X-Message-Number: 4976
Date: 12 Oct 95 23:14:55 EDT
From: Mike Darwin <>
Subject: CRYONICS: dendritic spines

I did not get a copy of the Cryonet with Mike Perry's article on dendritic
spines.  Joe Strout was kind enough to send it along.

I was aware of this work.  Furthermore, while it is nice systematic work which
*quantifies* what happens it is not a surprise.

Over a decade ago Jerry Leaf, Hugh Hixon and I looked at dog brains at post
mortem intervals out to 24 hours.  We observed the same phenomenon at an

accelerated rate since we were exposing the animals to room temperature ischemia
(24C) throughout the process.  The breakover point beyond which there was
largely hash (no synapses lots of debris) at the ultrastructural level was
betweenm 6-8 hours if I remember correctly.

There is lots of other literature out there on post-mortem ultramiscroscopic
changes.  I had a full file drawer on this when I left Alcor, and now have a
drawer and a half.

No one paid much attention to this work.  To his credit, I can remember talking
with Mike Perry about autolytic changes and cryoinjury and the questionable

inferrability of the healthy state of the tissue, in the crew room over at Alcor
when they were in Riverside and I was on staff, and he was very concerned.  He
should have been.  So should have a lot of others. 

For years I have been preaching about how rapidly some changes occur postmortem
and how quickly phospholipases, complement and other degradative processes are
activated: not only in global ischemia (cardiac arrest) but in the long, pre
arrest shock phase.  

The notion that the brain is getting adequate flow and not experiencing serious
injury during premortem shock is ridiculous and I have the data to prove it.

Furthermore, I have for years harped on the very troubling clinical phenomenon
observed in humans who sustain head injury with prolonged unconsciousness
usually in the presence of cerebral edema.  Most people injured in this fashion
do not recover.  Those that do are often profoundly compromised neurologically
running the spectum from near vegatative to severely "retarded" and child-like
often with serious motor and language deficits as well.

However, a SMALLER subset of these patients recover surprisingly well, in fact
the only way to determine their history of head injury is by giving them fairly
sophisticated neurological tests (here I speak of cognitive tests, not invasive
ones). Of the cohort that recover well a small but significant number have a

complete or nearly complete loss of declarative memory which does NOT resolve or
improve with time.  There is sometimes also frontal lobe disinhibition (I used
Roseanne Barr as an example of  frontal lobe injury related disinhibition) and
alterations in *character* and *personality*, but these are not universal. Such
people usually do not lose their skills (procedural) memories.  This suggests
that there are different mechanisms for the two kinds of memory.  A tired
example I trot out regularly is the one of piano playing.  The essentials of
playing the piano or driving a car can be easily inputed into declarative

memory.  However, mastery of these skills does not come with "book" knowledge or
"verbal knowledge" but rather with many repetitions and much time and effort.

Additional evidence, albeit indirect, of this seperation of mechanisms of
encoding declarative and procedural memories is most dramatically demonstrated
in Alzheimer's (ALZ) disease.  In the early to mid-phases of the disease the
victims can still drive.  A careful analysis was just completed on the rate of
accidents in ALZ patients versus pair matched (by age, sex , education etc.)
normals.  The accident rate was the same for the ALZ group as for the normal
controls.  Driving is like walking or riding a bicycle.  However, while the
accident rate was the same (indicating conservation of skills memory) the ALZ
group got lost and ended up coming into police or social agency custody at many
times the rate of the normals. 

Similarly, both Dr. Steve Harris (Steve is Gerontologist) and I have had the
experience of having a totally uncommunicative and demented ALZ  patients sat
down at the piano and their hands placed on the keys; they can often play
beautifully, usually only one or two pieces, but sometimes a wide range.  Here
too we see obliteration of declarative memory and relative conservation of
skills  memory (note they must of course have FIRST known how to play the
piano!).  A look at the frontal and temporal cortex of these patients (who have
entered the final phase of the disease) at autopsy shows massive cell loss,
plaque formation and neurofibrillary tangles.  There is, apparently, no
structure meaningfully preserved in advanced cases of this disease in these
areas.

There are of course, apologists for this phenomenon of selective loss of

declarative memory who posit that the memories are not really destroyed, but are
inaccessible.  This certainly may be true, but we have no compelling evidence
that this is the case.

If we look at various proposed mechanisms for storage of declarative memory and
procedural memory we are looking not only at synapse formation or elimination,

but at structural and biochemical changes within synapses and within brain cells
themselves (i.e., cell bodies).  I doubt seriously if these are very robust in
the face of autolytic degradation (self digestion) and in the face of highly
destructive free radicals which are unleashed in the shock and global ischemic
period.


Brian Wowk has, mistakenly I believe, minimized the significance of this kind of
injury in "optimum" cases and has pointed out that a substantial number (maybe
1/3rd) of cryopreserved people were treated under "optimum conditions."  I take
issue with this.  A large fraction of the "optimum" cases are far from optimum
and they are exposed to many hours of shock, trickle flow and finally ischemia
and reperfusion injury.  The immune-inflammatory cascade and the accompanying
activation of structure degrading processes is well underway in most optimum
cases before legal death is ever pronounced.  Far from being better than the
guniea pig model, these cases may be worse because they are exposed to injury
exacerbating conditions and active autolysis many hours before legal death,
cooling and blood washout occur.  We know from our continued deep hypothermic
blooodless perfusion work on dogs that this cascade, once activated is not
STOPPED by cooling, although its speed and severity are reduced.

I have spent 15 years of my cryonics career trying to quantify and understand
qualitatively what is happening in ischemia (of which shock is one species).  I

am not reassured by what I have found in cases of prolonged insult, folllowed by
flush-ice store-followed by CPA perfusion.  I also spent that time trying to

block ischemic injury and I believe I and others working with me have made great
progress.

Nevertheless, the fact remains that the majority of cryonics cases will not be
done under conditions where prolonged ischemic insult ante- or post- mortem has

not occurred.  It is questionable whether such patients will be recoverable with
their declarative memory intact.

The take home message here is quite simple, but one which I doubt will be
carried off by many: garbage in = garbarge out.  Ten minutes of ischemia is not
trivial. Ten hours is a disaster.


I for one am through running around with rosy scenarios.  We need solid data and

we need to mitigate this injury.  That is exactly what we are doing here and the
end point must be reversible brain cryopreservation.  Otherwise, as a growing

statistical base has demonstrated, 1/3rd (minimum) of patients are just going to
get hashed up in various imaginative ways: by not being found for hours after
cardiac arrest, by being autopsied, by long delays, etc.  And, many of our
so-called BEST cases will be far from it in reality.

The agony of worry and uncertainty, the lack of social and medicolegal change
will destroy or gravely injure many cryonicists and, perhaps as importantly or

more so, will make cryonics an "unbelieveable" option for most.  This represents

a staggering death toll.  It can only be avoided or mitigated by clear, rigorous
procedures which result in feedback.  Reversible brain cryopreservation is
certainly one milestone along the way.  Perhaps the most importat one.

Mike Darwin


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