a description will now be given of a diagnosis system using electrophysiological measurements according to the invention . this system is based on an active operation principle , in direct current mode as opposed to the impedance measuring systems of the prior art , whose drawbacks were described above . it will be seen firstly that the applicant has conducted in - depth research into the electrical behaviour of the cells of the human body and their environment . it was observed that an alternating electrical current , particularly at low frequency , flowed only in the interstitial water ( interstitium ) separating the cells , and practically not at all through the water of the cells themselves . in fact the membranes of the cells have a sufficient capacitive effect to attenuate , practically completely , the alternating current at the low frequencies . other research on the behaviour of the membranes of the cells have been used to demonstrate that they behave very differently according to the nature of the interstitium , in particular its ph and its electrical potential . to use these properties , it is possible to temporarily subject these environments to different conditions of potential and ph , and to measure their responsiveness . it is firstly recalled that chloride ions have the property , in the presence of water and a sufficient difference of potential and in presence of a ph of less than 7 . 5 , of converting to hclo and h 3 o + , delivering two electrons . on the other hand , for ph greater than 7 . 5 , the formation of clo − ions is observed . these transformations can take place only above a critical voltage that depends on the respective concentrations of cl − and hclo and on the value of the ph . this voltage is typically about 0 . 8v in the usual physiological conditions . it appears that this critical voltage rises when the ph reduces and when the concentration of hclo increases , so that in the course of a measurement on living tissue , a halting of this transformation is attained more or less rapidly according to the initial voltage applied , the initial value of the ph , and the behaviour of the concentrations of h + and hclo ions . by means of the cottrel chronoamperometry equation , this type of measurement is therefore used not only to gain access to the local concentrations of chloride ions but also to test the responsiveness of the tissue in vivo to a local increase in acidity . in fact without the presence of natural buffers such as bicarbonates ( or other ), this transformation of chloride ions would result in very sharp drops in ph , which in turn would themselves lead to a very rapid halting of the reaction and therefore of the resulting current . this reaction therefore also provides an indirect means of locally testing the state of the acid / alkali balance of the living being , namely the ability of the natural buffers to fulfill their role . given that the chloride ion is the anion most present in the extracellular compartments of living organisms , it is therefore possible to estimate , in real time and in vivo , and at various parts of the body such as the hands , the soles of the feet , the forehead , etc ., the ionic nature of the interstitium . these measurements of chloride concentrations and responsiveness of the acid / alkali balance can be used to trace homeostatic , hormonal , vascular , metabolic and other malfunctions . these malfunctions can themselves correspond to various pathologies or pathological predispositions , and in particular : the invention , as it will now be described in detail , aims to exploit the electrochemical techniques of chrono - amperometry or voltametry to measure the currents generated in the aforementioned electrochemical reactions and thus to estimate , in a realistic manner , the conditions that exist in the interstitium , which themselves are then used to describe the physiological state of living beings . it will now be noted that corrections may be necessary in accordance with the voltages actually applied and measured on the electrodes , in order to take account of the reverse currents that are liable to be generated if a voltage in excess of 0 . 8 volts appears on the distal electrode . fig1 schematically represents a system of diagnosis by electrophysiological measurements that can be used to exploit the aforementioned principles , which includes , in an appropriate cabinet ( not shown ), a stabilised low voltage supply circuit 10 ( typically a voltage that can be adjusted from about 1 to 5 volts ) and that is suitable to be connected , as will be seen in what follows , to connectors 21 to 24 for a plurality of corporal electrodes ( typically 4 to 8 in number ). in an example of application , four electrodes ( e 1 to e 4 ) are placed on the four members , that is on the hands and feet respectively . it will be seen that there are 6 possible pairs of usable electrodes , namely e 1 - e 2 , e 1 - e 3 , e 1 - e 4 , e 2 - e 3 , e 2 - e 4 and e 3 - e 4 . in order that the current measurements effected using the electrodes should suitably reflect the electrochemical behaviour of the interstitium , it is important that these electrodes each have a significant area , and preferably between about 1 and 15 cm 2 . using an electronic switching circuit 30 , one applies sequentially to these electrode pairs , continuous voltage pulses with a value that is chosen to be between 1 and 5 volts , where these pulses can be positive or negative by simple reversal of polarity . we thus obtain 12 possibilities for measurement of the current changes that traverse the body between two electrodes when the continuous voltage pulse waveform is applied . the switching circuit is controlled by a clock 31 , in a manner that can easily be understood by those skilled in the art . the system also includes an acquisition circuit ( sampling and analogue / digital conversion ) 40 which , on application of a continuous voltage pulse waveform , is designed to store the values taken by the current at predetermined short time intervals . for example , the system can generate a continuous voltage pulse waveform for a time of between 0 . 