Principles of General Physiology

STIMULATION OF THE CENTRAL END OF THE VAGUS IN THE DOG. — VaSO dilators Upper curves — volume of the leg. Rise indicates vaso-dilatation. Lower curves — arterial pressure. Zero is 24 mm. below the time signal. Time in ten seconds. The first stimulation shows vaso-dilatation produced by inhibition of tone in the vaso-constrictor centre. The arterial pressure falls. Before the second stimulation the abdominal sympathetic nerve was cut. The fact that this nerve was conveying tonic vaso-constrietor impulses is shown by the rise of the level of the volume of the leg seen in the tracing.

The second stimulation produces a similar fall in arterial pressure, hut the leg, instead of expanding, merely follows the blood pressure ; decrease in volume is due to the lower pressure at which the blood is driven in and to its being drained away by vascular dilatation in other parts. No inhibition of constrictor tone could be shown by the leg, since the vaso-constrictor nerves, passing to it from the centre by way of the sympathetic, were divided.

that, by properly choosing the relative strengths of the stimulation applied to the respective nerves, an exact neutralisation can be obtained. I found (1893, p. 318) this to be the case with the vaso-constrictor centre and give an example in Fig. 121. The tracing is that of the arterial pressure in the rabbit. During the rise of the upper signal, the depressor nerve was stimulated continuously, producing its normal fall of blood pressure ; this fall is interrupted, temporarily, during the rise of the lowest signal line, by a return to normal, resulting from simultaneous stimulation of an ordinary afferent nerve, the anterior crural, which, on its own account, would have produced a rise of arterial pressure above normal by excitation of the constrictor centre. The effect of this nerve lasts longer than the period of stimulation, but the continued stimulation of the inhibiting

nerve makes itself felt again and the blood pressure rises finally to normal only when the stimulation of the depressor ceases. In Fig. 122 two tracings are given from Sherrington's paper (1908) which show the same fact in the case of reflexes to skeletal muscle. The vasto-crureus muscle of a decerebrate cat traces its contraction by a rise in the curve. The upper signal indicates by a fall the stimulation of an inhibitory nerve, the central end of the peroneal of the same side, and the lower signal that of an exciting nerve, the central end of the popliteal of the opposite leg. In A, the inhibiting

nerve is first stimulated and the muscle is released from the tonic excitation of the centre. In the middle of this period of stimulation, the exciting nerve is stimulated, the inhibition of the centre is almost neutralised, so that the muscle returns nearly to its original length. While this stimulation is continued, the BALANCE OF REFLEX EXCITATION AND INHIBITION IN THE CASE OF SKELF.TAL MUSCLE (VASTO-CRFKKIs). In the left-hand tracing (A) the myogram (m) shows that medium (decerebrate) tonus is present at the commencement. The fall of the signal line / indicates that the central end of an inhibitory afferent nerve, the iiwelateral peroneal, is excited by 1W) units of the coil graduation. The level falls. It is brought back again nearly to its original height by concurrent stimulation (shown by signal K) of an excitatory nerve, contralateral popliteal, with MX) units. When the inhibitorx stimulus is cut off, the full effect of the excitatory one shows itself.

In the right-hand tracing (B) the order in which the two nerves are stimulated is reversed. Note the greater rapidity of the flnal fall in B than in A. This is due to the fact that in B it is produced by active inhibition, in A by mere cessation of excitation. inhibiting stimulus is removed, with the result that the exciting stimulus can produce its full effect unhindered. In B, the converse experiment is performed, commencing with the stimulation of the exciting nerve. Sherrington concludes that the eftect is a simple algebraic summation of the two single effects (see also

