an ALS Hypothesis - extended to all 'abnormal' neural atrophy
kenneth Collins
kpaulc at earthlink.net
Tue Feb 1 02:24:05 EST 2000
i've reformatted my prior post to make online reading easier.
as is most-often the case, in my prior posts in this thread, i've been 'looking-elsewhere', Trusting that folks who work in the traditional ways are able to do better, in those
ways, than anything i can, presently, add to those traditional ways.
it seems that there aren't many folks who agree with me, but my view is that the stuff that's converged-upon while 'looking-elsewhere' is always Valuable stuff because it tends
to be 'invisible' to folks who work in traditional ways, and it, so, it tends to present the opportunity to 'check-things-out' in ways that were 'impossible' before the
'looking-elsewhere'.
['editorial' comment: although i'm long-accustomed to it, the way that my 'looking-elsewhere' approach elicits unthinking 'criticism', nevertheless, gives me Sorrow.]
at any rate, in rereading my prior posts in this thread, it became apparent that i can 'brifge', a bit, between the new hypothesis that i've developed and the stuff of the
traditional, molecularly-focussed approach to Alzheimer's, ALS and Huntington's. i'll do so, a bit, below.
my 'time' online is drawing to a close. this may be the last thing i post until i can get back online at some unforseeable 'time' in the future (if ever).
kenneth Collins wrote:
>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.
in response to comments, elsewhere, by Dag, i stand on what i've posted. perhaps my view is skewed because my reading in this subject area has been only very-limited, but i
stand on what i've posted. there is a focus on striatal stuff, but an absence of discussion of stuff that's necessarily-correlated with striatal stuff.
>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
>bionet.neuroscience.
>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.
and, 'of course' (from the approach of the traditional perspective on these diseases), the 'lesion can be located in the DNA. disease-causing 'mutations' are 'lesions' in the
DNA, in a way that's completely-analogous to the way that lesions in the neural architecture are substrates for neurological dysfunction.
although it's been implicit in the hypothesis i'm discussing, i'll make it explicit by re-stating that activation-dependence is =continuous= from the 'level' of the DNA to the
'level' of the complete organism.
that is, as i discussed in the recent past with respect to nervous system development, the particular 'state' of a nervous-tissue cell's development 'addresses' the correlated
activation-dependencies in its correlated DNA, which invokes the next sequential developmental contribution of the DNA. this interaction is =continuous= at all 'levels', up to
the 'level' of the whole body. thus, in the cortical-'stripe' formation stuff, for instance, in my view, the stuff that can be considered to be 'molecular markers' is =in= the
DNA itself, and is 'triggered', in an activation-dependent way, by the current 'state' of the cells to which the DNA in question is correlated. it's be-cause of this that, in
the transplant experiment examples that i've discussed recently in another thread, the rewiring of frogs' optic nerves shows a 'group discipline'. the 'group-discipline' results
from the fact that all the neurons involved are experiencing relatively-similar activation-dependent trophic dynamics. 'exceptions' include all 'boundary conditions', in which
the asymmetric nature of the activation-dependent dynamics are what maintains the 'boundary' (i.e. of a neural tract), thus, giving the tract it's 'confined place' within the
rest of the nervous system.
'of course', if the DNA is activated in different activation-dependent ways, there will be different correlated metabolic by-products of such differentiated activation of the
DNA. such metabolic by-products can diffuse from the cellular structure of a cell, and these diffused by-products might function as 'signals' to other cells, but these diffused
by-products cannot be termed as 'molecular markers' because doing so artificially-separates a sub-part of the whole, and calls it 'the whole', which is =just=
activation-dependence "all the way down" (no 'turtles' :-).
i understand that this sub-discussion must seem 'persnickety', but the fact that all there is is activation-dependence must be gotten across.
>8. in this hypothesis
which focusses upon striatal stuff
>, 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.
i. e. an acquired 'alergic' reactivity
>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.
including mutated DNA that enters into activation-dependent dynamics that result in the development of 'lesion'-equivalents in the neural architecture.
in other words, the stuff that i addresed as chemically- or injury-induced lesions in the previous discussion clearly can derive in the DNA.
and so can specific mutations with respect to specific metabolic steps.
i was not 'arguing against' such in my prior discussion. i was =only= discussing the probability that the diseases in question result from dynamics that have globally-integrated
involvements, and not 'just' some single aberrant DNA-driven metabolic step.
the hypothesis i'm discussing is in these globally-integrated dynamics, an example of such i've outlined, including the way that demyelination in ALS is a =result= of
dysfunction at higher 'levels' of the neuraxis, and not the 'cause' of the disease.
this is a significant, and meaningful, difference from the traditional hypothesis.
