formed of a non-conductive material to further provide proper electrical isolation of the electrodes 104 and 108.

[0042] FIG. 9 illustrates another exemplary configuration of an ocular bioimpedance device 200 similarly formed from a first lens 202 and a second lens 204. In device 200, each lens includes both an injection electrode 206 and a sensing electrode 208. The patterning of electrodes 206 and 208 may vary in pattern and location as well. In the illustrated example, injection electrodes 206 are disposed closer to the center of gravity of each lens 202 and 204, while sensing electrodes 208 are positioned further distally from the center of gravity. Alternatively, the opposite orientation may be used. In some examples, electrodes 206 and 208 may be positioned alternately around the engagement surface of the lenses. As in device 100, in some examples, only one of each electrode type is used on each lens.

[0043] Although examples are shown of the device in contact with the skin, in yet other examples, contact is achieved between the corneal tissue and the device in a contact lens type manner.

[0044] The ocular bioimpedance techniques herein may be implemented in devices that provide a combination of functions. For example, a lens-based device for measuring bioimpedance may be combined with a lens-based device that also includes an optical transmitter in the lens cap, a transmitter capable of providing light therapy to a patient, such as white light therapy through light-emitting diodes (LEDs), high color temperature light therapy (500 lux, 1000 lux, 1500 lux or greater), blue light therapy devices (e.g., emitting at wavelengths of 450 nm and 500 nm or therebetween), cerebral blood oxygenation monitoring, various near-infrared and infrared wavelengths (730-770 nm, 850-890 nm, 880-920 nm, 950-970 nm) for mitochondrial repair. Some such devices are used in the treatment of seasonal affective disorder (SAD) as well as migraines and other brain-related conditions. In yet another example, the ocular bioimpedance techniques herein may be used in conjunction with acoustic energy application devices such as those described in U.S. Patent No. 8,172,769, entitled "Method and apparatus for monitoring intra ocular and intra cranial pressure," the entire specification of which is incorporated herein by reference.

[0045] Examples of devices are shown in Figures 11 and 12. Figure 11 shows an ocular treatment device 400 having a lens 402 and a lens 406, each embedded with a photon therapy LED array 410 and 412, respectively. The LED arrays 410 and 412 may be positioned on the central portion of a cap forming the lens 402 and 406. These caps, like other exemplary lenses herein, may be opaque and block external light from impinging on the subject. Instead, in these examples, only photons from the arrays 410 and 412 impinge on the subject. Of course, in other examples, the lenses described herein may be transparent or semi-transparent (i.e., translucent). The arrays 410 and 412 generate photon stimulation through this integrated goggle configuration, thereby providing therapy to the subject and / or diagnostic information to the subject. The device 400 may be controlled by a controller, an example of which is described in Figure 10, that controls both the photon stimulation and the electrical signal. As shown in the examples of Figures 8 and 9, photonic stimulation may be provided during delivery of an electrical signal that is applied and sensed through an electrode (not shown) that may be positioned at the lens edge for ocular area contact. The electrode (not shown) provides the electrical signal for bioimpedance sensing and / or treatment of the subject. In some examples, the photonic stimulation signal does not overlap with the delivery of the electrical signal.

[0046] FIG. 12 shows a device 500 having lenses 502 and 504 integrated with an acoustic stimulation stage formed by two speakers 506 configured to provide acoustic stimulation for therapeutic or diagnostic purposes to a subject. Without being limited to these examples, the speakers may be earplug style headphones, over-the-ear headphones, small speakers mounted near the side or ocular area of ​​the subject, including the temples of the subject, etc. That is, the speakers 506 may be configured to provide acoustic stimulation at the ocular area and / or areas on the subject other than the ocular area. Electrodes (not shown) provide electrical signals for bioimpedance sensing and / or treatment of the subject. A controller such as that of FIG. 10 is used to control both the electrical signals and the acoustic stimulation signals.

