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Excitability cycle of the visual cortex in normal subjects during psychosensory rest and cardiazolic activation
BRAIN RESEARCH
51
EXCITABILITY CYCLE OF THE VISUAL CORTEX IN NORMAL SUBJECTS DURING PSYCHOSENSORY REST AND CARDIAZOLIC ACTIVATION
B. BERGAMASCO
Neurological Clinic, University of Turin (Italy) (Received February 2nd, 1966)
INTRODUCTION
The excitability cycle of the visual cortex in man was first studied by Gastaut et al. 9-11 who employed a normal EEG recording technique. Other workers have since studied the problem: Pampiglione15, Gray and Schwab 12, Calvet et aL 4, Shagass
and Schwartz 19, Allison1, Schwartz and Shagass 16-1s. Cig~mek~, using Dawson's 7 superimposition technique, investigated the recovery cycle of the human visual cortex, obtaining results different from those of the above-mentioned workers. Our aim was to study the excitability cycle of the visual cortex in man and its variations under the influence of the drug, pentamethylenetetrazol, which has a synchronizing and recruitment action on cortical neuron activity. The evoked photic potential recorded from the scalp with the averaging technique was employed. MATERIALS AND METHODS
The behaviour of the recovery cycle of the evoked visual potential in basal conditions and after i.v. administration of 250 and 500 mg of Cardiazol was studied in 10 normal subjects, 6 males and 4 females between the ages of 20 and 30. The recovery cycle of the evoked response corresponds to the duration of the relative refractivity of the cortical neurons following their response to a corticipetal stimulus. The phenomenon is expressed by the ratio between the amplitude of the two responses evoked in the cortex by two stimuli with identical characteristics at varying time intervals. For this purpose the responses evoked by two paired flashes ('conditioning flash' and 'test flash') were studied. Hypodermic needle-electrodes were attached to the scalp at 3 cm at the side and 1 cm above the external occipital prominence and referred to an electrode at the vertex, according to Bergamasco et al. z. Bipolar recordings were made and evoked potentials were obtained by using a Mnemotron CAT 400 B. The voltage value of the cerebral biorhythms at the CAT input were measured Brain Research, 2 (1966) 51-60
52
B. BERGAMASCO
with a Tektronix Mod. 503 oscilloscope. The evoked potentials were then transcribed from the computer screen on to millimeter paper by an X-Y Plotter (Mosely). The subjects, with pupils in maximum mydriasis after application of atropine, were put in a dark, sound-proof room and made to close their eyes so as to be in a state of complete psychosensory rest. A flasher of an intermittent light stroboscope (Soneclat Alvar) was positioned 70 cm from the eyes of the subjects. At each flash 0.3 J of energy was delivered. Stimulation frequency was always 1 fl/sec in order to avoid interference with subsequent responses. Cortical responses to 40-50 flashes were averaged with an analysis time of 500 msec. The cortical excitability cycle was determined by administering simultaneously paired flashes at intervals of 20-30-40-50-70-80-100-120-150170-200-230 msec. After recording the potential evoked by a single flash the responses to double flashes were recorded for each type of interstimulus interval. The same procedure was adopted after slow intravenous injection of 250 mg of Cardiazol and the following day after slow intravenous injection of 500 mg of the same drug in the same subjects. RESULTS
(a) Evoked responses obtained during cardiazolic activation The evoked response obtained immediately after i.v. administration of Cardiazol presents alterations essentially involving the late components and the after-discharge (Fig. 1). The early components of the basal evoked potential (or primary response according to Cig~inekS), consisting of the first three negative-positive-negative waves of low amplitude, with a mean latency of 25-35-60 msec respectively, vary little from those recorded after i.v. administration of 250 and 500 mg of Cardiazol. However, the waves IV-V-VI-VI[ (secondary response according to Cig~nekS), with a mean latency of 70-75-90-125 msec, after Cardiazol administration are modified. The wave VI (positive) presents a higher voltage while the small positive-negative waves V-VI disappear. The latency of wave VI, however, remains absolutely constant. Wave VII is also decidedly increased in amplitude (1/4) (Fig. 2), and its latency remains unaltered. The after-discharge is more evident during recordings made after Cardiazol injection: all the alterations in evoked responses provoked by Cardiazol are more or less identical following administration of 250 and 500 mg of the drug. The EEG under cardiazolic action shows an increase in a rhythm frequency and a higher voltage with a fair abundance of rapid activities.
(b) Excitability cycle of the visual cortex in psychosensory rest When two paired flashes stimulate the sensory periphery the cortical response obtained (R1 q- R2) represents the sum of two evoked potentials, unless the test flash falls within the absolute cortical refractivity period. Using numerical ordinator with 400 memory points (ferrite nuclei) codified in BCD (binary coded decimal form) in
Brain Research, 2 (1966) 51-60
53
EXCITABILITY CYCLE OF THE VISUAL CORTEX
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C.5. 24 7, Fig. 1. Evoked photic responses obtained in the same normal subject from the average of 50 cortical responses to flashes in basal conditions (A), after i.v. administration of 250 mg of Cardiazol (B) and after administration of 500 mg of the same drug (C).
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, A m p l i t u d e of the basal evoked p o t o n t l a l Arnphtude of the ev potential att'er 250rag Cardlazol iv Amplitude of the ev potential after 500 mg Cardlazol ~v
Fig. 2. M e a n amplitudes o f the various waves o f the evoked p h o t i c potential in 10 subjects in basal conditions and after i.v. administration o f Cardiazo! in doses o f 250 and 500 mg.
