44

TINS - February 1981

probably at reduced levels of sensitivity,

until the child is 4 or 5 years of age. Such a
time course for the critical-period of
h u m a n visual system development is, of
course, similar to that suggested by the
behavioral studies described earlier ~,z~5.
The anatomical results described above
indicate that there are several structural
changes that take place during normal and
visually deprived development and that
these changes are similar in both the cat
and monkey. In addition, anatomical
studies in the h u m a n suggest that at least
some of these structural changes also occur
during the development of our visual system. In fact, one of the tenets underlying
these studies has been, and continues to be,
that anatomical studies of the h u m a n visual
system can pave the way for more direct
comparisons with experimental findings
derived from studies using n o n h u m a n animals. In most mammalian species comparisons between the results of anatomical and
electrophysiological experiments are possible and, where similarities between the
h u m a n and n o n h u m a n visual systems are
particularly striking, some of these comparisons can be extended to the human. In
this way one can analyse the structural
organization and development of the
human visual system itself and then make
some reasonable deductions about the
extent to which our visual system may
share the organizational, functional and
developmental features defined for other
species. For the topic considered here,
anatomical studies of the developing
h u m a n visual system are vital because they

(1) provide evidence as to when the

critical-period of development begins and
ends, (2) provide some descriptions of the
changes taking place during this period and
(3) provide new insights into the neurological mechanisms that underly the enhanced
plasticity that exists in the visual system
during this period. After all, while it is this
plasticity that makes the visual system particularly vulnerable to changes in its environment, this same plasticity may provide a
means by which our visual capabilities can
be improved and, certainly, can be used to
advantage by the clinician. Just as visual
deprivation exerts its most profound
effects when introduced early in the
critical-period, so too will clinical treatments be more effective when begun at this
time.

Acknowledgements
The author's laboratory is supported by
research grants EY01338 and EY02159 from
the National Eye Institute, National Institutes
of Health. The laboratory is a part of a Vision
Science Research Center which is supported in
part by a CORE Vision Research Center Grant
(EY03039), also from the National Eye Institute. National Institutes of Health.

Reading List
I Av, aya, S., Miyake, Y., lmaizumi, Y., Shiose, Y..

Kanda, T. and Komuro, K. (1973)Jpn. J. Ophthalmol. 17, 69-82

2 Banks, M. S., Aslin, R. N. and Letson, R D.
( 2975) Science 190, 675~o77
3 Boothe, R. G, Greenough, W. T., Land, J. S, and
Wrege. K. (1979)J. Comp. Neurol. 186,473-490
4 Cragg, B. G. (1975)J. Comp. Neurol. 260.
247-166

Sherrington's concept of
proprioception
Edward V. Evarts
Proprioceptors respond naturally to active movement, but experimentally these movements
must be produced by external means. Edward Evarts explains how this methodological
limitation has affected our interpretation o f proprioceptor function.
Sherrington 14 defined proprioceptors as
deep receptors for stimuli that 'are traceable to actions o f the organism itself,
a n d . . , s i n c e . . , the stimuli to the receptors are delivered by the organism itself, the
deep receptors may be termed proprioceptors, and the deep field a field of proprioception', The latin wordproprius, meaning own, provided a prefix which called
attention to the fact that the organism's
own acts created the adequate stimuli for
these deep receptors. Having defined
t". [=lse~ier/Norlh-HollandBiomedicalPress 10~.1

proprioception, Sherrington went on to

point out a property of proprioceptive
reflexes which is sometimes forgotten: the
amount of muscle activity mobilized by
proprioceptive inputs is relatively slight.
Careful attention to Sherrington's statements that (1) adequate stimuli for proprioceptors arise from the actions of the
organism itself and that (2) proprioceptive
effects on muscle discharge are 'mild', will
be most useful as we seek to interpret data
on reflex responses to muscle and joint

