an ALS Hypothesis - extended to all 'abnormal' neural atrophy
kpaulc at earthlink.net
Mon Jan 31 00:24:51 EST 2000
i've read enough to state, in a preliminary way, that the current focus upon neural atrophy in the basal ganglia is 'ill-considered. as is discussed in AoK, Ap5, the basal
ganglia constitute a high-'level' supersystem configuration mechanism that functions in accord with the TD E/I-minimization principle over the relatively-long term.
1. this means that degeneration within the basal ganglia =must= be correlated with wide-spread correlated observables, but in nothing i've read, as yet, are such
extra-striatal considerations addressed.
2. the hypothesis that the striatal degeneration is a result of a break-down in globally-ramifying TD E/I-minimization mechanisms has greatly solidified.
3. the 'break-down' addressed in 2, above, takes the form of the approach through which i previously addressed the pathology of Alzheimer's Disease, recently, here in
4. i now extend the realm of this hypothesis to include =all= 'degenerative' diseases, including Huntington's, Parkinson's, and the various Dystrophies.
5. all such diseases are variations on the single theme that was discussed in the Alzheimer's hypothesis, with the variation being correlated with differing
'points-of-failure' at levels below the diencephalon.
6. these 'points-of-failure' are variations on what's discussed below, with different 'lesions' precipitating the symptomology of the 'various' disease conditions.
7. the 'lesions' =can= have a genetic correlation, because various environmental factors can act differentially with respect to individual genetic variation. (some food
substances, for instance, are toxic to some folks, but not others. in the present hypothesis, it is probably naturally-occurring trace-element stuff, that escapes gustatory
'affect ('aversiveness'), that is responsible for the delayed onset of symptoms.
8. in this hypothesis, the degeneration that is presently being focused upon is a =result= of more-fundamental stuff, and a correlate of symptomology, rather than it's
cause. the basal ganglial 'degeneration' stuff is 'just' what happens, over the long term, when relative randomness occurs, interminably, within nervous systems. the =cause=
is located at the lower-'level' site(s) of the nervous-tissue 'break-down' at which the 'unstoppable' TD E/I(up) is interjected into, and distributed throughout, the rest of
the nervous system.
9. auto-imune activity is probably involved, as when a slowly-building reaction to a substance acquires the quality of 'toxicity' over an extended period.
10. various non-motor symptoms probably unfold in the analogous way, the difference being 'determined' by the particular low-'level' 'lesion' site involved. 'lesions' can be
anything that alters the functioning of a particular 'low-'level' site toward increased long-term TD E/I.
11. "Gulf War Syndrome" encapsulates =a lot= of what's in this hypothesis, with there being multiple low-'level' 'lesions' which 'tip-the-scales' toward TD E/I(up) at
12. so-called 'recreational' drug used typically results in, at least, short-term versions of the stuff that's being discussed in this hypothesis. reversibility of such
drug-induced effects depends on whether the drug has an 'anesthetic'-like effect, or a permanently-altering effect (for instance, some 'recreational' drugs permanently alter
the body's thermal homeostasis in a way that can be observed in long-term readings of any medical thermometer. although such long-term effects allow a person to function,
they still elevate TD E/I globally, enduringly, and must, therefore, be included in this hypothesis.)
13. one long-term approach that would probably yield useful information would be rigorously-restricted dietary information (a lot of which is probably already available, but
not being integrated.)
14. at any rate, the present standard with respect to the Disease classes which this hypothesis addresses, is inadequate. first, the stuff that's being focussed-upon as
being 'pathological' ('plaques', 'tangles', 'vacuoles', etc.) is probably 'just' the result of 'normal' neural function when subjected to interminable TD E/I(up). the
present focus must be bolstered with whole-nervous-system histology and analysis, and detailed case histories which include as complete-as-possible dietary
(nutritional-intake, drug use, environmental chemo factors, etc. information) because it can be said with certainty that the striatal neural degeneration that is being
focussed upon relatively exclusively has both trophic and activation correlates in wide-spread regions of the nervous system. it cannot be that this necessarily-correlated
stuff is 'swept under the rug'. no effective treatment can possibly result from such. all that can result from 'treatments' founded upon such is a 'shifting' of symptomology
because 'compensating' for only one portion of what is actually a wide-spread dynamic, only 'shifts' the aberant TD E/I(up), rather than ameliorating it. the ideal treatment
would trace the source of the aberant TD E/I(up) down to its low-'level' 'interjection' site, and act upon that locus, with a goal of returning that locus to it's 'normal'
comment: i understand that what's in this hypothesis is 'groaner'-stuff, but it cannot be that a 'chisel' is taken to this or that portion of exquisitly-integrated global
dynamics, with the expectation that the innate functionality will, in fact, be restored. all the mis-applied 'chisel' will accomplish is a further diminution of the overall
folks =really= need to come to terms with the integrated functioning of the nervous system, without 'taking any short cuts', =before= undertaking to 'help' the nervous
system in its information-processing dynamics.