Brain Research, 2 (1966) 51-60
54
B. BERGAMASCO
20 binary stages the evoked potential curve can be subdivided into 400 points corresponding to the 400 points of the ordinator. Each point can be expressed as a numerical value. It is understandably possible to separate from the double response (RI -t- R2) the responses of the conditioning flash (R1) and the test flash (R2) by subtracting the value of the basal evoked potential (Fig. 3) point by point from the double response. What remains will be the response to the test flash, which is stable within limits. The value of the R2/R1 ratio expresses the state of cortical excitability
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Fig. 3. A b o v e (R1 ÷ 112) cortical response evoked by two flashes at 100 msec interval in a n o r m a l subject in psychosensory rest. Centre (R1) response evoked by a single flash in the same subject. Below (112) response evoked by the second flash, obtained by subtracting R1 values from R1 + R2 point by point. In the response to the second flash (R2) so obtained, waves III and VII are evident. Their amplitudes are greater t h a n in basal conditions ( R I ) whereas their latencies are lengthened. The second flash falls within the period of maximal cortical facilitation.
Brain Research, 2 (1966) 51-60
EXCITABILITY CYCLE OF THE VISUAL CORTEX
55
in a particular moment. When this ratio equals zero the cortex is not excitable further (period of absolute refractivity), when it is higher than 1 the cortex is more excitable (period of supernormal facilitation) and when it is less than 1 the cortex has less excitability (period of subnormal excitability). Finally, when it equals 1 the cortex has the same excitability as in basal conditions. Only the amplitudes of the waves I I I and VII of the evoked photic potential were considered because of their greater constancy. In contrast with the other waves, these two are observed in all recordings and thus R 2 / R l m will indicate the ratio between the amplitudes of wave I I I of the two evoked responses and R 2 / R l v n , that of wave VII. With up to 40 msec intervals between the two flashes the evoked response obtained does not present significant differences with respect to that obtained with a single flash (R2/R1 = 0) (Fig. 4). Whereas when interstimulus intervals are between 40 and 80 msec there is an evoked response to the test flash which at 80 msec is already ~'~
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Fig. 4. Recovery cycle of the visual cortex in the same subject as Fig. 2. Basal evoked potential (A); the test flash is given at 40 msec (B), 70 msec (C), 100 msec (D), 160 msec (E) and 200 msec (F) after the conditioning flash. Fig. 5. Recovery cycle of the visual cortex in the same subject as Figs. 2 and 3 afteri.v, administration of 500 mg of Cardiazol. In A, basal evoked potential; the test flash is given at 40 msec (B), 70 msec (C), 100 msec (D), 160 msec (E) and 200 msec (F) after the conditioning flash. greater in amplitude ( R 2 / R I I n and R 2 / R l v I I > 1) than that of the conditioning flash. Amplitude becomes clearly greater with an interval between the two flashes of 100 msec ( R 2 / R l n r and R 2 / R l v I I > 1) (Fig. 3). ]n this stage the latencies of the peaks of waves I I I and VII are increased. With an interval between 120 and 150 msec on the other hand, the response to the test flash appears reduced (R2/RIIrI and R 2 / R l v I I < 1), becoming equal to the conditioning flash response where interstimulus intervals are longer than 200 msec ( R 2 / R l m and R 2 / R l v i r -~ 1). Brain Research, 2 (1966) 51-60
56
B. BERGAMASCO
Therefore, on the basis of these data, the excitability cycle of the visual cortex seems to be made up as follows: period of absolute refractivity up to 40 msec after the flash, period of supernormal facilitation from 80 to 100 msec. At 100 msec there is a period of maximum facilitation. Between 120 and 150 msec after the first flash there is a period of subnormal excitability with a maximum at 150 msec after the flash. With interstimulus intervals between 170 and 200 msec there is a return to normal excitability which is complete with interstimulus intervals longer than 200 msec. (c) Excitability cycle of the visual cortex after i.v. administration of Cardiazol The excitability cycle of the visual cortex is modified in normal subjects treated with i.v. Cardiazol. These modifications are not related to the quantity of the drug administered. In fact, the recovery cycle of the evoked photic potential is, in more or less all subjects, the same with doses of either 250 or 500 mg of i.v. Cardiazol. This datum contrasts with the different convulsant thresholds presented by normal individuals with the administration of suitable doses of Cardiazol. Probably different mechanisms are involved. Apart from the alterations in the basal evoked response already described, the essential datum is the fact that the recovery cycle of the visual cortex is abbreviated in these conditions. Namely, the response to the test flash occurs at an interstimulus interval of 40 msec. The facilitation period begins about 50 msec after the first flash and this is demonstrated by the fact that with an interval of 70 msec the response to the second flash clearly exceeds the response to the first in amplitude ( R 2 / R l m and R2/Rlvxr > 1) (Fig. 5). Maximum facilitation is present in these experimental condiTABLE I MEAN VALUES (10 s u b j e c t s ) oF THE LATENCIES OF WAVES III AND VII
Conditioning response (R1) Test response (R2)* in basal condition Test response after 500 mg i.v. Cardiazol*
Wave III msec
Wave VII msec
62 q- 6 78 :k 8 80 :k 7
124 ± 12 160 ± 16 162 ± 16
* Period of maximal facilitation. tions before 100 msec after the first flash, namely at 80 msec. In these conditions too, the peak latencies of the response evoked by the test stimulus are increased (Table I). The period of subnormal excitability begins after 100 msec and reaches its maximum 120 msec after the flash ( R 2 / R l m and R 2 / R I v I I < I). Moreover, the recovery cycle is shorter than normal; the response to the test flash has the same amplitude as those to the conditioning flash with interstimulus intervals between 150 and 200 msec ( R 2 / R l m and R 2 / R l v n = 1). Brain Research, 2 (1966) 51-60
57
EXCITABILITY CYCLE OF THE VISUAL CORTEX DISCUSSION
These data regarding the excitability cycle of the visual human cortex agree with one exception with those obtained by Cighnek 8. The one difference is that Cig/mek found another facilitation period at 200 msec. This difference is not essential and can be ascribed to the diversity of techniques employed (for recording evoked potential, Cig~mek uses a photographic superimposition technique which is less accurate than the present numerical computers). On the other hand, there are marked differences between the data of the recovery cycle of the human visual cortex and those obtained experimentally in animals. Evarts e t al. s and Palestini et al. la,14 found that in wakeful cats, a complete recovery in cortical excitability sets in only after 550 msec. However, the evoked responses recorded by these workers were obtained by direct stimulation of the optical pathways with electrical pulses. Furthermore, Evarts et al. found that by increasing the intensity of the stimulus the recovery cycle increases. These data apparently contradict those found in humans, but they can be explained by the fact that an electrical stimulus directly on the optical fibres has greater density because of its higher synchronism, and, according to Bremer 3, is therefore capable of producing longer excitation on a larger number of cortical neurons. The study of the recovery cycle of the visual cortex carried out after administration of Cardiazol, which Gastaut et al. 1° had found unchanged, demonstrates a greater cortical excitability. The amplitude of the evoked responses is quantitatively greater in basal conditions; the recovery cycle is shortened. In fact, the absolute refractivity period lasts 30 msec. The subsequent facilitation period begins from 50 to 80 msec and the relative refractivity from 100 to 120 msec. There is a total recovery of cortical excitability at about 150 msec (Fig. 6).