[0047] FIG. 10 is an exemplary block diagram 300 illustrating various components used in implementing an exemplary embodiment of the ocular bio-impedance measurement technique herein. The analyzer 302 is coupled to a patient 320 (e.g., human or animal) via an ocular bio-impedance device 316, more specifically by a current injection electrode 350 electrically coupled to an ocular region of the patient 320, and a sensing electrode 352 also electrically coupled to an ocular region of the patient 320, in accordance with the performance of the functions of the disclosed embodiments. The analyzer 302 may have a controller 304 operatively connected to a database 314 via a link 322 connected to an input / output (I / O) circuit 312. Although not shown, it should be noted that additional databases may be linked to the controller 304 in a known manner. The controller 304 includes a program memory 306, a processor 308 (sometimes referred to as a microcontroller or microprocessor), a random access memory (RAM) 310, and an input / output (I / O) circuit 312, all of which are interconnected via an address / data bus 320. Although only one microprocessor 308 is shown, it should be understood that the controller 304 may include multiple microprocessors 308. Similarly, the memory of the controller 304 may include multiple RAMs 310 and multiple program memories 306. Although the I / O circuitry 312 is shown as a single block, it should be understood that the I / O circuitry 312 may include several different types of I / O circuitry. The RAM(s) 310 and the program memory 306 may be implemented, for example, as semiconductor memory, magnetically readable memory, and / or optically readable memory. A link 324 may operably connect the controller 304 to an ocular bioimpedance device 316 through the I / O circuitry 312. The ocular bioimpedance device 316 is operably connected to the patient 320 via electrodes 350 and 352.

[0048] The program memory 306 and / or RAM 310 may store various applications (i.e., machine-readable instructions) for execution by the microprocessor 308. For example, an operating system 330 may generally control the operation of the test apparatus 302 and provide a user interface to the test apparatus 302 for implementing the processes described herein. The program memory 306 and / or RAM 310 may also store various subroutines 332 for accessing specific functions of the test apparatus 302. By way of example and not limitation, the subroutines 332 may include, among others, subroutines for applying current to an ocular region, subroutines for taking bioimpedance measurements with the ocular bioimpedance device 316, subroutines for determining brain health indicators such as MAP, ICP, CBF, CPP, and eye-brain impedance, and other subroutines, such as implementing software keyboard functionality, interfacing with other hardware within the analysis apparatus 302, and the like. For example, the processes described above may be stored on the program memory 306 for execution by the processor 308. The program memory 306 and / or RAM 310 may further store data related to the configuration and / or operation of the analyzer 302 and / or related to the operation of one or more subroutines 252. For example, the data may be data collected by the ocular bio-impedance device 316, data determined and / or calculated by the processor 308, etc. In addition to the controller 304, the analyzer 302 may include other hardware resources. The analyzer 302 may also include various types of input / output hardware, such as a visual display 326 and input device(s) 328 (e.g., keypad, keyboard, etc.). In one embodiment, the display 326 is touch sensitive and may cooperate with a software keyboard routine as one of the software routines 332 to accept user input.It may be advantageous for the analytical device to communicate with a broader medical network (not shown) through any of a number of known networking devices and techniques (e.g., through a commuter network such as a hospital or clinic intranet, the Internet, etc.). For example, the analytical device may be connected to medical record databases, hospital administrative processing systems, medical professional terminals (e.g., doctor stations, nurse stations), patient monitoring systems, automated drug delivery systems such as smart pumps, smart infusion systems, automated drug delivery systems, etc. Thus, the disclosed embodiments may be used as part of an automated closed loop system or as part of a decision support system. By way of example, a network interface 334 is coupled to the I / O interface 312 to connect the analytical device 302 to the network 336 through a wired or wireless connection.

