WO2012106593A2 - Devices, systems, and methods for assessing peripheral nerve damage - Google Patents

Abstract

A system for assessing peripheral nerve damage in a subject is disclosed. The system includes a pressure application device and a computer. The system applies pressure to a selected body part of a subject in a desired pattern and continues application of pressure until a pain threshold for the subject is achieved.

Description

DEVICES, SYSTEMS, AND METHODS FOR

ASSESSING PERIPHERAL NERVE DAMAGE

Cross-Reference to Related Application

[0001] This patent application claims priority to U.S. Provisional Patent Application Serial No. 61/439, 198, entitled "DEVICES, SYSTEMS, AND METHODS FOR

ASSESSING PERIPHERAL NERVE DAMAGE" and filed on February 3, 2011, which is incorporated herein by reference in its entirety.

Statement of Government Support

[0002] This invention was made with United States government support under Grant R01 NS048463 awarded by the National Institutes of Health. The government has certain rights in this invention.

Field of the Invention

[0003] This invention relates to devices, systems, and methods for assessing peripheral nerve damage in a subject by monitoring the subject's pain threshold.

BACKGROUND

[0004] Small-fiber, peripheral sensory neuropathy has a significant impact on health and economic outcomes in the United States. Some neuropathies are caused by chemical neurotoxicity (e.g., pharmaceutical interventions, alcoholism, environmental toxins) and work-related injuries (e.g., carpal tunnel and hand-arm vibration syndromes), while others are caused by oxidative stress related to metabolic syndrome, diabetes, and age-related diseases. Secondary consequences of peripheral neuropathy include silent heart attack; cutaneous ulceration and infection; hearing deficit; dizziness; or decreases in motor function, fine motor skill, and balance. In some cases, consequences can be life-threatening.

[0005] Dying-back neuropathies, which lead to an increased pain threshold, most commonly result from ingestion of therapeutic agents with neurotoxic side effects and from metabolic disorders (e.g., diabetes). The most common complication of diabetes is neuropathy. In fact, diabetes is the most common cause of neuropathy in the western world. From 1980 to 2008, diabetes in the United States has more than tripled. An estimated 24 million individuals (7.8%) of the general population of the United States currently have diabetes. In the over-65 subpopulation, the diabetes rate is much greater, ranging from 18- 25%. In addition, in the United States, 25.9% of adults, and 35.4% of adults 60 years or

#1267884vl older, suffer from impaired fasting glucose and obesity, both of which are significant diabetes risk factors. The Center for Disease Control estimates diabetes rates in the United States may approach 33% of the general population by 2050. About half of diabetic patients develop peripheral neuropathy, from which a majority (80-90%) exhibit painless symptoms (e.g., loss of pain-related sensation) that progress to complete sensory loss on the extremities. Inability to sense injury increases risk of trauma, infection and eventual amputation. These demographic changes have created an expanding market for products that diagnose and monitor neuropathic symptoms and complications.

[0006] A principal barrier to the diagnosis, monitoring and understanding of dying-back neuropathy is a limited ability to directly quantify its effects on neural function. Separately, a critical barrier to increased utility of central nervous system (CNS) imaging is the lack of non-magnetic stimulators that quantitatively activate peripheral sensory pathways.

[0007] Current clinical electrophysiological techniques are unable to measure pathological changes in unmyelinated sensory axons. A traditional alternative is to biopsy either a sensory nerve trunk or cutaneous innervation for histological diagnosis. However, these approaches have significant risks. Currently-marketed thermal devices can measure increases in nociceptor (pain receptor) threshold produced by dying back neuropathy.

However, these thermal devices can also cause burn trauma to a patient due to the patient's loss of sensation. With repeated applications, heat can also be sensitizing, leading to an inflammatory response. These problems are particularly concerning for diabetic patients, who typically have compromised skin repair mechanisms and may experience heat-induced skin damage before the patient senses the stimulus. In contrast, through application of mechanical pressure, elevations in the pain threshold of a patient can be measured without inflammatory response. Hand-held pressure-sensing devices (i.e., algometers) range from spring gauges to electronic load cells used to locate areas of tenderness and "trigger points."

[0008] Regardless of the approach used, detection of hyposensitivity from neuronal damage has unique challenges, including measurement of a wide range of thresholds, ranging from normal to total analgesia. In addition, tissue compliance varies widely over the body surface from bone to soft tissue. To track neuropathic progression over time requires precise, repeated positioning of a stimulus probe at the original point of contact. Moreover, stable contact between the stimulus probe and underlying tissue must be maintained. [0009] Thus, the current concepts, treatments, and preventative interventions that drive this field rely on measurement techniques that target hyperalgesic states (e.g., chronic pain) instead of hypoalgesic states, which are caused by the necrosis and death (apoptosis) of pain- signaling neurons. More particularly, these currently known concepts, treatments, and preventative interventions do not directly measure unmyelinated fiber status, lack resolution (e.g., monofilaments and hand-held algometers), risk tissue injury (e.g., thermal devices), and are not used in conjunction with brain imaging. Consequently, there is little focus on measuring inactivation and damage to nociception-related pathways.

[0010] Accordingly, there is a need in the pertinent art for a system that can provide enhanced detection of early nerve damage and quantitative tracking of progressive injury to patients. There is a further need in the pertinent art for a system that can measure the mechanical pain threshold of peripheral sensory neuropathy patients in a safe and reproducible manner. There is still a further need in the pertinent art for a quantitative means of peripheral pathway activation that can be combined with brain imaging to identify normal nervous responses as well as neuroplastic changes produced by peripheral sensory neuropathy and chronic pain.

SUMMARY

[0011] Described herein is a system for assessing peripheral nerve damage in a subject. In one aspect, the system has a pressure application device for applying pressure to a selected body part of the subject. The pressure application device has a platform for supporting the selected body part, a probe for contacting and applying pressure to the selected body part, and means for moving the probe along a displacement axis such that the probe contacts and applies pressure to the selected body part. In another aspect, the system has a computer equipped with a processor and a memory in communication with the processor. The processor is in further communication with the means for moving the probe along the displacement axis. The processor is configured to activate the pressure application device to apply pressure to the selected body part in a desired patter. The processor is further configured to instruct the pressure application device to discontinue application of pressure to the selected body part when a pain threshold for the subject or a predetermined pressure level is achieved. Methods of using the system and the pressure application device are also disclosed. BRIEF DESCRIPTION OF THE FIGURES

[0012] These and other features of the preferred embodiments of the invention will become more apparent in the detailed description in which reference is made to the appended drawings wherein:

[0013] Figure 1 is a schematic diagram of an exemplary system for assessing peripheral nerve damage in a subject, as described herein.

[0014] Figure 2 is a perspective view of an exemplary pressure application device as described herein.

[0015] Figure 3 is a schematic diagram of exemplary means for moving the probe of a pressure application devices a described herein. The exemplary means for moving the probe of the pressure application device includes a pressure regulator assembly and a solenoid valve.

[0016] Figure 4 is a schematic diagram depicting exemplary configurations of the solenoid valve depicted in Figure 3.

[0017] Figures 5-9 describe various exemplary applications of the pressure application devices described herein.

[0018] Figures 10-12 display the results of an exemplary experimental use of an exemplary pressure application device as described herein.

DETAILED DESCRIPTION

[0019] The present invention can be understood more readily by reference to the following detailed description, examples, drawings, and claims, and their previous and following description. However, before the present devices, systems, and/or methods are disclosed and described, it is to be understood that this invention is not limited to the specific devices, systems, and/or methods disclosed unless otherwise specified, and, as such, can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0020] The following description of the invention is provided as an enabling teaching of the invention in its best, currently known embodiment. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the invention described herein, while still obtaining the beneficial results of the present invention. It will also be apparent that some of the desired benefits of the present invention can be obtained by selecting some of the features of the present invention without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present invention are possible and can even be desirable in certain circumstances and are a part of the present invention. Thus, the following description is provided as illustrative of the principles of the present invention and not in limitation thereof.

[0021] As used throughout, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a probe" can include two or more such probes unless the context indicates otherwise.

[0022] Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0023] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0024] In one embodiment, and with reference to Figures 1-4, the invention relates to a system for assessing peripheral nerve damage in a subject. In one aspect, the system 10 can comprise a pressure application device 12 for applying pressure to a selected body part of the subject. In an exemplary aspect, the selected body part of the subject can be one of a nail bed of a selected finger, such as, for example and without limitation, a thumb, and a nail bed of a selected toe, such as, for example and without limitation, a big toe. In another aspect, as shown in Figure 1, the system 10 can comprise a computer 40 and/or microprocessor 42 in communication with the pressure application device 12.

[0025] In one aspect, as shown in Figures 2-3, the pressure application device 12 can comprise a platform 14 for supporting at least a portion of the selected body part of the subject. In another aspect, the pressure application device 12 can comprise a probe 16 having a tip 18. In this aspect, it is contemplated that the tip 18 of the probe 16 can be configured to contact and apply pressure to at least a portion of the selected body part of the subject. It is further contemplated that the shape and dimensions of the tip 18 of the probe 16 can be selectively varied depending on the selected body part of the subject to which the probe applies pressure. In a further aspect, the pressure application device 12 can comprise means for moving the probe 16 along at least one displacement axis 20 such that the probe contacts and applies pressure to the selected body part of the subject. Optionally, in this aspect, the means for moving the probe along the at least one displacement axis can be configured to move the probe such that the probe applies a predetermined pressure to the selected body part of the subject. Thus, it is contemplated that the means for moving the probe along the at least one displacement axis can comprise, for example and without limitation, any conventional electrical, motorized, or pneumatic means for axial advancement of an object, provided the electrical, motorized, or pneumatic means permits sufficient control of the pressure applied to the selected body part of the subject. In one aspect, the predetermined pressure can range from about 0 psi to about 50 psi. However, it is contemplated that the predetermined pressure can be any pressure that is tolerated by a normal subject without inducing significant tissue injury to the selected body part. Optionally, in another aspect, where the selected body part of the subject is the nail bed of a selected finger of the subject, the pressure application device 12 can further comprise a hand grip 17 shaped to conform to a hand of the subject. In this aspect, it is contemplated that a top portion of the hand grip 17 can define the platform 14 of the pressure application device 12 and, consequently, support the selected finger of the subject. In a further aspect, the platform can be spaced from the probe along the at least one displacement axis 20.

