Table Of ContentSTIMULUS AND RESPONSE
THE LAW OF INITIAL VALUE
BY
JOSEPH WILDER, M.D.
Clinical Professor of Neurology, Netv York Medical College
BRISTOL: JOHN WRIGHT & SONS LTD.
1967
© JOHN WRIGHT & SONS LTD., 1967
Distribution by Sole Agents:
United States of America: The Williams and Wilkins Company, Baltimore
Canada: The Macmillan Company of Canada Ltd., Toronto
PRINTED IN GREAT BRITAIN BY JOHN WRIGHT * SONS LTD. AT THE STONEBRIDGE PRESS, BRISTOL
PREFACE
THERE are many among us who do not realize that biological sciences, and
particularly medicine, are largely operating under the tacit assumption that
equal stimuli produce equal responses. Even those who pay either real or
only lip service to differences in responsiveness among individuals do not
fully acknowledge the frequency and extent of such differences in one and
the same individual, even under equal experimental conditions.
The present book purports to show that not only do such differences exist
on a large scale, but formulates at least one practically and theoretically most
important rule which must always be taken into consideration if we want
the results of our experiments on living organisms to be valid and our
treatment of diseases improved.
However, at present any proponent of any general rule in science seems
to need a kind of old-fashioned apologia per autorem. Scientists all over the
world have reached a tacit agreement not to draw any conclusions beyond
the precise field of their experimentation. If, for example, my work deals
with the white blood-cells of the rat I might have accidentally discovered a
most important secret of living matter, yet I would have no right to draw
conclusions going beyond the rat and beyond the white blood-cells.
This situation arose partly from the fact that premature generalizations
have often led in the past to much waste and delay in research. It is also
due to the unavoidable insight that a modern specialist cannot possibly
master all the other disciplines of science to a degree which would entitle
him to make valid statements about these areas. It is said that Erasmus of
Rotterdam (1469-1536) was the last polyhistor who could still encompass
the entire universe of knowledge in his time. How long ago the last universal
medical or biological scholar vanished and what his name was nobody
knows.
Thoughtful research workers are straining under this strict self-discipline.
They realize in their later and wiser years that mere accumulation of data is
not science. The noted English physiologist, Burn,^**^ complains that today
*it is dangerous to announce a theory'. The Russian physiologist, Bykov,^®'^
wrote: * Physiological data, the building blocks of our science, in and of
themselves, do not necessarily or automatically make for progress in our
knowledge of biological function. They receive rightful recognition as
contributions to physiology only if and when their connexion with other
biological events and their importance in the total economy of the organism
are properly assessed.'
However, this does not change the sad fact of the relative incompetence
of the specialist (the author is a neurologist and psychiatrist) who with the
vi PREFACE
progressive splitting up of specialties into sub- and sub-sub-specialties
knows more and more about less and less. Perhaps this book may serve as
a test to what extent it is still possible to work out general principles.
As specialists we are all tempted at times to show the * intruder* how many
things he has omitted, how much of his knowledge is outdated, etc. Such
(correct) criticisms are to be expected and we must be willing to bear them.
What we wish is that, in exercising his right to point out mistakes and omis
sions, the critic should not lose sight of the main issue.
There are two shortcomings of this book of which we are more proud
than ashamed. One is that it raises more questions than it can answer, and
that it contains quite a number of suggestions for future research and quite
a few hypotheses (always recognizable as such). For some of them Oscar
Wilde's words may apply that they are questions which arrive *a terribly
long time after the answer'.
The other shortcoming that pleases us rather than annoys us is that the
Law of Initial Value has quite a number of restrictions and exceptions.
Were it not so we would be hardly dealing with a biological law, perhaps not
even with reality but with some mathematical artefacts. And we know—to
quote Einstein—that mathematics, as far as it is certain, does not deal with
reality, and as far as it deals with reality it is not certain.
This book has been written in response to a wish, expressed by many
research workers, to have a more comprehensive presentation and discussion
of the Law of Initial Value and a source of references to the widely scattered
publications on the subject. It wishes to address itself to a broader scienti
fically oriented readership and at the same time to supply the specialist with
a subject index which would help him to find those references in which he
may be particularly interested.
The ultimate goal of the author, even at this stage of learning rather than
teaching about the Law of Initial Value, is to make that law an integral part
of biological, and particularly medical, thinking to a much greater extent
than has been the case in the past.
J. W.
iigg Park AvenuCy
New York, N.Y. 10028.
