Principles of General Physiology

The use of alternating currents of sinusoidal form presents some advantages on account of the equality and regularity with which they can be made to stimulate. Currents with an approximately sine curve can be obtained by the rotation of a coil in a magnetic field, or vice versa, but to obtain mathematically correct curves requires very accurate apparatus. The alternating current supplied by central stations has nearly a sine curve and, when available, forms a convenient means of getting very regular, graduated, tetanising stimuli from an induction coil of the Du Bois Reymond type. It can be sent through the secondary coil and the electrodes connected to the primary, or vice versa. In the latter case, of course, a lamp resistance must intervene between the mains and the coil. The strength of the induced currents is varied by altering the distance between the coils.

The various patterns of electrodes used for applying electrical stimulation to nerves will be found in Garten's article (1908, pp. 331-340). Two additional useful patterns may be mentioned here. The first is that used by Sherrington (1909, p. 382), especially for deep-lying nerves, and consists of a glass T-tube, into which the cut nerve is drawn, the current being applied by two platinum wires, one on each side of the nerve, passing through the side branch (see Fig. 103). They are also very good for superficial nerves, since they prevent drying and can be kept warm by a current of saline over the outside. The electrodes of Keith Lucas (1913, 2, and Fig. 104) are useful when it is necessary to excite nerves immersed in a saline solution, such as sea water or Ringer's solution, without the current spreading to neighbouring parts. The principle on which these electrodes are constructed is that the sectional area of the solution around the nerve is made to change very suddenly at the point where stimulation is desired and the current is made to pass by this course. Electrodes on the same principle, for the exact localisation of stimuli on the excised nerve muscle preparation, are described by the same investigator (1908, p. 114) and their degree of accuracy determined.

Nerves can also be excited by chemical means, as by crystals of salt or by Fio. 103. SHERRINUTON'S ELECTRODES FOR STIMULATINO NERVES. — The' nerve is protected from drying, and the electrodes can be sewn up in the wound, or kept warm by a current of warmed saline run over them. glycerol ; the action is perhaps more strictly physical, since it seems to depend on the removal of water. Mechanical methods, such as pinching, tapping, shaking, or snipping with scissors, are also effective stimuli, but obviously not capable of graduation. They produce more or less injury, so that they are used chiefly as a means of control when it is desired to exclude the possibility of a particular result obtained from a nerve being due to escape of electrical current to neighbouring parts. A simple apparatus for exciting nerves by dropping mercury upon them from different heights is that due to Schiifer (1901), which 'is capable, to a certain degree, of graduation in strength and rate of stimulus, and does not injure the nerve to an appreciable extent.

There are reasons for regarding all artificial modes of excitation as more or less unlike the natural one coming from the cell body of which the nerve fibre is a prolongation. It is possible, however, to exaggerate this difference ; as we shall see later, the natural excitation is accompanied by waves of electrical disturbance, similar to those produqed by artificial stimulation, and the optimal rate of incidence of energy, Waller's "characteristic," is probably very close to the natural one.

Nerves can be excited, then, by many and various forms of stimuli and, supposing that the nerve is in connection with some indicator, such as a muscle, different strengths of stimulation are found to produce different degrees of contrac tion. most careful experiments (see especially those by Keith Lucas (1909)) have shown that the degrees of contraction of a muscle, that can be produced by varying the strength of the excitation of the nerve to it, are not .as numerous as the degrees of strength of the exciting stimulus, but take place in a series of steps, which are no more numerous than the number of motor nerve fibres supplying the muscle. This fact obviously indicates that the varying degrees of contraction are due to differences in the number of muscle fibres in the state of contraction at one time, and that each fibre can only be excited to its maximal capacity or not at all. The fact had previously been established by Bowditch (1871, p. 687), for the heart muscle excited by stimuli applied directly to it. The possibility of its applying also to nerve itself was discussed by Gotch (1902, p. 407), who came to the conclusion that the magnitude of the electrical disturbance in nerve is conditioned far more, if not entirely, by the number of fibres excited, than by possible differences of intensity of the disturbance in individual fibres ; but the actual proof was not given until the work of Adrian (1912). If we consider for a moment the case of a muscle being excited by shocks of varying intensity applied to its nerve, it will be clear that all the nerve fibres are not in exactly the same favourable position for receiving the stimulus, either