[0026] As schematically depicted in Figure 1, in an additional aspect, the computer 40 can have a processor 42 and a memory 44 in communication with the processor. In this aspect, it is contemplated that the processor 42 can be in further communication with the means for moving the probe along the at least one displacement axis. In another aspect, the processor 42 can be configured to perform the step of activating the pressure application device 12 to apply pressure to the selected body part in a desired pattern. In a further aspect, the processor 42 can be configured to perform the step of instructing the pressure application device 12 to discontinue application of pressure to the selected body part when a pain threshold for the subject is achieved. In exemplary aspects, the system 10 can further comprise means for the subject to indicate that the pain threshold has been achieved.

Alternatively, in additional aspects, it is contemplated that the processor 42 can be configured to perform the step of instructing the pressure application device 12 to discontinue application of pressure to the selected body part when a predetermined pressure level is achieved. For example, and without limitation, it is contemplated that the predetermined pressure level can correspond to the maximal pressure level that can be achieved without causing tissue damage to the selected body part.

[0027] In one exemplary aspect, the desired pattern of applying pressure to the selected body part comprises application of a series of gradually increasing pressure stimulations. In this aspect, it is contemplated that each pressure stimulation can have a desired duration. In another aspect, it is contemplated that the increases in pressure between consecutive pressure stimulation can be substantially non-linear. In an additional aspect, it is contemplated that the desired duration of each pressure stimulation can vary among the series of pressure stimulations. In a further aspect, it is contemplated that, in between consecutive pressure stimulations of the series of pressure stimulations, there can be a release period corresponding to a time during which pressure is released from the selected body part of the subject. In this aspect, it is further contemplated that the duration of the release periods associated with the series of pressure stimulations can be variable. It is also contemplated that the desired series of pressure stimulations can be applied to the patient in a random sequence, i.e., not limited to a series of linear or non-linear step increases, but rather in a random application of varied pressure stimulations that can increase or decrease sequentially as the desired pattern of applying pressure to the selected body part is run.

[0028] In another aspect, the system 10 can further comprise a heart rate monitor 30 in electrical communication with the processor 42 of the computer 40. In this aspect, it is contemplated that the heart rate monitor 30 can be configured to produce a heart rate signal indicative of the heart rate of the subject. It is further contemplated that the system 10 can be configured to cease application of pressure to the selected body part of the subject when a predetermined heart rate of the subject is achieved. In an exemplary aspect, it is

contemplated that the heart rate monitor 30 can be incorporated into the hand grip 17 of the pressure application device 12.

[0029] In an additional aspect, the system 10 can further comprise a blood pressure monitor 32 in electrical communication with the processor 42 of the computer 40. In this aspect, it is contemplated that the blood pressure monitor 32 can be configured to produce a blood pressure signal indicative of the blood pressure of the subject. It is further contemplated that the system 10 can be configured to cease application of pressure to the selected body part of the subject when a predetermined blood pressure of the subject is achieved.

[0030] In a further aspect, the system 10 can further comprise an electrocardiogram device 34. In this aspect, the electrocardiogram device 34 can be positioned in electrical communication with the processor 42 of the computer 40.

[0031] In still another aspect, the system 10 can further comprise means for measuring skin conductance of the subject, such as, for example and without limitation, a conventional biofeedback monitor. In this aspect, it is contemplated that the means for measuring skin conductance can be in communication with the processor 42 of the computer 40. It is further contemplated that the means for measuring skin conductance can be configured to produce a signal indicative of the skin conductance of the subject.

[0032] In yet another aspect, the system 10 can further comprise a magnetic resonance imaging (MRI) machine 36. In this aspect, it is contemplated that the MRI machine 36 can be in communication with the processor 42 of the computer 40. In an exemplary aspect, it is contemplated that the pressure application device 12 can comprise non-magnetic materials that enable the pressure application device to be used effectively with the MRI machine 36.

[0033] In another aspect, the pressure application device 12 can further comprise at least one pressure sensor. Optionally, in one aspect, a pressure sensor 19 can be positioned within the tip 18 of the probe 16 and in electrical communication with the processor 42 of the computer. In an additional optional aspect, a pressure sensor 15 can be positioned within the platform 14 and in electrical communication with the processor 42 of the computer. In these aspects, it is contemplated that the at least one pressure sensor can be configured to produce a pressure signal indicative of the pressure applied to the selected body part of the subject.

[0034] In yet another aspect, the system 10 can further comprise at least one shield that is configured to be mounted between the patient and the pressure application device. It is contemplated that the at least one shield can be sized and shaped to block the visual sight lines of a patient being tested so that the sequence of pressure applications being applied by the pressure application device to the patient can be accomplished without the patient being able to visually discern the testing protocol.

[0035] In a further aspect, and with reference to Figure 1, the pressure application device 12 can further comprise a displacement monitor 22 for measuring axial movement of the probe 16 along the at least one displacement axis 20. In this aspect, it is contemplated that the displacement monitor 22 can be in communication with the processor 42 of the computer 40. It is further contemplated that the displacement monitor 22 can be configured to produce a displacement signal indicative of the distance by which the probe 16 is moved along the at least one displacement axis 20.

[0036] As shown in Figures 2-3, in one exemplary aspect, the means for moving the probe along the at least one displacement axis can comprise a chamber 24 containing a piston 26 operably coupled to the probe 16 of the pressure application device 12. In this aspect, it is contemplated that the piston 26 can be axially moveable within the chamber 24 along the at least one displacement axis 20. In another aspect, the means for moving the probe along the at least one displacement axis can further comprise at least one pressure regulator 28 in communication with the chamber 24. In this aspect, it is contemplated that the at least one pressure regulator 28 can be configured to generate sufficient pressure within the chamber 24 to advance the piston 26 along the at least one displacement axis 20 such that the probe 16 applies pressure to the selected body part of the subject in the desired pattern. In exemplary aspects, the at least one pressure regulator 28 can comprise an air inlet for receiving pressurized air. In another aspect, the at least one pressure regulator 28 can comprise a pump for pumping pressurized air into the air inlet. In an additional aspect, it is contemplated that each pressure regulator 28 of the at least one pressure regulator can comprise a conventional pressure valve, such as, for example and without limitation, a solenoid valve 29. In one exemplary aspect, each pressure regulator 28 can comprise a 2-port, 2-position (2/2) solenoid valve. In this aspect, it is contemplated that the solenoid valve of each pressure regulator 28 can be in selective electrical communication with a power switch that is moveable about and between an on position and an off position. It is further contemplated that the solenoid valve of each pressure regulator 28 can be in communication with the processor 42 of the computer 40. In another exemplary aspect, the at least one pressure regulator 28 can comprise three pressure regulators, and each pressure regulator can be configured to regulate pressure at predetermined pressure output levels. For example, as shown in Figure 3, the at least one pressure regulator can comprise a high-pressure regulator (labeled H), a medium-pressure regulator (labeled M), and a low-pressure regulator (labeled L).

[0037] In another aspect, and with reference to Figures 2-4, the chamber 24 can have a first port 25a and a second port 25b for receiving pressurized gas from the at least one pressure regulator 28. In this aspect, it is contemplated that the piston 26 can be positioned between the first port 25a and the second port 25b along the at least one displacement axis 20. In an additional aspect, as shown in Figures 3-4, the means for moving the probe along the at least one displacement axis can further comprise a solenoid valve 29 positioned between and in communication with the at least one pressure regulator 28 and the first port 25a and second port 25b of the chamber 24. In this aspect, it is contemplated that the solenoid valve 29 can be in electrical communication with the processor 42 of the computer 40. As depicted in Figure 4, in a further aspect, the solenoid valve 29 can be moveable between a first position and a second position. In this aspect, it is contemplated that, in the first position, the solenoid valve 29 can be configured to apply pressure to the piston 26 through the first port 25a such that the probe 26 is moved along the at least one displacement axis 20 toward the selected body part of the subject. It is further contemplated that, in the second position, the solenoid valve 29 can be configured to apply pressure to the piston 26 through the second port 25b such that the probe 16 is moved along the at least one displacement axis 20away from the selected body part of the subject. In exemplary aspects, the solenoid valve 29 can be a 4-port, 2-position solenoid valve or a 5-port, 2-position (5/2) solenoid valve.

[0038] As shown in Figure 2, it is contemplated that the system 10 can comprise a frame 50 configured to stabilize the pressure application device 12. In exemplary aspects, the frame 50 can define an open space within which the probe 16 of pressure application device 12 can be operatively positioned for selective movement along the at least one displacement axis 20. In exemplary aspects, the frame can comprise means for adjusting the position of the pressure application device within a plane substantially perpendicular to the displacement axis 20 along which the probe moves (as shown in Figure 2). In these aspects, as shown in Figure 2, it is contemplated that the means for adjusting the position of the pressure application device 12 within the described plane can comprise two pairs of spaced knobs 52 and 54 that are operatively coupled to the pressure application device. Each pair of knobs can be configured to effect movement of the pressure application device 12 along a particular axis; the first pair of knobs 52 can be configured to effect movement of the device along a first axis, and the second pair of knobs 54 can be configured to effect movement of the device along a second axis. Among each pair of knobs, rotation of a first knob can correspond to movement of the device 12 in a first direction along the axis, while rotation of a second knob can correspond to movement of the device in an opposite direction along the axis. In an exemplary aspect, the frame can comprise a threaded backer block that is coupled to the device 12 and at least one pair of knobs, thereby providing operative coupling between the at least one pair of knobs and the device. In another exemplary aspect, the knobs of the first and second pairs of knobs 52 and 54 can comprise knurled plastic knobs.

[0039] In use, the disclosed system can be incorporated into a method for assessing peripheral nerve damage in the subject. In one aspect, the method can comprise providing a pressure application device comprising a platform and a probe, as described herein. In another aspect, the method can comprise positioning the selected body part of the subject on the platform of the pressure application device.

[0040] In an additional aspect, the method for assessing peripheral nerve damage in the subject can comprise selectively moving the probe along the at least one displacement axis such that the tip of the probe contacts and applies pressure to the selected body part of the subject. In this aspect, the step of selectively moving the probe along the displacement axis can comprise moving the probe along the at least one displacement axis such that a series of gradually increasing pressure stimulations are applied to the selected body part of the subject. It is contemplated that each pressure stimulation can have a desired duration. It is further contemplated that the increases in pressure between consecutive pressure stimulations can be substantially non-linear. It is still further contemplated that the desired duration of each pressure stimulation can vary among the series of pressure stimulations. It is still further contemplated that, in between consecutive pressure stimulations of the series of pressure stimulations, there is a release period corresponding to a time during which pressure is released from the selected body part of the subject. It is still further contemplated that the duration of the release periods associated with the series of pressure stimulations can be variable. It is also contemplated that the desired series of pressure stimulations can be applied to the patient in a random sequence, i.e., not limited to a series of linear or non-linear step increases, but rather in a random application of varied pressure stimulations that can increase or decrease sequentially as the desired pattern of applying pressure to the selected body part is run.

