WO2005013820A1

WO2005013820A1 - Apparatus and method for direct detection of electrical activity of electrically excitable tissues in biological organisms

Info

Publication number: WO2005013820A1
Application number: PCT/AU2004/001015
Authority: WO
Inventors: J. W. Prichard
Original assignee: Neurosciences Building
Priority date: 2003-08-11
Filing date: 2004-07-30
Publication date: 2005-02-17
Also published as: AU2003904264A0

Abstract

The invention generally provides a method of detecting the electrical activity of an electrically excitable tissue in a biological organism, the method comprising the step of directly detecting in the tissue, changes in the characteristics of an electrical indicator of the function of that tissue, over a period of time.

Description

APPARATUS AND METHOD FOR DIRECT DETECTION OF ELECTRICAL ACTIVITY OF ELECTRICALLY EXCITABLE TISSUES IN BIOLOGICAL ORGANISMS

Field of the invention This invention relates to apparatus and methods for the detection of the electrical activity of electrically excitable tissues in biological organisms. It has particular, although not exclusive application to the direct detection of the electrical activity of the of electrically excitable tissues in the bodies of mammals, such as humans. One particular use to which the invention may be applied is in monitoring and analysing brain activity in humans and other mammals, and the background to the invention will therefore be described with particular reference to this application to which the invention is particularly suited.

Background to the Invention

The electrical activity of the brain and the nervous system have been studied by medical researchers for over a century. Although it was known as early as the nineteenth century that living brains have electrical activity, a German psychiatrist named Hans Berger was the first to record this activity in humans, in the late 1920s.

The development of the electroencephalogram (EEG) was a significant development in the study of brain function. The EEG is a record of changes in the electrical potential difference of the brain of a subject between two points on the scalp. The EEG is taken non-invasively, and allows an observer to follow electrical impulses across the surface of the brain and to observe changes over time. As a general rule, an EEG can provide an indication of the subject's state of consciousness - namely, whether the subject "is asleep, awake or anaesthetised - because the characteristic patterns of current differ for each of these states. A major drawback of the EEG however, is that the technique cannot show the structures or the anatomy of the brain. Nor can the EEG indicate which specific regions of the brain perform particular functions.

More recently, other non-invasive techniques have been developed by medical researchers, for studying and monitoring brain function. One of the techniques that has gained wide acceptance in the last three decades is the use of magnetic resonance imaging (MRI). MRI is based on the principles of nuclear magnetic resonance (NMR), a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules. Magnetic resonance imaging is based on the absorption and emission of energy in the radio frequency range of the electromagnetic spectrum.

Cognitive neuroscience was revolutionised in the early 1990s by the introduction of the blood oxygenation level dependent (BOLD) method for identifying active neural regions through changes the activity causes in local deoxyhaemoglobin concentration (Ogawa, Lee et al. 1990; Kwong, Belliveau et al. 1992; Ogawa, Lee et al. 2000). Implementation of this method came to be known as functional magnetic resonance imaging. This technique allows mapping of the function of the various regions of the human brain.

Activity-dependent changes in brain chemistry have been measured with increasing precision by magnetic resonance spectroscopy (MRS) of isotopic species, such as ¹H, ³¹P, ¹³C, and other magnetic nuclei (Prichard, Alger et al. 2002), since the first demonstration that biochemical changes known from earlier work to occur in status epilepticus, hypoglycaemia, and global cerebral ischaemia could be measured non-invasively in the living animal brain by ³¹P MRS (Prichard, Alger et al. 1983).

As much as the BOLD and MRS methods have elucidated, and continue to elucidate brain function, they measure events secondary to neural activity, rather than the activity itself. The direct detection of neural activity would be desirable for both clinical practice, as well as for research purposes. In terms of clinical practice, it would frequently be desirable to have techniques that would allow a clinician to identify with precision, foci of neural activity or pathology in the brain. The techniques described earlier assist the clinician to identify that a particular pattern of neural activity exists. Since they measure secondary indicators of neural activity however, they do not assist the clinician to identify the location of a source of neural activity, with accuracy. In some clinical situations, it would be highly desirable to know the location of that source unequivocally: for example, it would be helpful in situations where a neurosurgeon is attempting to identify the location of a source of electrical dysfunction in the brain of a patient that needs surgical attention, to know accurately where the source of the dysfunction is to be found. This would assist in the surgical correction of many conditions where accurate identification of the source of the problem is required, so that the surgery can optimise the correction of the patient's condition.