[0049] In this manner, the system 300 may be configured to determine the patient's bioimpedance and then further assess brain health, for example, by determining whether the bioimpedance changes over time, changes in response to a treatment, or changes based on some other condition. The system 300 is configured to determine and measure brain health indicators, such as MAP, ICP, CBF, CPP, and / or eye-brain impedance, over time. As will be further discussed, changes in brain impedance may be used to titrate certain therapies, such as MAP, ventilation parameters, ICP (by removing cerebrospinal fluid), blood and fluid infusions, to optimize CPP and preserve CAR to improve brain outcomes. For example, a decrease in brain impedance in response to an elevated MAP (indicating an abnormal CAR) may prompt a healthcare provider to reduce MAP. Another example may include an increase in impedance with no change in MAP, or current care may indicate an elevated ICP, thus prompting therapy to reduce ICP.

[0050] Thus, in further exemplary embodiments, the bioimpedance determination techniques herein are combined with treatment techniques to improve the effectiveness of such treatments.

[0051] For example, transcranial direct current stimulation (tDCS) has been proposed as a neuromodulation technique in the treatment of psychiatric disorders such as depression or schizophrenia, as well as in providing cognitive enhancements such as memory enhancement, executive function enhancement, attention enhancement, and fluency enhancement. The technique may involve applying direct current stimulation to the brain using electrodes placed externally on the skin at various locations on the scalp. However, the amount of current that actually penetrates the scalp and flows into the brain is believed to be very small. With the techniques herein, it is now possible to deliver higher levels of current to the brain by including electrodes in the ocular region, as outlined in the previous experiments that compared ocular-to-scalp pathways for their ability to penetrate the brain. This ocular pathway for the delivery of direct current may be combined with simultaneous or intermittent measurement of brain bioimpedance according to the present techniques, if desired, as a means to aid in monitoring therapy. This bioimpedance-based feedback may then be used to further guide treatment, either manually or by fully or partially automated computer processing of treatment signals. For example, in the context of determining enhanced PRx using the present techniques, a transcranial direct current stimulation controller that controls the electrical stimulation signal transmitted to the brain may be configured to automatically readjust the electrical signal (i.e., current value, frequency, waveform, voltage, etc.) in response to a change in enhanced PRx, e.g., from a change in PRx from a negative value to a positive value.

[0052] In some exemplary embodiments, conventional tDCS using the scalp as the current injection site can be directed by optimizing the location of the tDCS electrode using eye-brain bioimpedance signals. For example, the tDCS electrode can be positioned on the subject and treatment begins. The bioimpedance is measured, the electrode is placed in another location, and the bioimpedance is remeasured from there. By evaluating the bioimpedance at each location, or the brain health index determined from the bioimpedance at each location, the treatment professional can determine which tDCS electrode location is better for treating the subject, e.g., which location results in a better brain health index value.

[0053] These eye-brain region bioimpedance enhancement treatment techniques are not limited to tDCS. The techniques can be used in a similar manner with transcranial alternating current electrical stimulation (tACS) to control stimulation signal characteristics, tACS stimulation electrode location, etc. tACS is used similarly to tDCS for a number of neurological and neuro-psychiatric conditions ranging from stroke to depression. Thus, the eye-brain pathway techniques herein can be used to deliver tACS and / or tDCS and monitor brain bioimpedance, in addition to the eye-brain pathway of bioimpedance being used to optimize scalp electrode placement for tDCS and tACS.

[0054] In yet another example, these eye-brain bioimpedance enhancement procedures may include biophoton-based procedures and acoustic-based procedures. Biophoton procedures include proton photon stimulation of a subject and monitoring of the effects. These biophoton procedures include what are commonly referred to as red light therapy, blue light therapy, and infrared therapy, in which stimulating photons are provided through the subject's visual system. The bioimpedance technology described herein may be used to monitor the effectiveness of biophoton therapy, for example, by measuring brain health indicators during treatment and evaluating the effectiveness of the treatment accordingly.