[0041] In a further aspect, the method for assessing peripheral nerve damage in the subject can comprise measuring the pressure applied to the selected body part of the subject. In still another aspect, the method can comprise measuring the axial movement of the probe along the at least one displacement axis.

[0042] In yet another aspect, the method for assessing peripheral nerve damage in the subject can comprise monitoring whether a pain threshold for the subject is achieved. In this aspect, it is contemplated the step of monitoring whether the pain threshold is achieved can comprise receiving feedback from the subject in response to the application of pressure to the selected body part of the subject. It is further contemplated that the step of monitoring whether the pain threshold is achieved can comprise determining whether a predetermined threshold pressure is applied to the selected body part of the subject. It is still further contemplated that the step of monitoring whether the pain threshold is achieved can comprise determining whether the probe has been moved along the displacement axis by a

predetermined distance.

[0043] In still a further aspect, the method for assessing peripheral nerve damage in the subject can comprise discontinuing application of pressure to the selected body part of the subject when the pain threshold of the subject is achieved. Alternatively, in additional aspects, it is contemplated that the processor can be configured to perform the step of instructing the pressure application device to discontinue application of pressure to the selected body part when a predetermined pressure level is achieved. For example, and without limitation, it is contemplated that the predetermined pressure level can correspond to the maximal pressure level that can be achieved without causing tissue damage to the selected body part.

[0044] Optionally, in another aspect, the method for assessing peripheral nerve damage in the subject can further comprise the step of measuring the heart rate of the subject. In this aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise determining whether a predetermined threshold heart rate of the subject has been achieved.

[0045] Optionally, in an additional aspect, the method for assessing peripheral nerve damage in the subject can further comprise the step of measuring the blood pressure of the subject. In this aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise determining whether a predetermined threshold blood pressure of the subject has been achieved. It is further contemplated that

predetermined threshold blood pressure can be one of a predetermined mean, diastolic, or systolic blood pressure.

[0046] In additional aspects, the step of monitoring whether the pain threshold has been achieved can comprise receiving a report of pain from the subject. In one aspect, it is contemplated that the report of pain can be a verbal report of pain from the subject. For example, it is contemplated that the subject can provide a description of the experienced pain, such as, for example and without limitation, "sharp," "dull," or "aching." It is further contemplated that the subject can provide a numeral indicative of the magnitude of experienced pain, such as a number between 1 and 10, with 10 being indicative of the most intense pain. In another aspect, it is contemplated that the report of pain can be non-verbal. For example, and without limitation, it is contemplated that the non-verbal report of pain can be at least one of: a written description of pain; holding up a sign indicative of the magnitude of experienced pain; pointing to an indicator of the magnitude of experienced pain; pressing a button in communication with the processor of the system, the button being indicative of the magnitude of experienced pain; and entering an indicator of the magnitude of experienced pain using a keypad in communication with the processor of the system.

[0047] In a further aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise monitoring whether a predetermined threshold respiration rate of the subject has been achieved. In still a further aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise monitoring whether a pupil of the subject has expanded to a predetermined diameter. In yet another aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise whether the skin of the subject has reached a predetermined threshold skin resistance. In still another aspect, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise monitoring the activation of the subject's CNS pain pathway through analysis of an electroencephalogram (EEG) or other conventional monitoring technique. In exemplary aspects, it is contemplated that the step of monitoring whether the pain threshold has been achieved can comprise correlating changes in various monitored parameters, including, for example and without limitation, the parameters described herein. It is further contemplated that the step of monitoring whether the pain threshold has been achieved can comprise determining whether the correlated monitored parameters form a pattern that is indicative of achievement of the pain threshold.

[0048] Optionally, in a further aspect, the method for assessing peripheral nerve damage in the subject can further comprise comparing the measured pain threshold of the subject to the pain threshold of healthy subjects. It is further contemplated that the pain threshold of the subject can be age-corrected as appropriate to improve diagnostic accuracy. It is still further contemplated that the method can comprise tracking the progression of the subject's pain threshold over time.

[0049] In use, the disclosed system can also be incorporated into a method for monitoring changes of the pain threshold in the peripheral nerves of the subject. In one aspect, the method can comprise providing a pressure application device comprising a platform and a probe, as described herein. In another aspect, the method can comprise positioning the selected body part of the subject on the platform of the pressure application device.

[0050] In an additional aspect, the method for monitoring changes of the pain threshold of the subject can comprise selectively moving the probe along the displacement axis such that the tip of the probe contacts and applies pressure to the selected body part of the subject. In a further aspect, the method can comprise measuring the pressure applied to the selected body part of the subject. In still another aspect, the method can comprise measuring the axial movement of the probe along the displacement axis.

[0051 ] In yet another aspect, the method for monitoring changes of the pain threshold in the peripheral nerves of the subject can comprise measuring the pain magnitude experienced by the subject during application of pressure to the selected body part of the subject. In still another aspect, the method can comprise comparing the measured pain magnitude corresponding to a selected applied pressure to the pain magnitude experienced by normal patients upon application of the selected applied pressure. In yet another aspect, the method can comprise comparing the measured pain magnitude corresponding to a selected applied pressure to one or more previously recorded pain magnitudes for the subject corresponding to the selected applied pressure. In still a further aspect, the method can comprise determining whether the pain threshold for the subject has changed. In additional aspects, it is contemplated that the measured pain magnitude can be age-corrected as appropriate to improve diagnostic accuracy.

[0052] In one exemplary non-limiting aspect, the step of measuring the pain magnitude experienced by the subject can comprise receiving feedback from the subject indicative of the pain magnitude. In another aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the strength of the grip of the subject during application of pressure to the selected body part of the subject. In this aspect, it is contemplated that the magnitude of the strength of the grip can correspond to the pain magnitude experienced by the subject. In an additional aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the finger pinch strength of the subject during application of pressure to the selected body part of the subject. In this aspect, it is contemplated that the magnitude of the finger pinch strength can correspond to the pain magnitude experienced by the subject.

[0053] In a further aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring a movement by the subject. In this aspect, it is contemplated that the amount of movement by the subject can correspond to the pain magnitude experienced by the subject. In one exemplary aspect, the measured movement by the subject can be movement of a handle. In another exemplary aspect, the measured movement of the subject can be twisting of a pointer.

[0054] In another aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the intensity of a beam of light controlled by the subject. In this aspect, it is contemplated that the intensity of the beam of light can correspond to the pain magnitude experienced by the subject. In a further aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the finger span of the subject. In this aspect, it is contemplated that the finger span can be indicative of the separation between the thumb and the index finger of a hand of the subject. It is further contemplated that the measured finger span of the subject can correspond to the pain magnitude experienced by the subject. It is still further contemplated that the finger span of the subject can be measured using a conventional potentiometer coupled to the fingers of the subject. In still another aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the heart rate of the subject. In this aspect, it is contemplated that the heart rate of the subject can be indicative of the pain magnitude experienced by the subject.

[0055] In an additional aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the blood pressure of the subject. In this aspect, it is contemplated that the measured blood pressure of the subject can be indicative of the pain magnitude experienced by the subject. In still another aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the body temperature of the subject. In this aspect, it is contemplated that the body temperature of the subject can be indicative of the pain magnitude experienced by the subject. In still a further aspect, the step of measuring the pain magnitude experienced by the subject can comprise measuring the skin conductance of the subject. In this aspect, it is contemplated that the skin conductance of the subject can be indicative of the pain magnitude experienced by the subject. In additional aspects, the step of measuring the pain magnitude experienced by the subject can comprise measuring one of the respiration rate and the pupil diameter of the subject, which can be indicative of the pain magnitude experienced by the subject. In still a further aspect, the step of measuring the pain magnitude experienced by the subject can comprise monitoring the activation of the CNS pain pathway of the subject through analysis of an EEG or other conventional monitoring technique.

[0056] In additional aspects, it is contemplated that the disclosed devices and systems can be employed in methods for monitoring a subject's response to subthreshold (below the pain threshold of a subject) and/or suprathreshold (above the pain threshold of a subject) pressures. It is further contemplated that these methods can correspond to the methods previously described herein except that these methods are not used to monitor changes in pain threshold, but are instead used to monitor a subject's response to application of subthreshold and/or suprathreshold pressures. In one exemplary aspect, it is contemplated that the methods for monitoring a subject's response to subthreshold and/or suprathreshold pressures can be used to measure and track a subject's tactile sensation of touch. In other aspects, when the disclosed methods are used to apply suprathreshold pressures to a subject, it is contemplated that the subject's responses to particular qualities of pain can be measured and monitored. In these aspects, the qualities of pain can include, for example and without limitation, pricking, stinging, burning, sharpness, dullness, and the like. It is further contemplated that neuropathy and other chronic pain conditions can alter the ability of a subject to experience one or more qualities of pain.

[0057] In exemplary aspects, it is contemplated that the disclosed methods can be used in a "double-blind" manner such that neither the subject nor the doctor/operator is aware of when the application of pressure to the subject will occur. For example, it is contemplated that the subject can take an action as described herein to cease application of pressure. It is further contemplated that a sequential application of pressure can occur at a time that is unknown to both the subject and the doctor/operator.

[0058] Except where indicated to the contrary, it is contemplated that the components of the disclosed devices and systems can be used in combination with one another as necessary to appropriately assess peripheral nerve damage or changes to pain threshold in a subject. Exemplary Applications

[0059] It is contemplated that the nail bed of a finger or a toe of the subject can evenly distribute the applied pressure. It is further contemplated that the nail bed of a finger or a toe of the subject will not adapt to repeated stimulations and will not be damaged by applied pressures that are above a pain threshold of the subject. However, the selected body part of the subject can be any body part of the subject that permits assessment of changes in the pain threshold within the subject. It is contemplated that the selected body part can be selected depending on whether the disclosed devices, systems, and methods are being used to assess decreases in pain threshold, such as those related to increased sensitivity to pain, including hyperalgesia and allodynia, or increases in pain threshold, such as in hypoalgesia, including hypoalgesia produced by neuronal death associated with diabetes.