Fig. 123). In the case of the vasomotor reflexes I stated the same conclusion thus: the results "depend entirely on the relative strengths of the stimuli ; whichever nerve is under the stronger excitation shows its own effect, and when the excitation of this one is stopped, the effect of the other manifests itself. In fact, there appears to be a perfect antagonism " (1893, p. 318). " Inhibition of Inhibition."— Suppose that we have in tonic activity the centre from which nerves proceed which cause inhibition or relaxation of the smooth muscle which they supply. Such a case is that of the vaso-dilator centre under certain conditions, as will be seen later. Now there are afferent nerves which inhibit this centre, just as the depressor nerve inhibits the vaso-constrictor centre, so that we have, as Sherrington has called it, an " inhibition of inhibition." In Fig. 124 we have, in fact, a case which is incapable of explanation on any other view. This is from an experiment in which I was engaged in investigating the blood flow through the submaxillary gland of the rabbit. It will be seen that, when the central end of the vagus nerve of the opposite side was stimulated, there was a longer interval between the drops of blood from the vein, that is, the arterioles were narrowed. Now the vagus nerve in the rabbit is a pressor nerve, that is, it causes a rise of arterial pressure by reflex constriction of arterioles. This rise of pressure is not shown on the tracing, because an arrangement was used which kept the general blood pressure at a constant level by allowing blood to

escape (see my paper, 1908, 3, p. 272). Hence, if this cervical sympathetic nerve, conveying constrictor impulses to the gland vessels, had been intact, explanation would be simple, namely, by reflex excitation of vaso-constrictor nerves. But, in point of fact, the vaso-dilator fibres of the chorda tympani were the only vascular nerves left intact, so that the effect must have been produced through these and indeed by inhibiting a previously existing tonic state of an inhibitory centre. It may be noted that one inhibition acts on muscle, the other on nerve cells.

It is shown by the work of Pavlov on "Conditioned Reflexes" (see p. 506) that similar phenomena play an important part in the mechanism of the IKTM- centres themselves. Suppose that a motor nerve centre is inhibited by the action upon it of an inhibiting nerve, acting through an intermediate neurone. In other words, the state into which this intermediate neurone is put by the stimulation of a particular afferent nerve is such as to give rise to inhibition of the motor neurone. Now it is quite possible that another nerve, acting on this intermediate

neurone, might inhibit it ; in which case, the motor neurone previously kept in check by the intermediate neurone would be set free, and apparently excited by a nerve which was really inhibiting another neurone. The state of excitation of our motor neurone is, of course, assumed to arise from some independent cause, inherent, reflex, or chemical. We shall see presently that an inhibitory nerve can antagonise a chemical excitation as well as a nervous one, and, perhaps, the distinction ought not to be made in this form, since the ultimate process is probably identical in both cases, as remarked above (page 344).

"Shock" and " Decerebrate Rigidity" — When the spinal cord is cut across^ it is found that the portion posterior to the section remains for some time in a state of diminished excitability, so that no reflexes can be obtained from it. This state of " shock " is gradually recovered from. It has been supposed to be due to some effect of the injury, but Trendelenburg (1910) has made some experiments which indicate that this is not the explanation. Instead of cutting through the cord, he abolished its power of conduction by local cooling to a point just above its freezing point. The experiments were done on the rabbit, since the blood supply of the cord in this animal is such as to preclude the possibility of cooled blood passing to the posterior part of the cord and affecting its excitability directly. It was found that functional separation of the lumbar cord from the higher parts of the central nervous system could be made without any excitation. Notwithstanding this, the reflex excitability of the lumbar cord was abolished, but returned again when the temperature of the cooled segments

Fio. 124. CENTRAL INHIBITION OF EXCITATION OF INHIBITORY NERVES, Upper tracing— arterial pressure. Zero at level of upper signal Scale in millimetres. Top signal — drops of blood from vein of submaxillary gland. Middle signal— two stimulations of the cenlral end of the vagus of the opposite side (pressor nerve). The vagi, sympathetic, and depressor nerves were cut on both sides, so that the gland vessels were supplied only by dilator nerves in the chorda tympani nerve.

