GB2562297A - Apparatus for electrical impedance spectroscopy - Google Patents

Apparatus for electrical impedance spectroscopy Download PDF

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Publication number
GB2562297A
GB2562297A GB1707618.3A GB201707618A GB2562297A GB 2562297 A GB2562297 A GB 2562297A GB 201707618 A GB201707618 A GB 201707618A GB 2562297 A GB2562297 A GB 2562297A
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electrode
tissue
electrodes
current
set
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GB201707618D0 (en
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J P Alix James
Healey Jamie
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University of Sheffield
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University of Sheffield
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves
    • A61B5/053Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0537Measuring body composition by impedance, e.g. tissue hydration or fat content
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves
    • A61B5/053Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531Measuring skin impedance
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves
    • A61B5/053Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0535Measuring electrical impedance or conductance of a portion of the body impedance plethysmography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6802Sensor mounted on worn items
    • A61B5/681Wristwatch-type devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/683Means for maintaining contact with the body
    • A61B5/6838Clamps or clips
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means
    • G01N27/02Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means by investigating the impedance of the material
    • G01N27/026Dielectric impedance spectroscopy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/103Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/107Measuring physical dimensions, e.g. size of the entire body or parts thereof

Abstract

An electrical impedance spectroscopy (EIS) system for the detection of tissue abnormalities in amyotrophic lateral sclerosis (ALS). In particular, a EIS probe is disclosed having a three dimensional array of electrodes separated from one another in the x, y and z coordinates by quantitative separation distances. A first electrode set and a second electrode set comprising at least two electrodes are arranged in first and second x-y planes separated by a distance in a z direction, the distance is known quantitative value. A set of flanges 105 can be used to provide the predefined quantitative separation distance required.

Description

Apparatus for Electrical Impedance Spectroscopy

Field of invention

The present invention relates to apparatus and methods relating to the measuring of an electrical parameter transmitted through human or animal body tissue and in particular, although not exclusively, to method and apparatus for electrical impedance spectroscopy (EIS).

Background art

Neuromuscular diseases are a considerable source of mortality and morbidity. Their diagnosis often relies on multiple investigations including blood tests, nerve conduction studies and electromyography (EMG), imaging (e.g. MRI) and muscle biopsy. While each of these tests have their own strengths, each has its own limitations. For example, the muscle enzyme creatinine kinase can easily be detected in blood but is poorly predictive of an underlying muscle disorder [Shaibani A, Jabari D, Jabbour M, Arif C, Lee M, Rahbar MH. Diagnostic outcome of muscle biopsy. Muscle Nerve. 2015;51(5):662-8],

Taking motor neurone disease (MND) as an example of a severe neuromuscular disease requiring urgent research progress, there is no single diagnostic test and currently, the diagnosis is made clinically and, supported by multiple investigations, including nerve conduction studies and EMG. EMG examination may proceed across each of the four craniospinal segments but there is evidence to suggest that this test works better in some segments than others. For example, examination of the bulbar segment (most usually of the tongue) has a lower sensitivity than other segments but a higher specificity, making the contribution of tongue EMG to diagnostic classification limited [Jenkins TM, Alix JJ, Kandler RH, Shaw PJ, McDermott CJ. The role of cranial and thoracic EMG within diagnostic criteria for ALS. Muscle Nerve. 2016].

In addition, the development of effective biomarkers to track progression of MND is of great interest as efforts to develop new therapies continue. Recently, bioimpedance measurements have gained increasing interest as a biomarker of disease progression in amyotrophic lateral sclerosis (ALS) [Rutkove SB, Caress JB, Cartwright MS, Burns TM, Warder J, David WS, et al. Electrical impedance myography as a biomarker to assess ALS progression. Amyotroph Lateral Scler. 2012; 13(5):439-45]; [Rutkove SB, Zhang H, Schoenfeld DA, Raynor EM, Shefner JM, Cudkowicz ME, et al. Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials. Clin Neurophysiol. 2007;l 18(11):2413-8]; [Sanchez B, Rutkove SB. Electrical Impedance Myography and Its Applications in Neuromuscular Disorders. Neurotherapeutics. 2016]; and [Benatar M, Boylan K, Jeromin A, Rutkove SB, Berry J, Atassi N, et al. ALS Biomarkers for Therapy Development: State of the Field & Future Directions. Muscle Nerve. 2015], In this technique, alternating current (AC) of a given amplitude/frequency is applied and measurements of the electrical impedance are recorded. By applying AC over a range of frequencies, information relating to both the electrical resistive and reactive properties of the tissue is obtained. The authors of these works utilised impedance measurements in limb muscles [Tarulli AW, Garmirian LP, Fogerson PM, Rutkove SB. Localized muscle impedance abnormalities in amyotrophic lateral sclerosis. J Clin Neuromuscul Dis. 2009;10(3):90-6], and more recently, the tongue [Mcllduff C, Yim S, Pacheck A, Geisbush T, T, Mijailovic A, Rutkove SB. An improved electrical impedance myography tongue array for use in clinical trials. Clin Neurophysiol. 2016; 127(1):932-5] and [Shellikeri S, Yunusova Y, Green JR, Pattee GL, Berry JD, Rutkove SB, et al.