For the prevention of escape of current when immersed in saline. The points of stimulation are at D, where the current density suddenly increases to a high value. C, Loose cover, kept in position by an elastic band, G ; can be tipped up by E and P, Spirals of fine platinum wire, connected with the wires at the righthand end. because of their more internal position and consequent short circuiting of the stimulus to a certain extent, or, possibly, owing to differences in their own state of excitability. This being so, a very weak stimulus would excite some and not others, thus causing contraction of a portion only of the fibres of the muscle. Although these latter may respond by a maximal contraction, the fact alone does not, however, prove that the impulse in the nerve fibre was a maximal one, since it might be only just sufficient to cause contraction.

A very ingenious method was devised by Adrian for the investigation of this and similar questions. All methods of experiment agree in showing that the disturbance, as it passes along the fibres of a normal nerve, suffers no diminution in intensity. If, on the contrary, the nerve is narcotised by the application of an anaesthetic, such as alcohol or morphine, a disturbance, started at one end. decreases in magnitude progressively as it travels along and, if the length or the degree of narcosis is sufficiently great, it is completely wiped out. Since the diminution in the disturbance is a regularly progressive one, it is clear that a

smaller disturbance will be able to pass along a shorter distance of narcotised fibre without annihilation than one which was larger to start with. In practice, it is more convenient to vary the degree of narcosis, or period during which the anaesthetic is applied. The following description from Adrian's paper (p. 393) will assist the reader : — " The point to be decided is whether a disturbance which has passed through an area of decrement and entered normal tissue again is equal to or less than a disturbance which has been set up in normal tissue, peripheral to the area of decrement, and has consequently escaped any reduction. The following arrangement was adopted. Two muscle nerve preparations

RECOVERY OF A NERVE IMPULSE AFTER IT HAS (sciatic gastrocnem i us) are PASSED THROUGH A REGION OF DECREMENT. taken under exactly similar <•« >n- 105, A) two equal lengths of nerve, d and d', are narcotised. These lengths are separated by a variable length of normal nerve and the conductance of a disturbance through one or both of them can be tested by stimulating electrodes I. and II., placet 1 as shown in the figure. The other preparation is narcotised at the same rate o\ er a length, D, which is equal to the two lengths, d and oT, together. Conduction through D is tested by electrode III. Under these conditions the decrement suffered by the disturbance from II., in passing through d, will be equal to that suffered l>y the disturbance from III. in passing through the first (central) half of D. If the disturbance does not increase in size when it leaves d, it will enter d' in exactly the same condition as a disturbance which enters the peripheral half of D. In this case the depth of narcosis required to extinguish the disturbance altogether will be the same in both preparations, and stimuli at electrodes II. and III. will become ineffective at the same time. On the other hand, the disturbance from electrode I. will enter d' unreduced and therefore conduction from I. to the muscle will persist for some time after the failure at II.

"Fig. 105, B may help to make this clearer. Ordinates are intended to represent the size of the disturbance at different points along the nerve during the period when a stimulus at I. is effective as regards the muscle and a stimulus at II. is not. Ihus the full line shows the disturbance starting at II., undergoing in d a decrement which does not lead to complete extinction, emerging into normal nerve between d and d', where it persists at reduced magnitude, and then undergoing in d' a further decrement which does lead to extinction. The broken line shows the disturbance starting at I. undergoing in d' a decrement which does not lead to extinction and then passing on to the muscle in this reduced condition.

