Portable quantitative sensory stimulation devices and methods

Abstract

A thermal stimulation device for thermal sensory testing is provided. The device comprises a thermoelectric cooler (TEC) having a first surface configured for contact with a body-site of a subject and a second surface opposite the first surface; a temperature measurement system configured to determine the temperature of the first surface, wherein determining the temperature of the first surface comprises measuring a Seebeck voltage generated by the TEC, measuring the temperature of the second surface of the TEC, and calculating the temperature of the first surface of the TEC based on the Seebeck voltage and the temperature of the second surface; and a control unit configured to facilitate applying a thermal stimulus to the subject, based on the determined temperature, by applying a voltage to the TEC thereby controlling the temperature of the first surface.

Description

[0001] PORTABLE QUANTITATIVE SENSORY STIMULATION DEVICES AND METHODS

[0002] TECHNICAL FIELD

[0003] The present disclosure relates generally to quantitative sensory testing devices and methods.

[0004] BACKGROUND

[0005] Sensory nerve fibers and their receptors respond to various stimuli such as heat and cold, vibration and pressure. When a sensory stimulus is applied to the skin, the energy of the stimulus is converted into an electric impulse by sensory transduction in the receptors and nerve endings (depending on the nerve fiber type), known as an action potential. The action potential propagates along the nerve fiber towards the central nervous system where it is processed.

[0006] In testing functionality of the peripheral sensory nervous system, several techniques are applied. Quantitative sensory testing (QST) involves applying a sensory stimulus at various intensities to a test subject to identify the perception threshold, according to the feedback provided by the subject pressing a button or by verbal response. The threshold discovered is then compared to those of a dataset of healthy test subjects. This information is crucial in early detection of impairment in the peripheral sensory nerves and can serve as a screening method for peripheral small and / or large fiber neuropathy. Contact Heat Evoked Potential testing or Contact Cold Evoked Potential testing (CHEP and CCEP respectively) are additional methods whereby a stimulus formed as a thermal (hot or cold) pulse is applied to a body site, and a time-locked evoked potential recording by an electroencephalograph (EEG) quantifies signal strength and latency, indicating functional and anatomical condition of the peripheral nervous system primarily related to sensory small fiber nerves.

[0007] Other methods involve measuring of nerve local function or morphology include electromyography (EMG), nerve conduction studies (NCS) and skin punch biopsies. NCS involves applying an electrical stimulus to a skin site, and measuring the latency and amplitude of the compound action potential propagating to nearby recording electrodes. The known distance between the stimulation site and the recording electrodes, divided by the latency, provides a conduction velocity metric. However, in electrical stimulation of the skin, current travels to the skin, other tissues,and various nerve fibers in a non-specific manner. Conduction through the skin may attenuate the signal dependent on local skin thickness, making comparison with healthy subject reference results more difficult. Activation of specific thermoreceptors or mechanoreceptors exclusively is usually not possible, and information on numerous fiber types is acquired simultaneously. While limiting the electrical stimulation voltage and modulating the stimulation frequency provides more specific data by eliminating activation of large motor fibers, the test is still not sufficiently specific, and various types of fibers may be activated.

[0008] In addition, the electric stimulation bypasses the physiological sensory transduction at the receptor, opening the voltage-gated sodium channels indirectly to create the action potentials. Therefore, information can be gained on the functionality and myelination of the nerve fiber itself, but without gaining information on the receptor itself, and without any functional information, i.e., how the subject perceives the sensation or pain from the stimulus, if hypo- or hyperalgesia is present, central sensitization, allodynia and / or other presentations of sensory deficits. These alternative methods are often invasive and painful in themselves, and require large and complex devices to conduct the tests. QST testing and CHEP / CCEP testing is performed on intact skin and is non-invasive.

[0009] Bedside testing is a term used in the field for neurological evaluation tests performed by skilled physicians, containing thermal testing, pressure pain testing, pinprick testing and vibratory testing, performed at the subject’s bedside, or in any clinical setting that requires a neurological evaluation. The tools used are often basic and inaccurate, and require in their use a higher level of skill to have meaningful results due to operator bias. Often the methods used have no standardization at all. Thermal testing in particular is performed by heating or cooling metal and plastic objects in a water bath or refrigerator, removal and immediately placing on the subject’s skin.

[0010] Evaluating the subject’s response is a challenge in itself, as in the absence of controlled rate of temperature change with existing bedside testing devices, it is difficult to precisely record the moment of the subject’s sensation or pain threshold being reached with the existing bedside test devices. More complex higher end devices often include a separate response unit, with which a subject presses a button, sending a signal to the device to stop the stimulus at the perceived threshold. This increases costs since the response unit is an additional separate device.

[0011] Thermoelectric coolers (TECs), sometimes referred to as Peltier elements, are typically used as thermally stimulating elements in QST devices. They are constructed of opposing ceramic platesthat sandwich n-doped and p-doped thermoelectric semiconductor pellets connected injunctions. One or more TECs may be used in a thermal stimulation device, depending on the contact area for which it is designed. The TECs are powered in positive or negative polarity to induce a temperature change in either heating or cooling directions. Each side of the TEC presents a different temperature, one side cooling and the opposing side heating, or vice versa, depending on the voltage polarity. In order to maintain the desired temperature setpoints for functional and safety reasons, the surface of the TEC in contact with a body-site should be monitored using a temperature sensor such as an NTC thermistor, thermocouple or other sensor types known to those skilled in the art. Additional sensors may be needed on the side of the TEC opposing the body-site-contacting side, for instance on a heat sink that draws away excess heat. The body-site-contacting side is ideally a flat continuous surface of known contact area, without irregularities, such as would be with a thermistor or thermocouple attached to the surface. Having a sensor on the surface of the TEC introduces multiple manufacturing complexities and high costs. In some cases a metallic plate is placed over the TEC and the sensor, due to the necessity of protecting the wiring of the sensors, and to allow for a smooth contact surface. This, however, leads to increased thermal resistance between the TEC and subsequently higher power requirement in achieving the same surface temperature.