October, igoy.
THE LAW OF INITIAL VALUE (L.I.V.)
Given a standard stimulus and a standard period of time, the extent and
direction of response of a physiological function at rest depends to a large
measure on its initial (pre-experimental) level. The relations are as follows:
the higher the initial value, the smaller the response to function-raising, the
larger the response to function-depressing stimuli. Beyond a certain medium
range of initial values there is a tendency to paradoxic (reversed) responses,
increasing with the extremeness of initial values.
BASIMETRY
Basimetry (measuring of the baseline) is the study and application of the
Law of Initial Value.
vni
STIMULUS AND RESPONSE:
THE LAW OF INITIAL VALUE
CHAPTER I
THE LAW OF INITIAL VALUE
A. HISTORY OF THE LAW OF INITIAL VALUE
THE history of the Law of Initial Value (L.I.V.) begins with depressing
experiences familiar to every student of medicine: after he has learned his
lesson from his beautiful and clear textbooks, he goes out to practise it, only
to find that a great number, sometimes a majority, of his patients do not
respond to his drugs and operative procedures the way his books describe.
The variations may be major or minor, but they are there and they rob the
young doctor of his most important weapon in his fight with sickness: the
ability to predict the patient's reactions.
For one young doctor around 1920, it was not easy to accept such defeat
of science. Eppinger and Hess's ^^'^^ theory of 'vagotonia' seemed to bring
relief. Now it was clear: some patients are 'vagotonics', some 'sympathico
tonics', and correspondingly their responses to certain drugs, like adrenaline,
pilocarpine, and atropine, will differ. This hopeful enthusiasm was shared
by many. Unfortunately, it did not last long. One article after the other
appeared showing that the individual regularity of responses postulated by
Eppinger and Hess was a fiction.
Our young doctor—the present writer, of course—was now worse off than
before. How is it possible, he asked, that people so distinctly different from
each other in their autonomic functions should not show consistently distinct
differences in their responses ? And how can so many admired scientists,
using the same experimental method, come to such different conclusions ?
Something must have been overlooked here. Perhaps the experimental
conditions were not identical enough.
In the years 1921-30, the author, at that time assistant to the Viennese
neurologist, Professor Emil Redlich, used a great number of his hospital
patients, mostly neurotics and neurasthenics, for experiments with repeated
injections of atropine, adrenaline, and pilocarpine. It was in the nature of
2 STIMULUS AND RESPONSE: THE LAW OF INITIAL VALUE
the experimental conditions that many tests had to be interrupted, aban
doned, or otherwise discarded. Finally, a number of cases remained in
which the similarity of basic conditions seemed acceptable. They are pre
sented in the next chapter.
What followed is fairly typical in the history of science: the conclusion of
this work in the form of the Law of Initial Value (L.LV.) met with enthusiasm
and confirmation by many and opposition by others. It was clear that it
included generalizations reaching far beyond the original experiments. There
was nothing left for the author than to sit back and wait what investigators
competent in other specialities would have to say if they considered the
author's thesis worthy of their attention. This was fortunately the case. The
Russian physiologist, Leites, was one of the first to test the L.LV. on a
larger scale. His articles on the subject appeared in Russian, German, and
French, and, in 1936, also in English in the Lancet. During World War II,
German authors, especially the physiologist Wezler, continued to test and
apply the law. After the war, many German scientists, foremost being Zipf,
Selbach, Drischel, Holtz, pharmacologists, physiologists, neuropsychiatrists,
internists, neurosurgeons, etc., published confirmatory articles. In the
United States, Linn J. Boyd, in his book The Simile in Medicine,^"^^^ in 1936,
reported first on the L.LV. However, only since Lacey's monograph. The
Evaluation of Autonomic Responses^^^^^ in 1956, did a strong interest in this
law develop, particularly among psychophysiologists. The American Psycho
somatic Society showed also great activity in this direction, and there have
been in the past few years few issues of Psychosomatic Medicine not containing
references to the L.I.V.
This literature—almost entirely confirmatory—proved to be so scattered
among many disciplines and languages that collecting it seemed a hopeless
task. These articles rarely bear the L.LV. in their title and they refer to an
endless variety of subjects.