5 Crawford, M. L, J. (1978) Arch. OphthalmoL

Otolaryngol. 85,465-477
6 Davison. A. N. and Dobbing, 3. ( I t.~68) Applied
Neurochemistrv,
Contemporary
Neurology
Series: 4 and 5. Davis, Philadelphia, pp. 253-316
7 Deller, M. (1979) Trends NeuroSci. 2,226-218
8 Dobson. V. and Teller. D. Y. (2978) Vision Res.
28, 1469-1483
9 Fox, R.. Aslin, R. N., Shea, S. t.. and Dumais. S. 2'.
(1980) Science 207,323
20 Garey, L. J. ( 2979) Trends NeuroSci. 2, 213-226
12 VitaI-Durand, F., Garey, L. J. and Blakemore, C.
(1978) Brain Re~. 158, 45-64; Gonlieb, M.,
Pasik, T. and Pasik. P. (1980) Soc. Neurosci.
Abstr. 6. 662
12 Hiekey, T. L I 1977) Science 298, 836-838
13 Hiekey, T. L. (1980) J. Comp. Neurol. 189,
467-48l
24 Hitchcock, P. F. and Hickey, T. L. (2981)) Brain
Res. 182, 276-279
25 Hohmann. A. and Creutzfeldt. O. 1). (2975)
Nature (London) 254, 613~o 14
26 Hubel, D. H. and Wiesel. T. (297(I) J. Physiol.
(London) 206, 419-436
17 Hubel, D. H. and Wiesel, T, N. (1972)J. Comp.
Neurol. 146, 422-450
18 Hubel, D. H., Wiesel, T. N. and LeVay, S. (1977)
Phil. Tran,~. R. Soc. London 278, 377-409
19 2keda, H. (1979) Trends NeuroSei. 2,209-213
20 KaliL R. (1978)J. Comp. Neurol. 182,265-292
21 LeVay, S., Hubel, D. H. and Wiesel. Y. N. (1975)
J. Comp. Neurol. 159, 55%576
22 LeVay, S., Wiesel, T, N. and Hubel, D, H. (198(I)
J. Comp. Neurol. 191, 1-51
23 2.and, R. D. (1978) Development and Plasticity of
the Brain, Oxford University Press, New York
24 Rakic, P. (2977) Philos. Tran,~. R Soc. London
278, 245-260
25 Sherman, S. M. (1979) Trends NeuroSei, 2,
192-295
26 Teller, D. Y. ( 2982 ) Trends- NeuroSci. 4, 22-24

Dr Terry L. Hickey B at the School o f Optometry/The

Medical Center, University of Alabama in Birmingham, Birmingham, Alabama 35294, U.S.A,

afferent inputs. First, such careful attention

will prevent us from forgetting that passive
m o v e m e n t s (i.e. those resulting from
events arising within the environment) do
not affect proprioceptors in the same way
as active movements by the organism itself.
Unfortunately, the essential role of the
organism's own active movements in
generating adequate stimuli for proprioceptors puts neurophysiologists in a
quandry: systematic laboratory investigation of proprioceptive systems requires the
use of externally produced changes of
muscle length or tension, but these same
externally produced changes (though they
have marked effects on impulse frequencies of proprioceptive afferent fibers) do
not provide proprioceptors with adequate
stimuli. Perhaps the solution to this quandry lies in interpreting the consequences of
external stimulation of proprioceptors with
the same caution that we exercise in interpreting the consequences of electrical
stimulation of the nervous system. Cer-