>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 multiple loci.
>12. so-called 'recreational' drug use[...] 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.)
the main thing that stimmed this 'dietary' stuff was with respect to the problem represented by the 'late onset' of the disease conditions, which needs explication. if, in
accord with the traditional view, it actually is the case that a single DNA mutation results it the entirety of the disease condition(s), then why is it that the stuff of that
mutation is activated in such a delayed way?
of course, there's a lot of stuff that's analogous, such as 'baldness', which 'normally' occurs in a delayed fashion. with respect to the hypothesis i'm discussing, the
correlation that i'm focussing upon is like the one i've observed with respect to my use of this or that shampoo and the rate at which i experience hair loss. (which is why,
BTW, i'm a devoted 'fan' of Johnson's Baby Shampoo... minimizes hair-loss.) and by careful study with respect to this & that shampoo's effect on hair-loss, one can uncover the
way that external stuff 'pushes' the DNA's activation-dependence one way or the other with respect to hair-loss. which is exactly-analogous to the way that this or that external
stuff 'pushes' the DNA's activation-dependence one way or the other with respect to disease processes.
i'd ask if anyone knows if the study of such 'time'-hierarchical genetic activation is an established field of study, but no one ever answers when i ask such questions, so i
won't bother. (please forgive my 'sarcasm', if you can. i'm weary from the one-way flow of information, and the 'opinion' of me that's reflected in-it.)
anyway, it might be that, through restriction of normally-ingested stuff, the late-onset triggering of the disease processes can be controlled. (if so, it'd probably be
trace-element stuff. otherwise, there'd likely be an 'aversive' reaction that'd accompany ingestion of disease-triggering stuff.)
>14. at any rate, the present standard with respect to the
>Disease classes which this [striatal stuff] 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'physiological 'state'.
>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 integration.
>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.
>[...]
>>
>> >[...]
>>
>> > 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):
>>
>>
http://www.jneurosci.org/cgi/content/full/18/9/3241?maxtoshow=&
HITS=10&hits=10&RESULTFORMAT=&titleabstract=Amytrophic+lateral+
sclerosis&searchid=QID_NOT_SET&FIRSTINDEX=0
>>
>> 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 0-683-01461-7.
>>
>> 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 effects.
>>
>> 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'
[myelinated]
>> 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 out-of-sync.
>>
>> 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?
this 'delayed-onset' might be triggered by the unfolding of 'normal' biological dynamics, such as the onset of puberty, or other genetically-'staged' dynamics. in this
sub-hypothesis, the newly-activated (within an individual body's biological functioning) dynamics modify what had been functional genetic unfolding, so that the the
(formerly-functional stuff + the newly-triggered stuff) yields a non-functional 'state' that precipitates motor neuron degeneration.
if this sort of thing occurs, then the disease is treatable through methods that eliminate the functionality of the newly-triggered stuff, with, of course, side-effects with
respect to the elimination of the dysfunctional version of stuff that would, otherwise, be part of 'normal' Life.
at any rate, an explanation for the observed delayed onsets of Alzheimer's, ALS and Huntington's is necessary, and it will probably be the case that, when such delayed onset is
explained, treatment strategies will become apparent within such explanation. so explication of the delayed onset is an important problem.
>> 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 fluctuations.
>>
>> 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 genetics.
i repeat, i'm taking this position in this hypothesis because all of the so-called 'indicators' that i've read of can result from excitotoxic activation, which means that it's
possible that the 'indicators' are nothing of the kind, but 'only' by-products of a more-globally-correlated set of dynamics, such as those that i've been discussing in this
hypothesis.
an analogy from familiar experience is the way that some automobile electrical-system problems seem like one thing ("get a new battery"), when they are actually something quite
different (i. e. a shorted alternator armature).
the lack of 'charge' in the battery is not due to the battery being inoperable, but the electrical supply for the whole electrical system, of which the battery is just one small
part, having worn-out (having been 'lesioned').
no matter how many fully-charged batteries are put in-there, the problem will recure until the worn-out alternator is fixed or replaced.
the batteries just run-down because they experience the automobile version of 'excito toxicity" (more 'out-go' than 'in-come'... which, just-now, gains my sympathy :-))
>>
>> 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.
anyway, that's my contribution(?) to the efforts to extinguish these diseases. i could do more, but despite the fact that i've done this stuff at my own expense, i've only been
'ridiculed' for having tried (even though there are two "Jewels" of NDT discussed, publicly, in this hypothesis for the first time... which is the 'ridiculous' thing, no?
K. P. Collins
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