"Fig. 105, C shows what will happen if the disturbance recovers after leaving the region of decrement. In this case, the disturbance from II., when it travels through the normal tissue between d and d', is fully equal to the disturbance which starts at I. (broken line). Thus stimuli at I. and II. will become ineffective at the same moment when the narcotic has acted for such a time that a full-sized disturbance is extinguished in the length d or d'.

"Consequently, the only data required for the solution of our problem are the times from the beginning of narcosis to the moments when stimuli from electrodes I., II., and III. cease to evoke a muscular contraction. If the stimulus fails first at III. and afterwards at I. and II. simultaneously, the disturbance must recover to its original size after leaving the area of decrement ; if the stimulus fails first at II. and III. together and afterwards at I., the disturbance does not recover."

The actual experimental method used will be found in the original paper. Suffice it to say here that the results prove conclusively that a disturbance, after having been decreased by passing through a region of decrement, recovers its original magnitude when it re-enters a normal area. We may look upon the various magnitudes of the disturbance, as it emerges from regions of various degrees of narcosis and enters on the normal region, as being different degrees of intensity of a stimulus applied to the normal nerve. Experiment shows that the impulse then present in the normal legion is the same in all cases and maximal, whatever its strength was after subjection to decrement.

Attention may be called to the method of measuring the strength of an impulse by the extent of decrement it can suffer without extinction. An important point in Adrian's woik is that the strength was not measured by the magnitude of the electrical change alone, since the actual relationship of this change to the propagated disturbance itself is not, as yet, eompletety known. Another way, in which the result is confirmed, is by applying stimuli of various strengths and allowing the impulses produced to pass through a narcotised region. It was found that the same degree of narcosis abolished all, so that they must have been of equal intensity.

By similar methods it was shown that, if the impulse is altered in magnitude by passing through a cooled area, it regains its original size on emerging into normal tissue. Space does not permit discussion here of the results obtained by previous observers, which appeared to show a gradation of impulses in nerve fibres. Adrian has shown that they do not warrant the interpretation put upon them. There is one point, however, which should be referred to. It was thought at one time that a nerve might still be able to conduct a propagated disturbance through a narcotised area, when unable to respond to a stimulus applied directly to this area. The results of Adrian show that the phenomenon can be explained without this assumption, which, therefore, introduces an unnecessary complication. The phenomenon known as " Wedensky's inhibition" depends on the stage of diminished excitability immediately following the passage of an impulse which is known as the " refractory period " and will be discussed presently. With regard to the supposed distinction between conductivity and excitability, referred to above, the fact of the local excitatory change, which is antecedent to the setting up of a propagated disturbance and will be discussed below, should be kept in mind. This local state is not propagated and it does not appear improbable that the possibility of its occurrence might be prevented by the action of certain agents, although the nerve might still be able to conduct an impulse started elsewhere.

It appears to me that the results obtained by Adrian show quite clearly that there is no gradation of excitatory state in the normal condition, so that the fact must be accepted whatever consequences may follow from it. Its application to the phenomena in nerve centres and to heart muscle will be referred to later, but its NATURAL CONDITIONS. RECORDED BY THE STKINc i;.\l.\ \NnMKTER. First curve from above— Electrical changes in the part of the cut vagus in connection with the lung1. Second curve — Respiratory movements. Inspiration upwards. Third curve — Heart beats.

Note that the electrical change is congruent with the degree of distension of the lungs, and that there is no change corresponding to the heart beats. relation to the secreting glands may be mentioned here. If the varying degrees of secretory activity, to be obtained by gradation of the stimulus to the nerve, be due to maximal stimulation of a greater or less number of fibres, evidence should be obtained in microscopic appearances that some cells or alveoli are much more fatigued than others. If the figures on pp. 957 and 982 of Metzner's article (1907, 2) be referred to, it will be seen that this is actually the case.