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Fig. 6. Recovery cycle of waves III and VII of the evoked photic potential in the various situations. Evident shift in the recovery cycle after Cardiazol administration which also appears abbreviated.
Brain Research, 2 (1966) 51-60
58
B. BERGAMASCO
The behaviour of the R2/R1 ratio differs depending on whether wave HI or VII is considered. The recovery cycle of the two waves is substantially parallel in subjects in basal conditions and those under cardiazolic action. Particularly in this latter T A B L E II MEAN VALUES (10 n o r m a l subjects) OF THE RATIO (R2/R1)* AT AMPLITUDES OK WAVES m AND Vn OK THE EVOKEDVISUALRESPONSE
Interstimulus intervals ( msec )
R2/R1 ratio
Wave 111 20 30 40 50 70 80 100 120
150 170 200 230
After 500 mg i.v. Cardiazol
Basal
0 0 0 0 0.95 1.1 1.2 0.95 0.8 0.9 1.1 1
Wave 1Ill 0 0 0 1.05 1.1 1.4 1.6 1.05 0.9 1.1 1 1
Wave HI 0 0 0.3 0.9 1.2 1.3 1.1 0.8 1 1 1 1
Wave Vll 0 0 0.4 1.1 1.6 1.8 1.2 0.95 1.1 1.1 1 1
* R1 = conditioning flash; R2 = test flash.
situation, during the facilitation period we note a marked increase in wave VII in R2, and the R2/RlvlI ratio is always greater than that of R2/RIlII (Table II and Fig. 6). The increase in R2 amplitude and the lengthening in the latencies of its peaks can be attributed in the supranormal facilitation period to a spacial summation phenomenon due to recruitment. In this phase of the recovery cycle some neurons are partially excited by the first flash (subliminal fringe of excitation) and are further excited by the second flash up to the threshold. At the same time the great temporal dispersion of the discharge of these neurons causes an increase in latencies and a lengthening of the duration of the waves of the potential evoked by the test flash. It is clear that in the recovery of wave VII there exists a recruitment of the neuronal population greater than in the recovery of wave III. This situation is emphasized by Cardiazol administration. In conclusion, the recording of the visual response evoked in normal subjects after i.v. administration of Cardiazol in doses of 250 and 500 mg shows an increased amplitude compared to basal values but with morphology more or less identical to the standard. The recovery cycle values of the visual cortex during Cardiazol treatment, when compared with those of the same subjects in basal conditions, indicate a shorter duration of the whole cortical excitability cycle. In other words, it appears that modifications in both evoked visual potentials and cortical recovery cycle induced by Cardiazol depend on a greater cortical excitability and on a more rapid return to the Brain Research, 2 (1966) 51-60
EXCITABILITY CYCLE OF THE VISUAL CORTEX
59
norm after the arrival of the stimulus. This drug, therefore, seems to act as a real 'activator' of cortical excitability. At the same time, in these doses it seems to predispose the cortex, by shortening its recovery cycle, to a more intense (in the sense of frequency) utilization of the stimuli reaching it from the sensory periphery. SUMMARY
The recovery cycle of the human visual cortex in conditions of psychosensory rest and after i.v. administration of 250 and 500 mg of Cardiazol was studied in l0 normal subjects by means of the evoked photic potential. The evoked cortical responses were recorded from the scalp in bipolar derivation obtained by means of a CAT 400 B Mnemotron. Paired flashes were emitted at various intervals (20-3040-50-70-80-100-120-150-170-200-230 msec). From the complex response obtained from the two flashes (R1 + R2), the response (R1) evoked by the first flash (conditioning flash)was subtracted, thus obtaining the response (R2) to the second flash (test flash). The ratio (R2/R1) between the amplitudes of waves HI and VII of the two evoked responses so obtained was taken as the index of the state of cortical excitability in successive moments. Variations with respect to unity were then considered. If the ratio equals zero the cortex is not excitable further (R2 = 0), if less than one, excitability is reduced (R2 < R1), if greater than 1, it is increased (R2 > R1) and, finally, if it equals one, the cortex is in a condition of normal excitability (R2 = R1). The results obtained showed that the recovery cycle of the visual cortex in man in psychosensory rest consists of: (1) a period of absolute refractivity of 40 msec; (2) a period of supernormal facilitation lasting from 80 to 100 msec after stimulus with a maximum at 100 msec; (3) a period of subnormal excitability from 120 to 150 msec after the flash with a maximum at 150 msec, (4) the return to the state of normal excitability about 200 msec after the flash. l.v. administration of Cardiazol in doses of 250 and 500 mg provokes modifications in the evoked photic potential and in the cortical recovery cycle. The basal evoked response is increased in amplitude in its later components. The cortical recovely cycle has a shorter duration and is made up as follows: (I) period of absolute refractivity 30 msec; (2) phase of supernormal excitability from 50 to 80 msec after the flash with a maximum at 80 msec; (3) phase of subnormal excitability between 100 and 120 msec with a maximum at 120 msec; (4) recovery of normal excitability at 150 msec after the stimulus. The described modifications are quite similar with 250 and 500 mg of i.v. Cardiazol. Both in basal conditions and during Cardiazol administration an increase in latencies and durations of waves III and VII of the evoked potential was noted in the period of maximum facilitation. Like supranormal excitability itself, it seems that Brain Research, 2 (1966) 51-60
60
B. BERGAMASCO
these facts can be attributed to phenomena of spacial summation depending on the neuron contingent of the subliminal fringe excited by the second flash. In conclusion, the increase in cortical excitability produced by Cardiazol is pointed out. This also seems to predispose the cortex to respond to more frequent sensory stimuli by shortening the duration of the recovery cycle.