K. P. Collins
kenneth Collins wrote:
> kenneth Collins wrote:
> > be back with the ALS hypothesis later.
> > because ALS is a 'Disease' process, i'll expect anyone who can to contribute, pro or con,
> > Forthrightly (no need for 'tip-toing' on my account), with none of our typical 'waste'. the
> > sufferring will, then, be in our imediate presence, and we must be 'good soldiers' on behalf of
> > those who suffer.
> first, here's a URL that gives a view into the 'genetic' approach to ALS (you might have to copy the
> URL to a text file and join it back together if your browser breaks it up because of its length):
> a minor 'criticism':
> the article uses a genetically-altered mouse variety that does yield motor neuron atrophy, but the
> article isn't clear re. whether "mitochondrial vacuoles" occur in ALS (in Humans). the article cites
> refs. that refer to other papers that discuss "mitochondrial vacuoles", but the article isn't clear
> whether the other refs refer to the mutated mice or Humans. (i presume it's the mice, which doesn't
> get me very far along with the "mitochondrial vacuoles" hypothesis.)
> a 'Looking-Elsewhere' hypothesis re. Amytrophic Lateral Sclerosis:
> turns out that i worked with only the refs i had on-hand, which were:
> 1. _Human Neuroanatomy_ 8th Ed., by M. B. Carpenter and J. Sutin, © 1983, Williams & Wilkins, ISBN
> 2. _Principles of Neuroscience_ 3rd Ed., by E. R. Kandel, J. H. Schwartz and T. M. Jessell, © 1991,
> Elsevier, ISBN 0-444-01562-0.
> 3. _The Human Central Nervous System; A Synopsis and Atlas_ 3rd Ed., by R. Nieuwenhuys, J. Voogd, C.
> van Huijzen, © 1988, Springer-Verlag, ISBN 0-387-13441-7.
> 4. _Human Motor Control_, by D. A. Rosenbaum, © 1991,Academic Press, ISBN 0-12-597300-4.
> 5. clinical information re. chemically-induced (i.e. intravenus applications of Streptomycin,
> Gentamicin) vestibular hair cell degeneration, and brain stem stroke occurrences, communicated to me
> by James Michael Collins, Physical Therapist.
> 6. NDT (AoK+), by k. p. collins, unpublished.
> i reread several hundred pages, mostly in Nieuwenhuys, et. al. (to check the neuroanatomical
> plausibility of the hypothesis), i would have liked to have reread as thoroughly in Carpenter & Sutin,
> but didn't have 'time', and used it for spot-checks (because it's my 'favorite' Neuroanatomy text, i'm
> pretty-familiar with Carpenter & Sutin, anyway), and, since the sections i read will be obvious to
> anyone who wants to follow-up, i'll let it go at that.
> i relied on the discussion of ALS in Kandel, et. al. for my start. the factors that i found
> significant are as follows.
> the occurrence of fasciculations (visible) and fibrilations (non-visible; need myograph) muscle
> ('twitch') activation anomolies.
> the fact that ocular motor function in ALS is entirely 'normal'.
> the fact that sensation in ALS is entirely 'normal'.
> the Hypothesis:
> the demyelination results from a specific brain stem lesion, of a type analogous to the
> chemically-induced vestibular lesion, or a stroke-induced lesion.
> this hypothetical ALS-generating brain stem lesion 'releases' 'normal' function in a way that
> 'interjects' activation associated with the superior colliculi where activation correlated with spinal
> motor activation 'normally' exists. presently, the most-likely site seems to be one that affects
> inferior olivary function, most likely with reticular nucleus involvement.
> as is discussed in AoK, Ap6, the inferior olive is a 'crumpled-bag' nucleus, in which inputs including
> efferent activity from the joint receptors drives topological-map 'translation' as the body's 3-D
> conformation varies. the inferior olive accomplishes this 'translation', with respect to which
> 'crumpled-bag' nuclei are topologically-optimized (allowing TD E/I-minimized 'translation'
> functionality), via climbing fibers in the cerebellum, which have potent Purkinje cell excitatory
> what happens is that, since the hypothesized brain stem lesion alters the 'normal' balance between
> ocular motor inputs and spinal inputs to the inferior olive, activation pertaining to saccacadic
> movement, or ocular motor-via-reticular nuc(s) activation, gets crossed-up with the spinal inputs,
> resulting in outputs from the cerebellum getting 'out-of-sync', which, when projected back to the
> ascending and descending motor fibers, is what is reflected in the fasciculations and fibrilations.
> (Kandel, et. al. discusses the fact that the ALS-correlated fasciculations and fibrilations correlate
> with out-of-sync motor activation.)
> next the hypothesis invokes NDT's view on activation-dependent glial (myelin) trophy.