Electrical impedance myography in the evaluation of the tongue musculature in amyotrophic lateral sclerosis. Muscle Nerve. 2015]. As muscles change during disease, for example, through atrophy, impedance parameters also change; i.e., the rise in resistance values is thought to occur due to muscle replacement by fat and connective tissue [Rutkove SB. Electrical impedance myography: Background, current state, and future directions. Muscle Nerve. 2009;40(6):936-46],

Previous work in both muscle [Rutkove SB, Caress JB, Cartwright MS, Bums TM, Warder J, David WS, et al. Electrical impedance myography correlates with standard measures of ALS severity. Muscle Nerve. 2014;49(3):441 -3]; [Narayanaswami P, Spieker AJ,

Mongiovi P, Keel JC, Muzin SC, Rutkove SB. Utilizing a handheld electrode array for localized muscle impedance measurements. Muscle Nerve. 2012;46(2):257-63] and [Schwartz DP, Dastgir J, Salman A, Lear B, Bonnemann CG, Lehky TJ. Electrical impedance myography discriminates congenital muscular dystrophy from controls. Muscle Nerve. 2016;53(3):402-6] and mucosal surface bioimpedance recording has utilised 2-dimensional planar electrode arrays. One potential limitation to this approach is that the injected current is dissipated through the tissue and extends along diffuse pathways of minimum resistance. Since impedance is affected by geometry, as well as underlying tissue characteristics, (Z = G po; where Z = impedance, G = geometric variables and po = tissue variables) [Shiffman CA. Adverse effects of near current-electrode placment in non-invasive bioimpedance measurements. Physiol Meas. 2013;34(11):1513-29] changes in geometry, for example, due to muscle wasting, may lead to differing volumes of muscle being analysed. Furthermore, as biological tissue is rarely homogeneous the effect of geometric changes will be complex and difficult to define. In some muscles, for example the tongue, bioimpedance measurements are further complicated by the complex arrangement of muscle fibers which may run in multiple orientations.

Existing electrical impedance myography devices having a 2-dimensional array of electrodes are accordingly disadvantageous due to their generally limited reproducibility and sensitivity to change within the same subject over time (via different measurement sessions) and between different subjects (with measurements taken at the same time). Accordingly, what is required is apparatus and method for electrical impedance spectroscopy that addresses the above problems.

Summary of the Invention

It is an objective of the present invention to provide apparatus and method for measurement of an electrical parameter transmitted through human or animal body tissue that provides enhanced sensitivity, reproducibility and specificity over existing arrangements. It is a further specific objective to provide apparatus and method for electrical impedance spectroscopy (EIS) offering greater sensitivity for detection of pathology and a greater reliability of tissue status analysis.

The objectives are achieved via method and apparatus in which at least two sets of electrodes are provided and spatially separated by a quantitative separation distance so as to enable 3-dimensional tissue analysis. This 3-dimensional analysis is achieved via a 3-dimensional array of electrodes having at least a first set positioned approximately at a first plane and a second electrode set positioned approximately at a second plane with each plane separated by a quantitative separation distance to define a 3-dimensional electrode array. The quantitative separation distance between the electrode sets provides analysis of a fixed quantitative volume of tissue, between the opposed electrode sets.