REFERENCES 1 ALLISON, T., Recovery functions of somatosensory evoked responses in man, Electroenceph. clin. Neurophysiol., 14 (1962) 331-343. 2 BERGAMASCO,B., BERGAMINI,L., E MOMBELLI,A. i . , Studio suMpotenziali evocati fotici nell'uomo. Nota I. Sul fenomeno delrabitudine delle risposte corticali evocate da stimolazione fotica iterativa, Riv. Pat. nerv. ment., 85 (1964) 561-572. 3 BREMER, F., Neurogenic factors influencing the evoked potential of the cerebral cortex, In W. A. ROSENBLITH(Ed.), Sensory Communication, The M.I.T. Press, 1961, p. 675. 4 CALVET, J., CATHALA, H. P., CONTAMIN, F., HIRSCH, J., ET SCHERRER, J., Potentiels 6voqu6s corticaux chez l'homme, l~tude analytique, Rev. Neurol., 95 (1956) 445-454. 5 CIG~NEK, L., The EEG response (evoked potential) to light stimulus in man, Electroenceph. clin. Neurophysiol., 13 (1961) 165-172. 6 CIG~NEK, L., Excitability cycle of the visual cortex in man, Ann. N.Y. Acad. Sci., 112 (1964) 241-253. 7 DAWSON, G., Central responses to electrical stimulation of peripheral nerve in man, J. Neurol. Neurosurg. Psychiat., 10 (1947) 137-140. 8 EVARTS,E. V., FLEMING,T. C., AND HUTTENLOCHER,P. R., Recovery cycle of visual cortex of the awake and sleeping cat, Amer. J. PhysioL, 199 (1960) 373-376. 9 GASTAUT,H., CORRIOL,J., ET ROGER, A., Le cycle d'excitabilit6 des syst~mes aff6rents corticaux chez rhomme, Rev. Neurol., 84 (1951) 602-605. 10 GASTAUT,H., CORRIOL,J., ET ROGER, A., Le cycle d'excitabilit6 des syst~mes aff6rents corticaux chez l'homme, Electroenceph. clin. NeurophysioL, 4 (1952) 234-242. I l GASTAUT,H., GASTAUT,Y., ROGER, A., CORRIOL, J., ET NAQUET,R., l~tude 61ectrographique du cycle d'~xcitabilit6 cortical, Electroeneeph. clin. Neurophysiol., 3 (1951) 401-428. 12 GRAY, G. H., AND SCHWAB,R. S., A comparative study of the human occipital evoked response to single and paired flashes, Eleetroenceph. clin. NeurophysioL, 6 (1954) 689-706. 13 PALESTINI,i . , PISANO,i . , ROSADINI,G., E ROSSI, G. F., Studio sulla eccitabilit~ corticale durante il sonno e la veglia: ciclo di eccitabilit~t della corteccia visiva nel gatto, Boll. Soc. ital. Biol. sper., 39 (1963) 1662-1664. 14 PALESTINI,i . , PISANO, i . , ROSADINI,G., AND ROSSl, G. F., Excitability cycle of the visual cortex during sleep and wakefulness, Electroenceph. clin. NeurophysioL, 19 (1965) 276-283. 15 PAMPIGLIONE,G., Some observations on the variability of evoked EEG activity, Electroenceph. clin. NeurophysioL, 5 (1953) 123-124. 16 SCHWARTZ, M., AND SHAGASS,C., Somatosensory cortical excitability cycles in man, Electroenceph, clin. Neurophysiol., 5 (1961) 493-497. 17 SCHWARTZ, M., AND SHAGASS,C., Effect of different states of alertness on somatosensory and auditory recovery cycles, Electroenceph. clin. NeurophysioL, 14 (1962) 11-20. 18 SCHWARTZ,M., AND SHAGASS,C., Recovery functions of human somatosensory and visual evoked potentials, Ann. N. Y. Acad. Sci., 112 (1964) 510-525. 19 SHAGASS,C., AND SCHWARTZ, M., Reactivity cycle of somatosensory cortex in humans with and without psychiatric disorder, Science, 134 (1961) 1757-1759.