> this part of the hypothesis holds that the schwan cells comprising the myelin alter their
> configurations in a way that attempts to compensate with respect to the out-of-sync activation that's
> occuring in the motor fibers. it's part of NDT's activation-dependent neuralglia position that, during
> 'normal' motor neuron function, such activation-dependent schwan cell configuration alterations
> 'adjust' the inter-node Ranvier spacing so that impulses travel down axons in the optimal type II
> synchronized (AoK, Ap6; like gears in a clock, not like soldiers marching) way. the 'adjustment' that
> converges upon 'optimal' type II synchronization occurs because, when things are out-of-sync, ionic
> conductances, local to an axon, will be volumetrically-increased (which is just another another 'form'
> of "TD E/I(up)"). the schwan cells are living [:-)] things that, like all glia, get their 'marching
> orders' from these ionic conductances. (as i've discussed here in B.N in the past (with respect to
> long-term 'memory' addressing, and global 'plasticity'), the fact that these activation-dependent
> glial configuration dynamics =must= occur is why the brain is a semi-fluid 'pudding'. if anyone wants
> to receive this long-term 'memory-addressing' and global-plasticity stuff again please msg.)
> but, since the hypothesized brain stem lesion interjects saccadic activation, which is, innately,
> relatively 'random', no matter how the schwan cells 'adjust', the motor activation remains
> this 'struggle' by the schwan cells can only fail, and their continuous 'adjustment' constitutes
> hyper-excitation which precipitates their cell-deaths. 'hence', no upper/lower motor neuron myelin.
> but that's not the end of it.
> the overall relative randomness that results from the leison-interjected saccadic activation is acted
> upon by the cerebellum in the 'normal' way. the cerebellum reacts to it as if the lesion-interjected
> activation is spurious TD E/I(up), which means that, as the lesion-induced 'randomness' continues, the
> cerebellum will output more and more inhibitory activation both up and down the neuraxis, which,
> significantly, leads to the observed shrinking of motor cortex in ALS, which feeds back into the
> overall weakening of motor dynamics, augmenting the progressiveness of the atrophy.
> there are other attractive rationales for this sort of hypothesis. the problem of the 35+ years
> typical onset of ALS has to be explained. if there's a genetic flaw, then how is it that it shows
> itself only after 35+ years? what's the 'switch' that changes fully-functional motor neurons to
> dysfunctional 'motor' neurons?
> and the dynamics described can account for other phenomenon such as the 'laughing' behavior,
> dissociated from affect, in ALS, that's discussed in Rosenbaum, and other affective deficits and/or
> plus, 'sporadic ALS' can remit. if the hypothesized lesion is self-reparable, like a strong compresion
> injury, or a brain stem stroke that can nevertheless be recovered from via new capilary growth, then
> the remission of the ALS symptoms has an obvious means.
> it's more-difficult to accept that a genetic condition can 'remit' (although immune system function is
> extraordinarily-capable, which might be invoked to account for such).
> the one criterion that =must= be met in order to explore this hypothesis further is, since the ocular
> motor system is not affected in ALS, to culture examples of ocular motor neurons along with examples
> of upper and lower motor neurons, and look for differences that would allow the ocular motor neurons
> to survive while the upper/lower motor neurons would not survive.
> if there's no detectable difference, then ALS is probably due to a brain stem lesion, either
> chemically-induced, stroke-induced or 'contusion'-induced, not a function of single-neuron-correlated
> or, perhaps this sort of monotonic TD E/I(up)-inducing lesion paradigm could be tested in animals.
> anything that would defeat type II synchronization in the motor system would do it.
> caveats: the Neuroanatomy of the brainstem is Hugely-Complex. the discussion above is only one
> hypothetical example. i went with the inferior olivary 'connection' because it's straight-forward to
> arrive at the necessary unstoppable randomness within the inferior olive 'translation' dynamics.
> there are other lesion sites that attract one's mind, such as the interstitial nucleus of Cajal, and
> various reticular nuclei. (as i've said, this looking at disease conditions is a new-thing for me. i'm
> not yet up-to-speed with respect to such. i've no 'examples' database. if i were 'getting paid' to do
> this work, i'd not stop until i'd checked out every possible lesion locus, and worked all the brain
> stem Neuroanatomy through. it could very-well be that there's a round-about route involved. the only
> necessities is that there actually be a lesion, and that its result interacts with the cerebellum as
> was discussed above. brainstem lesions are not that uncommon. and it's =fun=. it's like doing a Living
> 3-D jigsaw puzzle. what makes it 'fun' is the hope, on behalf of those who suffer, of finding
> something that can be =Fixed=.)
> the other thing: while i was reading, i also saw ways that a similar lesion-induced activation
> abnormalities could act, in fashion analogous to what's here, upon the basal ganglia and the
> substantia nigra, which makes it plausible to 'wonder' with respect to Parkinson's.
> and, of course cognitive dysfunction, such as 'schizophrenia', is 'just' more of the same defeating of
> type II synchronization [forcing interminable TD E/I(up)], only more globally.
> which leads right back to the central concept discussed in AoK.
> i've not yet continued on to Huntington's. have to go back to the Library to check out the text that i
> forgot to check-out the other day.
> K. P. Collins
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