Another practical need lies in the field of drug development. In' many clinical situations, it would be very helpful for researchers or clinicians to know more precisely, the mechanisms by which drugs exert their effects on the brain or the central nervous system more generally. If researchers or clinicians could directly monitor the effects of drugs on brain or central nervous system events, this could assist greatly in developing drugs that more effectively treat the brain or the central nervous system. Such direct monitoring of the central nervous system effects of drugs could also assist, at the same time, in developing ways to avoid unwanted effects of the drugs either on the target tissue that the drugs are intended to treat, or on other tissues.

The present invention therefore aims to provide methods and apparatus for directly monitoring the electrical activity of electrically excitable tissues (such as the brain) of a subject, and thereby, to address one or more of the prior art problems previously discussed.

General disclosure of the Invention

The biological organism is preferably a mammal. The mammal may be a human or a non-human subject.

The electrically excitable tissue may be a neural tissue. Preferably, the neural tissue is the central nervous system of the subject, or a part of the central nervous system. In a particularly preferred embodiment of the invention, the electrically excitable tissue is the brain of the subject, or a part of the brain. Alternatively, the electrically excitable tissue may be a peripheral tissue, such as a peripheral nerve or part of a peripheral nerve.

Alternatively again, the electrically excitable tissue may be another body tissue or organ which has electrical activity. In this further embodiment of the invention, the tissue may be the heart or a part of the heart of the subject. For example, the tissue might be the Purkinje system of the subject's heart, or a part of that system.

Alternatively, the tissue could be cardiac muscle tissue in the heart of the patient.

Alternatively again, the tissue could be a muscle tissue. In this case, the tissue could be either a skeletal muscle tissue, a smooth muscle tissue or, as mentioned in the preceding paragraph, a cardiac muscle tissue.

Preferably, the means by which changes in that indicator are detected is by the use of nuclear magnetic resonance imaging. Preferably further, the indicator used in the method is the spin-echo acquisition sequence. Alternatively, the indicator is the gradient echo sequence. A preferred means for this purpose is a magnetic resonance imaging (MRI) scanner. In all applications of the invention, the MRI scanner also comprises, or co-operates with means suitable for detecting the electrical activity in the specific tissue under study. For example, in a subject undergoing a brain scan, the subject would be fitted with a head coil or like means for detecting brain electrical activity. Preferably, the output of readings taken by the MRI scanner would be displayed on a display means, such as a computer monitor or other visual monitor. The output would preferably also be recorded via recording means. Such means could take the form of an electronic file stored on a computer hard disk or another electronic recording medium (such as a compact disk). Alternatively, the output could be recorded on a video tape or cassette, or a Digital Versatile Disk (DVD), capable of being played back as and when desired. Alternatively, the output of the readings could be displayed via a printing means, such as a computer printer.

In some applications, it might also be useful for the method to be performed in association or in conjunction with other measurements taken on the subject. For example, at the same time as detecting changes over time in the spin-echo acquisition sequence (or gradient echo) of the tissue under observation, an electrencephalogram and/or other observations (for example, readings on the subject's blood pressure or blood chemistry) on the subject could be taken. Preferably, the method would permit the simultaneous detection and recording of changes over time in the spin-echo acquisition sequence or gradient echo of the tissue under observation, as well as other observations on the subject.

In yet further applications, it might also be useful for the method to be performed in association with other one or more other procedures being carried out on the subject. For example, it would be beneficial in some instances, if the method aspect of the invention were performed in conjunction with a surgical or other therapeutic procedure being performed on the subject.

In further embodiments of the invention, the method aspect of the invention could be used to detect the impact of specific stimuli on changes in the spin-echo acquisition sequence (or gradient echo or other indicator of function) in the tissue under study in the subject. Such stimuli could take the form of:

• Psychological stimuli, such as stimuli designed to induce a specific psychological or emotional state in the subject;

• Physiological stimuli, such as visual, aural, olfactory, proprioceptive, nociceptive, or temperature-related stimuli (eg, the application of heat or cold temperatures to the subject); or

• Pharmacological stimuli, such as those produced by applying one or more pharmacological agents to the subject.