[0012] Minimization of other mechanical influences, for example vibration from a fan used in a cooling system for a TEC, is also of high importance in achieving a purely thermal stimulation for the sensation threshold test.

[0013] Some body-sites to be tested for sensory and autonomic deficits are hard to reach, of small dimensions or require conforming contact surfaces. Non exhaustive examples of such body-sites include the eye or eyelid, intranasal, intraoral and facial sites, vaginal wall, clitoris and anal cavity. Typical devices described in prior art require bulky equipment and large stimulation probes that are unsuitable for such use cases.

[0014] There is therefore a need for a portable, low cost and easy to use solution to enabling evaluation of the peripheral sensory nervous system that can be used in the clinical setting.

[0015] SUMMARY

[0016] The presently disclosed subject matter is directed toward a portable, handheld device for thermal stimulation intended for evaluation of a test subject’s pain or sensation threshold in the context of quantitative sensory testing. The device comprises a TEC and cooling system with an integratedtemperature measurement based on the Seebeck effect, and a capacitive and / or optical touch sensor for capturing the moment of threshold sensing by said test subject. Innovative application methods are also described herein.

[0017] According to an aspect of the presently disclosed subject matter, there is provided a thermal stimulation device for thermal sensory testing, the device comprising:

[0018] a thermoelectric cooler (TEC) having a first surface configured for contact with a bodysite of a subject and a second surface opposite the first surface;

[0019] a temperature measurement system configured to determine the temperature of the first surface, wherein determining the temperature of the first surface comprises measuring a Seebeck voltage generated by the TEC, measuring the temperature of the second surface of the TEC, and calculating the temperature of the first surface of the TEC based on the Seebeck voltage and the temperature of the second surface; and

[0020] a control unit configured to facilitate applying a thermal stimulus to the subject, based on the determined temperature, by applying a voltage to the TEC thereby controlling the temperature of the first surface.

[0021] The temperature measurement system may comprise an analog-to-digital converter configured to measure the Seebeck voltage between terminals of the TEC.

[0022] The control unit may be configured to correlate the measured Seebeck voltage to temperature based on a calibration relationship.

[0023] The first surface may comprise a substantially continuous flat contact surface free of surface irregularities, for example due to the temperature measurement system facilitating measuring the temperate of the first surface without requiring providing a temperature sensor there.

[0024] Facilitating applying the thermal stimulus may further comprise applying a voltage to the TEC to vary the temperature at a rate between 0.1°C per second and 400°C per second.

[0025] The thermal stimulation device may further comprise a portable housing and a battery power source.

[0026] The thermal stimulation device may further comprise a memory configured to store test results and / or normative threshold values for multiple body-sites and demographics. Normative values according to any aspect and / or example of the presently disclosed subject matter may include, but is not limited to, body-site location, test subject age, and / or test subject gender.The thermal stimulation device may be configured to communicate with an electronic medical record of the subject to transmit test results thereto.

[0027] The thermal sensory testing may comprise quantitative sensory testing.

[0028] The thermal sensory testing may comprise contact heat evoked potential testing.

[0029] The thermal sensory testing may comprise contact cold evoked potential testing.

[0030] According to another aspect of the presently disclosed subject matter, there is provided a thermal stimulation device configured to facilitate thermal sensory testing, the device comprising:

[0031] a thermal stimulation element having a contact surface configured for contact with a bodysite of a subject;

[0032] a contact sensing system configured to detect contact between the contact surface and the body-site, and to detect detachment of the contact surface from the body-site, the contact sensing system comprising a capacitive touch sensor and / or an optical sensor; a temperature control system configured to facilitate applying a thermal stimulus to the body-site via the contact surface; and

[0033] a control unit configured to direct operation of the thermal stimulation device. The control unit may be being configured to record a temperature at the contact surface when detachment is detected, and to determine the recorded temperature as a thermal threshold.

[0034] Applying the thermal stimulus may comprise maintaining the contact surface at a predetermined test temperature.

[0035] The control unit may be configured to determine the temperature of the contact surface, and to determine the predetermined test temperature based, at least in part, on the temperature of the contact surface.

[0036] The control unit may be configured to determine the predetermined test temperature based, at least in part, on normative data.

[0037] The normative date may comprise threshold values.

[0038] The control unit may be further configured to determine sensory function of the subject based, at least in part, on whether detachment of the contact surface from the body-site is detected.

[0039] The control unit may be configured to determine sensory function of the subject based, at least in part, on whether detachment of the contact surface from the body-site is detected within a predetermined time period.

[0040] The thermal stimulation element may comprise a thermoelectric cooler (TEC).The thermal stimulation device may further comprise a temperature measurement system configured to facilitate determining the temperature of the contact surface of the thermal stimulation element, wherein determining the temperature of the contact surface comprises measuring a Seebeck voltage generated by the TEC.

[0041] The temperature measurement system may be further configured to determine the temperature of the contact surface of the thermal stimulation element by measuring the temperature of a second surface of the thermal stimulation element being opposite the contact surface, and calculating the temperature of the contact surface of the thermal stimulation element based on the Seebeck voltage and the temperature of the second surface.

[0042] The capacitive touch sensor may comprise a conductive layer positioned adjacent to the contact surface and electrically isolated from the thermal stimulation element.

[0043] The optical sensor may comprise an infrared emitter and a detector configured to detect the presence of the body-site based on reflected infrared radiation.

[0044] The optical sensor may be configured to detect proximity of the body-site to the contact surface.