Brain Research, 2 (1966) 51-.60
51
EXCITABILITY CYCLE OF THE VISUAL CORTEX IN NORMAL SUBJECTS DURING PSYCHOSENSORY REST AND CARDIAZOLIC ACTIVATION
B. BERGAMASCO
Neurological Clinic, University of Turin (Italy) (Received February 2nd, 1966)
INTRODUCTION
The excitability cycle of the visual cortex in man was first studied by Gastaut et al. 9-11 who employed a normal EEG recording technique. Other workers have since studied the problem: Pampiglione15, Gray and Schwab 12, Calvet et aL 4, Shagass
and Schwartz 19, Allison1, Schwartz and Shagass 16-1s. Cig~mek~, using Dawson's 7 superimposition technique, investigated the recovery cycle of the human visual cortex, obtaining results different from those of the above-mentioned workers. Our aim was to study the excitability cycle of the visual cortex in man and its variations under the influence of the drug, pentamethylenetetrazol, which has a synchronizing and recruitment action on cortical neuron activity. The evoked photic potential recorded from the scalp with the averaging technique was employed. MATERIALS AND METHODS
The behaviour of the recovery cycle of the evoked visual potential in basal conditions and after i.v. administration of 250 and 500 mg of Cardiazol was studied in 10 normal subjects, 6 males and 4 females between the ages of 20 and 30. The recovery cycle of the evoked response corresponds to the duration of the relative refractivity of the cortical neurons following their response to a corticipetal stimulus. The phenomenon is expressed by the ratio between the amplitude of the two responses evoked in the cortex by two stimuli with identical characteristics at varying time intervals. For this purpose the responses evoked by two paired flashes ('conditioning flash' and 'test flash') were studied. Hypodermic needle-electrodes were attached to the scalp at 3 cm at the side and 1 cm above the external occipital prominence and referred to an electrode at the vertex, according to Bergamasco et al. z. Bipolar recordings were made and evoked potentials were obtained by using a Mnemotron CAT 400 B. The voltage value of the cerebral biorhythms at the CAT input were measured Brain Research, 2 (1966) 51-60
52
B. BERGAMASCO
with a Tektronix Mod. 503 oscilloscope. The evoked potentials were then transcribed from the computer screen on to millimeter paper by an X-Y Plotter (Mosely). The subjects, with pupils in maximum mydriasis after application of atropine, were put in a dark, sound-proof room and made to close their eyes so as to be in a state of complete psychosensory rest. A flasher of an intermittent light stroboscope (Soneclat Alvar) was positioned 70 cm from the eyes of the subjects. At each flash 0.3 J of energy was delivered. Stimulation frequency was always 1 fl/sec in order to avoid interference with subsequent responses. Cortical responses to 40-50 flashes were averaged with an analysis time of 500 msec. The cortical excitability cycle was determined by administering simultaneously paired flashes at intervals of 20-30-40-50-70-80-100-120-150170-200-230 msec. After recording the potential evoked by a single flash the responses to double flashes were recorded for each type of interstimulus interval. The same procedure was adopted after slow intravenous injection of 250 mg of Cardiazol and the following day after slow intravenous injection of 500 mg of the same drug in the same subjects. RESULTS
(a) Evoked responses obtained during cardiazolic activation The evoked response obtained immediately after i.v. administration of Cardiazol presents alterations essentially involving the late components and the after-discharge (Fig. 1). The early components of the basal evoked potential (or primary response according to Cig~inekS), consisting of the first three negative-positive-negative waves of low amplitude, with a mean latency of 25-35-60 msec respectively, vary little from those recorded after i.v. administration of 250 and 500 mg of Cardiazol. However, the waves IV-V-VI-VI[ (secondary response according to Cig~nekS), with a mean latency of 70-75-90-125 msec, after Cardiazol administration are modified. The wave VI (positive) presents a higher voltage while the small positive-negative waves V-VI disappear. The latency of wave VI, however, remains absolutely constant. Wave VII is also decidedly increased in amplitude (1/4) (Fig. 2), and its latency remains unaltered. The after-discharge is more evident during recordings made after Cardiazol injection: all the alterations in evoked responses provoked by Cardiazol are more or less identical following administration of 250 and 500 mg of the drug. The EEG under cardiazolic action shows an increase in a rhythm frequency and a higher voltage with a fair abundance of rapid activities.
(b) Excitability cycle of the visual cortex in psychosensory rest When two paired flashes stimulate the sensory periphery the cortical response obtained (R1 q- R2) represents the sum of two evoked potentials, unless the test flash falls within the absolute cortical refractivity period. Using numerical ordinator with 400 memory points (ferrite nuclei) codified in BCD (binary coded decimal form) in
Brain Research, 2 (1966) 51-60
53
EXCITABILITY CYCLE OF THE VISUAL CORTEX
l~V!omse¢,
BV" ~
C.5. 24 7, Fig. 1. Evoked photic responses obtained in the same normal subject from the average of 50 cortical responses to flashes in basal conditions (A), after i.v. administration of 250 mg of Cardiazol (B) and after administration of 500 mg of the same drug (C).
/,~v
/
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5 5 4
///
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0
i
j
i
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I
WdVOS ...... '-- . . . . . . .
i
rv
i
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]E
i
VTr
, A m p l i t u d e of the basal evoked p o t o n t l a l Arnphtude of the ev potential att'er 250rag Cardlazol iv Amplitude of the ev potential after 500 mg Cardlazol ~v
Fig. 2. M e a n amplitudes o f the various waves o f the evoked p h o t i c potential in 10 subjects in basal conditions and after i.v. administration o f Cardiazo! in doses o f 250 and 500 mg.