[0060] When the disclosed devices, systems, and methods are used to assess increased sensitivity to pain, it is contemplated that the pain threshold of the subject should be measured at sensitive "trigger points." For example, it is contemplated that when the disclosed devices, systems, and methods are used to diagnose fibromyalgia or some headache symptoms, the "trigger points" can be located along the neck of the subject.

[0061] When the disclosed devices, systems, and methods are used to assess decreased sensitivity to pain, it is contemplated that pressure can be applied to areas of peripheral nerve innervation on the body of the subject as described herein to track and quantify nerve regeneration, such as nerve regeneration that occurs following nerve or surgical repair of tendons, including nerve regeneration associated with physical rehabilitation. In another aspect, when the disclosed devices, systems, and methods are used to assess decreased sensitivity to pain associated with late-stage carpal tunnel syndrome, in which scar tissue replaces nerve fibers, the selected body part of the subject can be selected depending on the distribution of nerve innervation. In additional aspects, the selected body part can be the glabrous surfaces of the hands and feet of the subject. It is contemplated that the glabrous surfaces can comprise small areas of denervation that can be at increased risk of injury. For example, the feet of a diabetic subject can have altered pressure profiles that can lead to nerve and tissue damage, as well as problems in detecting tissue injury and in selecting shoes to wear. In particular, it is contemplated that identification of areas on the selected body part with greatest loss of pain sensitivity can be used to design appropriate orthotics for the subject. [0062] In some nerve compression syndromes (radiculopathies), the nerves of a subject can compress where they enter the spine, thereby leading to either increased or decreased pain thresholds. It is contemplated that the disclosed devices, systems, and methods can be used to measure pain threshold over the spine of the subject to localize the area of nerve compression in the subject.

[0063] In exemplary aspects, the disclosed devices and systems can be coupled with brain imaging technologies to identify specific areas of the brain or spinal cord of the subject that are injured or have been modified by neuroplastic mechanisms associated with conditions such as chronic pain, depression, or stressful events, such as, for example and without limitation, events related to post-traumatic stress disorder. In these aspects, it is contemplated that pressure can be applied to a plurality of body parts of the subject to assess the subject's pain threshold at various body surfaces. In another exemplary aspect, it is contemplated that stimulation at different dermatome levels can be used to determine the location of a spinal cord tumor that is blocking transmission of pain-related information.

[0064] In one aspect, it is contemplated that the disclosed devices, systems, and methods can be used to detect nociceptor nerve damage within a foot of a subject. In this aspect, it is contemplated that nociceptor damage within the foot of a subject can be indicative of a generalized foot injury that can lead to compromised circulation, foot amputation, infection, and, potentially, death.

[0065] In another aspect, it is contemplated that the disclosed devices, systems, and methods can be used to assess damage to pain-signaling fibers within the heart of a subject. In this aspect, it is contemplated that damage to pain-signaling fibers within the heart can increase the risk of the subject suffering a silent heart attack and, subsequently, heart failure. It is further contemplated that, although the disclosed devices, systems, and methods cannot directly measure damage to these pain-signaling fibers, there can be a strong correlation between cutaneous nociceptor damage and nociceptor damage in the heart.

[0066] In an additional aspect, it is contemplated that the disclosed devices, systems, and methods can be used in a screening program for detecting heart attack risk factors. In this aspect, it is contemplated that peripheral diabetic neuropathy can be present in a subject before the subject fully develops diabetes. It is further contemplated that such subjects can suffer early damage to sensory nerves in the heart, thereby contributing to the heart attack risk of the subjects. [0067] In a further aspect, it is contemplated that the disclosed devices, systems, and methods can be used in the drug development process. In this aspect, it is contemplated that the disclosed devices, systems, and methods can be used to demonstrate efficacy of medications that are used to treat diabetic neuropathy in human populations.

[0068] Similarly, in another aspect, it is contemplated that the disclosed devices, systems, and methods can be used to identify drugs that are most efficacious at treating the diabetic neuropathies suffered by individual patients. It is further contemplated that the disclosed devices, systems, and methods can be used to determine appropriate dosing profiles for individual patients who are taking medications to treat diabetic neuropathy.

[0069] In still another aspect, it is contemplated that the disclosed devices, systems, and methods can be used in drug selection by helping patients to avoid ingestion of drugs that are likely to increase their risk of peripheral sensory neuropathy. For example, it is contemplated that the disclosed devices, systems, and methods can be used in drug selection and rotation for patients who are prescribed anti-arthritic drugs, which typically are associated with a high risk of peripheral sensory neuropathy.

[0070] In still a further aspect, it is contemplated that the disclosed devices, systems, and methods can be used to monitor peripheral nerve damage that is caused by drug interactions. In one exemplary aspect, it is contemplated that the disclosed devices, systems, and methods can be used to monitor whether combined therapy with platinum-based compounds, such as cisplatin, taxanes, such as Taxol, and other anti-cancer drugs is leading to peripheral sensory neuropathy. It is further contemplated that, if physicians can determine the extent of peripheral nerve damage in a patient, then the physicians can be more aggressive when prescribing medications.

Functional Magnetic Resonance Imaging (fMRI Applications

[0071 ] In a particular exemplary application, fJVIRI procedures can be performed on a normal subject population on three different days, with a one-week interval in between each of the three procedures (see Figure 5B). Each subject can be placed in an fMRI device, with the subject's vital signs (heart rate, blood pressure, respiratory rate) being monitored until they reach a stable, resting level (requiring about 5 min). Recording of endpoint

physiological variables can continue throughout the procedure. A baseline scan can be collected to document the central nervous system (CNS) "resting state." After about two- minutes, the stimulation can be applied using the pressure application devices and systems described herein. During the stimulus cycle (shown in Figure 5A), pressure can gradually increase until the pain threshold is reached. The pressure increase (0.1 psi/sec, as shown in Figure 5 A) can be slow enough for subjects to react before the stimulus pressure increases significantly beyond the pain threshold. During stimulation, the subject can always have the option of immediately stopping the stimulation by removing their thumb from the apparatus (see Figure 2), at which point pressure on the nail bed immediately decreases to zero.

[0072] Three different techniques can be tested to determine which provides the clearest indication of pain pathway activation with the least interference from co-activated neural circuitry. For example, CNS speech pathway activation is necessary to verbally indicate pain threshold. Alternatively, pressing an "event button" activates CNS pathways for hand/finger movement (e.g., somatosensory and motor areas). The order of trials can be randomized with at least a 4-min interval between trials. For example, the first trial can require the subject to push an event button when she/he detects pain, the second trial can require the subject to verbally indicate her/his pain threshold to the supervising user, and the third trial can be based upon an automatic response (in accordance with real-time monitoring of the subject's heart rate, blood pressure, and respiratory rate). When an upward trend (greater than 10%) of one or more variables is detected, it can be assumed that pain threshold has been exceeded.

[0073] When the stimulus pressure reaches pain threshold, the supervising user halts the increase in probe pressure being applied to the subject. Since approximately 2.5 seconds are required to perform a whole head scan, the stimulus probe pressure can be maintained at the threshold level for about 5.0 seconds to ensure that peak brain activation is captured, after which the probe pressure can be returned to zero. The lag between neural circuit activation and change in blood flow is approximately 20 sec; therefore, the brain imaging process can continue for at least 25 sec following pain detection in order to capture the entire dynamic change in neural activation. After the brain scan is completed, the subject can be asked to confirm that pain threshold has been exceeded and to estimate the maximum pain magnitude the subject experienced on a Visual Analog Scale (VAS, 0=no pain, 10= worst imaginable pain). An fMRI operator can oversee the brain-imaging and data analysis, and a

neuroanatomist can oversee the mapping of total brain activation patterns with each triggering technique discussed above. This information can be used to identify the technique for indicating pain threshold that provides the clearest discrimination of pain pathway activation. The neuroanatomist can be blinded as to the type of triggering event that is associated with each scan. [0074] As shown in Figure 5A, there is a Maximum Pressure Limit that cannot be exceeded during stimulation (The device can have a pressure limiting valve that regulates this level). It is contemplated that pressure at pain threshold in normal subjects can be about 6 pounds/square inch (psi, standard deviation [std dev] =2.3, N=10). It is further contemplated that the stimulus pressure required to produce a pain rating of 6-7 on a 10 point VAS scale (0=no pain, 10= maximum tolerable pain) can be about twice this threshold (mean = 12 psi, std dev = 5). It is contemplated that such a pressure level does not produce nail bed injury or sensitization. Thus, because it is contemplated that there will be no injury at 12 psi, the Maximum Pressure Limit for these applications can initially be set to about 24 psi (four times threshold). Of course, it is contemplated that this level can be lowered if necessary.

[0075] The study coordinator can examine the subject's nail bed and surrounding tissue for signs of injury before each procedure. In addition, the coordinator can examine the finger immediately following each stimulation (Visits 2, 3, 4) for signs of injury and ask the subject to report any tenderness or other sign of injury. If injury is observed before stimulation, the time and date of stimulation is delayed until the area to be stimulated has recovered. If recovery is delayed more than 2 weeks, the subject is removed from the study, but is followed up until the injury resolves. All injuries can be tracked daily by phone interview or direct observation until resolution. If injury is documented, the study physician can determine whether to lower the Maximum Pressure Limit for all remaining trials.

[0076] Given that repeated threshold measurements are collected, a mixed effects linear regression model can be fitted to the various outcome variables. This model correctly accounts for the lack of independence of the repeated measurements nested within study subject data. It also allows for an unequal number of completed follow-up visits, as well as unequal spacing of the visits as patients inevitably return to the clinic at varying time intervals. Age and gender can be included as covariates in this model.

[0077] A great disadvantage of using thermal devices to measure pain (in addition to the possibility of producing severe thermal injuries in patients with dying back neuropathy) is that they are sensitizing and therefore obtaining repeated measures during brain imaging is not feasible. It is contemplated that the above-described procedures can be used to test whether physiological indices of pain response (heart rate, blood pressure and respiration rate) differ significantly from baseline when pain threshold is exceeded using mixed effects linear regression models. It is further contemplated that the above-described procedures can be used to determine which physiological indicator of pain is the earliest indicator of pain threshold. It is still further contemplated that the above-described procedures can be used to determine whether the three different threshold triggering techniques correlate with activation of pain-related pathways in the fJVIRI imaging. Each triggering technique at the point of its time mark is an interval scale, or continuous variable. The pain-related pathway is likewise an interval scale that is recorded simultaneously with the pressure measurement. These pairs of measurements are collected three times during each of three visits. To test for correlation, then, a mixed effects linear regression model can be fitted to these data to account for the repeated measurements. It is still further contemplated that the above-described procedures can be used to determine which of the three triggering techniques produces the clearest indication of pain pathway activation and least "cross-talk" with non pain-related pathways. To perform this analysis, the neuroanatomy consultant, who is blinded as to category, can rank the scans according to which have the cleanest imaging. The category rankings will then be tested for significance using a Chi Square test. For each task where an intraclass correlation coefficient (ICC) is measured, a Bland-Altman analysis can be performed to assess if differences between repeated measurements of pain are within clinically acceptable agreement.