[0045] The thermal stimulation device may further comprise a heat pipe thermally coupled to the contact surface of the thermal stimulation element, the heat pipe comprising a body-site-contacting end having a contact area which is smaller than that of the contact surface.

[0046] The heat pipe may comprise a sealed metallic tube containing a working fluid therewithin. The heat pipe may be electrically conductive and constitute an electrode of the capacitive touch sensor.

[0047] The contact surface may a contact area between 0.25 cm2and 16 cm2.

[0048] The thermal stimulation device may further comprise a cooling system thermally coupled to a second surface of the thermal stimulation element being opposite the contact surface, wherein the cooling system comprises a heat sink and a fan configured to facilitate dissipating heat from the heat sink.

[0049] The cooling system may be configured to operate substantially without introducing vibrational artifacts during testing.

[0050] The thermal stimulation device may further comprise a portable housing and a battery power source.

[0051] The thermal stimulation device may further comprise a memory configured to store test resultsand / or normative threshold values for multiple body-sites and demographics.

[0052] The thermal stimulation device may be configured to communicate with an electronic medical record of the subject to transmit test results thereto.

[0053] The thermal sensory testing may comprise quantitative sensory testing.

[0054] The thermal sensory testing may comprise contact heat evoked potential testing.

[0055] The thermal sensory testing may comprise contact cold evoked potential testing.

[0056] According to another aspect of the presently disclosed subject matter, there is provided a method for thermal sensory testing of a subject, the method comprising:

[0057] contacting the body-site of the subject with a contact surface of a thermal stimulation element;

[0058] operating the thermal stimulation element to apply a thermal stimulus via the contact surface of the thermal stimulation element to the body-site at a predetermined test temperature; and

[0059] classifying sensory function based on subject response.

[0060] The predetermined test temperature may be based on normative threshold values for the bodysite.

[0061] The predetermined test temperature may be selected to be within (i.e., above or below) 1°C of the normative threshold value for the body-site.

[0062] The predetermined test temperature may be selected to be within 0.5°C of the normative threshold value for the body-site.

[0063] The thermal stimulation element may comprise a thermoelectric cooler (TEC).

[0064] The method may further comprise monitoring the temperature of the contact surface by measuring a Seebeck voltage generated by the TEC.

[0065] Monitoring the temperature of the contact surface may further comprise measuring the temperature of a second surface of the TEC being opposite the contact surface, and calculating the temperature of the contact surface based on the Seebeck voltage and the temperature of the second surface

[0066] The method may further comprise selectively applying a voltage to the TEC to control the temperature of the thermal stimulus.

[0067] Applying the thermal stimulus may comprise varying its temperature at a rate between 0.1°C per second and 5°C per second.Applying the thermal stimulus may comprise applying heat to the body-site to test warm sensation threshold and / or hot pain threshold.

[0068] Applying the thermal stimulus may comprise cooling the body-site to test cold sensation threshold and / or cold pain threshold.

[0069] The method may further comprise comparing the recorded thermal threshold to normative values to help identify peripheral sensory nerve functional impairment.

[0070] The method may further comprise:

[0071] providing a contact sensing system configured to detect contact between the contact surface and the body-site, and to detect detachment of the contact surface from the body-site, the contact sensing system comprising a capacitive touch sensor and / or an optical sensor;

[0072] detecting the contact between the contact surface and the body-site; and

[0073] monitoring for detachment of the contact surface from the body-site;

[0074] wherein the subject response comprises whether detachment of the contact surface from the body-site occurs.

[0075] Classifying the sensory function comprises determining a thermal threshold, the thermal threshold being determined as the temperature of the contact surface of the thermal stimulation element upon detecting detachment from the body-site.

[0076] The method may further comprise recording the thermal threshold.

[0077] The sensory function classified as normal or abnormal.

[0078] The method may further comprise determining a severity level of sensory abnormality by operating the thermal stimulation element to apply multiple thermal stimuli at different predetermined test temperatures.

[0079] The body-site may be a hand, a foot, an eyelid, an intranasal site, an intraoral site, a facial site, a vaginal site, a clitoral site, or an anal site.

[0080] The method may be used to facilitate detection of peripheral small fiber neuropathy.

[0081] The thermal sensory testing may comprise quantitative sensory testing.

[0082] The thermal sensory testing may comprise contact heat evoked potential testing.

[0083] The thermal sensory testing may comprise contact cold evoked potential testing.BRIEF DESCRIPTION OF THE FIGURES

[0084] Some embodiments of the disclosure are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments may be practiced. The figures are for the purpose of illustrative description and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the disclosure. For the sake of clarity, some objects depicted in the figures are not to scale. In the figures:

[0085] Fig. 1A shows a cross section of a device having a thermoelectric cooler (TEC), casing and capacitive touch sensor;

[0086] Fig. IB depicts a top view of the TEC with a surrounding touch capacitive sensor and terminal pad;

[0087] Fig. 1C shows an exploded view of the components of an embodiment of the device;

[0088] Fig. 2 schematically depicts the capacitive sensing voltage measured by the microcontroller according to some embodiments;

[0089] Fig. 3A schematically depicts the Seebeck voltage sensing circuit topology;

[0090] Fig. 3B depicts the same Seebeck voltage sensing topology but with an additional DPDT switch to isolate higher TEC voltages from damaging a differential amplifier;

[0091] Fig. 4A schematically depicts active and inactive periods of a driving voltage of the TEC, shown in positive polarity for generality, with each inactive period used for Seebeck voltage sampling; and

[0092] Fig. 4B schematically depicts a different regimen of Seebeck voltage sampling where every 5thinactive period is prolonged as a longer sampling period.

[0093] DETAILED DESCRIPTION

[0094] The principles, uses, and implementations of the teachings herein may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art will be able to implement the teachings herein without undue effort or experimentation.

