WO1992012705A1

WO1992012705A1 - Methods and apparatus for monitoring brain functions

Info

Publication number: WO1992012705A1
Application number: PCT/US1992/000464
Authority: WO
Inventors: Abraham Mayevsky; Britton Chance
Original assignee: Individual
Current assignee: Individual
Priority date: 1991-01-22
Filing date: 1992-01-21
Publication date: 1992-08-06
Anticipated expiration: 1993-07-22

Abstract

Methods and apparatus for collecting signals for intraoperatively determining the functional state of a tissue region, such as the brain, of a living subject are disclosed. Most preferably, the present invention provides a flowmeter means (38) for measuring relative blood flow, a fluorometer means (42) for monitoring NADH redox state, and a potassium ion specific electrode (14) for determining the extracellular level of K+ potassium ions. Additionally, in certain embodiments, further ion specific electrodes which monitor calcium hydrogen and sodium are included. These electrodes, along with a light guide containing fibers (28) which are used in a laser Doppler flowmeter, and fibers which are used in a fluorometer, such as a phase modulated spectrophotometer, are preferably disposed within a single multiprobe assembly which may be conveniently used intraoperatively on the subject, without invasion of the brain tissue. Methods and apparatus for processing the signals collected to store and display such signals are also disclosed.

Description

Methods and apparatus for monitoring brain functions

Cross-Reference to Related Applications

This application is related to co-pending application Serial No. 578,063, filed Sept. 5, 1990, which is a continuation of U.S. Patent application No. 307,066, filed February 6, 1989, now U.S. Patent No, 4,972,331, issued on July 25, 1990, all of which are incorporated by reference as if fully set forth herein.

Portions of the study which relate to the invention disclosed herein were supported by NIH grant NS- 22881. The United States therefore has certain rights in the present invention.

The present invention relates to the monitoring of the body functions of a living subject and, more specifically relates to the intraoperative monitoring of brain functions.

Background of the Invention

Intraoperative monitoring of various brain functions during different surgical procedures would provide a significant contribution to the neurosurgeon as a routine diagnostic tool. At this time, however, a standard technique of monitoring the brain has not been developed or adopted. Various attempts have been made to monitor intraoperative EEG during aneurysm surgery. See T.H. Jones, K.H. Chiappa, R.R. Young et al., "EEG monitoring for induced hypotension for surgery of intraσranial aneurysms," Stroke 10, 192-294, 1979; R. Tempelhoff, P.A. Modica, K.M. Rich and R.L. Grubb, "Use of computerized electroencephalographic monitoring during aneurysm surgery," J. Neurosurgery 71,24-31, 1989. Some researchers have used Laser Doppler flowmetry to monitor cerebral blood flow (CBF) in real-time and atraumatically. See B.R.

Rosenblum, R.F. Bonner and E.H. Oldfield, "Intraoperative measurement of cortical blood flow adjacent to cerebral AVM using Laser Doppler velocimetry," J. Neurosurgery, 66, 396-399, 1987. The same approach was adopted by other researchers who have measured cerebral blood flow during tumor operation. See E. Arbit, G.R. DiResta, R.F. Bedford, N.K. Shah and J.H. Galcich, "Intraoperative measurement of cerebral and tumor blood flow with Laser Doppler flowmetry," Neurosurgery, 24, 166-170, 1989. The usage of fluorometric monitoring of NADH redox state in the human brain is known and has been used to test the effect of direct cortical stimulation. See F.F. Jobsis, M.J. 0¹Conner, M. Rosenthal and J.M. Van Buren, "Fluorometric monitoring of metabolic activity in the intact cerebral cortex in Neurophysiology studied in man," International Cong. Series No. 253, Excerpta Medica, Amsterdam, pp. 18-26, 1971. Others have monitored three components of the respiratory chain in the operation room (O.R.). See G. Austin, R. Jutzy, B. Chance and C. Barlow, "Noninvasive monitoring of human brain oxidative metabolism,"

In:"Frontiers of Biological Energetics," Vol. 2, 1445-1455, 1978; C.H. Barlow, .R. Harden, A.H. Harken, M.B. Simon, J.C. Haselgrove, B. Chance, M. 0*Conner and G. Austin, "Fluorescence mapping of mitochondrial redox changes in heart and brain," Critical Care Med. 7, 402-406, 1979.