The 3-dimensional array of electrodes is advantageous to create better defined current pathways through the tissue in contrast to existing 2-dimensional electrode arrangements. In particular, the inventors have identified that for such existing arrangements, the current pathway from a current source to a current sink is poorly defined as the current is not confined to the shortest path between the electrodes and disperses outwardly into the tissue, having a ‘rugby-ball’’ like profile. In general, it is not possible to predict or control the current path between two current injection electrodes; although approximations may be made assuming a homogeneous conductivity distribution [Kotre CJ. EIT image reconstruction using sensitivity weighted filtered backprojection. Physiol Meas 1994; 15 Suppl 2a: A125-36. Inspecting a planar arrangement of electrodes in an x-y plane, the bulk of the current will flow in this plane, with significant current only flowing in the z direction close to the electrodes. By injecting current through the tissue the current can be made to flow substantially in the z direction. The present system optionally based on a cubic or rectangular cuboid arrangement of electrodes significantly improves the definition of the current pathways, allowing for a greater exploration of tissue anisotropy. This in combination with providing a quantitative tissue volume between the electrode sets significantly enhances the sensitivity and specificity of the present method and apparatus, giving greater reproducibility and accordingly a more sensitive and reliable tissue status assessment.

In particular, the inventors provide apparatus and method utilising a 3-dimensional array of electrodes for analysis of a fixed volume of tissue via multi-frequency alternating current AC) across multiple directions in both 2-dimensional and 3- dimensional electrode array configurations depending upon the choice of active electrodes within the array. In particular, the inventors provide an electrical impedance system for tissue analysis that reduces sensitivity to geometry variations of the tissue which otherwise affect the resulting electrical signals and in particular mask variations in tissue properties resultant from pathological disruptions or other disease induced anomalies. The present system providing a 3-dimensional tissue analysis via a x, y and z coordinate based electrode array has the potential to target identification of tissue abnormalities with regard to their position within the tissue under investigation and the extent of the abnormalities with regard to healthy tissue.

According to a first aspect of the present invention there is provided apparatus configured to provide measurement of an electrical parameter transmitted through human or animal body tissue, the apparatus comprising: a first electrode set comprising at least two electrodes arranged generally in a first x-y plane; a second electrode set comprising at least two electrodes arranged generally in a second x-y plane; wherein the second electrode set is separated from the first electrode set by a separation distance in a z direction to define a gap region between the first and second electrode sets to accommodate at least a portion of the human or animal body tissue; wherein the separation distance in the z direction between the first and second electrode sets is a known quantitative value.

Preferably, a separation distance between any two of the electrodes of the first set and/or the second set in the x-y plane is less than the separation distance between the first and second electrode sets in the z direction.

Preferably, the first and/or second electrode sets each comprise at least four electrodes. Optionally, the first and/or second electrode sets each comprise four electrodes or 5, 6, 7, 8, 9 or 10 electrodes.

Preferably, each of the electrodes of the first and second sets are positioned in the respective x-y plane at vertices of an imaginary rectangle or square.

Optionally, the apparatus comprises means to fix and maintain the first and second electrode sets at the separation distance in the z direction. Preferably, the first electrode set is provided at a first member and the second electrode set is provided at a second member, at least end regions of the first and second members being spaced apart by the separation distance in the z direction to define opposed prongs.

Optionally, the apparatus comprises at least one removable sheath disposed over at least the end regions of the first and second members.

Optionally, the electrodes of the first and second sets are formed as separate metal nodes provided at the end regions of the first and second members. Optionally, the electrodes of the first and second sets may be printed onto at least respective regions of the removable sheath disposed at the respective first and second members. Optionally the electrodes are nodes of gold. Optionally the electrodes/nodes are printed onto the sheath.

Optionally, the first and second members are generally positionally fixed relative to one another such that the separation distance in the z direction between the first and second electrode sets is a fixed quantitative value. Optionally, the first and second members are cantilever mounted in opposed relationship and are capable of flexing, bending or deforming slightly to be brought towards one another slightly to reach a predefined quantitative separation distance in the z direction. Preferably, the inward movement of the members is arrested/stopped by at least one flange to set the predefined quantitative separation distance in the z direction.

Optionally, at least a distal end portion of at least one of the first and/or second members is positionally adjustable (e.g., by sliding, moving, bending, or otherwise deforming) to provide variation of the separation distance in the z direction to provide a plurality of different quantitative values for the separation distance in the z direction as required to accommodate different respective volumes of tissue.