[0095] As illustrated in Fig. 1A, there is provided a handheld device configured for thermal stimulation of a test subject, for evaluation of their pain and / or sensation threshold in the context of quantitative sensory testing (QST) or CHEP / CCEP testing. The device, shown in cross section,comprises a thermoelectric cooler 100 with a body-site-contacting surface 120 and an opposing side 110 attached to a cooling system 104 (shown in Fig. 1 C), where the TEC is driven by control circuitry, in the context of thermal stimulation of said body-site. The body-site-contacting side 120 of may have any suitable contact area, for example between 1 mm2and 2500 mm2. According to some examples, it has a contact area of between 100 mm2and 1000 mm2. The cooling system may be as per or substantially similar to that described in WO 2013 / 168168 — the contents of which are incorporated herein in their entirety — for example that a fan may be attached via springs to a TEC and heat sink, thereby minimizing and / or isolating vibration from the fan from reaching the body-site. Alternatively, the cooling system may comprise a heat sink alone, and / or include a fluid-to-air heat exchanger.

[0096] The driving voltage may be inverted in polarity depending on whether cooling or heating is desired as a thermal stimulus. The term “cold side” is typically used in the art to refer to the bodysite-contacting side 120 of the TEC 100, and the term “hot side” is typically used in the art to refer to the opposing side 110 of the TEC. The TEC 100 may be driven using any suitable arrangement for example as is known in the art, including, but not limit to, a full- or half-bridge gated driver, a motor driver, a buck converter, a boost converter, a push-pull device, a resonant or flyback converter, a synchronous rectifier, and / or a switching linear amplifier. The TEC 100 is driven in either positive or negative polarity using a discontinuous voltage such as a pulse width modulation (PWM), whereby the duty cycle determines the effective power level to drive the TEC. The effective power level determines the temperature differential across the opposing surfaces of the TEC 100, and the actual temperature of the body-site-contacting side used for the thermal stimulation.

[0097] According to some examples, the driving switching frequency is beyond the auditory range of humans, i.e., above 20 kHz.

[0098] As shown in Fig. 4A, a PWM waveform used for driving the TEC 100 may comprise a square waveform, however, this is not to be construed as limiting, and in practice it may comprise any suitable shape having a well-defined “off’ period (or inactive, low period, 401) during which the voltage to the TEC is substantially zero, including, but not limited to, a sawtooth shape, a triangular shape, etc. During the inactive period the TEC 100 has a temperature gradient across its opposing surfaces (i.e., the “hot” opposing side 110 and “cold” body-site-contacting side 120; AT = Tcoidside - That side), which is proportional to the voltage across its positive and negative terminals via the Seebeck effect:

[0099]

[0100] (Equation 1)where is the Seebeck coefficient in V / K, and N is the number of junctions, e.g., thermocouples, in the TEC.

[0101] A temperature sensor such as a negative temperature coefficient (NTC) thermistor may be used to measure temperature on the opposing side 110 of the TEC 100, for the purpose of being a reference temperature used in calculating the temperature differential across the TEC.

[0102] In some embodiments the Seebeck voltage is 50-250 pV per 1°C temperature differential, and preferably above 100 pV per 1°C temperature differential, where the maximal difference being 100°C between the opposing side 110 and the body-site-contacting side 120, with the number of junctions typically being 127 for a 30 mm x 30 mm TEC contact area, and may be up to 500 junctions. According to some examples, the TEC comprises more than 500 junctions. A typical example of the differential voltage range may be calculated, per to Equation 1, as the product of a typical maximal AT range of 70°C, and a standard number of junctions of 127, divided by a Seebeck coefficient of 100 pV per 1°C, resulting in a differential voltage range of ±889 mV.

[0103] Attention is now drawn to Fig. 3A. In order to measure the Seebeck voltage, it needs to be sampled and offset using a dual supply high gain differential amplifier 312 with DC bias 306 (accounting for the possible negative polarity), in order to undergo analog to digital conversion (ADC) at sufficient resolution from the output 309. The differential amplifier is supplied with both positive and negative voltages (316 and 315 respectively), rather than only positive, to avoid clipping or malfunction of the amplifier due to negative input voltage across the TEC.

[0104] For a required measurement resolution of 0.1°C, the voltage should be detectable at a level of approximately 2.5 mV up to the exemplary ±889 mV (1.78 V range). The bias voltage may be set by resistors of voltage divider 307 to be a third of the positive supply (+Vs) 316. The gain of the differential amplifier may be set by additional resistors (not shown) to span a range of the ADC voltage, for example as is known in the art

[0105] The temperature differential increases with the applied power to the TEC. In some embodiments the temperature difference across the TEC 100 need not reach the full 70°C, for example in a device with a narrower temperature range, where the thermal stimulation is applied to only detect sensation thresholds rather than pain thresholds, which are at more extreme temperatures and are more power intensive. In this case the Seebeck voltage range is correspondingly smaller and the amplification gain, DC bias, and ADC voltage range are calculated to span the Seebeck voltage range accordingly.The TEC driver being connected to the TEC 100 at positive and negative terminals 300, 301 precludes exclusive measurement of the Seebeck voltage, as even during an inactive period when no power is applied, the TEC driver may clamp the effective TEC voltage to a substantially zero differential voltage. Therefore, the connection to the TEC driver may be switched off using switches 313 and 314, which may be N-channel enhancement mode MOSFETs with internal body diodes as illustrated in Figs. 3A and 3B, during a suitable measurement timeframe, for example during the inactive period of the PWM 401.

[0106] Driving the TEC 100 may involve voltages ranging from a few volts to tens of volts. In the topology provided in Fig. 3A, the differential amplifier is capable of withstanding the higher TEC voltage at the positive and negative input terminals 300, 301, higher than the supply voltage of the differential amplifier and higher than the expected TEC driving voltage. If this is not the case an additional double pole double throw switch 317, for example as illustrated in Fig. 3B, may be provided to allow for isolation of the TEC voltage from the differential amplifier during the active period.