These papers disclose the reduction of NADH, flavoproteins as well as Cyt a, a₃ during STA-MCA anastomosis patients. A more detailed study was later performed which disclosed monitoring of the NADH redox state during direct cortical stimulation of EC-IC bypass patients on verebro-vascular disease. See J.M. Fein, "NADH kinetics in patients with unruptured aneurysms versus cerebrovascular occlusive disease" J. CBF and Metabol, Vol. 3, Suppl. 1, S29-S30, 1983.

However, none of the above-referenced reports lead to the development of a practical tool to be used routinely. Furthermore, self retaining brain retractors are indispensable in intracranial surgery, but sometimes their use can create ischemic brain damage. For this reason it has been suggested that interoperative recording would be desirable. There is therefore, a need for an interoperative monitoring device capable of monitoring a variety of brain functions in real-time. See J. Rosenorn, "The risk of ischemic brian damage during the use of self- retaining brain retractors", Acta Neurol. Scand. Suppl.. 120, Vol. 79 1-30, 1989. The present invention meets these objectives as well as the challenge of providing the answers to many questions regarding the underlying pathophysiology and treatment of stroke which do not appear to lie with continued attempts to model the human situation perfectly in animals, but rather with development of techniques such as those disclosed herein that enable the study of more basic metabolism, pathophysiology and anatomical imaging detail in living humans. See D.O. Wiebers, H.P. Adams and J.P. hisnant, "Animal models of stroke: Are they relevant to human disease?," Stroke, 21, 1-3, 1990.

It is therefore an object of the present invention to provide methods and apparatus which can be used in an operating room environment for monitoring the functional state of the brain in real time.

Summary of the Invention

Accordingly, the present invention provides a multiprobe assembly comprising fiber optic probes and ion selective electrodes that, in particular combination, enable the assessment of relative cerebral blood flow, itochondrial redox state (NADH fluorescene) and ion homeostatis (K⁺, Ca ^*H⁺ and Na⁺) in real time, intraoperatively. Thus, in a preferred embodiment the present invention provides apparatus for collecting signals for intraoperatively determining the functional state of the tissue region of a living subject that comprise a flowmeter for measuring relative blood flow, a fluorometer for montioring NADH redox state, and a potassium ion specific electrode for determining the extracellular level of K⁺ potassium ions. Most preferably, the present invention is used to monitor the functional state of the brain that uses a laser doppler flowmeter and either a direct current or time-sharing fluorometer/reflectometer such as a phase modulated spectrophotometer. Additionally, in certain embodiments the apparatus of the present invention may also include means for creating analog signals representative of relative blood flow, NADH redox state, and ion concentration levels. In another embodiment of the present invention, additional ion specific electrodes are included which measure the extracellular levels of Ca 2+ calci.um i.ons and Na+ sodi.um i.ons, as well as other electrodes such as electrocortical electrodes which may be used with an EEG. Most preferably, the above described apparatus are housed in a single housing to provide a multiprobe apparatus, which may be easily used intraoperatively without invasion of the brain tissue. The present invention, in addition to the multiprobe assembly described above, also discloses methods and apparatus whereby the analog signals collected by the multiprobe apparatus are converted to digital signals and analyzed by a multichannel analyzer for recording software to produce digital processed digital signals. These signals are preferably stored in a storage media and then may be retrieved and further processed by playback software to create display signals. Display signals may be displayed, produced as a hard copy, or transmitted to further processing software to make further determinations regarding the condition of the subject. Brief Description of the Drawings

The present invention will be better understood, and its numerous objects and advantages will become apparent by reference to the following detailed description of the invention when taken in conjunction with the following drawings in which:

FIG. 1 pictorially represents the multiprobe apparatus of the present invention, partially in cross- section, configured for intra-operative monitoring of brain functions in real time.

FIG. 2 shows a cross-sectional plan view taken through line 2-2 of the combined light guide apparatus of the present invention for monitoring the CBF and NADH redox state and other parameters. FIG. 3 is a functional block diagram of the data acquisition and signal processing system used in a preferred embodiment of the present invention.

FIG. 4 is a cross-sectional plan view of the distribution of fibers within a portion of the apparatus depicted in FIG. 2.

FIG. 5A is a plot of NADH state and hemoglobin saturation for an animal undergoing an episode of hypoxia.

FIG. 5B is a plot of relative cerebral blood flow and NADH redox state generated using the present invention that depicts the correlation between blood flow and NADH.