TINS -February 1981

45

tainly, most of what we know about prop- reflexes are not natural does not mean that be tonic and larger gastrocnemius
rioceptive systems has been gained by they are unworthy of study - far from it. motoneurons to be phasic, and the importobserving the reflex consequences of But laboratory reflexes should be viewed ance of cell size in relation to tonic and
externally produced changes of muscle as tools for investigating the neuronal phasic properties has also been shown by
phasic
length and tension, and the use of these pathways whose existence they reveal Henneman et al 1'11. The
inadequate stimuli does not really lead us rather than as phenomena demanding a motoneurons which innervate fast-fatigue
muscles are at the upper end of the
astray until we place excessive reliance on teleological explanation.
recruitment order and are relatively inacthese consequences in seeking to arrive at
cessible to excitation by segmental inputs.
formulations as to the functional signifi- When are proprioceptive reflexes
important?
cance of proprioceptive reflexes.
Within the past few decades there have Errors: internal v. external
Reflex categories
All the above-mentioned findings point
been a number of investigations aimed at
Indeed, the importance of distinguishing assessing the extent to which propriocep- to the effectiveness of proprioceptive
between reflexes elicited by natural and tive reflex systems mediate adaptive motor ,inputs in modulating tonic motoneuron
contrived stimuli is such that one might responses to large external disturbances. discharge and to the ineffectiveness of
speak facetiously of two sorts of reflexes: Unfortunately, interpretations of the these same proprioceptive inputs in activatnatural reflexes and laboratory reflexes. results of these studies have sometimes ing the phasic motoneurons innervating
The natural reflexes are the familiar ones - failed to give sufficient attention to the pair fast fatigue muscle which, in its brief
those whose functional significance is clear of facts that Sherrington ~4 recognized so periods of activity, generates the abrupt
even to the person in the street, while the clearly: (1) muscular responses resulting increases in tension necessary to react to
laboratory reflexes are the unfamiliar ones from proprioceptive inputs are mild; (2) large errors generated by external disturwhose functional significance may be intense responses to afferent inputs arising bances. Numerous recent studies in man t5
unclear even to the laboratory worker who within the environment are mediated and subhuman primates tz show that comelicits them. Examples of natural reflexes primarily by exteroceptive inputs. Given pensation for large load disturbances is not
are the cough reflex, the corneal reflex, the these two facts, one should not be surprised achieved by segmental reflex mechanisms
pupillary light reflex, the vestibulo-ocular when it is demonstrated that propriocep- operating in the closed-loop mode. But
reflex (VOR) etc. The person in the street tive reflexes are ineffective in achieving while not suited to deal with large load dismight object to calling the V O R a natural load compensation in the face of large turbances, segmental reflex mechanisms
reflex, arguing that he or she hasn't the external disturbances (remember Sher- are suited to deal with smaller disturbances
slightest idea what the V O R is. True, but rington's point that proprioceptive inputs due to internal factors within the
one could explain to such a person that have mild effects and that exteroceptors neuromuscular system itself. When small
length changes occur during tonic muscle
VORs occur whenever he or she moves rather than proprioceptors underlie
about and that VORs provide for stability responses to external disturbances!). discharge as a subject seeks to maintain
of vision by generating eye movements Indeed, closed-loop feedback systems postural stability, these small length
changes will modulate the discharge frewhich exactly counterbalance head move- come into play primarily when errors are
ments. A laboratory reflex which may be small. Under conditions in which errors are quencies of tonically active motoneurons,
contrasted with the VOR is caloric nystag- large, open loop systems come into play but such modulation will be insufficient to
mus resulting from irrigation of the exter- and generate large movements which will achieve compensation for large external
nal auditory canal with warm or cold water. reduce error to a value such that closed- load changes, since high threshold
Caloric nystagmus is mediated by the same loop systems can function effectively. motoneurons with phasic properties must
pathways that mediate the VOR but is Thus, for both segmental and the transcor- be brought into play to re-establish a new
itself of no functional significance (of what tical reflexes, a priori considerations would steady state and proprioceptive inputs are
possible use is it to have nystagmus when lead one to believe that the systems should unable to excite these high threshold
someone puts cold or warm water in one's be effective for small errors and ineffective motoneurons. For this intense excitation
ear?). Of course, an individual who lacks a for large errors. According to this notion, the motoneurons must await signals genercaloric reflex will also lack a V O R and will small errors would be able to elicit effective ated by 'reprogramming' at spinal and/or
be impaired accordingly. But this does not proprioceptive reflex responses by control- supraspinal levels. But while inadequate to
mean that one should seek toattribute funcling that proportion of the motoneuronal
deal with large external disturbances, the
tional significance to the caloric reflex pool (or the cortico-motoneuronal pool) increase (with lengthening) and decrease
per se.
which is tonically active. The special capac- (with shortening) in tonic motoneuron disThis absurd discussion of laboratory and ity of segmental inputs to control discharge charge produced by proprioceptive reflex
natural reflexes has been engaged in of tonic motoneurons and the differences inputs points to the capacity of these inputs
because there are certain reflexes which in the properties of tonic as compared to
to modulate discharge either up or down.
are actually laboratory reflexes but whose phasic
motoneurons
have
been
And though compensation for large exterfunctional significance is sometimes discus- documented in a number of studies since nal disturbances cannot be achieved by this
sed as if they were natural reflexes. My own Granit et al. 8 found that axons of tonic feedback, modulation of tonic motoneuron
work on cerebral motor cortex outputs motoneurons - as revealed by post-tetanic discharge in relation to small internal disoccurring in response to externally pro- potentiations - were emitting smaller turbances can be carried out by these reflex
duced limb displacements must surely be spikes than phasic ones. An additional
mechanisms. Small internal disturbances
classified as dealing with laboratory study 9 showed that in both gastrocnemius (arising in muscle and/or nervous system)
reflexes, and the same may be said for a and soleus muscles, spike size from indi- create errors of movement even in the
variety of spinal cord reflexes (e.g. the ten- vidual fibers differentiated between tonic absence of any external load changes, and
don jerks and Babinski reflexes elicited by and phasic motor units. Burke s,4 found that
the high dynamic sensitivity of muscle
the neurologist). The fact that these smaller soleus motoneurons were likely to
stretch receptors~ for small length changes