[0107] With the Seebeck voltage sampled, amplified, and digitized, the voltage can be converted to degrees Celsius by an external calibration. For example, various points in the working temperature range of the TEC 100 may be tested by applying a driving voltage so as to reach a test point, and the resultant surface temperatures measured by an external sensor in thermal contact with the body-sitecontacting side 120, subtraction of the temperature value measured by the reference opposing-side sensor 110, comparison to the measured Seebeck voltage and a calibration curve made by polynomial regression. The calibration polynomial coefficients may then be stored on the microcontroller, so as to enable the device to function independently of a body-site-contacting side sensor. This enables the device to acquire and interpret the temperature for use as feedback in a control loop, for example using a proportional-integral-derivative (PID) control loop, to control the TEC temperature applied to the body-site.

[0108] As mentioned above and shown in Fig. 4A, in some embodiments an inactive period of the PWM used for sampling the Seebeck voltage may be after each active period 400, so that the maximal sampling time is directly determined by the ratio of the duty cycle and the frequency. Alternatively, in other embodiments for example as shown in Fig. 4B, the inactive period 401 used for sampling the Seebeck voltage may be lengthened across multiple PWM cycles. It is also possible to sample at any time of the active or inactive period; however, the longer the TEC is not powered during an active period or the longer the inactive period is extended for the purpose of Seebeck voltage sampling, thegreater the temperature control error may be. For example, in an extreme case of a required temperature change rate of 100°C / s, assuming that the error may begin to be significant above 0.1 °C, the total inactive time should be less than 1 ms, i.e., (0.1°C / 100°C) / s.

[0109] The device may be configured for use thermal QST for example as is known in the art, including, but not limited to, the test known as “Method of Limits” (or “Limits”), which involves gradually changing the temperature of the thermal stimulator until the subject senses warmth or cold or perceives pain (either hot or cold pain). At the moment the subject senses their threshold, their response needs to be acquired in order to stop the temperature change and record the threshold temperature.

[0110] In some embodiments, shown in Figs. 1 A, IB, and 1C, the device comprises a capacitive touch sensor 101 attached to the interior side of the device casing 102. The capacitive touch sensor may comprise a conductor following the outer circumference of the TEC 100 — either the entirety of the circumference or a portion thereof — or as a thin foil attached directly to and covering a portion or all of the TEC body-site contacting surface. Some embodiments may include a capacitive sensor comprising several adjacent terminals where the differential capacitance across the conductors may be measured. In other embodiments a single terminal 103 may be used and the capacitance change measured directly.

[0111] In some examples, the device contact surface is detached from the subject when their perceived temperature threshold is reached, either removing their hand themselves or by the subject verbalizing that the threshold has been reached and the device operator detaching the device from the skin.

[0112] As illustrated in Fig. 2, a capacitive touch sensor may be powered by applying a series of electrical pulses, and at each pulse the voltage reaches a voltage threshold at the end of the pulse. The pulse may be square wave or of any other waveform, for example as described above. The voltage threshold during no contact 200 may be configured to reach 0 V; during skin contact the voltage at the end of the pulse, being influenced by the capacitive exponential decay 201, in the time period between pulses 202, may decay to a non-zero voltage 203. This non-zero voltage may serve as a preconfigured voltage threshold sufficient to indicate to the microcontroller that the device contact surface has been detached from the subject contact has been discontinued, and the temperature reached in that moment may then be set as the threshold of the subject. The time period to sample the capacitive change 202 in the touch sensor may be between about 0.5 microseconds and about 10 milliseconds, either sampled by the microcontroller over a single pulse period or across multiple pulse periods.In other examples the subject may verbalize that the threshold has been reached and the device operator may detach the device from the skin, thereby changing the capacitance measured by the capacitive touch sensor to a similar effect as when the subject removes their hand / foot or other bodysite independently from the body-site-contacting surface of the thermal stimulator. In other embodiments, an optical sensor may be used in place of the aforementioned capacitive sensor, such as an ambient light sensor or an infrared light sensor. The optical sensor may comprise a phototransistor or a photodiode, and may include a light source integrated in the sensor, or utilize a light source integral to the device but separate from the sensor. The sensor detects a body-site surface based on light reflected from the body-site surface, either from ambient light sources or from the light source integrated in the device. During the thermal stimulation, the body site undergoing the test is lifted away from the TEC body-site contacting surface and this separation is detected to set the temperature threshold that was reached. This method is advantageous as it does not depend on or influence the function or control of the TEC, is less susceptible from electrical fields induced by the surrounding device electronics and is more immune to electromagnetic and safety testing as in IEC 60601 standard testing.

[0113] It is foreseeable that some test subjects undergoing a test may have difficulty in responding with sufficiently short reaction time from the moment of perception until the moment of reporting the perception or sensation. It is known to those skilled in the art of an alternate test protocol known as “Method of Levels,” in which a thermal stimulus at a certain temperature is applied to a test subject’s body-site, thereafter the test subject is asked whether the thermal stimulus was perceived. If the answer is positive, for example for assessing the test subject’s heat or warm threshold, a subsequent lower temperature is applied. If the answer is negative a more intense or higher temperature is applied. In this manner temperatures are applied until the test converges upon a threshold, whereby the stopping criterion is predefined as a minimal temperature difference between the last positive and last negative response. The threshold is then selected as the average of those said last positive and last negative responses. For example, the response may be positive for 45°C, negative for 44.5°C, and the temperature difference predefined to be 0.5°C, and therefore the threshold should be 44.75°C as the average of the last positive and last negative responses. It is obvious that such a test may be prolonged to several minutes, which is a long timeframe to devote in the clinical setting.