Detailed Description

The present invention provides a multiprobe assembly capable of interoperative, real-time monitoring of cerebral blood flow, NADH redox state, and ion homeostasis activities within the brain. A preferred embodiment of the multiprobe assembly is shown in FIG. 1 and generally designated 10. For illustrative purposes, the multiprobe assembly of the present invention will be described in a configuration used to monitor cerebral blood flow, NADH redox state and extracellular (K⁺, Ca²⁺, H⁺ Na⁺ and NA⁺) ion concentrations within the brain, although the multiprobe assembly 10 could more generally be used to monitor other brain activities and may be simplified, as explained below. In the drawings like numerals, represent like elements. Referring to FIG. 1, the multiprobe holder 12, which is preferably made of Delrin 12 or similar plastic material, contains a bundle of optical fibers 11, three ion specific electrodes 14, 16, 18, each combined with a surrounding DC steady potential electrode, electrocortical electrodes (shown in FIG. 2) , and a reference electrode 20. The ion selective electrodes 14, 16, 18 are electrically connected to Ag/AgCl electrode holders 22 that are protected by a plexiglass sleeve 24.

The optical fiber bundle 11, also known as a light guide comprises two groups of fibers shown generally in FIG. 1 and explained in further detail below that are the laser Doppler fibers 26 used for flowmetry. The second group of fibers 28 in the light guide 11 are used to monitor the NADH redox state. The principle of NADH monitoring from the surface of the brain is that excitation light, preferably at a wavelength of 360 nm, is passed from the fluorometer 42, shown as a functional block in FIG. 1, to the brain 31. Emitted light at 450 nm together with the reflected light at the excitation wavelength is transferred back to the fluorometer 42. The changes in the reflected light are correlated to changes in tissue blood volume and also serve for correction of hemodynamic artifacts appearing in the NADH measurement.

Further details of the multiprobe assembly 10 are shown in FIG. 2. As shown, the ion selective electrodes 14, 16, 18 are preferably arrayed around the light guide 11, further details of which are explained below with reference to FIG. 4. Also disposed within the housing of the multiprobe assembly 10 are electrocortical electrodes 19 which are fed to an EEG amplifier 40, and a thermocouple electrode 21 for monitoring temperature. Adjacent the multiprobe assembly is the push-pull cannula 32 for monitoring KC1 concentration. The light guide 11 depicted in FIG. 2 is itself comprised of several components. Referring now to FIG. 4, ten 200μ excitation fibers 66 and ten 200μ emission fibers 68, such as those manufactured by General Fiber, Inc. or similar substitutes are randomly mixed between and around the fibers 62, 64 used for the laser Doppler flowmetry and which comprise the bundle 26 discussed above. This is a preferred embodiment of optical fibers because it enables cerebral blood flow and NADH redox state monitoring from substantially the same tissue volume. As explained above, the first group 26 are fluorometer emission and excitation fibers 66, 68 and the second group 26, comprised of fibers 62, 64 are used to measure cerebral blood flow in real-time using a laser Doppler flowmeter technique or other suitable analytical method. Thus, one 50μ input fiber 62 and two lOOμ output fibers 64 are preferably in a triangular arrangement with approximately 0.7 mm separation between each vertex of the triangle. The laser Doppler flowmeter input fiber 62 and output fibers 64 are connected to the standard commercial plug of the laser Doppler flow meter such as that manufactured by TS, Inc. or Perimed, Inc., for example.

The electrodes 14, 16, 18 of the multiprobe assembly 10 are preferably held to the cannula using epoxy glue so that the multiprobe assembly 10 can be used during the awake state or to avoid artifacts in the operating room environment. In the experimental apparatus embodiment, as shown in FIG. 1, dental acrylic cement 30, or a similar material, was used to noninvasively interface the multiprobe assembly 10 to the surface of the cortex 31 by cementing it to the skull. In certain embodiments the multiprobe assembly 10 can be removed without damage from the brain at the end of the measurements and repetitive applications can be performed in a short period of time with minimal technical support. Furthermore, such noninvasive surface contact with the tissue permits for monitoring of the human brain. The multiprobe assembly 10 is most preferably located on the exposed cortex 31 using a micromanipulator.