46

"FINS - February 1 981

allows the segmental reflex apparatus to be

effective in compensating for such small
disturbances. This relatively greater effectiveness of the stretch reflex in dealing with
small disturbances has been dealt with at
length by Matthews TM. The role of reflex
mechanisms in relation to internal properties of muscle has also been proposed by
Nichols and Houk TM in a report showing
that autogenic reflexes can compensate for
the marked hysteresis effects which would
otherwise cause great differences in muscle
tension responses during lengthening and
shortening. In considering their results,
Nichols and Houk stated that 'Our data do
not allow us to distinguish which function
is more
important. The
evidence
r e v i e w e d . . , favors a higher gain of force
feedback in normal animals. If this is true,
compensation for variations in muscle
properties would be greater, whereas compensation for variations in load would be
less."
The notion that signals from muscle
spindle afferents are important in minimizing the consequences of small internal disturbances would imply that postural
instabilities should increase when inputs
from spindle afferents are eliminated, and
demonstration of such an effect has been
provided by the work of Goodwin et al. e on
control of voluntary jaw movements in the
monkey. The authors note that the jawclosing musculature affords a unique
opportunity to disrupt the afferent limb of
the stretch reflex with minimal damage to
the rest of the sensory innervation of the
region. In these studies it was found that
surgical interruption of the reflex arc led to
a considerable increase in the amplitude of
spontaneous tremor during steady contraction, suggesting an important role for muscle spindle afferents in 'reducing errors of
muscle length produced by fluctuating
levels of motor d i s c h a r g e . . . ' The work of
Goodwin et al. also demonstrated that the
stretch reflex made a marked contribution
to muscle stiffness in response to external
disturbances involving 500 micrometer
(peak-to-peak 1 mm) stretches of steadily
contacting muscle. In this experiment, a
1 mm jaw movement corresponded to
approximately 1 of rotation at the temporomandibular joint, and was thus a relatively small movement in relation to the full
range of jaw movement available to the
monkey, whose jaw was held at a 6 opening during the voluntary force exertion of
this experiment. Interruption of the afferent limb of the stretch reflex arc reduced
resistance to stretch to less than one-half of
that present in the intact animal.
Finally, recordings of spindle afferent
discharge in man TM give dramatic demonI I,cxieriNorlhHidlandBiomedicalPres~ 19Sl

stration of the high dynamic sensitivity of

the reflex system in relation to small
internally-generated
irregularities
of
movement in such a way as to maintain
smooth shortening during isotonic muscular contractions. Vallbo reasoned that this
same exquisitely sensitive reflex system
would be relatively ineffective in compensating for large external load disturbances.
It would thus seem that several lines of evidence converge in support of Sherrington's ~4 original notion that proprioceptive
reflexes operate in relation to events arising from within the muscles of the organism
itself.