[0114] According to the presently disclosed subject matter, there is provided a test method in which a profile of a test subject is assigned based on relevant parameters. According to some examples, theparameters comprise their gender, and age, stimulus type, and body-site to be tested (for example, a 45-year-old female to be tested on her foot for her cold sensation threshold temperature).

[0115] Normative data is used to provides a threshold temperature for the profile assigned. Sources of normative data may include, but are not limited to, those listed in “Thermal testing: normative data and repeatability for various test algorithms” (David Yarnitsky and Elliot Sprecher, Journal of Neurological Sciences 125 (1194) 39-45); “Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values” (Rolke et al, Pain 123 (2006) 231-243).

[0116] In some embodiments the device according to the presently disclosed subject matter provides a thermal stimulus to serve as a “go / no-go” thermal stimulus, e.g., a cold thermal stimulus, i.e., if the test subject senses the thermal stimulus at that temperature, the threshold for them is in the normal range, and if they do not sense that thermal stimulus, an abnormality in the cold sensation threshold is identified and recorded. In other embodiments two or more thresholds may be used; one slightly above and one slightly below the normative value, e.g., 0.5°C or 1°C above and below the threshold, thereby providing a confirmatory measure of that abnormality or lack thereof in the test, or in order to serve as a measure of severity of the abnormality or lack thereof. The normative values may be programmed to be selectable as thermal stimuli to be applied, in the user interface of the device, for a plurality of body-sites and age groups, for example all combinations of: males and females; bodysites possibly including hand and foot; age groups possibly including above 40 years of age, between 20 and 40 years of age and below 20; thermal sensation thresholds of cold and warm, and thermal pain thresholds of cold and hot.

[0117] Using the device according to the presently disclosed subject matter to carry out a testing method for example as described herein may increase the uniformity of test results, e.g., by electronically controlling, inter alia, the stimulation temperature applied, and by minimizing complexity and number of components.

[0118] In some embodiments of this invention a heat pipe may be affixed to a TEC to conduct heat to or from a body-site with contact area smaller than that of the TEC. The heat pipe may comprise a sealed metallic tube or flat pad, for example made of copper or aluminum, containing a working fluid such as water, acetone, or methanol, and featuring a wick or grooved structure along its interior, for example as is known in the art. The fluid is maintained at low pressure to allow evaporation upon applying of heat by the TEC at the hot side of the heat pipe. The fluid evaporates and rapidly transportsheat to the cooler side of the heat pipe, where it condenses back into liquid form. The condensed fluid is then returned to the hot side via capillary action along the wick or groove structure. This mechanism provides an extremely efficient method of heat transfer, and enhances the system's thermal control and efficiency in delivering a thermal stimulus to hard to reach or small body-sites. The heat pipe may be attached to the TEC by conductive adhesive bonding, silver brazing, and / or by mechanical clamping with thermal compound. In some embodiments the heat pipe may be encased in an insulating sheath with only one portion exposed for body-site contact. In further embodiments the exposed portion may be covered or bonded to a metallic contact plate in order to provide a flat contact area of certain dimensions, for example if the heat pipe has a round cross-section and / or has surface irregularities at its ends. In yet other embodiments the heat pipe may be fully exposed, and a disposable cover may be provided in order to prevent cross contamination between body-sites of the same or different subjects and between tests. The heat pipe may be fixed in the device or be interchangeable with other heat pipes to allow for different interchangeable sizes to be used with the same device.

[0119] It will be appreciated that while herein the specification and claims the term “control unit” is used with reference to a single element, in practice it may comprise one or more components, which may or may not be in physical proximity to one another, without departing from the scope of the presently disclosed subject matter, mutatis mutandis. According to some examples, the control unit comprises or is embodied by the disclosed microcontroller. Moreover, disclosure herein, including recitation in the appended claims, of a control unit carrying out a function, being configured to carry out a function, or other similar language, implicitly encompasses examples wherein other elements of the device carry out, are configured to carry out, etc., the function — alone, in concert with the control unit, in concert with other elements of the device , in concert with one or more external devices, etc. — without departing from the scope of the presently disclosed subject matter, mutatis mutandis.

[0120] The heat pipe may have a diameter (or equivalent dimension for non-round examples) of between about 1 mm and about 20 mm, and may have a length of between about 50 mm and about 200 mm. Monitoring of the temperature at the body-site-contacting end of the heat pipe may be performed for example as described above, e.g., by measuring the Seebeck voltage at the TEC with which the heat pipe is in thermal contact. A small lag in thermal conduction may be present, and accounted for during calibration, e.g., by correlating the actual temperature at the end of the heat pipe and the temperature at the side contacting the TEC. The impact of this lag may be minimized by working at slower temperature change rates.Similarly to aspects of the invention that do not include a heat pipe, relating to detection of a subject’s response to thermal threshold testing for sensation or pain, in some embodiments a capacitive or optical touch sensor may be incorporated between the heat pipe and the sheath or casing. In other embodiments the heat pipe, being metallic and electrically conductive, may serve the same purpose by acting as the electrode which is used to detect the capacitive changes of the contact with the bodysite, and subsequent detection of capacitive change during detachment from the body-site when the temperature threshold is detected. In such a case a wire may be soldered, brazed, bonded using conductive adhesive or otherwise attached in electrical contact to the heat pipe and the relevant touch capacitive sensor acquisition circuitry located on a printed circuit board.

[0121] In some aspects of the invention, test results such as temperature sensation or pain thresholds that are acquired, may be transmitted to a hospital information system to an emergency medical record (EMR) in order to provide a means for long-term or inter-visit monitoring of the state of the test subject’s small fiber nervous system.

[0122] Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more other technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.

[0123] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the indefinite articles “a” and “an” mean “at least one” or “one or more” unless the context clearly dictates otherwise.

[0124] In the description and claims of the application, the words “include” and “have,” and forms thereof, are not limited to members in a list with which the words may be associated.