As further shown by the functional block diagram portion of FIG. 1, in addition to the fluorometer 42 and the laser Doppler flowmeter 38 discussed, an EEG amplifier 40 monitors various brain functions and a six channel electrometer 44 monitors the ion concentration changes. Data acquisition may commence immediately after the multiprobe assembly 10 is located on the cortex 31. As shown in FIG. 3, the analog signals from the laser Doppler flowmeter 38, EEG amplifier 40, fluorometer 42, and electrometer 44 are digitized at the input of the acquisition set up 45. The acquisition set up 45 comprises a data processor 46 (386 Dell processor) which includes an analog-to-digital converter which provides for up to 16 channels (DA7AQ ATC) . The data processor 46 further includes other appropriate hardware, such as a multichannel analyzer and the hardware necessary to input digitized waveforms into the control and data acquisition system (CODAS) recording software 48. A display 52 and storage device 54, which may include both hard disk and/or floppy disk storage, are also provided, along with an interfacing keyboard control 50 that is connected to the acquisition software 48. As further illustrated in FIG. 3, after the cerebral blood flow, NADH redox state and ion concentrations have been monitored and recorded by the acquisition set up 45, the data are analyzed by the analysis system 60. The CODAS playback software 58 retrieves the recorded data from the storage device 54. The data are then analyzed by further software 62 appropriately chosen for the required computation and the capabilities of the processors being used. The selection and use of such software 62 is well known to those skilled in the art. An interactive keyboard control 50 is again provided. Finally, the data, either before or after final processing, may be displayed on the display 52, or printed out as a hard copy report using a printer 56.

In a preferred embodiment, the fluorometer 42 uses the concepts of phase modulated spectroscopy to determine the concentration of scattering constituents within the tissues. These systems use pulses of light, preferably of two wavelengths, which are time shared into the tissue. The migrating light is then collected and signals generated which permit concentration determinations to be made. Further details of such systems are known in the art and may also be found in the co-pending patent application referenced above, which is incorporated herein by reference.

For monitoring NADH redox state the fluorometer 42 in a preferred embodiment can be calibrated as follows: the reflectance and fluorescence signals obtained from photomultipliers (RCA 93IB) are calibrated to a standard signal (0.5 V) by variation of photomultiplier dynode voltage obtained from the high voltage power supply. The fluorometer or the standard 0.5 gain is increased as required by a factor of two or four to give 50% or 25% of the full scale respectively. The changes in fluorescence and reflectance signals are calculated relative to the calibrated signals under normoxic conditions. This type of calibration is not absolute, but provides reliable and reproducible results from different subjects and between different fluorometers.

Based upon animal experiments, it has now been found that a more preferable embodiment of the multiprobe analyzer 10 may be constructed for use on humans. Due to the short time available for monitoring under the complex conditions of the operating room environment, this embodiment requires only three probes. In order to monitor the functional state of the human brain, it would be necessary to include at a minimum the laser Doppler flowmeter 38 discussed above to measure relative cerebral blood flow; the fluorometer/reflectometer system 42 to monitor the intramitochondrial NADH redox state and the potassium (K⁺) ion specific electrode 14 to provide data on the extracellular level of K⁺ ions. It has been found that monitoring cerebral blood flow or NADH redox state alone will not provide reliable information due to various unclear responses to pathological events such as hypoxia, ischemia or brain stimulation, e.g., epileptic activity or spreading depression. The minimum requirements for a multiprobe assembly set forth immediately above have been validated by experiments performed upon a group of gerbils exposed to graded hypoxia, ischemia and spreading depression.