Brain Research, 2 (1966) 51-60
54
B. BERGAMASCO
20 binary stages the evoked potential curve can be subdivided into 400 points corresponding to the 400 points of the ordinator. Each point can be expressed as a numerical value. It is understandably possible to separate from the double response (RI -t- R2) the responses of the conditioning flash (R1) and the test flash (R2) by subtracting the value of the basal evoked potential (Fig. 3) point by point from the double response. What remains will be the response to the test flash, which is stable within limits. The value of the R2/R1 ratio expresses the state of cortical excitability
1
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Fig. 3. A b o v e (R1 ÷ 112) cortical response evoked by two flashes at 100 msec interval in a n o r m a l subject in psychosensory rest. Centre (R1) response evoked by a single flash in the same subject. Below (112) response evoked by the second flash, obtained by subtracting R1 values from R1 + R2 point by point. In the response to the second flash (R2) so obtained, waves III and VII are evident. Their amplitudes are greater t h a n in basal conditions ( R I ) whereas their latencies are lengthened. The second flash falls within the period of maximal cortical facilitation.
Brain Research, 2 (1966) 51-60
EXCITABILITY CYCLE OF THE VISUAL CORTEX
55
in a particular moment. When this ratio equals zero the cortex is not excitable further (period of absolute refractivity), when it is higher than 1 the cortex is more excitable (period of supernormal facilitation) and when it is less than 1 the cortex has less excitability (period of subnormal excitability). Finally, when it equals 1 the cortex has the same excitability as in basal conditions. Only the amplitudes of the waves I I I and VII of the evoked photic potential were considered because of their greater constancy. In contrast with the other waves, these two are observed in all recordings and thus R 2 / R l m will indicate the ratio between the amplitudes of wave I I I of the two evoked responses and R 2 / R l v n , that of wave VII. With up to 40 msec intervals between the two flashes the evoked response obtained does not present significant differences with respect to that obtained with a single flash (R2/R1 = 0) (Fig. 4). Whereas when interstimulus intervals are between 40 and 80 msec there is an evoked response to the test flash which at 80 msec is already ~'~
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Fig. 4. Recovery cycle of the visual cortex in the same subject as Fig. 2. Basal evoked potential (A); the test flash is given at 40 msec (B), 70 msec (C), 100 msec (D), 160 msec (E) and 200 msec (F) after the conditioning flash. Fig. 5. Recovery cycle of the visual cortex in the same subject as Figs. 2 and 3 afteri.v, administration of 500 mg of Cardiazol. In A, basal evoked potential; the test flash is given at 40 msec (B), 70 msec (C), 100 msec (D), 160 msec (E) and 200 msec (F) after the conditioning flash. greater in amplitude ( R 2 / R I I n and R 2 / R l v I I > 1) than that of the conditioning flash. Amplitude becomes clearly greater with an interval between the two flashes of 100 msec ( R 2 / R l n r and R 2 / R l v I I > 1) (Fig. 3). ]n this stage the latencies of the peaks of waves I I I and VII are increased. With an interval between 120 and 150 msec on the other hand, the response to the test flash appears reduced (R2/RIIrI and R 2 / R l v I I < 1), becoming equal to the conditioning flash response where interstimulus intervals are longer than 200 msec ( R 2 / R l m and R 2 / R l v i r -~ 1). Brain Research, 2 (1966) 51-60
56
B. BERGAMASCO
Therefore, on the basis of these data, the excitability cycle of the visual cortex seems to be made up as follows: period of absolute refractivity up to 40 msec after the flash, period of supernormal facilitation from 80 to 100 msec. At 100 msec there is a period of maximum facilitation. Between 120 and 150 msec after the first flash there is a period of subnormal excitability with a maximum at 150 msec after the flash. With interstimulus intervals between 170 and 200 msec there is a return to normal excitability which is complete with interstimulus intervals longer than 200 msec. (c) Excitability cycle of the visual cortex after i.v. administration of Cardiazol The excitability cycle of the visual cortex is modified in normal subjects treated with i.v. Cardiazol. These modifications are not related to the quantity of the drug administered. In fact, the recovery cycle of the evoked photic potential is, in more or less all subjects, the same with doses of either 250 or 500 mg of i.v. Cardiazol. This datum contrasts with the different convulsant thresholds presented by normal individuals with the administration of suitable doses of Cardiazol. Probably different mechanisms are involved. Apart from the alterations in the basal evoked response already described, the essential datum is the fact that the recovery cycle of the visual cortex is abbreviated in these conditions. Namely, the response to the test flash occurs at an interstimulus interval of 40 msec. The facilitation period begins about 50 msec after the first flash and this is demonstrated by the fact that with an interval of 70 msec the response to the second flash clearly exceeds the response to the first in amplitude ( R 2 / R l m and R2/Rlvxr > 1) (Fig. 5). Maximum facilitation is present in these experimental condiTABLE I MEAN VALUES (10 s u b j e c t s ) oF THE LATENCIES OF WAVES III AND VII
Conditioning response (R1) Test response (R2)* in basal condition Test response after 500 mg i.v. Cardiazol*
Wave III msec
Wave VII msec
62 q- 6 78 :k 8 80 :k 7
124 ± 12 160 ± 16 162 ± 16
* Period of maximal facilitation. tions before 100 msec after the first flash, namely at 80 msec. In these conditions too, the peak latencies of the response evoked by the test stimulus are increased (Table I). The period of subnormal excitability begins after 100 msec and reaches its maximum 120 msec after the flash ( R 2 / R l m and R 2 / R I v I I < I). Moreover, the recovery cycle is shorter than normal; the response to the test flash has the same amplitude as those to the conditioning flash with interstimulus intervals between 150 and 200 msec ( R 2 / R l m and R 2 / R l v n = 1). Brain Research, 2 (1966) 51-60
57
EXCITABILITY CYCLE OF THE VISUAL CORTEX DISCUSSION
These data regarding the excitability cycle of the visual human cortex agree with one exception with those obtained by Cighnek 8. The one difference is that Cig/mek found another facilitation period at 200 msec. This difference is not essential and can be ascribed to the diversity of techniques employed (for recording evoked potential, Cig~mek uses a photographic superimposition technique which is less accurate than the present numerical computers). On the other hand, there are marked differences between the data of the recovery cycle of the human visual cortex and those obtained experimentally in animals. Evarts e t al. s and Palestini et al. la,14 found that in wakeful cats, a complete recovery in cortical excitability sets in only after 550 msec. However, the evoked responses recorded by these workers were obtained by direct stimulation of the optical pathways with electrical pulses. Furthermore, Evarts et al. found that by increasing the intensity of the stimulus the recovery cycle increases. These data apparently contradict those found in humans, but they can be explained by the fact that an electrical stimulus directly on the optical fibres has greater density because of its higher synchronism, and, according to Bremer 3, is therefore capable of producing longer excitation on a larger number of cortical neurons. The study of the recovery cycle of the visual cortex carried out after administration of Cardiazol, which Gastaut et al. 1° had found unchanged, demonstrates a greater cortical excitability. The amplitude of the evoked responses is quantitatively greater in basal conditions; the recovery cycle is shortened. In fact, the absolute refractivity period lasts 30 msec. The subsequent facilitation period begins from 50 to 80 msec and the relative refractivity from 100 to 120 msec. There is a total recovery of cortical excitability at about 150 msec (Fig. 6).