Conduction Velocity Applications

[0078] In additional exemplary applications, the devices and systems described herein can be used to study subjects that have been diagnosed with diabetic neuropathy. Subjects can participate in a sensory nerve conduction latency experiment in which stimulating electrodes are placed over the median nerve proximal to the wrist and recording electrodes in the sensory nerves of the middle finger. Standard electrophysiology equipment (Viking Quest, Nicolet, Inc.) can record the latency of the sensory compound action potential at the level of the middle finger. Conduction velocity can be calculated by distance between stimulating and recording electrodes by the conduction latency from stimulus artifact to peak of compound wave. Patients with a history of carpal tunnel or other non-diabetic peripheral neuropathy can be excluded from the study.

[0079] Diabetic skin can be damaged more easily than normal skin and loss of protective sensation in diabetic neuropathy can increase risk of injury. It is contemplated that pressure at pain threshold in normal subjects can be about 6 pounds/square inch (psi, standard deviation [std dev] =2.3, N=10). It is further contemplated that the stimulus pressure required to produce a pain rating of 6-7 on a 10 point VAS scale (0=no pain, 10= maximum tolerable pain) can be about twice this threshold (mean = 12 psi, std dev = 5). It is contemplated that such a pressure level does not produce nail bed injury or sensitization. Thus, because it is contemplated that there will be no injury at 12 psi, the Maximum Pressure Limit for these applications can initially be set to 12 psi on the first stimulation visit (Visit 2, see Figure 6) as discussed below. Pressure can be increased at about 0.5 psi/sec, as shown in Figure 6A, which is slow enough for subjects to react before there is a significant increase in stimulus intensity beyond threshold. When the stimulus exceeds pain threshold, the subject can stop the stimulus by instructing the operator to release the stimulus or by removing their thumb from the apparatus (see Figure 2), at which point pressure on the nail bed immediately decreases to zero. Stimulus pressure can increase until it reaches either threshold or the Maximum Pressure Limit (see Figure 6A). If threshold is below the Maximum Pressure Limit, the stimulus cycle can be repeated twice more (see Figure 6B) to measure

repeatability) with a 3 minute rest interval between stimuli. If pressure is above the

Maximum Pressure Limit, stimulation stops and does not repeat until the next visit day. The study coordinator can examine the subject after the stimulus (and on the next visit day) for sign of injury. If there is no injury, the Maximum Pressure Limit (Figure 6A) is

incrementally increased (by 20%, Figure 7) on the next visit. To measure repeatability, the trial continues until three repeated runs have been measured on three visit days, or until the final experimental day is reached (Visit 8, Figure 7). Physiological variables of blood pressure, heart rate, respiration rate, galvanic skin response and pupil diameter are monitored continuously during each experiment.

[0080] The study coordinator can examine the subject's nail bed and surrounding tissue for signs of injury before each experiment and ask the subject to report any tenderness or other sign of injury. If any abnormality is observed, or the subject reports injury or sensitization, the subject can be examined by a health care professional (physician's assistant) under the supervision of the study physician. If the health care professional feels that there is injury, the subject is examined by a study physician who decides whether the Maximum Pressure Limit defined in Figure 7 should be reduced. If injury is observed before stimulation, stimulation day is delayed until the area to be stimulated has recovered. If recovery is delayed more than 2 weeks, the subject is removed from the study, but is followed up until the injury resolves. All injuries are tracked daily by phone interview or direct observation until resolution. [0081] Given that repeated threshold measurements are collected, a mixed effects linear regression model can be fitted to the various outcome variables. It is contemplated that the model can correctly account for the lack of independence of the repeated measurements nested within study subject data and also allow for an unequal number of completed follow- up visits (as well as unequal spacing of the visits), as patients inevitably return to the clinic at varying time intervals. Age and gender can be included as covariates in this model. It is contemplated that the above-described procedures can be used to test whether the threshold in the diabetic sample is significantly greater than the control sample using standard parametric means tests. It is further contemplated that the above-described procedures can be used to test whether physiological indices of pain response (heart rate, blood pressure and respiration rate) differed significantly from baseline when pain threshold was exceeded using mixed effects linear regression models. It is still further contemplated that the above-described procedures can be used to determine which physiological indicator of pain is the earliest indicator of pain threshold using mixed effects linear regression models. It is still further contemplated that the above-described procedures can be used to determine whether deficits in clinical median nerve conduction velocity measures were correlated with pain threshold in the patient sample. The median nerve conduction velocity is a single interval scaled measurement taken at the baseline visit. It can be correlated with the pressure measurement at the point of pushing the button to indicate pain threshold, an interval scaled variable measured three times at each of the three visits. To test for correlation, a mixed effects linear regression model can be fitted to these data to account for the repeated measurements. In this model, the median nerve conduction velocity can be a fixed value repeated nine times for each patient. For each task where an intraclass correlation coefficient (ICC) is measured, a Bland-Altman analysis can be performed to assess if differences between repeated measurements of pain are within clinically acceptable agreement.

Automated Threshold and Suprathreshold Protocols

[0082] In additional exemplary applications, the devices and systems described herein can be used to detect the pain threshold of a subject in an automated manner. Recording of endpoint physiological variables starts before stimulation and continues throughout the stimulation procedures. During Visit 2, pressure can be increased until pain threshold is reached. The pressure increase (0.1 psi/sec, see Figure 8A) can be slow enough for subjects to react before stimulus pressure increases significantly beyond threshold. The subject can stop the stimulus by instructing the operator to release the stimulus (or by removing their thumb from the apparatus, see Figure 2), at which point pressure on the nail bed immediately decreases to zero. To determine repeatability, three threshold measures can be obtained per visit (Figure 8B), with a 4-min interval between stimuli.

[0083] For each subject, after the above threshold protocol is completed, a

suprathreshold protocol can be performed. Pressure can be gradually increased (0.1 psi/sec) until the subject reports pain threshold and then continue to increase at the same rate until either the subject's maximum pain tolerance is reached (at which point the probe pressure is immediately reduced to zero (Figure 9 A)) or a preset Maximum Pressure Limit (see below) is exceeded (Figure 9A). If the pressure reaches the subject's level of maximum pain tolerance, the stimulus cycle can be repeated two more times to measure repeatability, with a 4-min interval between stimuli (Figure 9B). Alternatively, if the pressure climbs above the Maximum Pressure Limit, stimulation can stop, and the stimulation site can be examined for signs of injury. If there is no evidence of injury, the investigators can consult with the study physician to determine whether the Maximum Pressure Limit can be increased. Review boards can be consulted as appropriate before the Limit is increased. If the risk is judged to be minimal, the Limit can be increased 20% and the trial repeated. If not, then the subject can remain in the study with the Limit remaining at its original level. To measure visit-to- visit repeatability, suprathreshold measures can be obtained on three days.

[0084] It is contemplated that pressure at pain threshold in normal subjects can be about 6 pounds/square inch (psi, standard deviation [std dev] =2.3, N=10). It is further

contemplated that the stimulus pressure required to produce a pain rating of 6-7 on a 10 point VAS scale (0=no pain, 10= maximum tolerable pain) can be about twice this threshold (mean = 12 psi, std dev = 5). It is contemplated that such a pressure level does not produce nail bed injury or sensitization. Thus, because it is contemplated that there will be no injury at 12 psi, the Maximum Pressure Limit for these applications can initially be set to about 24 psi (four times threshold).

[0085] When maximum pain tolerance is reached, it is contemplated that the subject can quantify her/his pain rating using a O-to-10 Visual Analog Scale (VAS), where 0 equals no pain and 10 equals the maximum imaginable pain. Since "maximum tolerable pain" may be less than "maximum imaginable pain," the subject's pain rating at exit from the procedure can be less than 10. [0086] The study coordinator can examine the subject's nail bed and surrounding tissue for signs of injury before, and immediately following, each trial (Visits 2, 4, 6, 8) [as well as on the subsequent observation day (Visits 3, 5, 7, 9)] and ask the subject to report any tenderness or other sign of injury. If abnormality is observed, or the subject reports injury or sensitization, the subject can be examined by a health care professional (physician's assistant) under the supervision of the study physician. If the health care professional determines that there is injury, the subject can be examined by the study physician who decides whether the Maximum Pressure Limit (see above) should be reduced. If recovery is delayed more than 2 weeks, the subject can be removed from the study, but followed up with until the injury resolves. All injuries can be tracked daily by phone interview or direct observation until resolution.

[0087] Given that repeated threshold measurements are collected, a mixed effects linear regression model can be fitted to the various outcome variables. It is contemplated that this model correctly accounts for the lack of independence of the repeated measurements nested within study subject data and allows for an unequal number of completed follow-up visits, as well as unequal spacing of the visits as subjects inevitably return for repeated testing at varying time intervals. Age and gender are included as covariates in this model. It is contemplated that both the threshold and suprathreshold protocols can be used to: (a) test whether there is a significant increase in heart rate after stimulus exceeds pain threshold using a mixed effects linear regression model; (b) prepare a histogram of percent increase in heart rate above baseline versus percent increase in stimulus pressure above threshold to investigate autonomic response sensitivity; (c) analyze all endpoints (heart rate, blood pressure, pupil diameter, respiration rate, and skin resistance) to determine which has the greatest percentage change from baseline after pain threshold is exceeded; (d) determine whether the threshold measure obtained during threshold-only measurement (Visit 2) differs significantly from threshold measured using the suprathreshold stimulation (Visit 4); (e) measure reproducibility in the same-day, repeated measures of pain threshold using an intraclass correlation coefficient (ICC), reported with a 95% confidence interval; (f) measure reproducibility in the visit-to-visit, repeated measures of pain threshold using an intraclass correlation coefficient (ICC), reported with a 95% confidence interval (CI); (g) measure reproducibility in the same-day, repeated measures of maximum pain tolerance using an intraclass correlation coefficient (ICC), reported with a 95% confidence interval (CI); and (h) measure reproducibility in the visit-to-visit, repeated measures of maximum pain tolerance using an intraclass correlation coefficient (ICC), reported with a 95% confidence interval (CI). For each task where an ICC was measured, a Bland-Altman analysis can be performed to assess if differences between repeated measurements of pain are within clinically acceptable agreement. These pairs of measurements can be collected three times at each of three visits. To test for correlation, then, a mixed effects linear regression model can be fitted to these data to account for the repeated measurements.