1 and 5 seconds ( typically 3 seconds ), and during the existence of this pulse , samples are taken of the current every millisecond . more generally , a sampling frequency of between 20 and 10 , 000 samples per second is employed . the system then switches to the next electrode pair to repeat the process , and so on . the system also includes a processing device or arrangement 50 with a view to analysis of the values acquired during the process described above , where this device typically includes a processor in association with a memory . it is connected to indicating means ( display screen , printer , or any other indicating device ) for the operator . preferably , this device or arrangement is designed firstly to perform a set of tests for validation of the measurements on the values of current collected by the sampling circuit 40 . a first test aims to determine if the measurements effected are normal , and to reject any measurements containing errors or anomalies such that they must be non - meaningful . this first test is performed on completion of 36 sets of measurements , namely the 12 measurements described above , effected here in three passages . here we describe , as a curve , the set of measurements of the current obtained for each continuous voltage pulse waveform . for each of the 36 curves , the device stores the values of the samples of the first two samples read and digitised , and also calculates an average of the first twelve samples . the device then determines whether , for each curve , the averages calculated for each of the second and third passages are identical to each other to within x %, where x is preferably between 1 and 10 %. in the case where , for at least one of the curves , the difference between the averages is above this limit , then the set of 36 curves is rejected . if the set of curves passes the first test above , the processing device ( 50 ) does a second validity test that consists of checking whether the last x values ( where x is of the order of a few units to a few tens of units ) of the second and third sets of measurements are close to each other with a given margin of error , also preferably of the order of 1 to 10 %. naturally any other combinations of the current values taken can be used to determine the validity of the measurements . in the negative , then all the equipment is checked ( positioning and stability of the electrodes in particular ) and the campaign of measurements is repeated . from the validated measurements , the device then performs a more - or - less complex transformation that is intended to guarantee the intrinsic reproducibility of the data collected . in this present example , this transformation consists of taking the mean , over the three seconds that each pulse lasts here , of each of the 12 curves of the last ( here the third ) passage , and generates output information to be displayed on a diagram of the so - called radar type , where this diagram also includes , in a manner stored beforehand in the system , measurement templates corresponding to healthy patients and sick patients . an example of such a radar diagram is illustrated in fig2 of the drawings . naturally , many other transformations can be envisaged , in particular according to the characteristics of the current and the pathologies sought . such a diagram of the radar type is well known in terms of its ergonomic usefulness . it consists of distributing the results of the measurements obtained with the different electrode pairs in a polar coordinate system , where a given angular position is dedicated to the representation of a level of signal obtained ( as a result of appropriate processing ) for a given electrode pair as identified in the figure . this has the advantage of giving a good visual indication of the similarities and differences between sets of measurements coming , for example , from different patients or from the same patient at different times , and to facilitate the comparison with templates of healthy patients and sick patients . other than the display intended for the operator , the processing device is also designed to effect a quantitative comparison between the measurements and the templates , using algorithms that are available to those skilled in the art . in particular , if the template of a healthy person is exceeded at more than three points , or by more than x % ( 30 % for example ) at any point , the operator applies , to the processing device , a command for comparison with a template associated with a given pathology , and these comparisons are repeated until a template is found that conforms to the potential pathology . naturally , many other forms of embodiment and variants are possible . in particular , it is possible to vary the number of electrodes , and to make use of eight electrodes for example ( four for the ends of the members , two for the forehead and two for the chest ). in particular in accordance with the possibilities ( computing power and memory ) of the processing device , it is possible to adjust the sampling period of the current measurement , with the latter being capable of descending to 0 . 