The most crucial test of the correlation between the intramitochondrial NADH redox state and the signals to be obtained from the phase modulation spectrophotometer are in a hypoxia or oxygen lack where the inspired oxygen or the animal is reduced to the point where it can no longer maintain hemoglobin oxygenated nor NADH oxidize. This is depicted in the traces of FIG. 5A. In this figure, the abscissa is time and the ordinate is NADH fluoresence increase upward, and hemoglobin desaturation [using 816-754 nm pulses]. The third trace is the sum of the pathlength of the phase changes, which may be regarded as a blood volume signal. The animal is caused to breathe nitrogen at time zero and it is seen that there is a blood volume response, i.e., a downward deflection and a few seconds later an upward response of the desaturation indicating desaturation of hemoglobin. As this trace approaches its maximum, the oxygen concentration in the tissue now reaches the critical level for the NADH response. Both traces reach a plateau where very little if any oxygen is present in the brain tissue. Under these conditions the blood volume signal remains approximately constant or decreases slightly due to decreased cardiac output. However, on restoration of oxygen breathing to the animal all three traces abruptly respond. The NADH returns to the initial baseline prior to hypoxia, and the hemoglobin trace swings to a much more oxygenated state than prior to hypoxia, termed "hyperemia," which is caused by the blood volume flowing through the opened capillaries of the brain being greatly increased, a typical response to the restoration of oxygen in tissue following a hypoxia. As appreciated by those of ordinary skill familiar with these biochemical phenomena, this correlation validates the close coupling of desaturation and resaturation of hemoglobin with reduction and oxidation of NADH. Referring now to FIG. 5B, there is shown a graphic plot of the percent change in NADH vs. the percent change in relative cerebral blood flow under three different conditions. The data represented in FIG. 5 were derived using a multiprobe assembly and related processing equipment as described above. Those of ordinary skill will immediately appreciate the clear and significant correlation between relative cerebral blood flow and NADH redox state under reduced ischemia and hypoxia. In the case of ischemia, the decrease in flow, induced by occlusion of one or two carotid arteries, led to an increase in NADH. Under hypoxia, due to the autoregulation response an increase in cerebral blood flow was recorded simultaneously with the increase in NADH. See A. Mayevsky and N. Zarchin, E. Yoles and B. Tannenbaum, "Oxygen supply to the brain under hypoxic and hyperoxic conditions. In: Oxygen Transport in Red Blood Cells, C. Niclau, Ed., Pergamon Press, pp. 119-132, 1986. When spreading depression was induced, the increase in energy requirement led to an activation of the mitochondrial respiration and oxidation of NADH was recorded (decrease in CF) . See B. Chance and G. R. Williams, "Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization". J.Biol.Chem. 17, 383-393, 1955; and B. Chance, P. Cohan, F.F. Jobsis and B. Schoener, "Intracellular oxidation-reduction states in vivo" ,

Science, 137, 499-508. This increase in 0₂ consumption led to an increase in cerebral blood flow in the range of up to 200-350% as compared to the normoxic values. See L.D. Lukayanova, J. Bures, "Changes in p0₂ due to spreading depression in the cortex and nuclear caudatus of the rat". Physiol.Bohemsolov. 16,449-455, 1967. If cerebral blood flow was the only parameter to be monitored, the differentiation between hypoxia and spreading depression would be impossible. The same is true for the differentiation between hypoxia and ischemia if one is monitoring the NADH redox state by itself. By monitoring the cerebral blood flow and NADH redox state together and using the appropriate algorithm it will be possible to predict and describe more accurately the pathological state. However, since the outcome of any pathological state is the brain is projected in the ionic homeostatic situation monitoring of this parameter is necessary for the evaluation of the functional state of the brain. Due to the large energy consumption by the Na⁺K⁺- ATPase any change in the energy supply will be correlated to the extracellular level of K⁺. See A.J. Hansen, "The effects of anoxia on ion distribution in the brain".

Ph siol.Rev. 65, 101-148, 1985; A. Mayevsky, "Metabolic ionic and electrical responses to experimental epilepsy in the awake rat", Proc. First Intl. Cong. CBF Metabolism & Epilepsy, Baldey Moulinier, M. , Ingvar, D.H. , Meldrum, B.S. Eds. John Libbey pp. 263-270, 1984; and A. Mayevsky, "Level of ischemia and brain functions in the Mongolian gerbil in vivo" . Brain Res., 524:1-9, 1990. Since changes in extracellular levels of Ca 2+ and Na+ are expected mainly during massive depolarization event it is not expected that it will happen during surgical situations. Therefore the monitoring of extracellular K⁺ will represent the ionic state of the brain. Also, if massive depolarization will occur, it will be detected by the potassium level. The usage of an animal model is the only way by which one can develop the appropriate algorithm of the clinical situation. The same kind of measurements have been done by other groups but not in real time and not with a multiprobe approach. See A.J.Hansen, B. Quistorff and A. Gjedde, "Relationship between local changes in cortical blood flow and extracellular K+ during spreading depression". Acta Physiol.Sσan. 109, 1-6, 1980; G. Mies, W. Paschen, "Regional changes of blood flow, glucose and ATP content determined on the brain sections during a single passage of spreading depression in the rat brain cortex". Exp.Neurol. 84, 249-258, 1984; M. Lauritzen, M. Balslev Jorgensen, N.H. Diemer, A. Gjedde and A.J. Hansen, "Persistent oligemia of rat cerebral cortex in the wake of spreading depression". Ann. Neurol. 12, 469-474, 1982; and M. Lauritzen, "Cerebral blood flow in migraine and cortical spreading depression". Acta Neurol. Scand. 76 (Suppl 113), 1-14, 1987. Very recently it has become possible to correlate in vivo data of NADH redox state and extracellular K⁺ with CBF and 0₂ consumption data measured by microspectrophotometry. Significant correlation was found between those parameters in rats exposed to spreading depression. In the multiprobe assembly of the present invention we are using surface probes which do not penetrate the tissue. On the other hand this approach is applicable to the human brain and also allows the comparison with the surface probes such as the NADH redox state and Laser Doppler flowmeter. The difference between ischemic depolarization and spreading depression are very significant in prediction of the functional state of human brain under observation. Since potassium levels may be comparable in the two conditions, the NADH and CBF will be in opposite directions and may determine the actual state.