Preferably, the apparatus comprises electronic components to provide and/or support current flow between the electrodes of the first and second electrode sets, the apparatus further comprising a housing to contain the electronic components.

According to a second aspect of the present invention there is provided a method of measuring an electrical parameter transmitted through human or animal tissue, the method comprising: providing a first electrode set comprising at least two electrodes arranged generally in a first x-y plane, providing a second electrode set comprising at least two electrodes arranged generally in a second x-y plane, wherein the second electrode set is separated from the first electrode set by a separation distance in a z direction to define a gap region between the first and second electrode sets to accommodate at least a portion of the human or animal body tissue, the separation distance in the z direction between the first and second electrode sets being a known quantitative value; passing a current through the tissue using at least some of the electrodes of the first and/or second electrode sets; and measuring an electrical signal resultant from passing the current through the tissue using at least some of the electrodes of the first and second electrode sets.

Preferably, the method comprises analysing the current passed though the tissue and the electrical signal to determine an electrical transfer impedance of the tissue.

Preferably, the method comprises analysing the electrical transfer impedance of the tissue to determine a status of the tissue.

Preferably, the electrical signal is a voltage resultant from passing the current through the tissue between electrodes of the first and/or second electrode sets. Optionally, each of the first and second electrode sets comprise at least four electrodes.

Optionally, the step of passing the current through the tissue and measuring the electrical signal comprises using at least a first and second electrode of the first electrode set as a respective current source and a current sink and using a first and second electrode of the second electrode set as respective sensing electrodes.

Optionally, the step of passing the current through the tissue and measuring the electrical signal comprises: using a first electrode of the first electrode set as a current source and a first electrode of the second electrode set as a current sink; and using a respective second electrode of the first and second electrode sets as respective sensing electrodes.

Optionally, the step of passing current through the tissue and measuring the electrical signal comprises: using a first electrode of the first electrode set as a current source; using a second electrode of the first electrode set as a current sink; and using at least a third and a fourth electrode of the first electrode set as respective sensing electrodes.

Optionally, the step of passing current through the tissue and measuring the electrical signal comprises: using a first electrode of the second electrode set as a current source; using a second electrode of the second electrode set as a current sink; and using at least a third and a fourth electrode of the second electrode set as respective sensing electrodes.

Preferably, the step of passing the current through the tissue comprises applying current at a plurality of different frequencies and the step of measuring the electrical signal comprises measuring a plurality of electrical signals resultant from the passing of the current through the tissue at the plurality of different frequencies.

Optionally, the plurality of frequencies comprises frequencies in a range 10Hz to 10 MHz.

According to further aspects of the present invention there is provided a method of detection of bulbar disease in ALS or other relevant motor system disorders. According to further aspects of the present invention there is provided a system for detection of abnormalities in ALS and in particular the detection of abnormalities in tongue tissue.

According to further aspects of the present invention there is provided a method, apparatus and system of multi-frequency and multi-directional EIS.

Brief description of drawings A specific implementation of the present invention will now be described, by way of example only, and with reference to the accompanying drawings in which:

Figure 1 is a perspective view of an EIS probe according to a specific implementation having a pair of members (tongs) that mount respectively first and second sets of electrodes to define a 3-dimensional electrode array according to a specific implementation of the present invention;

Figure 2 is a side view of the EIS probe of figure 1;

Figure 3 is a perspective view of the terminal end of the probe of figure 1 according to a magnified view;

Figure 4 is a perspective illustrative view of the 3-dimensional electrode array having a first electrode set provided at a first tong (omitted for illustrative purposes) and a second electrode set provided at a second tong with the sets being separated in a z direction by a quantitative separation distance according to a specific implementation of the present invention;

Figure 5 is a graph of median resistivity versus frequency based on the real component of complex impedance results obtained by EIS investigations of a set of patients with ALS and volunteers using the probe of figure 1;

Figure 6 is a graph of median phase angle versus frequency based on real and imaginary components of complex impedance results obtained by EIS investigations of a set of patients with ALS and volunteers using the probe of figure 1;

Figure 7 is a graph of median reactance versus frequency based on imaginary components of complex impedance results obtained by EIS investigations of a set of patients with ALS and volunteers using the probe of figure 1;

Figure 8 is a graph of median magnitude versus frequency based on real and imaginary components of complex impedance results obtained by EIS investigations of a set of patients and volunteers using the probe of figure 1.