[0055] Acoustic-based treatments may be analyzed in a similar manner. In some examples, acoustic energy is applied to the subject's head to detect an increase in intracranial pressure. For example, an acoustic eye patch is applied to the patient's eye or eyelid, and an ultrasonic sweep generator applies an acoustic signal across the patient's skull, and the signal is swept across a predetermined range. The eye patch has a piezoelectric film sensor for measuring the acoustic signal. In one embodiment, the predetermined range is within the ultrasonic band, and the analyzer determines a resonant frequency from the output of the sensor and an attenuation of the acoustic amplitude at said resonant frequency, and there is a correlation between said attenuation and the intracranial pressure. In another embodiment, the predetermined range includes a range below 20 kHz, and the analyzer determines retinal artery pulsation upon application of pressure to the eye until the pulsation disappears, and such pressure is a measure of intracranial pressure. These acoustic eye patches are composed of bioimpedance electrodes that measure the subject's eye-brain region bioimpedance during application of the acoustic signal. The effectiveness of the acoustic signal may then be evaluated based on changes in bioimpedance values ​​or brain health indicator(s) derived therefrom. Also, as with other treatment examples herein (tDCS, tACS, biophoton, etc.), treatment signals can be adjusted to improve brain health based on the measured bioimpedance response.

[0056] Throughout this specification, multiple instances may implement components, operations, or structures described as a single instance. Although individual operations of one or more methods have been illustrated and described as separate operations, one or more of the individual operations may be performed simultaneously, and the operations need not be performed in the order illustrated. Structures and functions presented as separate components in an example configuration may be implemented as a combined structure or component. Similarly, structures and functions presented as a single component may be implemented as separate components. These and other variations, modifications, additions, and improvements are within the scope of the subject matter of this specification.

[0057] Additionally, certain embodiments are described herein as including logic or a number of routines, subroutines, applications, or instructions. These may constitute either software (e.g., code embodied on a machine-readable medium or transmission signal) or hardware. In hardware, routines, etc. are tangible units capable of performing certain operations and may be configured or arranged in a certain way. In an exemplary embodiment, one or more computer systems (e.g., standalone, client or server computer systems), or one or more hardware modules of a computer system (e.g., processors or groups of processors), may be configured by software (e.g., applications or application portions) as hardware modules that operate to perform certain operations described herein.

[0058] In various embodiments, a hardware module may be implemented mechanically or electronically. For example, a hardware module may include dedicated circuitry or logic that is permanently configured (e.g., as a dedicated processor, such as a field programmable gate array (FPGA) or application specific integrated circuit (ASIC)). A hardware module may also include programmable logic or circuitry that is temporarily configured by software to perform certain operations (e.g., contained within a general-purpose processor or other programmable processor). It will be appreciated that the decision to mechanically implement a hardware module in a dedicated and permanently configured circuitry or in a temporarily configured circuitry (e.g., configured by software) may be made based on cost and time considerations.

[0059] Thus, the term "hardware module" should be understood to encompass tangible entities, that is physically constructed, permanently configured (e.g., hardwired), or temporarily configured (e.g., programmed) to operate in a certain manner or to perform certain operations described herein. Considering embodiments in which the hardware modules are temporarily configured (e.g., programmed), each of the hardware modules need not be configured or instantiated at any one instance of time. For example, if the hardware modules comprise a general-purpose processor configured using software, the general-purpose processor may be configured as different hardware modules at different times. Thus, the software may, for example, configure the processor to configure a particular hardware module at one instance of time and a different hardware module at a different instance of time.

[0060] Hardware modules can provide information to and receive information from other hardware modules. Thus, the described hardware modules can be considered to be communicatively coupled. When multiple such hardware modules are present simultaneously, communication can be achieved through signal transmission (e.g., via appropriate circuits and buses) connecting the hardware modules. In embodiments in which multiple hardware modules are configured or instantiated at different times, communication between such hardware modules can be achieved, for example, through storage and retrieval of information in a memory structure accessed by the multiple hardware modules. For example, one hardware module may perform an operation and store the output of that operation in a memory device to which it is communicatively coupled. An additional hardware module may then later access the memory device to retrieve and process the stored output. Hardware modules can also initiate communication with input or output devices and operate on resources (e.g., collecting information).