The invention also generally provides an apparatus for detecting the function of an electrically excitable tissue in a biological organism, the apparatus comprising means for directly detecting in the tissue, changes in a direct indicator of electrical activity over a period of time.

Preferably, the changes in the indicator over time are detected by using nuclear magnetic resonance imaging means. Preferably further, the indicator used is the spin echo acquisition sequence or the gradient echo, as described earlier. Preferably further, the means by which changes in that indicator are detected is by the use of nuclear magnetic resonance imaging. A preferred means for this purpose is a magnetic resonance imaging (MRI) scanner, as described above. The apparatus may have any one or more of the features described above in connection with the general disclosure of the method aspect of the invention, and the preferred features of the method.

Preferably, the MRI scanner used in the invention has a magnetic field of between 0.5 tesla and 7.0 tesla. A scanner with a magnetic field of 3.0 and 7.0 tesla is particularly preferred.

Preferably, the MRI scanner also comprises, or co-operates with means suitable for detecting the electrical activity in the specific tissue under study. For example, in a subject undergoing a brain scan, the subject would be fitted with a head coil or like means for detecting brain electrical activity. For conducting brain scans, a birdcage radiofrequency head coil is particularly preferred.

Preferably, the MRI scanner also comprises, or co-operates with means for analysing, recording and/or displaying readings detected in the subject by the scanner. Preferably, those means would be computerised means. Preferably, the scanner also comprises, or co-operates with computer hardware and/or software for analysing, recording and/or displaying readings detected in the subject by the scanner. Those means could also analyse, record and detect other measurements taken in the subject (such as, for example, measurements of the subject's EEG, blood pressure and/or blood chemistry).

Preferably, the MRI scanner and any associated means for analysing, recording and/or displaying readings detected in the subject by the scanner would be capable of taking readings observed over very short periods of time. Preferably, those means would be able to analyse events occurring over time periods as short as between 25 and 100 milliseconds.

The invention also provides a method of detecting or diagnosing the presence or status of a pathological condition in an electrically excitable tissue in a subject, the method comprising the step of detecting in the tissue, changes in the characteristics of a direct electrical indicator of the function of that tissue over a period of time, wherein a pattern of the changes detected correspond with the presence or status of a particular pathological condition. The invention also provides an apparatus for detecting or diagnosing the presence or status of a pathological condition in an electrically excitable tissue in a subject, the apparatus comprising means for detecting in the tissue, changes in the characteristics of a direct electrical indicator of the function of that tissue over a period of time, wherein a pattern of the changes detected correspond with the presence or status of a particular pathological condition.

Pathological conditions for this purpose include:

Demyelinating diseases (such as multiple sclerosis);

The dementias (and including specifically, Alzheimer's disease);

Schizophrenia and other major psychoses; • Parkinson's disease;

Deep peripheral neuropathies; and

Amyotrophic lateral sclerosis.

Detailed description of a preferred embodiment of the invention

A preferred embodiment of the invention will now be described by way of example only with reference to the accompanying drawings, in which:

Fig 1 depicts a chart tracing which shows measurement of the blink reflexes and brain electrical responses in a subject to a visual stimulus, relative to the timing of events in the MR sequence; and

Fig 2 depicts a brain scan in a human subject, showing (through the areas shown in white) the signal change in response to a visual stimulus - compared to a signal change without the visual stimulus, the change being overlaid on the anatomy of the brain structures.

Theory All neural signalling activity precedes by the flow of ionic currents across the plasma membranes electrically active cells, such as neurones and glial cells. Electric current of any kind is, by definition, accompanied by magnetic field alternations in the immediate vicinity of the current. For the time that they are present in the vicinity of brain (or other electrically excitable tissue), such currents therefore contribute to local magnet field inhomogeneity.

The spin-echo sequence (Hahn, 1950) is useful in MRI and MRS because the second half of the sequence corrects the signal loss due to local magnetic field inhomogeneities during the first half (these are referred to as T2^* losses as they are known in the NMR literature. The spin-echo sequence is useful in MRI and MRS because the second half of it corrects the signal loss due to local magnetic field inhomogeneities during the first half - T2^* losses, as they are known in the NMR literature. However, the spin-echo procedure can only correct T2* losses than remain the same throughout the acquisition, typically tens of milliseconds. Transient inhomogeneities which are not uniform during the whole acquisition period cannot be corrected and must cause changes in the final signal obtained. Therefore, magnetic resonance images which include transient effects must be different from images which do not. Subtraction of such image pairs should reveal the parts of the brain active due to the stimulus, if the active contents of single MRI voxels is a large enough fraction of the whole voxel volume - usually several cubic millimetres - to produce a detectable signal change.