Experimental Examples

[0088] The following examples are meant to provide an indication of the ability to characterize cardiac tissue using fluorescence imaging methods and should not be construed as limiting the scope of the claimed systems and methods.

[0089] The study described below addressed the effects of certain and uncertain pain expectations in fibromyalgia (FM) patients, yoga practitioners (YP) and healthy volunteers (HV). The study provided preliminary data to evaluate whether practicing yoga can reduce pain and improve cognitive and emotional function as a possible mechanism for reducing pain.

[0090] Twenty-six participants enrolled in the study: 9 FM patients, 7 yoga practitioners (YP), and 10 healthy volunteers (HV). Sample sizes were based on a prospective power analysis as described further below. As FM patients are predominantly female, enrollment for all groups was restricted to females.

[0091] FM patients had physician diagnosed FM, confirmed by standard tender point (TP) examination and self-reported body pain areas according to the American College of Rheumatology classification criteria. Patients were able to maintain normal levels of daily activities including regular exercise but did not practice yoga or meditation. FM patients were recruited from community pain clinics.

[0092] Yoga practitioners (YP) were free of chronic pain and practiced yoga regularly for three or more years prior to enrollment. Participants practiced yoga three or more days a week for at least one hour a day and included vigorous physical, breathing and meditation exercises in their regular practice. Yoga practitioners who practiced kundalini yoga were recruited because this style uses standardized techniques and includes all the required elements as a regular part of daily practice. Practitioners of kundalini yoga often adopt lifestyle changes as well. YPs were recruited from contacts with local kundalini yoga instructors. [0093] Healthy volunteers had normal health without chronic pain complaints and normal activity levels that may include regular exercise but not yoga or meditation.

Volunteers from all three groups were excluded if they had health history of heart disease, hypertension, seizure disorder, multiple sclerosis or other nervous system condition, diabetes, or using psychoactive or blood pressure medication. HVs were recruited by advertisements in the community.

[0094] Pain ratings were provided using an 1 1 -point numerical rating scale (NRS) with 0 indicating no pain and ten indicating the maximum tolerated pain.

[0095] Following each block of stimulations participants rated whether the pain just experienced was more than, less than, or the same as expected.

[0096] All subjects completed a series of visual analog scales in the Fibromyalgia Impact Questionnaire (FIQ) representing six components measuring pain, fatigue, anxiety, depression, morning stiffness, awakening unrefreshed, and disability.

[0097] The 40 item State-Trait Anxiety Inventory was used to assess current (STAI- State) and enduring anxiety as a characteristic of the subject (STAI-Trait).

[0098] The catastrophizing subscale of the Coping Strategies Questionnaire (CSQ) was used to assess catastrophizing as a measure of the degree to which pain is thought of as overwhelming and unendurable.

[0099] Changes in skin conductance response (SCR) provide an indicator of increased sympathetic activity in response to pain and associated arousal. SCR was measured using two silver-silver chloride electrodes placed on the palmar surface of the medial phalanx of the index and ring fingers on the dominant (non-stimulated) hand of each subject. SCR electrodes passed a low current (1 μΑΓηρεΓε8) through the skin surface and recorded fluctuations in skin conductance using signal conditioning amplifiers (BioSemi, B.V., Amsterdam, Netherlands) and signal acquisition software developed in-house using LabView (National Instruments Corporation, Austin, TX).

[00100] To deliver noxious and innocuous stimulations, we employed a pressure application device as described herein that applied constant pressure to the nail bed of the thumb on the non-dominant hand. Participants placed their thumbs on a small flat platform attached to a handgrip. A round flat tipped plunger 3 mm in diameter was positioned directly over the thumbnail. A system of pressure limiting valves controlled the pressure level applied, allowing for gradually increasing pressure. The system provided precise pressure level measurement and delivered constant pressure at three different repeatable pressure levels, thereby providing square wave patterns of sustained pressure and release. The pressure application device, as employed in this study, produced an aching sensation that became increasingly painful with increasing pressure.

[00101] Pain threshold and three pressure levels were established for testing. Pressure was gradually increased until participants indicated they began to feel pain. The increase in pressure was continued until participants' reported pain reached 6 on the NRS. This process was repeated twice, and the pain threshold was set as the average of the three pressure levels. Three stimulus levels were then established: Very Low pressure (no pain) set at 20% below the individual's pain threshold, Low pressure (low pain) set at pain threshold, and High pressure (moderate pain) set at the average level corresponding to the individual's pain rating of six. This procedure was performed independently for each participant in order to determine the pressure levels required to produce moderate and low pain for that individual. After setting the pressure levels, the settings were tested to verify that they produced pain ratings corresponding to the desired levels.

[00102] Previous investigations of pain anticipation and certainty/uncertainty had employed either continuously varying or discrete manipulations of certainty and uncertainty. In the first method, participants were told that a painful stimulus might happen at any time and the more time elapsed the more intense the stimulus; thus, certainty of pain increased and uncertainty decreased over time. In the second approach, the probability of receiving a painful stimulation was given immediately prior to each stimulus delivered. Neither approach satisfied the protocol requirements described herein. The first approach did not allow for clearly distinguished conditions of certain and uncertain pain. The second approach could have introduced phasic changes in SCR as an artifact of the instruction rather than as and effect of condition.

[00103] An alternative approach was developed based on uncertainty theory that allows for continuous anticipation of pain while maintaining experimental control over the relative certainty or uncertainty of stimulus intensities. The relationship between probability and certainty/uncertainty varies along a U-shaped curve. A condition of certainty holds when the probability of an event's occurrence is either very high (say p > .75) or very low (say p < .25). When the probability of occurring is high there is strong certainty the event will occur; when the probability of occurring is low, there is strong certainty the event will not occur. A condition of uncertainty holds when the probability an event will occur is about equal to the probability it won't occur (p = .50).

[00104] This association was operationalized between probability and

certainty/uncertainty in the experimental protocol using two levels of stimulus intensity: low pressure (slightly painful) and high pressure (moderately painful), presented in sequences of eight stimuli and varying the odds of receiving a high pressure stimulus during any given sequence (Figure 10). In the Low Odds condition, only one high pressure stimulus out of eight stimuli occurred (1 :7 odds; ^=0.125). In the High Odds condition, six high pressure stimuli out of eight occurred (3 : 1 odds; p=0 5). In the Even Odds condition, an equal number of high and low pressure stimuli occurred (1 : 1 odds; p=0.5). Thus, the Even Odds condition had maximal uncertainty, whereas the High Odds condition had maximal certainty for high pressure (painful) and the Low Odds condition had maximal certainty for low pressure (nonpainful) stimuli, respectively. Before each block, participants were informed of the likelihood of receiving high pressure during the block. Although in actuality participants received 1, 4, and 6 high pressure stimuli in each condition, respectively, in order to maintain the expectation of a possible high pressure stimulation to the end of the sequence, participants were told they may receive 1 additional high pressure stimulation.

[00105] In order to assure that participants understood the manipulation, each subject underwent uncertainty training prior to testing. This comprised picking colored marbles from a bag, with marble colors corresponding to the number of high and low pressure stimuli in each condition. Subjects practiced each condition until they correctly identified the corresponding condition, typically requiring one repetition for each condition.

[00106] Condition order was randomized across subjects. To allow participants to adapt to the experimental conditions and provide a response baseline, a control block of non- noxious stimuli (8 stimulations at sub-pain threshold pressure) was given before and after the three experimental conditions. Thus, participants received a total of 5 stimulus blocks, totaling 40 stimulations: 16 control and 24 experimental (Figure 10).

[00107] After providing informed consent, FM patients underwent a tender points (TP) examination. A trained project coordinator digitally palpated 18 American College of Rheumatology (ACR)-determined TPs and 3 control points in a predetermined order at 4kg force, at the rate of lkg/sec. Following each palpation, patients rated the pain from 0 (no pain) to 10 (worst pain). All patients met the ACR criterion of having at least 1 1 positive TPs. The wide-spread pain assessment was done using the Manual Tender Point Survey instrument.

[00108] Prior to testing, participants completed the self-report inventories, received procedure instructions and had sensors for psychophysiological measurement attached. The test procedure comprised two phases. During Phase 1, participants' pain thresholds were established, and uncertainty training was conducted. Phase 2 comprised presentation of stimulus blocks. Stimulus trials comprised a 20 second rest period (pressure off) and a 20 second application of continuous and constant pressure (pressure on). Participants rated their pain after pressure release on each trial. At the end of each block, participants provided a pain expectation rating.

[00109] To determine numbers for participant enrollment, a prospective power analysis was performed requiring 80% power, at alpha=0.05, to detect a difference of one unit on an 1 1 -point pain rating scale in the certainty/uncertainty conditions, as defined below, between any two groups. With eight repeated trials per condition, the effective sample size is increased relative to unreplicated designs, and specific computations consistent with the analytic method yielded target sample sizes of eight per group.

[00110] Phase 1 comprised an evaluation of pain threshold differences between subject groups. For this comparison a general linear model was used with pressure at pain threshold as the dependent measure and group as the fixed effect. A mixed effects linear models was employed to analyze Phase 2 data, with stimulus level and pain certainty/uncertainty as manipulated within-subjects fixed effects and group association as a non-manipulated fixed effect. The CSQ scale, STAI-Trait and STAI-State were treated as primary covariates in the analysis accounting for individual variation in affective influences. Contributions of descriptive measures including BMI and age, and FMS symptom measures were evaluated as secondary covariates in the analysis. Subjects' corresponding SCR, pain report, and expectancy measures were predicted by applying the following analytical model expressing a measure of subject i and combined fixed effects conditions j on dependent variable F as:

where jj represents the expected cell mean j conditional on the covariates, represents individual differences (random effects) across subjects, and βι and β2 are the cell-specific regression coefficients for the covariates. This model permitted the usual analysis of variance hypothesis tests, including between groups comparisons on each measure and intervention comparisons, as well as evaluation of within subject repeated measures. Models were evaluated with all fixed effects factors and interactions included, and with the error structure providing the best parsimonious fit as determined by the Bayesian Information Criterion (BIC). The joint effects of the covariates were evaluated by likelihood ratio test among models with no covariates, linear covariates, and covariate-by-factor interactions. Contrasts among the model parameters were constructed to test custom a priori hypotheses regarding the differential effects of certain and uncertain pain expectation within and between groups at each stimulus level and across stimulus levels. All contrasts were evaluated at the means of significant covariates.