Reading list
1 Bizzi,E., Dev,P., Morasso,P. and Polit, A. (1978)
J. Neurophysiol. 41,542-556
2 Bizzi. E.. Polit, A. and Morasso, P. (1976)J.
Neurophysiol. 39, 435-444
3 Burke, R. E. (1968)J. Physiol. London 196,
605-630
4 Burke, R. E. (1968)J. Physiol. London 196,
631-654
5 Burke, R.E.(1973)inNewDevelopmentsinElectromyography and Clinical Neurophysiology,
(Desmedt, J. E.. ed.) vol. 3. pp. 69-94, Karger,
Basel

6 Goodwin,G. M., Hoffman,D. and l.uschci, E. S.

(1978)J. Physiol. London 279. 81-I 11
7 Granit, R. and Henatsch, H. D (1956) J.
Neurophysiol. 19. 356-366
8 Granit, R., Henatsch, H.-D. and Steg, G. (1956)
Acta Phy.siol, Seand. 37, 114-126
9 Granit. R., Pascoe, J. E. and Steg. (k (1957) J.
Physiol. London 138, 381-400
10 Henneman,E., Somjen,G. and Carpenter, D. O.
(1965) J. Neurophysiol. 28, 560-580
1I Henneman,E., Somjen,G. and Carpenter, D. O.
(1965) J. Neurophysiol. 28, 599-620
12 Matthews, P. B. C. (1972) Mammalian Muwle
Receptor~ and "[heir Central Actions, Arnold,
I.ondon
13 Nichols.T. R. and Houk,J.C.(1973)Seience 181,
182-184
14 Sherrington,C, S. (1906) Brain 29, 467-482
15 Vallbo, A. B. (1973)in Control of Posture and
Locomotion, Advances in Behavioral Biology,
(Stein. R. B., Pearson, K. G., Smith, R, S. and
Redford, J. B.. eds). vol. 7, pp. 211-226. Plenum,
London
16 Vallbo. A. B. (1973) in New Developments in
Electromyography and Clinical Neurophysiology,
(Desmedt, J. E, ed.) vol. 3. pp. 251-262, Karger,
Basel

Edward V. Evart~ is Chief of the Laboratory of

Neurophysiology, National Institute of Mental Health,
Bethesda. .Maryland20205, U.S.A.

Detection and m sum nt

of intraceitular calcium
A comparison of techniques
J. Stinnakre
Calcium detection and measurement in living cells can be achieved using a variety o f techniques. Three o f these are based on the optical detection o f changes in luminescence, fluorescence or absorbance of a n organic indicator produced on binding with calcium ions. However, when the preparation is completely opaque, the only available technique is the
calcium-selective m&ropipette which provides a direct electrical signal related to the calcium
ion concentration at its tip ~,9,17.~8 (see also articles by Nicholson and by Tsien, TINS, September, 1980). In this review Jacques Stinnakre compares and contrasts the usefulness o f
these methods.
fluorescence, due to an exciting light, is
enhanced and decreased by the presence of
calcium and magnesium ions respectively*.
Since the selected indicator, or the tip of
a calcium-selective microlectrode, must be
inserted within the cell, application of these
methods is restricted to those cells which
can be impaled with at least one microelectrode and which can withstand injection of
the indicator. One exception is chlorotetracycline which will cross the membrane and
thus can be applied externally.
In this paper, I shall compare these techniques and explain some of their advantages and disadvantages, ending with a
*The fluorescent lanthanides (europium, terbium) brief description of some of the important
will not be reviewedhere for they are calciumbinding problems which may be solved by using
them. Further description of the techsite probesrather than free calciumindicators.

The indicators used in the optical techniques fall into three main categories. These
are the calcium sensitive luminescent proteins (photoproteins) which emit light
upon binding to calcium. (The two used
most commonly are aequorin and obelin =,
named after the jellyfish Aequorea and
Obelia, from which they are isolated); calcium sensitive dyes such as murexide, tetramethylmurexide TM, arsenazo IIP, antipyrylazo III=1and chlorophosphonazo liP,
which show large changes in their absorption spectra due to Ca =+ binding; and the
fluorescent
Ca=+-chelators
such
as
chlorotetracycline 6 or calcein 8 in which