Stimulation of the vagus produced no rise of blood pressure, because the animal was eviscerated and the aorta was connected with an automatic arrangement, by which rise of pressure was prevented. We note that although there was no vaso-constrictor supply, yet vascular constriction was produced in the submaxillary gland, as shown by the longer intervals between the drops of blood escaping. Since the only vasomotor nerves were dilators, constriction could only be caused by inhibiting the impulses from the centre which kept these nerves in a state of tonic stimulation.

was allowed to return to the normal height. It seems that the " shock " effect must be due to the removal of some influence exerted by the higher parts of the nervous system, an influence of such a kind as to increase the excitability of the cord. Sherrington (1906, pp. 240-248) had previously come to the conclusion that spinal shock has nothing to do with the injury of the section, and that it was probably caused by some influence exerted by the mid-brain on the lower centres. He shows that, when recovery from a transection of the cord has taken place, a second transection just below the first has practically no effect.

The work of Pike (1909, 1912, 1913) shows that the phenomena are not due to the traumatic stimulation of long inhibitory tracts from the higher centres to the spinal cord. He looks upon the normal path for what are called spinal reflexes as having been diverted in the course of evolution, so that the impulses do not pass directly across the cord, but ascend to the higher centres first and from these return to the motor neurones. The direct path has thus become more or less impassable from disuse, but it can, after a time, regain the power of conduction to a certain extent, when the path through the higher centres is cut. This point of view will be better understood when Chapter XV. on the nerve centres has been read.

Decerebrate Rigidity.— Sherrington found (1898, 1906, pp. 299-303) that when the crura cerebri are cut through, the centres of certain groups of muscles are so much increased in excitability that the ordinary slight stimuli arising from the periphery are sufficient to maintain these muscles in a state of reflex tonic contraction. The centres in question are situated somewhere between the crura and the lower part of the spinal bulb, but not in the cerebellum. Under normal conditions, their excitability is restrained by the inhibitory influence of the cerebral cortex.

Weed (1914) comes to the following conclusions as the result of extensive investigation. The main reflex centre for decerebrate tonus is in the mid-brain, probably the red nucleus. The cerebellum, although not the absolutely essential pathway for the afferent impulses concerned, is the most important one. It is also the link in the inhibitory channel from the cerebral cortex, which prevents this rigidity in normal conditions. This condition of "decerebrate rigidity" is very useful in the investigation of reflex inhibition, since we have centres in a state of tonic excitation, which can be played upon by the stimulation of various nerves. We have seen an example of this in Fig. 118 (page 4 10).

The Action of the Anode. — We have seen that excitation proceeds from the cathode. The simplest way of showing the fact is by the use of the device of J. S. New (1899). Since excitation is associated with increased concentration of cations at a particular membrane, it is natural to suppose that the effect of the anode, being to decrease this concentration, would result in inhibition. It is clear, however, that this cannot show itself unless the tissue is in a state of excitation when the anode is applied. Biedermann (1895, p. 227) has made use of the drug, veratrine, to produce this state of excitation in voluntary muscle. A muscle under the influence of veratrine gives a prolonged contraction in response to a single stimulus and, during this state, a current can be sent through the muscle in such a way that the effects of the anode and cathode can be observed separately. It was found that the anode causes relaxation, the cathode, increased contraction. A still simpler way of seeing the fact, as Biedermann points out (1895, p. 219), is to place the anode on the beating ventricle of the frog's heart, the cathode on some other part of the body. It will be seen that the neighbourhood of the anode remains permanently in a state of relaxation, while the remainder of the ventricle undergoes periodic contraction.

Another aspect of the action of the anode is manifested in the case of nerve. The exciting effect of a constant current is only shown when it is made or broken ; in other words, while it is really constant no excitation occurs. It must change its strength at or above a certain minimal rate in order to excite. But the nerve is not unaffected during the period of a constant flow of current. In the neighbourhood of the cathode, a propagated disturbance can be set up by a smaller stimulus than in the normal state, and in the neighbourhood of the anode a stronger stimulus is required. The excitability is increased at the cathode ; diminished at the anode.

