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an ALS Hypothesis

kenneth Collins kpaulc at earthlink.net
Sun Jan 30 10:09:09 EST 2000

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 NDT (AoK+), by k. p. collins, unpublished.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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