Detailed description of preferred embodiment of the invention

Referring to figures 1 to 4, a handheld EIS probe 100 comprises a housing 101 from which extend, in a cantilever mounted arrangement, a pair of opposed members (or tongs) 102 that form a dual prong arrangement. In particular, a first elongate member 102a extends parallel and opposed to a second elongate member 102b. A distal end region 106a, 106b at each respective member 102a, 102b carries respective electrode mount discs 103, 104. The discs 103, 104 are positioned so as to be spaced apart in a z direction and are mounted on respective inward facing surfaces 102c of each member 102a, 102b. Each electrode disc 103, 104 comprises a generally circular planar face 103a, 104a with the planar faces 103a, 104a being aligned parallel with one another and separated by a quantitative separation distance D. Accordingly, a gap region 108 is defined between the opposed faces 103a, 104a which represents a distal end region of a general mouth or cavity 107 defined between the opposed members 102a, 102b. A pair of flanges 105 project inwardly into and across the mouth 107 from each respective member 102a, 102b so as to overlap one another in the z direction. Each flange 105 does not extend the full separation distance between the respective surfaces 102c and carries at each respective end region, an electrical spring contact (not shown) that when contacted forms a circuit connection. Each cantilever mounted member 102a, 102b is configured with a degree of \ flex' in the z direction so as to provide a degree of opening and closing of the mouth 107. Such an arrangement is beneficial to allow some 'play' or adjustment of the quantitative separation distance D as the probe is manipulated to accommodate a predetermined/desired volume of body tissue into the mouth 107 and in particular into the region 108 between the opposed electrode discs 103, 104. Once the tissue is appropriately accommodated within the mouth 107 (and region 108) a user may then apply pressure onto external facing surfaces of each member 102a, 102b. The flanges 105 are then capable of abutting against the respective inward facing surface 102c so as to provide the desired and predefined quantitative separation distance D between the disc surfaces 103a, 104a.

As illustrated in figures 3 and 4, a first set of electrodes 111 are provided at first electrode disc 103 and a second set of electrodes 110 are provided at second electrode disc 104.

Each electrode set 111, 110 comprises four respective electrodes positioned at the vertices of an imaginary square such that all the electrodes of each respective set are separated from one another by an equal separation distance in an x and y directions (within the z-y plane). According to the specific implementation, each of the electrodes comprises a small metal node coupled to support electronics (not shown) accommodated within housing 101. Such electronic components comprise known configurations as will be appreciated by those skilled in the art for delivering electrical signals such as current and measuring corresponding electrical signals (such as voltage) resulting from the electrical signals delivered. In particular, housing 101 may include one or a plurality of circuits including an amplifier for impedance measurement, a computer, processor or chip to perform calculations, data storage utilities, a battery, wired or wireless communication means, communication ports and the like as will be understood.

According to the specific implementation, the first electrode set 111 comprises four electrodes including a first electrode 11 la, a second electrode 11 lb, a third electrode 111c and a fourth electrode 11 Id. Similarly, the second electrode set 110 comprises four electrodes including a first electrode 110a, a second electrode 110b, a third electrode 110c and a fourth electrode 11 Od. Each corresponding pair of opposed electrodes (e.g. 111a, 110a) is separated from one another by the same quantitative separation distance D in the z direction. Neighbouring electrodes in each respective set 111, 110 are separated from one another in the x direction by a separation distance E and in the y direction by a separation distance F. According to the specific implementation, separation distance E and F are equal and separation distance D is greater than each of the separation distances E and F.

The electronics are coupled to the respective electrode sets 111, 110 and in particular each electrode within each set 111, 110 such that current may be delivered to any one of the eight electrodes, current may be received at any one of the eight electrodes whilst an electrical signal or parameter may be sensed by any of the alternate electrodes within the first or second electrode sets 111, 110. That is, in normal use, selective electrodes of the 3-dimensional array include at least one electrode operating to deliver current (referred to herein as a 'current source'), at least one electrode being configured to receive current (referred to herein as a ‘current sink') and at least two electrodes operating as sensing electrodes (referred to herein as 'potential sense'). According to the specific implementation, the electrical signal that is sensed, as the current is transmitted through the body tissue (within region 108), is voltage. However, the present apparatus and method is not restricted to voltage sensing and/or voltage output with the present apparatus and method capable of outputting any one or a plurality of electrical parameters useful in the identification and assessment of body tissue including in particular pathological disruptions or tissue abnormalities within otherwise healthy tissue.