[0061] Various operations of the example methods described herein may be performed, at least in part, by one or more processors that are temporarily configured (e.g., by software) or permanently configured to perform the associated operations. Whether temporarily or permanently configured, such processors may constitute processor-implemented modules that operate to perform one or more operations or functions. Modules referred to herein may, in some example embodiments, include processor-implemented modules.

[0062] Similarly, the methods or routines described herein may be at least partially implemented in a processor. For example, at least some of the operations of the method may be performed by one or more processors or by hardware modules implemented in the processor. Certain performance of the operations may be distributed among one or more processors that are not only present in a single machine (having different processing capabilities) but also deployed across many machines. In some exemplary embodiments, the processor may be located at a single location (e.g., deployed in a field, office environment, or as part of a server farm), while in other embodiments, the processor may be distributed across many locations.

[0063] Unless otherwise indicated, discussions herein using terms such as "processing," "computing," "calculating," "determining," "presenting," "displaying," and the like may refer to actions or processes on a GPU thread that manipulate or transform data represented as physical (e.g., electrical, magnetic, or optical) quantities in one or more memories (e.g., volatile memory, non-volatile memory, or a combination thereof), registers, or other mechanical components that receive, store, transmit, or display information.

[0064] As used herein, any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment.

[0065] Some embodiments may be described using the terms "coupled" and "connected," along with their derivatives. For example, some embodiments may be described using the term "coupled" to indicate that two or more elements are in direct physical or electrical contact. However, the term "coupled" may also mean that two or more elements are not in direct contact with each other, but still co-operate or interact with each other. The embodiments are not limited in this context.

[0066] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," or any other variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, article, or apparatus that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Furthermore, unless expressly stated to the contrary, "or" means an inclusive or, not an exclusive or. For example, a condition A or B is satisfied by any one of A being true (or present) and B being false (or absent), A being false (or absent) and B being true (or present), and both A and B being true (or present).

[0067] In addition, the use of "a" or "an" is used to describe elements and components of the embodiments herein. This is done merely for convenience and to give a general sense of the description. This description and the following claims should be interpreted to include one or at least one, and the singular also includes the plural unless it is clear that this is not meant.

[0068] This detailed description should be construed as merely exemplary and does not describe every possible embodiment, as describing every possible embodiment would be impractical, if not impossible. Many alternative embodiments may be implemented using either current technology or technology developed after the filing date of this application.

Claims

1. 1. An apparatus for treating a brain condition in a subject, comprising: a housing configured to engage an ocular region of the subject, the housing having one or more electrodes configured to deliver an electrical signal to the ocular region of the subject; one or more processors; When executed by the one or more processors, the device and a computer-readable memory storing non-transitory instructions for causing the one or more electrodes to deliver electrical signals in the form of transcranial direct current stimulation (tDCS) and / or transcranial alternating current stimulation (tACS) to the ocular region of the subject to treat the brain condition.

2. 2. The device of claim 1, wherein the housing is a goggle having a first lens and a second lens, and the one or more electrodes are positioned on the inner surface of the first and second lenses, respectively, to provide an electrical conduction pathway from the ocular region to the brain of the subject.

3. 3. The device of claim 2, further comprising photon stimulation integrated with the goggles for providing therapeutic and / or diagnostic information, and configured to provide photon stimulation for therapeutic and / or diagnostic information to the brain through the ocular region.

4. The device of claim 3 , wherein the photonic stimulation is provided during delivery of the electrical signal.

5. The device of claim 3 , wherein the photon stimulation does not overlap with the providing of the electrical signal.

6. 3. The apparatus of claim 2, further comprising an acoustic stimulation stage configured to provide acoustic stimulation to the subject for therapeutic or diagnostic purposes.

7. The apparatus of claim 6 , wherein the acoustic stimulation stage is configured to provide the acoustic stimulation at the ocular region.

8. 7. The apparatus of claim 6, wherein the acoustic stimulation stage is configured to provide the acoustic stimulation in a region of the subject other than the eye region.

Images