[0125] According to some embodiments, “about” may specify the value of a parameter to be between 80% and 120% of the given value. According to some embodiments, “about” may specify the value of a parameter to be between 90% and 110% of the given value. According to some embodiments, “about” may specify the value of a parameter to be between 95% and 105% of the given value.

[0126] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of asingle embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the disclosure. No feature described in the context of an embodiment is to be considered an essential feature of that embodiment, unless explicitly specified as such.

[0127] Although steps of methods according to some embodiments may be described in a specific sequence, methods of the disclosure may include some or all of the described steps carried out in a different order. A method of the disclosure may include a few of the steps described or all of the steps described. No particular step in a disclosed method is to be considered an essential step of that method, unless explicitly specified as such.

[0128] Although the disclosure is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. Accordingly, the disclosure embraces all such alternatives, modifications and variations that fall within the scope of the appended claims. It is to be understood that the disclosure is not necessarily limited in its application to the details of construction and the arrangement of the components and / or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways.

[0129] The phraseology and terminology employed herein are for descriptive purpose and should not be regarded as limiting. Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the disclosure. Section headings are used herein to ease understanding of the specification and should not be construed as necessarily limiting.

Claims

CLAIMS1. A thermal stimulation device for thermal sensory testing, the device comprising:a thermoelectric cooler (TEC) having a first surface configured for contact with a bodysite of a subject and a second surface opposite the first surface;a temperature measurement system configured to determine the temperature of the first surface, wherein determining the temperature of the first surface comprises measuring a Seebeck voltage generated by the TEC, measuring the temperature of the second surface of the TEC, and calculating the temperature of the first surface of the TEC based on the Seebeck voltage and the temperature of the second surface; anda control unit configured to facilitate applying a thermal stimulus to the subject, based on the determined temperature, by applying a voltage to the TEC thereby controlling the temperature of the first surface.

2. The thermal stimulation device according to claim 1, the temperature measurement system comprising an analog-to-digital converter configured to measure the Seebeck voltage between terminals of the TEC.

3. The thermal stimulation device according to any one of the preceding claims, the control unit being configured to correlate the measured Seebeck voltage to temperature based on a calibration relationship.

4. The thermal stimulation device according to any one of the preceding claims, the first surface comprising a substantially continuous flat contact surface free of surface irregularities.

5. The thermal stimulation device according to any one of the preceding claims, wherein facilitating applying the thermal stimulus further comprises applying a voltage to the TEC to vary the temperature at a rate between 0.1°C per second and 400°C per second.

6. The thermal stimulation device according to any one of the preceding claims, further comprising a portable housing and a battery power source.

7. The thermal stimulation device according to any one of the preceding claims, further comprising a memory configured to store test results and / or normative threshold values for multiple body-sites and demographics.

8. The thermal stimulation device according to any one of the preceding claims, being configured to communicate with an electronic medical record of the subject to transmit test results thereto.

9. The thermal stimulation device according to any one of the preceding claims, wherein the thermal sensory testing comprises quantitative sensory testing.

10. The thermal stimulation device according to any one of the preceding claims, wherein the thermal sensory testing comprises contact heat evoked potential testing.

11. The thermal stimulation device according to any one of the preceding claims, wherein the thermal sensory testing comprises contact cold evoked potential testing.

12. A thermal stimulation device configured to facilitate thermal sensory testing, the device comprising:a thermal stimulation element having a contact surface configured for contact with a bodysite of a subject;a contact sensing system configured to detect contact between the contact surface and the body-site, and to detect detachment of the contact surface from the body-site, the contact sensing system comprising a capacitive touch sensor and / or an optical sensor;a temperature control system configured to facilitate applying a thermal stimulus to the body-site via the contact surface; anda control unit configured to direct operation of the thermal stimulation device.

13. The thermal stimulation device according to claim 12, the control unit being configured to record a temperature at the contact surface when detachment is detected, and to determine the recorded temperature as a thermal threshold.

14. The thermal stimulation device according to any one of claims 12 and 13, wherein applying the thermal stimulus comprises maintaining the contact surface at a predetermined test temperature.

15. The thermal stimulation device according to claim 14, the control unit being configured to determine the temperature of the contact surface, and to determine the predetermined test temperature based, at least in part, on the temperature of the contact surface.

16. The thermal stimulation device according to any one of claims 14 and 15, the control unit being configured to determine the predetermined test temperature based, at least in part, on normative data.

17. The thermal stimulation device according to claim 16, wherein the normative date comprises threshold values.

18. The thermal stimulation device according to any one of claims 12 through 17, the control unitbeing further configured to determine sensory function of the subject based, at least in part, on whether detachment of the contact surface from the body-site is detected.

19. The thermal stimulation device according to claim 18, the control unit being configured to determine sensory function of the subject based, at least in part, on whether detachment of the contact surface from the body-site is detected within a predetermined time period.

20. The thermal stimulation device according to any one of claims 12 through 19, wherein the thermal stimulation element comprises a thermoelectric cooler (TEC).

21. The thermal stimulation device according to claim 20, further comprising a temperature measurement system configured to facilitate determining the temperature of the contact surface of the thermal stimulation element, wherein determining the temperature of the contact surface comprises measuring a Seebeck voltage generated by the TEC.

22. The thermal stimulation device according to claim 21, wherein the temperature measurement system is further configured to determine the temperature of the contact surface of the thermal stimulation element further by measuring the temperature of a second surface of the thermal stimulation element being opposite the contact surface, and calculating the temperature of the contact surface of the thermal stimulation element based on the Seebeck voltage and the temperature of the second surface.

23. The thermal stimulation device according to any one of claims 12 through 22, wherein the capacitive touch sensor comprises a conductive layer positioned adjacent to the contact surface and electrically isolated from the thermal stimulation element.