1 ms for example ( a sampling frequency of 10 khz ). it is also possible to provide a variable sampling frequency that is higher at the start of the current measurements for a given pulse and lower at the end of the pulse . the processing device can also be designed to provide a signal that is representative of the slope ( derivative ) of the current signal just after the start of the voltage pulse , and to calculate the time passed between the start of the voltage pulse and the instant at which , while the pulse lasts , the current stabilises ( to within x %, where x is chosen in particular in accordance with the sampling precision ). such values , which are determined for a given set of electrode pairs and polarity of the pulses , can then be compared to limit values , here again with the use of radar diagrams if appropriate . more generally , different types of algorithms can be executed in order to process the n lots of curves ( according to the number of electrodes and successive tests ) to validate finer sensitivity and specificity curves by comparison with receiver operating characteristic ( roc ) curves obtained with patients on which clinical tests have been validated . according to another preferred characteristic , the processing circuit is designed to generate results obtained from a probability , according to algorithms which are also known to those skilled in the art . if the probability is not satisfactory , it is possible to re - run a measurement campaign with different voltage values ( increasing for example ) for each passage on all of the electrode pairs . in this regard , the switching circuit 30 , and the power - supply circuit 10 where appropriate in order to vary the voltage level , are advantageously programmable so as to be able to execute different measurement scenarios , with pulses of variable length ( duration ) and height ( voltage level ) if appropriate . fig3 illustrates one possible embodiment of a system according to the invention . this system is constructed around a conventional personal pc - type computer designed to communicate with a portable mp module that includes : the power source 10 , if power is not supplied by the pc ; the set of connectors 21 to 24 for the body electrodes ; the switching circuit 30 used to apply , to the aforementioned connectors , voltage pulses according to one or more determined scenarios as explained above ; the acquisition module 40 capable of sampling and digitising , at a given frequency or several given frequencies , as explained above , the current flowing from one electrode to another while this electrode pair is subjected to the voltage pulse , a buffer memory module 60 if necessary , to store the current measurements thus acquired ; an interface or communication module 70 a to communicate with the pc , either over a wire link ( serial , usb , etc . ), or via a wireless link ( bluetooth ®, wifi ®; infrared , etc .). a set of electrodes e 1 to e 4 with their cables . in such an architecture , the processing device 50 for the current measurements received from the portable unit is constituted by the pc , which includes an interface or communication module 70 b providing the link with the portable module . advantageously , the pc has the means to communicate with one or more public or private servers , from which templates of healthy or sick patients can be transferred for purposes of comparison as described in the foregoing , and / or to which the information generated by the processing device 40 can be sent . on this subject , a description will now be given of a real - time or semi - real - time system for the processing of clinical data obtained from data supplied by a diagnosis system such as that described in the foregoing . more precisely , this aspect of the invention consists of exploiting the simplicity and specificity of the chronoamperometry measurements supplied by a set of diagnosis systems so as to be able to propose the most up - to - date information in real time or semi - real - time . approval from a certain number of reference clinical centres , equipped with the diagnosis system and connected by an appropriate communication system to a central server or distributed servers ( subscriber systems with the possibility of payment for each transaction ); centralisation , at the level of the server or servers , preferably with a daily frequency at least , of the measurements effected on patients for which well established and standardised clinical diagnoses are held , where these measurements are accompanied by data which are preferably structured or encoded , representing the said established clinical diagnoses ; data validation , and more particularly statistical validation and verification of the application of normal laws ; analyse of the consistency of the data ( by correlation methods in particular ) and treatment of any excessive differences with specific surveys by staff who are skilled on these data ; a search for algorithms that are relevant to the data , and more particularly from set of known algorithm tests and stored beforehand in the server or servers and based in particular on the following tools : approach by the bayes theorem ( bayesian networks ); approach by multiple neurone networks with at least two layers approach by decision trees ; approach by genetic algorithms ; comparison of the results produced by these algorithms with the existing diagnostic knowledge ; where appropriate , comparison of the collected data with pre - existing data using other rules such as classification rules ; validation of existing algorithms , using each new data lots as an estimator of the predictive positive and negative values for each pathology or pathological predisposition selected as capable of being diagnosed ; validation of new algorithms identified and representative of a new diagnostic knowledge on all of the data previously existing in the database . preferably , all of the process described above , from loading of the data from the distant diagnosis systems up to the validations of existing and new algorithms , is automated , with only detected errors being subject to particular indication for examination by competent experts . all of the foregoing processes for collection and analysis are effected on a daily basis at least for example , and so they supply an up - to - date service practically in real time , with the new diagnostic features identified by these processes . according to one advantageous aspect , in the case where the local diagnosis systems possess the appropriate processing capacity , these new features ( new algorithms and the information on their diagnostic role for the use of practicians ) are advantageously downloaded from servers to the subscriber systems ( with secure unitary payment at the moment of the transaction ) when they have been identified , in accordance with conventional computer techniques for the updating of software or of their libraries , plug - ins or other associated modules . in a non - limiting manner , the system of the invention can be used for the diagnosis of pathologies of the cardiac , endocrinal , or neurological or other type . one particular application of this present invention is diagnosis by the exercise test on patients suffering from coronary artery disease ( cad ). in a population of 95 men chosen at random , with ages between 21 and 83 years and an average age of 57 years , this present invention was used to detect angiocoronarographical affections of the arteries . the chronoamperometric measurements , effected using the system of this present invention , were taken before and after the exercise test , conducted according to the bruce protocol . the population included subjects identified as suffering from affection , and other subjects identified as healthy . the affected population was also broken down into subjects suffering from diabetes and into subjects without diabetic affection . in this case , the system of the invention included two surface electrodes applied to the hands and two other surface electrodes placed on the head at the left and right frontal lobes . the currents appearing in response to the voltage pulses , indicating electrochemical reactions in accordance with cottrell law , are stored . the currents between the two electrodes of the hands are read off , as are the currents between the two electrodes on the forehead . the total time taken to collect the current measurements was less than 1 minute . the graph shown in fig4 of the drawings shows a set of test points whose coordinates are the relative electrochemical conductance obtained between the electrodes on the hands ( abscissa ) and between the electrodes on the forehead ( ordinate ) for the different subjects . it will be seen here that the relative electrochemical conductance is the difference , positive or negative , of the absolute electrochemical conductance read off using this present invention , before the exercise and after the exercise , according to the bruce protocol . among the subjects are the aforementioned population of 95 affected and healthy subjects , where the measurements corresponding to the healthy subjects are illustrated by squares and the measurements corresponding to the subjects with an affection are illustrated by circles . fig4 also shows the measurements obtained with a population of 150 young men in good health , normally with no coronary affection . the graph in fig4 shows that the system and the method of this present invention can be used to obtain a diagnosis specificity of about 82 % and a diagnosis sensitivity of about 83 %, leading to a positive prediction value of 81 % and to a negative prediction value of 83 % ( 5 % risk intervals less than 10 %). the corresponding thresholds have been identified at about + 43 % for the electrochemical conductance at the hands and about + 19 % for the electrochemical conductance at the forehead . it can be seen here that the age , the body mass index ( bmi ), the current medicinal treatments , the offset of the st segment , and other parameters associated with the exercise test , had no significant influence on the results . it can also be seen from the readings in fig4 that the group of 14 subjects identified beforehand as diabetic is also very localised , with a threshold of relative electrochemical conductance at the hands of less than − 6 %, thus allowing the diagnosis function to be enriched without any additional operation . the population of 150 healthy young men shown in fig4 confirms the validity of the identified criteria , with a negative prediction value greater than 90 %. advantageously , a diagnosis system by analysis of the currents before and after exercise can be incorporated into exercise equipment in commercial centres , such as home exercise machines , running tracks , etc ., allowing the subject to directly assess his or her predisposition to coronary problems , by simple application of electrodes to the wrists and forehead , at home or in the gymnasium , and with no need of a specialist . from the foregoing information , those skilled in the art will be able to develop diagnosis systems for a wide variety of pathologies or pathological predispositions , essentially by examining the measurements produced by the system and the method of this present invention , on populations of healthy or sick subjects respectively .
the disclosure relates to an electrophysiological analysis system which includes a plurality of electrodes , a power supply for successively applying a substantially continuous voltage ranging approximately from 1 to 5 volts and lasting from 0 . 1 to 5 seconds to different slotted electrode pairs , a collecting and storing device for recording the variation of a current flow in the electrode pairs to which the voltage slots are applied , a device enabling the current variations obtained by comparison between at least two current variations caused by supposed identical conditions and a device comparing data related to the current variations recorded for several electrode pairs and enabled with reference data . the system can be used for chronoamperometrically detecting pathologies , pathological areas and organ dysfunctions .