These ideas are illustrated schematically in Figure 1. A brief physiological stimulus - visual in this study - is timed to occur during only part of the spin-echo sequence. Since brain activity due to such a stimulus runs its course in tens to hundreds of milliseconds, a spin-echo sequence with a similar time course can be unbalanced reproducibly by stimuli which always bear the same temporal relation to the sequence. Provided that the neural response to the stimulus is the same from one trial to the next, separate acquisitions can be averaged to improve the signal-to-noise ratio of the activity-related difference between control and test images. Practice

The exemplary practice of the invention discussed in this specification comprise studies performed in human subjects in a General Electric™ LX 3 tesla magnetic resonance scanner equipped with a birdcage radiofrequency head coil. A range of acquisition parameters was explored, including repetition times (TRs) of 1-20 sec and excitation times (TEs) of 25, 50, or 100 milliseconds. Single 4 or 5 mm slices oriented to include various components of the visual system were used. The field of view was 24 cm with a matrix either 64² or 128². Nominal voxel volume therefore varied between 1.875² x 4 = 14.1 and 3.75² x 5 = 70.3 mm³. Acquisition was by a General Electric spin-echo echoplanar imaging (EPI) sequence which lasted 88 or 25 msec with matrices of 128² or 64².

Visual stimuli were flashes from an array of 1-6 bright white light emitting diodes positioned in various parts of the visual field in the initial experiments and visible to the subject in a right-angle mirror attached to the head coil. Later these were delivered through 1 mm, 10 m fibre optic cables to eliminate erratic unwanted flashes caused by gradient switching and pulses through the head coil. In a second set of experiments, stimuli were black-white checkerboard patterns which were flashed from a black background, reversed at 40 Hz, or moved laterally as independent right and left hemifields towards the centre of the visual field and back in eight 17 msec steps.

Results

Initial studies exploring the stimulus and acquisition parameter ranges indicated above showed that responses plausibly due to electrical activity in the visual system from retina to calcarine cortex occurred commonly. We therefore concentrated our effort on eliminating the possibility that these could be in whole or in part artefacts of motion, especially startle and blink reflexes, or anomalous BOLD responses. Figure 2 illustrates an experiment which minimised the likelihood of such artefacts. The stimulus was movement of each hemifield of a checkerboard pattern toward the centre of the visual field in a single run of 210 scans at a repetition time (TR) of 1 second. The stationary checkerboard pattern was present during all rest periods, to hold total luminosity constant throughout the measurement. The first 10 scans of the series were excluded to allow for T1 stabilisation, leaving 100 interleaved rest-motion pairs for analysis.

Figure 2 shows significant differences between stimulus and rest acquisitions in what appear to be several parts of the visual system, including the optic nerves, optic chiasm, lateral geniculate bodies, and optic radiations. Few significant differences are present elsewhere.

Discussion The simplest interpretation of these data is that they represent direct detection of, visually-evoked electrical activity in the human brain. While theoretical considerations dictate that such activity must be accompanied by transient alterations in local magnetic field due to current flow, studies were necessary to determine whether the changes were large enough to be detected on the anatomical scale of single voxels, 14-70 mm³ in our studies, and can reliably be distinguished from movement artefact. Our results indicate that the answer to both questions is affirmative.

Motion and BOLD artefacts are not likely to have caused the signals evident in Figure 2. Artefacts of eye movement due to blink or startle reflexes might mimic physiological activity in the retina and optic nerves, which move slightly with eye movement, but the signals in the immobile chiasm and more posterior structures cannot be explained that way. Head movement artefact would be distributed around regions of high image contrast, not, as in the Figure, mostly along the visual pathways.

BOLD responses can hardly have occurred from 1 second to the next repeatedly throughout the experiment in such a way as to produce the observed patterns of activation. Any BOLD response cumulative throughout the run should have achieved an early plateau and been subtracted out by subtraction from stimulus acquisitions of stimulus-free ones obtained one second earlier.