Table 1 below details various electrode configurations considered by the inventors as beneficial for an EIS system to detect abnormalities in motor neurone disease (MND) and in particular for the detection of tongue abnormalities in ALS. In principal there are 70 possible combinations of electrodes that may be used; however, it is possible using circuit theory [Geselowitz DB. Introduction to “Some Laws Concerning the Distribution of Electric Currents in Volume Conductors with Applications to Experiments on Animal Electricity”. Proceedings of the IEEE. 2004;92(5):864-7] to derive some sets from arithmetic combinations of other sets and only 20 are truly independent of each over.

Table 2 details an example of additional electrode configurations that if used, would allow the derivation of any of the possible 70 sets. Most of these arrangements have not been used as yet and optimisation of the exact measurement sets used is almost certainly possible. Referring to figure 4 and table 1 below, the z direction may be labelled the superior direction, the x direction the anterior direction and the y direction the lateral direction. Table 1 identifies the current source, sink and sensing electrodes according to various different positional configurations for variation of the current pathways through the body tissue in which all electrodes of the 3-dimensional array are separated from one another by the respective quantitative separation distances D, E, F in the respective superior, anterior and lateral directions.

Table 1. Electrode configurations suitable for EIS investigations using a tongue probe 100 according to figures 1 to 4.

Table 2. Additional electrode configurations that could be used in EIS investigations using a tongue probe 100.

As will be noted, the twelve electrode configurations of table 1 include both 2-dimensional and 3-dimensional configurations, the latter being configurations not contained only within either the upper or lower electrode sets. Via the electronics within housing 101 all electrodes within each of the first and second electrode sets 111, 110 may be activated differentially via a cross-point switch (not shown).

Example 1

According to a specific implementation, each electrode within each of the first and second electrode sets 111, 110 is formed as a gold node at each surface 103a, 104a. Separation distance E and F may be 5 mm and separation distance D may be 7 mm when members 102a, 102b are compressed together (and flanges 105 abut surfaces 102c). According to the specific implementation, once members 102a, 102b are depressed, the spring contacts (not shown) provided at the respective end regions of flanges 105 and the adjacent region of surfaces 102c, make contact with one another to complete the electrical circuit and allow current to be delivered to a designated current source electrode.

Patient recruitment

In order to evaluate the present method and apparatus a test study was undertaken to identify the electrical signal differences between patients (with known ALS) and

volunteers (with assumed healthy tissue). Bioimpedance was measured using the 3-dimensional electrode array of figure 4 including in particular consideration of the fixed electrode separation distances D, E and F. Such quantitative electrode separation distances provide identification and inclusion within the EIS system calculations of a quantitative fixed volume of tissue (present within region 108). This is beneficial to increase the sensitivity and specificity of the present apparatus and method which in turn means that the present system is less susceptible to arbitrary geometric variations between different measurement sessions and/or between different subjects. A more sensitive and reliable system is therefore provided.

Multi-frequency and multi-directional EIS spectra were recorded for 22 patients with ALS and 19 healthy volunteers. An inclusion criteria was applied to the 22 patients involving diagnosis of ALS according to the Awaji-Shima criteria [de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008;l 19(3):497-503]. Evidence of lower motor neuron (LMN) involvement of the tongue by either clinical detection of bulbar symptoms by either an experienced clinician, or through EMG examination (using the Awaji-Shima criteria) was required.

Calibration and Measurements

Current with an intensity of 5 pV was injected across 14 frequencies; starting at 76 Hz and then doubling at each step increase to a maximum of 625,000 Hz. Data were downloaded from the probe 100 to a standard laptop via Bluetooth. The probe was calibrated in a number of ways. Firstly, corrections were made to compensate for phase and gain errors introduced by various time constants. Spectra were measured across a precision 1 1<Ω resistor. This curve was stored in the probe and all measurements calibrated against this. Secondly, the cell constant of the device was measured by placing the device in saline solutions ranging from 10 fim to 1 Om. The solutions were also measured using a Jenway 470 conductivity meter. The cell constant was also stored within the probe so that all recordings made by the probe 100 were reported in units of Bm. Before and after use the probe was cleaned using the Tristel Wipes system.