A question cognate to the last, and of considerable importance, is whether electrical or other stimuli of different time course are able to produce nerve disturbances of different kinds. This would appear from Adrian's results to be improbable, but it has been found that the comparatively slowly rising current, to be obtained from a rheonome, caused an abnormally long twitch of the muscle to which the nerve was attached. Subsequent investigation with an instrument able to detect the existence of disturbances following one another at very brief intervals, showed that several successive impulses passed down the nerve in such cases. It appears that different nerve fibres are excited by the slowly rising current at different times after it begins to pass. Dr Keith Lucas, to whom I owe this information, also states that he is unaware of any evidence to show that the nerve impulse is in any way modified by the nature of the stimulus. The different forms of electrical change in nerve must, therefore, be ascribed to a series of impulses, if it be supposed that they represent the process in a single fibre ; but it seems more likely that a varying number of fibres are being excited in rotation. A case of this kind is shown in Fig. 106, D and E (Einthoven), where the electrical change in the vagus nerve, produced by inflation of the lungs, is seen to follow precisely the degree of inflation, and might be explained on the hypothesis that the receptive end organs in the lung tissue are of varying degrees of sensibility, so that all would be excited by a strong inflation, but fewer and fewer in proportion as the degree of stretching decreases.

That the result produced by the impulses travelling in a nerve depends on the way the fibres end, arid not on any difference in the impulses themselves, is shown by Langley's experiments (1898) on the union of different nerves. When the central end of the vagus is joined to the peripheral end of the cervical sympathetic, and regeneration has taken place, stimulation of the vagus produces the same effects as that of the cervical sympathetic did previously. Moreover, reflexes produced by afferent impulses, which excite efferent fibres of the vagus in the normal state, instead of producing cardiac inhibition, cause contraction of the arterioles of the ear, together with the other effects of stimulation of the sympathetic. The central end of the lingual was joined to the peripheral end

First curve — Electrical change in the heart end of the cut depressor nerve. Note the electrical change with each heart beat, none with the respirations. First curve— Electrical changes in the thoracic end of the cut vagus. Note that both heart and lung produce electrical effects in the nerve, since the vagus trunk contains the depressor fibres. At the rise of the signal the peripheral end of the vagus of the opposite side was stimulated. Respiration

continues, with its electrical effect. The heart beat stops and, with it, the depressor waves cease. D and E, Vagus. Dog under artificial respiration. In D air is rhythmically blown into the lungs. In E, after a pause, air is sucked out four times, commencing at a. First curves— Electrical change in thoracic end of vagus. Second curves— Movements of chest upwards means inflation. Third curves— Blood pressure with heart beats. Fourth line— Signal.

1 mm. abscissae = 0'2 second. 1 mm. ordinates = 9 microvolts. Note how the electrical change coincides with the curves of distension and continues during the whole the same as that with distension, but of less magnitude, seen, owing to the decreased sensibility of the galvanoposite vagus was stimulated. of the cer\ iml svinpathetic in another experiment. Feeding the animal, which normally produces reflex stimulation of vaso-dilators to the tongue and salivary glands, caused vaso-constrictor phenomena in the ear ; direct stimulation of the lingual nerve produced vaso-constrictor effects instead of dilator effects. The conclusion seems inevitable that the excitation process in the nerve fibre is the same in all cases.

The question has important relations to the physiology of the sense-organs and is known as "Miiller's law of the specific energies of the senses." It may be mentioned here that mechanical, chemical, or electrical stimulation of the chorda tympani nn\c in the tympanic ca\itv cause equally sensation of taste. The sensation of light said to be caiiM-d by section of the optic nerve is not quite so certain, on account of the possibility of disturbance of the retina.

Differences in the state of excitation of a single nerve fibre, accordingly, can only be such as would be brought about by differences in the rate at which the separate stimuli follow one another. We see now the difficulty of accepting the view of Babkin (1913) that the different effects of " secretory " and " trophic " nerves to the salivary glands are due to qualitative differences in the nature of the impulses passing to the gland cells along fibres of the same kind, that is, with similar peripheral and central connections.