Although specific embodiments of the present invention have been described above, these are meant to be exemplary of the present invention and not limiting. Upon review of the instant specification, one of ordinary skill will immediately realize useful modifications and adaptations of the methods and apparatus disclosed herein. For example, numerous rearrangements and combinations of the electrodes used and signals collected are possible, as well as the provision of equivalent means to make the determinations of blood flow, NADH redox state and ion concentrations. Accordingly, reference should be made to the appended claims in order to determine the scope of the present invention.

Claims

What is claimed is:

1. Apparatus for collecting signals for intraoperatively determining the functional state of a tissue region of a living subject comprising: flowmeter means for measuring relative blood flow; fluorometer means for monitoring NADH redox state; and a potassium ion specific electrode for determining the extracellular level of K⁺ potassium ions.

2. The apparatus of claim 1, wherein the tissue region is the brain and the blood flow is cerebral blood flow.

3. The apparatus of claim 1, wherein the flowmeter comprises a laser doppler flowmeter.

4. The apparatus of claim 1, wherein the fluorometer comprises a phase modulated fluorometer/reflectometer.

5. The apparatus of claim 4, wherein the fluorometer comprises a time sharing fluorometer/reflectometer.

6. The apparatus of claim 1, further comprising means for creating analog signals representative of relative blood flow, NADH redox state, and potassium ion concentration level.

7. The apparatus of claim 1, wherein the flowmeter means and the fluorometer means each receive signals from a plurality of light guide fibers.

8. The apparatus of claim 1, further comprising: ion specific electrodes for determining the extracellular levels of Ca 2+ calci.um ions and Na⁺ sodium ions; at least two electrocortical electrodes; and a thermocouple electrode, wherein the flowmeter means and the fluorometer means each receive signals from a plurality of light guide fibers, said light guide fibers being bundled into a light guide means.

9. The apparatus of claim 8, further comprising a housing surrounding said electrodes and said light guide means, said housing retaining said electrodes and said light guide means in fixed relation to each other.

10. A method of collecting signals for intraoperatively determining the functional state of a tissue region of a living subject comprising: measuring the relative blood flow within the tissue region; monitoring the NADH redox state within the tissue region; and determining the extracellular level of K⁺ potassium ions within the tissue region.

11. The method of claim 10, further comprising the steps of: determining the extracellular levels of both Ca ⁺ calcium ions and Na⁺ sodium ions within the tissue region; monitoring the electrical currents developed within the tissue region; and monitoring the temperature of the tissue region.

12. The method of claim 10, further comprising the step of creating analog signals representative of relative blood flow, NADH redox state and potassium ion concentration.

13. Apparatus for intraoperatively monitoring the functional state of the brain comprising: a multiprobe assembly comprising means for collecting signals indicative of relative cerebral blood flow, NADH redox state and extracellular levels of K⁺ potassium ions; analog to digital conversion means for digitizing said signals; multichannel analyzer means and recording software for processing said digitized signals to create processed signals; and storage media for storing said processed signals.

14. The apparatus of claim 13, further comprising means for retreiving said processed signals from said storage media and playback software to create display signals.

15. The apparatus of claim 14 further comprising display means for displaying said processed signals and said display signals.

16. The apparatus of claim 14 further comprising further processing means for determining additional information from said display signals.

17. The apparatus of claim 14 further comprising an interactive keyboard control for controlling said recording and playback software.

18. The apparatus of claim 13, further comprising means for collecting signals indicative of extracellular levels of Ca ⁺ calcium ions and Na⁺ sodium ions.

19. The apparatus of claim 13, further comprising EEG means for monitoring the electrical activity of the brain.