[0011 1] Groups differed for age, body mass index (BMI), and exercise (Table 1). HVs were younger, FMs had the highest BMI, and YPs exercised the most. FM had significantly higher catastrophizing scores than HV (p=0.016) and YP (p=0.003). Pair-wise group comparisons for the FIQ factors revealed FMs had significantly higher scores than HVs and YPs for all components except fatigue. Although main effects for anxiety were not significant, pair-wise group comparisons revealed significant differences between FM and YPs for trait (p=0.036) and state (p=0.035) anxiety, but not between FMs and HVs or HVs and YPs. YPs had significantly higher pain thresholds on average than FMs (p=0.010). Mean pain threshold for HVs fell between FMs and YPs but did not significantly differ from either group.

Table 1. Comparison of Groups for Descriptive Characteristics, Catastrophizing, Fibromyalgia Impact Questionnaire, Anxiety, and Pain Threshold

FM HV YOGA Group

Mean S.D Mean S.D Mean S.D

Age 37.0 13.0 24.4 8.8 45.4 16.2 0.000 BMI 32.7 6.7 22.2 2.6 21.0 1.9 0.000

Exercise (hours/week) 3.0 .96 4.1 1.3 9.6 5.3 0.000

Sleep (hours) 7.4 7.3 6.9 .93 6.8 1.2 N.S.

CSQ-Cat 7.38 4.60 3.13^s 2.64 1.50^a 1.80 0.007

FIQ

Pain 4.69 1.99 0.88^a 0.84 0.97^a 0.74 0.000

Fatigue 5.95 2.94 4.16 3.21 2.90^a* 3.04 0.177

Awaken unrefreshed 6.26 2.63 3.55^a 2.85 2.10^a 1.67 0.012

Morning stiffness 5.73 1.94 2.16^a 2.45 0.97^a 0.98 0.000

Anxiety 5.09 3.08 1.26^a 2.14 0.91^a 1.27 0.002

Depression 3.60 3.02 0.91^a 1.74 0.83^a 1.07 0.022

STAI-Trait 34.63 11.58 28.80 6.83 24.86' 5.79 0.103

STAI-State 37.87 8.18 33.89 6.33 30.14' 4.95 0.105

Pain Threshold 4.35 2.03 6.05 2.31 7.94^a 3.54 0.032

(pounds/in )

Abbreviations: FM = fibromyalgia; FfV = healthy volunteers; YP = yoga practitioners; S.D. = standard deviation; N.S. = non-significant; CSQ-Cat = Coping Strategies Questionnaire- Catastrophizing; FIQ = Fibromyalgia Impact Questionnaire; STAI = State-Trait Anxiety Inventory. [00112] Box plots reveal the value distributions for skin conductance (Figure 1 1A) and pain ratings (Figure 1 IB) in response to high pressure stimulation for each group at each certainty/uncertainty level. SCR and pain ratings for FM were highest for the Even Odds (uncertain) condition, while the highest values for both HV and YP were found for the High Odds condition. HV had considerable individual variation in values on both measures, particularly for the Even Odds condition, indicating high group heterogeneity.

[00113] A mixed effects model evaluating SCR change applying fixed effects for group, condition, stimulus, and the interactions, with random intercepts, trials within condition as repeated effects, and an autoregressive covariance structure, provided the best fit to the data. Primary and secondary covariates did not contribute significantly to the model. Table 2 provides model estimated marginal means and standard errors for SCR for the group-by- condition-by-stimulus interaction. Figure 12A shows the pattern of mean SCR responses, adjusted for all other effects, for FM, HV, and YP for the three stimulus conditions. If participants responded more to calculated number of high pressure stimuli delivered during an experimental sequence, their SCR responses should show a linear trend having its high point at High Odds (more high than low pressure stimuli), midpoint for Even Odds (equal numbers of high and low pressure stimuli), and low point for Low Odds (more low than high pressure stimuli). If participants responded more to the effects of uncertainty, SCR responses should show a nonlinear pattern, with the highest response occurring for the uncertain condition.

Table 2. Skin conductance responses to pressure stimulus by

group, stimulus level, and condition.

Group Condition Stimulus Mean S.E. df

Level Response

(in mMohs)

FM Certain-Mod Low 7.465 1 .406 25.476

High 7.501 1 .407 25.533

Uncertain Low 8.595 1 .404 25.285

High 9.01 1 1 .413 25.946

Certain-Low Low 7.685 1 .403 25.258

High 7.480 1 .427 26.967

HV Certain-Mod Low 8.097 1 .332 25.893

High 8.043 1 .331 25.822

Uncertain Low 7.030 1 .330 25.808

High 7.679 1 .336 26.225

Certain-Low Low 6.721 1 .334 26.051

High 6.777 1 .353 27.612

YP Certain-Mod Low 5.980 1 .623 25.379

High 6.107 1 .626 25.609

Uncertain Low 5.512 1 .621 25.274

High 5.616 1 .634 26.078

Certain-Low Low 5.588 1 .621 25.290

High 5.569 1 .643 26.657

Abbreviations: Groups: FM = fibromyalgia; HV = healthy volunteers; YP = yoga practitioners.

Conditions: Certain-Mod = high probability of receiving moderate pain (high certainty); Uncertain = equal probability of receiving moderate and low pain (high uncertainty); Certain-Low = high probability of receiving low pain (high certainty). Levels: High = high pressure titrated to the individual participant's pain rating of 6 (0-10 scale); Low = low pressure titrated to 10% above the individual participant's pain threshold. S.E. = standard error; df = degrees of freedom.

[00114] A nonlinear pattern was observed for FM but a linear response for the other two groups was observed. HV responded most to High Odds (most high pressure stimuli) and least to Low Odds (fewest high pressure stimuli). YP responded most for High odds but the differences between conditions was very slight. Custom hypothesis tests forming contrast estimates (CE) were constructed to evaluate these apparent differences within and between groups. Comparing Even Odds with High Odds and Low Odds for each group revealed a significant difference only for the FM group (CE=1.27, /?=0.01). Thus, only FM responded more to uncertain than to certain pain. For HV, SCR was significantly greater for High Odds than for Low Odds (CE=1.32, ^=0.02). SCR for YP did not differ significantly between any of the three conditions. A further comparison evaluated the size of the effect of uncertainty for each group compared to the other groups. This contrast compared Even Odds with High and Low Odds combined both within and between groups. These comparisons revealed that FM and YP differed significantly (CE=1.742, ^=0.032), whereas the difference between FM and HV failed to reach significance (CE= 1.252, ^=0.088).

[00115] For pain ratings data, a mixed effects model using fixed effects for group, certainty/uncertainty condition, and stimulus level, and the interactions, with trials as repeated effects and a random intercept provided the best fit. CSQ and STAI-trait covariates slightly improved prediction of Pain Rating (p<.00l main effects, p<.001 linear-by-factor interactions). No additional covariates made significant contributions. Table 2 provides estimated marginal means for pain ratings for the group-by -condition-by-stimulus level interaction conditioned on the significant covariates. The pattern of adjusted mean pain ratings for FM shows higher values for the Uncertain condition and considerably lower values for both High and Low Odds (Figure 12B). HV pain ratings appear higher overall compared to the other groups with a slight linear decrease from High Odds through Uncertain to Low Odds. YP pain ratings appear highest for High Odds but considerably lower for both Uncertain and Low Odds conditions. Custom hypothesis tests showed pain ratings for the Uncertain condition were significantly greater than for High and Low Odds conditions for FM (CE=0.60, p= 0.012) but not for HV or YP. High Odds pain ratings were significantly greater than Low Odds for YP (CE=1.24, =0.006) but not HV. The comparison of the within and between group effects of uncertainty for pain ratings revealed that FM and YP differed significantly (CE= 1.001, ^=0.004), whereas FM and HV differed only marginally (CE=0.557, =0.059).

[00116] Although several embodiments of the invention have been disclosed in the foregoing specification, it is understood by those skilled in the art that many modifications and other embodiments of the invention will come to mind to which the invention pertains, having the benefit of the teaching presented in the foregoing description and associated drawings. It is thus understood that the invention is not limited to the specific embodiments disclosed hereinabove, and that many modifications and other embodiments are intended to be included within the scope of the appended claims. Moreover, although specific terms are employed herein, as well as in the claims which follow, they are used only in a generic and descriptive sense, and not for the purposes of limiting the described invention, nor the claims which follow.

Claims

What is claimed is:

1. A system for assessing peripheral nerve damage in a subject, the system comprising: a pressure application device for applying pressure to a selected body part of the subject, the pressure application device comprising:

a platform for supporting at least a portion of the selected body part of the subject;

a probe having a tip configured to contact and apply pressure to at least a portion of the selected body part of the subject; and

means for moving the probe along a displacement axis such that the probe contacts and applies pressure to the selected body part of the subject; and

a computer having a processor and a memory in communication with the processor, wherein the processor is in further communication with the means for moving the probe along the displacement axis, and wherein the processor is configured to perform the steps of:

activating the pressure application device to apply pressure to the selected body part in a desired pattern; and

instructing the pressure application device to discontinue application of pressure to the selected body part when a pain threshold for the subject is achieved.

2. The system of Claim 1, wherein the pressure application device further comprises a pressure sensor positioned within the tip of the probe and in electrical communication with the processor of the computer, and wherein the pressure sensor is configured to produce a pressure signal indicative of the pressure applied to the selected body part of the subject.

3. The system of Claim 2, wherein the pressure application device further comprises a displacement monitor for measuring axial movement of the probe along the displacement axis, wherein the displacement monitor is in communication with the processor of the computer, and wherein the displacement monitor is configured to produce a displacement signal indicative of the distance by which the probe is moved along the displacement axis.

4. The system of Claim 1, wherein the pressure application device further comprises a pressure sensor positioned within the platform and in electrical communication with the processor of the computer, and wherein the pressure sensor is configured to produce a pressure signal indicative of the pressure applied to the selected body part of the subject.

5. The system of Claim 4, wherein the pressure application device further comprises a displacement monitor for measuring axial movement of the probe along the displacement axis, wherein the displacement monitor is in communication with the processor of the computer, and wherein the displacement monitor is configured to produce a displacement signal indicative of the distance by which the probe is moved along the displacement axis.