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Fig. 6. Recovery cycle of waves III and VII of the evoked photic potential in the various situations. Evident shift in the recovery cycle after Cardiazol administration which also appears abbreviated.
Brain Research, 2 (1966) 51-60
58
B. BERGAMASCO
The behaviour of the R2/R1 ratio differs depending on whether wave HI or VII is considered. The recovery cycle of the two waves is substantially parallel in subjects in basal conditions and those under cardiazolic action. Particularly in this latter T A B L E II MEAN VALUES (10 n o r m a l subjects) OF THE RATIO (R2/R1)* AT AMPLITUDES OK WAVES m AND Vn OK THE EVOKEDVISUALRESPONSE
Interstimulus intervals ( msec )
R2/R1 ratio
Wave 111 20 30 40 50 70 80 100 120
150 170 200 230
After 500 mg i.v. Cardiazol
Basal
0 0 0 0 0.95 1.1 1.2 0.95 0.8 0.9 1.1 1
Wave 1Ill 0 0 0 1.05 1.1 1.4 1.6 1.05 0.9 1.1 1 1
Wave HI 0 0 0.3 0.9 1.2 1.3 1.1 0.8 1 1 1 1
Wave Vll 0 0 0.4 1.1 1.6 1.8 1.2 0.95 1.1 1.1 1 1
* R1 = conditioning flash; R2 = test flash.
situation, during the facilitation period we note a marked increase in wave VII in R2, and the R2/RlvlI ratio is always greater than that of R2/RIlII (Table II and Fig. 6). The increase in R2 amplitude and the lengthening in the latencies of its peaks can be attributed in the supranormal facilitation period to a spacial summation phenomenon due to recruitment. In this phase of the recovery cycle some neurons are partially excited by the first flash (subliminal fringe of excitation) and are further excited by the second flash up to the threshold. At the same time the great temporal dispersion of the discharge of these neurons causes an increase in latencies and a lengthening of the duration of the waves of the potential evoked by the test flash. It is clear that in the recovery of wave VII there exists a recruitment of the neuronal population greater than in the recovery of wave III. This situation is emphasized by Cardiazol administration. In conclusion, the recording of the visual response evoked in normal subjects after i.v. administration of Cardiazol in doses of 250 and 500 mg shows an increased amplitude compared to basal values but with morphology more or less identical to the standard. The recovery cycle values of the visual cortex during Cardiazol treatment, when compared with those of the same subjects in basal conditions, indicate a shorter duration of the whole cortical excitability cycle. In other words, it appears that modifications in both evoked visual potentials and cortical recovery cycle induced by Cardiazol depend on a greater cortical excitability and on a more rapid return to the Brain Research, 2 (1966) 51-60
EXCITABILITY CYCLE OF THE VISUAL CORTEX
59
norm after the arrival of the stimulus. This drug, therefore, seems to act as a real 'activator' of cortical excitability. At the same time, in these doses it seems to predispose the cortex, by shortening its recovery cycle, to a more intense (in the sense of frequency) utilization of the stimuli reaching it from the sensory periphery. SUMMARY
The recovery cycle of the human visual cortex in conditions of psychosensory rest and after i.v. administration of 250 and 500 mg of Cardiazol was studied in l0 normal subjects by means of the evoked photic potential. The evoked cortical responses were recorded from the scalp in bipolar derivation obtained by means of a CAT 400 B Mnemotron. Paired flashes were emitted at various intervals (20-3040-50-70-80-100-120-150-170-200-230 msec). From the complex response obtained from the two flashes (R1 + R2), the response (R1) evoked by the first flash (conditioning flash)was subtracted, thus obtaining the response (R2) to the second flash (test flash). The ratio (R2/R1) between the amplitudes of waves HI and VII of the two evoked responses so obtained was taken as the index of the state of cortical excitability in successive moments. Variations with respect to unity were then considered. If the ratio equals zero the cortex is not excitable further (R2 = 0), if less than one, excitability is reduced (R2 < R1), if greater than 1, it is increased (R2 > R1) and, finally, if it equals one, the cortex is in a condition of normal excitability (R2 = R1). The results obtained showed that the recovery cycle of the visual cortex in man in psychosensory rest consists of: (1) a period of absolute refractivity of 40 msec; (2) a period of supernormal facilitation lasting from 80 to 100 msec after stimulus with a maximum at 100 msec; (3) a period of subnormal excitability from 120 to 150 msec after the flash with a maximum at 150 msec, (4) the return to the state of normal excitability about 200 msec after the flash. l.v. administration of Cardiazol in doses of 250 and 500 mg provokes modifications in the evoked photic potential and in the cortical recovery cycle. The basal evoked response is increased in amplitude in its later components. The cortical recovely cycle has a shorter duration and is made up as follows: (I) period of absolute refractivity 30 msec; (2) phase of supernormal excitability from 50 to 80 msec after the flash with a maximum at 80 msec; (3) phase of subnormal excitability between 100 and 120 msec with a maximum at 120 msec; (4) recovery of normal excitability at 150 msec after the stimulus. The described modifications are quite similar with 250 and 500 mg of i.v. Cardiazol. Both in basal conditions and during Cardiazol administration an increase in latencies and durations of waves III and VII of the evoked potential was noted in the period of maximum facilitation. Like supranormal excitability itself, it seems that Brain Research, 2 (1966) 51-60
60
B. BERGAMASCO
these facts can be attributed to phenomena of spacial summation depending on the neuron contingent of the subliminal fringe excited by the second flash. In conclusion, the increase in cortical excitability produced by Cardiazol is pointed out. This also seems to predispose the cortex to respond to more frequent sensory stimuli by shortening the duration of the recovery cycle.