That apparently qualitative differences in a reflex can be obtained by altering the character of the stimulus is shown also by the experiments of Sherrington and Sowton (1911, p. 439), where the form of the reflex contraction of the vasto-crureus muscle, produced by excitation of the central end of the popliteal nerve of the same side, varies in form according to the time course of the electrical stimulus used. For example, that produced by the rheoimi incurrent has the character of a long-maintained, steady contraction, without evidence of fatigue and with slow subsidence after the end of stimulation; in fact, 'it has the properties of the tonic contraction to be described in a later chapter (see Fig. 107). Of course, there are more varied possibilities in reflexes than in the phenomena to be obtained by direct excitation of the nerve observed; but it must be admitted that the explanation of reflex phenomena on the hypothesis of the "all or nothing" nature of the nerve impulse presents difficulties, as is pointed out by Graham Brown (1913). On the other hand, the tracings of reflex

The first period of stimulation is that of the central end of the popliteal nerve by weak rheonome currents. The form* increase*. The second period of stimulation is that of the same nerve, through the same electrodes, by a weak faradic current from an induction coil for one second only. Inhibition immediately results. contraction given by this experimenter show a number of steps of gradation which do not sufficiently exceed the possible number of motor fibres in the nerve to be satisfactory proof of the law failing to apply in this case.

As far as the number of separate nerve fibres in the motor nerves to the eye-muscles is concerned, it seems that they are fully sufficient to provide for all the degrees of contraction required. In the sixth cranial nerve, which supplies the external rectus muscle, the number of fibres is given by Zoth (1905) as 2,500 in man, and those in the nerve to the superior oblique muscle as 2,150. This fact, in itself, obviously suggests that different degrees of contraction are effected by changes in the number of muscle fibres stimulated. If there were a possibility of different degrees of activity in the same nerve— or muscle — fibre, a very much smaller number of individual fibres would be sufficient.

Refractory State. — It was first shown by Gotch and Burch (1899) that, if a stimulus is followed by a second one at an interval less than about O'OOS second, differing according to temperature, the second one does not give rise to a FIG. 108. CURVE OF RECOVERY OF EXCITABILITY OF NERVE AFTER A PREVIOUS STIMULUS. — The refractory state is, at first, absolute ; excitability returns gradually, and becomes normal at about 0'012 second. It is followed by a brief stage of supernormal excitability.

propagated disturbance, as indicated by an electrical change. This means that the nerve is inexcitable immediately after a state of excitation. Further investigation of the state of the nerve during the period succeeding the passage of a disturbance was made by Adrian and Lucas (1912), by a method in which contraction of the attached muscle was used as indication of the disturbance in the nerve. Fig. 108 represents the percentage of normal excitability present at various intervals of time after the excitation, at a temperature of H0>8 C. It will be seen that for 0-0025 second after a previous stimulus there is complete inexcitability to any strength of stimulus (" absolute " refractory period). From this time to about 0-012 second the excitability is lower than normal, gradually increasing ; this is the period of " relative " refractory state, in which a stimulus stronger than normal is required to set up any propagated disturbance. Following this, until 0'028 second, there is a period during which the nerve shows increased excitability, to which reference will be made again presently.

During the relative refractory period, the disturbance set up by a stimulus which is just strong enough to excite is less than the normal one, as measured by its ability to traverse a narcotised region. In the normal nerve, as we have seen, if a propagated disturbance is produced at all, it is a maximal one, and it is impossible to produce one of the smaller magnitude of those excited in the refractory state. The question arises, then, whether these smaller disturbances can be made greater by stronger stimuli. Adrian (1913) finds that this is impossible. So that the magnitude of the disturbance is conditioned only by the state of the nerve at the time.