Recording Procedure

Recordings were undertaken with the patient either sitting or lying in an upright position with the tongue resting in a neutral position in the mouth. Recordings were taken with the probe placed in the midline of the tongue. Data were also collected with placement on the left and right halves of the tongue (not shown). In patients able to protrude the tongue, these positions were repeated with the tongue protruded beyond the teeth. These latter recordings were to ascertain if there was any difference in the spectra between the intra-and extra-oral recording positions.

The output values for both the real and imaginary components at each discrete frequency and in each electrode configuration represent an average of eight measurements. The present apparatus was programmed to calculate the standard deviation of this average and to reject the value if it exceeded a pre-defined cut-off of 10% of the mean. The pseudocode for the measurement process is as follows:

While (not timedout) {

Take measurement Store measurement If(n>=8){

Calculated measurement magnitude Calculate mean of measurement magnitudes Calculate stddev of measurement magnitudes

If(stddev/mean<threshold){ //threshold = 0.1 Finish(success) }

Remove oldest set } }

Finish(Timeout)

At completion of the recording the real and imaginary components for each electrode configuration were visually inspected on custom written software. If data were rejected (as described above) then no spectra would be plotted for that electrode configuration. In some instances data with negative real part values or values of extremely high and constant resistance were obtained which passed the dispersion criteria; these likely reflect poor electrode contact. These were removed during data analysis as were other spurious data. If no usable data were evident during visual inspection, for example, due to patient movement during recording, then the recording was re-attempted (providing the patient was happy to proceed).

Data acquisition and statistical analyses

Real and imaginary components of complex impedance were downloaded from the probe using Bluetooth to custom written software, saved (as XML files) and exported for further analysis. Real part (or resistivity, R, measured in ohms), imaginary part (or reactance, X, measured in ohms) were exported and phase angle (PhA = arctan2(X/R), and magnitude (Z = ^(R2 + X2)) were calculated by additional custom software used to export the impedance parameters for further statistics and graphing of data in IBM SPSS statistics. Median and 95% confidence intervals were plotted.

Results

Median values for real and imaginary components, phase angle and magnitude are shown in figures 5 to 8 for the direction SUPANTJSUPANT detailed in table 1.

In particular, figure 5 is a graph of median resistivity versus frequency based on the real component of complex impedance results obtained by EIS investigations of a set of patients and volunteers using the probe of figure 1; Figure 6 is a graph of median phase angle versus frequency based on real and imaginary components of complex impedance results obtained by EIS investigations of a set of patients and volunteers using the probe of figure 1; Figure 7 is a graph of median reactance versus frequency based on the imaginary component of complex impedance results obtained by EIS investigations of a set of patients and volunteers using the probe of figure 1; and Figure 8 is a graph of median magnitude versus frequency based on real and imaginary components of complex impedance results obtained by EIS investigations of a set of patients and volunteers using the probe of figure 1.

These data represent the muscle bioimpedance recordings in which current has been provided and voltage sensed through a known quantitative volume of tissue in contrast to voltage sensed along the surface of muscle. The subtle differences in the data reveal underlying changes in muscle. The data can be combined with results from other electrode configurations (not shown) to further study changes in the tongue muscle of patients with ALS.

Claims (23)