The method we disclose in this specification brings NMR measurements of brain activity onto the same time scale as the activity itself. By stepping the stimulus along the acquisition sequence in millisecond increments, the method can make finely resolved temporal maps of brief responses which do not adapt..

The method should also work well in the somatosensory system, where one might hope to map activity from spinal nerve roots to cerebral cortex by appropriate coil placement. Scanner noise will make auditory responses more difficult to detect initially, but a number of solutions to the problem are possible. Motor activity which can be timed accurately should be detectable, as should peripheral nerve activity in the depths of the body where it is beyond reach of direct measurement by conventional electrophysiological methods.

A principal application of the present method will be investigation of normal neurophysiology in most parts of the nervous system. Being non-invasive, such measurements can be repeated as often as necessary within limits of personal tolerance in any subject with no contraindication to MRI examination. Detailed study of central conduction times, routes, and refractory periods will lead to new understanding of how the human brain works. Animal experimentation offers another approach to the same problem along different dimensions of normal activity. The invention can also be used in many other applications. One of the broadest is in neuropharmacology, as the method of the present invention can be used in the study of central drug' effects. Alzheimer's disease and other degenerative diseases of the nervous system can be probed in a new way; subtle effects on brain physiology may well be detectable early in the course of such diseases and serve as surrogate markers of efficacy in trials of new treatments. These and other applications are all embraced within the spirit and scope of the present invention.

It will therefore be understood that the invention disclosed in this specification extends to all combinations of two or more of the individual features mentioned or evident from or implicit in the text of this specification or the accompanying drawings. All such different combinations constitute various alternative aspects of the invention.

It is also to be understood that wherever used in this specification (including both the description and the claims), forms of the word 'comprise' are equivalent in meaning to the corresponding forms of the word 'include', and are thus not to be taken as excluding or implying the exclusion of a feature or integer.

References Bodurka, J. and P. A. Bandettini (2002). "Toward direct mapping of neuronal activity: MRI detection of ultraweak, transient magnetic field changes." Magn Reson Med 47(6): 1052-8. Hahn, E. L. (1950). "Spin echos." Phys. Rev. 80: 580-594. Kwong, K. K., J. W. Belliveau, et al. (1992). "Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation." Proc. Natl. Acad. Sci. USA. 89: 5675-5679. Ogawa, S., T. M. Lee, et al. (1990). "Brain magnetic resonance imaging with contrast dependent on blood oxygenation." Proceedings of the National Academy of Sciences of the United States of America 87(24): 9868-72. Ogawa, S., T. M. Lee, et al. (2000). "An approach to probe some neural systems interaction by functional MRI at neural time scale down to milliseconds." Proc Natl Acad Sci U S A 97(20): 11026-31. Prichard, J. W., J. R. Alger, et al. (2002). Windows on the working brain: magnetic resonance spectroscopy. Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles. A. K. Asbury, W. I. McDonald, J. C. McArthur, G. McKhann and P. J. Goadsby. Cambridge, Cambridge University Press: (in press). Prichard, J. W., J. R. Alger, et al. (1983). "Cerebral metabolic studies in vivo by 31 P NMR." Proc Natl Acad Sci U S A 80(9): 2748-2751.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of detecting the electrical activity of an electrically excitable tissue in a biological organism, comprising the step of directly detecting in the tissue, changes in the characteristics of an electrical indicator of the function of that tissue, over a period of time.

2. A method as claimed in claim 1 , in which the biological organism is a mammal.

3. A method as claimed in either claim 1 or claim 2 in which the biological organism is a human subject.

4. A method as claimed in either claim 1 or claim 2, in which the biological organism is a non-human subject.

5. A method as claimed in any of the preceding claims in which the electrically excitable tissue comprises one or more of the following: (a) neural tissue;

(b) smooth muscle tissue;

(c) skeletal muscle tissue; and

(d) cardiac muscle tissue.

6. A method as claimed in claim 5, in which the electrically excitable tissue comprises the central nervous system of the subject.

7 A method as claimed in claim 6, in which the electrically excitable tissue is the brain of the subject, or a part of the brain.

8. A method as claimed in any of the preceding claims, in which the means by which changes in the electrical indicator of function of the tissue are detected is by the use of nuclear magnetic resonance imaging.