Chemical Ayents. — We see then that inhibition, as well as excitation, can be brought about by means other than stimulation of nerves. Various chemical agents, as we saw in discussing the action of electrolytes in general, can produce a state of inexcitability. The hypothesis of Howell, as to the functipn of potassium in the action of the vagus nerve, was also referred to in that It is interesting to note that excitation by rlicinir.-il nit-fins can be antagonised by nervous inhibition, as shown in Fig. 125, which shows that the excitation of the vaso-constri<-t Hi- centre by asphyxi;il blood is neutralised by simultaneous stimulation of the depressor nerve (see Bayliss, 1893, p.

Fig. 126 is another interesting case. The tracing is that of the respiratory movements of the slip of the diaphragm in the rabbit which is attached to tinend of the sternum, as used by Head for the investigation of respiratory reflexes. At the commencement of the figure it is completely relaxed and at rest, the vagus nerves being intact. The series of contractions was caused by the administration of air containing carbon dioxide. At x the vagus nerves were cut; the

muscle is seen to pass into a state of partial tonic contraction, owing to excitation from the respiratory centre, which had previously been inhibited by impulses from the vagus endings in the lungs. A second inhalation of carbon dioxide excites respiratory movements of the slip, and the point of interest is that its tonus is inhibited, so that in expiration th'e position is that of nearly complete relaxation. ASPHYXIAt, STIMULATION OF THE VASO-CONSTRICTOR CENTRE. — Curarised rabbit. Arterial pressure curve.

The pressure would have remained throughout at the level of B if the artificial respiration had not been stopped at this point. The result of the asphyxial excitation is to bring back the arterial pressure to normal. Respiration was resumed at C, and, as the asphyxial state disappears, the depressor fall again shows itself until the final cessation of the stimulus to the nerve. The facts brought out in the several cases described above will, as it seems to me,- serve to show that it is not" to be supposed that the inhibition of a process is in all cases effected in the same way. A general theory of inhibition is thus improbable, although there is no doubt that all the cases have the same essential basis and, when we consider that the process of inhibition is the opposite of that pf excitation, we realise that when we know more about the latter, we shall know

more about the former also. It is to be feared that the consideration to be given to certain theories of inhibition will leave us with very little of definite value. It is necessary to do this, however, since some theories, proposed as of more or less general application, will be found to be inapplicable to any case whatever. It appears, on superficial examination, that we must consider the possibility of two different modes of inhibition. When a smooth muscle is in a state of tonus, due to its own inherent properties, the action of an inhibitory nerve is to quell this state of excitation by acting on the excitable substance of the muscle directly. When the state of excitation is due to the action of an excitatory nerve fibre upon the muscle cell, it would seem more appropriate to block the point of synapse where the nerve fibre conveys the excitation to the muscle. Similarly, a nerve cell may

FIG. 126. TONUS OF RESPIRATORY CENTRE AND EFFECT OF THE VAGUS NERVE THEREON. — Tracing of diaphragm slip of rabbit by Head's method (see page 418). At the beginning, with the vagus nerves intact, the slip was completely relaxed, showing very small respiratory contractions. The series of large contractions was produced by the addition of carbon dioxide to the air breathed. At x , the vagi were cut. It will be noted that the diaphragm passed into partial tonus.

A second inhalation of air containing carbon dioxide caused increased respiratory movements, and it is interesting to note that, between each respiration, the tone was relaxed. be in a state of excitation, due to chemical changes in itself or to chemical influence of constituents of the blood, and, in this case, inhibition may be brought about by action on the actual cell substance. If, on the contrary, the state of excitation is due to nerve impulses acting through synapses with the cell, it would seem to be a simpler hypothesis to suppose that the action of an inhibitory nerve fibre is exercised on the synapse, making it impermeable to the excitatory impulses. The cell substance itself is thus left free to respond to other stimuli. It does not seem impossible that experiment may decide whether there is any real distinction of this kind, and it is quite likely that it is the synapse that is concerned in all cases. Sherrington (1906, p. 103), in fact, is inclined to regard the process of inhibition as of the same fundamental nature in all cases, whether on nerve cell or on peripheral muscle.