REFERENCES 1 ALLISON, T., Recovery functions of somatosensory evoked responses in man, Electroenceph. clin. Neurophysiol., 14 (1962) 331-343. 2 BERGAMASCO,B., BERGAMINI,L., E MOMBELLI,A. i . , Studio suMpotenziali evocati fotici nell'uomo. Nota I. Sul fenomeno delrabitudine delle risposte corticali evocate da stimolazione fotica iterativa, Riv. Pat. nerv. ment., 85 (1964) 561-572. 3 BREMER, F., Neurogenic factors influencing the evoked potential of the cerebral cortex, In W. A. ROSENBLITH(Ed.), Sensory Communication, The M.I.T. Press, 1961, p. 675. 4 CALVET, J., CATHALA, H. P., CONTAMIN, F., HIRSCH, J., ET SCHERRER, J., Potentiels 6voqu6s corticaux chez l'homme, l~tude analytique, Rev. Neurol., 95 (1956) 445-454. 5 CIG~NEK, L., The EEG response (evoked potential) to light stimulus in man, Electroenceph. clin. Neurophysiol., 13 (1961) 165-172. 6 CIG~NEK, L., Excitability cycle of the visual cortex in man, Ann. N.Y. Acad. Sci., 112 (1964) 241-253. 7 DAWSON, G., Central responses to electrical stimulation of peripheral nerve in man, J. Neurol. Neurosurg. Psychiat., 10 (1947) 137-140. 8 EVARTS,E. V., FLEMING,T. C., AND HUTTENLOCHER,P. R., Recovery cycle of visual cortex of the awake and sleeping cat, Amer. J. PhysioL, 199 (1960) 373-376. 9 GASTAUT,H., CORRIOL,J., ET ROGER, A., Le cycle d'excitabilit6 des syst~mes aff6rents corticaux chez rhomme, Rev. Neurol., 84 (1951) 602-605. 10 GASTAUT,H., CORRIOL,J., ET ROGER, A., Le cycle d'excitabilit6 des syst~mes aff6rents corticaux chez l'homme, Electroenceph. clin. NeurophysioL, 4 (1952) 234-242. I l GASTAUT,H., GASTAUT,Y., ROGER, A., CORRIOL, J., ET NAQUET,R., l~tude 61ectrographique du cycle d'~xcitabilit6 cortical, Electroeneeph. clin. Neurophysiol., 3 (1951) 401-428. 12 GRAY, G. H., AND SCHWAB,R. S., A comparative study of the human occipital evoked response to single and paired flashes, Eleetroenceph. clin. NeurophysioL, 6 (1954) 689-706. 13 PALESTINI,i . , PISANO,i . , ROSADINI,G., E ROSSI, G. F., Studio sulla eccitabilit~ corticale durante il sonno e la veglia: ciclo di eccitabilit~t della corteccia visiva nel gatto, Boll. Soc. ital. Biol. sper., 39 (1963) 1662-1664. 14 PALESTINI,i . , PISANO, i . , ROSADINI,G., AND ROSSl, G. F., Excitability cycle of the visual cortex during sleep and wakefulness, Electroenceph. clin. NeurophysioL, 19 (1965) 276-283. 15 PAMPIGLIONE,G., Some observations on the variability of evoked EEG activity, Electroenceph. clin. NeurophysioL, 5 (1953) 123-124. 16 SCHWARTZ, M., AND SHAGASS,C., Somatosensory cortical excitability cycles in man, Electroenceph, clin. Neurophysiol., 5 (1961) 493-497. 17 SCHWARTZ, M., AND SHAGASS,C., Effect of different states of alertness on somatosensory and auditory recovery cycles, Electroenceph. clin. NeurophysioL, 14 (1962) 11-20. 18 SCHWARTZ,M., AND SHAGASS,C., Recovery functions of human somatosensory and visual evoked potentials, Ann. N. Y. Acad. Sci., 112 (1964) 510-525. 19 SHAGASS,C., AND SCHWARTZ, M., Reactivity cycle of somatosensory cortex in humans with and without psychiatric disorder, Science, 134 (1961) 1757-1759.
Brain Research, 2 (1966) 51-.60