9. A method as claimed in any of the preceding claims, in which the electrical indicator of the function of the tissue is the spin-echo acquisition sequence.

10. A method as claimed in any of claims 1 to 8, in which the electrical indicator of the function of the tissue if the gradient echo sequence.

11. A method as claimed in any of claims 8 to 10, in which:

(a) the nuclear magnetic resonance imaging means used comprise the use of a magnetic resonance imaging scanner; and

(b) the subject is fitted with an apparatus for detecting brain electrical activity.

12. A method as claimed in claim 11 , in which the means for detecting brain electrical activity comprise an apparatus fitted to the head of the subject, in use of the method.

13. A method as claimed in any one of claims 8 to 12, in which the output of readings taken by the magnetic resonance imaging scanner is displayed on a display means.

14. A method as claimed in claims 8 to 12, in which the output of readings taken by the magnetic resonance imaging scanner is recorded via recording means.

15. A method as claimed in any of the preceding claims, in which the method is performed in association or in conjunction with other measurements taken on the subject.

16. A method as claimed in claim 15, in which the other measurements taken on the subject comprise one or more of:

(a) an electroencephalogram;

(b) measurements of the subject's blood pressure; and

(c) measurements of the subject's blood chemistry.

17. A method as claimed in any of the preceding claims, in which the method is performed in conjunction or in association with a surgical or therapeutic procedure carried out on the subject.

18. A apparatus for detecting the function of an electrically excitable tissue in a biological organism, the apparatus comprising means for directly detecting in the tissue, changes in a direct indicator of electrical activity over a period time.

19. An apparatus as claimed in claim 18, in which the apparatus comprises a magnetic resonance imaging scanner.

20. An apparatus as claimed in claim 19, in which the magnetic resonance imaging scanner has a magnetic field of between 0.5 and 7.0 Tesla.

21. An apparatus as claimed in claim 20, in which the magnetic resonance imaging scanner has a magnetic field of between 3.0 and 7.0 Tesla.

22. An apparatus as claimed in any of claims 18 to 21 in which the magnetic resonance imaging scanner additionally comprises or cooperates with means suitable for detecting the electrical activity in the tissue under study in the subject.

23. An apparatus as claimed in claim 22, in which the subject is fitted with an apparatus for detecting brain electrical activity.

24. An apparatus as claimed in claim 23, in which the apparatus additionally comprises a birdcage radio frequency head coil for taking brain scans.

25. An apparatus as claimed in any of claims 18 to 24, in which the magnetic resonance imaging scanner additionally comprises or co-operates with means for analysing, recording and/or displaying recordings detected in the subject via the scanner.

26. An apparatus as claimed in claim 25, in which the magnetic resonance imaging scanner additionally comprises, or co-operates with computer hardware or software capable of: (a) analysing,

(b) recording and/or

(c) displaying readings detected in the subject over time, by the scanner.

27. An apparatus as claimed in any one of claims 18 to 26, in which the apparatus is capable of taking readings over periods of time between 25 and 100 milliseconds.

28. A method of detecting or diagnosing the presence or status^'of a pathological condition in an electrically excitable tissue in a subject, the method comprising the step of detecting in the tissue, changes in the characteristics of a direct electrical indicator of the function of that tissue over a period of time, in which a pattern of the changes detected corresponds with the presence or status of a particular pathological condition.

29. An apparatus for detecting or diagnosing the presence or status of a pathological condition in an electrically excitable tissue in a subject, comprising means of detecting in the tissue, changes in the characteristics of a direct electrical indicator of the function of that tissue over a period of time, in which a pattern of the changes detected corresponds with the presence or status of a particular pathological condition.

30. A method as claimed in claim 28, in which the pathological condition comprises one or more of the following:

(a) a demyelinating disease; (b) the dementias;

(c) major psychoses;

(d) Parkinson's Disease;

(e) deep peripheral neuropathies; and

(f) amyotrophic lateral sclerosis.

31. An apparatus as claimed in claim 29, in which the pathological condition comprises one or more of the following:

(a) a demyelinating disease; (b) the dementias;

(c) major psychoses;

(d) Parkinson's Disease;

(e) deep peripheral neuropathies; and

(f) amyotrophic lateral sclerosis.