For forty years, the author, while continuing some experimentation,
combed regularly not only neurological but also general medical and science
journals and books for articles containing data on initial values (I.V.s). Such
articles were few and widely scattered. Even in Germany, where the L.I.V.
found greatest acceptance and is required from medical students at their
examinations (as in Austria and Switzerland), we found in a random selec
tion of Naunyn-Schmiedeberg's Archiv among 131 relevant articles only 23
per cent which reported their I.V.s and only 4-5 per cent taking the I.V.s
into account. In an American journal of pharmacology (100 articles) and
physiology (100 articles), the corresponding figures were even worse: 15-8
per cent and ι·8 per cent respectively. On the other hand, as our AUTHOR
INDEX {pp. 347-53) shows, we could collect over 1000 articles containing such
data, including over 400 referring directly to our law.
Yet, the L.I.V. was just a beginning (Wilder^''^^^). It called not only for
further corroborations but for improvements of its methodology, theoretical
understanding, study of exceptions to that law, etc. For these endeavours
we coined the name, *basimetry'.
THE LAW OF INITIAL VALUE 3
To co-ordinate these efforts, at least partly, the International Basimetric
Society was founded in New York in 1956. It has members from many
disciplines: medicine, biochemistry, biostatistics, psychology, etc. It has
issued a semi-annual bulletin, Basimetry, since 1957. This contains reports,
original articles, and abstracts of the literature on the L.I.V. Other kinds of
attempts at co-ordination and exchange are national and international meetings.
Some devoted special sessions to various lectures on the L.I.V. (Society for
Biological Rhythms, Siena, i960; Symposium on Rhythmic Functions in
Living Systems, New York Academy of Medicine, 1961). Needless to say, the
subject is often discussed at local meetings as well as at national and inter
national congresses, not only in the field of psychiatry and neurology, but,
for example, in Air Pollution Research (Los Angeles, 1966) and others. In
some it was chosen as one of the principal topics (Society for Biological
Rhythms, Semmering, Austria, 1957; Association for Advancement of
Psychotherapy, Toronto, 1962, etc.). We know of many scientific projects
going on at present in the United States and abroad.
On the other hand, one would search in vain for any mention of the L.I.V.
in the medical textbooks in the United States with the exception of psychiatry
(Wilder^*^'^) and experimental pharmacology (Irwin^^^aij
Today, in spite of hundreds of confirmatory articles, we still view the
L.I.V. as being in its infancy, but the infant seems to grow vigorously at an
ever-increasing pace. We feel strongly that it is destined to play a major role
in medical and biological research and practice.
B. THE FIRST PUBLICATIONS ON THE L.I.V.
THE THEORY OF VAGOTONIA (EPPINGER AND HESS)
The wish has been expressed from several sides that at least one of my
original papers on the subject should be translated and reprinted. However,
this would require too much space and an extended abstract will suflSice.
The first publication on the subject was a paper read at the Congress of
the Society of German Neurologists in Dresden, printed in 1930. There I
merely reported about the results of my tests with injections of atropine,
adrenaline, and pilocarpine in man (Wilder^^^'^^). My own investigation of
the pharmacodynamic tests of Eppinger and Hess^^^^^ dealt mainly with the
question: Does an individually characteristic reaction to the above drugs
exist at all ? My new approach took the form of serial tests repeated on one
and the same individual, I tried to operate with an optimal identity of external
test conditions. Pulse and systolic blood-pressure were chosen as the yard
stick of drug effect and were plotted for at least i hour. The area enclosed
between this curve and a horizontal line indicating the initial level of pulse
and blood-pressure (before the injection), which I call 'curve plane', was
measured. If the curve rose above this level it received a plus, if it dropped
below it, a minus sign. Where both plus and minus values appeared, they
were subtracted from each other, the result obtained in the end being either
a plus or minus or zero.
4 STIMULUS AND RESPONSE: THE LAW OF INITIAL VALUE
The group of individuals examined consisted of 25 per cent normal
individuals and 75 per cent patients, mainly so-called vegetative neuroses,
i.e., neuroses with predominantly somatic, autonomic symptomatology.
The latter cases, presenting a sort of caricature of normal responses,
are very good test material provided the external conditions are strictly
identical.
I then presented as the only positive result of my investigations my Law
of Initial Value (L.I.V.) (in German Ausgangswertgesetz). In its first formu
lation it sounded as follows:—
FIRST FORMULATION OF THE L.I.V.