Physical Interference. — Although it is possible that this view is not seriously advocated at the present time by any competent physiologist, there are still traces of it to be found, especially in certain work of the Verworn school. We must, therefore, devote a few words to it. It is a familiar fact that a wave motion can be annulled by another similar wave motion of the same period, if the phase difference is of half a wave length. In this case, the hollows produced by the one are exactly filled up by the crests of the other. But it is essential to remember that these wave motions are, both of them, movements to alternate positions at an equal distance on opposite sides of a mean position, and that it is to this mean position that the process is reduced when the two wave motions mutually counteract one another.

For example, take an alternating electric current, as perhaps most analogous to a nerve impulse. This raises the potential of a point on a conductor alternately, say, to 100 volts above the potential of the earth and 100 volts below this value. Another similar current, with a phase difference of half a wave length, reduces the potential to a constant one of that of the earth, that is to zero. Now, in a series of nerve impulses, the state of excitation is merely raised periodically from zero to one of a certain potential, and by no possibility could another similar set of disturbances reduce this potential to zero. In the nm-t favourable case, it could be reduced only to one-half of its value. Inhibition, as Sherrington points out (1906, p. 99), is complete, and we see the fact in Figs. 107, 113, and 118. This could only happen, on the assumption of a process analogous to physical interference, if we could apply a nerve process of the opposite nature to that of excitation. This is just the fact which has to be explained. We may, then, dismiss the hypothesis as inadequate.

It will be clear that if a nerve is stimulated at the same moment at two points A and B, at equal distances on opposite sides of the two leading off electrodes, C and D, the waves arriving at C and D simultaneously will produce an equal and opposite electrical potential at the two electrodes, so that no external change will be obvious. It is incorrec-t, however, to speak of this as an "interference," as is sometimes done. It is also unnecessary to point out that the non effect of a stimulus falling in the refractory period, or the disappearance of a disturbance in a region of decrement, cannot be spoken of as interference in any physical sense.

In a certain sense, the refractory period after an excitation is itself an inhibition, since the excitable tissue is incapable of entering into activity ; so that there is a certain superficial resemblance to inhibition when a stimulus applied in this period is ineffective. But it does not quell a state of excitation already present, as a true inhibition does. At the same time, the phenomenon known as the " Wedensky inhibition" requires a little consideration. Although this is a somewhat special case, it is of interest as showing the complex possibilities involved in joint action of refractory period and "all-or-nothing" law, as worked out by Adrian (1913). At a certain stage in narcosis or fatigue of a nerve-muscle preparation, a rapid series of strong stimuli applied to the nerve produces a small initial twitch only, whereas a similar series of weak stimuli produces a continued tetanus. After the first stimulus, in either case, a refractory period is present ; if the next succeeding stimulus is strong, it will set up a propagated disturbance early in the relative refractory state, but this will only be a very small one and consequently unable to pass the region of decrement between the excited spot and the muscle. This region of decrement may be in the place of synapse between the nerve and the muscle, or in a narcotised area of the nerve itself. Although it is a small disturbance, it will leave behind it a refractory period, which will have the corresponding effect on the next succeeding stimulus and so on ; thus no excitation will reach the muscle. If the stimuli are weak, on the contrary, no propagated disturbance can l>e set up by any one until the refractory period is practicall}1 at an end, and then the disturbance, although set up by a weak stimulus, will be of the full normal magnitude and able to pass the region of decrement and excite the muscle. Further details will be found in the original paper ; those given above will suffice for our present purpose.