Claims
1. Apparatus configured to provide measurement of an electrical parameter transmitted through human or animal body tissue, the apparatus comprising: a first electrode set comprising at least two electrodes arranged generally in a first x-y plane; a second electrode set comprising at least two electrodes arranged generally in a second x-y plane; wherein the second electrode set is separated from the first electrode set by a separation distance in a z direction to define a gap region between the first and second electrode sets to accommodate at least a portion of the human or animal body tissue; wherein the separation distance in the z direction between the first and second electrode sets is a known quantitative value.
2. The apparatus as claimed in claim 1 wherein a separation distance between any two of the electrodes of the first set and/or the second set in the x-y plane is less than the separation distance between the first and second electrode sets in the z-direction.
3. The apparatus as claimed in claims 1 or 2 wherein the first and/or second electrode sets each comprise at least four electrodes.
4. The apparatus as claimed in claim 3 wherein each of the electrodes of the first and second sets are positioned in the respective x-y plane at vertices of an imaginary rectangle or square.
5. The apparatus as claimed in any preceding claim further comprising means to fix and maintain the first and second electrode sets at the separation distance in the z direction.
6. The apparatus as claimed in any preceding claim wherein the first electrode set is provided at a first member and the second electrode set is provided at a second member, at least end regions of the first and second members being spaced apart by the separation distance in the z direction to define opposed prongs.
7. The apparatus as claimed in claim 6 further comprising at least one removable sheath disposed over at least the end regions of the first and second members.
8. The apparatus as claimed in claim 6 wherein the electrodes of the first and second sets are formed as separate metal nodes provided at the end regions of the first and second members.
9. The apparatus as claimed in claim 7 wherein the electrodes of the first and second sets are printed onto at least respective regions of the removable sheath disposed at the respective first and second members.
10. The apparatus as claimed in claims 6 or 7 wherein the first and second members are positionally fixed relative to one another such that the separation distance in the z direction between the first and second electrode sets is a fixed quantitative value.
11. The apparatus as claimed in claims 6 or 7 wherein at least one of the first and/or second member is positionally adjustable to provide variation of the separation distance in the z direction to provide a plurality of quantitative values of the separation distance in the z direction.
12. The apparatus as claimed in any preceding claim further comprising electronic components to provide and/or support current flow between the electrodes of the first and second electrode sets, the apparatus further comprising a housing to contain the electronic components.
13. A method of measuring an electrical parameter transmitted through human or animal tissue, the method comprising: providing a first electrode set comprising at least two electrodes arranged generally in a first x-y plane, providing a second electrode set comprising at least two electrodes arranged generally in a second x-y plane, wherein the second electrode set is separated from the first electrode set by a separation distance in a z direction to define a gap region between the first and second electrode sets to accommodate at least a portion of the human or animal body tissue, the separation distance in the z direction between the first and second electrode sets being a known quantitative value; passing a current through the tissue using at least some of the electrodes of the first and/or second electrode sets; and measuring an electrical signal resultant from passing the current through the tissue using at least some of the electrodes of the first and/or second electrode sets.
14. The method as claimed in claim 13 further comprising analysing the current passed though the tissue and the electrical signal to determine an electrical transfer impedance of the tissue.
15. The method as claimed in claim 14 further comprising analysing the electrical transfer impedance of the tissue to determine a status of the tissue.
16. The method as claimed in any one of claims 13 to 15 wherein the electrical signal is a voltage resultant from passing the current through the tissue between electrodes of the first and/or second electrode sets.
17. The method as claimed in any one of claims 13 to 16 wherein each of the first and second electrode sets comprise at least four electrodes.
18. The method as claimed in any one of claims 13 to 17 wherein the step of passing the current through the tissue and measuring the electrical signal comprises using at least a first and second electrode of the first electrode set as a respective current source and a current sink and using a first and second electrode of the second electrode set as respective sensing electrodes.
19. The method as claimed in any one of claims 13 to 17 wherein the step of passing the current through the tissue and measuring the electrical signal comprises: using a first electrode of the first electrode set as a current source and a first electrode of the second electrode set as a current sink; and using a respective second electrode of the first and second electrode sets as respective sensing electrodes.
20. The method as claimed in any one of claims 13 to 17 wherein the step of passing current through the tissue and measuring the electrical signal comprises: using a first electrode of the first electrode set as a current source; using a second electrode of the first electrode set as a current sink; and using at least a third and a fourth electrode of the first electrode set as respective sensing electrodes.
21. The method as claimed in any one of claims 13 to 17 wherein the step of passing current through the tissue and measuring the electrical signal comprises: using a first electrode of the second electrode set as a current source; using a second electrode of the second electrode set as a current sink; and using at least a third and a fourth electrode of the second electrode set as respective sensing electrodes.
22. The method as claimed in any one of claims 13 to 21 wherein the step of passing the current through the tissue comprises applying current at a plurality of different frequencies and the step of measuring the electrical signal comprises measuring a plurality of electrical signals resultant from the passing of the current through the tissue at the plurality of different frequencies.
23. The method as claimed in claim 22 wherein the plurality of frequencies comprises frequencies in a range 1 kHz to 10 MHz.
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