* The factor which in the first place determines intensity, direction, and form
of a puke or blood-pressure curve is the level of pulse or blood-pressure prior to
the injection. The higher this initial value, the more pronounced is the tendency
to a drop, the smaller, the tendency to a rise of the curve. Thus, with high
I.V.s, there is a particular tendency to paradoxic or "vagotonic** reactions,
with low ones to "sympathicotonic** reactions.*
I emphasized that the initial value (LV.) is certainly not the only factor
determining those curves and we are far from being able to say that a certain
type of curve is typical for a certain initial level of pulse and blood-pressure
in an individual. However, the hope to construct some day such norms
seemed to be the only hope for the application of Eppinger and Hess*s
theories.
I showed with the help of graphs that this rule can explain a surprising
number of contradictory phenomena in the literature. We are not dealing
simply with the tendency to achieve always the same maximum or minimum,
regardless of the LV. On the contrary, a small lowering in I.V.s will often
cause an overshooting of the previous maximum.
The logical conclusion was that all experimental results of pharmacologic
tests undertaken without consideration of these facts are imprecise, to say
the least. Two curves are to be considered as different only if this difference
does not follow from the L.I.V. alone. A marked rise in blood-pressure
following, e.g., an adrenaline injection is to be considered as strong reaction
only if the I.V. is not very low.
Thus, a * sympathicotonic' individual, whose sympathetic system is over
excited anyway at the moment of experiment (high blood-pressure), will
easily respond to adrenaline with a flat or even paradoxic (*vagotonic*)
blood-pressure curve.
If we disregard the I.V., we would come to the same faulty conclusion as
Kylin^^''*^ did: that the hypertensive is * vagotonic*.
I emphasized that the application of this law is not limited to pulse and
blood-pressure but extends to the entire autonomic system. There, too, it
explains many a paradox.
I tried to demonstrate by examples the heuristic value of the new law.
Thus the problem of large and small doses with their paradoxic eflFects can
be seen in a new light (an obvious reference to the Arndt-Schultz Law).
THE LAW OF INITIAL VALUE 5
Occasionally one may inhibit or prevent a reaction to a large dose by pre-
injecting the patient with a small dose of the drug. This reminded me of
homeopathy.
Taking the I.V.s into consideration, one finds that the drugs so investi
gated have most probably an after-effect extending for many days. This
shows itself not only in the change of I.V.s, but also by deviations from the
L.I.V. in the successive experiments with the same drug.
I also found the phenomenon of cumulation of paradoxic effects in this way.
All this may explain easily various failures of therapy.
This little paper (Wilder"^''^^) contains already in a nutshell the essential
points of my theories. We shall therefore use parts of the following much
larger articles (Wilder["4-77e, 778, 782. 784]) mainly for the purpose of
elaboration and documentation. A great deal of material presented in these
papers is repetitious.
FULL REPORT ON MY EXPERIMENTS
The longest article (Wilder'^ "^'β^) appeared in 1931. The title is more
inclusive: *The "Law of Initial Value", an unnoticed biological law; its
importance for research and practice*. The paper consists of two parts: (i) a
somewhat more extensive report on my experiments; (2) the outline of what I
call *a biologic theory' based on these data. The latter claim I find today
too presumptuous. I wrote in the introduction: *I present that part to the
reader not without trepidation. The reason is not only that I dare entering
here into areas remote from my specialty, which appears somewhat bold
nowadays for a specialist to do; the main reason is not that this theory
requires a certain deviation from deeply rooted concepts and habits of
thinking; it is rather that just this theoretical part appears to me, in case-of
its confirmation, as incomparably more important than the concrete special
results. *
My own experiments resulted in the following statements:—
1. It is not true—as Eppinger and Hess claimed—that with the usual
experimental set-up there is an individually characteristic reaction to atropine,
adrenaline, and pilocarpine. The differences of reactions in one and the
same individual are not just quantitative but also qualitative, i.e., in the
type of curve.
2. It is not true that under conditions of rigid uniformity of experimental
set-up, individually typical reactions can be regularly obtained.
The method used by me was as follows: i mg. atropine sulphate, i mg.
adrenaline, or 10 mg. pilocarpine hydrochloride were given subcutaneously.
The following experimental conditions were rigidly maintained: patients
were male (to avoid menstrual periodic fluctuations); prior to the test they
remained in bed all night without medication and without food, and the
test was performed in bed; we found that the interval between tests had to
be at least 8 days in order to avoid after-effects of prior injections; the I.V.s
were established by repeated testing and cases with unusually unstable basal
levels were rejected. Cases with serious organic disease were also rejected.