6. The system of Claim 1, wherein the means for moving the probe along the displacement axis comprise:

a chamber containing a piston operably coupled to the probe of the pressure application device, wherein the piston is axially moveable within the chamber along the displacement axis; and

at least one pressure regulator in communication with the chamber, wherein the at least one pressure regulator is configured to generate sufficient pressure within the chamber to advance the piston along the displacement axis such that the probe applies pressure to the selected body part of the subject in the desired pattern.

7. The system of Claim 6, wherein the chamber has a first port and a second port for receiving pressurized gas from the at least one pressure regulator, wherein the piston is positioned between the first port and the second port along the displacement axis, wherein the means for moving the probe along the displacement axis further comprise a solenoid valve positioned between and in communication with the at least one pressure regulator and the first port and second port of the chamber, and wherein the solenoid valve is in electrical communication with the processor of the computer.

8. The system of Claim 7, wherein the solenoid valve is moveable between a first position and a second position, wherein, in the first position, the solenoid valve is configured to apply pressure to the piston through the first port such that the probe is moved along the displacement axis toward the selected body part of the subject, and wherein, in the second position, the solenoid valve is configured to apply pressure to the piston through the second port such that the probe is moved along the displacement axis away from the selected body part of the subject.

9. The system of Claim 1, further comprising means for the subject to indicate that the pain threshold has been achieved.

10. The system of Claim 1, wherein the selected body part of the subject is one of a nail bed of a finger and a nail bed of a toe.

1 1. The system of Claim 1 , wherein the desired pattern of applying pressure to the selected body part comprises application of a series of gradually increasing pressure stimulations, wherein each pressure stimulation has a desired duration.

12. The system of Claim 1 1, wherein the increases in pressure between consecutive pressure stimulations are substantially non-linear.

13. The system of Claim 1 1, wherein the desired duration of each pressure stimulation varies among the series of pressure stimulations.

14. The system of Claim 1 1, wherein, between consecutive pressure stimulations of the series of pressure stimulations, there is a release period corresponding to a time during which pressure is released from the selected body part of the subject, and wherein the duration of the release periods associated with the series of pressure stimulations is variable.

15. The system of Claim 1, further comprising a heart rate monitor in electrical communication with the processor of the computer, wherein the heart rate monitor is configured to produce a heart rate signal indicative of the heart rate of the subject.

16. The system of Claim 1, further comprising a blood pressure monitor in electrical communication with the processor of the computer, wherein the blood pressure monitor is configured to produce a blood pressure signal indicative of the blood pressure of the subject.

17. The system of Claim 1, further comprising an electrocardiogram device in electrical communication with the processor of the computer.

18. The system of Claim 1, further comprising means for measuring skin conductance of the subject, wherein the means for measuring skin conductance is in communication with the processor of the computer, and wherein the means for measuring skin conductance is configured to produce a signal indicative of the skin conductance of the subject.

19. The system of Claim 1, further comprising a magnetic resonance imaging machine in communication with the processor of the computer.

20. The system of Claim 19, wherein the pressure application device comprises nonmagnetic materials.

21. A pressure application device for applying pressure to a nail bed of a selected finger of a subject, the pressure application device comprising:

a hand grip shaped to conform to a hand of the subject, wherein a top portion of the hand grip defines a platform for supporting the selected finger of the subject;

a probe having a tip configured to contact and apply pressure to at least a portion of the nail bed of the selected finger of the subject;

means for moving the probe along a displacement axis such that the probe contacts and applies pressure to the nail bed of the selected finger of the subject; and

a displacement monitor for measuring axial movement of the probe along the displacement axis, wherein the displacement monitor is configured to produce a displacement signal indicative of the distance by which the probe is moved along the displacement axis.

22. The pressure application device of Claim 21, wherein the means for moving the probe along the displacement axis is configured to move the probe such that the probe applies a predetermined pressure to the nail bed of the selected finger of the subject.

23. The pressure application device of Claim 21, further comprising a pressure sensor positioned within the tip of the probe, wherein the pressure sensor is configured to produce a pressure signal indicative of the pressure applied to the nail bed of the selected finger of the subject.

24. The pressure application device of Claim 21, further comprising a pressure sensor positioned within the platform, wherein the pressure sensor is configured to produce a pressure signal indicative of the pressure applied to the nail bed of the selected finger of the subject.

25. The pressure application device of Claim 21, wherein the means for moving the probe along the displacement axis comprise:

a chamber containing a piston operably coupled to the probe of the pressure application device, wherein the piston is axially moveable within the chamber along the displacement axis; and

at least one pressure regulator in communication with the chamber, wherein the at least one pressure regulator is configured to generate sufficient pressure within the chamber for advancing the piston along displacement axis such that the probe applies pressure to the nail bed of the selected finger of the subject.

26. The pressure application device of Claim 25, wherein the chamber has a first port and a second port for receiving pressurized gas from the at least one pressure regulator, wherein the piston is positioned between the first port and the second port along the displacement axis, and wherein the means for moving the probe along the displacement axis further comprise a solenoid valve positioned between and in communication with the at least one pressure regulator and the first port and second port of the chamber.

27. The pressure application device of Claim 26, wherein the solenoid valve is moveable between a first position and a second position, wherein, in the first position, the solenoid valve is configured to apply pressure to the piston through the first port such that the probe is moved along the displacement axis toward the nail bed of the selected finger of the subject, and wherein, in the second position, the solenoid valve is configured to apply pressure to the piston through the second port such that the probe is moved along the displacement axis away from the nail bed of the selected finger of the subject.

28. A method for assessing peripheral nerve damage in a subject, the method comprising: providing a pressure application device comprising a platform and a probe having a tip, wherein the platform is spaced from the probe along a displacement axis;

positioning a selected body part of the subject on the platform of the pressure application device;

selectively moving the probe along the displacement axis such that the tip of the probe contacts and applies pressure to the selected body part of the subject;

measuring the pressure applied to the selected body part of the subject;

measuring the axial movement of the probe along the displacement axis;

monitoring whether a pain threshold for the subject is achieved; and

discontinuing application of pressure to the selected body part of the subject when the pain threshold for the subject is achieved.

29. The method of Claim 28, wherein the selected body part of the subject is one of a nail bed of a finger and a nail bed of a toe.

30. The method of Claim 28, wherein the step of monitoring whether a pain threshold for the subject is achieved comprises receiving feedback from the subject in response to the application of pressure to the selected body part of the subject.

31. The method of Claim 28, wherein the step of selectively moving the probe along the displacement axis comprises moving the probe along the displacement axis such that a series of gradually increasing pressure stimulations are applied to the selected body part of the subject, wherein each pressure stimulation has a desired duration.

32. The method of Claim 31, wherein the increases in pressure between consecutive pressure stimulations are substantially non-linear.

33. The method of Claim 31 , wherein the desired duration of each pressure stimulation varies among the series of pressure stimulations.

34. The method of Claim 31 , wherein, between consecutive pressure stimulations of the series of pressure stimulations, there is a release period corresponding to a time during which pressure is released from the selected body part of the subject, and wherein the duration of the release periods associated with the series of pressure stimulations is variable.

35. The method of Claim 28, wherein the step of monitoring whether the pain threshold for the subject has been achieved comprises determining whether a predetermined threshold pressure is applied to the selected body part of the subject.

36. The method of Claim 28, wherein the step of monitoring whether the pain threshold for the subject has been achieved comprises determining whether the probe has been moved along the displacement axis by a predetermined distance.

37. The method of Claim 28, further comprising the step of measuring the heart rate of the subject.

38. The method of Claim 37, wherein the step of monitoring whether the pain threshold for the subject has been achieved comprises determining whether a predetermined threshold heart rate of the subject has been achieved.

39. The method of Claim 28, further comprising the step of measuring the blood pressure of the subject.

40. The method of Claim 39, wherein the step of monitoring whether the pain threshold for the subject has been achieved comprises determining whether a predetermined threshold blood pressure of the subject has been achieved.

41. A method for monitoring changes of the pain threshold in the peripheral nerves of a subject, the method comprising:

providing a pressure application device comprising a platform and a probe having a tip, wherein the platform is spaced from the probe along a displacement axis;

positioning a selected body part of the subject on the platform of the pressure application device;

selectively moving the probe along the displacement axis such that the tip of the probe contacts and applies pressure to the selected body part of the subject;

measuring the pressure applied to the selected body part of the subject;

measuring the axial movement of the probe along the displacement axis;

measuring the pain magnitude experienced by the subject during application of pressure to the selected body part of the subject;

comparing the measured pain magnitude corresponding to a selected applied pressure to one or more previously recorded pain magnitudes for the subject corresponding to the selected applied pressure; and

determining whether the pain threshold for the subject has changed.

42. The method of Claim 41, wherein the step of measuring the pain magnitude experienced by the subject comprises receiving feedback from the subject indicative of the pain magnitude.

43. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the strength of the grip of the subject during application of pressure to the selected body part of the subject, wherein the magnitude of the strength of the grip corresponds to the pain magnitude experienced by the subject.

44. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the finger pinch strength of the subject during application of pressure to the selected body part of the subject, wherein the magnitude of the finger pinch strength corresponds to the pain magnitude experienced by the subject.

45. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring a movement by the subject, wherein the amount of movement corresponds to the pain magnitude experienced by the subject.

46. The method of Claim 45, wherein the measured movement of the subject is movement of a handle.

47. The method of Claim 45, wherein the measured movement of the subject is twisting of a pointer.

48. The method of Claim 41, wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the intensity of a beam of light controlled by the subject, wherein the intensity of the beam of light corresponds to the pain magnitude experienced by the subject.

49. The method of Claim 41, wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the finger span of the subject, wherein the finger span is indicative of the separation between the thumb and the index finger of a hand of the subject, and wherein the finger span corresponds to the pain magnitude experienced by the subject.

50. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the heart rate of the subject, and wherein the heart rate of the subject is indicative of the pain magnitude experienced by the subject.

51. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the blood pressure of the subject, and wherein the blood pressure of the subject is indicative of the pain magnitude experienced by the subject.

52. The method of Claim 41, wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the body temperature of the subject, and wherein the body temperature of the subject is indicative of the pain magnitude experienced by the subject.

53. The method of Claim 41 , wherein the step of measuring the pain magnitude experienced by the subject comprises measuring the skin conductance of the subject, and wherein the skin conductance of the subject is indicative of the pain magnitude experienced by the subject.