24. The thermal stimulation device according to any one of claims 12 through 23, wherein the optical sensor comprises an infrared emitter and a detector configured to detect the presence of the body-site based on reflected infrared radiation.

25. The thermal stimulation device according to any one of claims 12 through 24, wherein the optical sensor is configured to detect proximity of the body-site to the contact surface.

26. The thermal stimulation device according to any one of claims 12 through 25, further comprising a heat pipe thermally coupled to the contact surface of the thermal stimulation element, the heat pipe comprising a body-site-contacting end having a contact area which is smaller than that of the contact surface.

27. The thermal stimulation device according to claim 26, wherein the heat pipe comprises a sealed metallic tube containing a working fluid therewithin.

28. The thermal stimulation device according to any one of claims 26 and 27, wherein the heat pipe is electrically conductive and constitutes an electrode of the capacitive touch sensor.

29. The thermal stimulation device according to any one of claims 12 through 28, wherein the contact surface has a contact area between 0.25 cm2and 16 cm2.

30. The thermal stimulation device according to any one of claims 12 through 29, further comprising a cooling system thermally coupled to a second surface of the thermal stimulation element being opposite the contact surface, wherein the cooling system comprises a heat sink and a fan configured to facilitate dissipating heat from the heat sink.

31. The thermal stimulation device according to claim 30, wherein the cooling system is configured to operate substantially without introducing vibrational artifacts during testing.

32. The thermal stimulation device according to any one of claims 12 through 31, further comprising a portable housing and a battery power source.

33. The thermal stimulation device according to any one of claims 12 through 32, further comprising a memory configured to store test results and / or normative threshold values for multiple body-sites and demographics.

34. The thermal stimulation device according to any one of claims 12 through 33, being configured to communicate with an electronic medical record of the subject to transmit test results thereto.

35. The thermal stimulation device according to any one of claims 12 through 34, wherein the thermal sensory testing comprises quantitative sensory testing.

36. The thermal stimulation device according to any one of claims 12 through 35, wherein the thermal sensory testing comprises contact heat evoked potential testing.

37. The thermal stimulation device according to any one of claims 12 through 36, wherein the thermal sensory testing comprises contact cold evoked potential testing.

38. A method for thermal sensory testing of a subject, the method comprising:contacting the body-site of the subject with a contact surface of a thermal stimulation element;operating the thermal stimulation element to apply a thermal stimulus via the contact surface of the thermal stimulation element to the body-site at a predetermined test temperature; andclassifying sensory function based on subject response.

39. The method according to claim 38, further comprising selecting the predetermined testtemperature based on normative threshold values for the body-site.

40. The method of according to claim 39, wherein the predetermined test temperature is selected to be within 1 °C of the normative threshold value for the body-site.

41. The method of according to claim 40, wherein the predetermined test temperature is selected to be within 0.5°C of the normative threshold value for the body-site.

42. The method according to any one of claims 38 through 41, wherein the thermal stimulation element comprises a thermoelectric cooler (TEC).

43. The method according to claim 42, further comprising monitoring the temperature of the contact surface by measuring a Seebeck voltage generated by the TEC.

44. The method according to claim 43, wherein monitoring the temperature of the contact surface further comprises measuring the temperature of a second surface of the TEC being opposite the contact surface, and calculating the temperature of the contact surface based on the Seebeck voltage and the temperature of the second surface45. The method according to any one of claims 42 through 44, further comprising selectively applying a voltage to the TEC to control the temperature of the thermal stimulus.

46. The method according to any one of claims 38 through 45, wherein applying the thermal stimulus comprises varying its temperature at a rate between 0.1 °C per second and 5°C per second.

47. The method according to any one of claims 38 through 46, wherein applying the thermal stimulus comprises applying heat to the body-site to test warm sensation threshold and / or hot pain threshold.

48. The method according to any one of claims 38 through 47, wherein applying the thermal stimulus comprises cooling the body-site to test cold sensation threshold and / or cold pain threshold.

49. The method according to any one of claims 38 through 48, further comprising comparing the recorded thermal threshold to normative values to help identify peripheral sensory nerve functional impairment.

50. The method according to any one of claims 38 through 49, further comprising:providing a contact sensing system configured to detect contact between the contact surface and the body-site, and to detect detachment of the contact surface from the body-site, the contact sensing system comprising a capacitive touch sensor and / or an optical sensor;detecting the contact between the contact surface and the body-site; andmonitoring for detachment of the contact surface from the body-site;wherein the subject response comprises whether detachment of the contact surface from the body-site occurs.

51. The method according to claim 50, wherein classifying the sensory function comprises determining a thermal threshold, the thermal threshold being determined as the temperature of the contact surface of the thermal stimulation element upon detecting detachment from the body-site.

52. The method according to claim 51, further comprising recording the thermal threshold.

53. The method according to any one of claims 38 through 52, wherein the sensory function is classified as normal or abnormal.

54. The method according to any one of claims 38 through 53, further comprising determining a severity level of sensory abnormality by operating the thermal stimulation element to apply multiple thermal stimuli at different predetermined test temperatures.

55. The method according to any one of claims 38 through 54, wherein the body-site is selected from the group including: a hand, a foot, an eyelid, an intranasal site, an intraoral site, a facial site, a vaginal site, a clitoral site, and an anal site.

56. The method according to any one of claims 38 through 55, being used to facilitate detection of peripheral small fiber neuropathy.

57. The thermal stimulation device according to any one of claims 38 through 56, wherein the thermal sensory testing comprises quantitative sensory testing.

58. The thermal stimulation device according to any one of claims 38 through 57, wherein the thermal sensory testing comprises contact heat evoked potential testing.

59. The thermal stimulation device according to any one of claims 38 through 58, wherein the thermal sensory testing comprises contact cold evoked potential testing.

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